U.S. patent application number 10/506906 was filed with the patent office on 2007-10-04 for scd fingerprints.
This patent application is currently assigned to Cambridge University Technical Service Limited (CUTS). Invention is credited to Charles Nicholas Hales, Margaret Hales, Celia Prilleltensky Milstein, Cesar Milstein, Adrian Woolfson.
Application Number | 20070233391 10/506906 |
Document ID | / |
Family ID | 27791909 |
Filed Date | 2007-10-04 |
United States Patent
Application |
20070233391 |
Kind Code |
A1 |
Milstein; Cesar ; et
al. |
October 4, 2007 |
Scd fingerprints
Abstract
The present invention relates to the use of cluster of
differentiation (CD) molecules in detecting the presence and
progression of one or more disease states in an individual. In
particular it relates to the use of profiles of shed CD (sCD)
molecules in detecting and assessing the progression of one or more
disease states in an individual. Further uses of sCD profiles
according to the present invention are also described.
Inventors: |
Milstein; Cesar; (Cambridge,
GB) ; Milstein; Celia Prilleltensky; (Cambridge,
GB) ; Woolfson; Adrian; (Cambridge, GB) ;
Hales; Charles Nicholas; (Cambridge, GB) ; Hales;
Margaret; (Cambridge, GB) |
Correspondence
Address: |
BROOKS KUSHMAN P.C.
1000 TOWN CENTER
TWENTY-SECOND FLOOR
SOUTHFIELD
MI
48075
US
|
Assignee: |
Cambridge University Technical
Service Limited (CUTS)
Cambridge
GB
CB2 1SB
Medical Research Council
London
GB
W1B 4AL
Addenbrookes NHS Trust
Cambridge
GB
CB 2QQ
|
Family ID: |
27791909 |
Appl. No.: |
10/506906 |
Filed: |
March 7, 2003 |
PCT Filed: |
March 7, 2003 |
PCT NO: |
PCT/GB03/00974 |
371 Date: |
June 27, 2006 |
Current U.S.
Class: |
702/19 ;
705/3 |
Current CPC
Class: |
Y02A 90/10 20180101;
G01N 33/54306 20130101; G16H 40/63 20180101; G01N 33/6803 20130101;
G01N 33/6845 20130101; A61P 35/00 20180101; G01N 33/68 20130101;
G16H 70/60 20180101 |
Class at
Publication: |
702/019 ;
705/003 |
International
Class: |
G06F 19/00 20060101
G06F019/00; G06Q 50/00 20070101 G06Q050/00 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 7, 2002 |
GB |
0205394.0 |
Apr 3, 2002 |
GB |
0207746.9 |
Dec 3, 2002 |
GB |
0228195.4 |
Claims
1.-24. (canceled)
25. A shed Cluster of Differentiation (sCD) fingerprint comprising:
levels of five or more sCDs wherein the sCD fingerprint represents
one or more disease states.
26. The sCD fingerprint of claim 25 wherein the one or more disease
states comprise a disease state selected from the group consisting
of: infectious, neoplastic, autoimmune, metabolic, immunological,
degenerative, psychological, psychiatric, iatrogenic, inflammatory,
drug or toxin related, vascular traumatic, endocrine diseases and
combinations thereof.
27. The sCD fingerprint of claim 25 wherein the one or more disease
states comprise a disease state selected from the group consisting
of: infection, Bence Jones Proteinuria, Chronis Myeloid Leukemia,
Colorectal cancer, chronic renal failure, Crohn's Disease, Diabetic
Nephropathy, Cardiac pathology, Infection, Liver damage, Lymphoma,
Macrocytic anaemia, Prostate Cancer, Oligoclonal Banding, Pulmonary
Embolism/Deep Vein Thrombosis and appendicitis.
28. The sCD fingerprint of claim 25 wherein the five or more sCDs
comprise sCDs selected from the group consisting of: CD14, CD25,
CD31, CD44, CD50, CD54, CD62E, CD62L, CD86, CD95, CD106, CD116,
CD124, CD138, CD141, CD40L, CD8, CD23, CD30, CD40 and their
homologues present in mammalian or non-mammalian species, and
combinations thereof.
29. A method of generating a shed Cluster of Differentiation (sCD)
fingerprint of one or more disease states, the method comprising:
measuring levels of five or more shed CDs from one or more
individuals.
30. The method of claim 29 wherein sCD levels are measured in
samples of one or more body fluids from an individual.
31. The method of claim 29 wherein the body fluid is serum.
32. The method of claim 29 wherein sCD levels are measured using a
method selected from the group consisting of immunoassay, flow
cytometry and combinations thereof.
33. The method of claim 29 wherein sCD levels are measured using a
method selected from the group consisting of the following:
multiplexed particle flow cytometry, chip based monoclonal antibody
technology, chips comprising engineered antibodies and non-protein
agents which bind to one or more sCDs.
34. The method of claim 29 wherein steps for calculating a sCD
level include: measuring a tested level of sCD, divided by an upper
limit of normal (ULN) from sCD levels from healthy individuals;
performing a statistical analysis for the sCD level compared to an
ULN; and coding each sCD in a low to high scale to determine a sCD
level.
35. A method for predicting the presence of one or more disease
states in an individual, the method comprising: comparing one or
more sCD fingerprints generated from that individual with one or
more reference sCD fingerprints to detect the presence of the one
or more disease states.
36. A method for detecting the extent of the presence of one or
more disease states in an individual, the method comprising:
comparing sCD fingerprints generated from that individual with one
or more reference sCD fingerprints to determine the extent of the
one or more disease states, the sCD fingerprints levels of five or
more sCDs wherein the sCD fingerprint represents one or more
disease states.
37. A method for assessing the progression of a disease state in an
individual, the method comprising: comparing an sCD fingerprint of
an individual at two or more periods during the occurrence of the
disease state to assess the progression of the disease state, the
sCD fingerprint comprising levels of five or more sCDs wherein the
sCD fingerprint represents one or more disease states.
38. A method for assessing the effect of one or more therapeutic or
potentially therapeutic agents on one or more disease states in an
individual; the method comprising: comparing an sCD fingerprint of
an individual at two or more different time periods to assess the
effect of the one or more therapeutic or potentially therapeutic
agents, the sCD fingerprint comprising levels of five or more sCDs
wherein the sCD fingerprint represents one or more disease
states.
39. A method for assessing the effect of one or more interventions
on an individual, the method comprising: comparing an sCD
fingerprint of an individual exposed to the intervention with one
or more reference sCD fingerprints to assess the effect of the one
or more interventions, the sCD fingerprint comprising levels of
five or more sCDs wherein the sCD fingerprint represents one or
more disease states.
40. The method according to claim 39 for assessing the effect of
one or more interventions selected from the group comprising:
treatment with chemotherapeutic agents, other agents, exposure to
radiation and exposure to pathogens.
41. A method for sub-categorizing a sCD fingerprint profile, the
method comprising: identifying within one disease category one or
more groups of sCDs wherein each group of sCDs exhibits common
characteristics distinguishing it from any other group within that
disease category.
42. A method according to claim 41 wherein the steps for
sub-categorizing disease states comprises: performing a cluster
analysis on the sCD fingerprints having common characteristics
within sCD levels; and sorting the sCD fingerprint data collected
into sub-categories within disease states.
43. A sCD database comprising a plurality of pathological and/or
normal sCD fingerprint patterns.
44. A method according to claim 43 wherein generating a sCD
database of one or more disease states comprises the step of
measuring the sCD levels for five or more sCDs and collating the
presence or absence of said sCDs.
45. A method according to claim 43 wherein a sCD fingerprint
database is computer generated.
46. A sCD fingerprint database according to claim 43 wherein sCD
fingerprints are supplemented with reference data, disease
characteristics and clinical data for individual sCD
fingerprints.
47. A method according to claim 43 wherein a sCD fingerprint
database are included in software facilitating data retrieval.
48. A method according to claim 47 wherein a sCD fingerprint
database is searchable by one or more of the following criteria:
sCDs; treatment agent, toxicological substance; one or more disease
states; disease subcategory; and by disease stage and combinations
thereof.
Description
[0001] The present invention relates to the use of cluster of
differentiation (CD) molecules in detecting the presence and/or
assessing the progression and/or assessing the response to
therapeutic intervention of one or more disease states in an
individual. In particular it relates to the use of
profiles/fingerprint/s of shed CD (sCD) molecules in body fluids in
detecting and/or assessing the progression of one or more disease
states in an individual. Further uses of sCD profiles according to
the present invention are also described.
BACKGROUND TO THE INVENTION
[0002] Rapid and accurate diagnosis is essential in medicine as in
many cases early diagnosis and successful treatment correlates with
a better outcome and reduced hospitalisation. Currently, the
clinical diagnosis and staging of many diseases of global
significance involve different invasive procedures such as
histopathological analysis of biopsy samples which are usually
obtained when the disease process is at a relatively advanced
stage. In many cases, a classic histopathological approach may not
be sufficient to produce accurate diagnosis and any delay in
confirming the diagnosis would have financial and morbidity
repercussions for the healthcare institution and most importantly
for the individual. Disease states and disease staging are also
determined by different imaging techniques such as X-rays, nuclear
magnetic resonance (NMR), CT analysis and others, however, these
are expensive and impractical when dealing with large numbers of
individuals, or when it is necessary to monitor disease progression
closely, or in health institutes or clinical situations where such
equipment is unavailable. Furthermore such investigations are
impractical for individuals because it would result in such
individuals obtaining high radiation doses. For this reason such
tests cannot be carried out serially and are thus of little use in
monitoring drug responses and monitoring disease progression.
[0003] A variety of diseases or the predisposition to such a
disease can be characterised by changes in the overall patterns
and/or expression levels of various genes and their proteins. For
example, some cancers are associated with changes in the expression
of oncogenes or tumour suppressor genes. Furthermore, disease
conditions or disorders associated with disregulated cell cycle and
development can be attributed to changes in transcriptional
regulation of specific genes.
[0004] Although there are several genetic assays available to
assess gene mutations, the identification of specific genetic
changes may not always be a direct indicator of a disease or
disorder and thus cannot be relied upon as an accurate prognostic
indicator.
[0005] Certain genetic changes are exhibited by alterations in cell
surface antigens. Again, however, prior attempts to develop a
diagnostic assay for complex disease conditions or disorders based
on the identification of single antigen or very small numbers of
antigens have not been uniformly successful.
[0006] In addition, or alternatively, biochemical analysis of a
patient may be used to diagnose a disease state. For example, the
presence of Bence Jones proteins in urine is an indicator that an
individual has multiple myeloma. However, classical biochemical
methods are limited, for example an elevated cholesterol in serum
indicates hypercholesterolaemia but does not definitively indicate
atherosclerosis. A further disadvantage of biochemical methods of
diagnosis is that they generally permit the measurement of only one
or two indicator/s of disease in any one test. Consequently, they
provide an incomplete picture of the disease state of an
individual. Moreover, if several tests are performed in an attempt
to provide a more complete picture, this inevitably increases the
number of variables which complicates interpretation. Furthermore,
for many diseases there are no reliable biochemical markers,
especially for diseases of global importance such as breast cancer,
colorectal cancer and lung cancer. In the case of solid tumours
such as colorectal cancer, a number of carcinoembryonic antigen
(CEA) markers have been identified, however they have poor
sensitivity and very low specificity. The situation is similar with
disease conditions requiring surgical intervention. There is still,
for example, no marker for acute appendicitis and consequently, a
great many patients undergo unnecessary invasive surgery. It has
been estimated that more than 40,000 unnecessary appendicitis
operations occur each year due to misdiagnosis with associated
costs of $700 million. In a recent larger retrospective study,
Flume and colleagues show that misdiagnosis occurs in 15% of
instances.
[0007] Therefore, there is a pressing need in the art to provide a
simple and complete picture of the disease state or condition of an
individual. Such a `picture` would be of use in predicting and/or
detecting the presence of a disease or condition, in assessing the
therapeutic strategies and the potential of various agents and in
monitoring the progression and successful treatment of disease
states or conditions
[0008] Lymphocytes and other leukocytes express a large number of
different antigens associated with their outer plasma membranes
that can be used to identify distinct functional cell subsets. Many
of these antigens were "classically" known to be receptors for
growth factors, cell-cell interactions, viruses eg CD4, CD 112 and
CD 155 are the HIV, poliovirus receptor 2 and poliovirus receptor
respectively), and immunoglobulins; molecules for cell adhesion or
complement stimulation; enzymes and ion channels. A single
systematic nomenclature has been adopted to classify monoclonal
antibodies to human leukocyte cell surface antigens termed cluster
of differentiation (CD) antigens, also referred to as CD
molecules/antigens (Kishimoto et al., 1996 Proceedings of the Sixth
International Workshop and Conference held in Kobe, Japan. 10-14
Garland Publishing Inc, NY, USA). This work originated as the
direct result of the work of one of the inventors (Dr. Cesar
Milstein) of the present application who invented monoclonal
antibody technology with his colleague Georges Kohler (Kohler and
Milstein. Continuous cultures of fused cells secreting antibody of
defined specificity (1975), Nature August 7, 256 (5517), 495-7) and
who identified and raised the first monoclonal antibodies to both
non-human and human CD antigens (McMichael et al. A human thymocyte
antigen defined by a hydrid myeloma monoclonal antibody).
[0009] The data required in order to define a CD has changed over
the years, not surprisingly in view of the advances in modern
technology. Initially, clustering depended absolutely on the
statistical revelation of similarities in reaction pattern of two
or more antibodies, analysed on multiple tissues. It is now
accepted that CD molecules may also be classified by molecular
characteristics. Thus it has become customary to use the CD marker
(for example CD21) to indicate the molecule recognised by each
group of monoclonal antibodies. The current list of CD markers is
constantly updated as new antigens are identified and eventually,
the CD list will encompass all human lymphocyte cell surface
antigens and their homologues in other mammalian and non-mammalian
species (Mason et al., 2001, Immunology, 103, 401-406). It should
be noted that although CD antigens were initially defined in the
basis that they are expressed on the cell surface of leukocytes, a
great many of them are also expressed on numerous other cell types
including brain, liver, kidney, red blood cells, bone marrow,
dendritic antigen presenting cells, epithelial cells, stem cells,
thymocytes, osteoclasts, NK cells, B cells, macrophages, to name
but a few.
[0010] Historically, CD cell surface antigens have been used as
markers in diagnosis. Indeed leukemias are diagnosed on the basis
of cell morphology, expression of specific CD antigens, lymphoid
(LY) and myeloid (MY) antigens, enzyme activities and cytogenetic
abnormalities such as chromosome translocations. The expression of
up to three CD antigens on leukemia cells is determined using
labelled antibodies to particular CD antigens with analysis by flow
cytometry.
[0011] Significantly, however, it has been observed that often (if
not always in normal or disease states) the surface bound CD
immunological specificity molecules (intact CD molecules or
fragments thereof) are found soluble in the serum and in other body
fluids. Subsequent research has shown that indeed CD molecules can
be secreted from cells as a result of "active" processes such as
alternative splicing (Woolfson and Milstein, PNAS, 91 (14)
6683-6687 (1994)) or "passive" processes such as cell surface
shedding. Thus, CD molecules can be found in three forms, membrane
associated CD molecules, shed CD molecules (sCD) produced by
alternative splicing or other mechanisms and intracellular CD
molecules. Each of these can be complete molecules or fragments
thereof.
[0012] It is generally accepted however that the change in levels
of any one sCD is not specific to a given disease state and cannot
therefore usefully be used in the diagnosis of disease states.
[0013] Recent studies (those of WO 00/39580) have described a
system for the diagnosis of haematological malignancies, whereby
immunoglobulins are immobilised on a solid support and are used to
detect cell-surface antigen levels, in particular cell-surface CD
antigen levels in samples of cells. Using this approach, a pattern
of expression of cell-surface bound CD antigens is generated which
the inventors have shown to be indicative of the presence of
various defined leukemias in a patient. However, there are several
disadvantages with this technique. Firstly and importantly, it is a
cell-based technique. Such techniques have many disadvantages
associated with them, for example that of background noise and the
difficulty of measuring antigen levels accurately. Such methods
only allow semiquantitative determination of the relative densities
of sub-populations of cells of distinct immunophemotypes, indeed
absolute quantification using this method may not be possible.
Another problem with this prior art method is that at equilibrium,
the number of cells captured by the immobilised antibody dot
depends not only on the affinities of the interactions, the
concentration of the antibody dot, the level of expression of the
CD antigen on the cell surface and in addition to this the
stereochemical availability and accessibility of the monoclonal
antibody immobilised on the nitrocellulose membrane of the CD
antibody array. Furthermore computerised quantification of the cell
density as indicated by the pixel intensity corresponding to each
dot of arrayed antibody, depends not only on the number of cells in
the test sample, but in addition to the cell size and morphology.
In addition to all of these factors, the absolute requirement for
purification of cells from whole blood and the possible need to
fractionate blood cells still further makes such an approach both
labour intensive and time consuming.
[0014] Therefore, there still exists a need in the art for a simple
method for diagnosis of different diseases and conditions by the
measurement of CD antigens wherein such method produces a complete,
sensitive, specific and accurate picture of disease.
SUMMARY OF THE INVENTION
[0015] The present inventors have surprisingly found that
particular disease states can be characterised by specific patterns
of levels of shed/soluble/secreted (sCD) (as herein defined) CD
molecules derived from the body fluids of an individual. That is,
the profile or `sCD print` of the levels of sCD antigens correlate
with particular diseases or disorders or physiological states such
as those induced by administration of a drug or toxin. This finding
is especially surprising since the levels of sCDs found in the body
fluids of an individual are generally very low, and the sCD
released by cells would only be expected to change in some, and not
all cell types of an individual when affected by one or more
diseases, the change of levels of shed CD levels, as herein defined
detectable in the body fluids of diseased individuals as compared
with non-diseased individuals would be expected to be minimal.
[0016] Thus, in a first aspect, the present invention provides a
shed CD (sCD) fingerprint (sCD print) of one or more disease
states.
[0017] In the context of the present invention, the term `CD`
refers to a different cell surface leukocyte molecule recognised by
a given monoclonal or group of monoclonal antibodies which
specifically `cluster` to the antigen/molecule in question. Many,
if not all of these molecules produce forms which are released from
the cell surface by alternative splicing, proteolytic cleavage,
dissociation or other mechanisms. Thus in the context of the
present invention, the term `shed CD molecule (sCD)` is synonymous
with the term secreted/soluble CD (sCD) and refers to a released
form of a cell surface leukocyte molecule in which at least a
portion of that molecule is recognised by a given monoclonal or
group of monoclonal antibodies as herein described. It should be
noted however, that the antibody used to recognise the CD molecule
may not be monoclonal. It may be engineered, an artificial
construct consisting of an expressed fragment derived from an
antibody molecule with intact recognition, or it may be a
non-protein molecular recognition agent, or a protein recognition
agent which is not an antibody, or is an antibody hydrid, for
example made by introducing antibody binding sites into a different
scaffolding. Advantageously, as herein defined a shed form of sCD
is generated by various mechanisms including but not limited to any
of those selected from the group consisting of the following:
alternative splicing, proteolytic cleavage and dissociation.
[0018] In the context of the present invention it is important to
note that the CD nomenclature is a simple method for representing a
whole range of molecules. For example: CD14 is the
lipopolysaccharide receptor, LP5-R; CD21 is the EBV receptor; CD 25
is the IL-2Ralpha receptor; CD 31 is PECAM-1; CD 44 is H-CAM; CD 50
is ICAM-3; CD 54 ICAM-1; CD 62E is LECAM-2; CD 62L is LECAM-1; CD
86 is B 70; CD 95 is FAS apoptosis antigen; CD 102 is ICAM-2; CD
106 is VCAM-1; CD 116 is GM-CSFR alpha; CD 117 is c-kit stem cell
factor receptor; CD 124 is IL-4R alpha; CD 126 is L-6Ralpha; CD 130
is gp 130; CD 138 is syndican-1; CD 141 is thrombomodulin; CD 91 is
low density lipoprotein receptor-related antigen; CD 132 is common
cytokine receptor gamma), CD 89 is IgA Fc receptor, CD 74 is class
II specific chaperone, CD is 95 is apoptosis antigen; CD220 is the
insulin receptor and CD 184 is the chemokine receptor 4. (CXCR4)
CD8 is Lin 2; CD 27 is low affinity IgE-R; CD 30 is Ki-1.
[0019] The present inventors realised that sCDs act as
representatives/ambassadors for the families of molecules from
which they are shed. Thus sCD 184 stands as an ambassador for all
shed (as defined herein) cell surface chemokine receptors and for
example sCD54 acts as an ambassador for all intercellular adhesion
molecules. Furthermore they realised that cell behaviour can be
interregated on the basis of the patterns of sCD molecules shed by
cells.
[0020] In this regard it should be noted, as mentioned above that
sCDs are ambassadors for a vast range of molecules including but
not limited to the following: integrins, adhesion molecules, Fc
receptors, apoptosis antigens, blood group antigens, viral
receptors, coagulation factors, selectins, chemokine receptors,
macrophage receptors, insulin receptors, prion proteins,
glycophorins, rhesus antigens, T cell receptor zeta chain and
pregnancy specific antigens.
[0021] As herein defined, the term `shed CD fingerprint (sCD)`
describes the pattern or profile of levels of more than one shed
CDs in one or more individuals. A sCD fingerprint as herein defined
may be representative of one or more non-diseased individual/s or
one or more diseased individual/s. Preferably, a shed CD
fingerprint describes the level of five or more shed CD molecules,
more preferably it is 6, 7, 8, 9, 10 or more sCD molecules, more
preferably still a shed CD fingerprint describes the levels of 15
or more sCD molecules. More preferably a shed CD fingerprint
describes the levels of 20 or more sCD molecules. Most preferably,
it comprises the levels of sCDs for the complete set of sCDs for a
given individual.
[0022] sCD levels from normal and/or diseased individuals may be
collated in order to generate one or more reference sCD
fingerprints. A `reference` sCD fingerprint (sCD print) is a
fingerprint which is advantageously generated from sCD measurements
from more than one individual and is representative of the sCD
levels of either a `normal` or diseased individual. Advantageously,
these reference fingerprints are collected together to form a
database so that abnormal fingerprints generated from patient
samples can be distinguished from normal reference fingerprints in
the database. In addition, by comparing one or more patient sample
fingerprints with one or more reference fingerprint/s corresponding
to one or more diseases, then the disease state of an individual
may be established.
[0023] A shed CD (sCD) fingerprint (sCDprint) may be generated from
one individual. Preferably however, each fingerprint is generated
from more than one individual. Advantageously, it is generated from
more than five, ten, fifteen or twenty, 50, 100, 500, 1000, 5000,
10,000, 50,000 or 100,000 individuals. One skilled in the art will
appreciate that the greater the number of individuals used to
generate the reference fingerprint, then the more representative of
any given disease state or of a normal individual the reference sCD
profile/s will be. Fingerprints may be simplified by using the
average values of the data obtained for each sCD for a number of
individuals. For example, the modal value is used for data obtained
from a very small number of samples. Such information may then be
placed within a database as herein described.
[0024] One skilled will appreciate that often more than one disease
state may be present in an individual at a given time. This may
complicate the CD fingerprint obtained, such that the fingerprint
is an aggregate fingerprint of several disease states. The effect
of multiple disease states (composites) in an individual may be
minimised if the reference fingerprint for any given disease state
is generated from several or many individuals. Importantly,
composites may generate their own patterns and be used as reference
in their own right.
[0025] Measuring the levels of sCD molecules is carried out using
methods known to one skilled in the art and described herein.
[0026] sCD levels are measured in samples of body fluids. Suitable
body fluids for measuring sCDs include any one or more selected
from the group consisting of the following: tissue fluid, serum,
blood, cerebrospinal fluid, synovial fluid, urine, plural fluid,
saliva, lymphatic fluid, aspirate, bone marrow aspirate and mucus.
One skilled in the art will appreciate that this list is not
intended to be exhaustive.
[0027] In a further aspect the present invention provides a method
of generating a shed CD (sCD) fingerprint of one or more disease
state/s comprising the step of measuring in parallel the levels of
more than one shed CD in one or more samples from one or more
individuals and collating the data.
[0028] According to the above aspect of the invention, the term
`measuring in parallel` (sCD levels) refers to the process where
sCD levels are measured in one or more samples taken from an
individual at substantially the same time. Those skilled will
appreciate that in the case where sCD levels are measured from more
than one body fluid sample, then it may not be practical to take
more than one sample of body fluid from the same individual at
precisely the same time. Thus according to the above aspect of the
invention, when more than one body fluid sample is to be taken from
an individual for the generation of a sCDprint, then such samples
should be taken from the same individual as close together in time
as possible. Advantageously, the term `close together` (in time)
means within 5 hrs of one another, more advantageously within 4
hrs, 3 hrs, 2 hrs, 1 hr, 30 mins, 20 mins, 10 mins, 5 mins, 1 min
of one another. Those skilled will appreciate that so long as there
is no change in levels of measured sCDs between the first sample
and the last sample being taken, then such a time interval can be
considered `close together` as described herein. Thus so long as
there is no change in sCD levels between the first sample and the
last sample being taken, then such samples can be considered to be
taken `in parallel` and likewise such sCD levels can be considered
to be measured `in parallel` as referred to herein.
[0029] According to the above aspect of the invention, the samples
for testing are used to generate a given sCD
profile/fingerprint/pattern/barcode (sCDprint) and may be from one
body fluid type or more than one body fluid type. Advantageously
the one or more samples for testing and used to generate a sCD
profile are taken from more than one body fluid for any given
disease state. Advantageously, a number of sCD levels are measured
from the same body fluid sample. More advantageously, all of the
sCD levels comprising a fingerprint are measured in parallel from
one body fluid sample.
[0030] As used herein, the term `collating` the data means to put
the data into a form so that one or more pattern/s of the levels of
sCDs within that disease state is apparent. Advantageously, the
data will be entered into a database as described herein. More
advantageously, the database is an integrated database as described
herein, comprising clinical data linked to specific sCD fingerprint
patterns/profiles.
[0031] As the present inventors surprisingly found that a sCD
fingerprint/profile (sCDprint) of a diseased individual is
different from that of a non-diseased individual, it was realised
that by comparing the sCD fingerprint/profile (sCDprint) of a
sample from a diseased patient with that of one or more reference
sCD fingerprints representing one or more defined disease states
then the presence and nature of a disease in that individual could
be ascertained.
[0032] Thus, in a further aspect, the present invention provides a
method for predicting the presence of one or more disease states in
an individual comprising the step of comparing one or more sCD
fingerprint/s (sCDprint/s) generated from that individual with one
or more reference sCD fingerprint/s.
[0033] In the context of the present invention, the term
`predicting the presence of one or more disease states` refers to
the process of detecting the presence of one or more disease states
before the onset of the clinical signs of the disease are apparent
in the individual. The clinical signs of disease are characteristic
of each disease state or group of disease states, as long as the
disease is present in that individual.
[0034] As referred to herein, the comparing step may refer to
comparing an individuals sCD fingerprint/profile (sCDprint) with
one or more reference sCD fingerprint/s of one or more disease
state/s and/or with a reference sCD fingerprint of a non-diseased
`normal` individual.
[0035] In a further aspect still, the present invention provides a
method for detecting the presence of one or more disease states in
an individual comprising the step of comparing one or more sCD
fingerprint/s generated from that individual with one or more
reference sCD fingerprint/s.
[0036] The term `detecting the presence of one or more disease
states` refers to the detection of the presence of one or more
disease states in an individual once the clinical signs of one or
more disease states are apparent in that individual. In addition,
the term refers to the process of detecting the presence of one or
more disease states in an individual other than the disease state
whose clinical signs are apparent in that individual.
[0037] According to the above two aspects of the invention, the
reference sCD fingerprint/s may be from non-diseased (normal)
individuals and/or from diseased individuals. Alternatively, or in
addition the reference sCD fingerprints/profiles may be derived
from normal subjects who have undergone some form of intervention.
Such interventions include but are not limited to treatment with
chemotherapeutic or other agents, exposure to radiation and
exposure to pathogens. Those skilled in the art will be aware of
other interventions as used herein. According to the above two
aspects of the invention, preferably, the sCD
fingerprint/s/profiles (sCDprint) are from diseased
individuals.
[0038] In a further aspect still, the present invention provides a
method for detecting the extent of one or more disease states in an
individual comprising the step of comparing one or more sCD
fingerprint/s generated from that individual with one or more
reference sCD fingerprint/s.
[0039] As referred to above, the term `detecting the extent of one
or more disease states` includes within its scope detecting the
severity of one or more disease states within an individual. For
example it may allow low grade and high grade forms of the disease
to be distinguished. It allows localised and metastasised forms of
a particular disease to be distinguished. In such cases one or more
sCD fingerprints of an individual are compared with one or more
reference disease sCD fingerprints representative of disease states
at one or more degrees of severity. For example, in the case of
neoplastic disease the presence or absence of metastasis may be
detected using the method of the present invention.
[0040] In a further aspect, the present invention provides a method
for assessing the progression of a disease state in an individual
comprising the step of comparing the sCD fingerprint of an
individual at two or more periods during the occurrence of the
disease.
[0041] In the context of the present invention, the term `assessing
the progression of a disease state` means assessing whether the
disease has increased in severity, decreased in severity or remains
the same severity compared with a different period during the
life-span of the disease. In addition the term `assessing the
progression of a disease state` includes within its scope
monitoring the progression of a disease state.
[0042] The term `period` in the context of the present invention,
generally refers to a time period.
[0043] As defined herein, the term a `disease state` refers to any
impairment of the normal physiological functions affecting an
organism or any disease condition, disorder or the presence of a
particular microbial, viral, parasitic or other pathogenic agent
known to one skilled in the art. Suitable disease states for
analysis as described herein include but are not limited to:
infectious, neoplastic, autoimmune, immunological, metabolic,
degenerative, psychological, psychiatric, iatrogenic, inflammatory,
drug or toxin related, vascular, traumatic and endocrine diseases.
Advantageously, `a disease state` as herein defined refers to any
one or more disease selected from the group which includes but is
not limited to: infections such as bacterial, fungal, protozoan,
parasitic, prion and viral infections, non-neoplastic disorders;
stroke; heart condition; atherosclerosis; pain; diabetes, obesity;
anorexia; bulimia; asthma; Parkinson's disease; thrombosis; acute
heart failure; hypotension; hypertension; urinary retention;
metabolic bone diseases such as osteoporosis and osteo petrosis;
angina pectoris; hepatitis; myocardial infarction; ulcers; asthma;
allergies; rheumatoid arthritis; inflammatory bowel disease;
irritable bowel syndrome benign prostatic hypertrophy;
pancreatitis; chronic renal failure and psychotic and neurological
disorders, including anxiety, schizophrenia, manic depression,
delirium, dementia, severe mental retardation and dyskinesias, such
as Huntington's disease or Gilles de la Tourett's syndrome and
others. Most preferably it refers to appendicitis; Bence Jones
Proteinuria; Chronic Myoloid Leukemia; Colorectal cancer; chronic
renal failure; Crohn's Disease; Diabetic Nephropathy; Cardiac
pathology; Infection; Liver damage; Lymphoma; macrocytic anaemia;
Prostate Cancer; Oligoclonal Banding and Pulmonary Embolism/Deep
Vein Thrombosis (eg DVT/PE). One skilled in the art will appreciate
that this list is not intended to be exhaustive. Indeed this method
should be suitable for most if not all diseases.
[0044] Examples of shed cluster of differentiation molecules
suitable for measurement to generate a sCD fingerprint for use in
the methods of the present invention include but are not limited to
CD14, CD25, CD31, CD44, CD50, CD54, CD62E, CD62L, CD86, CD95,
CD106, CD116, CD124, CD138, CD141, CD40L, CD8, CD23, CD30, CD40.
Those skilled in the art will be aware of other suitable sCD
molecules for analyses according to the methods of the present
invention. They will also be aware of other members of the family
that each sCD stands as an ambassador for, such as chemokine
receptors, interleukin receptors and inter-cellular adhesion
molecules.
[0045] Measuring CD levels may be carried out using methods known
to those skilled in the art and described herein. Shed CD (sCD)
levels may suitably be measured in samples of tissue fluids which
include, but are not limited to: serum, plasma, lymph fluid,
pleural fluid, synovial fluid, follicular fluid, seminal fluid,
amniotic fluid, milk, whole blood, urine, cerebrospinal fluid
(CSF), ascites, saliva, sputum, tears, perspiration, and mucus.
Advantageously, sCD levels are measured from samples of serum using
reagents suitable for detecting shed CDs that include but are not
limited to antibodies raised against those CDs. Preferably
monoclonal antibodies or engineered antibodies, including phage
antibodies raised against shed CDs or their membrane bound forms
are used for their detection. However non-protein agents may also
in principle be used to detect sCD molecules. Similarly the
detecting molecule may contain antibody bonding site fragments
incorporated into the scaffold of another molecules or an
engineered scaffold. Commercially available kits for measuring CD
levels include those from Diaclone 1, Bd A Fleming BP 1985 F-25020
Besancon Cedex-France and Medsystems Diagnostics GmbH, Rennweg 95b,
A-1030 Vienna Austria.
[0046] Suitable techniques for measuring levels of sCDs include but
are not limited to immunoassay including ELISA using commercially
available kits such as those described above, flow cytometry
particularly multiplexed particle flow cytometry as herein
described. Those skilled in the art will be aware of other suitable
techniques for measuring CD levels in samples from an individual
including antibody `chip` array type technologies or chip
technologies utilizing non-classical antibody binding site grafted
molecules. Suitable techniques for measuring levels of sCDs are
described in more detail in the detailed description of the
invention.
[0047] Shed CD levels are also measured in a number of individuals
with one or more disease states as herein defined, such as
appendicitis and the like. Generally one or more shed CDs levels
will be elevated in a given disease state as compared with the
range found in normal individuals. However, some sCD levels
decrease in some disease states compared with the range found in
`normal` individuals and such decreases may also form part of a sCD
fingerprint of the present invention. Thus, by measuring the ranges
of levels of various shed CDs found in a number of individuals with
one or more defined disease state/s a `fingerprint` of shed CD
levels for any defined one or more diseases is generated. Likewise
by measuring the ranges of levels of various shed CDs found in a
number of individuals who have undergone one or more interventions
(such as chemotherapeutic treatment, exposure to pathogens,
exposure to radiation, individuals who have undergone a given
vaccination program etc) then a `fingerprint` (sCDprint) of shed CD
levels for a given intervention may be generated. Those skilled 10
in the art will appreciate that a sCD fingerprint (sCDprint)
representative of an intervention may be generated form diseased or
non-diseased individuals.
[0048] Preferably, the sCD fingerprint of an individual is
generated from any two or more sCDs selected from the group
consisting of the following: CD14, CD25, CD31, CD44, CD50, CD54,
CD62E, CD62L, CD86, CD95, CD106, CD116, CD124, CD138, CD141, CD40L,
CD8, CD23, CD30, CD40. One skilled in the art will appreciate that
this list is not intended to be exhaustive and may include CD
homologues of human and other mammalian or non-mammalian species.
One skilled in the art will appreciate though that in general
animal reference sCD fingerprints cannot be used to analyse human
diseases and vice-versa. For instance sCD
patterns/profiles/fingerprints could be defined in the rat or mouse
using rat or mouse equivalent CD monoclonal antibodies as herein
described. This would be an invaluable adjunct for studying these
animal model systems, especially in the area of therapeutics, gene
knockouts and other such proteomic and genomic studies.
[0049] The invention can also be used for testing human and other
mammalian and non-mammalian species using sCD fingerprints from the
appropriate animal.
[0050] One skilled in the art will appreciate that the methods of
the present aspect of the invention can be used to test potential
therapeutic agents suitable for the prophylaxis and/or treatment of
diseases. An agent of therapeutic potential will affect the sCD
profile or `fingerprint` of the disease: If several fingerprints
are taken at various stages of a disease and compared with those
obtained from samples in which an individual has been treated with
a potential therapeutic agent, then the effect on one or more sCD
fingerprints can readily be assessed.
[0051] In addition, the method of the present invention may also be
used to monitor patient compliance with taking a particular drug
(agent), and/or undergoing a particular treatment regime.
[0052] Thus, in a further aspect still, the present invention
provides a method for assessing the effect of one or more agent/s
on one or more disease states in an individual comprising the step
of comparing a sCD fingerprint of an individual at two or more
different time periods.
[0053] According to the above aspect of the invention, preferably
the agent is a potentially therapeutic agent.
[0054] In the context of the present invention the term to `assess
the effect` means to detect any changes in the severity or other
characteristics of any one or more diseases in an individual. Such
changes will be reflected in a change in sCD profile/fingerprint of
an individual.
[0055] Preferably the agent is a potentially therapeutic agent. The
term `potentially therapeutic agent` means any agent that may cause
a beneficial effect on an individual suffering from one or more
diseases. Such beneficial effects may be for example reducing the
clinical signs of the one or more diseases. It is an important
feature of the present invention though, that a change in level of
any one sCD in isolation is not always indicative of a change in
severity of a disease. It will appreciated though that in some
cases, a change in the level of one sCD in isolation will be
indicative of a change in severity of a disease.
[0056] Generally, individual sCD levels will be elevated in a
disease state as compared with a `normal` non-diseased individual.
Occasionally however, the level of an individual sCD will decrease
in a disease state as compared with a normal non-diseased
individual. However, according to the present invention, it is the
changes of the profile of a number of sCDs (that is a fingerprint)
during a disease which provides an accurate measure of the effect
of one or more agents on a disease state in an individual.
[0057] One skilled in the art will appreciate that on occasion a
selection of the complete repertoire of sCDs available for testing
may be measured. The selection chosen may vary according to the
disease state being tested.
[0058] According to this aspect of the invention, sCDs suitable for
generating a sCD fingerprint are as described herein.
[0059] Therapeutic agents may be tested for their effect on any one
or more disease states selected from the group consisting of the
following: infections, autoimmune disease, neoplastic, vascular
endocrinological, metabolic, inflammatory degenerative, psychiatric
psychological, traumatic, drug/toxin-related, bacterial, fungal,
protozoan and viral infections, non-neoplastic disorders; pain;
diabetes, obesity; anorexia; bulimia; asthma; pregnancy; endocrine;
vascular; metabolic; gastro-intestinal; iatrogenic; psychiatric;
psychological; exercise-induced; diet-related; ME; degenerative;
Parkinson's disease; thrombosis; atherosclerosis; acute heart
failure; hypotension; hypertension; erectile dysfunction; urinary
retention; metabolic bone diseases such as osteoporosis; angina
pectoris; hepatitis; myocardial infarction; ulcers; allergies;
rheumatoid arthritis; inflammatory bowel disease; irritable bowel
syndrome benign prostatic hypertrophy; psychosis; psychiatric
disorders; including anxiety; schizophrenia; manic depression;
delirium; dementia; severe mental retardation and dyskinesias, such
as Huntington's disease or Gilles de la Tourett's syndrome; and
preferably tumours which can be benign or malignant cancers; breast
cancer; myeloma; melanoma; bladder cancer; leukaemia; plasmocytoma
and others, but most preferably appendicitis; Bence Jones
Proteinuria; Chronic Myeloid Leukaemia; Colorectal cancer; chronic
renal failure; Crohn's Disease; Diabetic Nephropathy; Cardiac
pathology; Infection; Liver damage; Lymphoma; macrocytic anaemia;
Prostate Cancer; Oligoclonal Banding and PE/DVT
[0060] Suitable agents for assessment according to the method of
the present invention may be naturally occurring or synthetic.
Naturally occurring agents include proteins, peptides or nucleic
acids. They may be agents known to be of therapeutic value or they
may be of unknown therapeutic value.
[0061] In a further aspect, the present invention provides a method
for sub-categorising a sCD fingerprint profile comprising the steps
of identifying within one or more disease states one or more
sub-group/s of sCDs wherein each sub-group of sCDs exhibits common
characteristics distinguishing it from any other sub-group within
that disease category.
[0062] As used herein the term a `sCD sub-category` describes a
sub-group of sCDs which show a defined fingerprint/profile
(sub-fingerprint) of sCD levels within a larger fingerprint of one
or more disease states wherein each sub-group of sCDs exhibits
common characteristics distinguishing it from any other sub-group
within those one or more disease states.
[0063] In a further aspect still, the present invention provides a
sCD reference database comprising pathological and/or normal sCD
fingerprint patterns.
[0064] As herein described the term `a reference database` refers
to a collection of sCD fingerprints from normal `non-diseased`
and/or diseased individuals. Advantageously, the database is
computer generated and/or stored. Advantageously the data from more
than 5 individuals is present in the database. More advantageously
the data from more than 10, 100, or 1000 individuals comprises the
database. More advantageously still the data from more than 10,000
or more than 50,000 individuals comprises the database. Most
advantageously the data from more than 100,000 individuals
comprises the database. Advantageously the database, in addition to
sCD data will also comprise clinical information relating to
various patients and/or disease conditions. Alternatively or in
addition, a database according to the present invention comprises
genomic information such as mRNA expression profiles, and/or sCD
body fluid profiling data, and/or CD cell surface pattern data,
and/or clinical data. Most advantageously, the database will be in
the form of an integrated clinical database comprising accurate
patient details including co-morbidity, age, sex, smoking status
etc.
[0065] Recent studies which have investigated the impaired
expression of NKG2D and T-cell activation by tumour-derived soluble
MHC ligands (Nature, vol 419, 17 Oct. 2002). Studies have shown
that tumours release large amounts of the MHC class I homologue MIC
into the serum. Activation of the NKG2D receptor on natural T cells
is known to stimulate their ability to destroy tumours, but the
high levels of tumour derived MIC seem to downregulate the NKG2D
receptor and block the antitumour effect. (Nature, vol 419, 17 Oct.
2002, p679, pg 734). These soluble forms of MHC are produced either
by enzymatic cleavage or by alternative splicing (Nature, vol 419,
17 Oct. 2002, p679, pg 734).
[0066] It is apparent from the present disclosure that sCDs may be
produced by alternative splicing (Woolfson and Milstein, PNAS Vol
91, pp 6683-6687), enzymatic cleavage or other mechanisms and that
such shed forms are associated with disease (Sugiyama et al.,
Non-invasive detection of bladder cancer by identification of
abnormal CD44 proteins in exfoliated cancer cells in urine, Journal
of Clinical pathology, 48, 3, 142-147; Yoshida, K et al, Abnormal
retention of intron 9 in CD44 transcripts in human gastrointestinal
tumours. Cancer research 55, 4273-4277). The present inventors
consider that sCD molecules may also bind to a ligand/receptor and
thereby block down stream effects. Thus, the present inventors have
realised that the blockage of the production of sCD molecules via
the inhibition of any of the methods of sCD generation described
herein, may be a therapeutically useful method for the prophylaxis
or treatment of one or more diseases or disorders including but not
limited to any of those in the group consisting of infections,
inflammation, vascular, iatra genic, endocrine, drug-related
disorders, toxin related disorders, and cancer in particular
metastasis and leukemia.
[0067] Thus in a further aspect still, the present invention
provides a method for treating one or more diseases comprising the
step of inhibiting the production of one or more sCDs within an
individual.
[0068] In a further aspect still, the present invention provides
the use of an inhibitor of the production of one or more sCDs in
the preparation of a medicament for the treatment of disease.
[0069] According to the above aspect of the invention, the term `an
inhibitor of the production of one or more sCDs` refers to one or
more agents which inhibit the production of a shed form of sCD as
herein defined. Advantageously, the inhibitor is a specific
inhibitor of those one or more sCDs. Suitable inhibitors include
alternative splicing inhibitors and/or enzymatic cleavage
inhibitors. Advantageously, the inhibitor is an alternative
splicing inhibitor. Such alternative splicing inhibitors include
for example inhibitors of exonic splicing enhancers (Fairbrother et
al, Science, vol 297, 9 Aug. 2002).
[0070] According to the above aspects of the invention, the
production of any one or more sCDs present in the body fluid of an
individual may be inhibited. Advantageously, the one or more sCDs
are any one of those selected from the group consisting of the
following: CD14, CD25, CD31, CD44, CD50, CD54, CD62E, CD62L, CD86,
CD95, CD106, CD116, CD124, CD138, CD141, CD40L, CD8, CD23, CD30,
CD40. More advantageously the sCD is CD1. Advantageously, the sCD
is CD1 and the inhibitory agent is an alternative splicing
inhibitor and/or a gene specific CD1 inhibitor.
[0071] It should be noted that the present inventors consider that
the invention described herein can be used to post hoc re-analyse
clinical trial data, assigning patients to different sub-groups for
analysis on the basis of their sCDprints and in doing so
potentially revealing previously unseen statistical effects and at
the same time identifying responders or non-responders to a
therapeutic intervention, and those who respond adversely to the
intervention in the case in which a therapeutic agent has not been
taken further due to adverse responses in small numbers of
individuals.
Definitions
[0072] The term `CD` refers to a different cell surface leukocyte
molecule recognised by a given monoclonal or group of monoclonal
antibodies which specifically `cluster` to the antigen/molecule in
question. Many, if not all of these molecules produce forms which
are released from the cell surface by alternative splicing,
proteolytic cleavage, dissociation or other mechanisms.
[0073] Thus in the context of the present invention, the term `shed
CD molecule (sCD)` refers to a released form of a cell surface
leukocyte molecule in which at least a portion of that molecule is
recognised by a given monoclonal or group of monoclonal antibodies
as herein described. Advantageously, as herein defined a shed form
of sCD is generated by various mechanisms including but not limited
to any of those selected from the group consisting of the
following: alternative splicing, proteolytic cleavage and
dissociation.
[0074] As herein defined, the term `shed CD fingerprint/profile
(sCD)` or `sCDprint` describes the pattern or profile of levels of
more than one shed CD measured in one or more body fluids from one
or more individuals. A sCD fingerprint as herein defined may be
representative of one or more non-diseased individual or a one or
more diseased individual/s. Preferably, a shed CD fingerprint
describes the level of five or more shed CD molecules, more
preferably it is 6, 7, 8, 9, 10 or more sCD molecules, more
preferably still a shed CD fingerprint describes the levels of 15
or more sCD molecules. Most preferably a shed CD fingerprint
describes the levels of 20 or more sCD molecules.
[0075] As used herein the term a `sCD sub-category` describes a
sub-group of sCDs which show a defined fingerprint/profile
(sub-fingerprint) of sCD levels within a larger fingerprint of one
or more disease states wherein each sub-group of sCDs exhibits
common characteristics distinguishing it from any other sub-group
within those one or more disease states.
[0076] As defined herein, the term a `disease state` refers to any
impairment of the normal physiological functions affecting an
organism or any disease condition, disorder or the presence of a
particular microbial, viral, parasitic or other pathogenic agent
known to one skilled in the art. Suitable disease states for
analysis as described herein include but are not limited to:
infectious, neoplastic, autoimmune, immunological, metabolic,
degenerative, psychological, psychiatric, iatrogenic, inflammatory,
drug or toxin related, vascular, traumatic and endocrine diseases.
Advantageously, `a disease state` as herein defined refers to any
one or more disease selected from the group which includes but is
not limited to: infections such as bacterial, fungal, protozoan,
parasitic, prion, and viral infections, non-neoplastic disorders;
stroke; heart condition; atherosclerosis; pain; diabetes, obesity;
anorexia; bulimia; asthma; Parkinson's disease; thrombosis; acute
heart failure; hypotension; hypertension; urinary retention;
metabolic bone diseases such as osteoporosis and osteo petrosis;
angina pectoris; hepatitis; myocardial infarction; ulcers; asthma;
allergies; rheumatoid arthritis; inflammatory bowel disease;
irritable bowel syndrome benign prostatic hypertrophy;
pancreatitis; chronic renal failure and psychotic and neurological
disorders, including anxiety, schizophrenia, manic depression,
delirium, dementia, severe mental retardation and dyskinesias, such
as Huntington's disease or Gilles de la Tourett's syndrome and
others. Most preferably it refers to appendicitis; Bence Jones
Proteinuria; Chronic Myoloid Leukemia; Colorectal cancer; chronic
renal failure; Crohn's Disease; Diabetic Nephropathy; Cardiac
pathology; Infection; Liver damage; Lymphoma; macrocytic anaemia;
Prostate Cancer; Oligoclonal Banding (myaesthenis gravis) and
Pulmonary Embolism/Deep Vein Thrombosis (eg DVT/PE). One skilled in
the art will appreciate that this list is not intended to be
exhaustive.
[0077] Examples of shed cluster of differentiation molecules
suitable for measurement to generate a sCD fingerprint for use in
the methods of the present invention include but are not limited to
CD14, CD25, CD31, CD44, CD50, CD54, CD62E, CD62L, CD86, CD95,
CD106, CD116, CD124, CD138, CD141, CD40L, CD8, CD23, CD30, CD40.
Those skilled in the art will be aware of other suitable sCD
molecules for analyses according to the methods of the present
invention.
[0078] As defined herein the term `an antibody` includes within its
scope for example IgG, IgM, IgA, IgD or IgE) or fragment (such as a
FAb, F(Ab').sub.2, Fv, disulphide linked Fv, scFv, diabody) whether
derived from any species naturally producing an antibody, or
created by engineered DNA technology (for example fluorobodies,
green fluorescently labelled antibodies); whether isolated from
serum, B-cells, hybridomas, transfectomas, yeast or bacteria). It
also includes within its scope, non-protein binding agents which
comprise the binding specificity of an antibody molecule, or a
binding capacity in general for a determinant or sub-determinant of
a component of the protein structure/glycoprotein structure of a CD
molecule.
BRIEF DESCRIPTION OF THE FIGURES
[0079] FIG. 1. Disease Groups. Multiples of upper limit of normal
(ULN). All sCD's included
[0080] The limits indicated by each point are: [0081] No shading
.ltoreq.1.times.ULN [0082] Lightly shaded 1-2.times.ULN [0083]
Darkly shaded >2.times.ULN [0084] A white slash in the box
indicates no data available.
[0085] FIG. 2. All sCD's that appear not to discriminate from the
normals (sCD's 21; 102; 117, 126; 130; 26; 44v5; 44v6; 62P).
[0086] FIG. 3. Disease Groups. Mode of Response for Remaining 20
sCD's.
[0087] To simplify the data further the modal response for each
disease group was plotted.
[0088] FIG. 4. Disease Groups. Mode of Response for remaining
sCD's.
[0089] Data has been ranked in order of increased expression.
[0090] FIG. 5. Disease Groups. Mode of Response for remaining
sCD's.
[0091] FIG. 6. Disease Groups. Mode of Response for all sCD's.
[0092] As for FIG. 3 (except all sCD's are included).
[0093] The limits indicated by each point are: [0094] No shading
.ltoreq.1.times.ULN [0095] Lightly shaded 1-2.times.ULN [0096]
Darkly shaded >2.times.ULN
[0097] A white slash in the box indicates no data available.
[0098] FIG. 7. Disease Groups. Mode of Response for all sCD's.
[0099] FIG. 8. Disease Groups. Mode of Response for all sCD's.
[0100] FIG. 9. Shows the patterns of levels of sCDs during various
infectious disease states as compared with a group of `normal`
non-diseased individuals. [0101] Key: Lightly shaded box-sCD levels
unchanged [0102] Darkly shaded box-sCD levels increased [0103]
Shaded box with diagonal line-sCD levels decreased.
[0104] FIG. 10. Shows the patterns of levels of sCDs during various
inflammatory/autoimmune diseases as compared with a group of
`normal` non-diseased individuals. [0105] Key: Lightly shaded
box-sCD levels unchanged [0106] Darkly shaded box-sCD levels
increased [0107] Shaded box with diagonal line-sCD levels
[0108] FIG. 11. Shows the patterns of levels of sCDs during various
`other diseases` as compared with a group of `normal` non-diseased
individuals. [0109] Key: Lightly shaded box-sCD levels unchanged
[0110] Darkly shaded box-sCD levels increased [0111] Shaded box
with diagonal line-sCD levels decreased
[0112] FIG. 12. Shows the patterns of levels of sCDs during various
neoplastic disease states as compared with a group of `normal`
non-diseased individuals. [0113] Key: Lightly shaded box-sCD levels
unchanged [0114] Darkly shaded box-sCD levels increased [0115]
Shaded box with diagonal line-sCD levels decreased
[0116] FIG. 13. Shows the patterns of levels of sCDs during various
cardiovascular diseases as compared with a group of `normal`
non-diseased individuals. [0117] Key: Lightly shaded box-sCD levels
unchanged [0118] Darkly shaded box-sCD levels increased [0119]
Shaded box with diagonal line-sCD levels decreased
[0120] FIG. 14. Shows the patterns of levels of sCDs during various
metabolic and haematological diseases as compared with a group of
`normal` non-diseased individuals. [0121] Key: Lightly shaded
box-sCD levels unchanged [0122] Darkly shaded box-sCD levels
increased [0123] Shaded box with diagonal line-sCD levels
decreased
[0124] FIG. 15. Shows the patterns of levels of sCDs during various
haematological malignancies as compared with a group of `normal`
non-diseased individuals. [0125] Key: Lightly shaded box-sCD levels
unchanged [0126] Darkly shaded box-sCD levels increased [0127]
Shaded box with diagonal line-sCD levels decreased
DETAILED DESCRIPTION OF THE INVENTION
[0127] General Techniques
[0128] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art (e.g., in cell culture, molecular
genetics, nucleic acid chemistry, hybridisation techniques and
biochemistry). Standard techniques are used for molecular, genetic
and biochemical methods (see generally, Sambrook et al., Molecular
Cloning: A Laboratory Manual, 2d ed. (1989) Cold Spring Harbor
Laboratory Press, Cold Spring Harbor, N.Y. and Ausubel et al.,
Short Protocols in Molecular Biology (1999) 4.sup.th Ed, John Wiley
& Sons, Inc. which are incorporated herein by reference) and
chemical methods. In addition Harlow & Lane., A Laboratory
Manual Cold Spring Harbor, N.Y., is referred to for standard
Immunological Techniques.
sCD Molecules According to the Invention
[0129] In a first aspect, the present invention provides a shed CD
(sCD) fingerprint (sCD print) of one or more disease states.
[0130] In the context of the present invention, the term `CD`
refers to a different cell surface leukocyte molecule recognised by
a given monoclonal or group of monoclonal antibodies which
specifically `cluster` to the antigen/molecule in question. Many,
if not all of these molecules produce forms which are released from
the cell surface by alternative splicing, proteolytic cleavage,
dissociation or other mechanisms.
[0131] Thus in the context of the present invention, the term `shed
CD molecule (sCD)` refers to a released form of a cell surface
leukocyte molecule in which at least a portion of that molecule
recognised by a given monoclonal or group of monoclonal antibodies
as herein described.
Location of sCD Molecules.
[0132] Although first identified on leukocytes. CD antigens have
been located on other blood cells and non-blood cells. CD molecules
have been found on many different blood cell types including the
following blood cell types: erythroid, dendritic cells, B cells,
pre-B cells, T cells (cytotoxic, suppressor and helper subtypes),
monocytes, myeloid cells, endothelial cells, platelets, NK cells
(natural killer cells), red blood cells, thymocytes. Those skilled
in the art will appreciate that this list is not intended to be
exhaustive.
[0133] In addition, CD antigens have been found on the following
non-immune cells myocytes, peripheral nerve, liver, platelet
precursors, lung cells, cerebellum, cortex, glia, neuroepithelium,
placenta, prostate, spinal cord, brain, muscle, kidney, salivary
glands, muscle, melanomas, leukemias, lymphoma, hematopoietic
cells, lymphoid progenitor cells, breast, astrocytes, thyroid,
lung, pancreas, trachea, schwann cells, trophoblast, erthroblast,
microglia.
[0134] In the context of the present invention it is important to
note that the CD nomenclature is a simple method for representing a
whole range of molecules. For example: CD14 is the
lipopolysaccharide receptor, LP5-R; CD21 is the EBV receptor; CD 25
is the IL-2Ralpha receptor; CD 31 is PECAM-1; CD 44 is H-CAM; CD 50
is ICAM-3; CD 54 ICAM-1; CD 62E is LECAM-2; CD 62L is LECAM-1; CD
86 is B 70; CD 95 is FAS apoptosis antigen; CD 102 is ICAM-2; CD
106 is VCAM-1; CD 116 is GM-CSFR alpha; CD 117 is c-kit stem cell
factor receptor; CD 124 is IL-4R alpha; CD 126 is IL-6Ralpha; CD
130 is gp 130; CD 138 is syndican-1; CD 141 is thrombomodulin; CD8
is Lin 2; CD 27 is low affinity IgE-R; Cd 30 is Ki-1;
[0135] The present inventors realised that sCDs act as
representatives/ambassadors for the molecules from which they are
shed. Furthermore they realised that cell behaviour can be
interrigated on the basis of the patterns of sCD molecules shed by
cells.
Generation of a Fingerprint of One or More Disease States
[0136] In a first aspect, the present invention provides a shed CD
(sCD) fingerprint of one or more disease states.
[0137] Clinical signs and symptoms and various biochemical
indicators of disease are used to identify individuals with one or
more defined disease states. sCD levels are then measured for a
number of sCDs present in one or more body fluid samples from each
individual, preferably in a number of individuals using methods
known to those skilled in the art and described herein, in order to
generate a reference disease state or reference composite disease
state fingerprint for those one or more given disease states.
(A) Diagnosis of Disease States
i. Diagnostic Indicators Used.
Appendicitis
[0138] Request for Amylase at admission A&E/MAU Subsequent
Histopathological Diagnosis Bence Jones Proteinuria [0139] Multiple
myeloma in which the malignant plasma cells excrete only light
chains of one type (either 2 or 3); lytic bone lesions occur in
about 60% of the cases, and light chains (Bence Jones protein) can
be detected in the urine [0140] Positive finding Chronic Myeloid
Leukaemia [0141] Histopathological Diagnosis Colorectal Carcinoma
[0142] Histopathological Diagnosis Chronic Renal Failure [0143]
Prolonged elevation of serum creatinine. Crohn's Disease [0144]
Histopathological diagnosis Diabetic Nephropathy [0145] Identified
by abnormal urine Albumin/Creatinine ratio from subjects attending
diabetic clinic. Cardiac Pathology [0146] MI (as diagnosed by
increased CK, symptoms and ECG changes). Infection [0147] CRP (C
reactive protein)>250 g/l (e.g. Staphylococcus aureus
infections). Liver Damage [0148] Clinical Details Alcoholic Liver
Disease/Poisoning. Abnormal liver function tests. Lymphoma [0149]
Histopathological Diagnosis Macrocytic Anaemia [0150] Diagnosed by
haematological parameters. Hb<10 g/dL; MCV>100 fL Oligoclonal
Banding [0151] small discrete bands in the gamma globulin region of
the spinal fluid electrophoresis, indicating local central nervous
system production of IgG; bands are frequently seen in patients
with multiple sclerosis but can also be found in other diseases of
the central nervous system including syphilis, sarcoidosis, and
chronic infection or inflammation. VQ (Pulmonary Angiogram)
Pulmonary Embolism/Deep Vein Thrombosis [0152] ultrasound VQ or CT
pulmonary angiogram scan (ventilation perfusion mismatch) Prostate
Carcinoma [0153] Histopathological diagnosis and elevated PSA.
[0154] In general, a combination of the patient's history, medical
examination, general health and indicators provided from
biochemical, histochemical, radiochemical and other types of tests
and disease and/or clinical signs of disease will be used in the
diagnosis of disease. For the avoidance of doubt, the term
`clinical signs and symptoms of disease` means the same as
`clinical details` of disease.
(B) Samples of Body Fluids from Disease States
[0155] For each sCD the following information is generally obtained
a) the dynamic range of the assay b) the range of concentrations
expected in health c) the range of concentrations expected in
disease. From this information an approximate dilution factor for
each assay may be obtained, allowing maximum use of subject
samples. One skilled will appreciate thought that in some
circumstances body fluid samples may not be diluted for
testing.
[0156] Suitable body fluids for measuring sCD levels as herein
defined include whole blood, serum, urine, tissue fluid,
cerebrospinal fluid, lymphatic fluid, synovial fluid, aspirate,
bone marrow aspirate, mucus or other tissue or body fluid. One
skilled in the art will appreciate that this list is not intended
to be exhaustive. Preferably sCD levels are measured in serum which
is prepared from whole blood using methods familiar to those
skilled in the art At least 1.5 ml of sample is required for
testing of all the sCDs. Advantageously, less than 1.5 mls of
sample is required for such testing. More advantageously, much
smaller volumes of sample will be needed for such testing. In
addition, the present inventors have shown that haemolysis and
lipaemia can interfere with some immunoassays used for detecting
sCDs and therefore samples are used which exhibit minimal
haemolysis and lipaemia.
[0157] Body fluid samples may be diluted in order to measure the
sCD levels and the dilution factor for each sCD should be the same
for the generation of the fingerprints for all disease states
tested. One skilled in the art will appreciate that the dilution
factor may be adjusted in order to focus on either high or low
concentrations of sCDs. Advantageously, the dilution factor will be
adjusted to focus on high concentrations of sCDs.
(C) Methods of Measuring sCD Levels.
[0158] Suitable methods for measuring levels of sCDs in body fluids
include flow cytometry, in particular multiplexed particle flow
cytometry, immunoassay and microarray technologies utilising
antibody or ligand interactions. Advantageously, sCDs levels are
measured using multiplexed particle flow cytometry and/or chip
based monoclonal antibody technology, engineered antibody molecules
or non-antibody or non-protein molecules that recognise sCD
antigens. These methods will be familiar to those skilled in the
art.
(i) Immunoassays
[0159] Immunoassays such as immunoblotting (detecting
membrane-bound and soluble proteins), and enzyme linked
immunoassays (ELISA) provide a sensitive and specific means of
detecting target substances.
[0160] Although the various types of immunoassays are performed
differently, they have one thing in common they all involve
antibodies. Used in an appropriate immunoassay system, specificity
leads to sensitivity. As herein defined the term `antibodies`
includes antibody fragments, engineered immunoglobulin folds or
scaffolds which have a binding affinity for soluble CD
molecules.
[0161] One skilled in the art will appreciate that the `immunoassay
technique` may be adapted to use other molecules which selectively
bind sCDs. Those skilled in the art will be aware of such
molecules.
[0162] In a direct immunoassay, the antibody used as the primary
reagent is advantageously given a fluorescent, enzymatic, or
radio-active detection means. In indirect immunoassays, the
secondary antibody-usually polyclonal antisera produced by a goat
or a rabbit against human immunoglobulins-carries the detection
means. When a secondary antibody is used, the initial immune
reaction between the primary antibody and the target antigen is
amplified, producing a more readily detectable signal.
[0163] Western blots of electrophoretically separated proteins
(immunoblots), on the other hand, are generally probed with
antibodies labeled with an enzyme or a radioisotope such as 125I.
Chromogenic or chemiluminescent substrates can also be used. For
example, enzymes such as HRP and AP catalyze chromogenic reactions,
in which a colourless substrate is converted into a coloured
compound, and also chemiluminescent reactions where light is
emitted.
[0164] Chromogenic substrate kits are commercially available and
include but are not limited to for example alkaline phosphatase,
horseradish peroxidase, and TMB peroxidase (TMB is
tetramethylbenzidine, the substrate in this case). Boehringer
Mannheim also has several enzyme substrates for immunoassays
available. They include but are not limited to for example ABTS
(2,2+-azino-di-3-ethylbenzthiazoline sulfonate) and TMB
(tetramethylbenzidine), which are used with HRP; and 4-nitrophenyl
phosphate and 5-bromo-4-chloro-3-indolyl phosphate (BCIP) for
immunoassays in which an alkaline phosphatase-conjugated antibody
is used.
[0165] Chemiluminescent substrates are available from companies
such as Pierce, which for example, produces the SuperSignal CL-HRP
Substrate, an enhanced chemiluminescent substrate for horseradish
peroxidase. This system detects specific proteins on immunoblots
with a sensitivity that rivals radioactivity (reportedly to
picogram levels). When the chemiluminescent substrate is applied to
membrane-bound proteins on an immunoblot, an instantaneous but
long-lasting flash of light is produced.
[0166] Commercially available immunoassay kits for measuring sCD
levels include those from Diaclone 1, Bd A. Fleming BP 1985 F-25020
Besancon Cedex-France which provides kits for the measurement of a
number of CD molecules including CD 14, CD21, CD25, CD31, CD44,
CD50, CD54, CD62E, CD62L, CD86, CD95, CD102, CD106, CD116, CD117,
CD124, CD126, CD130, CD138, CD141, CD40L. Medsystems diagnostics
GmbH, Rennweg 95b, A-1030 Vienna Austria, also provides kits which
measure sCD levels.
(ii) Flow Cytometry
[0167] Techniques for carrying out flow cytometry are familiar to
those skilled in the art and are described in Flow Cytometry: A
Practical Approach. Edited by MG Ormerod. IRL Press, Oxford. 1994.
ISBN 0-19 963461-0. Practical Flow Cytometry. 3rd Edition. Howard M
Shapiro. Alan R Liss, Inc. ISBN 0-471-30376-3. Flow Cytometry.
First Principles. Alice Longobardi Givan. Wiley-Liss, New York,
1992. ISBN 0-471-56095-2. Handbook of Flow Cytometry Methods.
Edited by J Paul Robinson. Wiley-Liss, New York, 1993. ISBN
0-471-59634-5.
(iii) Multiplexed Particle Flow Cytometry Assay
[0168] Methods for simultaneously assaying different proteins in
individual samples are commercially available. Some of those
commercially available are detailed below:
[0169] The versatile laboratory multianalyte profiling (LabMAP.TM.)
system developed by Luminex Corp. of Austin, Tex., can be used for
virtually any bioassay that is based on the specific binding of one
molecule to another, for example a monoclonal antibody raised
against a sCD and a CD molecule.
[0170] LabMAP assays for a sCD molecule can be based on the
immunological detection, and/or may follow the gain or loss of
fluorescence (e.g., when a mAb raised against a sCD binds to a sCD
target). LabMAP assays employ three different fluorochromes: two to
create color-coded microspheres, and the third for quantifying the
reaction. Polystyrene microspheres are internally dyed with precise
ratios of two spectrally distinct fluorochromes. This ratio confers
a unique identifying "signature" or "spectral address" to each
microsphere set.
[0171] Bioassays are conducted on the surfaces of the microspheres.
Each capture probe (e.g., sCD-specific antibody or other
affirmative detection reagent) is immobilized onto a color-coded
set of microspheres using any of a variety of different surface
chemistries. Luminex offers microspheres bearing Lumavidin.TM. (an
avidin derivative), for immobilizing biotinylated molecules, or
carboxyl groups, for covalently coupling protein. The binding of
analyte to an immobilized probe is detected via a detection reagent
labeled with the third fluorochrome. Luminex currently offers 100
different microsphere sets, each of which can be used for the
simultaneous measurement of a different analyte. Thus, in theory,
up to 100 different species can be simultaneously measured in a
single tube or microplate well.
[0172] The Luminex microsphere product line is designed
specifically to work with the instruments available from Luminex or
their partners. The Luminex 100.TM. instrument uses microfluidics
to align the microspheres in single file and employs two lasers,
one for the detection of the fluorescent microsphere itself, and
the other for the reporter reagent. The colour signals are captured
by an optics system and translated into binding data via digital
signal processing.
[0173] Instrumentation, reagents, and custom services for LabMAP
technology users are also available from companies other than
Luminex. For example, Bio-Rad Laboratories of Hercules, Calif.,
introduced the Bio-Plex.TM. Protein Array System. This system
combines a fluorescent reader with the software, protocols, and
supplies needed for performing LabMAP-based assays in a 96-well
microplate format. The primary benefits of the Bio-Plex Protein
Array System, other than up to a 100-fold increase in data, include
significantly reduced sample requirements.
[0174] The Cytometric Bead Array (CBA) system from BD Biosciences
of San Diego is flexible in that it accommodates multiple sizes and
fluorescent intensities of particles. The system includes
everything the researcher needs to implement this technology,
including a cytometer setup kit with the requisite software,
reagents and standards. The company's CBA assay kits employ their
proprietary bead sets, which are internally dyed with varying
intensities of a proprietary fluorophore. These sets are
distinguished via one fluorescence parameter and two size
discriminators. However, the system is also capable of handling
assays based on the use of other types of spectrally distinct
microsphere sets. The CBA analysis software is an "add-in" for
Microsoft Excel.RTM., and is compatible with contemporary data
acquisition software such as CellQuest.TM.. Researchers can employ
a variety of preset configurations for generating standard dilution
series and calibration curves, and data reports can be generated at
each step in the process.
(iv) "Antibody Chip" Array Technology.
[0175] The array format has revolutionised biomedical
experimentation and diagnostics, enabling ordered high-throughput
analysis. During the past decade, classic solid phase substrates,
such as microtitre plates, membrane filters and microscopic slides,
have been turned into high-density, chip-like structures.
[0176] Protein array technology allows high throughput screening
for gene expression and molecular interactions. Protein arrays
appear as new and versatile tools in functional genomics, enabling
the translation of gene expression patterns of normal and diseased
tissues into protein product. Protein function, such as enzyme
activity, antibody specificity, and other ligand-receptor
interactions and binding of nucleic acids or small molecules can be
analysed on a whole genome level.
[0177] As the array technology develops, an ever increasing variety
of formats become available (eg nanoplates, patterned arrays,
three-dimensional pads, flat-surface spot arrays, microfluidic
chips), and proteins can be arrayed onto different surfaces (e.g.,
membrane filters, polystyrene film, glass, silane, gold). Various
techniques are being developed for producing arrays. The emerging
future array systems will be used for high-throughput functional
annotation of gene products.
[0178] Protein microarrays are particularly useful in molecular
diagnostics The concept of the array library was central to this
development which now extends from DNA to protein. Similar to the
gene chip arrays measuring mRNA levels on a genome wide scale, the
protein product of expressed cells can be used for the simultaneous
assessment of protein levels on a proteome wide scale.
Additionally, protein specific antibodies can be arrayed to produce
"antibody chip arrays" (Cahill D., 2001, J. Imm. Meth. 250, 81-91).
The availability of such antibody chip arrays can be used to
simultaneously analyse numerous interactions within a single
sample. The "antibody chip" can be used to demonstrate
antibody-protein interactions by incubating the chip with target
proteins which have been labelled with a traceable marker
(ProteinChip, Ciphergen Biosystems, Fremont, Calif., USA; BIAcore
chips, Biacore, Upsala, Sweden) or by incubating the chip with
protein molecules or fragments thereof and detecting association
between antibody and protein molecule or fragment thereof using
ELISA type assays (Caliper Technologies, Mountain View, Calif.,
USA; Orchid Biocomputer Inc., Princeton, N.J., USA). It should be
noted that sCDs according to the invention may be found complexed
with a ligand and thus chip based technology described herein may
be used to measure/demonstrate interactions of ligand bound sCD
with other molecules.
[0179] Techniques for preparing antibody arrays are described
below:
[0180] The antibodies may be covalently linked to a suitable
membrane such as an Immobilon P membrane (PVDF; Millipore
Corporation) Subsequent blocking with an excess of a protein
solution such as a skim milk preparation is preferred. A blocking
agent is designed to eliminate non-specific binding on the binding
surface Other suitable blocking agents are Irish moss extract or
other source of carrageenan or gelatin. The antibodies are also
adsorbed to a nitrocellulose film on a glass microscope slide
(Schleicher and Schuell, NH, USA) and the unbound nitrocellulose is
then blocked with skim milk. Antibodies are also adsorbed to Nylon
membranes. To increase the accessibility of bound anti-CD
antibodies to antigens on cells, the solid support used for the
array is initially coated with a recombinant, truncated form of
Protein G from Streptococcus which retains its affinity for the Fc
portion of IgG lacks albumin and Fab binding sites, and
membrane-binding regions (Goward et al., 1990). Antibodies are
applied to this coat of Protein G and bind via their domains
leaving the Fab domains free to interact with cells. The Fab
domains are also further from the solid support providing greater
accessibility of CD antigens on cell membranes to antibodies.
[0181] The array of antibodies is also constructed on a membrane or
a coverslip. In this case, the antibodies are covalently linked to
the membrane as duplicate spots in a two dimensional matrix. The
spots are arranged in a matrix such as but not limited to a
15.times.15 matrix.
[0182] The antibodies are advantageously monoclonal and are
specific for the cluster of differentiation (cluster designation)
antigens (CD antigens). Details of CD antigens are available at
http://www.ncbi.nlm.nih.gov/prow/cd/index molecule.htm. The spots
are of microscopic size and are produced by the application of a
drop (-10 nanolitres) of antibody solution (e.g. 10/.tg protein/ml)
on designated portions of a membrane or glass surface such as a
coverslip, first washed with a non-specific protein absorbent such
as 30% w/v skim milk (Dutch Jug, Bonlac Foods Ltd, Melbourne,
Australia) and then rinsed. Other protein solutions and other
brands of skim milk may also be employed. The antibodies may be
covalently coupled to the solid support such as through amino
groups of lysine residues, the carboxylate groups of aspartate or
glutamic acid residues or the sulfhydryl groups of cysteine
residues. The array of antibodies selectively binds cells from body
fluids which express the respective antigens or may bind free
antigens. A positive and/or negative control is included such as an
antibody for surface molecules or soluble molecules known to be
present in the sample. An example of one form of the assay device
is shown in FIG. 3. The solid support is conveniently of similar
size and shape to a microscope slide and may be constructed of
glass or other polymeric material.
[0183] A wall around the microscope slide may be separately added
or moulded with the slide and this facilitates retention of fluid
material. The present invention extends to any other device capable
of fulfilling the method of the present invention.
[0184] In the case of nitrocellulose based antibody arrays are
preferably constructed using a Biodot Aspirate and Dispense System
(Cartesian Technologies) where 5 nL dots are applied to a
nitrocellulose film. on glass microscope slides (Schleicher and
Schuell, Cat. No. 10484182). Purified monoclonal antibodies
(Beckman Coulter, Becton Dickinson or Biosource International) are
used at concentrations recommended for flow cytometric analysis and
are applied in the same buffers as supplied by the manufacturers.
The nitrocellulose is then blocked by incubation with 5% w/v skim
milk (Dutch Jug) for 1.5 h at 37.degree. C. These blocking
conditions are chosen to minimize background binding.
[0185] The stability of the arrays is further enhanced by adding
protein stabilizing agents to the antibodies (e.g. polyethylene
glycol or stabilizer products commercially available from
Surmodics, Minn., USA).
[0186] The following description provides a preferred method for
preparing the antibody arrays: The panel of antibodies is generally
used to construct antibody arrays with the Cartesian Technologies
PixSys.TM. 3200 Aspirate and Dispense System. The antibodies are
chosen for use in a particular diagnosis or detection protocol.
Each antibody is generally applied in the volume of from about 1 to
about 10 nanoliters in a dot format at approximately from 0.5 to
1.5 min intervals to create an appropriate array on a
nitrocellulose film generally laid on a solid support such as but
not limited to a microscope slide, plastic or gold support. After
dotting, the supports are assessed on a light box and the corners
of the arrays marked gently using, for example, a lead pencil. The
antibody arrays are then immersed in a blocking agent such as but
not limited to skim milk, Irish moss extract or other source of
carrageenan or gelatin. From about 2% to about 15% w/v skim milk
powder in PBS at 4.degree. C. overnight or at 37.degree. C. for
from about 60-120 minutes is particularly useful. After application
of the blocking agent, the solid supports are washed gently with
purified water and allowed to dry at room temperature for a period
of time from about 60-120 minutes.
[0187] The solid supports are then stored in an airtight bag at
4.degree. C. in the dark
[0188] An alternative method of detection is the use of acoustic
detection based methods, such as those described by Akubio
Technology. (DDT vol 7, No 5 (Suppl.) 2002). This form of detection
technology is based on the sound made as molecular interactions are
disrupted. It does not use any form of electromagnetic radiation.
Very high accelerations, millions of times the force of gravity are
used to disrupt such interactions. Such forces are generated by an
acoustic wave device such as a quartz crystal resonator. By
monitoring the change in resonant frequency of the crystal, which
occurs on adsorption of mass to the surface, quartz crystal
resonators can be used together with appropriate surface chemistry
and fluidics to detect the adsorption of proteins,
oligonucleotides, cells and other particles to surface-bound
receptors. This allows the label-free determination of interaction
affinities and kinetics in real time. (Janshoff A et al (2000)
Piezoelectric mass-sensing devices as biosensors. An alternative to
optical biosensors. Angew. Chem, 39, 4004-4032); Ward et al, (1990)
In situ interfacial mass detection with piezoelectric transducers,
Science 249, 1000-1007).
(D) A sCD Fingerprint for One or More Disease States According to
the Present Invention
[0189] Advantageously, levels of sCDs are measured in diseased
individuals and absolute values may be divided by the upper limit
of normal (ULN) obtained from healthy individuals. The data is
collated and the resultant pattern of values obtained for each sCD
for one or more given disease states, from one or more individuals
forms the basis of a sCD fingerprint of one or more given disease
states.
[0190] The statistical significance of the increases or decreases
in sCD levels found in various disease states can be assessed using
a number of methods.
[0191] The sCD fingerprint can advantageously be simplified by
removing those sCDs whose levels do not generally change
significantly during one or more given disease states. Examples of
such sCDs include but are not limited to CD21, CD102, CD117, CD
126, CD130, CD 26, CD44v5, CDv6, CD62P. For example see FIG. 2.
[0192] To simplify the fingerprint further, instead of showing the
data from each individual for any given sCD during a disease, a
modal value for each sCD calculated from the group of individuals
may be plotted. The rational of this is demonstrated in FIGS. 3, 5,
6, 7, 8. This provides an easily readable and simple `fingerprint`
of a disease.
[0193] One skilled in the art will appreciate that there are many
methods suitable for the statistical analysis of the sCD level data
measured as herein described. These include but are not limited to
cluster analysis and other statistical methods for the detection of
patterns.
Statistical Analysis
[0194] Methods for the statistical analysis of data are known to
those skilled in the art. An example of a suitable protocol for the
analysis of data is outlined below:
[0195] (i) The statistical analysis procedures described here
relate to immunoprecipitation assays of soluble CD molecules in
samples arrayed in 96-well microtitre trays.
[0196] Statistical analysis of the proposed antibody-chip arrays
could essentially follow the same procedures, although
modifications would inevitably need to be made to account for
experimental design and data quality issues specific to that
technology.
[0197] In the present analysis, each tray was designed to measure
the concentration of a specific soluble CD molecule in a number of
samples. Trays were prepared for each of 29 soluble CD molecules,
for each of three sets of 37 patients. In all, the three sets of
patients represented 17 disparate disease groups, including one
group of healthy individuals. The 96 wells on each tray contained:
sera from each of the 37 patients of one set (duplicated); a
standard control preparation containing the target antigen at each
of 7 different concentrations (duplicated); pooled sera from
`normal` control patients (replicated 3 times); and the same pooled
sera spiked with the target antigen (replicated 3 times).
[0198] Each tray was washed with a solution containing
fluorescently labelled monoclonal antibody specific to its
designated target antigen, and exposed to light. For each well, a
measurement of light absorption was recorded.
(ii) Statistical Analysis Using Artificial Intelligence Type Neural
Networking
[0199] This method describes the ability of the computer system
which analyses the data to learn to recognise patterns in data.
Thus the more the system is used, the better able the system is to
recognise patterns. Such a system is described in amongst other
documents Sven Olsson et al (2002), Clin Physiol & Func Im
(2002) 22, pp 295-299; Sijo Perekattil et al (March 2003), Journal
of Virology, vol 169, pg 917-920. This approach is reviewed in PJG
Lisboa, (2002), Neural Networks 15, 11-39. All of these documents
are herein incorporated by reference.
Data Preparation
[0200] The recorded light absorptions were mathematically
transformed, as follows. [0201] Absorptions were converted to
antigen concentrations, via a calibration curve based on the
absorptions recorded for the antigen standards in the same tray.
Absorptions of dubious quality were flagged missing, and omitted
from subsequent analysis. [0202] Concentrations exceeding that of
the most concentrated antigen standard of the tray were flagged as
high. Concentrations corresponding to absorptions at the limit of
instrumentation were similarly flagged. [0203] Each flagged
concentration was replaced by the concentration of its duplicate in
the tray, provided the duplicate concentration was not also
flagged. [0204] The average of each concentration with its
duplicate was computed. We refer to these as mean
concentrations.
[0205] For each CD, the 10th and 90th centiles of the distribution
of mean concentrations in normal individuals was computed. We refer
to these as CD.sub.10 and CD.sub.90. Subtracting CD.sub.10 from
CD.sub.90 gives a range, which we denote CD.sub.range.
Concentration categories were defined for each CD as follows:
TABLE-US-00001 Category from to -1 0 CD.sub.10 0 CD.sub.10
CD.sub.90 1 CD.sub.90 CD.sub.90 + CD.sub.range 2 CD.sub.90 +
CD.sub.range CD.sub.90 + 2 .times. CD.sub.range 3 CD.sub.90 + 2
.times. CD.sub.range CD.sub.90 + 3 .times. CD.sub.range 4 CD.sub.90
+ 3 .times. CD.sub.range --
[0206] To control for differences in the scale of reactivity of
different CDs, to stabilise variability between duplicates across
the range of concentrations, and to relate concentrations to values
obtained for normal individuals, each mean concentration was put
into the appropriate concentration category of its CD. All
concentrations flagged high were put into the highest category. We
refer to these as categorised concentrations. Data Analyses Cluster
Analysis
[0207] A cluster analysis was performed to identify clusters of CDs
having similar patterns of reactivity across the patients,
standards and controls. Likewise, a second cluster analysis was
performed to identify clusters of patients with similar profiles of
reactivity across the CDs. Cluster analyses were hierarchical and
based on the categorised concentrations, described above, using a
Euclidean distance metric and the average linkage criterion for
cluster merging.
[0208] The results from the cluster analyses were displayed in the
form of a level plot, a part of which is given in FIG. 16. In this
level plot, the rows correspond to CDs and the columns correspond
to patients, standards and controls. Rows and columns are ordered
so that those in the same cluster are adjacent. Also, dendrograms
were produced showing the hierarchy of clusters, separately for the
clustering of CDs and for the clustering of patients, standards and
controls. Each cell in the level plot is toned to indicate its
categorised concentration, deep blue corresponding to Category -1
(below normal), and deep red corresponding to Category 4 (high).
Missing concentrations are denoted by an `X`.
A sCD Fingerprint Database According to the Invention
[0209] In a further aspect still, the present invention provides a
sCD reference database comprising pathological and/or normal sCD
fingerprint patterns.
[0210] As herein described the term `a database` refers to a
collection of sCD fingerprints from normal `non-diseased` and/or
diseased individuals. Advantageously, the database is computer
generated and/or stored. Advantageously the data from more than 5
individuals is present in the database. More advantageously the
data from more than 10, 100, or 1000 individuals comprises the
database. More advantageously still the data from more than 10,000
or more than 50,000 individuals comprises the database. Most
advantageously the data from more than 100,000 individuals
comprises the database.
[0211] Advantageously the database, in addition to sCD data also
comprises clinical information relating to various patients and/or
disease conditions. Alternatively or in addition, a database
according to the present invention comprises genomic information
and/or sCD profiles relating to specific disease states and other
pathological states and clinical data. Thus the inventors
contemplate the use of a database in which sCD data and other data
may be integrated and used to obtain a more complete analysis of
one or more disease states.
Uses of One or More `Fingerprints of Disease` According to the
Present Invention
[0212] In a further aspect, the present invention provides a method
for predicting the presence of one or more disease states in an
individual comprising the step of analysing the sCD fingerprint in
that individual.
[0213] In a further aspect still, the present invention provides a
method for detecting the presence of one or more disease states in
an individual comprising the step of analysing the pattern/s of
shed CD levels of more than one shed CD which is present in that
individual.
[0214] In a further aspect still, the present invention provides a
method for detecting the extent of one or more disease states in an
individual comprising the step of comparing one or more sCD
fingerprint/s generated from that individual with one or more
reference sCD fingerprints.
[0215] In yet a further aspect, the present invention provides a
method for assessing the progression of a disease state in an
individual comprising the step of comparing the sCD fingerprint of
an individual at two or more periods during the occurrence of the
disease.
[0216] In a further aspect still, the present invention provides a
method for assessing the effect of one or more agent/s on one or
more disease states in an individual comprising the step of
comparing a sCD fingerprint of an individual at two or more time
periods.
[0217] In a further aspect, the data generated by the present
invention is used to compile a reference database, comprising
pathological and/or normal sCD fingerprints, against which the
expression sCD pattern of any individual will be compared.
[0218] In a further aspect still, the present invention provides
the use of a sCD fingerprint to assess the effect of one or more
agents in an individual.
[0219] An embodiment of the present invention is its use as a tool
for assessing the affect different diet and exercise regimes may
have on human or other mammals.
[0220] Additionally, the present invention may be used to construct
sub-categories of sCD fingerprint profiles, suitable for common
therapeutic treatment.
The Therapeutic Inhibition of the Production of One or More sCDs
According to the Invention
[0221] Recent studies which have investigated the impaired
expression of NKG2D and T-cell activation by tumour-derived soluble
MHC ligands (Nature, vol 419, 17 Oct. 2002). Studies have shown
that tumours release large amounts of the MHC class I homologue MIC
into the serum. Activation of the NKG2D receptor on natural T cells
is known to stimulate their ability to destroy tumours, but the
high levels of tumour derived MIC seem to downregulate the NKG2D
receptor and block the antitumour effect. (Nature, vol 419, 17 Oct.
2002, p679, pg 734). These soluble forms of MHC are produced either
enzymatic cleavage or by alternative splicing (Nature, vol 419, 17
Oct. 2002, p679, pg 734).
[0222] It is apparent from the invention described herein that sCDs
may be produced by alternative splicing (Woolfson and Milstein,
PNAS Vol 91, pp 6683-6687), enzymatic cleavage or other mechanisms.
The present inventors consider that sCD molecules may also bind to
a ligand/receptor and thereby block down stream effects. Thus, the
present inventors have realised that the blockage of the production
of sCD molecules via the inhibition of any of the methods of sCD
generation described herein, may be a therapeutically useful method
for the prophylaxis or treatment of one or more diseases in
particular tumourigenesis.
[0223] Thus in a further aspect still, the present invention
provides a method for treating one or more diseases comprising the
step of inhibiting the production of one or more sCDs within an
individual.
[0224] In a further aspect still, the present invention provides
the use of an inhibitor of the production of one or more sCDs in
the preparation of a medicament for the treatment of disease.
[0225] According to the above aspect of the invention, the term `an
inhibitor of the production of one or more sCDs` refers to one or
more agents which inhibit the production of a shed form of sCD as
herein defined. In reducing the amount of shed molecule produced,
the level of cell surface molecule should increase correspondingly.
This should be advantageous to the cell. Advantageously, the
inhibitor is a specific inhibitor of those one or more sCDs.
Suitable inhibitors include alternative splicing inhibitors and/or
enzymatic cleavage inhibitors. Advantageously, the inhibitor is an
alternative splicing inhibitor. Such alternative splicing
inhibitors are include for example inhibitors of exonic splicing
enhancers (Fairbrother et al, Science, vol 297, 9 Aug. 2002).
[0226] According to the above aspects of the invention, the
production of any one or more sCDs present in the body fluid of an
individual may be inhibited. Advantageously, the one or more sCDs
are any one of those selected from the group consisting of the 15
following: CD14, CD25, CD31, CD44, CD50, CD54, CD62E, CD62L, CD86,
CD95, CD106, CD116, CD124, CD138, CD141, CD40L, CD8, CD23, CD30,
CD40. More advantageously the sCD is CD1. Advantageously, the sCD
is CD1 and the inhibitory agent is an alternative splicing
inhibitor.
[0227] According to the above aspects of the invention, one or more
inhibitory agents may be used for the prophylaxis or treatment of
any one or more disease states selected from the group consisting
of the following: infections, autoimmune disease, neoplastic,
vascular endocrinological, metabolic, inflammatory degenerative,
psychiatric psychological, traumatic, drug/toxin-related,
bacterial, fungal, protozoan and viral infections, non-neoplastic
disorders; pain; diabetes, obesity; anorexia; bulimia; asthma;
pregnancy; endocrine; vascular; metabolic; gastrointestinal;
iatrogenic; psychiatric; psychological; exercise-induced;
diet-related; ME; degenerative; Parkinson's disease; thrombosis;
atherosclerosis; acute heart failure; hypotension; hypertension;
erectile dysfunction; urinary retention; metabolic bone diseases
such as osteoporosis; angina pectoris; hepatitis; myocardial
infarction; ulcers; allergies; rheumatoid arthritis; inflammatory
bowel disease; irritable bowel syndrome benign prostatic
hypertrophy; psychosis; psychiatric disorders; including anxiety;
schizophrenia; manic depression; delirium; dementia; severe mental
retardation and dyskinesias, such as Huntington's disease or Gilles
de la Tourett's syndrome; and preferably tumours which can be
benign or malignant cancers; breast cancer; myeloma; melanoma;
bladder cancer; leukaemia; plasmocytoma and others, but most
preferably appendicitis; Bence Jones Proteinuria; Chronic Myoeloid
Leukaemia; Colorectal cancer; chronic renal failure; Crohn's
Disease; Diabetic Nephropathy; Cardiac pathology; Infection; Liver
damage; Lymphoma; macrocytic anaemia; Prostate Cancer; Oligoclonal
Banding and PE/DVT. Advantageously, the disease is
tumourigenesis.
[0228] The invention will now be described by the following
examples which are in no way limiting of the invention.
EXAMPLE 1
FIG. 1. Disease Groups. Multiples of ULN All sCD's Included
[0229] Two values obtained (CD40L and CD30) for the individual,
classified as normal, with a suspected drug overdose were omitted
from the calculation of the upper limit of normal. The dilution
factor for each sCD was fixed throughout the study. The results
obtained are those of the diluted sample and have not been
multiplied by the dilution factor. The absolute value of each data
point was divided by the upper limit of normal (ULN) as defined
above. Where the absolute value was greater than the dynamic range
of the assay the result [9999] was recorded.
[0230] The limits indicated by each point are: [0231] Green
.ltoreq.1.times.ULN [0232] Blue 1-2.times.ULN [0233] Red
>2.times.ULN [0234] A white block indicates no data
available.
EXAMPLE 2
FIG. 2 Remove All sCD's that Appear not to Discriminate from the
Normals (sCD's 21; 102; 117; 126; 130; 26; 44v5; 44v6; 62P)
[0235] To simplify the diagram the above sCD plots were
removed.
[0236] The data suggests (FIG. 1.) that the concentration of some
of these sCD may actually be lowered in disease. As we initially
worked on the premise that there would be over-expression of these
molecules in disease, samples have been diluted optimally to focus
on high, rather than low concentrations.
EXAMPLE 3
FIG. 3. Disease Groups. Mode of Response for Remaining 20 sCD's
[0237] To simplify the data further the modal response for each
disease group has been plotted. As the lymphoma and
"oligoclonal-banding positive" group contain only a single subject,
they have been omitted. Where there is no clear mode, both
responses have been shown.
EXAMPLE 4
FIG. 4. Disease Groups. Mode of Response for Remaining sCD's
[0238] Data has been ranked in order of increased expression.
EXAMPLE 5
FIG. 5. Disease Groups. Mode of Response for Remaining sCD's
[0239] As for FIG. 4. except responses have been classified as
"normal" and "abnormal". Values>1 ULN have been classified as
abnormal.
[0240] Both FIGS. 4 and 5 suggest that each disease state exhibit a
unique pattern of elevated sCD expression.
EXAMPLE 6
[0241] FIG. 6. Disease Groups. Mode of Response for All sCD's
[0242] As for FIG. 3 (except all sCD's are included).
[0243] The limits indicated by each point are: [0244] Green
.ltoreq.1.times.MoM [0245] Blue 1-2.times.MoM [0246] Red
>2.times.MoM [0247] A white block indicates no data
available.
EXAMPLE 7
FIG. 7. Disease Groups. Mode of Response for All sCD's
[0248] As for FIG. 4.
EXAMPLE 8
FIG. 8. Disease Groups. Mode of Response for All sCD's
[0249] As for FIG. 5. (except that values>2 MoM have been
classified as abnormal).
[0250] Comparison of FIGS. 5 and 8 illustrate the importance of
determining the cut-off threshold values in order to obtain a
defined pattern.
[0251] All publications mentioned in the above specification are
herein incorporated by reference. Various modifications and
variations of the described methods and system of the present
invention will be apparent to those skilled in the art without
departing from the scope and spirit of the present invention.
Although the present invention has been described in connection
with specific preferred embodiments, it should be understood that
the invention as claimed should not be unduly limited to such
specific embodiments. Indeed, various modifications of the
described modes for carrying out the invention which are obvious to
those skilled in biochemistry, molecular biology and biotechnology
or related fields are intended to be within the scope of the
following claims.
Appendix.1
Disease Associations of Soluble sCD2 to sCD157 Antigens Found in
Human Serum.
Adrian Woolfson and Cesar Milstein
[0252] (note: this document was compiled from paper abstracts.
Consequently when any numerical information such as mean serum
level, SD, statistical significance or patient numbers is missing,
this is because the relevant information was not specified in the
paper abstract. All such information can, however, in principle be
obtained by going back to the paper in question.
sCD2 (LFA-2, T11)
[0253] HIV (Schlesinger et al 1990) TABLE-US-00002 Normal controls:
(n = 63) Asymptomatic HIV: (n = 13) AIDS: (n = 12)
[0254] Levels of serum sCD2 in asymptomatic HIV patients were very
significantly reduced (mean absorbance at 492 nm: 0.00093+/-0.0048)
as compared with normal controls (mean absorbance at 492 nm:
0.154+/-0.033). No further numerical data given. Serum sCD2 levels
were elevated in 25% of patients. No numerical data given.
Infectious Mononucleosis (Motohashi 1993)
[0255] Levels of serum sCD2 were significantly increased in acute
stages of the disease. No numerical data given.
Kawasaki Disease (Furukawa et al 1993)
[0256] No information given.
sCD4 (L3T4, T4)
[0257] Infectious Mononucleosis (Yoneyama et al 1995)
TABLE-US-00003 Patients: (n = 44) Normal controls: (n = not
specified)
[0258] A very significant (p<0.0001) elevation in serum sCD4
levels was found in patients (19.3+/-0.9) as compared with normal
controls (8.1+/-0.2).
[0259] Wegener's Granulomatosis (D'Cruz et al 1999) TABLE-US-00004
patients (n = 23) healthy controls (n = 20)
[0260] Median levels of serum sCD4 were significantly higher
(p<0.005) in patients (17.0 U/ml) than in controls (15.2 U/ml).
Levels correlated with disease activity scores. No further
numerical data given.
[0261] Nasopharyngeal Carcinoma (Kuo et al 1994) TABLE-US-00005
Patients (n = 12) Normal controls (n = 12) Skin cancer controls (n
= 12)
[0262] Increased levels of sCD4 in patient group. No numerical data
given.
[0263] Acute Pancreatitis (Pezzilli et al 1994) TABLE-US-00006
acute pancreatitis patients (n = 35) healthy controls (n = not
specified)
[0264] Levels of serum sCD4 were measured for 6 days following
admission. Levels of sCD4 significantly decreased from day 2 to day
6 relative to normal controls. No numerical data given.
[0265] Sjogren's Syndrome (Sawada et al 1992) TABLE-US-00007
primary sjorgen's syndrome patients (n = 28) secondary sjorgen's
syndrome patients (n = 13) normal controls (n = 43)
[0266] Levels of serum sCD4 were significantly increased in
patients with both primary and secondary disease as compared with
controls. No numerical data given.
[0267] Rheumatoid Arthritis (Kuryliszyn-Moskal et al 1998)
TABLE-US-00008 patients (n = 80) healthy controls (n = 30)
[0268] Serum levels of sCD4 were significantly higher in RA
patients than in controls. No numerical data given.
[0269] Polytransfused Patients with Beta-Thalassemia Major
(Lombardi et al 1994) TABLE-US-00009 transfusion-dependent patients
(n = 45) normal controls (n = not specified)
[0270] Patients had lower values of serum sCD4 as compared with
normal controls. No numerical data given.
[0271] Pregnancy (Watanabe et al 1996) TABLE-US-00010 Pregnant
mothers (1st, 2nd, 3rd trimesters and 1, 4, 7, 10-12 (n = 182)
months post-partum) Healthy non-pregnant women (n = 25)
[0272] The serum value of sCD4 decreased throughout pregnancy from
the first trimester and recovered gradually after delivery. No
numerical data given.
Leishmaniasis (Vitale et al 1994)
[0273] Levels of serum sCD4 were raised significantly in patients
as compared with controls. Levels returned to the normal range
after recovery. No numerical data given. TABLE-US-00011 IDDM
patients (n = 32) normal controls: (n = 34)
[0274] Increased levels of serum sCD4 were found in only 1/32 of
the patients. No numerical data given.
[0275] Leishmaniasis (Schriefer et al 1995) TABLE-US-00012 Patients
(n = not specified)
[0276] Pre-treatment levels of serum sCD4 were significantly
(p<0.05) higher in patients than in healthy controls. No
significant change following antimonial therapy. Levels of serum
sCD4 fell significantly in patients that were refractory to drug
treatment. No numerical data given.
[0277] Scleroderma (Sato et al 1996) TABLE-US-00013 Patients with
generalized morphea: (n = 15) Controls (n = not specified)
[0278] Levels of serum sCD4 were significantly elevated in patients
as compared with controls. No numerical data given.
[0279] High Dose Chemotherapy and Blood Stem Cell Transplantation
(Ho et al 1994) TABLE-US-00014 chemotherapy patients (n = 12)
[0280] Highly statistically significant increase in serum sCD4
levels up to a maximum at day 21. No numerical data given.
[0281] Polymyalgia Rheumatica (Salvarani et al 1994) TABLE-US-00015
Patients with active polymyalgia rheumatica (n = 19) Normal
controls (n = not specified)
[0282] Decreased levels of serum sCD4 were found in patients as
compared with controls. No numerical data given.
[0283] Vogt-Koyanagi-Harada's Disease (Uchio et al 1999)
TABLE-US-00016 Active disease (n = 24) Normal controls (n = 20)
[0284] Significantly different levels in levels of serum sCD4 were
found in the acute stages of the disease as compared with normal
controls. No numerical data given.
[0285] Kawasaki Disease (Furukawa et al 1991) TABLE-US-00017
Patients (n = not specified) Controls (n = not specified)
[0286] Levels of serum sCD4 were significantly elevated in patients
during acute stages of the disease as compared with controls. No
numerical data given.
[0287] Measles (Furukawa et al 1991) TABLE-US-00018 patients (n =
not specified) controls (n = not specified)
[0288] Levels of serum sCD4 were significantly raised in patients
during the acute stages of the disease. No numerical data
given.
[0289] Behcet's Disease (Uchio et al 1999) TABLE-US-00019 Active
Behcet's disease: (n = 20) Innactive Behcet's disease: (n = 15)
Normal controls: (n = 20)
[0290] Significantly increased levels of serum sCD4 were found in
both the acute and convalescent stages of the disease as compared
with normal controls. No numerical data given.
CD8 (T8)
[0291] Chronic Lymphocytic Leukemia (CLL) (Beguin et al 1993)
TABLE-US-00020 CLL patients (n = 42) Normal controls (n = 31)
[0292] CLL patients had significantly (p<0.001) increased levels
of serum sCD8 (510+/-191 U/ml) as compared with normal controls
(234+/-89 U/ml).
[0293] Graves Disease (Balazs et al 1994) TABLE-US-00021 patients
(n = 58) normal controls (n = not stated)
[0294] Levels of serum sCD8 were significantly (p<0.001)
elevated in Grave's disease patients (609+/-118 U/ml) as compared
with normal controls (264.1+/-98.8). sCD8 levels returned to normal
(278.7+/-89.1) following treatment with methimazole.
[0295] Infectious Mononucleosis (Vinante et al 1994) TABLE-US-00022
patients (n = 55) normal controls (n = not specified)
[0296] Levels of serum sCD8 were very significantly elevated levels
in patients (17,172+/-12,885 U/ml) as compared with normal controls
(334+/-95 U/ml). By day 30, serum sCD8 levels fell to 20+/-21
U/ml.
[0297] Multiple Sclerosis (Franciotta et al 1997) TABLE-US-00023
Clinically active MS patients (n = 16) Non-inflammatory
neurological disease controls (n = not stated) Normal healthy
controls (n = not stated)
[0298] Levels of serum sCD8 were significantly higher in MS
patients than in healthy controls. Levels of sCD8 increased
significantly (p=0.002) following therapy with 6-methylprednisolone
and median serum sCD8 levels at day 21 were 1136 IU/ml (range
790-1416) versus 447 IU/ml (range 94-713) prior to therapy. No
further numerical data given.
[0299] Angioimmunoblastic Lympadenopathy (AILD) (Pizzolo et al
1990) TABLE-US-00024 patients (n = 24) normal controls (n = not
specified)
[0300] A significant (p<0.01) increase in serum sCD8 was
detected in patients (978+/-646 U/ml) a compared with controls
(334+/-95 U/ml).
[0301] Advanced Renal Cell Carcinoma (Hobarth et al 1996)
TABLE-US-00025 patients (n = 16) healthy controls (n = 20)
[0302] Levels of serum sCD8 were significantly (p<0.05) elevated
in patients (564 U/L) as compare with controls (336 U/L).
[0303] Wegener's Granulomatosis (D'Cruz et al 1999) TABLE-US-00026
patients (n = 23) healthy controls (n = 20)
[0304] Median levels of serum sCD8 were higher (p<0.001) in
patients (260.5 U/ml) than in healthy controls (127 U/ml). Levels
of serum sCD8 correlated with disease activity.
[0305] Infectious Mononucleosis (Yoneyama et al 1995)
TABLE-US-00027 Patients: (n = 44) Normal controls: (n = not
specified)
[0306] Levels of serum sCD8 were very significantly (p<0.0001)
elevated in patients (22366+/-270 U/ml) as compared with normal
controls (219+/-10 U/ml).
[0307] Acute Graft-Versus-Host Disease (Bavaro et al 1994)
TABLE-US-00028 Patients with grade II-III aGvDH (n = not stated)
Patients with grade 0-I aGvDH (n = not stated)
[0308] The serum sCD8 levels at day 21 in patients with grade
II-III aGvDH were significantly (p<0.002) lower (447 IU/ml,
range 94-713) than in patients with grade 0-I aGvDH (1136 IU/ml,
range 790-1416).
[0309] Juvenile Rheumatoid Arthritis (Lipnick et al 1993)
TABLE-US-00029 afebrile JRA patients (n = 49) normal controls (n =
16)
[0310] Levels of serum sCD8 were significantly elevated in patients
with severe JRA as compared with normal controls. No numerical data
given.
[0311] High dose chemotherapy and blood stem cell transplantation
(Ho et al 1994) TABLE-US-00030 chemotherapy patients (n = 12)
[0312] A highly statistically significant increase in serum sCD8
levels was observed up to a maximum at day 21. No numerical data
given.
[0313] Acute pancreatitis (Pezzilli et al 1994) TABLE-US-00031
acute pancreatitis patients (n = 35) healthy controls (n = not
specified)
[0314] Levels of serum sCD8 were measured for 6 days following
admission. Levels of serum sCD were significantly increased for the
entire observation period relative to normal controls. No numerical
data given.
[0315] Kawasaki Disease (Furukawa et al 1991) TABLE-US-00032
patients (n = not specified) controls (n = not specified)
[0316] Levels of serum sCD8 were significantly raised in patients
during acute stages of the disease. No numerical data given.
[0317] Measles (Furukawa et al 1991) TABLE-US-00033 patients (n =
not specified) controls (n = not specified)
[0318] Levels of serum sCD8 were significantly elevated in patients
during acute stages of the disease No numerical data given.
[0319] Sjogren's Syndrome (Sawada et al 1992) TABLE-US-00034
primary sjorgen's syndrome patients (n = 28) secondary sjorgen's
syndrome patients (n = 13) normals individuals (n = 43)
[0320] Levels of serum sCD8 were significantly decreased in
patients with primary disease. No numerical data given.
[0321] Lymphoproliferative Diseases (Frydecka 1994) TABLE-US-00035
adult T cell leukemia (n = not stated) hairy cell leukemia (n = not
stated) hodgkin's disease (n = not stated) non-hodgkin's lymphoma
(n = not stated) chronic lymphocytic leukemia (n = not stated)
controls (n = not stated)
[0322] Increased levels of serum sCD8 were found in patients as
compared with controls. No numerical data given.
[0323] Polytransfused Patients with Beta-Thalassemia Major
(Lombardi et al 1994) TABLE-US-00036 transfusion-dependent patients
(n = 45) normal controls (n = not specified)
[0324] Patients had increased values of serum sCD8 as compared with
normal controls. No numeric data given.
[0325] Chronic Viral Hepatitis (Onji et al 1994) TABLE-US-00037
Patients with chronic active hepatitis, autoimmune (n = not stated)
hepatitis, primary biliary cirrhosis, acute hepatitis, fulminant
hepatitis and liver cirrhosis Normal controls (n = not stated)
[0326] Levels of serum sCD8 were significantly higher in patients
as compared with controls. No numerical data given.
[0327] Tuberculosis (Barlan et al 1995) TABLE-US-00038 children
with active pulmonary tuberculosis (n = 66) healthy controls (n =
20)
[0328] Levels of serum sCD8 in children with active pTB were
significantly (p<0.05) different to those in healthy controls.
No numerical data given.
[0329] Depression (Maes et al 1996) TABLE-US-00039 Major depression
(n = 37) Minor depression (n = 27) Normal controls (n = 22)
[0330] Serum levels of sCD8 were significantly higher in depressed
patients than in normal controls 35% of depressed patients had
increased (>560 U/ml) levels of sCD8. No further numerical data
given.
[0331] Solid Tumours (Orditurra et al 1998) 60 TABLE-US-00040
Patients (n = 84) Normal controls (n = not stated)
[0332] Elevated levels of serum sCD8 were found in 32% of the
patients. No numerical data given.
[0333] Interferon Therapy in Chronic Hepatitis C (Maekawa et al
1997) TABLE-US-00041 patients with chronic hepatits C (n = not
stated)
[0334] Levels of serum sCD8.sup.- correlated with levels of ALT
during treatment and decreased with I treatment. No numerical data
given.
[0335] Asymptomatic HIV+ (Lenkei et al 1998) TABLE-US-00042 HIV+
patients (n = not stated) Healthy controls (n = not stated)
[0336] Patients had elevated levels of serum sCD8 as compared with
healthy controls. No numerical data given.
[0337] Liver Disease (Hagihara et al 1997) TABLE-US-00043 patients
(n = not specified) normal controls (n = not specified)
[0338] Serum sCD8 levels were significantly (p<0.001) higher in
patients than in normal controls. Serum sCD8 levels were highest in
acute hepatitis, followed by hepatocellular carcinoma, liver
cirrhosis and chronic hepatitis. No further numerical data
given.
[0339] Gynecological Malignancies (Frydecka et al 1996)
TABLE-US-00044 Patients (n = 30) Normal controls (n = not
stated)
[0340] Levels of serum sCD8 were significantly increased before
treatment as compared with normal controls. The decrease of tumor
mass which followed radiotherapy correlated with serum levels of
sCD8. No numerical data given.
[0341] IDDM (Ng et al 1995) TABLE-US-00045 IDDM patients (n = 32)
normal controls (n = 34)
[0342] Levels of serum sCD8 were elevated in 5/32 patients. No
numerical data given.
[0343] Nasopharyngeal Carcinoma (Kuo et al 1994) TABLE-US-00046
Patients (n = 12) Normal controls (n = 12) Skin cancer controls (n
= 12)
[0344] Levels of serum sCD8 were significantly elevated in patients
as compared with controls. No numerical data given.
[0345] IDDM (Di Cesare et al 1994) TABLE-US-00047 newly diagnosed
IDDM patients (n = 33) IDDM patients (duration of disease more than
1 year) (n = 29) healthy siblings of IDDM patients (n = 37) healthy
controls (n = 19)
[0346] All 3 groups had significantly higher levels of serum sCD8
than normal controls (p<0.0001, P<0.003 and p<0.03
respectively). In 54% of newly diagnosed patients, sCD8 levels were
significantly higher than in those with long-standing disease
(p<0.0005) and healthy siblings (p<0.002). No further
numerical data given.
[0347] Localized Scleroderma (Sato et al 1996) TABLE-US-00048
Patients with generalized morphea: (n = 15) Patients with systemic
sclerosis (n = not specified)
[0348] Levels of serum sCD8 were significantly elevated in patients
with generalized morphea. Levels of sCD8 were significantly higher
than those in patients with systemic sclerosis. No numerical data
given.
[0349] Leishmaniasis (Schriefer et al 1995) TABLE-US-00049 Patients
(n = not specified) Controls (n = not specified)
[0350] Pre-treatment levels of serum sCD8 were significantly
(p<0.05) higher in patients than in healthy controls. Levels of
serum sCD8 fell significantly (p<0.05) following antimonial
therapy. No further numerical data given.
[0351] Leishmaniasis (Vitale et al 1994) TABLE-US-00050 Patients (n
= not specified Controls (n = not specified)
[0352] Serum sCD8 levels were raised significantly in patients as
compared with controls. sCD8 levels returned to normal range after
recovery. No numerical data given.
[0353] Vogt-Koyanagi-Harada's Disease (Uchio et al 1999)
TABLE-US-00051 patients with active disease (n = 24) normal
controls (n = 20)
[0354] Levels of serum sCD8' were significantly different in both
the acute and convalescent stages of the disease as compared with
controls. No numerical data given.
[0355] Polymyalgia Rheumatica (Salvarani et al 1994) TABLE-US-00052
Active polymyalgia rheumatica: (n = 19) Normal controls: (n = not
specified)
[0356] Levels of serum sCD8 were significantly elevated in patients
as compared with controls. In 15/15 patients sCD8 levels fell
significantly following steroid therapy. No numerical data
given.
[0357] HIV-1 Infection (Jiang et al 1997) TABLE-US-00053 Patients
(n = not specified) Controls (n = not specified)
[0358] Serum sCD8 levels were elevated in HIV-1 patients as
compared with controls. No numerical data given.
[0359] Endometriosis (Matalliotakis et al 1997) TABLE-US-00054
Normal controls: (n = 20) Endometriosis patients (pre-treatment
with danazol) (n = 10) Endometriosis patients (post-treatment with
danazol for 6/12) (n = 10)
[0360] Administration of the drug significantly reduced levels of
serum sCD8 (p<0.001). No numerical data given.
[0361] Behcet's Disease (Uchio et al 1999) TABLE-US-00055 Active
Behcet's disease: (n = 20) Inactive Behcet's disease: (n = 15)
Normal controls: (n = 20)
[0362] Significantly different levels of serum sCD8 were found in
both the acute and convalescent stages of the disease as compared
with normal controls. No numerical data or direction of change
given.
sCD14
[0363] HIV (Nockher et al 1994) TABLE-US-00056 HIV-infected
asymptomatic patients (n = not specified) HIV-infected with
lymphadenopathy (n = not specified) ARC (n = not specified) AIDS (n
= not specified) normal controls (n = not specified)
[0364] Levels of serum sCD14 were significantly (p<0.001)
elevated in HIV-infected asymptomatic patients and HIV-infected
with lymphadenopathy (2.9+/-0.8 mg/L) as compared with normal
controls (2.2+/-0.8 mg/L). A further significant rise in levels of
serum sCD14 was seen in patients with ARC and AIDS (3.8+/-1.1 and
5.7+/-2.5 mg/L respectively, p<0.01 in both cases).
[0365] Systemic Lupus Erythematosus (Nockher et al 1994)
TABLE-US-00057 patients with inactive phase (remission) SLE (n =
35) SLE relapse (n = 17) healthy controls (n = 65)
[0366] Increased levels of serum sCD14 were found in all SLE
patients as compared with normal controls. Patients with SLE
relapse had significantly (p<0.0001) higher levels (6.9 mg/L)
than those in remission (4.1 mg/L). No further numerical data
given.
[0367] Acute Plasmodium falciparum Malaria (Wenisch et al 1996)
TABLE-US-00058 patients with complicated malaria (n = 45) patients
with gram negative septicaemia (n = 14) healthy controls (n =
24)
[0368] Malaria patients with renal failure (n=16) had significantly
(p<0.05) higher levels of serum sCD14 (9453+1017 micrograms/L)
than those (n=29) without renal failure (8116+1440 micrograms/L).
Both had higher levels of sCD14 than patients with septicaemia
(6155+1635 micrograms/L) and normal subjects (2776+747
micrograms/L).
[0369] Polytraumatized Patients (Kruger et al 1991) TABLE-US-00059
polytraumatized patients (n = 16) healthy controls (n = 30)
[0370] Levels of serum sCD14 were significantly decreased
immediately following trauma (3.7+/-0.005 micrograms/ml) as
compared with healthy normal controls (1.7+/-0.3 micrograms/ml).
Levels of serum sCD14 in trauma patients increased to 4.9+/-0.3
micrograms/ml within 6 days. In patients with the most severe
injuries these remained elevated for 14 days.
[0371] Neonatal Sepsis (Blanco et al 1996) TABLE-US-00060 neonates
with positive blood culture (gram +'ve) (n = 11) neonates with
positive blood culture (gram -'ve) (n = 9) normal newborns (n =
40)
[0372] Neonates with a positive blood culture had significantly
(p<0.001) increased levels of serum sCD14 (3.20+/-1.26
micrograms/L) as compared with normal controls. Neonates with gram
+'ve sepsis had significantly (p<0.05) lower levels of sCD14
(2.63+/-1.2 micrograms/L) than those with gram -'ve sepsis
(4.04+/-1.0 micrograms/L).
[0373] Tuberculosis (Juffermans et al 1998) TABLE-US-00061 TB
patients (n = 124) contacts (n = not specified) declined during
treatment (n = not specified) controls (n = not specified)
[0374] Levels of serum sCD14 were elevated in patients with active
TB as compared with controls, contacts and declined during
treatment groups. No numerical data given.
[0375] HIV (Lien et al 1998) TABLE-US-00062 HIV seropositive
patients (n = 92) seronegative controls (n = not specified)
[0376] Levels of serum sCD 14 were elevated in patients as compared
with controls and highest in patients with advanced clinical and
immunological disease. Patients with ongoing clinical events had
significantly higher levels of serum sCD14 than symptomatic
HIV-infected individuals without clinical events. sCD14 levels were
especially elevated in individuals with mycobacterium avium
complex. In a longitudinal study (n=26), increasing levels of serum
sCD14 were associated with death. No numerical data given.
[0377] Burns Patients (Kruger et al 1991) 65 TABLE-US-00063
patients (n = 5) healthy controls (n = not specified)
[0378] Patients had significantly elevated levels of serum sCD14 as
compared with healthy controls. No numerical data given.
[0379] Chronic Inflammatory Diseases (Scherberich et al 1999)
TABLE-US-00064 patients (n = not specified) normal controls (n =
not specified)
[0380] Levels of serum sCD14 were elevated in patients (>3
microg/ml). No numerical data given.
[0381] Periodontitis (Hayashi et al 1999) TABLE-US-00065 Patients
(n = 38) Healthy controls (n = 25)
[0382] Levels of serum sCD14 were significantly higher in patients
than in healthy controls and decreased after treatment. No
numerical data given.
sCD15 (Lewis X-i Antigen)
[0383] Non-Small Cell Lung Cancer (Satoh et al 1998) TABLE-US-00066
untreated NSCLC patients (n = 100) NO-1 patients (n = not
specified)
[0384] Levels of serum sCD15 in patients with N2 were significantly
(p=0.0049) higher than those of NO-1 patients. No numerical data
given.
Liver Disease (Sunayama et al 1994)
[0385] Elevated levels of serum sCD15 were found in various liver
disease patients. No numerical data given.
[0386] Lung Abscess (Suzuki et al 1997) TABLE-US-00067 patient (n =
1)
[0387] Elevated serum sCD15 was found in the patient. Levels
returned to the normal range post-operatively. No numerical data
given.
sCD16 (Fc gammaRIII) 67
[0388] Multiple Myeloma (Mathiot et al 1993) TABLE-US-00068 myeloma
patients (n = 165) MGUS (n = 29)
[0389] Levels of serum sCD16 were significantly decreased in
myeloma patients (25 a.u./ml) as compared with MGUS patients (144
a.u./ml). No further numerical data given.
[0390] Multiple Myeloma (Mathiot et al 1993) TABLE-US-00069
multiple myeloma patients (MM) (n = 165) monocolonal gammopathies
of unknown (n = 29) significance (MGUS) normal controls (n =
20)
[0391] Levels of serum sCD16 were significantly (p=0.0001)
decreased in sera from patients with multiple myeloma as compared
with normal controls and MGUS. In addition a stage-dependent
decrease in serum sCD16 was observed, with a highly significant
(p=0.004) difference between stage I and II/III myeloma patients.
No further numerical data given.
[0392] Sepsis (Kobold et al 1988) TABLE-US-00070 patients n = 19
healthy controls n = 10
sCD16 correlated with disease seventy (p<0.05, r=0.53). No
numerical data given:
[0393] Multiple Myeloma and Monoclonal Gammopathy (Mathiot et al
1996) of Unknown Significance TABLE-US-00071 MGUS patients (n = 54)
multiple myeloma patients (n = 35) healthy controls (n = 29)
[0394] Levels of serum sCD16 were significantly lower in multiple
myeloma patients than in controls (83% had a value<1.3
micrograms/ml as compared with only 17% of controls). A low sCD16
identified a group of MGUS which rapidly progress towards multiple
myeloma (ie for a sCD16 level of 1.3, sensitivity and specificity
were 70% and 79% respectively. No numerical data given.
sCD21 (CR2)
[0395] EBV Mediated Persistent Polyclonal B-Cell Lymphocytosis
(Larcher et al 1995) TABLE-US-00072 Patient (n = 1)
[0396] Levels of serum sCD21 were elevated in the patient. No
numerical data given.
sCD23 (FceRII)
[0397] Chronic Lymphocytic Leukemia (CLL) (Beguin et al 1993)
TABLE-US-00073 CLL patients (n = 42) Normal controls (n = 31)
[0398] CLL patients had very significantly (p<0.001) increased
levels of serum sCD23 (98.4+/-127.7) as compared with normal
controls (0.9+/-0.3 U/ml). The values correlate with tumour mass
and clinical stage.
[0399] High Risk IDDM Subjects (Avanzini et al 1988) TABLE-US-00074
first degree relatives of IDDM patients (n = not specified) newly
diagnosed patients (n = not specified) long-standing IDDM patients
(n = not specified) normal controls (n = not specified)
[0400] Serum sCD23 levels were significantly higher in all three
experimental groups as compared with normal controls, median: 3.2
U/ml (p<0.001), 3.3 U/ml (p<0.001), 2.5 U/ml (p=0.01)
respectively as compared with 1.2 U/ml in controls. Newly diagnosed
patients had higher levels than those with long-standing disease
(p=0.026).
[0401] Hepatitis C (HCV) Infection (Bansal et al 1997)
TABLE-US-00075 HCV patients (n = not specified) alcoholic cirrhosis
(AC) (n = not specified) healthy controls (n = not specified)
[0402] Levels of sCD23 elevated in HCV (median 34.0 arbitrary
units) as compared with alcoholic cirrhosis (median 10.1 units) and
normal controls (11.1 units). HCV vs AC (p<0.0004). HCV vs
controls (p<0.0001).
[0403] Asthma (Hoeger at al 1994) TABLE-US-00076 astma patients (n
= not specified) healthy controls (n = not specified)
[0404] Levels of serum sCD23 was lower (p<0.05) in patients with
asthma (mean 4.93-2.29 micrograms/L as compared with controls
(6.92-4.11 micrograms/L). Levels of serum sCD25 normalized with
clinical improvement. No further numerical data given.
[0405] Graves' Disease (Sayinalp et al 1996) TABLE-US-00077 Graves'
disease patients (n = 15) Non-toxic diffuse or multinodular goitre
(n = 15) toxic nodular goitre (n = 10)
[0406] 46.7% Graves' disease patients had detectable levels of
serum sCD23 (99.60+/-105.1). 47.89% of non-toxic diffuse or
multinodular goitre patients had detectable levels of serum sCD23
(47.89+/-53.42) and 10% of patients with toxic nodular goitre
(46.48+/-35.9). Levels of serum sCD23 were significantly
(p<0.02) higher in Graves' patients than in other groups. No
further numerical data given.
[0407] Sjogren's Syndrome (Suzuki et al 1996) TABLE-US-00078
patients (n = 13) normal controls (n = not specified)
[0408] Serum sCD23 levels were significantly (p<0.01) higher in
patients (443.77+/-71.94 micrograms/L) than in normal controls
(211.26+/-12.01). Values were higher in patients with
complications.
[0409] Helminth Parasite Infection (Pritchard et al 1993)
TABLE-US-00079 patients (n = not stated) controls (n = not
stated)
[0410] Levels of serum sCD23 were significantly elevated levels in
infected individuals. No numerical data given.
[0411] Undifferentiated Nasopharyngeal Carcinoma (Rousselet et al
1993) TABLE-US-00080 UNPC patients treated with chemotherapy and
radiotherapy (n = 65)
[0412] Serum sCD23 levels showed a significant association with
disease-free survival (p=0.08) and overall survival (p=0.08). No
further numerical data given.
[0413] Scleroderma (Sato et al 1996) TABLE-US-00081 Patients with
generalized morphea: (n = 15) Controls (n = not specified)
[0414] Levels of serum sCD23 were significantly elevated in
patients compared with controls. No numerical data given.
[0415] Juvenile Chronic Arthritis (Massa et al 1998) TABLE-US-00082
patients with s-JCA (n = 22) patients with ANA and p-JCA (n = 40)
healthy controls (n = 38)
[0416] Levels of serum sCD23 were increased in both patient groups
as compared with healthy controls. No correlation with activity or
severity was found. No numerical data given.
[0417] Lepromatous Leprosy (Bansal et al 1998) TABLE-US-00083
Patients with lepromatous leprosy (n = not specified) Patients with
tuberculoid leprosy (n = not specified) Normal controls (n = not
specified)
[0418] Levels of serum sCD23 were significantly elevated in
lepromatous leprosy patients as compared with tuberculoid leprosy
patients and healthy controls. No numerical data given.
[0419] Renal Transplant Patients with EBV Virus Reactivation
(Hornef et al 1997) TABLE-US-00084 patients (n = 14) control
patients without reactivation (n = 10)
[0420] Levels of serum sCD23 were significantly (p<0.05)
elevated following reactivation.
[0421] Coeliac Disease (Bansal et al 1997) TABLE-US-00085 Coeliac
patients (n = not specified) Control patients with non-specific
upper (n = not specified) GI symptoms
[0422] Levels of serum sCD23 were significantly (p<0.002)
decreased in coeliac disease patients. No further numerical data
given.
[0423] Haemorrhagic Fever with Renal Syndrome (Alexeyev et al 1997)
TABLE-US-00086 patients (n = 15) controls (n = not specified)
[0424] In the acute phase 11/15 patients had significantly
increased levels of serum sCD23 (>91 U/ml), whereas in
convalescence, in 8/10 of the patients the values normalized
(r=0.597, p=0.025).
[0425] Giant Cell Arteritis (Roblot et al 1996) TABLE-US-00087 GCA
patients (n = not specified) controls (n = not specified)
[0426] Levels of serum sCD23 levels were increased in patients and
returned to normal within 24 hrs following initiation of
corticotherapy. No numerical data given.
[0427] Low Grade Non-Hodgkin's Lymphoma (Zinzani et al 1996)
TABLE-US-00088 newly diagnosed patients (n = 40) healthy controls
(n = not specified)
[0428] Serum sCD23 was detected in 35/40 patients at diagnosis and
levels were significantly (p=0.005) increased as compared with
normal controls. Patients with advanced stage disease presented
with higher values of serum sCD23 than those with early stage
disease (p=0.002). All of the complete responders to chemotherapy
(50%) showed a decrease in sCD23 levels. No further numerical
values given.
[0429] EBV Infectious Mononucleosis (Hashimoto et al 1997)
TABLE-US-00089 patients (n = not specified) normal controls (n =
not specified)
[0430] Levels of serum sCD23 were elevated in patients as compared
with normal controls. Levels decreased to normal during
convalescence. No numerical data given.
[0431] B-Cell Chronic Lymphocytic Leukemia (CLL) (Knauf et al 1997)
TABLE-US-00090 newly diagnosed B-cell CLL patients (n = 105)
[0432] High levels of serum sCD23 at diagnosis were linked with
disease progression. No numerical data given.
[0433] Primary Sclerosing Cholangitis (PSC) (Bansal et al 1997)
TABLE-US-00091 PSC patients (n = 31) Alcoholic cirrhosis (AC)
patients (n = 12) Normal controls (n = 20)
[0434] Levels of serum sCD23 were significantly elevated in PSC
patients relative to AC patients (p<0.0001) and normal controls
(p<0.001). No numerical data given.
[0435] Nasal Allergy (Ito et al 1998) TABLE-US-00092 patients (n =
not specifeid)
[0436] Serum levels of sCD23 were significantly reduced in patients
treated with Azelastine for 4 weeks. No numerical data given.
[0437] High Risk IDDM Subjects (Kretowski et al 1999)
TABLE-US-00093 first degree relatives of IDDM patients (n = 28) age
and sex matched healthy controls (n = 28)
[0438] Median levels of serum sCD23 were lower in first degree
relatives as compared with controls and statistically significant
(p<0.02) in the subgroup of subjects with the lowest values of
first phase insulin release. No numerical data given.
[0439] B-Cell Chronic Lymphocytic Leukemia CLL (Molica et al 1999)
TABLE-US-00094 B-cell CLL patients (n = 106)
[0440] Increased combined levels of serum sCD23 and serum beta-2
microglobulin were associated with high-risk disease. No numerical
data given.
[0441] Perennial Allergic Rhinitis (Tanaka et al 1999)
TABLE-US-00095 patients (n = 139) nonatopic controls (n = 31)
[0442] Levels of serum sCD23 in patients were significantly
(p<0.0001) higher than in controls. The level decreased
significantly (p<0.0001) in patients who received immunotherapy.
No further numerical data given.
[0443] B-Cell Chronic Lymphocytic Leukemia CLL (Molica et al 1996)
TABLE-US-00096 B-cell CLL untreated patients (n = 90) normal
controls (n = 15)
[0444] Levels of serum sCD23 were very significantly (p<0.0005)
elevated in patients as compared with controls. This reflected
tumour mass as defined either by clinical stage (p<0.0005) or
bone marrow histology (p<0.0005). Life expectancy was
significantly shorter in patients with high serum levels of sCD23
(p<0.0005). No further numerical data given.
[0445] Atopic Patient Allergic to Parietaria (Di Lorenzo et al
1999) TABLE-US-00097 atopic patients (n = 42) nonatopic controls (n
= 10)
[0446] Levels of serum sCD23 are elevated in atopic patients as
compared with controls. No numerical data given.
[0447] Post-Renal Transplantation (Traindl et al 1994)
TABLE-US-00098 patients (n = not specified)
[0448] In the majority of patients, levels of serum sCD23 increased
up to 3 days before the manifestation of an acute rejection (82% of
cases) or infection episode (73% of cases). No further numerical
data given.
[0449] Rheumatoid Arthritis (Rezonzew et al 1994) TABLE-US-00099 RA
patients (n = not specified) normal controls (n = not
specified)
[0450] Patients had a significantly increased level of serum sCD23
as compared with controls. sCD23 levels in the serum correlated
with RF titer (p<0.0001). No further numerical data given.
[0451] Multiple Sclerosis (Zaffaroni et al 1995) TABLE-US-00100 MS
patients (n = not specified) Other neurological diseases (n = not
specified) Normal controls (n = not specified)
[0452] MS patients had a significantly elevated level of serum
sCD23. No numerical data given.
[0453] Localized Scleroderma (Sato et al 1996) TABLE-US-00101
generalized morphoea (n = 15) linear scleroderma (n = 22) morphoea
(n = 12) healthy controls (n = not specified)
[0454] Levels of serum sCD23 were highly elevated in patients with
localized scleroderma as compared with healthy controls. Patients
with generalized morphoea had the highest levels. No numerical data
given.
[0455] B-Cell Chronic Lymphocytic Leukemia (Callea et al 1996)
TABLE-US-00102 advanced/progressive stage B-CLL (n = 37)
smouldering B-CLL (n = 10) Normal controls (n = 20)
[0456] Advanced/progressive stage B-CLL patients had significantly
higher levels of serum sCD23 than normal controls. Levels of sCD23
directly correlated with tumour mass. Levels lowered significantly
following chemotherapy. No numerical data given.
[0457] Chronic Lymphocytic Leukemia (CLL) (Saati et al 1996)
TABLE-US-00103 CLL patients (n = 153) controls (n = not
specified)
[0458] Levels of serum sCD23 were a prognostic factor for survival
(p=0.03). Patients with a sCD23 value above median value (>574
U/ml) had a significantly (p=0.0001) worse prognosis than those
with lower values (median survival 53 vs 100+ months). Serum sCD23
doubling time increased the risk of death by a factor of 3.2
(p=0.001). Amongst stage A patients (n=100), sCD23 levels at the
time of study entry were the sole variable predictive of disease
progression. Patients with values>574 U/ml had a median
progression time of 42 months vs 88 months for those with lower
levels (p=0.0001). Stage A patients who doubled their sCD23 level
exhibited a 15-fold increased risk of progression (p=0.0001). No
further numerical data given.
[0459] Polytransfused Patients with Beta-Thalassemia Major
(Lombardi et al 1994) TABLE-US-00104 transfusion-dependent patients
(n = 45) normal controls (n = not specified)
[0460] Patients had increased values compared to normal controls.
Serum levels of sCD23 correlated directly with annual transfusion
requirement. No numerical data given.
sCD25 (sIL-2R alpha)
[0461] Infectious Mononucleosis (Vinante et al 1994) TABLE-US-00105
patients (n = 55) controls (n = not specified)
[0462] Levels of serum sCD25 were very significantly elevated
levels in patients (2,922+/-2,813 U/ml) vs controls (331+/-115
U/ml). No further numerical data given.
[0463] Angioimmunoblastic Lympadenopathy (AILD) (Pizzolo et al
1990) TABLE-US-00106 patients (n = 24) normal controls (n = not
specified)
[0464] Very high levels (p<0.001) of serum sCD25 were found in
100% of patients (6315+/-3374 U/ml) as compared with 271+/-112 U/ml
in normal controls.
[0465] Ulcerative Colitis (Dalekos et al 1998) TABLE-US-00107
patients with active disease (n = 32) patients with inactive
disease (n = 43)
[0466] Mean serum levels of sCD25 were significantly (p=0.0001)
higher in active disease (604.3+/-213) than in inactive disease
(411.5+/-165.1).
[0467] Acute Asthma (Kim et al 1998) TABLE-US-00108 patients with
acute attack (n = 50)
[0468] Mean serum levels of sCD25 were significantly (p<0.01)
higher at acute exacerbation (854+/-248 U/ml) than at clinical
remission (676+/-211 U/ml). Levels correlated positively with the
severity of exacerbation (r=0.47, p<0.01).
[0469] Chronic Lymphocytic Leukemia (CLL) (Beguin et al 1993)
TABLE-US-00109 CLL patients (n = 42) Normal controls (n = 31)
[0470] CLL patients had significantly (p<0.001) increased levels
of sCD25 (6080+/-7030 as compared with 1420+/-640 pg/ml in normal
controls).
[0471] Chronic Hepatitis B Infection (Sawayama et al 1999)
TABLE-US-00110 patients (n = 105) healthy controls (n = 21)
[0472] Serum sCD25 levels were significantly (p<0.05) higher in
chronic HBV-infected patients with chronic hepatitis (508+/-310
U/ml) and liver cirrhosis (543+/-283 U/ml) than in healthy controls
(331+/-106 U/ml). Moreover, sCD25 levels were significantly
(p<0.01) higher in patients with chronic hepatitis or liver
cirrhosis than in asymptomatic HBV carries (341+/-150 U/ml).
[0473] Wegener's Granulomatosis (D'Cruz et al 1999) TABLE-US-00111
patients (n = 23) healthy controls (n = 20)
[0474] Median levels of serum sCD25 were significantly higher
(p<0.01) in patients (789.5 U/ml) than in healthy controls (551
U/ml). Levels correlated with disease activity scores.
[0475] Chronic Hepatitis B Infection (Sawayama et al 1999)
TABLE-US-00112 patients (n = 105) healthy controls (n = 21)
[0476] Serum sCD25 levels were significantly (p<0.05) higher in
chronic HBV-infected patients with chronic hepatitis (508+/-310
U/ml) and liver cirrhosis (543+/-283 U/ml) than in healthy controls
(331+/-106 U/ml). Serum sCD25 levels were also significantly
(p<0.01) higher in patients with chronic hepatitis or liver
cirrhosis than in asymptomatic HBV carriers (341+/-150 U/ml). Serum
sCD25 levels in most patients decreased to the same level as
asymptomatic HBV carriers and healthy controls at 48 weeks after
the end of treatment.
[0477] Myeloproliferative Disorders (Bourantas et al 1999)
TABLE-US-00113 patients (n = 55) controls (n = not stated)
[0478] High levels of serum sCD25 were found in all patients. The
elevation was found to be progressive. No numerical data given.
[0479] Pancreatic Adenocarcinoma (Gansauge et al 1998)
TABLE-US-00114 Patients (n = not specified) Normal controls (n =
not specified)
[0480] Serum sCD25 levels were significantly higher in cancer
patients than in normal control subjects or in chronic pancreatitis
patients. Patients with adenocarcinoma of the pancreas with low
sCD25 levels (<500 U/ml) lived significantly (p<0.01) shorter
than patients with levels above 500 U/ml. No further numerical data
given.
[0481] Colorectal Cancer (Saito et ala 1998) TABLE-US-00115
patients (n = 38) healthy controls (n = 98)
[0482] Serum levels of sCD25 were significantly (p<0.05) higher
in patients than in controls. Levels were markedly elevated in
patients with stage 1V cancer, with Duke's Stage D cancer, or with
liver metastasis. No further numerical data given.
[0483] Renal Diseases (Sugimoto et al 1998) TABLE-US-00116 patients
(n = not specified) healthy controls (n = not specified)
[0484] Serum sCD25 levels were significantly higher in patients
with renal diseases than in healthy controls. No numerical data
given.
Ovarian Cancer (Gebauer et al 1998)
[0485] Changes in levels of serum sCD25 post-surgery may be a
useful prognostic factor. No other information given.
[0486] IDDM (Ng et al 1995) TABLE-US-00117 normal controls: (n =
34) IDDM: (n = 32)
[0487] Levels of serum sCD25 were elevated in 3/32 patients. No
numerical data given.
[0488] Systemic Lupus Erythematosus (Swaak et al 1995)
TABLE-US-00118 patients (n = 69)
[0489] Levels of serum sCD25 were elevated during all periods of
increased disease activity. No numerical data given.
IL-2 Therapy (Bogner et al 1992)
Pediatric and Adult Cancer Patients Receiving IL-2 Therapy
(n=51)
[0490] A statistically significant dose effect of IL-2 on serum
levels of sCD25 was observed. No numerical data given.
[0491] Non-Hodgkin's Lymphoma (Perez-Encinas et al 1998)
TABLE-US-00119 patients (n = not specified)
[0492] sCD25 is a sensitive serum marker of tumour burden. No
numerical data given.
[0493] B-Cell Chronic Lymphocytic Leukemia (Callea et al 1996)
TABLE-US-00120 advanced/progressive stage B-CLL (n = 37)
smouldering B-CLL (n = 10) Normal controls (n = 20)
[0494] Advanced/progressive stage B-CLL patients had significantly
higher levels of serum sCD25 than smouldering B-CLL and normal
controls. Levels directly correlated with tumour mass. Levels of
sCD25 were lowered significantly following chemotherapy. No
numerical data given.
[0495] Juvenile Rheumatoid Arthritis (Lipnick et al 1993)
TABLE-US-00121 afebrile JRA patients (n = 49) normal children (n =
16)
[0496] Statistically increased levels of serum sCD25 were found in
patients with severe JRA. No numerical data given.
[0497] Lymphoproliferative Diseases (Sawada et al 1992)
TABLE-US-00122 adult T cell leukemia (n = not stated) hairy cell
leukemia (n = not stated) hodgkin's disease (n = not stated)
non-hodgkin's lymphoma (n = not stated) chronic lymphocytic
leukemia (n = not stated)
[0498] Increased levels of serum sCD25 were found in all groups of
patients. No numerical data given.
[0499] High Dose Chemotherapy and Blood Stem Cell Transplantation
(Ho et al 1994) TABLE-US-00123 chemotherapy patients (n = 12)
[0500] A highly statistically significant increase in levels of
serum sCD25 were found from day 7 to 21. No numerical data
given.
Cervical Neoplasia (Hildensheim et al 1997)
[0501] Levels of serum sCD25 were positively associated with
cervical neoplasia. No further information given.
[0502] Rematalogic Malignancies (Srivastava et al 1994)
TABLE-US-00124 hairy cell leukemia (n = not stated) acute
myelomonocytic leukemia (n = not stated) acute myelocytic leukemia
(n = not stated) B chronic lymphocytic leukemia (n = not stated)
prolymphocytic leukemia (n = not stated) non-T/non-B acute
lymphoblastic leukemia (n = not stated) B-acute lymphoblastic
leukemia (n = not stated) mixed lineage acute lymphoblastic
leukemia (n = not stated) T chronic lymphocytic leukemia (n = not
stated) active mycosis fungoides (n = not stated)
[0503] Elevated levels of serum sCD25 were found in all of the
patient groups. Reduced levels were found in hairy cell leukemia,
pre-T acute lymphoblastic leukemia and active mycosis fungoides
patients in remission. No numerical data given.
[0504] Polytransfused Patients with Beta-Thalassemia Major
(Lombardi et al 1994) TABLE-US-00125 transfusion-dependent patients
(n = 45) normal controls (n = not specified)
[0505] Patients had increased values of serum sCD25 as compared
with normal controls. Serum levels of sCD25 correlated directly
with annual transfusion requirement. No numerical data given.
[0506] Disease Exacerbations in Systemic Lupus Erythematosus
(Spronk et al 1994) TABLE-US-00126 Patients (n = 6)
[0507] During major disease exacerbations, levels of serum sCD25
increased significantly (p<0.001). No further numerical data
given.
[0508] Major Depression (Sluzewska et al 1996) TABLE-US-00127
patients (n = 49) normal controls (n = 15)
[0509] Serum sCD25 levels were significantly elevated in patients
as compared with controls. No further numerical data given.
[0510] Solid Tumours (Orditurra et al 1998) TABLE-US-00128 Patients
(n = 84) Normal controls (n = not stated)
[0511] High levels of serum sCD25 were found in 82% of the
patients. No numerical data given.
[0512] Malignant Lymphoma (Motokura et al 1995) TABLE-US-00129
patients (33 non-Hodgkin's, 3 Hodgkins) (n = 36) controls (n = not
stated)
[0513] The serum level of sCD25 was significantly elevated in
patients with active disease as compared to those in remission and
correlated with the clinical stage of the lymphoma. No numerical
data given.
[0514] Tuberculosis (Barlan et al 1995) TABLE-US-00130 children
with active pulmonary tuberculosis (n = 66) healthy controls (n =
20)
[0515] There were significant (p<0.05) differences between the
levels of serum sCD25 in children with active pTB and healthy
controls. No numerical data given.
[0516] Gynecological Malignancies (Frydecka et al 1996)
TABLE-US-00131 Patients (n = 30) Normal controls (n = not
stated)
[0517] Levels of serum sCD25 were significantly increased before
treatment as compared with normal controls. No numerical data
given. The decrease of tumor mass following radiotherapy,
correlated with serum levels of sIL-2R. No numerical data
given.
[0518] Polymyalgia Rheumatica (Salvarani et al 1994) TABLE-US-00132
Active Polymyalgia rheumatica: (n = 19) Normal controls: (n = not
specified)
[0519] Levels of sCD25 were significantly elevated levels in
patients as compared with controls. In 15/15 patients levels fell
significantly 7 days following steroid therapy. No numerical data
given.
[0520] Psoriasis (De Rie et al 1996) TABLE-US-00133 Patients
treated with cyclosporin A: (n = 17) Patients treated with FK506 (n
= 5)
[0521] Levels of serum sCD25 correlated with disease activity
(rs=0.89; sp<0.05). No numerical data given.
[0522] Behcet's Disease (Uchio et al 1999) TABLE-US-00134 Active
Behcet's disease: (n = 20) Inactive Behcet's disease (n = 15)
Normal controls: (n = 20)
[0523] Significantly increased levels of serum sCD25 were found in
both the acute and convalescent stages of the disease as compared
with normal controls. No numerical data given.
[0524] Acute Pancreatitis (Pezzilli et al 1994) TABLE-US-00135
acute pancreatitis patients (n = 35) healthy controls (n = not
specified)
[0525] Levels of serum sCD25 were measured for 6 days following
admission. Levels significantly increased for the entire
observation period relative to normal controls. Serum sCD25
concentrations were significantly higher in patients with severe
pancreatitis than in those with the mild form of the disease. No
numerical data given.
[0526] Nasopharyngeal Carcinoma (Kuo et al 1994) TABLE-US-00136
Patients (n = 12) Normal controls (n = 12) Skin cancer controls (n
= 12)
[0527] Increased levels of serum sCD25 were found in the patient
group (early stages of the disease). No numerical data given.
[0528] Leishmaniasis (Schriefer et al 1995) TABLE-US-00137 patients
(n = not specified) healthy controls (n = not specified)
[0529] Pre-treatment levels of serum sCD25 were significantly
(p<0.05) higher in patients than in healthy controls. Levels
fell significantly (p<0.05) following antimonial therapy. The
pre-treatment levels of sCD25 in responders and patients refractory
to antimonial therapy differed significantly (p=0.02), suggesting
that they could be used as predictors of antimonial therapy
response. No further numerical data given.
[0530] Vogt-Koyanagi-Harada's Disease (Uchio et al 1999)
TABLE-US-00138 Active disease: (n = 24) Normal controls: (n =
20)
[0531] Levels of serum sCD25 were significantly elevated in the
acute stages of the disease as compared with controls. No numerical
data given.
[0532] Pulmonary Mycobacterial Diseases (Tada et al 1999)
TABLE-US-00139 untreated pTB patients (n = 24) treated multi-drug
resistant intractable pTB (n = 7) pulmonary non-tuberculous
mycobacteriosis (n = 27) controls (n = not specifed)
[0533] Serum sCD25 levels were elevated in patients with pulmonary
mycobacterial diseases and in untreated pTB patients as compared
with controls. No numerical data given.
[0534] Gastric Carcinoma (Maeta et al 1998) TABLE-US-00140 Patients
(n = 91) normal controls (n = not specified)
[0535] Pre-operative levels of serum sCD25 were significantly
higher than in normal controls and levels were a useful indicator
of lymph node involvement. Patients with progressive post-operative
increases in levels had both a significantly higher frequency of
post-operative relapse and a poor prognosis. No numerical data
given.
[0536] Gastric Cancer (Saito et al 1999) TABLE-US-00141 patients (n
= 121) normal controls (n = not specified)
[0537] Pre-operative levels of serum sCD25 in patients with gastric
cancer were significantly higher than those in normal controls. An
elevated level of sCD25 was significantly correlated with
clinicopathalogical features, including lymph node metastasis. The
post-operative survival time of patients with elevated levels of
sCD25 was significantly lower than those with normal levels.
[0538] Neuroleptic Treatment in Schizophrenia (Muller et al 1997)
TABLE-US-00142 schizophrenic patients (n = 39) healthy controls (n
= 42)
[0539] During neuroleptic treatment there was a significant
increase in serum sCD25 levels. No further numerical data
given.
[0540] Brain Damage (Rogers et al 1998) TABLE-US-00143 Patients (n
= not stated)
[0541] Serum levels of sCD25 were significantly elevated in
individuals with unilateral brain damage. No numerical data
given.
[0542] Bone Marrow Transplant (Liem et al 1998) TABLE-US-00144
Patients (n = 46)
[0543] Serum levels of sCD25 were significantly increased following
transplantation. Increased level were correlated with graft vs host
disease. No numerical data given.
[0544] Heatstroke (Hammammi et al 1998) TABLE-US-00145 patients (n
= not specified) controls (n = not specified)
[0545] Serum levels of sCD25 were elevated in patients as compared
with controls. No numerical data given.
[0546] Autoimmune Rheumatic Disease (Sfikakis et al 1999)
TABLE-US-00146 Rheumatoid arthritis (RA), systemic sclerosis (SSc)
and SLE (n = 75) patients
[0547] Levels of serum sCD25 levels in patients with active RA, SSc
and SLE were almost double the normal level. No numerical data
given.
[0548] Cervical Neoplasia (Ung et al 1999) TABLE-US-00147 Low grade
squamous intraepithelial lesions (LSIL) (n = 191) High grade
squamous intraepithelial lesions (HSIL) (n = 130) Cervical cancer
(n = 37) normal controls (HPV negative) (n = 120)
[0549] Women with LSIL had higher serum sCD25 levels than controls
(OR for upper quartile of sCD25, 2.3; 95% CI, 1.1-5.2; comparing
LSIL cases with controls. Women diagnosed with HSIL were similar to
the LSIL group (OR for upper quartile of sCD25, 1.1; 95% CI,
0.5-2.4; comparing HSIL cases with LSIL cases. Those with cancer
had higher levels than subjects with an HSIL diagnosis (OR for
upper quartile of sCD25=1.8; 95% CI, 0.5-7.1)
[0550] B Cell Chronic Lymphocytic Leukemia (Mavridis et al 1998)
TABLE-US-00148 B-CLL patients (n = 20)
[0551] Serum sCD25 levels were significantly elevated in patients.
There was an excellent correlation between levels and disease
activity. Patients with aggressive disease had increased levels.
Patients who responded to therapy and with improved clinical status
had decreased sCD25 levels. No numerical data given.
[0552] Hepatocellular Cancer (Izzo et al) TABLE-US-00149 patients
with HCC (n = 99) healthy volunteers (n = 174)
[0553] Serum sCD25 levels were elevated in 98/99 patients
(p<0.01). Serum sCD25 levels returned to normal in 27/99
patients after treatment. No numerical data given.
[0554] Behcet's Disease (Alpsoy et al 1998) TABLE-US-00150 patients
(n = 32) healthy controls (n = 20)
[0555] Serum sCD25 levels in patients with active disease were
significantly higher than in either patients with inactive disease
(p<0.001) or the control group (p<0.05).
[0556] Multiple Sclerosis (Bilinska et al 1999) TABLE-US-00151
Patients (n = not stated)
[0557] Levels of serum sCD25 were significantly increased in
patients as compared with normal controls. No numerical data
given.
sCD27
[0558] B-Cell Chronic Lymphoblastic Leukemia (CLL) (Molica et al
1998) TABLE-US-00152 B-cell CLL (previously untreated patients) (n
= 82) Healthy controls (n = not specified)
[0559] Serum sCD27 levels were significantly (p<0.0001) higher
in CLL patients (2150 U/ml) than in controls (220 U/ml). Changes in
sCD27 correlated with clinical stage.
[0560] B-Cell Malignancies (van Oers et al 1993) TABLE-US-00153
Patients (n = not specified)
[0561] Very high levels of serum sCD27 were found in patients with
B cell malignancies (6,000 U/ml) as compared with normal levels
(<190 U/ml). There was a strong correlation with tumour load.
The highest levels were found in CLL and low grade non-Hodgkin's
lymphomas.
[0562] Systemic Lupus Erythematosus (Font et al 1996)
TABLE-US-00154 SLE patients (n = 70) Healthy controls (n = 20)
[0563] The mean level of sCD27 was significantly (p=0.02) higher in
SLE patients (48.29+/-23.86 U) as compared with controls
(36.13+/-7.48). Patients with active SLE (58.20+/-31.06 U) had
significantly (p<0.01) higher levels than those in remission
(42.77+/-16.71 U).
[0564] Psoriasis (De Rie et al 1996) TABLE-US-00155 Patients
treated with cyclosporin A: (n = 17) Patients treated with FK506 (n
= 5)
[0565] Levels of serum sCD27 were elevated in patients and
decreased following treatment. No numerical data given.
[0566] Graves' Disease (Kallio et al 1998) TABLE-US-00156 Patients
(n = not stated)
[0567] Levels of serum sCD27 were elevated in untreated Graves'
disease. Levels normalized with treatment. No numerical data
given.
[0568] Systemic Lupus Erythematosus (Swaak et al 1995)
TABLE-US-00157 Patients (n = 69)
[0569] Levels of serum sCD27 were elevated in all periods of
increased disease activity. No numerical data given.
[0570] Lympatic Filariasis (Yazdanbakhsh et al 1993) TABLE-US-00158
patients (n = 145)
[0571] Levels of serum sCD27 were significantly (p<0.002)
elevated in elephantitis and microfilaremic patients as compared
with endemic normals. No further numerical data given.
sCD30 (Ki-1)
[0572] HIV (Pizzolo et al 1997) TABLE-US-00159 acute primary HIV
infection (n = 17) following seroconversion (n = 13) normal
controls (n = not specified)
[0573] Levels of serum sCD30 during acute infection were
consistently very significantly (p<0.0001) elevated
(137.58+/-120.33) as compared with normal controls (6.4+/-5.4
U/ml). Levels of serum sCD30 decreased significantly (p=0.0018)
following sero-conversion (49.1+/-66.17) as compared with acute
infection levels.
[0574] Hashimoto's Thyroiditis (Okumura et al 1997) TABLE-US-00160
HS patients (n = 37) normal subjects (n = 21)
[0575] Levels of serum sCD30 were significantly (p<0.0001)
elevated in HS patients (29.9+/-26.0 U/ml) as compared with
controls (7.1+/-4.5 U/ml). Levels were significantly higher
(p<0.05) in patients with transient destructive thyrotoxicosis
caused by aggrevation of the disease (48.8+/-34.4 U/ml) than in
euthyroid patients (24.2+/-19.4 U/ml).
[0576] Rheumatoid Arthritis (Wang et al 1997) TABLE-US-00161 RA
patients (n = 25) Normal controls (n = 21)
[0577] Levels of serum sCD30 were significantly (p<0.05)
elevated in RA patients (15.2+/-2.1 U/ml) as compared with normal
controls (8.8+/-0.9 U/ml).
[0578] Wegner's Granulomatosis (WG) (Wang et al 1997)
TABLE-US-00162 WG patients (n = 57) Normal controls (n = 21)
[0579] Levels of serum sCD30 were very significantly (p<0.0001)
elevated in generalized (22.5+/-1.5 U/ml) but not initial phase
(12.1+/-4.0 U/ml) WG patients, as compared with normal controls
(8.8+/-0.9 U/ml). Levels declined significantly (p=0.0001) in
patients (n=11) that were in remission (29.1+/-1.9 U/ml to
15.9+/-1.8 U/ml).
[0580] Multiple Sclerosis (McMillan et al 1998) TABLE-US-00163
Primary progressive MS (n = not specified) Secondary progressive MS
(n = not specified) Relapsing/remitting MS (RRMS) (n = not
specified) Inflammatory neurological disease patients (IND) (n =
not specified) Non-inflammatory neurological disease (NIND) (n =
not specified)
[0581] Higher levels of serum sCD30 were detected in all MS
subgroups and IND patients as compared with NIND controls. RRMS
patients had significantly (p=0.04) higher levels (45.7 U/ml) than
those in relapse (18.3 U/ml).
[0582] Atopic Disorders (Latza et al 1999) TABLE-US-00164 Atopic
patients (n = 60) Normal controls (n = 59)
[0583] The mean level of serum sCD30 was 75 U/ml (SD 110 U/ml) in
patients as compared with 35 U/ml (SD 59 U/ml) in controls. Serum
levels of sCD30 were elevated in 65% of patients as compared with
32% of the controls.
[0584] Angioimmunoblastic Lympadenopathy (AILD) (Pizzolo et al
1990) TABLE-US-00165 patients (n = 24) normal controls (n = not
specified)
[0585] Very high levels of serum sCD30 were detected 19/24 patients
(722+/-895 U/ml) as compared with the lack of detectable levels in
controls.
[0586] Childhood Tuberculosis (Hanekom et al 1999) TABLE-US-00166
patients (n = 91)
[0587] High levels of serum sCD30 were found at diagnosis (median
98 U/L, range 11 to 1,569 U/L). Levels were statistically higher in
patients with nutritional compromise. Levels of sCD30 decreased
following vitamin A therapy.
[0588] Hodgkin's Disease (Nadali et al 1994) TABLE-US-00167
patients (n = 117) controls (n = not specified)
[0589] Serum sCD30 levels were significantly increased
(p<0.0001) in 87.2% of patients (mean+/-SD 108+/-134 U/ml) as
compared with controls (5.3+/-5.7 U/ml). Levels correlated with the
stage of disease.
[0590] Atopic Dermatitis (AD) (Bengtsson et al 1997) TABLE-US-00168
AD patients (n = 49) healthy non-atopic controls (n = 94)
[0591] Levels of serum sCD30 in AD were significantly (p<0.001)
higher in patients (29 U/ml, ran 1-708 U/ml) as compared with
controls (11 U/ml, range 1-1042).
[0592] Chronic Hepatitis B Infection (Fattovich et al 1996)
TABLE-US-00169 patients (n = 90) healthy carriers (n = not
specified) normal controls (n = not specified)
[0593] Significantly (p<0.00005) elevated levels (median value
26.7 U/ml) of serum sCD30 were detected in 57/90 (63%) of patients
as compared with healthy carriers (median 10.5 U/ml) are normal
controls (3 U/ml, p<0.00001). Raised levels correlated with
acute illness.
[0594] Anaplastic Large-Cell Lymphoma (Nadali et al 1995)
TABLE-US-00170 patients (n = 24) controls (n = not specified)
[0595] Significantly (p<0.0001) elevated levels of serum sCD30
(median 842.5 U/ml, range 16-37,250) at diagnosis were found in
23/24 patients as compared with controls. The highest median value
was observed in patients with T-ell-type ALCL (1,690 U/ml). No
further numerical data given.
[0596] Systemic Lupus Erythematosus (Caligaris-Cappio et al 1995)
TABLE-US-00171 SLE patients (n = 21) Undiffereniated connective
tissue disease (UCTD) (n = 17) normal donors (n = 40)
[0597] Serum sCD30 values were (53.84+/-58.24 U/ml) in SLE,
(22.65+/-9.82 U/ml) in UCTD, and (5.3+/-5.7 U/ml) in normal
controls. Levels of serum sCD30 in SLE patients were significantly
(p<0.0005) elevated as compared with controls and UCTD
(p<0.05). Levels of serum sD30 were directly related to disease
activity (p<0.002).
[0598] Infectious Mononucleosis (Vinante et al 1994) TABLE-US-00172
patients (n = 55) controls (n = not specified)
[0599] Levels of sCD30 were highly elevated levels in patients
(477+/-452 U/ml) as compared with controls (4.9+/-6.4 U/ml). By day
30, levels in patients fell to 20+/-21 U/ml. No further numerical
data given.
[0600] Graves' Disease (Okumura et al 1997) TABLE-US-00173 patients
(n = 71) normal subjects (n = 21)
[0601] Levels of sCD30 were significantly (p<0.0001) elevated in
Graves' disease patients (29.2+25.2 U/ml) as compared with controls
(7.1+/-4.5 U/ml). Levels were significantly (p<0.00 higher in
thyrotoxic patients (41.7+/-31.2 U/ml) than in remission
(15.8+/-11.0 U/ml).
Atopic Dermatitis (Bottari et al 1999)
[0602] sCD30 elevated in patients. Levels decreased following
cyclosporin A treatment. No numeric data given.
[0603] HIV Infected Hemophiliacs (Sabin et al 1997) TABLE-US-00174
hemphiliac men (n = 85) controls (n = not specified)
[0604] Serum sCD30 levels were elevated in patients. No numerical
data given.
[0605] Anaplastic Large-Cell Lymphoma (ALCL) (Zinzani et al 1998)
TABLE-US-00175 previously untreated ALCL-CT patients (n = 38)
previously untreated ALCL-HL patients (n = 32) stage matched
patients with Hodgkin's disease (HD) (n = 50) healthy controls (n =
not specified)
[0606] Levels of serum sCD30 were highly elevated in HD patients as
compared with healthy controls. Median sCD30 levels in patients
with ALCL-CT and ALCL-HL were 18 and 7 time higher respectively
than in patients with HD. The serum sCD30 level normalised with
treatment. No numerical data given.
[0607] Hodgkin's Disease (Nadali et al 1998) TABLE-US-00176
patients (n = 303)
[0608] Serum sCD30 levels were correlated with stage, presence of B
symptoms and tumour burden High serum sCD30 levels entailed a
higher risk of poor outcome. No numerical data given.
[0609] Kawasaki Disease (Vagliasindi et al 1997) TABLE-US-00177
Patients (n = 10) Controls (n = not specified)
[0610] Very high levels of serum sCD30 were found in patients. No
numerical data given.
sCD31 (PECAM-1)
[0611] Thrombolytic Therapy in Acute Myocardial Infarction (AMI)
(Serebruany et al 1999) TABLE-US-00178 AMI patients (n = 23)
healthy controls (n = 22)
[0612] Levels of sCD31 increased significantly (p=0.02) 3 hrs
following thrombolysis, followed by significant (p=0.03) decrease
24 hrs later. No further numerical data given.
sCD32 (FcgRII)
[0613] Multiple Myeloma (Tartour et al 1995) TABLE-US-00179
patients (n = not specified)
[0614] Levels of serum sCD32 levels slightly increased in MM
patients. No numerical data given.
Heparin-Induced Thrombocytopenia (Saffroy et al 1997)
[0615] No data given.
sCD35 (CR1)
[0616] End-Stage Renal Failure on Dialysis (Pascual et al 1993)
TABLE-US-00180 patients (n = 36) normal controls (n = 31)
[0617] Levels of serum sCD35 were significantly (p<0.0001)
elevated in patients (54.8+/-11.7 ng/ml) as compared with normal
controls (31.4+/-7.8 ng/ml).
[0618] Liver Cirrhosis (Pascual et al 1993) TABLE-US-00181 patients
(n = 22) normal controls (n = 31)
[0619] Levels of serum sCD35 were significantly (p<0.0001)
elevated in patients (158.3+/-49.9 ng/ml) as compared with normal
controls (31.4+/-7.8). The mean sCD35 dropped significantly
(p<0.001) from (181+/-62.7 ng/ml) to (52.1+/-24.0 ng/ml) in 9
patients undergoing liver transplantation.
[0620] Leukemia (Sadallah et al 1999) TABLE-US-00182 patients (n =
180) normal controls (n = not specified)
[0621] 50% of patients had levels of serum sCD35 above the normal
range. Highest levels were in T-ALL patients (n=17). No numerical
data given.
sCD38
Multiple Myeloma (Funaro et al 1996)
[0622] Serum sCD38 levels are detectable in these patients. No
numerical data given.
AIDS (Funaro et al 1996)
[0623] Levels of serum sCD38 are detectable in these patients. No
numerical data given.
sCD40
[0624] Chronic Renal Failure, Haemodialysis, CAPD (Schwabe et al
1999) TABLE-US-00183 haemodialysis (HD) patients (n = 22) CAPD
(chronic ambulatory peritoneal dialysis patients (n = 10) healthy
controls (n = 41)
[0625] Levels of serum sCD40 were highly elevated in all patients
with impaired renal function. HD patients had up to a 100-fold
elevated (8.32+/-4.11 ng/ml) level of serum sCD40 levels as
compared with healthy controls (0.14+/-0.12 ng/ml). CAPD patients
had increased levels of 3.58+/-2.4 ng/ml. No further numerical data
given.
sCD44
[0626] Non-Hodgkin's Lymphoma (Snachez et al 1999) TABLE-US-00184
patients with stage IV non-Hodgkin's lymphoma (n = 48) controls (n
= 80)
[0627] Mean serum levels of sCD44 were 398+/-160 ng/ml in patients
as compared with 223+/-5 ng/ml in controls. No further numerical
data given.
[0628] Acute Leukemia and Myelodysplastic Syndromes (Nasu et al
1998) TABLE-US-00185 AML (n = 18) ALL (n = 16) CML (n = 18) MDS (n
= 43) normal controls (n = 51)
[0629] Serum sCD44 levels as compared with normal controls (24.6
ng/ml) were significantly elvat in: AML (99.0 ng/ml, p=0.0001), ALL
(427.8 ng/ml, p=0.0001), MDS (54.9 ng/ml, p=0.0071) and CML (97.5
ng/ml, p=0.0001). In patients with acute leukemia, serum sCD44
decreased significantly in response to treatment and reached nearly
normal levels after complete remission (p=0.0005 in AML and
p=0.0032 in ALL).
[0630] Colorectal Cancer (Weg-Remers et al 1998) TABLE-US-00186
colorectal cancer patients (n = not specified) IBD (n = not
specified) chronic renal failure (n = not specified) controls (n =
not specified)
[0631] Serum sCD44 and sCD44 (variant 6) levels were significantly
elevated in most of the patient groups (medians sCD44 330-709
ng/ml, sCD44v6 125-160 ng/ml) as compared with control (sCD44 346
ng/ml, sCD44v6 106.5 ng/ml).
[0632] Cervical Cancer (Gadducci et al 1998) TABLE-US-00187
cervical cancer patients (n = 37) benign gynecological disease
controls (n = 36)
[0633] Median serum sCD44 (standard form) levels were significantly
higher (p=0.004) in cervical cancer patients (547 ng/ml, range
244-880 ng/ml) as compared with controls (400.5 ng/ml, range
217-723 ng/ml). sCD44v5 and sCD44v6 were significantly lower in
cervical cancer patients than in controls (34 ng/ml range 0-140
ng/ml vs 44 ng/ml, range 111-109 ng/ml and 37 ng/ml, range 1-191
ng/ml vs 52.5 ng/ml, range 11-173 ng/ml respectively, p=0.007).
[0634] Rheumatoid Arthritis (Kittl et al 1997) TABLE-US-00188
patients (RA) (n = 56) miscellaneous inflammatory rheumatic
diseases (MIRD) (n = 31)
[0635] Very significantly higher (p<0.001) levels of serum
sCD44v5 were found (81+/-54 ng/ml v 33+/-13 ng/ml) and v6
(237+/-124 ng/ml vs 166+/-53 ng/ml) in RA patients than in those
with MIRD. In RA patients elevated sCD44v5 correlated with disease
activity.
[0636] Renal Cancer (Kan et al 1996) TABLE-US-00189 patients (n =
47) healthy controls (n = 16)
[0637] Serum sCD44 was significantly (p=0.001) elevated in patients
(745+/-170 ng/ml) as compared with healthy controls (563+/-159
ng/ml).
[0638] Metastatic Gastric Carcinoma (Harn et al 1996)
TABLE-US-00190 patients with various stages of gastric carcinoma (n
= 41) normal controls (n = 10)
[0639] Levels of serum sCD44v5 (69.39+/-6.06 vs 25.49+/-1.7 ng/ml)
and sCD44v6 216.62+/-32.98 vs 148.32+/-3.15 ng/ml) were elevated in
patients with advanced gastric carcinoma as compared with normal
controls. Serum sCD44v5 correlated with the extent of tumour
invasion, status of lymph node involvement and distant metastasis
(p<0.05). No further numerical data given.
[0640] Gastrointestinal Cancer (Guo et al 1994) TABLE-US-00191
advanced gastric cancer (n = not specified) colon cancer (n = not
specified) normal controls (n = not specified)
[0641] Levels of serum sCD44 were elevated in both advanced gastric
cancer (24.2+/-9.8 nM vs 2.7+/-1.1 nM in normal controls) and colon
cancer (30.8+/-11 nM vs 2.7+/-1.1 nM in normal controls).
[0642] Pancreatic Carcinoma (Gansauge et al 1997) TABLE-US-00192
pancreatic carcinoma patients (n = 93) controls (n = not
specified)
[0643] Serum sCD44 and sCD44v6 were significantly reduced in
patients (p<0.001 and p<0.00005 respectively). The median
survival in the group with sCD44v6 below 100 ng/mL was
significantly decreased compared with those with serum values above
10 ng/mL (6.7 vs 15.1 months, p<0.0005).
[0644] Gastric Carcinoma (Saito et al 1998) TABLE-US-00193 patients
(n = 102) controls (n = not specified)
[0645] Levels of serum sCD44 (variant 6) were significantly
associated with the depth of tumour invasion, lymph node metastasis
and clinical stage in patients with diffuse type gastric carcinoma.
No numerical data given.
[0646] Colorectal Cancer (Yamane et al 1999) TABLE-US-00194
patients prior to surgery (n = 44) controls (n = not specified)
[0647] Serum sCD44 (variant 6) levels were significantly
(p<0.05) associated with lymph node metastasis. The 5 year
survival rate was significantly lower (P<0.05) in patients with
high (52.4%) sCD44 (variant 6). sCD44 served as prognostic
indicator in these patients (no numerical data given).
[0648] Non-Hodgkin's Lymphoma (Ristamaki et al 1998) TABLE-US-00195
patients (n = 123) controls (n = not specified)
[0649] Significantly higher levels of sCD44 were found in patients
as compared with controls, and were associated with high
histological grade of malignancy and poor overall survival.
[0650] Ovarian Cancer (Zeimet et al 1997) TABLE-US-00196 ovarian
cancer patients (n = 96) healthy age-matched female controls (n =
50)
[0651] Serum sCD44 was found to be higher and sCD44v5 to be lower
in patients than in controls. No numerical data given. A high
pre-treatment serum level of sCD44v5 is associated with a
favourable clinical outcome.
[0652] Breast Cancer (Kittl et al 1997) TABLE-US-00197 active
metastatic breast cancer (n = 53) recurrence of breast cancer (n =
13) breast cancer at presentation patients (n = 85) non-malignant
breast disease controls (n = 53) healthy controls (n = 147)
[0653] Elevated levels (>58 ng/ml) of serum sCD44 were found in
50% of cases with metastatic disease, with marked elevation in 26%.
In these cases sCD44v5 correlated with the extent of metastatic
disease and fell during clinical response to cytoreductive
therapy.
[0654] Epithelial Ovarian Cancer (Gadducci et al 1997)
TABLE-US-00198 patients (n = 51) controls (n = not specified)
[0655] Levels of serum sCD44v5 and sCD44v6 were significantly lower
in FIGO stage III-IV thn in stage I disease (p<0.0001 and
p=0.001 respectively).
[0656] Breast Cancer (Lackner et al 1998) TABLE-US-00199 single
organ metastasis breast cancer patients (n = 57) multiple organ
metastasis breast cancer patients (n = not specified) metastasis
free breast cancer patients (n = not specified) normal controls (n
= not specified)
[0657] When metastases were detected, sCD44v5 and v6 serum levels
were increased as compared to levels measured one month after
tumour surgery in patients free of metastases (p=0.0025 and
p=0.0004 respectively). In patients with single organ metastases,
elevated sCD44v6 were associated with liver and bone metastasis
(p=0.0025).
[0658] B Cell Chronic Lymphocytic Leukemia (B-CLL) (De Rossi et al
1997) TABLE-US-00200 B-CLL patients (n = not specified) controls (n
= not specified)
[0659] Levels of serum sCD44 are elevated in about 50% of patients.
No numerical data given.
[0660] Breast Cancer (Martin et al 1997) TABLE-US-00201 node
positive breast cancer patients (n = not specified) node negative
breast cancer patients (n = not specified) healthy controls (n =
not specified)
[0661] Node-positive breast cancer patients had significantly
elevated levels of serum sCD44v5 and v6 as compared with the two
control groups (P<0.01). No numerical data given.
[0662] Chagas Disease (Laucella et al 1996) TABLE-US-00202 patients
with Chagas disease (n = 56) controls (n = not specified)
[0663] sCD44 levels were significantly increased in the sera of
patients during the acute phase of the infection. No numerical data
given.
[0664] Urological Malignancies (Lein et al 1997) TABLE-US-00203
prostatic cancer patients (n = 49) benign prostatic hypperplasia
(BPH) (n = 30) renal cell carcinoma (RCC) (n = 31) bladder cancer
(n = 29) healthy male controls (n = 30) healthy female controls (n
= 30)
[0665] Levels of serum sCD44v5 in patients with prostate cancer,
BPH and RCC were significantly lower than those in the male control
group (p<0.01, p<0.001, p<0.001 respectively). No further
numerical data given.
Urological Malignancies (Lein et al 1996)
[0666] No data given.
Chronic Inflammatory Bowel Disease (Folwaczny et al 1996)
[0667] No data given.
[0668] Prostate Cancer (Jung et al 1996) TABLE-US-00204 locally
advanced prostate cancer (n = 19) prostatic cancer without
metastasis (n = 30) benign prostatic hyperplasia (BPH) (n = 30)
controls (n = 30)
[0669] Mean serum sCD44v5 levels were significantly lower in
prostate cancer and BPH patients than in controls. No numerical
data given.
[0670] Liver Disease (Falleti et al 1997) TABLE-US-00205 acute
hepatitis (AH) (n = 14) non-cirrhotic liver disease (CLD) (n = 45)
cirrhosis (C) (n = 34) extrahepatic diseases (EHD) (n = 35) healthy
controls (HC) (n = 14)
[0671] Patients with AH or C had significantly (p<0.01) higher
levels of serum sCD44 as compared with CLD, EHD and HC patients. No
further numerical data given.
sCD46 (MCP)
[0672] Systemic Lupus Erythematosus (Kawano et al 1999)
TABLE-US-00206 active SLE (n = not specified) inactive SLE (n = not
specified) RA (n = not specified) Primary Sjogren's syndrome (n =
not specified) normal controls (n = not specified)
[0673] Serum sCD46 levels were significantly (p=0.0003) higher in
active SLE (30.5+/-14.1 ng/ml) than those in inactive SLE
(5.8+/-7.1 ng/ml), RA (14.9+/-11.6 ng/ml, p=0.0218), primary
Sjogren's syndrome (12.3+/-11.6 ng/ml, p=0.0039) and normal
controls (7.3+/-3.6 ng/ml, p=0.0005). The elevated level in active
SLE patients decreased significantly (p=0.018) to 8.0=/-6.3 ng/ml
after effective therapy.
sCD48 (Blast-1)
[0674] Lymphoid Leukemias and Arthritis (Smith et al 1997)
TABLE-US-00207 lymphoproliferative disease (LPD) patients (n = not
specified) arthritis patients (n = not specified) acute EBV
infection (n = not specified) normal controls (n = not
specified)
[0675] Elevated levels of serum sCD48 were detected in some
patients with LPD (median 41 ng/ml, range 1548), arthritis
(median=42 ng/ml, range 13-67) and acute EBV infection (174 ng/ml
as compared with normal controls (29 ng/ml, range 15-48). No
further numerical data given.
sCD50 (ICAM-3)
[0676] Systemic Lupus Erythematosus (Pino-Otin et al 1995)
TABLE-US-00208 SLE patients (n = not specified) normal controls (n
= not specified)
[0677] Levels of serum sCD50 were elevated in SLE patients. No
numerical data given.
[0678] Rheumatoid Arthritis (Littler et al 1997) TABLE-US-00209 RA
patients (n = 22) Healthy controls (n = 10)
[0679] Levels of serum sCD50 were significantly elevated (p=0.0327)
as compared with healthy controls. No numerical data given.
[0680] Rheumatoid Arthritis (Nasonov et al 1997) TABLE-US-00210
patients (n = 36) controls (n = not specified)
[0681] Serum levels of sCD50 were elevated in 28.6% of patients. No
numerical data given.
[0682] HIV-1 (Galea et al 1997) TABLE-US-00211 patients (n = not
specified) controls (n = not specified)
[0683] Serum sCD50 levels were increased in HIV-1 patients. No
numerical data given.
[0684] Psoriasis (Griffiths et al 1996) TABLE-US-00212 psoriasis
patients (n = 32) healthy controls (n = 112)
[0685] Levels of serum sCD50 were significantly elevated in
patients and correlated with clinical severity. No numerical data
given.
sCD54 (ICAM 1)
[0686] Giant Cell Arteritis (GCA) (Coll-Vincent et al 1999)
TABLE-US-00213 GCA patients (n = 64) healthy controls (n = 35)
[0687] At the time of diagnosis GCA patients had significantly
(p<0.001) higher levels of serum sCD54 (360.55 ng/ml, SD 129.78)
than controls (243.25 ng/ml, SD 47.43). Values normalized with
clinical remission.
[0688] Acute Lymphoblastic Leukaemia (Hatzistilianou et al 1997)
TABLE-US-00214 ALL patients (n = 35) healthy controls (n = 35)
[0689] Levels of serum sCD54 were significantly (p<0.001)
elevated in patients (646.6+/-80.9 ng/ml) as compared with normal
controls (245.8+/-25.7 ng/ml). During remission following
treatment, levels did not differ significantly from controls.
During relapse, serum sCD54 level were significantly (p<0.001)
higher (923.9+/-110.1 ng/ml) than those of the control group and
those at the time of remission (p<0.001).
[0690] Metastatic Hepatocellular Carcinoma (Sun et al 1999)
TABLE-US-00215 patients with non-metastatic HCC (n = not specified)
patients with metastatic HCC (n = not specified)
[0691] Serum sCD54 levels were significantly (p<0.05) higher in
HCC patients with metastatsis (12.18+/-0.25) than in non-metastatic
HCC patient controls (9.77+/-0.54).
[0692] Leukemia and Lymphoma (Tacyildiz et al 1999) TABLE-US-00216
child patients with leukemia or lymphoma (n = 54) age-matched
healthy child controls (n = 12)
[0693] Serum sCD54 levels were significantly higher (p<0.01 in
each comparison) in ALL (median value 350.9 ng/ml) or HD (286.4
ng/ml) patients as compared with controls (138.4 ng/ml). These
levels significantly declined in ALL and HD patients in complete
remission (185 and 145.4 ng/nl respectively, p<0.05). High
levels of serum sCD54 were associated with poor outcome and
survival.
[0694] Cervical Carcinoma (Okamoto et al 1999) TABLE-US-00217
cervical cancer patients n = not specied patients with benign
disease n = not specified normal controls n = not specified
[0695] Pateints with cervical cancer had significantly (p<0.001)
higher levels (884.4+/-332.4 ng/ml) of sCD54 than normal controls
(364.6+/-134.8 ng/ml) and patients with benign disease (536+/-204.8
ng/ml).
[0696] Bronchial Asthma (El-Sawy et al 1999) TABLE-US-00218
asthmatic children (mild) (n = 15) asthmatic children (moderate) (n
= 15) asthmatic children (severe) (n = 15) healthy controls (n =
20)
[0697] Mean serum sCD54 levels in asthmatic children were
significantly higher than in controls (390.0+/-108.3 ng/ml vs
193.2+/-33.95 ng/ml). An increase in serum sCD54 correlated well
with asthma severity.
[0698] Pre-Eclampsia (Daniel et al 1999) TABLE-US-00219 patients (n
= 20) controls (normotensive) (n = 20) healthy non-pregnant women
(n = 10)
[0699] Mean serum sCD54 level in patients were significantly higher
than in normotensive controls (1831 ng/ml+/-534 ng/ml vs 1254
ng/ml+/-386 ng/ml respectively, p<0.05).
[0700] Graves' Disease (Massart et al 1999) TABLE-US-00220 patients
3, 6, 12, 18 months following carbimazole therapy (n = 30) patients
relapsing (n = 11) patients 2 years following therapy and in
remission (n = 13) untreated patients (n = 41) healthy controls (n
= 30)
[0701] Mean sCD54 concentration was significantly higher in
untreated Graves' disease patients than in controls (mean+/-SD:
371+/-108 ng/ml vs 243+/-47 ng/ml, p<0.0001), until 6 months of
therapy. The number of patients with sCD54 levels>mean of
controls +2 SD declined from 56% ( 23/41) at the time of diagnosis
to 10% ( 3/29) at 18 months. At relapse, mean sCD54 levels
increased compared with that at 18 months of therapy (288+/-48
ng/ml vs 236+/-59 ng/ml, p=0.005).
[0702] Advanced Renal Cell Carcinoma (Hobarth et al 1996)
TABLE-US-00221 patients (n = 16) healthy controls (n = 20)
[0703] Compared with healthy controls, significantly (p<0.01)
elevated baseline circulating levels of sCD54 (mean 1166 vs 230
ng/ml) were found in all patients.
[0704] Renal Cell Carcinoma (Dosquet et al 1997) TABLE-US-00222
patients n = 76 healthy controls n = 41
[0705] Levels of sCD54 were significantly higher in patients with
renal cell carcinoma than in controls. Levels were higher in
metastatic patients (median=687 ng/ml, range 294-1091, n=12), than
in non-metastatic patients (median=408 ng/ml, range 217-1375,
n=64). No further numerical data given.
[0706] Connective Tissue Disease (Laucella et al 1999)
TABLE-US-00223 juvenile chromic arthritis patients (JCA) (n = 37)
Systemic lupus erythematosis patients (SLE) (n = 18) Healthy
controls (n = 25)
[0707] Mean values of sCD54 in JCA patients, SLE patients and
controls were: 609+/-184, 513+/-139 and 210+/-95 ng/ml
respectively. These levels were significantly different (no
numerical data given). In JCA patients, higher levels were found in
patients with systemic disease. Levels of sCD54 were positively
correlated with disease activity in SLE patients.
[0708] Sarcoidosis (Kim et al 1999) TABLE-US-00224 patients (active
disease) (n = 16) patients (inactive disease) (n = 11)
[0709] Levels of serum sCD54 were significantly higher in patients
with active disease than in those with inactive disease: 575+/-221
ng/ml vs 263=/-98.5 ng/ml, p=0.0001. In patients with active
disease, levels decreased significantly following steroid therapy:
284+/-118 ng/ml (level of significance not stated).
[0710] Unstable Angina (Ogawa et al 1999) TABLE-US-00225 unastable
angina patients (n = 20) stable exertional angina controls (n = 19)
normal controls (n = 16)
[0711] Levels of serum sCD54 were significantly (p<0.01) higher
in unstable angina patients (217+/-14) than in stable exertional
angina (126+/-8) and normal (120+/-10) controls.
[0712] Polyarteritis Nodosa (Coll-Vinent et al 1997) TABLE-US-00226
PAN patients with active disease (n = 22) Healthy controls (n =
13)
[0713] Serum sCD54 levels were significantly (p<0.0001) elevated
in patients (488.5+/-201.3 ng/ml) as compared with controls. No
further numerical data given.
[0714] Inflammatory Bowel Disease (Goke et al 1997) TABLE-US-00227
Crohn's disease patients (n = 65) Ulcerative colitis patients (n =
28) Normal controls (n = 58)
[0715] Serum sCD54 levels were significantly elevated in both
Crohn's patients (420+/-19 ng/ml, p=0.0001) and UC patients
(375+/-40 ng/ml, p=0.0473) as compared with controls (297+/-8
ng/ml).
[0716] Leishmaniasis (Schriefer et al 1995) TABLE-US-00228 patients
(n = not specified) healthy controls (n = not specified)
[0717] Serum sCD54 levels were similar in healthy controls and in
patients refractory to treatment, but significantly higher in
patients responsive to treatment (p=0.02). In refractory patients
levels post-treatment were significantly higher than those
pre-treatment (p=0.03). The pre-treatment levels of sCD54 in
responders and patients refractory to antimonial therapy differed
significantly (p=0.02) suggesting that they could be used as
predictors of antimonial therapy response. No numerical data
given.
[0718] Endometriosis (Wu et al 1998) TABLE-US-00229 patients (n =
36) controls (n = 35)
[0719] Significantly increased serum sCD54 levels were found in
patients with endometriosis, especially in those with advanced
disease. No numerical data given.
[0720] Head and Neck Cancer (Liu et al 1999) TABLE-US-00230
Nasopharyngeal carcinoma (n = 30) Oral carcinoma (n = 22) Laryngeal
carcinoma (n = 22) Normal controls (n = 20)
[0721] Levels of serum sCD54 were significantly increased in
laryngeal carcinoma patients as compared with normal controls. No
numerical data given.
[0722] Myastenia Gravis (Tesar et al 1998) TABLE-US-00231 patients
(n = 20) controls (n = not specified)
[0723] Serum levels of sCD54 were higher in patients than in
controls. Levels fell substantially following plasmapheresis
therapy. No numerical data given.
[0724] Acute Stroke (Bitsch et al 1998) TABLE-US-00232 patients
with completed stroke (n = 26)
[0725] sCD54 levels peaked within 24 hrs (P=0.04). Levels did not
correlate with infarct volume or clinical disability. No further
numerical data given.
Smokers (Bergmann et al 1998)
[0726] Serum levels of sCD54 were significantly higher is smokers
than in non-smokers. No numerical data given.
Common Cold (Becker et al 1992)
[0727] Statistically significant relationship between reduced serum
sCD54 and frequency of common cold. No numerical data given.
[0728] B-Cell Chronic Lymphocytic Leukemia (Callea et al 1996)
TABLE-US-00233 advanced/progressive stage B-CLL (n = 37)
smouldering B-CLL (n = 10) Normal controls (n = 20)
[0729] Advanced/progressive stage B-CLL patients had significantly
higher levels of serum sCD54 than smouldering B-CLL and normal
controls. Levels directly correlated with tumour mass. No numerical
data given.
[0730] Multiple Sclerosis (Franciotta et al 1997) TABLE-US-00234
Clinically active MS patients (n = 16) Non-inflammatory
neurological disease (n = not stated) controls Normal healthy
cntrols (n = not stated)
[0731] Levels of serum sCD54 higher in MS patients than in
controls. Levels decreased following therapy
(6-methylprednisolone). No numerical data given.
[0732] Behcet's Disease (Uchio et al 1999) TABLE-US-00235 Normal
controls: (n = 20) Innactive Behcet's disease: (n = 15) Active
Behcet's disease: (n = 20)
[0733] Significantly increased levels of serum sCD54 were found in
the convalescent stage of the disease as compared with controls,
but not in the acute stage. No numerical data given.
[0734] NIDDM (Gasic et al 1999) TABLE-US-00236 microalbuminuric
NIDDM patients (n = 11) healthy controls (n = 82)
[0735] sCD54 was significantly higher in patients (p<0.001) as
compared with controls. No further numerical data given.
[0736] Metastatic Renal Cell Carcinoma (Hoffman et al 1999)
TABLE-US-00237 patients (n = 99)
[0737] Serum sCD54 levels>360 ng/ml was identified as a
pre-treatment risk factor. No numerical data given.
[0738] Rheumatoid Arthritis (Nasonov et al 1997) TABLE-US-00238
patients (n = 36) controls (n = not specified)
[0739] Serum levels of sCD54 were elevated in 74.2% of the
patients. No numerical data given.
[0740] Multiple Sclerosis (McDonnell et al 1999) TABLE-US-00239
primary progressive disease (PPMS) (n = 78) RRMS (n = 71) SPMS (n =
65) other neurological diseases (n = 66)
[0741] Levies of serum sCD54 were significantly elevated in PPMS
patients as compared with the other MS groups (vs SPMS, p=0.006, vs
RRMS in relapse, p=0.0001, vs RRMS in remission, p=0.0001). No
further numerical data given.
[0742] Intermediate Uveitis (Klok et al 1999) TABLE-US-00240 (a)
patients (n = 61) (b) patients with a systemic disease: 26 sarcoid
(n = 56) associated, 30 HLA-B27 associated (c) patients without
systemic disease: 30 toxoplasma (n = 58) chorioretinitis, 28 Fuch's
(d) normal controls (n = 21)
[0743] Increased sCD54 levels in 34/61 patients. These levels were
significantly different in groups (c) and (d), (p<0.001).
[0744] Radiation Pneumonitis (Ishii et al 1999) TABLE-US-00241 lung
malignancy patients receiving radiotherapy (n = 30)
[0745] 12/30 cases developed radiation pneumonitis following
radiotherapy. Serum levels of sCD54 were significantly elevated in
the pneumonitis group but not in the non-pneumonitis group (data
not given).
Tuberculosis (Behr-Perst 1999)
[0746] Increased levels of serum sCD54 were found in patients. No
numerical data given.
[0747] Diffuse Panbronchiolitis (Mukae et al 1997) TABLE-US-00242
DPB patients (n = 27) bronchiectasis patients (n = 13) normal
controls (n = 15)
[0748] Serum levels of sCD54 were significantly elevated in DPB
patients as compared with normal controls. No numerical data
given.
Multiple Sclerosis (Bilinska et al 1999)
[0749] Levels of sCD54 significantly increased in patients as
compared with normal controls. No numerical data given.
[0750] Non-Hodgkin's Lymphoma (Perez-Encinas et al 1999)
TABLE-US-00243 patients (n = 63)
[0751] In high grade patients sCD54 levels correlated with tumour
mass. No numerical data given.
[0752] Hepatitis C (Bagnasco et al 1998) TABLE-US-00244 Hepatitis C
patients (all treated with interferon) (n = 42) Long-term
responders (in remission) (n = 18) Non-responders/relapsers (n =
24)
[0753] Basal serum levels of sCD54 were significantly higher in
long-term responders than in non-responders/relapsers. Very high
levels of sCD54 (>1000 ng/ml) were closely associated with
long-term clinical response. No numerical data given. During
treatment, levels fell significantly in the responder group.
[0754] Metastatic Breast Carcinoma (Zhang et al 1999)
TABLE-US-00245 patients with metastatic breast cancer (n = 49)
[0755] Significantly higher serum levels of sCD54 were found in
patients with liver and/or bone metastases (p<0.05). Mean serum
sCD54 levels were significantly higher in patients with two or more
metastatic sites compared with one metastatic site (p=0.001). No
other numerical data given.
[0756] Psoriasis (Ameglio et al 1994) TABLE-US-00246 patients (n =
14) normal controls (n = 14)
[0757] Significant correlations were found between serum sCD54
levels and psoriasis area and severity index (R=0.62). No further
numerical data given.
[0758] Non-Small Cell Lung Cancer (De Vita et al 1998)
TABLE-US-00247 patients (n = 112)
[0759] Serum concentrations of sCD54 were related to tumour burden
and progression. No numerical data given.
[0760] Schistosoma mansoni Infection (Esterre et al 1998)
TABLE-US-00248 Patients (n = not specified)
[0761] Levels of serum sCD54 were increased in infected
individuals. Serum levels were furthermore significantly correlated
with disease severity. No numerical data given.
[0762] Ovarian Cysts and Tumours (Darai et al 1998) TABLE-US-00249
patients (ovarian carcinoma) (n = 11) patients (luteal cysts) (n =
23) patients (cystadenomas) (n = 29) patients (dermoid cysts) (n =
9) patients (borderline tumours) (n = 5) normal controls (n = not
stated)
[0763] Serum levels of sCD54 were significantly higher than normal
controls. No numerical data given.
[0764] Hepatitis B (Knolle et al 1997) TABLE-US-00250 patients
(with chronic hepatitis B) (n = 31)
[0765] Serum sCD54 levels correlated with delta AST (p=0.001) and
delta ALT (p=0.002).
[0766] Hepatitis C (Kaplanski et al 1997) TABLE-US-00251 patients
(n = 22) healthy seronegative controls (n = 20)
[0767] Serum sCD54 levels were significantly elevated in patients.
No numerical data given.
[0768] Scleroderma (Stratton et al 1998) TABLE-US-00252 patients (n
= not specified) controls (n = not specified)
[0769] Serum sCD54 were significantly raised both in limited
(p<0.001) and diffuse (p<0.001) scleroderma. No further
numerical data given.
[0770] Gastric Cancer (Beneldi et al 1998) TABLE-US-00253 Patients
with previously untreated gastroadenocarcinoma (n = 27) Healthy
controls (n = 18)
[0771] Serum sCD54 levels were significantly (p<0.0001) elevated
in patients as compared with normal controls. No further numerical
data given.
[0772] HIV-1 (Galea et al 1997) TABLE-US-00254 patients (n = not
specified) controls (n = not specified)
[0773] Serum sCD54 levels were elevated in HIV-1 patients. No
numerical data given.
[0774] Sarcoidosis (Mukae et al 1997) TABLE-US-00255 Patients (n =
not specified) Controls (n = not specified)
[0775] Serum levels of sCD54 were significantly elevated in
patients as compared with controls. No numerical data given.
[0776] Behcet's Disease (Uchio et al 1999) TABLE-US-00256 patients
(n = 20) normal controls (n = 20)
[0777] Patients in convalescent stage had significantly higher
serum sCD54 levels than those in the acute stage (no numerical data
given).
[0778] HIV-Associated Kaposi's Sarcoma (Becker et al 1997)
TABLE-US-00257 AIDS patients (suffering from acute infections) (n =
16) AIDS patiens (with Kaposi's sarcoma) (n = 23) AIDS patient
controls (free of active opportunistic disorders) (n = 15) healthy
HIV negative controls (n = 18)
[0779] Serum sCD54 levels were significantly (p<0.005) elevated
in all AIDS patients, irrespective of concurrent opportunistic
disorders. No numerical data given.
sCD56 (sNCAM)
[0780] Multiple Myeloma (Kaiser et al 1996) TABLE-US-00258 Multiple
myeloma (n = 125) Waldenstrom's disease (n = 20) Monoclonal
gammopathy unknown significance (n = 25)
[0781] Levels of serum sCD56 proved superior to those of serum
beta-2 microglobulin and IL6 in distinguishing multiple myeloma
from paraproteinemias of various causes, (specificity of 95.5%, but
a low sensitivity of 40%).
sCD58 (LFA-3)
[0782] Chronic Liver Disease (Hoffman et al 1996) TABLE-US-00259
chronic viral liver disease (n = 39) autommune liver disease (n =
30) alcoholic cirrhosis (n = 12) other types of cirrhosis (n = 3)
hepatocellular carcinoma (n = 24) normal controls (n = 61)
[0783] Serum levels of sCD58 were significantly elevated in
patients with liver cirrhosis due to autoimmune liver disease
(p<0.0001) and viral liver disease (p=0.001), but not in
patients with alcoholic cirrhosis. No further numerical data
given.
[0784] Inflammatory Bowel Disease (Hoffman et al 1996)
TABLE-US-00260 patients with Crohn's disease (n = 41) paatients
with ulcerative colitis (n = 19) normal controls (n = 24)
[0785] Serum sCD58 levels were significantly decreased in UC
patients (p=0.025) and even more sc in Crohn's disease patients
(p<0.0001) as compared with normal controls. Reduction in serum
sCD58 levels correlated significantly with various humoral (e.g.
ESR: r=-0.48, p=0.0002) an clinical (e.g. CDAI: r=-0.44, p=0.005)
parameters of disease activity.
[0786] Rheumatoid Arthritis (Hoffmann et al 1996) TABLE-US-00261 RA
patients (n = 60) Osteoarthritis patients (OA) (n = 13) patients
with psoriatic arthropathy (n = 16) patients with
spondylarthropathy (SpA) (n = 15) normal controls (n = 61)
[0787] Serum levels of sCD58 were significantly reduced in RA
patients as compared with normal controls (p<0.0001), OA
patients (p=0.019) and SpA patients (p<0.0001).
Common Cold (Becker et al 1992)
[0788] Statistically significant relationship between reduced sCD58
and occurrence of common cold. No numerical data given.
sCD62E (sELAM-1, E-Selectin)
[0789] Polyarteritis Nodosa (Coll-Vinent et al 1997) TABLE-US-00262
PAN patients with active disease (n = 22) Healthy controls (n =
13)
[0790] Serum sCD62E levels were significantly (p=0.003) elevated in
patients (60.6+/-27 ng/ml) as compared with controls. No further
numerical data given.
[0791] Advanced Renal Cell Carcinoma (Hobarth et al 1996)
TABLE-US-00263 patients (n = 16) healthy controls (n = 20)
[0792] Levels of serum sCD62E were significantly (p<0.01)
elevated in all patients (70 ng/ml) as compared with healthy
controls (17 ng/ml).
[0793] Acute Lymphoblastic Leukaemia (Hatzistilianou et al 1997)
TABLE-US-00264 ALL patients (n = 35) healthy controls (n = 35)
[0794] Levels of serum sCD62E were significantly (p<0.001)
elevated in patients (140.5+/-17.3 ng/ml) as compared with normal
controls (44.7+/-18.2 ng/ml). During remission following treatment,
levels did not differ significantly from controls. During relapse,
serum sCD62E levels were significantly (p<0.001) higher
(258.2+/-5.1 ng/ml) than those of the control gro and those at the
time of remission (p<0.001).
[0795] Pre-Eclampsia (Daniel et al 1998) TABLE-US-00265 patients (n
= 20) normotensive controls (n = 20)
[0796] The mean serum level of sCD62E was significantly (p<0.01)
higher in the pre-eclamptic group (61 ng/ml+/-30 ng/ml) than in
normotensive controls (40 ng/ml+/-17 ng/ml).
[0797] Sarcoidosis (Mukae et al 1997) TABLE-US-00266 Patients (n =
not specified) Controls (n = not specified)
[0798] Serum levels of sCD62E were significantly elevated in
patients as compared with controls. N numerical data given.
[0799] HIV-Associated Kaposi's Sarcoma (Becker et al 1997)
TABLE-US-00267 AIDS patients (suffering from acute infections) (n =
16) AIDS patiens (with Kaposi's sarcoma) (n = 23) AIDS patient
controls (free of active opportunistic disorders) (n = 15) healthy
HIV negative controls (n = 18)
[0800] Serum sCD62E levels were significantly decreased in the
Kaposi's sarcoma group as compared to both healthy (p=0.0007) and
ADIS controls (p=0.04). No numerical data given.
[0801] Kawasaki Disease (Takeshita et al 1997) TABLE-US-00268
Kawasaki patients (n = 16) Henoch-Schonlein purpura (n = 6) Healthy
controls (n = 10)
[0802] Serum levels of sCD62E were significantly (p<0.01) higher
in the acute phase of Kawasaki patients than in the other
groups.
[0803] Diffuse Panbronchiolitis (Mukae et al 1997) TABLE-US-00269
DPB patients (n = 27) bronchiectasis patients (n = 13) normal
controls (n = 15)
[0804] Serum levels of sCD62B were significantly elevated in DPB
patients as compared with norms controls. No numerical data
given.
[0805] Neuroimmunological Disorders (Sakai et al 1998)
TABLE-US-00270 MS patients (n = 35) Guillain-Barre syndrome
patients (GBS) (n = 18) Miller-Fisher syndrome patients (MFS) (n =
7) Chronic inflammatory demylenating (n = 8) myelopathy (CIDP)
Human T-lymphotropic virus type-1 (n = 25) associated myelopathy
(HAM) Controls (n = not specified)
[0806] Serum levels of sCD62E were significantly (p<0.05) higher
in HAM patients (37.6+/-25.7 ng/ml) as compared with controls.
[0807] Schistosoma mansoni Infection (Esterre et al 1998)
TABLE-US-00271 Patients (n = not specified)
[0808] Levels of serum sCD62E were increased in infected
individuals. No numerical data given.
[0809] Metastatic Breast Carcinoma (Zhang et al 1999)
TABLE-US-00272 patients with metastatic breast cancer (n = 49)
[0810] Significantly (p<0.05) higher serum levels of sCD62E were
found in patients with liver and/or bone metastases.
[0811] Acute Stroke (Bitsch et al 1998) TABLE-US-00273 patients
with completed stroke (n = 26)
[0812] sCD62E levels decreased significantly (p=0.002) after 5
days. Levels did not correlate with infarct volume or clinical
disability. No further numerical data given.
[0813] Scleroderma (Stratton et al 1998) TABLE-US-00274 patients (n
= not specified) controls (n = not specified)
[0814] Serum sCD62E levels were significantly elevated both in
limited (p<0.05) and diffuse (p<0.0001) scleroderma. No
further numerical data given.
[0815] Renal Cell Carcinoma (Dosquet et al 1997) TABLE-US-00275
patients n = 76 healthy controls n = 41
[0816] Levels of sCD62E were significantly lower in patients with
renal cell carcinoma than in controls. No numerical data given.
[0817] Head and Neck Cancer (Liu et al 1999) TABLE-US-00276
Nasopharyngeal carcinoma (n = 30) Oral carcinoma (n = 22) Laryngeal
carcinoma (n = 22) Normal controls (n = 20)
[0818] Levels of serum sCD62E were significantly increased in
laryngeal, oral and nasopharyngeal carcinoma. No numerical data
given
[0819] Systemic Sclerosis (Ihn et al 1998) TABLE-US-00277 patients
(n = 80) healthy controls (n = 20)
[0820] Serum levels of sCD62E were significantly higher in patients
than in controls. No numerical data given.
[0821] Gastric Cancer (Benekli et al 1998) TABLE-US-00278 Patients
with previously untreated (n = 27) gastroadenocarcinoma Healthy
controls (n = 18)
[0822] Serum sCD62E levels were significantly (p=0.033) elevated in
patients with peritoneal metastasis. Elevated levels were
associated with a poor prognosis. No further numerical data
given.
[0823] Graves' Disease (Hara et al 1996) TABLE-US-00279 Graves'
disease patients (n = not specified) Normal controls (n = not
specified)
[0824] Serum levels of sCD62E were significantly (p=0.033) higher
in patients than in normal controls. No further numerical data
given.
[0825] Hepatitis C (Kaplanski et al 1997) TABLE-US-00280 patients
(n = 22) healthy seronegative controls (n = 20)
[0826] Serum levels of sCD62E were significantly elevated in
patients. No numerical data given.
[0827] Ventilation Associated Pneumonia (Froon et al 1998)
TABLE-US-00281 patients (n = 42)
[0828] Serum levels of sCD62E increased from the day of diagnosis
onwards in patients who died within 10 days of diagnosis.
sCD62L (sL-Selectin)
[0829] Neuroimmunological Disorders (Sakai et al 1998)
TABLE-US-00282 MS patients (n = 35) Guillain-Barre syndrome
patients (GBS) (n = 18) Miller-Fisher syndrome patients (MFS) (n =
7) Chronic inflammatory demylenating myelopathy (n = 8) (CIDP)
Human T-lymphotropic virus type-1 associated (n = 25) myelopathy
(HAM) Normal controls (n = not specified)
[0830] Serum levels of ssCD62L were significantly (p<0.05)
higher in the active phase of the disease (2.20+/-0.6 mg/ml) as
compared with the inactive phase (0.6+/-0.25 mg/ml) and controls
(1.47+/-0.24 mg/ml).
[0831] Major Trauma (Muller et al 1998) TABLE-US-00283 patients
(with isolated moderate and severe head injuries) (n = 18) multiple
trauma patients without head injuries (n = 13) Healthy controls (n
= 22)
[0832] Serum levels of sCD62L were significantly (p<0.001)
decreased in trauma patients upon admission (5.7 pmol/ml+/-1.6) as
compared with normal controls (11 pmol/ml+/-1.7). In all patients,
levels remained suppressed throughout then study period.
[0833] Ulcerative Colitis (Seidelin et al 1998) TABLE-US-00284 UC
patients (n = not stated) Crohn's patients (n = not stated)
[0834] Serum sCD62L levels were found to be significantly
(p<0.001)-elevated in UC patients but not in patients with
Crohn's disease. UC patients with quiescent and severe disease
activity had significantly lower (p<0.005) and higher
(p<0.002) levels of sCD62L respectively. No numerical data
given.
[0835] Graves' Disease (Hara et al 1996) TABLE-US-00285 Graves'
disease patients (n = not specified) Normal controls (n = not
specified)
[0836] Serum sCD62L levels were significantly higher in patients
than in normal controls. No numerical data given.
[0837] Sarcoidosis (Mukae et al 1997) 122 TABLE-US-00286 Patients
(n = not specified) Controls (n = not specified)
[0838] Serum levels of sCD62L were significantly elevated in
patients as compared with controls. No numerical data given.
[0839] Autoimmune Rheumatic Disease (Sfikakis et al 1999)
TABLE-US-00287 Rheumatoid arthritis (RA), systemic sclerosis (SSc)
and SLE (n = 75) patients
[0840] sCD62L levels were significantly higher in SLE patients as
compared with controls. No numerical data given.
[0841] Diffuse Panbronchiolitis (Mukae et al 1997) TABLE-US-00288
DPB patients (n = 27) bronchiectasis patients (n = 13) normal
controls (n = 15)
[0842] Serum levels of sCD62L were significantly elevated in DPB
patients as compared with normal controls. No numerical data
given
[0843] Acute Lymphoblastic Leukemia (Olejnik et al 1999)
TABLE-US-00289 ALL patients (n = 30)
[0844] Serum sCD62L levels decreased significantly from the time of
diagnosis to the end of intensive chemotherapy and increased at the
time of relapse. No numerical data given.
[0845] Atopic Dermatitis (Shimada et al 1999) TABLE-US-00290 atopic
dermatitis patients (n = 70) contact dermatitis patients (n = 18)
psoriasis patients (n = 23) normal controls (n = 30)
[0846] Serum sCD62L levels were significantly elevated in atopic
dermatitis patients as compared with normal controls. Levels
correlated positively with disease severity. No numerical data
given.
sCD62P (sP-Selectin)
[0847] Acute Myocardial Infarction (Tomoda et 1998) TABLE-US-00291
AMI patients (undergoing angioplasty) (n = 20) AMI patients
(undergoing TPA thrombolytic therapy) (n = 10) Patients with stable
angina pectoris (undergoing angioplasty) (n = 10)
[0848] Serum sCD62P levels were significantly (p<0.001) elevated
in AMI patients (176.6 ng/ml+/-12.9) as compared with stable angina
patients (91.4 ng/ml+/-9.5). Serum sCD62P levels were significantly
(p<0.001) decreased following angioplasty in all 20 of the AMI
patients (from 176.2 ng/ml+/-17.17 to 141.7 ng/ml+/-12.6). Levels
increased significantly (p<0.005) in 90% 0f AMI patients
undergoing TPA thrombolytic therapy (from 177.4 ng/ml+/-17.2) to
248.8 ng/ml+/-17.3).
[0849] Inflammatory Bowel Disease (Goke et al 1997) TABLE-US-00292
Crohn's disease patients (n = 65) Ulcerative colitis patients (n =
28) Normal controls (n = 58)
[0850] Serum sCD62P levels were significantly (p=0.0067) elevated
in both Crohn's patients (399+/-33 ng/ml) and UC patients (385+/-42
ng/ml, p=0.0193) as compared with controls (251+/-33 ng/ml).
[0851] Neuroimmunological Disorders (Sakai et al 1998)
TABLE-US-00293 MS patients (n = 35) Guillain-Barre syndrome
patients (GBS) (n = 18) Miller-Fisher syndrome patients (MFS) (n =
7) Chronic inflammatory demylenating (n = 8) myelopathy (CIDP)
Human T-lymphotropic virus type-1 (n = 25) associated myelopathy
(HAM) Normal controls (n = not specified)
[0852] Serum levels of sCD62P were increased in the active phase of
MS (179.5+/-103.8 ng/ml), GBS (151.2+/-81.6 ng/ml), CIDP
(198.6+/-81.9 ng/ml) and HAM (115.3+/-73.5 ng/ml). No further
numerical data given.
[0853] Abdominal Aortic Aneurysm/Peripheral Arterial Disease (Blann
et al 1998) TABLE-US-00294 AAA patients (n = 21) peripheral arteril
disease patients (n = 42) healthy controls (n = 42)
[0854] Serum sCD62P values were increased in AAA patients
(p<0.01) and in peripheral arterial disease patients
(p<0.05). No numerical data given.
Atherosclerosis (Blann et al 1998)
[0855] Levels of serum sCD62P were elevated in peripheral arterial
disease. No other data given.
[0856] Kawasaki Disease (Takeshita et al 1997) TABLE-US-00295
Kawasaki patients (n = 16) Henoch-Schonlein purpura (n = 6) Healthy
controls (n = 10)
[0857] Serum levels of sCD62P were significantly (p<0.01) higher
in the subacute phase of Kawasak patients than in the other
groups.
[0858] Graves' Disease (Hara et al 1996) TABLE-US-00296 Graves'
disease patients (n = not specified) Normal controls (n = not
specified)
[0859] Serum sCD62P levels were significantly higher in patients
than in normal controls. No numerical data given.
[0860] Diffuse Panbronchiolitis (Mukae et al 1997) TABLE-US-00297
DPB patients (n = 27) bronchiectasis patients (n = 13) normal
controls (n = 15)
[0861] Serum levels of sCD62P were significantly elevated in DPB
patients as compared with normal controls. No numerical data
given.
[0862] Autoimmune Rheumatic Disease (Sfikakis et al 1999)
TABLE-US-00298 Rheumatoid arthritis (RA), systemic (n = 75)
sclerosis (SSc) and SLE patients
[0863] Serum sCD62P levels were significantly higher in RA and SSc
patients as compared with controls. No numerical data given.
[0864] Sarcoidosis (Mukae et al 1997) TABLE-US-00299 Patients (n =
not specified) Controls (n = not specified)
[0865] Serum levels of sCD62P were significantly elevated in
patients as compared with controls. No numerical data given.
[0866] Peripheral Arterial Occlusive Disease (Tsakiris et al 1999)
TABLE-US-00300 patients (n = 71)
[0867] Patients with predominantly femoropopliteal peripheral
arterial occlusive disease were investigated before and after
angioplasty (PT A). Serum sCD62P levels were found to be
statistically significant (p<0.01 at 6 months) indicative
factors for late restenosis in a logistic regression risk factor
analysis, with an overall predictive value of 72%. No numerical
data given.
sCD66b (Protein not Defined, But Member of CEA Family)
[0868] Tumour Patients (Grunert et al 1995) TABLE-US-00301 kidney
carcinoma patients (n = not specified) uterine carcinoma patients
(n = not specified) benign tumours patients (n = not specified)
inflammatory disease patients (n = not specified) healthy controls
(n = not specified)
[0869] Sensitivities of 40% have been determined for sCD66b in a
high percentage of patients with uterine and kidney carcinomas. CML
patients had sensitivities of 47%. No numerical data given.
sCD66c (NCA)
[0870] Tumour Patients (Grunert et al 1995) TABLE-US-00302 kidney
carcinoma patients (n = not specified) uterine carcinoma patients
(n = not specified) benign tumours patients (n = not specified)
inflammatory disease patients (n = not specified) healthy controls
(n = not specified)
[0871] In the sera of most patients suffering from solid tumours,
sensitivities for sCD66c are comparable to or lower than those for
CEA. The sensitivity was much higher in early colon tumour stages.
CML patients had sensitivities of 84%. No numerical data given.
sCD66e (CEA)
[0872] Gastric Cancer (Ogoshi et al 1998) TABLE-US-00303 gastric
cancer patients (post-resection) (n = 872)
[0873] Patients with detectable serum sCD66e who received
polysacchride K (PSK) immunotherapy had a significantly (p=0.0136)
higher survival rate than those not receiving therapy. No numerical
data given.
Cancer (Moser et al 1980)
[0874] Serum sCD66e is of value in the monitoring of cancer, as
values in the serum may rise before the progression of the disease
or relapse.
Breast Cancer (Hayes et al 1994)
[0875] Serum sCD66e provides an indication of the clinical course
of breast carcinoma. No further information given.
sCD71 (Transferrin Receptor)
[0876] Chronic Liver Disease (Nagral et al 1999) TABLE-US-00304
patients with iron deficiency anaemia (IDA) (n = 10) patients with
anaemia due to other causes (n = 16)
[0877] Median range of sCD71 is chronic liver disease patients with
IDA was significantly (p=0.01) higher (16.6 mg/ml, 11.2-24.8) than
that in patients with anaemia due to other causes (6.6 mg/ml
(11.2-24.8). The sensitivity of serum sCD71 levels for diagnosing
iron deficiency was 91.6%, with a specificity of 84.6%.
[0878] Chronic Lymphocytic Leukemia (CLL) (Beguin et al 1993)
TABLE-US-00305 CLL patients (n = 42) Normal controls (n = 31)
[0879] CLL patients had significantly (p<0.001) increased levels
of sCD71 (12,100+/-11,250 vs 5000+/-1050 ng/ml).
Haematological Malignancies (Takubo et al 1998)
[0880] No information given.
[0881] Chronic Transfusion (Tancabelic et al 1999) TABLE-US-00306
chronically transfused patients: (with sickle cell (SC) disease) (n
= 19) (with thalassemia) (n = 8)
[0882] Serum sCD71 were elevated in all SS patients, even when on
chronic transfusion, but were in the normal range in patients with
thalassemia.
[0883] Polycythemia (Manteiga et al 1998) TABLE-US-00307
Polycythemia vera patients (n = 22) Patients with secondary
polycythemia (n = 26)
[0884] Serum levels of sCD71 were elevated in both groups and
related to iron deficiency. No numerical data given.
Beta-Thalassemia (Gimferrer et al 1997)
[0885] Serum sCD71 levels are elevated in beta-thalassemia
patients. No numerical data given.
[0886] Aplastic Anaemia and Myelodystplastic Syndromes (Piedrs et
al 1998) TABLE-US-00308 patients with aplastic anaemia (n = 22)
patients with myelodystplastic syndromes (n = 31) Healthy controls
(n = 29)
[0887] Serum sCD71 levels were higher in treated than in untreated
anaemic patients. No numerical data given.
sCD73 (ecto-50-nucleotidase, 5'nucleotidase)
[0888] Breast Cancer (Walia et al 1995) TABLE-US-00309 patients (n
= 25) normal controls (n = 25)
[0889] Serum sCD73 levels was found to have a diagnostic
significance for breast cancer. After mastectomy a significant
decrease was found in serum levels of sCD73. No numerical data
given.
[0890] Graft-Versus-Host Disease in Bone Marrow Transplant
Recipients (Yasmineh et al 1989) TABLE-US-00310 group 1 -
autologous transplant controls (n = 22) group 2 - patients with no
GVHD (n = 33) group 3 - patients with grades 1 and 2 GVHD (n = 21)
group 4 - patients with grade 3 GVHD (n = 12) group 5 - patients
with grade 4 GVHD (n = 7)
[0891] Comparison between the 5 groups showed that serum sCD73 and
Alk phos were the best discriminants among all possible
combinations of group pairs.
[0892] Head and Neck Cancer (Lal et al 1989) TABLE-US-00311
patients (n = 50) controls (n = not specified)
[0893] Mean serum sCD73 levels were significantly higher in
patients as compared with controls. Activity was found to be
increased with the advancement in the stage of the cancer. No
numerical data given.
[0894] Chronic Liver and Biliary Disease (Longinov et al 1989)
TABLE-US-00312 patients with diffuse hepatic diseases with and
without (n = 86) cholestasis
[0895] High serum sCD73 was found in patients with cholestasis and
mechanical jaundice due to cancer of the prstatic head. A moderate
rise was seen in cases of active cirrhosis without cholestasis and
in choledocholithiasis.
[0896] Liver Cancer (Tozzoli et al 1988) TABLE-US-00313 patients (n
= 64) controls (n = not specified)
[0897] In primary liver cancer, the specificity of serum sCD73 was
100%. In secondary tumours it was 67%. Sensitivity was 75% and
90.5% respectively. No numerical data given.
sCD75 (Sialyltransferase)
[0898] Cancer (Licata et al 1982) TABLE-US-00314 Hyperparaathyroid
patients (n = 15) cancer patients without skeletal metastases (n =
10)
[0899] The mean serum sCD75 levels were significantly elevated
(p<0.005) in cancer patients (21.1, range 9-46.8) as compared
with hyperparathyroid patients (9.2, range 1-17.8).
[0900] Bronchial Carcinoma (Ronquist et al 1983) TABLE-US-00315
paatients with malignant pulmonary disease (n = 27) patients with
benign pulmonary disease (n = 14) patients with benign surgical
diseases (n = 56)
[0901] Mean serum sCD75 levels in bronchial carcinoma group were
significantly higher (583 cpm) than those in the benign surgical
disease control group (428 cpm). No further numerical data
given.
[0902] Alzheimer's Disease (Maguire et al 1994) TABLE-US-00316
Alzheimer's disease patients (n = not specified) Age matched
elderly controls (n = not specified) Young controls (n = not
specified)
[0903] Serum levels of sCD75 were significantly decreased in
patients as compared with controls. No numerical data given.
[0904] Multiple Myeloma (Cohen et al 1989) TABLE-US-00317 multiple
myeloma patients (n = 14) monoclonal gammopathy (of unknown (n = 7)
significance) patients controls (n = 10)
[0905] Serum sCD75 levels were significantly elevated in multiple
myeloma patients as compared with the other groups. No numerical
data given.
[0906] Brain Tumours (Shen et al 1984) TABLE-US-00318 patients (n =
not specified) normal controls (n = not specified)
[0907] Serum sCD75 levels were significantly elevated in the
pre-operative brain metastasis group.
[0908] Multiple Myeloma (Frithz et al 1985) TABLE-US-00319
untreated patients (n = 19) treated patients (n = 13) controls (n =
not specified)
[0909] Serum sCD75 levels were significantly elevated in patients.
Levels were significantly lower in patients treated for 1-30 months
with alkylating drugs and prednisolone. In untreated patients,
significantly higher levels were found in those (n=11) belonging to
stage III, than amongst the others (n=8) with stages I and II,
suggesting a link between serum levels and tumour burden. No
numerical data given.
Hepatic Disease (Watanabe et al 1983)
[0910] No information given.
[0911] Colon Adenocarcinoma (Griffiths et al 1982) TABLE-US-00320
patients (n = not specified) controls (n = not specified)
[0912] Serum sCD75 levies were elevated in patients. 86% of
patients with advanced metastatic disease had abnormal levels as
compared with 33% with no evidence of metastases. No numerical data
given.
Cancer (Moser et al 1980)
[0913] Serum sCD75 is of value in the monitoring of cancer, as
values in the serum may rise before the progression of the disease
or relapse.
Breast Cancer (Dao et al 1986)
[0914] No information given.
sCD87 (Urokinase Receptor, uPAR, suPAR)
[0915] Colorectal Cancer (Stephens et al 1999) TABLE-US-00321
pre-operative patients with colorectal cancer (n = 591) controls (n
= not specified)
[0916] Elevated serum sCD87 levels were significantly (p<0.0001)
associated with an increased risk of mortality. Serum sCD87 levels
independently predicted survival (p<0.0001). No numerical data
given.
sCD95 (Apo-1, Fas)
[0917] Renal Cell Cancer (Kimura et al 1999) TABLE-US-00322
patients (n = 72) healthy controls (n = 17)
[0918] 21/72 patients had elevated serum sCD95 levels. Survival
rates were significantly lower in the sCD95 elevated group. No
numerical data given.
[0919] Liver Transplantation (Seino et al 1999) TABLE-US-00323
patients (n = not specified) controls (n = not specified)
[0920] Serum sCD95 levels were significantly elevated in patients.
The increase in sCD95 was positively associated with the incidence
of infection, rejection and graft ischaemia. No numerical data
given.
[0921] HIV-1 Infection (Jiang et al 1997) TABLE-US-00324 Patients
(n = not specified) Controls (n = not specified)
[0922] Serum sCD95 levels were increased in HIV-1 patients as
compared with controls. No further data given.
sCD102 (ICAM-2)
[0923] HIV-1 (Galea et al 1997) TABLE-US-00325 patients (n = not
specified) controls (n = not specified)
[0924] Serum sCD102 levels are increased in HIV-1 patients as
compared with controls. Among an HIV-1 infected population, levels
were higher in an asymptomatic group compared with an AIDS group.
No numerical data given.
sCD106 (VCAM-1)
[0925] Polyarteritis Nodosa (Coll-Vinent et al 1997) TABLE-US-00326
PAN patients with active disease (n = 22) Healthy controls (n =
13)
[0926] Serum sCD106 levels were significantly (p=0.001) elevated in
patients (1176.5+/-514.1 ng/ml) as compared with controls. No
further numerical data given.
[0927] Acute Lymphoblastic Leukaemia (Hatzistilianou et al 1997)
TABLE-US-00327 ALL patients (n = 35) healthy controls (n = 35)
[0928] Levels of serum sCD106 were significantly (p<0.001)
elevated in patients (1786+/-151.8 ng/ml) as compared with normal
controls (798.6+/-78.9 ng/ml). During remission following
treatment, levels did not differ significantly from controls.
During relapse, serum sE-selectin levels were significantly
(p<0.001) higher (2945.7+/-349.9 ng/ml) than those of the
control group and those at the time of remission (p<0.001).
[0929] Inflammatory Bowel Disease (Goke et al 1997) TABLE-US-00328
Crohn's disease patients (n = 65) Ulcerative colitis patients (n =
28) Normal controls (n = 58)
[0930] Serum sCD106 levels were significantly elevated in both
Crohn's patients (664+/-43 ng/ml, p=0.0222) and UC patients
(963+/-162 ng/ml, p=0.0121) as compared with controls (510+/-31
ng/ml).
[0931] Non-insulin dependent diabetes mellitus (Yoshizawa et al
1998) patients (n=68) Patients with proliferative diabetic
retinopathy (n=11) showed a significant (p=0.02) increase in serum
sCD106 (1281.8+/-166.3) as compared with patients without signs of
retinopathy (978.8+/-48.9).
[0932] Takayasu Arteritis (Noguchi et al 1998) TABLE-US-00329
patients (n = 73) normal controls (n = 36)
[0933] Levels of serum sCD106 were significantly (p<0.01) higher
in patients (871.4 ng/ml) than in controls (607.9 ng/ml).
Multiple Sclerosis (Bilinska et al 1999)
[0934] Levels of serum sCD106 were significantly increased in
patients as compared with normal controls. No numerical data
given.
[0935] Non-Hodgkin's Lymphoma (Christiansen et al 1998)
TABLE-US-00330 NHL patients (n = 116) healthy controls (n = 31)
[0936] Levels of serum sCD106 was elevated in advanced stage
disease (stages III+IV) only.
[0937] Elevated levels were associated with significantly poorer
disease-free (p=0.024) and overall (p=0.02) survival.
[0938] HIV-Associated Kaposi's sarcoma (Becker et al 1997)
TABLE-US-00331 AIDS patients (suffering from acute infections) (n =
16) AIDS patiens (with Kaposi's sarcoma) (n = 23) AIDS patient
controls (free of active opportunistic disorders) (n = 15) healthy
HIV negative controls (n = 18)
[0939] Serum sCD106 levels were significantly (p<0.005) elevated
in all AIDS patients, irrespective of concurrent opportunistic
disorders. No numerical data given.
[0940] Diffuse Panbronchiolitis (Mukae et al 1997) TABLE-US-00332
DPB patients (n = 27) bronchiectasis patients (n = 13) normal
controls (n = 15)
[0941] Serum levels of sCD 106 were significantly elevated in DP13
patients as compared with normal controls. No numerical data
given.
[0942] Vernal Keratoconjunctivitis (Uchio et al 1999)
TABLE-US-00333 VKC patients (n = 30) allergic conjunctivitis
patients (n = 30) normal controls (n = 20)
[0943] Serum sCD106 levels were significantly higher in VKC
patients than in controls. No numerical data given.
[0944] Renal Cell Carcinoma (Dosquet et al 1997) TABLE-US-00334
patients n = 76 healthy controls n = 41
[0945] Levels of sCD106 were significantly higher in patients with
renal cell carcinoma than in controls. No numerical data given.
Seasonal Allergic Rhinitis (Masamoto et al 1999)
[0946] Serum sCD106 levels in patients were significantly higher
than those in nonatopic controls. No numerical data given.
[0947] Acute Stroke (Bitsch et al 1998) TABLE-US-00335 patients
with completed stroke (n = 26)
[0948] Serum sCD106 levels reached a maximum after 5 days (P=0.02).
Levels did not correlate with infarct volume or clinical
disability. No numerical data given.
[0949] Myastenia Gravis (Tesar et al 1998) TABLE-US-00336 patients
n = 20 controls n = not specified
[0950] Serum levels of sCD106 were higher in patients than controls
(no numerical data given). Levels fell substantially following
plasmapheresis therapy (no numerical data given).
[0951] Head and Neck Cancer (Liu et al 1999) TABLE-US-00337
Nasopharyngeal carcinoma (n = 30) Oral carcinoma (n = 22) Laryngeal
carcinoma (n = 22) Normal controls (n = 20)
[0952] Levels of serum sCD106 were significantly increased in
nasopharyngeal and laryngeal carcinoma. No numerical data
given.
[0953] Chronic B-Lymphocytic Leukaemia (Christiansen et al 1998)
TABLE-US-00338 patients (n = 106)
[0954] Serum levels of sCD106 reflected tumour burden more closely
than any other marker. It also showed elevated levels in
smouldering disease as compared with controls. Serum sCD106 levels
added independent prognostic information relating to survival
[0955] Systemic Sclerosis (Ihn et al 1998) TABLE-US-00339 patients
(n = 80) healthy controls (n = 20)
[0956] Serum levels of sCD106 were significantly higher in patients
than in controls. No numerical data given.
[0957] Hepatitis C (Kaplanski et al 1997) TABLE-US-00340 patients
(n = 22) healthy seronegative controls (n = 20)
[0958] Serum sCD106 levels were significantly elevated in patients.
No numerical data given.
[0959] Scleroderma (Stratton et al 1998) TABLE-US-00341 patients (n
= not specified) controls (n = not specified)
[0960] Serum sCD106 were significantly raised both in limited
(p<0.05) and diffuse (p<0.05) scleroderma. No further
numerical data given.
[0961] HIV-1 (Galea et al 1997) TABLE-US-00342 patients (n = not
specified) controls (n = not specified)
[0962] Serum sCD106 levels were increased in HIV-1 patients. No
numerical data given.
[0963] Hodgkin's Disease (Christiansen et al 1998) TABLE-US-00343
patients (n = 101) controls (n = 31)
[0964] Levels of serum sCD106 were significantly (p<0.0001)
elevated in patients as compared with controls. Levels correlated
with histology, stage, B-symptoms, and prognostic markers. No
further numerical data given.
[0965] Vernal Keratoconjunctivitis (Uchio et al 1999)
TABLE-US-00344 patients (n = 30) normal controls (n = 20)
[0966] Serum levels of sCD106 in patients were significantly higher
than those in controls. No numerical data given.
sCD117 (Soluble c-Kit)
[0967] Delayed Engraftment in Bone Marrow Transplantation (Hashino
et al 1997) TABLE-US-00345 patients undergoing BMT (n = 28)
[0968] Serum sCD117 levels in patients undergoing delayed
engraftment were significantly lower than those with early
engraftment. No numerical data given.
sCD120a (sTNFR-I)
[0969] Breast Cancer (Tesarova et al 1998) TABLE-US-00346 breast
cancer patients with various stages of disease (n = 31) controls (n
= not specified)
[0970] Serum levels of sCD120a were significantly (p<0.001)
higher in patients with breast cancer (2166.6+/-568.9 pg/ml) than
in controls (1121.3+/-260.6 pg/ml).
[0971] Guillain-Barre Syndrome (Patzold et al 1998) TABLE-US-00347
GBS patients (n = 18) Multiple sclerosis patient controls (n = 50)
Healthy controls (n = not stated)
[0972] Serum sCD120a levels were significantly higher in GBS
patients (1544 pg/ml SD 834) than in healthy controls (918 pg/ml SD
180) or MS patients (1064 pg/ml SD 262). No further numerical data
given.
[0973] Pre-Eclampsia/Eclampsia (Williams et al 1998) TABLE-US-00348
pregnant women with eclampsia (n = 33) pregnant women with
pre-eclampsia (n = 138) pregnant women normotentive controls (n =
185)
[0974] Levels of serum sCD120a were significantly (p<0.001)
higher in women with eclampsia (1.87 ng/ml) than in controls (1.35
ng/ml). Levels were also significantly (p<0.001) higher in
pre-eclampsic women (1.69 ng/ml) than in controls (1.35 ng/ml).
[0975] HIV (Sulkowski et al 1998) TABLE-US-00349 patients (n =
32)
[0976] Changes in serum HIV RNA were significantly associated with
changes in sCD120a. No numerical data given.
[0977] Partial Liver Resection (Schroder et al 1998) TABLE-US-00350
patients (n = not stated)
[0978] Uncomplicated liver resections were associated with a
prolonged and significantly increased release of sCD120a until the
3rd post-operative day. No numerical data given.
[0979] Septic Shock (Fraunbergerr et al 1998) TABLE-US-00351
Patients (n = not stated) Healthy controls (n = not stated)
[0980] Patients with septic shock had significantly elevated levels
of serum sCD120a as compared with healthy controls. No numerical
data given.
[0981] Neonatal Sepsis (Doelllner et al 1998) TABLE-US-00352 septic
patients (n = 22) non-infected neonate controls (n = 127)
[0982] Both pre-term and term infected neonates had significantly
(p<0.01) higher serum levels of sCD120a. No numerical data
given.
[0983] Systemic Lupus Erythematosus (Gabay et al 1997)
TABLE-US-00353 SLE patients (n = 73) RA patients (n = 42) SpA
patients (n = 18)
[0984] Levels of serum sCD120a were significantly higher in SLE
patients than in the other groups. Levels correlated with disease
activity. No numerical data given.
[0985] Pancreatic Cancer (Barber et al 1999) TABLE-US-00354
patients (n = 13) healthy controls (n = 6)
[0986] Serum sCD120a levels were significantly higher in patients
than in healthy controls. No numerical data given.
sCD120b (sTNFR-II)
[0987] Breast Cancer (Tesarova et al 1998) TABLE-US-00355 breast
cancer patients with various stages of disease (n = 31) controls (n
= not specified)
[0988] Serum levels of sCD120b were significantly (p<0.001)
higher in patients with breast cancer (3792.8+/-958.9 pg/ml) than
in controls (1996.2+/-404.3 pg/ml).
[0989] HIV (Sulkowski et al 1998) TABLE-US-00356 patients (n =
32)
[0990] Changes in serum HIV RNA were significantly associated with
changes in serum sCD120b. No numerical data given.
[0991] Renal Disease (Tesar et al 1998) TABLE-US-00357 patients
with ANCA-A +'ve renal vasculitis (AARV) (n = 12) Patients with
active lupus nephritis (LN) (n = 9) healthy subjects (n = 5)
[0992] Patients with LN and AARV had significantly elevated serum
sCD120b levels as compared with controls. No numerical data
given.
[0993] Partial Liver Resection (Schroder et al 1998) TABLE-US-00358
patients (n = not stated)
[0994] Uncomplicated liver resections were associated with a
prolonged and significantly increased release of serum sCD120b
until the 5th post-operative day. No numerical data given.
[0995] Septic Shock (Fraunbergerr et al 1998) TABLE-US-00359
Patients (n = not stated) Healthy controls (n = not stated)
[0996] Patients with septic shock had significantly elevated levels
of serum sCD120b as compared with healthy controls. No numerical
data given.
[0997] Neonatal Sepsis (Doelllner et al 1998) TABLE-US-00360 septic
patients (n = 22) non-infected neonate controls (n = 127)
[0998] Both pre-term (p=0.01) and term (p=0.05) infected neonates
had higher serum levels of sCD120b. No numerical data given.
[0999] Atherosclerosis (Blann et al 1998) TABLE-US-00361 patients
with peripheral vascular disease (n = 20) survivors of myocardial
infarction (n = 20) healthy controls (n = 20)
[1000] Levels of sCD120b were significantly (p<0.01) elevated in
both patient groups. No numerical data given.
[1001] Pancreatic Cancer (Barber et al 1999) TABLE-US-00362
patients (n = 13) healthy controls (n = 6)
[1002] Serum sTNFR-II levels were significantly higher in patients
than in controls. No numerical data given.
sCD122 (sIL-2Rb)
[1003] HIV (Sulkowski et al 1998) TABLE-US-00363 patients (n =
32)
[1004] Changes in serum HIV RNA were significantly associated with
changes in sCD122. No numerical data given.
sCD124 (sIL-4R)
[1005] Visceral Leishmaniasis (Sang et al 1999) TABLE-US-00364
Patients (n = not specified) Controls (n = not specified)
[1006] Patients have 8- to 10-fold more serum sCD124 than
uninfected controls and patients with documented filariasis. No
numerical data given.
[1007] Plasmodium falciparum Malaria (Jakobsen et al 1996)
TABLE-US-00365 patients with p. falciparum malaria (n = not
specified) asymptomatic p. falciparum controls (n = not specified)
healthy controls (n = not specified)
[1008] Higher levels of serum sCD124 were found in patients with
malaria as compared with controls. No numerical data given.
sCD126 (sIL-6R)
[1009] Adult T-Cell Leukaemia (Horriuchi et al 1998) TABLE-US-00366
ATL patients (n = 12) healthy controls (n = 23)
[1010] Serum levels of sCD126 were significantly (p<0.0001)
higher in ATL patients (28.7+/-20.4 ng/ml) than in healthy controls
(4.5+/-2.1 ng/ml).
[1011] Multiple Myeloma (Stasi et al 1998) TABLE-US-00367 patients
with multiple myeloma (MM) (n = 164) patients with monoclonal
gammopathy of (n = 81) undetermined significance (MGUS) normal
controls (n = 55)
[1012] Serum sCD126 levels were significantly elevated in MM
patients (162+/-134.6 ng/ml) as compared with MGUS controls
(58.9+/-36.7 ng/ml) or normal controls (45.6+/-22.3 ng/ml). No
further numerical data given.
[1013] Immunotherapy Following Bone Marrow Transplantation (Toren
et al 1996) TABLE-US-00368 patients (who received cytokine-mediated
(n = 15) immunotherapy) patients (who received cell-mediated (n =
15) immunotherapy) normal controls (n = not specified)
[1014] Serum sCD126 levels increased significantly (p<0.05)
during cytokine-mediated immunotherapy (74+/-9 ng/ml) as compared
with pre-immunotherapy (46+/-6 ng/ml) and post-immunotherapy
(50+/-9 ng/ml) levels. Levels were also significantly increased
(p<0.05) following cell-mediated immunotherapy (87+/-3 ng/ml vs
60+/-2 ng/ml).
[1015] HTLV-1 Associated myelopathy (Horriuchi et al 1998)
TABLE-US-00369 patients (n = 13) healthy controls (n = 23)
[1016] Serum levels of sCD126 were significantly (p<0.0001)
higher in ATL patients (27.5+/-12.1 ng/1 ml) than in healthy
controls (4.5+/-2.1 ng/ml).
[1017] Multiple Myeloma (Kyrtsonis et al 1996) TABLE-US-00370 MM
patients (n = 80) normal controls (n = 25)
[1018] Serum sCD126 levels were significantly (p<0.01) elevated
in patients (38 ng/ml, range 10-200) as compared with normal
controls (28 ng/ml, range 1440). Median serum sIL-6R at diagnosis
was significantly (p<0.001) higher in non-responding patients
(82 ng/ml, range 20-200) than in responding patients (36 ng/ml,
range 10-120). High serum sCD126 levels correlated with poor
survival.
[1019] Severe Plasmodium Falciparum Malaria (Wenisch et al 1999)
TABLE-US-00371 total number of patients with malaria (n = 32)
patients with cerebral malaria (n = 8) patients with assocaited
renal failure (n = 10)
[1020] Serum sCD126 levels were significantly higher in the
cerebral malaria and associated renal failure groups than in the
others (p<0.01 for both). No numerical data given.
[1021] Bronchial Asthma (Yokoyama et al 1997) TABLE-US-00372
patients with stable asthma (n = 20) patients with a spontaneous
attack of asthma (n = 10) healthy controls (n = 18)
[1022] Serum levels of sCD126 were significantly (p<0.05)
elevated in asthmatic patients (132+/-3: ng/ml) as compared with
healthy controls (111+/-16 ng/ml). Levels were significantly
elevated 2 and 3 days following an acute attack as compared to the
stable state. No further numerical data given.
[1023] Rheumatoid Arthritis (Kuryliszyn-Moskal et al 1998)
TABLE-US-00373 patients (n = 80) healthy controls (n = 30)
[1024] Serum levels of sCD126 were significantly higher in RA
patients than in controls. No numerical data given.
[1025] Neuroleptic Treatment in Schizophrenia (Muller et al 1997)
TABLE-US-00374 schizophrenic patients (n = 39) healthy controls (n
= 42)
[1026] During neuroleptic treatment there was a significant
decrease in sCD126 levels. No further numerical data given.
[1027] Major Depression (Sluzewska et al 1996) TABLE-US-00375
patients (n = 49) normal controls (n = 15)
[1028] Serum sCD126 levels were significantly elevated in patients
as compared with controls. No further numerical data given.
[1029] Rheumatoid Arthritis (Robak et al 1998) TABLE-US-00376
patients (n = 66) healthy controls (n = 24)
[1030] Patients with stage 3 and 4 of RA activity had significantly
higher levels of serum sCD126 than controls. No numerical data
given.
[1031] Periodontitis (Pietruska et al 1998) TABLE-US-00377 patients
(n = 15)
[1032] Levels of serum sCD126 were significantly increased in
patients. No numerical data given.
[1033] Acute Pyelonephritis (Jacobson et al 1998) TABLE-US-00378
patients (n = 29) healthy controls (n = 12)
[1034] 2 weeks post-infection and following antibiotic treatment,
serum sCD126 levels in patients was significantly higher than it
was on admission (p<0.001), and significantly higher than levels
in controls (p=0.001). Patients with increased levels of sCD126 at
2 weeks had significantly lower GFR at follow-up (p<0.05).
Patients infected by strains producing hemolysin had lower
concentrations of sIL-6r (p<0.001). No numerical values,
given.
[1035] Plasma Cell Dyscrasias (Zhao et al 1997) TABLE-US-00379
patients with multiple myeloma (MM) (n = 62) patients with
macroglobulinemia (Mac) (n = 5) patient with mu heavy chain disease
(HCD) (n = 1) healthy controls (n = 15)
[1036] Serum sCD126 levels in Mac and MM stage II and III were
significantly (p<0.01) higher than those in MM stage I and
healthy controls. Serum sCD126 levels were furthermore
significantly (p<0.01) higher in MM stage III as compared with
stage II. No numerical data given.
[1037] Multiple Myeloma (Wierzbowska et al 1999) TABLE-US-00380 MM
patients (n = 67) healthy controls (n = 24)
[1038] Serum sCD126 was detectable in 97% of patients. Levels were
significantly (p<0.001) higher in MM patients as compared with
controls. No numerical data given.
[1039] Multiple Myeloma (Usnarska-Zubkiewicz et al 1998)
TABLE-US-00381 MM patients (n = 36) healthy controls (n = not
specified)
[1040] Serum sCD126 levels were significantly higher in patients
than in controls. No numerical data given.
[1041] Renal Disease (Tesar et al 1998) TABLE-US-00382 patients
with ANCA-A +'ve renal vasculitis (AARV) (n = 12) Patients with
active lupus nephritis (LN) (n = 9) healthy subjects (n = 5)
[1042] Patients with LN and AARV had significantly elevated serum
sCD126 levels as compared with controls. No numerical data
given.
[1043] Juvenile Chronic Arthritis (Keul et al 1998) TABLE-US-00383
patients (n = 54) controls (n = 10)
[1044] Serum sCD126 levels were significantly elevated in patients
as compared with controls. No numerical data given.
sCD137 (41-BR)
[1045] Rheumatoid Arthritis (Michel et al 1998) TABLE-US-00384 RA
patients (n = 12) Healthy controls (n = 12)
[1046] Serum levies of sCD137 were significantly elevated in RA
patients (3.58 ng/ml, present in 12/12 patients), as compared with
controls (0.18 ng/ml, present in 5/12 individuals).
sCD141 (Thrombomodulin, TM)
[1047] Respiratory Distress Syndrome (Distefano et al 1998)
TABLE-US-00385 patients with RDS (n = 18) controls (n = not
specified)
[1048] Serum sCD141 levels were significantly (p<0.05) elevated
in patients (276.1 ng/ml) as compared with controls (141.3 ng/ml).
Levels in mechanically ventilated babies with severe RDS were
significantly (p<0.05) higher than those with moderate RDS and
treated with CPA(340.9 ng/ml vs 174.2 ng/ml).
[1049] Ischaemic Heart Disease (Blann et al 1997) TABLE-US-00386
patients (following myocardial infarction) (n = 54) patients from
above group who experienced another (n = 24) MI within 49
months
[1050] Serum sCD141 was 65+/-24 ng/ml in patients who suffered an
end-point and 49+/-19 ng/ml in patients who were free of an end
point (p=0.009).
[1051] Coronary Heart Disease (Salomaa et al 1999) TABLE-US-00387
patients with coronary heart disease (n = 258) patients with
carotid atherosclerosis (n = 449) controls (n = 753)
[1052] Serum sCD141 showed a strong, graded, inverse association
(p=0.005) with coronary heart disease. A high level of serum sCD141
may thus be associated with a decreased risk for coronary heart
disease.
[1053] Peripheral Occlusive Arterial Disease (Seigneur et al 1995)
TABLE-US-00388 patients (n = not specified) controls (n = not
specified)
[1054] Serum levels of sCD141 were closely related both to
transcutaneous oxygen pressure (p=0.01.degree. and the graded
clinical stages of the disease (p=0.02).
Heparin Therapy (Cella et al 1997)
[1055] Exogenous heparing reduces serum sCD141 levels. No numerical
data given
[1056] Cerebral Thrombosis (Seki et al 1997) TABLE-US-00389
patients with cerebral thrombosis (within 3 days of onset) (n = 28)
patients with cerebral thrombosis (more than 1 months after (n =
36) onset) patients with cerebral thrombosis (more than 3 months
after (n = 6) onset) healthy volunteers (n = 37)
[1057] In patients with chronic phase thrombosis serum sCD141
levels were significantly higher than in controls. No numerical
data given.
sCD143 (ACE)
[1058] Sarcoidosis (Mukae et al 1997) TABLE-US-00390 Patients (n =
not specified) Controls (n = not specified)
[1059] A significant correlation was found between serum sCD143,
sICAM-1 and sVCAM-1. No numerical data given.
sCD154 (CD40L)
[1060] Chronic Lymphocytic Leukaemia (Younes et al 1998)
TABLE-US-00391 CLL patients (n = 51) healthy donors (n = 55)
[1061] Serum sCD154 levels were significantly (p<0.001) elevated
in patients (0.8 ng/ml) as compared with normal donors (0.29
ng/ml).
sCD157 (BST-1)
[1062] Rheumatoid Arthritis (Lee et al 1996) TABLE-US-00392 RA
patients (n = 143) healthy controls (n = not specified)
[1063] In 7% of RA patients ( 10/143), concentrations of serum
sCD157 were approximately 30 to 50 fold higher than in non-RA
samples.
* * * * *
References