مجال
التميز
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التميز البحثي والدراسي
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البحوث المنشورة
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البحث (1):
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عنوان البحث:
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Use of ruxolitinib to successfully treat chronic mucocutaneous
candidiasis caused by gain-of-function signal transducer and activator of
transcription 1 (STAT1) mutation
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رابط إلى البحث:
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تاريخ النشر:
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February
2015
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موجز عن البحث:
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Recently, Xing et al1
demonstrated the role of cytotoxic T lymphocytes in alopecia areata (AA) and
provided important mechanistic information on the pathogenic T-cell
inflammatory pathways in patients with this autoimmune condition. They
described 3 patients with AA successfully treated with the oral Janus kinase
(JAK) family protein tyrosine kinase inhibitor ruxolitinib. The inhibitory
effectiveness of this small molecule in vitro was also reported
in a novel interferonopathy coined stimulator of interferon genes
(STING)–associated vasculopathy, which is caused by a gain-of-function (GOF)
mutation in the TMEM173 gene encoding STING, resulting in
hyperactivation of the signal transducer and activator of transcription
(STAT) 1/STAT2 signaling pathways.
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البحث ( 2 ):
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عنوان البحث:
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Antiphosphatidylserine antibodies as diagnostic indicators of
antiphospholipid syndrome
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رابط إلى البحث:
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تاريخ النشر:
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February
2015
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موجز عن البحث:
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BACKGROUND:
Antiphospholipid syndrome (APS) is an autoimmune condition that
is diagnosed by the presence of at least one of the clinical manifestations
(thrombosis and/or pregnancy failure) and one of antiphospholipid antibodies
(aPL) laboratory tests. The most relevant aPL are lupus anticoagulant (LA),
anti-beta2 glycoprotein I (aβ2GPI) and anticardiolipin (aCL). The clinical
significance of other antibodies like anti-phosphatidylserine antibodies
(aPS) is still under investigation.
OBJECTIVES:
The aim of the study was to assess the diagnostic value of aPS
antibodies, and to compare their utility to that of other aPL antibodies.
METHODS:
We conducted a prospective observational study consisting of 212
patients with suspected thrombosis, pregnancy failure, or unexplained,
prolonged clotting time. Data on demography, clinical presentation and
autoantibody levels were assessed. Descriptive analysis, accuracy analysis,
sensitivity, specificity, predictive value and likelihood ratio were
calculated for aPS in comparison to other aPL.
RESULTS:
The diagnostic value of aPS versus other aPL antibodies revealed
the high specificity of aPS (87%), with 70% of aPS-positive patients being
confirmed APS. When the aPS test was used as a single test, it was effective
for detection of confirmed APS cases (p < 0.01). Among 28 confirmed
primary APS cases, 75% of patients were positive for aPS (p < 0.003). Moreover,
by using aPS we detected three additional confirmed APS cases and another
three probable cases.
CONCLUSION:
Our findings reveal a significant association between aPS and
APS, especially when used to diagnosis clinical cases with other negative aPL
tests. There is an independent association between aPS and primary APS. In
addition, these results demonstrated the advantages of using aPS as a
diagnostic test for APS.
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البحث (3):
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عنوان البحث:
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Gain-of-function STAT1 mutations impair STAT3
activity in patients with chronic mucocutaneous candidiasis (CMC)
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رابط إلى البحث:
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تاريخ النشر:
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01/10/2015
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موجز عن البحث:
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Signal transducer and activator of transcription 3
(STAT3) triggered production of Th-17 cytokines mediates protective immunity
against fungi. Mutations affecting the STAT3/interleukin 17 (IL-17) pathway
cause selective susceptibility to fungal (Candida) infections, a hallmark of
chronic mucocutaneous candidiasis (CMC). In patients with autosomal dominant
CMC, we and others previously reported defective Th17 responses and
underlying gain-of-function (GOF) STAT1 mutations, but how this affects STAT3
function leading to decreased IL-17 is unclear. We also assessed how
GOF-STAT1 mutations affect STAT3 activation, DNA binding, gene expression,
cytokine production, and epigenetic modifications. We excluded impaired STAT3
phosphorylation, nuclear translocation, and sequestration of STAT3 into
STAT1/STAT3 heterodimers and confirm significantly reduced transcription of
STAT3-inducible genes (RORC/IL-17/IL-22/IL-10/c-Fos/SOCS3/c-Myc) as likely
underlying mechanism. STAT binding to the high affinity sis-inducible element
was intact but binding to an endogenous STAT3 DNA target was impaired.
Reduced STAT3-dependent gene transcription was reversed by inhibiting STAT1
activation with fludarabine or enhancing histone, but not STAT1 or STAT3
acetylation with histone deacetylase (HDAC) inhibitors trichostatin A or
ITF2357. Silencing HDAC1, HDAC2, and HDAC3 indicated a role for HDAC1 and 2.
Reduced STAT3-dependent gene transcription underlies low Th-17 responses in
GOF-STAT1 CMC, which can be reversed by inhibiting acetylation, offering
novel targets for future therapies.
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البحث (4):
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عنوان البحث:
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Oesophageal candidiasis and squamous cell cancer in
patients with gain-of-function STAT1 gene mutation
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رابط إلى البحث:
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تاريخ النشر:
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06/12/2016
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موجز عن البحث:
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Background:
Oesophageal
candidiasis is a common, usually self-limiting opportunistic infection, but
long-term infection with Candida is known to predispose to
oral and oesophageal squamous cell cancer (SCC). Permissive factors that lead
to immune deficiencies can underlie persistent or recurring candidiasis,
called chronic mucocutaneous candidiasis (CMC). Secondary immune deficiencies
are most often due to human immunodeficiency virus (HIV) infection,
antibiotic use and immunosuppressive treatment (steroids, chemotherapy).
Inborn errors of the immune system (primary immune deficiencies) can present
with isolated CMC known as CMC disease (CMCD), which is most often found in
patients with autoimmune polyendocrinopathy syndrome type 1 (APS1)/APECED or
in patients with an underlying gain-of-function STAT1 mutation (GOF-STAT1).
Objective:
To
describe a new form of inherited/familial CMC with a high risk for developing
squamous cell carcinoma of the oesophagus, due to a gain-of-function mutation
in the STAT1 gene.
Methods and Results:
This
report describes a family of patients with CMC with confirmed GOF-STAT1
mutation. These patients usually present with CMCD in childhood, have severe
oral and oesophageal candidiasis accompanied by severe difficulty swallowing,
chest pain, heartburn, and are at risk of developing oral and/or oesophageal
SCC. This case series describes six patients in three generations of the same
family, two of whom developed and died of SCC. We recommend regular
endoscopic surveillance to detect early oesophageal neoplasia in patients
with CMCD as well as urgent endoscopy in symptomatic patients.
Conclusion:
CMC is
not a well-recognised condition in gastroenterology practice and clinicians
need to be aware of the genetics of the condition as well as the risk for
oesophageal cancer so that they can counsel their patients and arrange
surveillance appropriately.
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البحث
(5): |
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عنوان
البحث: |
Double
Trouble? CMC with a Mutation in both AIRE and STAT1 |
رابط
إلى البحث: |
Click Here
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تاريخ
النشر: |
27
July 2018 |
موجز
عن البحث: |
To the
Editor,
We
report the case of a patient presenting with chronic muco- cutaneous
candidiasis (CMC) and mutations in both the auto- immune regulator (AIRE) and
signal transducer and activator of transcription 1 (STAT1) genes.
Conclusion
In patients with CMC
heterozygous for a mutation in AIRE, especially patients who lack anti-cytokine
antibodies, a mutation in a second gene such as STAT1 should be considered,
particularly now that knowledge of the molecular basis of CMC may influence
treatment strategy. |
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المؤتمر (1):
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عنوان المؤتمر:
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The UK Primary Immunodeficiency Network Meeting 2015
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تاريخ الإنعقاد:
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19/11/2015
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مكان
الإنعقاد:
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Belfast, Northern
Ireland
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طبيعة المشاركة:
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Poster presentation
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عنوان المشاركة:
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Is gain-of-function STAT1 CMC an Interferonopathy?
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ملخص المشاركة:
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Introduction: The type I interferonopathies represent a newly
defined class of disease where tissue damage is hypothetically caused by
excessive type I interferon (IFN) signalling (Aicardi-Goutieres syndrome,
SPENCD, SAVI syndrome etc.). Gain of function (GOF) STAT1 mutations underlie
chronic mucocutaneous candidiasis (CMC), a primary immune deficiency where
patients display susceptibility to fungal/bacterial/viral infections but also
demonstrate autoimmune phenomenon (hypothyroidism, alopecia, vitiligo) and a
vasculopathy (intracranial aneurysms). The associated mutations lead to
increased activity of STAT1, a protein central to signalling of both IFN type
1 (IFNα) and type 2 (IFNγ). Enhanced responses to the latter molecules are
believed to be responsible for CMC, whilst an effect of excessive IFNα
signalling has not been explored. We hypothesised that the disease state due
to underlying GOFSTAT1 mutations might also include features consequent upon enhanced
type I interferon signalling. Methods: in 11 patients with CMC (9 with
GOFSTAT1 mutations, 2 without) and 2 healthy siblings we assessed IFNα status
by measuring: 1) whole blood ex vivo expression of IFN stimulated genes (ISG)
IFI27, IFI44L, IFIT1, ISG15, RSAD2 and SIGLEC1 by qRTPCR and 2) STAT1
phosphorylation of IFNα stimulated patient cells. Results: 7/9 GOFSTAT1
patients demonstrated ISG upregulation albeit at lower levels than reported
for interferonopathies, whilst 2/9 did not. All GOFSTAT1 patients showed
increased STAT1 phosphorylation following IFNα stimulation. CMC patients
without STAT1 mutations, healthy siblings and controls did not demonstrate
increased responses to IFNα. Conclusion: Our findings suggest that enhanced
IFNα signalling may be relevant to some pathology associated with GOF
mutations in STAT1.
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المؤتمر (2):
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عنوان المؤتمر:
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9th Saudi Students’ Conference
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تاريخ الإنعقاد:
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19/11/2015
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مكان
الإنعقاد:
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Birmingham,
UK
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طبيعة المشاركة:
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Poster presentation
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عنوان المشاركة:
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Is gain-of-function STAT1 CMC an Interferonopathy?
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ملخص المشاركة:
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Introduction: The
type I interferonopathies represent a newly defined class of disease where
tissue damage is hypothetically caused by excessive type I interferon (IFN)
signalling (Aicardi-Goutieres syndrome, SPENCD, SAVI syndrome etc.).
Gain-of-function (GOF) STAT1
mutations underlay chronic mucocutaneous candidiasis (CMC), a primary immune
deficiency where patients display susceptibility to fungal/bacterial/viral
infections but also demonstrate autoimmune phenomenon (hypothyroidism,
alopecia, vitiligo) and a vasculopathy (intracranial aneurysms). The
associated mutations lead to increased activity of STAT1, a protein central
to signalling of both IFN type 1 (IFNα) and type 2 (IFNγ). Enhanced response
to the latter molecule is believed to be responsible for CMC, whilst an
effect of excessive IFNα signalling has not been explored. We hypothesised
that the disease state due to underlying GOF-STAT1 mutations might also include features consequent upon
enhanced type I interferon signalling.
Methods: in 11
patients with CMC (9 with GOF-STAT1
mutations, 2 without) and 2 healthy siblings we assessed IFNα status by
measuring: 1) whole blood ex-vivo
interferon signature for IFN-stimulated genes (ISG) IFI27, IFI44L, IFIT1,
ISG15, RSAD2 and SIGLEC1 by qRT-PCR and 2) STAT1 phosphorylation of IFNα
stimulated patient cells.
Results: 7/9
GOF-STAT1 patients demonstrated ISG
upregulation albeit to lower levels than reported for interferonopathies,
whilst 2/9 did not. All GOF-STAT1
patients showed increased STAT1 phosphorylation following IFNα stimulation.
CMC patients without STAT1
mutations, healthy siblings and controls did not demonstrate increased responses
to IFNα.
Conclusion: Our
findings suggest that enhanced IFNα signalling may be relevant to some
pathology associated with GOF mutations in STAT1.
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المؤتمر (3):
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عنوان المؤتمر:
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17th Biennial Meeting of the European Society
for Immunodeficiencies
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تاريخ الإنعقاد:
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21/09/2016
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مكان
الإنعقاد:
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Barcelona, Spain
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طبيعة المشاركة:
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Poster presentation
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عنوان المشاركة:
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GAIN-OF-FUNCTION STAT1 MUTATIONS MEDIATE ENHANCED
EFFECTS OF TYPE I INTERFERONS
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ملخص المشاركة:
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Background:
Chronic mucocutaneous candidiasis (CMC) is a primary
immune deficiency disease where patients present with persistent superficial
candidiasis, which in most patients is due to an underlying STAT1 gain-
of-function (GOF) mutation. This mutation leads to hyperactivity of STAT1, a
protein central to signaling of both interferon (IFN) type1 (IFNα) and type2
(IFNγ). Patients present with a broad phenotype including autoimmune
phenomena (hypothyroidism, alopecia, vitiligo) and vasculopathy (intracranial
aneurysms) reminiscent of findings in interferonopathies – a recently defined
group of diseases where tissue damage is caused by excessive effects of type1
IFNs. However, as opposed to currently reported interferonopathies, in
GOF-STAT1 CMC these effects are due to increased responsiveness to, rather
than increased production of IFN type1 (Clin Exp Immunol 2015,182(S1):15,
abstract P29).
Aim: We
hypothesise that disease pathogenesis in patients with GOF-STAT1 mutations
may include features resulting from enhanced IFN type1 signalling, following
stimulation of the STAT1 pathway.
Methods:
In PBMCs and fibroblast cell lines from CMC patients
with and without GOF-STAT1 mutations and healthy controls, differential
responsiveness to IFNα/IFNγ were assessed by: 1) levels of STAT1
phosphorylation using flow cytometry; 2) expression of IFN-stimulated genes
(IFI27, IFI44L, ISG15) using qPCR and genomic RNAseq.
Results:
All GOF-STAT1 CMC patients showed increased STAT1
phosphorylation and increased transcription of IFNα-dependent genes
confirming enhanced responses to IFNα stimulation; this was not seen in CMC
patients without GOF-STAT1 mutations nor healthy donors.
Conclusion:
Our findings suggest that enhanced IFNα signalling
may play a role in pathology (and phenotype) associated with GOF mutations in
STAT1.
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المؤتمر (4):
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عنوان المؤتمر:
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2017 Meeting of the
European Society for Immunodeficiencies
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تاريخ الإنعقاد:
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11-14/09/2017
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مكان
الإنعقاد:
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Edinburgh,
UK
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طبيعة المشاركة:
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Poster presentation
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عنوان المشاركة:
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NEW STAT1 MUTATION IN SUMOYLATION SITE CONFERS GAIN
OF FUNCTION AND COMBINED IMMUNODEFICIENCY RESPONSIVE TO RUXOLITINIB
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ملخص المشاركة:
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Background:
Gain of
function STAT1 mutations in the coiled coil and DNA binding domains are
reported to be due to delayed de-phosphorylation and underlie autosomal
dominant chronic mucocutaneous candidiasis/combined immunodeficiency.
Methods:
We report a
case of combined immunodeficiency in a 10 year old boy due to a novel
mutation in the C-terminal region of STAT1 that is predicted to alter
sumoylation of STAT1, thereby increasing phosphorylation by a novel mechanism
and leading to gain of function.
Results:
Features both
of autoimmunity and immunodeficiency improved after commencing treatment with
ruxolitinib, a janus kinase 1/2 inhibitor, and functional testing after
treatment confirmed reversal of the STAT1 hyperphosphorylation.
Conclusions:
A mutation
in the C-terminal region of STAT1 can lead to gain of function and associated
combined immunodeficiency. Janus kinase inhibitors may represent a treatment
option for such patients, particularly in the absence of a suitable haematopoietic
stem cell donor.
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