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"Brain, Oliver"
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نزعة إلى الموسيقى : حكايات الموسيقى والدماغ
يتناول الكتاب حكايات الموسيقى والدماغ ومن المعلوم أن الموسيقى تشكل أحد أهم المحددات الثقافية التي قد يشترك فيها جميع البشر بغض النظر عن الاختلافات الحضارية بين بلد وآخر وعلى الرغم من التغير الذي يطرأ على الموسيقى في عصور مختلفة فإن أساسياتها وقواعدها العامة ما تزال هي عينها التي ابتدعها الإنسان قبل آلاف السنين وما الاختلاف الظاهر سوى انعكاس للواقع الثقافي الذي يتم معايشته في كل عصر ومن موقعه كمتخصص في علم الأعصاب يعرض لنا الطبيب \"أوليفر ساكس\" في كتابه المعنون \"نزعة إلى الموسيقى\" لجملة من الحكايات عن مرضى أصيبوا بحالات مختلفة من التفاعل غير الطبيعي مع الموسيقى ومن خلال معرفته الواسعة والمتميزة يستكشف شاعر الطب الأول كما أسمته \"النيويورك تايمز\" والمكانة التي تحتلها الموسيقى في الدماغ وكيف تؤثر في الحالة البشرية.
Book
NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation
Mutations in NOD2—a bacterial sensor in dendritic cells—and mutations in genes related to autophagosome function have been linked to Crohn's disease. Alison Simmons and her colleagues link these susceptibility genes in a single functional pathway. They show that triggering of NOD2 induces autophagy, resulting in increased bacterial antigen presentation on the surface of the dendritic cell. They also show that this process goes awry in dendritic cells expressing the susceptibility variants from individuals with Crohn's disease.
Nucleotide-binding oligomerization domain–containing-2 (NOD2) acts as a bacterial sensor in dendritic cells (DCs), but it is not clear how bacterial recognition links with antigen presentation after NOD2 stimulation. NOD2 variants are associated with Crohn's disease, where breakdown in self-recognition of commensal bacteria leads to gastrointestinal inflammation. Here we show NOD2 triggering by muramyldipeptide induces autophagy in DCs. This effect requires receptor-interacting serine-threonine kinase-2 (RIPK-2), autophagy-related protein-5 (ATG5), ATG7 and ATG16L1 but not NLR family, pyrin domain containing-3 (NALP3).We show that NOD2-mediated autophagy is required for both bacterial handling and generation of major histocompatibility complex (MHC) class II antigen-specific CD4
+
T cell responses in DCs. DCs from individuals with Crohn's disease expressing Crohn's disease—associated NOD2 or ATG16L1 risk variants are defective in autophagy induction, bacterial trafficking and antigen presentation. Our findings link two Crohn's disease–associated susceptibility genes in a single functional pathway and reveal defects in this pathway in Crohn's disease DCs that could lead to bacterial persistence via impaired lysosomal destruction and immune mediated clearance.
Journal Article
نزعة إلى الموسيقى : حكايات الموسيقى والدماغ
يتناول الكتاب حكايات الموسيقى والدماغ ومن المعلوم أن الموسيقى تشكل أحد أهم المحددات الثقافية التي قد يشترك فيها جميع البشر بغض النظر عن الاختلافات الحضارية بين بلد وآخر وعلى الرغم من التغير الذي يطرأ على الموسيقى في عصور مختلفة فإن أساسياتها وقواعدها العامة ما تزال هي عينها التي ابتدعها الإنسان قبل آلاف السنين وما الاختلاف الظاهر سوى انعكاس للواقع الثقافي الذي يتم معايشته في كل عصر ومن موقعه كمتخصص في علم الأعصاب يعرض لنا الطبيب \"أوليفر ساكس\" في كتابه المعنون \"نزعة إلى الموسيقى\" لجملة من الحكايات عن مرضى أصيبوا بحالات مختلفة من التفاعل غير الطبيعي مع الموسيقى ومن خلال معرفته الواسعة والمتميزة يستكشف شاعر الطب الأول كما أسمته \"النيويورك تايمز\" والمكانة التي تحتلها الموسيقى في الدماغ وكيف تؤثر في الحالة البشرية.
BOOK
A dynamic CD2-rich compartment at the outer edge of the immunological synapse boosts and integrates signals
The CD2–CD58 recognition system promotes adhesion and signaling and counters exhaustion in human T cells. We found that CD2 localized to the outer edge of the mature immunological synapse, with cellular or artificial APC, in a pattern we refer to as a ‘CD2 corolla’. The corolla captured engaged CD28, ICOS, CD226 and SLAM-F1 co-stimulators. The corolla amplified active phosphorylated Src-family kinases (pSFK), LAT and PLC-γ over T cell receptor (TCR) alone. CD2–CD58 interactions in the corolla boosted signaling by 77% as compared with central CD2–CD58 interactions. Engaged PD-1 invaded the CD2 corolla and buffered CD2-mediated amplification of TCR signaling. CD2 numbers and motifs in its cytoplasmic tail controlled corolla formation. CD8
+
tumor-infiltrating lymphocytes displayed low expression of CD2 in the majority of people with colorectal, endometrial or ovarian cancer. CD2 downregulation may attenuate antitumor T cell responses, with implications for checkpoint immunotherapies.
The adhesion receptor CD2 plays an important role in the full activation of T cells. Dustin and colleagues show that CD2 occupies a region in the periphery of the immunological synapse where it amplifies cognate antigen signals, whereas the presence of PD-1 disrupts this effect.
Journal Article
Immune checkpoint inhibitor-related colitis assessment and prognosis: can IBD scoring point the way?
Background
Immune checkpoint inhibitors (ICI) improve survival but cause immune-related adverse events (irAE). We sought to determine if CTCAE classification, IBD biomarkers/endoscopic/histological scores correlate with irAE colitis outcomes.
Methods
A dual-centre retrospective study was performed on patients receiving ICI for melanoma, NSCLC or urothelial cancer from 2012 to 2018. Demographics, clinical data, endoscopies (reanalysed using Mayo/Ulcerative Colitis Endoscopic Index of Severity (UCEIS) scores), histology (scored with Nancy Index) and treatment outcomes were analysed.
Results
In all, 1074 patients were analysed. Twelve percent (134) developed irAE colitis. Median patient age was 66, 59% were male. CTCAE diarrhoea grade does not correlate with steroid/ infliximab use. G3/4 colitis patients are more likely to need infliximab (
p
< 0.0001) but colitis grade does not correlate with steroid duration. CRP, albumin and haemoglobin do not correlate with severity. The UCEIS (
p
= 0.008) and Mayo (
p
= 0.016) scores correlate with severity/infliximab requirement. Patients with higher Nancy indices (3/4) are more likely to require infliximab (
p
= 0.03).
Conclusions
CTCAE assessment does not accurately reflect colitis severity and our data do not support its use in isolation, as this may negatively impact timely management. Our data support utilising endoscopic scoring for patients with >grade 1 CTCAE disease, and demonstrate the potential prognostic utility of objective histologic scoring.
Journal Article
Single-cell atlas of colonic CD8+ T cells in ulcerative colitis
Colonic antigen-experienced lymphocytes such as tissue-resident memory CD8
+
T cells can respond rapidly to repeated antigen exposure. However, their cellular phenotypes and the mechanisms by which they drive immune regulation and inflammation remain unclear. Here we compiled an unbiased atlas of human colonic CD8
+
T cells in health and ulcerative colitis (UC) using single-cell transcriptomics with T-cell receptor repertoire analysis and mass cytometry. We reveal extensive heterogeneity in CD8
+
T-cell composition, including expanded effector and post-effector terminally differentiated CD8
+
T cells. While UC-associated CD8
+
effector T cells can trigger tissue destruction and produce tumor necrosis factor (TNF)-α, post-effector cells acquire innate signatures to adopt regulatory functions that may mitigate excessive inflammation. Thus, we identify colonic CD8
+
T-cell phenotypes in health and UC, define their clonal relationships and characterize terminally differentiated dysfunctional UC CD8
+
T cells expressing IL-26, which attenuate acute colitis in a humanized IL-26 transgenic mouse model.
Multimodal single-cell profiling reveals heterogeneity of colonic CD8
+
T cells in patients with ulcerative colitis, including expansion of a chronically activated IL-26-expressing subpopulation with innate-like features.
Journal Article
Beyond endoscopic mucosal healing in UC: histological remission better predicts corticosteroid use and hospitalisation over 6 years of follow-up
BackgroundEndoscopic mucosal healing is an established treatment target for UC, yet the value of achieving histological remission remains unclear.AimsTo evaluate histological remission compared to endoscopic mucosal healing for predicting patient outcomes in UC.MethodsBlinded assessment of endoscopic and histological measures of disease activity was performed on patients with established UC at baseline. Concordance and prognostic values of endoscopic mucosal healing (defined by Baron score ≤1) and histological remission (defined by Truelove and Richards’ index) for predicting outcomes of corticosteroid use, hospitalisation and colectomy were determined over a median 6 years follow-up, including κ statistics and Cox regression multivariate analysis.Results91 patients with UC were followed up for a median 72 months (IQR 54–75 months). Overall, concordance between endoscopic and histological remission was moderate (κ=0.56, 95% CI 0.36 to 0.77); 24% patients had persistent inflammation despite endoscopic remission. Histological remission predicted corticosteroid use and acute severe colitis requiring hospitalisation over the follow-up period (HR 0.42 (0.2 to 0.9), p=0.02; HR 0.21 (0.1 to 0.7), p=0.02; respectively), whereas endoscopic mucosal healing did not (HR 0.86, 95% CI 0.5 to 1.7, p0.65; HR 0.83 95% CI 0.3 to 2.4, p0.74; respectively).ConclusionsHistological remission is a target distinct from endoscopic mucosal healing in UC and better predicts lower rates of corticosteroid use and acute severe colitis requiring hospitalisation, over a median of 6 years of follow-up. Our findings support the inclusion of histological indices in both UC clinical trials and practice, towards a target of ‘complete remission’.
Journal Article
Early management of acute severe UC in the biologics era: development and international validation of a prognostic clinical index to predict steroid response
ObjectivesWe aimed to determine whether changes in acute severe colitis (ASC) management have translated to improved outcomes and to develop a simple model predicting steroid non-response on admission.DesignOutcomes of 131 adult ASC admissions (117 patients) in Oxford, UK between 2015 and 2019 were compared with data from 1992 to 1993. All patients received standard treatment with intravenous corticosteroids and endoscopic disease activity scoring (Ulcerative Colitis Endoscopic Index of Severity (UCEIS)). Steroid non-response was defined as receiving medical rescue therapy or surgery. A predictive model developed in the Oxford cohort was validated in Australia and India (Gold Coast University Hospital 2015–2020, n=110; All India Institute of Medical Sciences, New Delhi 2018–2020, n=62).ResultsIn the 2015–2019 Oxford cohort, 15% required colectomy during admission vs 29% in 1992–1993 (p=0.033), while 71 (54%) patients received medical rescue therapy (27% ciclosporin, 27% anti-tumour necrosis factor, compared with 27% ciclosporin in 1992–1993 (p=0.0015). Admission C reactive protein (CRP) (false discovery rate, p=0.00066), albumin (0.0066) and UCEIS scores (0.015) predicted steroid non-response. A four-point model was developed involving CRP of ≥100 mg/L (one point), albumin of ≤25 g/L (one point), and UCEIS score of ≥4 (1 point) or ≥7 (2 points). Patients scoring 0, 1, 2, 3 and 4 in the validation cohorts had steroid response rates of 100, 75.0%, 54.9%, 18.2% and 0%, respectively. Scoring of ≥3 was 84% (95% CI 0.70 to 0.98) predictive of steroid failure (OR 11.9, 95% CI 10.8 to 13.0). Colectomy rates in the validation cohorts were were 8%–11%.ConclusionsEmergency colectomy rates for ASC have halved in 25 years to 8%–15% worldwide. Patients who will not respond to corticosteroids are readily identified on admission and may be prioritised for early intensification of therapy.
Journal Article
Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor–neutralizing therapy in patients with inflammatory bowel disease
The cytokine oncostatin M drives intestinal inflammation in mice, and its abundance in the intestine of patients with inflammatory bowel disease predicts response to tumor necrosis factor–neutralizing therapy.
Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are complex chronic inflammatory conditions of the gastrointestinal tract that are driven by perturbed cytokine pathways. Anti-tumor necrosis factor-α (TNF) antibodies are mainstay therapies for IBD. However, up to 40% of patients are nonresponsive to anti-TNF agents, which makes the identification of alternative therapeutic targets a priority. Here we show that, relative to healthy controls, inflamed intestinal tissues from patients with IBD express high amounts of the cytokine oncostatin M (OSM) and its receptor (OSMR), which correlate closely with histopathological disease severity. The OSMR is expressed in nonhematopoietic, nonepithelial intestinal stromal cells, which respond to OSM by producing various proinflammatory molecules, including interleukin (IL)-6, the leukocyte adhesion factor ICAM1, and chemokines that attract neutrophils, monocytes, and T cells. In an animal model of anti-TNF-resistant intestinal inflammation, genetic deletion or pharmacological blockade of OSM significantly attenuates colitis. Furthermore, according to an analysis of more than 200 patients with IBD, including two cohorts from phase 3 clinical trials of infliximab and golimumab, high pretreatment expression of OSM is strongly associated with failure of anti-TNF therapy. OSM is thus a potential biomarker and therapeutic target for IBD, and has particular relevance for anti-TNF-resistant patients.
Journal Article