X-linked Inhibitor of Apoptosis Complicated by Granulomatous Lymphocytic Interstitial Lung Disease (GLILD) and Granulomatous Hepatitis

The X-linked inhibitor of apoptosis (XIAP) deficiency is a primary immunodeficiency characterized by Epstein-Barr virus (EBV)-driven hemophagocytic lymphohistiocytosis (HLH), splenomegaly, and colitis. Here, we present, for the first time, granulomatous hepatitis and granulomatous and lymphocytic interstitial lung disease (GLILD) as manifestations of XIAP deficiency. We report successful treatment of GLILD in XIAP deficiency with rituximab and azathioprine and discuss the role of XIAP deficiency in immune dysregulation

Molecular profiling of signet ring cell colorectal cancer provides a strong rationale for genomic targeted and immune checkpoint inhibitor therapies

We would like to thank all patients whose samples were used in this study. We are also thankful to the Northern Ireland Biobank and Grampian Biorepository for providing us with tissue blocks and patient data; and Dr HG Coleman (Queen’s University Belfast) for her advice on statistical analyses. This work has been carried out with financial support from Cancer Research UK (grant: C11512/A18067), Experimental Cancer Medicine Centre Network (grant: C36697/A15590 from Cancer Research UK and the NI Health and Social Care Research and Development Division), the Sean Crummey Memorial Fund and the Tom Simms Memorial Fund. The Northern Ireland Biobank is funded by HSC Research and Development Division of the Public Health Agency in Northern Ireland and Cancer Research UK through the Belfast CRUK Centre and the Northern Ireland Experimental Cancer Medicine Centre; additional support was received from Friends of the Cancer Centre. The Northern Ireland Molecular Pathology Laboratory which is responsible for creating resources for the Northern Ireland Biobank has received funding from Cancer Research UK, Friends of the Cancer Centre and Sean Crummey Foundation.Peer reviewedPublisher PD

Chemotherapy and diffuse low-grade gliomas: a survey within the European Low-Grade Glioma Network.

Diffuse low-grade gliomas (DLGGs) are rare and incurable tumors. Whereas maximal safe, functional-based surgical resection is the first-line treatment, the timing and choice of further treatments (chemotherapy, radiation therapy, or combined treatments) remain controversial. An online survey on the management of DLGG patients was sent to 28 expert centers from the European Low-Grade Glioma Network (ELGGN) in May 2015. It contained 40 specific questions addressing the modalities of use of chemotherapy in these patients. The survey demonstrated a significant heterogeneity in practice regarding the initial management of DLGG patients and the use of chemotherapy. Interestingly, radiation therapy combined with the procarbazine, CCNU (lomustine), and vincristine regimen has not imposed itself as the gold-standard treatment after surgery, despite the results of the Radiation Therapy Oncology Group 9802 study. Temozolomide is largely used as first-line treatment after surgical resection for high-risk DLGG patients, or at progression. The heterogeneity in the management of patients with DLGG demonstrates that many questions regarding the postoperative strategy and the use of chemotherapy remain unanswered. Our survey reveals a high recruitment potential within the ELGGN for retrospective or prospective studies to generate new data regarding these issues

Beyond Antagonism? The Discursive Construction of ‘New’ Teachers in the United Arab Emirates

The UAE, which celebrated independence in 1971, is a rapidly changing environment where aspects of traditional Bedouin culture co-exist with the immense changes being wrought by the forces of globalization and the wealth brought about by the development of the oil industry. Emirati nationals are a minority within the UAE, comprising approximately 20% of the population, and the majority of the schoolteachers are expatriates drawn from other Arabic speaking countries. Within this context, the Higher Colleges of Technology's Bachelor of Education degree in Teaching English to Young Learners prepares young UAE national women for English language teaching positions in local government schools. The research presented in this paper is drawn from this two-year study of student teachers and explores the discursive construction of the students' systems of knowledge and belief. The paper concludes with a critical consideration of the study's implications and some possible recommendations for teacher education in the UAE that may also have resonance for teacher education programs in other contexts

K201 improves aspects of the contractile performance of human failing myocardium via reduction in Ca2+ leak from the sarcoplasmic reticulum

In heart failure, intracellular Ca2+ leak from cardiac ryanodine receptors (RyR2s) leads to a loss of Ca2+ from the sarcoplasmic reticulum (SR) potentially contributing to decreased function. Experimental data suggest that the 1,4-benzothiazepine K201 (JTV-519) may stabilise RyR2s and thereby reduce detrimental intracellular Ca2+ leak. Whether K201 exerts beneficial effects in human failing myocardium is unknown. Therefore, we have studied the effects of K201 on muscle preparations from failing human hearts. K201 (0.3 μM; extracellular [Ca2+]e 1.25 mM) showed no effects on contractile function and micromolar concentrations resulted in negative inotropic effects (K201 1 μM; developed tension −9.8 ± 2.5% compared to control group; P < 0.05). Interestingly, K201 (0.3 μM) increased the post-rest potentiation (PRP) of failing myocardium after 120 s, indicating an increased SR Ca2+ load. At high [Ca2+]e concentrations (5 mmol/L), K201 increased PRP already at shorter rest intervals (30 s). Strikingly, treatment with K201 (0.3 μM) prevented diastolic dysfunction (diastolic tension at 5 mmol/L [Ca2+]e normalised to 1 mmol/L [Ca2+]e: control 1.26 ± 0.06, K201 1.01 ± 0.03, P < 0.01). In addition at high [Ca2+]e, K201 (0.3 μM) treatment significantly improved systolic function [developed tension +27 ± 8% (K201 vs. control); P < 0.05]. The beneficial effects on diastolic and systolic functions occurred throughout the physiological frequency range of the human heart rate from 1 to 3 Hz. Upon elevated intracellular Ca2+ concentration, systolic and diastolic contractile functions of terminally failing human myocardium are improved by K201

Encrypted federated learning for secure decentralized collaboration in cancer image analysis.

Artificial intelligence (AI) has a multitude of applications in cancer research and oncology. However, the training of AI systems is impeded by the limited availability of large datasets due to data protection requirements and other regulatory obstacles. Federated and swarm learning represent possible solutions to this problem by collaboratively training AI models while avoiding data transfer. However, in these decentralized methods, weight updates are still transferred to the aggregation server for merging the models. This leaves the possibility for a breach of data privacy, for example by model inversion or membership inference attacks by untrusted servers. Somewhat-homomorphically-encrypted federated learning (SHEFL) is a solution to this problem because only encrypted weights are transferred, and model updates are performed in the encrypted space. Here, we demonstrate the first successful implementation of SHEFL in a range of clinically relevant tasks in cancer image analysis on multicentric datasets in radiology and histopathology. We show that SHEFL enables the training of AI models which outperform locally trained models and perform on par with models which are centrally trained. In the future, SHEFL can enable multiple institutions to co-train AI models without forsaking data governance and without ever transmitting any decryptable data to untrusted servers

Biological Misinterpretation of Transcriptional Signatures in Tumor Samples Can Unknowingly Undermine Mechanistic Understanding and Faithful Alignment with Preclinical Data

PURPOSE Precise mechanism-based gene expression signatures (GES) have been developed in appropriate in vitro and in vivo model systems, to identify important cancer-related signaling processes. However, some GESs originally developed to represent specific disease processes, primarily with an epithelial cell focus, are being applied to heterogeneous tumor samples where the expression of the genes in the signature may no longer be epithelial-specific. Therefore, unknowingly, even small changes in tumor stroma percentage can directly influence GESs, undermining the intended mechanistic signaling. EXPERIMENTAL DESIGN Using colorectal cancer as an exemplar, we deployed numerous orthogonal profiling methodologies, including laser capture microdissection, flow cytometry, bulk and multiregional biopsy clinical samples, single-cell RNA sequencing and finally spatial transcriptomics, to perform a comprehensive assessment of the potential for the most widely used GESs to be influenced, or confounded, by stromal content in tumor tissue. To complement this work, we generated a freely-available resource, ConfoundR; https://confoundr.qub.ac.uk/, that enables users to test the extent of stromal influence on an unlimited number of the genes/signatures simultaneously across colorectal, breast, pancreatic, ovarian and prostate cancer datasets. RESULTS Findings presented here demonstrate the clear potential for misinterpretation of the meaning of GESs, due to widespread stromal influences, which in-turn can undermine faithful alignment between clinical samples and preclinical data/models, particularly cell lines and organoids, or tumor models not fully recapitulating the stromal and immune microenvironment. CONCLUSIONS Efforts to faithfully align preclinical models of disease using phenotypically-designed GESs must ensure that the signatures themselves remain representative of the same biology when applied to clinical samples

Pressure and pain In Systemic sclerosis/Scleroderma - an evaluation of a simple intervention (PISCES): randomised controlled trial protocol

Background: foot problems associated with Systemic Sclerosis (SSc)/Scleroderma have been reported to be both common and disabling. There are only limited data describing specifically, the mechanical changes occurring in the foot in SSc. A pilot project conducted in preparation for this trial confirmed the previous reports of foot related impairment and reduced foot function in people with SSc and demonstrated a link to mechanical etiologies. To-date there have been no formal studies of interventions directed at the foot problems experienced by people with Systemic Sclerosis. The primary aim of this trial is to evaluate whether foot pain and foot-related health status in people with Systemic Sclerosis can be improved through the provision of a simple pressure-relieving insole. Methods: the proposed trial is a pragmatic, multicenter, randomised controlled clinical trial following a completed pilot study. In four participating centres, 140 consenting patients with SSc and plantar foot pain will be randomised to receive either a commercially available pressure relieving and thermally insulating insole, or a sham insole with no cushioning or thermal properties. The primary end point is a reduction in pain measured using the Foot Function Index Pain subscale, 12 weeks after the start of intervention. Participants will complete the primary outcome measure (Foot Function Index pain sub-scale) prior to randomisation and at 12 weeks post randomisation. Secondary outcomes include participant reported pain and disability as derived from the Manchester Foot Pain and Disability Questionnaire and plantar pressures with and without the insoles in situ. Discussion: this trial protocol proposes a rigorous and potentially significant evaluation of a simple and readily provided therapeutic approach which, if effective, could be of a great benefit for this group of patients