The PRL2 Phosphatase Upregulates miR-21 through Activation of the JAK2/STAT3 Pathway to Downregulate the PTEN Tumor Suppressor.

The Phosphatases of Regenerating Liver (PRLs) are members of the protein tyrosine phosphatase (PTP) superfamily that play pro-oncogenic roles in cell proliferation, migration, and survival. We previously demonstrated that PRLs can post-translationally downregulate PTEN, a tumor suppressor frequently inactivated in human cancers, by dephosphorylating PTEN at Tyr336, which promotes the NEDD4-mediated PTEN ubiquitination and proteasomal degradation. Here we report that PRLs can also reduce PTEN expression by upregulating MicroRNA-21 (miR-21), which is one of the most frequently overexpressed miRNAs in solid tumors.

Effects of cladribine on intrathecal and peripheral B and plasma cells.

Introduction: Cladribine is a deoxyadenosine analogue that can penetrate the blood-brain barrier. It is used to treat multiple sclerosis (MS). However, the mechanistic understanding of the effect of this highly effective therapy on B cells and plasma cells in the central nervous system compartment is limited.

Development and initial evaluation of a clinical prediction model for risk of treatment resistance in first-episode psychosis: Schizophrenia Prediction of Resistance to Treatment (SPIRIT).

Background: A clinical tool to estimate the risk of treatment-resistant schizophrenia (TRS) in people with first-episode psychosis (FEP) would inform early detection of TRS and overcome the delay of up to 5 years in starting TRS medication.

Aims: To develop and evaluate a model that could predict the risk of TRS in routine clinical practice.

Method: We used data from two UK-based FEP cohorts (GAP and AESOP-10) to develop and internally validate a prognostic model that supports identification of patients at high-risk of TRS soon after FEP diagnosis.

Spontaneous EBV-Reactivation during B Cell Differentiation as a Model for Polymorphic EBV-Driven Lymphoproliferation.

Epstein-Barr virus (EBV)-driven B cell neoplasms arise from the reactivation of latently infected B cells. In a subset of patients, EBV was seen to drive a polymorphous lymphoproliferative disorder (LPD) in which B cell differentiation was retained. In this work, spontaneous EBV reactivation following B cell mitogen stimulation was shown to provide a potential model of polymorphic EBV-driven LPD.

B-cell capacity for expansion and differentiation into plasma cells are altered in osteoarthritis.

Objective: Autoantibody (autoAbs) production in osteoarthritis (OA), coupled with evidence of disturbed B-cell homoeostasis, suggest a potential role for B-cells in OA. B-cells can differentiate with T-cell help (T-dep) or using alternative Toll like recptor (TLR) co-stimulation (TLR-dep). We analysed the capacity for differentiation of B-cells in OA versus age-matched healthy controls (HCs) and compared the capacity of OA synovitis-derived stromal cells to provide support for plasma cell (PC) maturation.

Metabolic Reprogramming During B-Cell Differentiation.

B cells engaging with antigen and secondary signals provided by T cell help, or ligands for Toll-like receptors, undergo a step-wise process of differentiation to eventually produce antibody-secreting plasma cells. During the course of this conversion, the cells transition from a resting, non-growing state to an activated B-cell state engaged in DNA synthesis and mitosis to a terminally differentiated, quiescent cell state with expanded organelles necessary for high levels of secretion. Each of these phases is accompanied by considerable changes in metabolic requirements.

Inherited CD19 Deficiency Does Not Impair Plasma Cell Formation or Response to CXCL12.

Background: The human CD19 antigen is expressed throughout B cell ontogeny with the exception of neoplastic plasma cells and a subset of normal plasma cells. CD19 plays a role in propagating signals from the B cell receptor and other receptors such as CXCR4 in mature B cells. Studies of CD19-deficient patients have confirmed its function during the initial stages of B cell activation and the production of memory B cells; however, its role in the later stages of B cell differentiation is unclear.

Cognitive performance at first episode of psychosis and the relationship with future treatment resistance: Evidence from an international prospective cohort study.

Background: Antipsychotic treatment resistance affects up to a third of individuals with schizophrenia, with recent research finding systematic biological differences between antipsychotic resistant and responsive patients. Our aim was to determine whether cognitive impairment at first episode significantly differs between future antipsychotic responders and resistant cases.

Methods: Analysis of data from seven international cohorts of first-episode psychosis (FEP) with cognitive data at baseline (N = 683) and follow-up data on antipsychotic treatment response: 605 treatment responsive and 78 treatment resistant cases.

Cytokine receptor IL27RA is an NF-κB-responsive gene involved in CD38 upregulation in multiple myeloma.

Multiple myeloma (MM) shows constitutive activation of canonical and noncanonical nuclear factor κB (NF-κB) signaling via genetic mutations or tumor microenvironment (TME) stimulations. A subset of MM cell lines showed dependency for cell growth and survival on the canonical NF-κB transcription factor RELA alone, suggesting a critical role for a RELA-mediated biological program in MM pathogenesis. Here, we determined the RELA-dependent transcriptional program in MM cell lines and found the expression of the cell surface molecules interleukin-27 receptor-α (IL-27Rα) and the adhesion molecule JAM2 to be responsive to RELA at the messenger RNA and protein levels.

Intrathymic dendritic cell-biased precursors promote human T cell lineage specification through IRF8-driven transmembrane TNF.

The cross-talk between thymocytes and thymic stromal cells is fundamental for T cell development. In humans, intrathymic development of dendritic cells (DCs) is evident but its physiological significance is unknown. Here we showed that DC-biased precursors depended on the expression of the transcription factor IRF8 to express the membrane-bound precursor form of the cytokine TNF (tmTNF) to promote differentiation of thymus seeding hematopoietic progenitors into T-lineage specified precursors through activation of the TNF receptor (TNFR)-2 instead of TNFR1.

Usability: An introduction to and literature review of usability testing for educational resources in radiation oncology.

Usability, or the ease with which something can be used, is a key aspect in ensuring end-users can achieve the best possible outcomes from a given educational resource. Ideally usability testing should take place iteratively throughout the design of the resource, and there are several approaches for undertaking usability testing described in the wider literature. Within radiation oncology education, the extent to which usability testing occurs remains unclear.

Clinical predictors of antipsychotic treatment resistance: Development and internal validation of a prognostic prediction model by the STRATA-G consortium.

Introduction: Our aim was to, firstly, identify characteristics at first-episode of psychosis that are associated with later antipsychotic treatment resistance (TR) and, secondly, to develop a parsimonious prediction model for TR.

Methods: We combined data from ten prospective, first-episode psychosis cohorts from across Europe and categorised patients as TR or non-treatment resistant (NTR) after a mean follow up of 4.18 years (s.

APRIL Drives a Coordinated but Diverse Response as a Foundation for Plasma Cell Longevity.

Ab-secreting cells survive in niche microenvironments, but cellular responses driven by particular niche signals are incompletely defined. The TNF superfamily member a proliferation-inducing ligand (APRIL) can support the maturation of transitory plasmablasts into long-lived plasma cells. In this study, we explore the biological programs established by APRIL in human plasmablasts.

Barriers and facilitators for implementation of a national recommended specialty core-curriculum across UK medical schools: a cross-sectional study using an online questionnaire.

Objectives: The National Health Service (NHS) Long-Term plan published in 2019 set out healthcare reforms to meet the healthcare demands of UK. Undergraduate specialty core-curricula like dermatology aligns well to the training needs of the future workforce but lacks representation, consistency and implementation. This study explores the barriers and facilitators influencing the implementation of a specialty-specific (dermatology) national core-curriculum across UK medical schools.

Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants With Treatment Resistance in Schizophrenia.

Importance: About 20% to 30% of people with schizophrenia have psychotic symptoms that do not respond adequately to first-line antipsychotic treatment. This clinical presentation, chronic and highly disabling, is known as treatment-resistant schizophrenia (TRS). The causes of treatment resistance and their relationships with causes underlying schizophrenia are largely unknown.

A System for In Vitro Generation of Mature Murine Plasma Cells Uncovers Differential / Promoter Usage.

Upon encounter with Ag, B cells undergo a sequential process of differentiation to become Ab-secreting plasma cells. Although the key drivers of differentiation have been identified, research has been limited by the lack of in vitro models recapitulating the full process for murine B cells. In this study, we describe methodology using BCR or TLR ligation to obtain plasma cells that are phenotypically mature, have exited cell cycle and express a gene signature concordant with long-lived plasma cells.

Biallelic mutations in ) cause a primary immunodeficiency disorder.

CRAC channel regulator 2 A (CRACR2A) is a large Rab GTPase that is expressed abundantly in T cells and acts as a signal transmitter between T cell receptor stimulation and activation of the Ca-NFAT and JNK-AP1 pathways. CRACR2A has been linked to human diseases in numerous genome-wide association studies, however, to date no patient with damaging variants in CRACR2A has been identified. In this study, we describe a patient harboring biallelic variants in [paternal allele c.

The experience of widening participation students in undergraduate medical education in the UK: A qualitative systematic review.

Most widening participation (WP) research is focused on medical school recruitment; there is a paucity of research examining whether the experience of medical school itself is an equal experience for both 'traditional' and WP students. This qualitative systematic review used the Joanna Briggs Institute (JBI) meta-aggregative approach to characterise the experience of undergraduate medical education in the UK from the perspective of WP students. Seven databases were searched, 27 studies were critically appraised, and 208 findings were grouped into 12 categories and four synthesised findings.

Auto-antibodies to post-translationally modified proteins in osteoarthritis.

Objective: Autoantibodies (AutoAbs) have been observed in osteoarthritis (OA) with broad antigenicity, although their prevalence and role remain unclear. Post-translational modification (PTMs) of proteins (oxidation, carbamylation, citrullination) is associated with synovitis and can lead to AutoAb development. Given the prevalence of synovitis, we explored whether AutoAbs to PTM-antigens are common in OA compared with rheumatoid arthritis (RA).

B-cell capacity for differentiation changes with age.

Background: Age-related immune deficiencies are thought to be responsible for increased susceptibility to infection in older adults, with alterations in lymphocyte populations becoming more prevalent over time. The loss of humoral immunity in ageing was attributed to the diminished numbers of B cells and the reduced ability to generate immunoglobulin.

Aims: To compare the intrinsic B-cell capacity for differentiation into mature plasma cells (PCs), between young and old donors, using in vitro assays, providing either effective T-cell help or activation via TLR engagement.

Continuing medical education during pandemic waves of COVID-19: Consensus from medical faculties in Asia, Australia and Europe.

This article was migrated. The article was marked as recommended. Medical faculties have the responsibility to train tomorrow's doctors and in a crisis face the challenge of delivering students into the workforce promptly and safely.

Rethinking the course of psychotic disorders: modelling long-term symptom trajectories.

Background: The clinical course of psychotic disorders is highly variable. Typically, researchers have captured different course types using broad pre-defined categories. However, whether these adequately capture symptom trajectories of psychotic disorders has not been fully assessed.