Assessing Ethnic Minority Representation in Fibromyalgia Clinical Trials: A Systematic Review of Recruitment Demographics.

The under-representation of non-White participants in Western countries in clinical research has received increased attention, due to recognized physiological differences between ethnic groups, which may affect the efficacy and optimal dosage of some treatments. This review assessed ethnic diversity in pharmaceutical trials for fibromyalgia, a poorly understood chronic pain disorder. We also investigated longitudinal change to non-White participant proportions in trials and non-White participants' likelihood to discontinue with fibromyalgia research between trial stages (retention). First, we identified relevant trials conducted in the United States and Canada between 2000 and 2022, by searching PubMed, Web of Science, Scopus, and the Cochrane Library databases. In trials conducted both across the United States and Canada, and exclusively within the United States, approximately 90% of participants were White. A longitudinal analysis also found no change in the proportion of non-White participants in trials conducted across the United States and Canada between 2000 and 2022. Finally, we found no significant differences in trial retention between White and non-White participants. This review highlights the low numbers of ethnic minorities in fibromyalgia trials conducted in the United States and Canada, with no change to these proportions over the past 22 years. Furthermore, non-White participants were not more likely to discontinue with the fibromyalgia research once they were recruited.

Targeting of multiple tumor-associated antigens by individual T cell receptors during successful cancer immunotherapy.

The T cells of the immune system can target tumors and clear solid cancers following tumor-infiltrating lymphocyte (TIL) therapy. We used combinatorial peptide libraries and a proteomic database to reveal the antigen specificities of persistent cancer-specific T cell receptors (TCRs) following successful TIL therapy for stage IV malignant melanoma. Remarkably, individual TCRs could target multiple different tumor types via the HLA A∗02:01-restricted epitopes EAAGIGILTV, LLLGIGILVL, and NLSALGIFST from Melan A, BST2, and IMP2, respectively. Atomic structures of a TCR bound to all three antigens revealed the importance of the shared x-x-x-A/G-I/L-G-I-x-x-x recognition motif. Multi-epitope targeting allows individual T cells to attack cancer in several ways simultaneously. Such "multipronged" T cells exhibited superior recognition of cancer cells compared with conventional T cell recognition of individual epitopes, making them attractive candidates for the development of future immunotherapies.

Upregulation of ß-catenin due to loss of miR-139 contributes to motor neuron death in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motor neurons (MNs). There are no effective treatments and patients usually die within 2-5 years of diagnosis. Emerging commonalities between familial and sporadic cases of this complex multifactorial disorder include disruption to RNA processing and cytoplasmic inclusion bodies containing TDP-43 and/or FUS protein aggregates. Both TDP-43 and FUS have been implicated in RNA processing functions, including microRNA biogenesis, transcription, and splicing. In this study, we explore the misexpression of microRNAs in an iPSC-based disease model of FUS ALS. We identify the downregulation of miR-139, an MN-enriched microRNA, in FUS and sporadic ALS MN. We discover that miR-139 downregulation leads to the activation of canonical WNT signaling and demonstrate that the WNT transcriptional mediator ß-catenin is a major driver of MN degeneration in ALS. Our results highlight the importance of homeostatic RNA networks in ALS.

Increased frequency of CD4+ PD-1+ HLA-DR+ T cells is associated with disease progression in CLL.

Chronic lymphocytic leukaemia (CLL) patients often have abnormal expansions of CD4+ and CD8+ T cells and this can be associated with progressive disease. To characterise the key T-cell populations involved in this phenomenon, we used flow cytometry and 11 phenotypic markers to study 74 CLL patients and 14 controls. T cells of CLL patients were more phenotypically complex than those of healthy controls with significant increases in the frequencies of CD4 and CD8 memory T cells expressing exhaustion-, activation- and senescence-associated markers. Multivariate analysis of 111 different T-cell subsets showed that high frequencies of four subsets (three CD8 and one CD4) were associated with shorter progression-free survival. The most significant association was with CD4+ HLA-DR+ PD-1+ T cells, and patients could be stratified into high- and low-risk groups based on the frequency of these T cells. The expansion of this CD4+ subset could not be accounted for by age, cytomegalovirus infection or increases in Treg cells. Overall, these results highlight two relatively simple biomarkers, percentage CD8+ and percentage CD4+ PD-1+ HLA-DR+ T cells, which can be used to risk-stratify CLL patients, independent of other tumour-associated markers. They also provide further evidence for the pivotal role of T cells in modulating the pathology of CLL.

Chronic lymphocytic leukaemia: the role of T cells in a B cell disease.

Chronic lymphocytic leukaemia (CLL) has long been thought to be an immunosuppressive disease and abnormalities in T-cell subset distribution and function have been observed in many studies. However, the role of T cells (if any) in disease progression remains unclear and has not been directly studied. This has changed with the advent of new therapies, such as chimeric antigen receptor-T cells, which actively use retargeted patient-derived T cells as "living drugs" for CLL. However complete responses are relatively low (~26%) and recent studies have suggested the differentiation status of patient T cells before therapy may influence efficacy. Non-chemotherapeutic drugs, such as idelalisib and ibrutinib, also have an impact on T cell populations in CLL patients. This review will highlight what is known about T cells in CLL during disease progression and after treatment, and discuss the prospects of using T cells as predictive biomarkers for immune status and response to therapy.

Decreased sensitivity to 1,25-dihydroxyvitamin D3 in T cells from the rheumatoid joint.

1,25-dihydroxyvitaminD3 (1,25(OH)2D3), has potent anti-inflammatory effects, including suppression of IL-17 + and IFNγ+ T cells implicated in rheumatoid arthritis (RA), but efficacy at the site of active disease is unclear. To investigate this, T cells from synovial fluid (SF) and paired blood of patients with active RA were studied. 1,25(OH)2D3 had significantly less suppressive effect on Th17 cells (IL-17+IFNγ-) and Th17.1 cells (IL-17+IFNγ+) from SF compared to those from blood, and had no effect on SF CD4+ or CD8+ IFNγ+ T cell frequencies. Memory T cells (CD45RO+) predominate in SF, and 1,25(OH)2D3 had less effect on memory T cells relative to naïve (CD45RA+) T cells. RT-PCR and flow cytometry showed that this was not due to decreased expression of the vitamin D receptor or its transcription partners in memory T cells. Further studies using stimulated CD4+ T cells sorted according to IL-17 and IFNγ expression confirmed the ability of 1,25(OH)2D3 to suppress pre-existing cytokines. However, 1,25(OH)2D3 was most effective at suppressing de novo IL-17 and IFNγ induction. Correspondingly, T cell responses to 1,25(OH)2D3 correlated directly with capacity for phenotype change, which was lower in cells from SF compared to blood. These findings indicate that anti-inflammatory effects of 1,25(OH)2D3 in active RA are impaired because of reduced effects on phenotype-committed, inflammatory memory T cells that are enriched in SF. Restoration of 1,25(OH)2D3 responses in memory T cells may provide a new strategy for treatment of inflammatory diseases such as RA.

Progressive Changes in CXCR4 Expression That Define Thymocyte Positive Selection Are Dispensable For Both Innate and Conventional αßT-cell Development.

The ordered migration of immature thymocytes through thymic microenvironments generates both adaptive MHC restricted αßT-cells and innate CD1d-restricted iNKT-cells. While several chemokine receptors and ligands control multiple stages of this process, their involvement during early thymocyte development often precludes direct analysis of potential roles during later developmental stages. For example, because of early lethality of CXCR4-/- mice, and stage-specific requirements for CXCR4 in thymus colonisation and pre-TCR mediated selection, its role in thymic positive selection is unclear. Here we have examined CXCR4-CXCL12 interactions during the maturation of CD4+CD8+ thymocytes, including downstream stages of iNKT and αßT-cell development. We show CXCL12 expression is a common feature of cortical thymic epithelial cells, indicating widespread availability throughout the cortex. Moreover, CXCR4 expression by CD4+CD8+ pre-selection thymocytes is progressively downregulated following both MHC and CD1d-restricted thymic selection events. However, using CD4Cre-mediated deletion to bypass its involvement in CD4-CD8- thymocyte development, we show CXCR4 is dispensable for the maintenance and intrathymic positioning of CD4+CD8+ thymocytes, and their ability to generate mature αßT-cells and CD1d-restricted iNKT-cells. Collectively, our data define dynamic changes in CXCR4 expression as a marker for intrathymic selection events, and show its role in T-cell development is restricted to pre-CD4+CD8+ stages.