Impairment of organ-specific T cell negative selection by diabetes susceptibility genes: genomic analysis by mRNA profiling

BACKGROUND T cells in the thymus undergo opposing positive and negative selection processes so that the only T cells entering circulation are those bearing a T cell receptor (TCR) with a low affinity for self. The mechanism differentiating negative from positive selection is poorly understood, despite the fact that inherited defects in negative selection underlie organ-specific autoimmune disease in AIRE-deficient people and the non-obese diabetic (NOD) mouse strain RESULTS Here we use homogeneous populations of T cells undergoing either positive or negative selection in vivo together with genome-wide transcription profiling on microarrays to identify the gene expression differences underlying negative selection to an Aire-dependent organ-specific antigen, including the upregulation of a genomic cluster in the cytogenetic band 2F. Analysis of defective negative selection in the autoimmune-prone NOD strain demonstrates a global impairment in the induction of the negative selection response gene set, but little difference in positive selection response genes. Combining expression differences with genetic linkage data, we identify differentially expressed candidate genes, including Bim, Bnip3, Smox, Pdrg1, Id1, Pdcd1, Ly6c, Pdia3, Trim30 and Trim12. CONCLUSION The data provide a molecular map of the negative selection response in vivo and, by analysis of deviations from this pathway in the autoimmune susceptible NOD strain, suggest that susceptibility arises from small expression differences in genes acting at multiple points in the pathway between the TCR and cell death.This work was supported by grants from the NHMRC and the Juvenile Diabetes Research Foundation

Diagnosis, treatment and survival from bladder, upper urinary tract and urethral cancers: Real world findings from NHS England between 2013 and 2019

Objective We report NHS England data for patients with bladder cancer (BC), upper tract urothelial cancer (UTUC: renal pelvic and ureteric), and urethral cancers from 2013 to 2019. Materials and Methods Hospital episode statistics, waiting times, and cancer registrations were extracted from NHS Digital. Results Registrations included 128 823 individuals with BC, 16 018 with UTUC, and 2533 with urethral cancer. In 2019, 150 816 persons were living with a diagnosis of BC, of whom 113 067 (75.0%) were men, 85 117 (56.5%) were aged >75 years, and 95 553 (91.7%) were Caucasian. Incidence rates were stable (32.7–34.3 for BC, 3.9–4.2 for UTUC and 0.6–0.7 for urethral cancer per 100 000 population). Most patients 52 097 (mean [range] 41.3% [40.7–42.0%]) were referred outside the 2-week-wait pathway and 15 340 (mean [range] 12.2% [11.7–12.6%]) presented as emergencies. Surgery, radiotherapy, chemotherapy, or multimodal treatment use varied with disease stage, patient factors and Cancer Alliance. Between 27% and 29% (n = 6616) of muscle-invasive BCs did not receive radical treatment. Survival rates reflected stage, grade, location, and tumour histology. Overall survival rates did not improve over time (relative change: 0.97, 95% confidence interval 0.97–0.97) at 2 years in contrast to other cancers. Conclusion The diagnostic pathway for BC needs improvement. Increases in survival might be delivered through greater use of radical treatment. NHS Digital data offers a population-wide picture of this disease but does not allow individual outcomes to be matched with disease or patient features and key parameters can be missing or incomplete

Impairment of organ-specific T cell negative selection by diabetes susceptibility genes: genomic analysis by mRNA profiling

Background: T cells in the thymus undergo opposing positive and negative selection processes so that the only T cells entering circulation are those bearing a T cell receptor (TCR) with a low affinity for self. The mechanism differentiating negative from positive selection is poorly understood, despite the fact that inherited defects in negative selection underlie organ-specific autoimmune disease in AIRE-deficient people and the non-obese diabetic (NOD) mouse strain.status: publishe

Providing a Framework for Meaningful Patient Involvement in Clinical Practice Guideline Development and Implementation

Acknowledgments: The EVOLVE research team acknowledges the valuable support and participation of Guideline Office staff and Guideline Panel members at the European Association of Urology (EAU). We would like to thank all study participants and patient and medical organisations who promoted the EVOLVE study. We also thank the following organisations for their help in study recruitment: Action Bladder Cancer; Cancer Research UK; Europa Uomo; EAU; European Association of Urology Nurses; European Cancer Patient Coalition; Fight Bladder Cancer; International Kidney Cancer Coalition; Kidney Cancer Support Network; UCAN Urological CANcer Charity; Prostate Cancer UK; and World Bladder Cancer Patient Coalition. The EVOLVE study is funded by the NHS Grampian Endowment Fund via the urological cancer charity UCAN.Peer reviewedPostprin

Diagnosis, treatment and survival from bladder, upper urinary tract and urethral cancers: Real world findings from NHS England between 2013 and 2019

Objective We report NHS England data for patients with bladder cancer (BC), upper tract urothelial (UTUC: renal pelvic and ureteric) and urethral cancers from 2013 to 2019. Materials and methods Hospital episode statistics, waiting times and cancer registrations were extracted from NHS Digital. Results Registrations included 128,823 individuals with BC, 16,018 with UTUC and 2,533 with urethral cancer. In 2019, 150,816 persons were living with a diagnosis of BC, of whom 113,067 (75.0%) were men, 85,117 (56.5%) aged over 75 yrs, and 95,553 (91.7%) Caucasian. Incidence rates were stable (32.7-34.3 for BC, 3.9-4.2 for UTUC and 0.6-0.7 for urethral cancer per 100,000 population). Most patients (52,097 (41.3% (40.7-42.0%)) were referred outside the two week wait pathway and 15,340 (12.2% (11.7-12.6%)) presented as emergencies. Surgery, radiotherapy, chemotherapy or multimodal treatment use varied with disease stage, patient factors and Cancer Alliance. Between 27-29% (6,616) of muscle-invasive BCs did not receive radical treatment. Survival rates reflected stage, grade, location and tumour histology. Overall survival rates did not improve over time (relative change: 0.97 (95%CI: 0.97-0.97) at 2 years) in contrast to other cancers. Conclusion The diagnostic pathway for BC needs improvement. Increases in survival might be delivered through greater use in radical treatment. NHS Digital data offers a population-wide picture of this disease but does not allow individual outcomes to be matched with disease or patient features and key parameters can be missing or incomplete

Foxp3+ regulatory T cells exert asymmetric control over murine helper responses by inducing Th2 cell apoptosis

Foxp3+ regulatory T cells play a pivotal role in maintaining self-tolerance and immune homeostasis. In the absence of regulatory T cells, generalized immune activation and multiorgan T cell–driven pathology occurs. Although the phenomenon of immunologic control by Foxp3+ regulatory T cells is well recognized, the comparative effect over different arms of the immune system has not been thoroughly investigated. Here, we generated a cohort of mice with a continuum of regulatory T-cell frequencies ranging from physiologic levels to complete deficiency. This titration of regulatory T-cell depletion was used to determine how different effector subsets are controlled. We found that in vivo Foxp3+ regulatory T-cell frequency had a proportionate relationship with generalized T-cell activation and Th1 magnitude, but it had a surprising disproportionate relationship with Th2 magnitude. The asymmetric regulation was associated with efficient suppression of Th2 cells through additional regulations on the apoptosis rate in Th2 cells and not Th1 cells and could be replicated by CTLA4-Ig or anti–IL-2 Ab. These results indicate that the Th2 arm of the immune system is under tighter control by regulatory T cells than the Th1 arm, suggesting that Th2-driven diseases may be more responsive to regulatory T-cell manipulation