Hanwei Zhang

Gamma-aminobutyric acid (GABA) is both a major inhibitory neurotransmitter in the CNS and a product of beta cells of the peripheral islets. Our previous studies, and those of others, have shown that T cells express functional GABAA receptors. However, their subunit composition and physiological relevance are unknown. In this study, we show that a subset of GABAA receptor subunits are expressed by CD4+ T cells, including the delta subunit that confers high affinity for GABA and sensitivity to alcohol. GABA at relatively low concentrations down-regulated effector T cell responses to beta cell Ags ex vivo, and administration of GABA retarded the adoptive transfer of type 1 diabetes (T1D) in NOD/scid mice. Furthermore, treatment with low dose of GABA (600 microg daily) dramatically inhibited the development of proinflammatory T cell responses and disease progression in T1D-prone NOD mice that already had established autoimmunity. Finally, GABA inhibited TCR-mediated T cell cycle progression in vitro, which may underlie GABA's therapeutic effects. The immunoinhibitory effects of GABA on T cells may contribute to the long prodomal period preceding the development of T1D, the immunological privilege of the CNS, and the regulatory effects of alcohol on immune responses. Potentially, pharmacological modulation of GABAA receptors on T cells may provide a new class of therapies for human T1D as well as other inflammatory diseases.

OBJECTIVE: To assess the usefulness of measuring serum matrix metalloproteinase 3 (MMP-3) and macrophage colony-stimulating factor (M-CSF) in patients with ankylosing spondylitis (AS). METHODS: Serum levels of MMP-3 and M-CSF were measured in AS patients who did and did not receive infliximab treatment. These were compared with those of 28 healthy subjects. RESULTS: In the group of AS patients not treated with biologics, both M-CSF and MMP-3 correlated with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) values, but not with each other. Logistic regression analysis showed that MMP-3 values were high in those with severely active disease. Infusions of infliximab in AS patients led to a significant decrease in the values of the BASDAI as well as the serum MMP-3, but no change in the serum M-CSF values. CONCLUSION: MMP-3 and M-CSF are potentially useful markers of AS disease activity.

INTRODUCTION: We hypothesized that hypertensive patients harbor a higher risk of urinary bladder (UB) cancer. MATERIAL AND METHODS: We performed a population-based cohort study on adults using a National Health Insurance Research Database (NHIRD) dataset. Hypertension and comparison non-hypertensive (COMP) groups comprising 39,618 patients each were propensity score-matched by age, sex, index date, and medical comorbidities. The outcome was incident UB cancer validated using procedure codes. We constructed multivariable Cox models to derive adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). Cumulative incidence was compared using a log-rank test. RESULTS: During a total follow-up duration of 380,525 and 372,020 person-years in the hypertension and COMP groups, 248 and 186 patients developed UB cancer, respectively, representing a 32% increase in the risk (aHR, 1.32; 95% CI, 1.09-1.60). Hypertensive women harbored a significantly increased risk of UB cancer (aHR, 1.55; 95% CI, 1.12-2.13) compared with non-hypertensive women, whereas men with hypertension had a statistically non-significant increased risk (aHR, 1.22; 95% CI, 0.96-1.55). The sensitivity analysis demonstrated that the increased risk was sustained throughout different follow-up durations for the entire cohort; a statistical increase in the risk was also noted among hypertensive men. CONCLUSION: This nationwide population-based propensity score-matched cohort study supports a positive association between hypertension and subsequent UB cancer development.

< 0.001). To conclude, based on these data, epileptic individuals ≥50 years were at a greater risk of developing dementia than people who do not have epilepsy, which indicates that a diagnosis of epilepsy presents a greater risk for the development of dementia.

Small cell carcinoma of the bladder (SCCB) is a rare and lethal phenotype of bladder cancer. The pathogenesis and molecular features are unknown. Here, we established a genetically engineered SCCB model and a cohort of patient SCCB and urothelial carcinoma samples to characterize molecular similarities and differences between bladder cancer phenotypes. We demonstrate that SCCB shares a urothelial origin with other bladder cancer phenotypes by showing that urothelial cells driven by a set of defined oncogenic factors give rise to a mixture of tumor phenotypes, including small cell carcinoma, urothelial carcinoma, and squamous cell carcinoma. Tumor-derived single-cell clones also give rise to both SCCB and urothelial carcinoma in xenografts. Despite this shared urothelial origin, clinical SCCB samples have a distinct transcriptional profile and a unique transcriptional regulatory network. Using the transcriptional profile from our cohort, we identified cell surface proteins (CSPs) associated with the SCCB phenotype. We found that the majority of SCCB samples have PD-L1 expression in both tumor cells and tumor-infiltrating lymphocytes, suggesting that immune checkpoint inhibitors could be a treatment option for SCCB. We further demonstrate that our genetically engineered tumor model is a representative tool for investigating CSPs in SCCB by showing that it shares a similar a CSP profile with clinical samples and expresses SCCB-up-regulated CSPs at both the mRNA and protein levels. Our findings reveal distinct molecular features of SCCB and provide a transcriptional dataset and a preclinical model for further investigating SCCB biology.