University of Tennessee Health Science Center

About: University of Tennessee Health Science Center is a education organization based out in Memphis, Tennessee, United States. It is known for research contribution in the topics: Population & Transplantation. The organization has 15716 authors who have published 26884 publications receiving 1176697 citations.

A novel retinoblastoma therapy from genomic and epigenetic analyses

Abstract: Retinoblastoma is an aggressive childhood cancer of the developing retina that is initiated by the biallelic loss of RB1. Tumours progress very quickly following RB1 inactivation but the underlying mechanism is not known. Here we show that the retinoblastoma genome is stable, but that multiple cancer pathways can be epigenetically deregulated. To identify the mutations that cooperate with RB1 loss, we performed whole-genome sequencing of retinoblastomas. The overall mutational rate was very low; RB1 was the only known cancer gene mutated. We then evaluated the role of RB1 in genome stability and considered non-genetic mechanisms of cancer pathway deregulation. For example, the proto-oncogene SYK is upregulated in retinoblastoma and is required for tumour cell survival. Targeting SYK with a small-molecule inhibitor induced retinoblastoma tumour cell death in vitro and in vivo. Thus, retinoblastomas may develop quickly as a result of the epigenetic deregulation of key cancer pathways as a direct or indirect result of RB1 loss.

Stability and function of regulatory T cells is maintained by a neuropilin-1–semaphorin-4a axis

Abstract: Neuropilin-1 (Nrp1) on regulatory T (Treg) cells is shown to interact with semaphorin-4a (Sema4a) to promote a program of Treg-cell stability and survival, in part through PTEN-mediated modulation of Akt signalling; Nrp1-deficient Treg cells can maintain immune homeostasis but fail to suppress in inflammatory sites, such as tumours, providing an attractive immunotherapeutic target for the treatment of cancers. Regulatory T cells (Treg) constitute a barrier to effective anti-tumour immunity. Their depletion can induce reduction and clearance of many tumours, but as the cells perform an important balancing role in the immune system, depletion also results in unchecked autoimmunity and death. This paper describes an interaction between semaphorin-4a — an activator for T-cell-mediated immunity — and the neuropilin receptor Nrp1 on Treg cells that is required for Treg cells to limit anti-tumour immune responses and to cure established inflammatory colitis, but is dispensable for suppression of autoimmunity and maintenance of immune homeostasis. It remains to be determined whether it is feasible to limit tumour growth by targeting Treg cells without unleashing autoimmunity. The two biological activities may be inseparable, but this work points to ways in which this important system can be further characterized. Regulatory T cells (Treg cells) have a crucial role in the immune system by preventing autoimmunity, limiting immunopathology, and maintaining immune homeostasis1. However, they also represent a major barrier to effective anti-tumour immunity and sterilizing immunity to chronic viral infections1. The transcription factor Foxp3 has a major role in the development and programming of Treg cells2,3. The relative stability of Treg cells at inflammatory disease sites has been a highly contentious subject4,5,6. There is considerable interest in identifying pathways that control the stability of Treg cells as many immune-mediated diseases are characterized by either exacerbated or limited Treg-cell function. Here we show that the immune-cell-expressed ligand semaphorin-4a (Sema4a) and the Treg-cell-expressed receptor neuropilin-1 (Nrp1) interact both in vitro, to potentiate Treg-cell function and survival, and in vivo, at inflammatory sites. Using mice with a Treg-cell-restricted deletion of Nrp1, we show that Nrp1 is dispensable for suppression of autoimmunity and maintenance of immune homeostasis, but is required by Treg cells to limit anti-tumour immune responses and to cure established inflammatory colitis. Sema4a ligation of Nrp1 restrained Akt phosphorylation cellularly and at the immunologic synapse by phosphatase and tensin homologue (PTEN), which increased nuclear localization of the transcription factor Foxo3a. The Nrp1-induced transcriptome promoted Treg-cell stability by enhancing quiescence and survival factors while inhibiting programs that promote differentiation. Importantly, this Nrp1-dependent molecular program is evident in intra-tumoral Treg cells. Our data support a model in which Treg-cell stability can be subverted in certain inflammatory sites, but is maintained by a Sema4a–Nrp1 axis, highlighting this pathway as a potential therapeutic target that could limit Treg-cell-mediated tumour-induced tolerance without inducing autoimmunity.

Mid-trimester endovaginal sonography in women at high risk for spontaneous preterm birth.

Abstract: ContextAlthough shortened cervical length has been consistently associated with spontaneous preterm birth, it is not known when in gestation this risk factor becomes apparent.ObjectiveTo determine whether sonographic cervical findings between 16 weeks' and 18 weeks 6 days' gestation predict spontaneous preterm birth and whether serial evaluations up to 23 weeks 6 days' gestation improve prediction in high-risk women.Design, Setting, and ParticipantsBlinded observational study performed between March 1997 and November 1999 at 9 university-affiliated medical centers in the United States in 183 women with singleton gestations who previously had experienced a spontaneous birth before 32 weeks' gestation.ObservationCertified sonologists performed 590 endovaginal sonographic examinations at 2-week intervals. Cervical length was measured from the external os to the functional internal os along a closed endocervical canal. Funneling and dynamic cervical shortening were also recorded.Main Outcome MeasureSpontaneous preterm birth before 35 weeks' gestation, analyzed by selected cutoff values of cervical length.ResultsForty-eight women (26%) experienced spontaneous preterm birth before 35 weeks' gestation. A cervical length of less than 25 mm at the initial sonographic examination was associated with a relative risk (RR) for spontaneous preterm birth of 3.3 (95% confidence interval [CI], 2.1-5.0; sensitivity = 19%; specificity = 98%; positive predictive value = 75%). After controlling for cervical length, neither funneling (P = .24) nor dynamic shortening (P = .054) were significant independent predictors of spontaneous preterm birth. However, using the shortest ever observed cervical length on serial evaluations, after any dynamic shortening, the RR of a cervical length of less than 25 mm for spontaneous preterm birth increased to 4.5 (95% CI, 2.7-7.6; sensitivity = 69%; specificity = 80%; positive predictive value = 55%). Compared with a single cervical measurement at 16 weeks' to 18 weeks 6 days' gestation, serial measurements at up to 23 weeks 6 days significantly improved the prediction of spontaneous preterm birth in a receiver operating characteristic curve analysis (P = .03).ConclusionsCervical length assessed by endovaginal sonography between 16 weeks' and 18 weeks 6 days' gestation, augmented by serial evaluations, predicts spontaneous preterm birth before 35 weeks' gestation in high-risk women.

Clinical epidemiology and disease burden of nonalcoholic fatty liver disease

Abstract: Nonalcoholic fatty liver disease (NAFLD) is defined as the presence of hepatic fat accumulation after the exclusion of other causes of hepatic steatosis, including other causes of liver disease, excessive alcohol consumption, and other conditions that may lead to hepatic steatosis. NAFLD encompasses a broad clinical spectrum ranging from nonalcoholic fatty liver to nonalcoholic steatohepatitis (NASH), advanced fibrosis, cirrhosis, and finally hepatocellular carcinoma (HCC). NAFLD is the most common liver disease in the world and NASH may soon become the most common indication for liver transplantation. Ongoing persistence of obesity with increasing rate of diabetes will increase the prevalence of NAFLD, and as this population ages, many will develop cirrhosis and end-stage liver disease. There has been a general increase in the prevalence of NAFLD, with Asia leading the rise, yet the United States is following closely behind with a rising prevalence from 15% in 2005 to 25% within 5 years. NAFLD is commonly associated with metabolic comorbidities, including obesity, type II diabetes, dyslipidemia, and metabolic syndrome. Our understanding of the pathophysiology of NAFLD is constantly evolving. Based on NAFLD subtypes, it has the potential to progress into advanced fibrosis, end-stage liver disease and HCC. The increasing prevalence of NAFLD with advanced fibrosis, is concerning because patients appear to experience higher liver-related and non-liver-related mortality than the general population. The increased morbidity and mortality, healthcare costs and declining health related quality of life associated with NAFLD makes it a formidable disease, and one that requires more in-depth analysis.