T cell surveillance of oncogene-induced prostate cancer is impeded by T cell-derived TGF-β1 cytokine

Tolerance induction in T?cells takes place in most tumors and is thought to account for tumor evasion from immune eradication. Production of the cytokine TGF-β is implicated in immunosuppression, but the?cellular mechanism by which TGF-β induces T?cell dysfunction remains unclear. With a transgenic model of prostate cancer, we showed that tumor development was not suppressed by the adaptive immune system, which was associated with heightened TGF-β signaling in T?cells from the tumor-draining lymph nodes. Blockade of TGF-β signaling in T?cells enhanced tumor antigen-specific T?cell responses and inhibited tumor development. Surprisingly, T?cell- but not Treg cell-specific ablation of TGF-β1 was sufficient to augment T?cell cytotoxic activity and blocked tumor growth and metastases. These findings reveal that T?cell production of TGF-β1 is an essential requirement for tumors to evade immunosurveillance independent of TGF-β produced by tumors.     

Antibiotic susceptibility and arsenic tolerance of urinary bacteria isolated from arsenic-exposed people in Nepal

Community-based information on antibiotic susceptibility of urinary bacteria is useful in clinical practice, including empiric therapy. Owing to evidence of coselection of metal and antibiotic resistance, there is growing concern on testing of such selective pressure in clinical as well as environmental bacterial isolates. We examined arsenic tolerance and antibiotic resistance in urinary isolates and their possible coselection among arsenic-exposed subjects. Urinary arsenic levels were assessed by atomic absorption spectrophotometer. Antibiotic resistance and arsenic tolerance of urinary bacteria were observed by modified Kirby-Bauer and minimum inhibitory concentration methods, respectively. The percentage of one, two, and multidrug-resistant urinary isolates were 30.4%, 37%, and 30.4%, respectively. Isolates showed variable tolerance to arsenic species. Gram-negative isolates were more tolerant to arsenic species than Gram positive. Although statistically insignificant, arsenic tolerance tended to increase from total susceptible to two-drug resistance. However, multiple drug resistance was not induced by the urinary arsenic (p>0.05). We observed moderately positive correlation between urinary arsenic level to arsenic tolerance of isolates (p<0.05). Although tolerance significantly correlated to urinary arsenic level, coselection/coresistance of arsenic to the antibiotic resistance in urinary isolates is inconclusive and remains to be further elucidated.     

High-fat feeding promotes obesity via insulin receptor/PI3K-dependent inhibition of SF-1 VMH neurons

Steroidogenic factor 1 (SF-1)-expressing neurons of the ventromedial hypothalamus (VMH) control energy homeostasis, but the role of insulin action in these cells remains undefined. We show that insulin activates phosphatidylinositol-3-OH kinase (PI3K) signaling in SF-1 neurons and reduces firing frequency in these cells through activation of K(ATP) channels. These effects were abrogated in mice with insulin receptor deficiency restricted to SF-1 neurons (SF-1(ΔIR) mice). Whereas body weight and glucose homeostasis remained the same in SF-1(ΔIR) mice as in controls under a normal chow diet, they were protected from diet-induced leptin resistance, weight gain, adiposity and impaired glucose tolerance. High-fat feeding activated PI3K signaling in SF-1 neurons of control mice, and this response was attenuated in the VMH of SF-1(ΔIR) mice. Mimicking diet-induced overactivation of PI3K signaling by disruption of the phosphatidylinositol-3,4,5-trisphosphate phosphatase PTEN led to increased body weight and hyperphagia under a normal chow diet. Collectively, our experiments reveal that high-fat diet-induced, insulin-dependent PI3K activation in VMH neurons contributes to obesity development.     

Diagnosis of abnormal uterine bleeding with biopsy or hysteroscopy

Abnormal uterine bleeding in women is a common cause for gynecologic consultation. Physicians must maintain a low threshold for endometrial assessment in abnormal uterine bleeding. Accurately determining the etiology of the bleeding permits appropriate treatment, minimizes unnecessary delays in therapy, and prevents needless worry in women. There are few national consensus guidelines, best practice guidelines, or treatment algorithms that provide gynecologists with scrupulous data to make concise decisions for the utilization of technology such as endometrial biopsy, transvaginal ultrasound, saline infusion sonography, or hysteroscopy in the evaluation of menstrual aberrations. Using technology that has a high sensitivity to detect a disease allows a physician to make concise decisions for proceeding with minimally invasive procedures or reliance on medical therapies that will probably be effective.     

Antigen presentation,autoantibody production,and therapeutic targets in autoimmune liver disease

The liver is an important immunological organ that controls systemic tolerance. The liver harbors professional and unconventional antigen-presenting cells that are crucial for tolerance induction and maintenance. Orchestrating the immune response in homeostasis depends on a healthy and well-toned immunological liver microenvironment, which is maintained by the crosstalk of liver-resident antigen-presenting cells and intrahepatic and liver-infiltrating leukocytes. In response to pathogens or autoantigens, tolerance is disrupted by unknown mechanisms. Intrahepatic parenchymal and nonparenchymal cells exhibit unique antigen-presenting properties. The presentation of microbial and endogenous lipid-, metabolite- and peptide-derived antigens from the gut via conventional and nonconventional mechanisms can educate intrahepatic immune cells and elicit effector responses or tolerance. Perturbation of this balance results in autoimmune liver diseases, such as autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. Although the exact etiologies of these autoimmune liver diseases are unknown, it is thought that the disruption of tolerance towards self-antigens and microbial metabolites and lipids, as well as alterations in bile acid composition, may result in changes in effector cell activation and polarization and may reduce or impair protective anti-inflammatory regulatory T and B cell responses. Additionally, the canonical and noncanonical transmission of antigens and antigen:MHC complexes via trogocytosis or extracellular vesicles between different (non) immune cells in the liver may play a role in the induction of hepatic inflammation and tolerance. Here, we summarize emerging aspects of antigen presentation, autoantibody production, and the application of novel therapeutic approaches in the characterization and treatment of autoimmune liver diseases.     

Human NK cells,their receptors and function

NK cells are cytotoxic components of innate lymphoid cells (ILC) that provide a first line of defense against viral infections and contribute to control tumor growth and metastasis. Their function is finely regulated by an array of HLA-specific and non-HLA-specific inhibitory and activating receptors which allow to discriminate between healthy and altered cells. Human NK cells gained a major attention in recent years because of the important progresses in understanding their biology and of some promising data in tumor therapy. In this review, we will outline well-established issues of human NK cells and discuss some of the open questions, debates, and recent advances regarding their origin, differentiation, and tissue distribution. Newly defined NK cell specializations, including the impact of inhibitory checkpoints on their function, their crosstalk with other cell types, and the remarkable adaptive features acquired in response to certain virus infections will also be discussed.