L-Cell Differentiation Is Induced by Bile Acids Through GPBAR1 and Paracrine GLP-1 and Serotonin Signaling.

Glucagon-like peptide 1 (GLP-1) mimetics are effective drugs for treatment of type 2 diabetes, and there is consequently extensive interest in increasing endogenous GLP-1 secretion and L-cell abundance. Here we identify G-protein-coupled bile acid receptor 1 (GPBAR1) as a selective regulator of intestinal L-cell differentiation. Lithocholic acid and the synthetic GPBAR1 agonist, L3740, selectively increased L-cell density in mouse and human intestinal organoids and elevated GLP-1 secretory capacity. L3740 induced expression of Gcg and transcription factors Ngn3 and NeuroD1 L3740 also increased the L-cell number and GLP-1 levels and improved glucose tolerance in vivo. Further mechanistic examination revealed that the effect of L3740 on L cells required intact GLP-1 receptor and serotonin 5-hydroxytryptamine receptor 4 (5-HT4) signaling. Importantly, serotonin signaling through 5-HT4 mimicked the effects of L3740, acting downstream of GLP-1. Thus, GPBAR1 agonists and other powerful GLP-1 secretagogues facilitate L-cell differentiation through a paracrine GLP-1-dependent and serotonin-mediated mechanism.Wellcome Trust (106262/Z/14/Z, 106263/Z/14/Z) UK Medical Research Council (MRC_MC_UU_12012/

The direct oral anticoagulants rivaroxaban and dabigatran do not inhibit orthotopic growth and metastasis of human breast cancer in mice

Factor Xa‐targeting DOACs were recently found to reduce recurrentVTE efficiently in cancer patients when compared to the standard treatment withlow‐molecular‐weight heparins (LMWHs). While the anticancer effects of LMWHshave been extensively studied in preclinical cancer models, the effects of FXa‐targetingDOACs on cancer progression remain to be studied.We investigated whether the FXa‐targeting DOAC rivaroxaban and thethrombin‐targeting DOAC dabigatran etexilate (DE) affected human breast cancergrowth and metastasis in orthotopic xenograft models.Mice that were put on a custom‐made chow diet supplementedwith rivaroxaban (0.4 or 1.0 mg/g diet) or dabigatran etexilate (DE) (10 mg/g diet)showed prolonged ex vivo coagulation times (prothrombin time [PT] and activatedpartial thromboplastin time [aPTT] assay, respectively). However, rivaroxabanand DE did not inhibit MDA‐MB‐231 tumor growth and metastasis formationin lungs or livers of 7‐week‐old fully immunodeficient NOD/SCID/ƴC−/− (NSG) mice.Comparable data were obtained for rivaroxaban‐treated mice when using NOD‐SCIDmice. Rivaroxaban and DE treatment also did not significantly inhibit tumor growthand metastasis formation when using another human triple negative breast cancer(TNBC) cell line (HCC1806) in NOD‐SCID mice. The FXa and thrombin‐induced geneexpression of the downstream target CXCL8 in both cell lines, but FXa and thrombin,did not significantly stimulate migration, proliferation, or stemness in vitro.Although effectively inhibiting coagulation, the DOACs rivaroxaban andDE did not inhibit orthotopic growth and metastasis of human TNBC. It remains to beinvestigated whether DOACs exert antitumorigenic effects in other types of cancer.Toxicolog

What's in the lunchbox : stigma or exploitation? : understanding teenage food choices in an urban school in Durban, South Africa.

M. Ed. University of KwaZulu-Natal, Durban 2015.Abstract available in PDF file

Role of Tissue Factor in Tumor Progression and Cancer-Associated Thrombosis

It has been long-established that cancer and thrombosis are linked, but the exact underlying pathological mechanism remains to be unraveled. As the initiator of the coagulation cascade, the transmembrane glycoprotein tissue factor (TF) has been intensely investigated for its role in cancer-associated thrombosis and cancer progression. TF expression is regulated by both specific oncogenes and environmental factors, and it is shown to regulate primary growth and metastasis formation in a variety of cancer models. In clinical studies, TF has been shown to be overexpressed in most cancer types and is strongly associated with disease progression. While TF clearly associates with cancer progression, a prominent role for TF in the development of cancer-associated thrombosis is less clear. The current concept is that cancer-associated thrombosis is associated with the secretion of tumor-derived TF-positive extracellular vesicles in certain tumor types. To date, many therapeutic strategies to target TF-both in preclinical and clinical phase-are being pursued, including targeting TF or the TF:FVIIa complex by itself or by exploiting TF as a docking molecule to deliver cytotoxic compounds to the tumor. In this review, the authors summarize the current understanding of the role of TF in both cancer progression and cancer-associated thrombosis, and discuss novel insights on TF as a therapeutic target as well as a biomarker for cancer progression and VTE.Thrombosis and Hemostasi

Factors associated with rectal pH among men who have sex with men

Background Rectal chlamydia treatment failures up to 22% with azithromycin 1 g have been reported, but low tissue concentrations are unlikely to be the cause. Anecdotally, low rectal pH could reduce rectal azithromycin concentrations, with in vitro studies reporting higher minimum inhibitory concentrations (MICs) with lower pHs for antibiotics used to treat sexually transmissible infections (STIs). Leucocytes arising from an inflammatory immune response could also lower pH and efficacy. We examined factors that may alter rectal pH and potentially influence treatment outcomes. METHODS: We recruited consecutive men who have sex with men (MSM) from a Dutch STI clinic between October 2016 and July 2018 who had not used antibiotics in the past fortnight. Rectal mucus collected under anoscopy using a cotton swab was used to wet a pH indicator strip. Logistic regression was used to examine the association of pH <8.0 to demographic, dietary, sexual health and behaviour data, recent medication use and STI diagnosis. RESULTS: In total, 112 MSM were recruited (median age 37 years). It was found that 45% and 39% of men were HIV positive or had a rectal infection, respectively. And 50% had a rectal pH <8.0, with 27% reporting a pH between 6.0 and 6.5 where treatment failure is thought to occur for azithromycin. The adjusted odds ratio (OR) of a pH <8.0 showed that being aged 36-45 years (OR 6.7; 95%CI: 1.9-23.4) or having high rectal leucocytes in a Gram smear (OR 0.3; 95%CI: 0.1-0.7) were significantly associated with a low and high rectal pH, respectively. CONCLUSIONS: Lower rectal pH among MSM is associated with older age and could influence the rectal pharmacokinetics of azithromycin and other drugs influenced by pH and may therefore affect treatment outcomes