STAT signaling in the intestine.

The Janus kinase (JAK), signal transducer of activation (STAT) pathway, discovered by investigating interferon gene induction, is now recognized as an evolutionary conserved signaling pathway employed by diverse cytokines, interferons, growth factors, and related molecules. Since its discovery, this pathway has become a paradigm for membrane-to-nucleus signaling and explains how a broad range of soluble factors such as cytokines and hormones, mediate their diverse functions. The understanding of JAK-STAT signaling in the intestine has not only impacted basic science research, particularly in the understanding of intercellular communication and cell-extrinsic control of gene expression, but it has also become a prototype for transition of bench to bedside research, culminating in the clinical implementation of pathway-specific therapeutics.

Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals.

We analyzed the effects of a single 14-day course of teplizumab treatment on metabolic function and immune cells among participants in a previously reported randomized controlled trial of nondiabetic relatives at high risk for type 1 diabetes (T1D). In an extended follow-up (923-day median) of a previous report of teplizumab treatment, we found that the median times to diagnosis were 59.6 and 27.1 months for teplizumab- and placebo-treated participants, respectively (HR = 0.457, P = 0.01). Fifty percent of teplizumab-treated but only 22% of the placebo-treated remained diabetes-free. Glucose tolerance, C-peptide area under the curve (AUC), and insulin secretory rates were calculated, and relationships to T cell subsets and function were analyzed. Teplizumab treatment improved beta cell function, reflected by average on-study C-peptide AUC (1.94 versus 1.72 pmol/ml; P = 0.006). Drug treatment reversed a decline in insulin secretion before enrollment, followed by stabilization of the declining C-peptide AUC seen with placebo treatment. Proinsulin:C-peptide ratios after drug treatment were similar between the treatment groups. The changes in C-peptide with teplizumab treatment were associated with increases in partially exhausted memory KLRG1+TIGIT+CD8+ T cells (r = 0.44, P = 0.014) that showed reduced secretion of IFNγ and TNFα. A single course of teplizumab had lasting effects on delay of T1D diagnosis and improved beta cell function in high-risk individuals. Changes in CD8+ T cell subsets indicated that partially exhausted effector cells were associated with clinical response. Thus, this trial showed improvement in metabolic responses and delay of diabetes with immune therapy.

gC1qR/HABP1/p32 Is a Potential New Therapeutic Target Against Mesothelioma.

Mesothelioma is an aggressive cancer of the serous membranes with poor prognosis despite combination therapy consisting of surgery, radiotherapy, and platinum-based chemotherapy. Targeted therapies, including immunotherapies, have reported limited success, suggesting the need for additional therapeutic targets. This study investigates a potential new therapeutic target, gC1qR/HABP1/p32 (gC1qR), which is overexpressed in all morphologic subtypes of mesothelioma. gC1qR is a complement receptor that is associated with several cellular functions, including cell proliferation and angiogenesis. In vitro and in vivo experiments were conducted to test the hypothesis that targeting gC1qR with a specific gC1qR monoclonal antibody 60.11 reduces mesothelioma tumor growth, using the biphasic mesothelioma cell line MSTO-211H (MSTO). In vitro studies demonstrate cell surface and extracellular gC1qR expression by MSTO cells, and a modest 25.3 ± 1.8% (n = 4) reduction in cell proliferation by the gC1qR blocking 60.11 antibody. This inhibition was specific for targeting the C1q binding domain of gC1qR at aa 76-93, as a separate monoclonal antibody 74.5.2, directed against amino acids 204-218, had no discernable effect. In vivo studies, using a murine orthotopic xenotransplant model, demonstrated an even greater reduction in MSTO tumor growth (50% inhibition) in mice treated with the 60.11 antibody compared to controls. Immunohistochemical studies of resected tumors revealed increased cellular apoptosis by caspase 3 and TUNEL staining, in 60.11 treated tumors compared to controls, as well as impaired angiogenesis by decreased CD31 staining. Taken together, these data identify gC1qR as a potential new therapeutic target against mesothelioma with both antiproliferative and antiangiogenic properties.

Commercially available glutenases: a potential hazard in coeliac disease.

BACKGROUND: The only treatment for celiac disease (CD) is a gluten-free diet (GFD). However, there is interest among patients in a medical therapy to replace or help with a GFD. Therapies include gluten-degrading enzymes (glutenases). There are glutenases available marketed as dietary supplements that have not been demonstrated to digest the toxic epitopes of gluten. METHODS: We investigated the contents, claims, and disclaimers of glutenase products and assessed patient interest using Google AdWords to obtain Google search frequencies. RESULTS: Among 14 glutenase product, all contained proteases, eight contained X-prolyl exopeptidase dipeptidyl peptidase IV, two did not state the protease contents, and eight failed to specify the name or origin of all proteases. Eleven contained carbohydrases and lipases and three probiotics. One declared wheat and milk as allergens, two contained herbal products (type not stated) and one Carica papaya. Thirteen claimed to degrade immunogenic gluten fragments, four claimed to help alleviate gastrointestinal symptoms associated with eating gluten. Disclaimers included not being evaluated by the US Food and Drug Administration and products not intended to diagnose, treat, cure, or prevent any disease. On Google AdWords, the search frequency for the product names and the search terms was 3173 searches per month. CONCLUSIONS: The names of these products make implicit claims that appear to be supported by the claims on the labels and websites for which there is no scientific basis. Google search data suggest great interest and therefore possible use by patients with CD. There needs to be greater oversight of these 'drugs'.