Islet β-Cells Deficient in Bcl-xL Develop but Are Abnormally Sensitive to Apoptotic Stimuli

OBJECTIVE: Bcl-xL is an antiapoptotic member of the Bcl-2 family of proteins and a potent regulator of cell death. We investigated the importance of Bcl-xL for beta-cells by deleting the Bcl-x gene specifically in beta-cells and analyzing their survival in vivo and in culture. RESEARCH DESIGN AND METHODS: Islets with beta-cells lacking the Bcl-x gene were assessed in vivo by histology and by treatment of mice with low-dose streptozotocin (STZ). Islets were isolated by collagenase digestion and treated in culture with the apoptosis inducers staurosporine, thapsigargin, gamma-irradiation, proinflammatory cytokines, or Fas ligand. Cell death was assessed by flow cytometric analysis of subgenomic DNA. RESULTS: Bcl-xL-deficient beta-cells developed but were abnormally sensitive to apoptosis induced in vivo by low-dose STZ. Although a small proportion of beta-cells still expressed Bcl-xL, these did not have a survival advantage over their Bcl-xL-deficient neighbors. Islets appeared normal after collagenase isolation and whole-islet culture. They were, however, abnormally sensitive in culture to a number of different apoptotic stimuli including cytotoxic drugs, proinflammatory cytokines, and Fas ligand. CONCLUSIONS: Bcl-xL expression in beta-cells is dispensible during islet development in the mouse. Bcl-xL is, however, an important regulator of beta-cell death under conditions of synchronous stress. Bcl-xL expression at physiological levels may partially protect beta-cells from apoptotic stimuli, including apoptosis because of mediators implicated in type 1 diabetes and death or degeneration of transplanted islets

First EMC3-EIRENE modeling of JT-60SA edge plasmas with/without RMP field

For the ITER and DEMO reactors, transient heat load induced by large edge localized mode (ELM) must be mitigated or suppressed to maintain the surface condition of the divertor plate. From recent studies in tokamak devices, an application of the resonant magnetic perturbation (RMP) field is thought to be one of the effective solutions. The RMP has an inherently three-dimensional (3D) nature, causing a non-axisymmetric modification of the divertor heat flux profile. Due to the RMP, splitting of a strike point is observed. Recent experiment in ASDEX-U indicated that the RMP induces the modification of toroidal and radial distributions of the heat flux, although the toroidally averaged radial heat flux is the same with that without the RMP case. In addition, the degree of the heat flux variation was found to depend on the upstream plasma condition. The research of the RMP effect for the divertor heat load is being conducted in both experiments and numerical simulations. The ELM mitigation experiment with RMP in JT-60SA tokamak, which is being constructed, is scheduled as a key research item. Before the experiment, it is important to predict the divertor footprint pattern and its characteristics by using a modeling code. For this aim, the 3D plasma fluid transport and kinetic neutral transport code, “EMC3-EIRENE”, is suitable, and it has been applied to several devices. Therefore, we have started the EMC3-EIRENE modeling of JT-60SA edge plasmas with/without the RMP field. At first, we calculated pure deuterium plasma in an axisymmetric magnetic configuration grid, and then results were compared with those from the two-dimensional (2D) transport code “SONIC”. As a result, similar amplitude and decay of the heat flux profile on the divertor plate were obtained. After that, the grid equipping the RMP field with the toroidal mode number of n = 3 was generated (so-called an ITER-like scenario). From a 120-degree range calculation in the toroidal direction, lobe structures and a footprint splitting were first confirmed in the EMC3-EIRENE calculation of JT-60SA, being consistent with the previous magnetic field tracing. We will present the above-mentioned results and discuss RMP effects on footprint profile, flow, recycling, and so on

A phase I clinical and pharmacokinetic study of CS-682 administered orally in advanced malignant solid tumors.

CS-682 (1-(2-C-cyano-2-deoxy-beta-D-arabino-pentofuranosyl)-N4-palmitoylcytosine) is a novel orally administered 2'-deoxycytidine-type antimetabolite, which has a wide spectrum of antitumor activity in human tumor xenograft models. We conducted a phase I study to define the toxicity, pharmacokinetics and antitumor activity of CS-682 in patients with advanced solid tumors. Forty patients were enrolled to receive escalating doses of CS-682. CS-682 was given orally, once daily three times a week (Monday, Wednesday and Friday), for four weeks consecutively, followed by a two-week rest period. Twenty-two men and 18 women, median age 63.5 (range 31 to 82) were treated. The most common tumor type was colorectal cancer with 15 patients. Others tumors occurring in 3 or more patients included prostate, breast and lung carcinomas. Sixty percent of the patients had received greater than 2 prior chemotherapy programs. Patients have been treated at each of the following dose levels (mg/m2/day): 1.5, 12, 20, 25, 30, 50, 67, 90, 120, 160 and 220. Non hematologic toxicities grade 3 [NCI Common Toxicity Criteria (version 2.0)] related to treatment included nausea in 2, vomiting in 1, anorexia and asthenia in 2, and dehydration in 1. Severe hematologic toxicities (grade 3-4) were seen more frequently with 10 patients experiencing grade 3-4 neutropenia, 2 with grade 4 thrombocytopenia and 2 with grade 3 anemia. Neutropenia requiring hospitalization occurred in 3 patients. Dose-limiting neutropenia was observed at 220 mg/m2/day. The maximum tolerated dose was determined to be 160 mg/m2/day. No tumor responses were observed in this study. Six patients experienced stable disease, including one who has stable disease after having received 34 courses of CS-682. After oral administration, CS-682 is rapidly absorbed and metabolized to CNDAC, which is further metabolized by cytidine deaminase to the inactive product CNDAU. Peak plasma concentrations of CNDAC were achieved 2.2 +/- 0.9 h after drug administration and the terminal elimination half-life was 1.7 +/- 1.5 h. Measurable concentrations of CNDAU were first seen 0.60 +/- 0.31 h, peak plasma concentrations were achieved 3.1 +/- 0.9 h after the CS-682 dose, and the terminal elimination half-life was 2.3 +/- 1.7 h. The recommended phase 2 starting dose for the 3 days/week regimen of CS-682 is 160 mg/m2/day for 4 weeks repeated after a 2-week rest period.Clinical Trial, Phase IJournal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe