Status of the Stardust ISPE and the Origin of Four Interstellar Dust Candidates

Some bulk properties of interstellar dust are known through infrared and X-ray observations of the interstellar medium. However, the properties of individual interstellar dust particles are largely unconstrained, so it is not known whether individual interstellar dust particles can be definitively distinguished from interplanetary dust particles in the Stardust Interstellar Dust Collector (SIDC) based only on chemical, mineralogical or isotopic analyses. It was therefore understood from the beginning of the Stardust Interstellar Preliminary Examination (ISPE) that identification of interstellar dust candidates would rest on three criteria - broad consistency with known extraterrestrial materials, inconsistency with an origin as secondary ejecta from impacts on the spacecraft, and consistency, in a statistical sense, of observed dynamical properties - that is, trajectory and capture speed - with an origin in the interstellar dust stream. Here we quantitatively test four interstellar dust candidates, reported previously [1], against these criteria

Four Interstellar Dust Candidates from the Stardust Interstellar Dust Collector

In January 2006, the Stardust sample return capsule returned to Earth bearing the first solid samples from a primitive solar system body, Comet 81P/Wild2, and a collector dedicated to the capture and return of contemporary interstellar dust. Both collectors were approx. 0.1 sq m in area and were composed of aerogel tiles (85% of the collecting area) and aluminum foils. The Stardust Interstellar Dust Collector (SIDC) was exposed to the interstellar dust stream for a total exposure factor of 20 sq m/day. The Stardust Interstellar Preliminary Examination (ISPE) is a consortium-based project to characterize the collection using nondestructive techniques. The goals and restrictions of the ISPE are described . A summary of analytical techniques is described

Phase II study of an all-oral combination of vinorelbine with capecitabine in patients with metastatic breast cancer

Purpose: Combination of intravenous (i.v.) vinorelbine and capecitabine was shown to be feasible and effective in metastatic breast cancer (MBC). In an effort to improve patient convenience and to prolong infusion-free survival, we investigated in first-line treatment a regimen combining oral vinorelbine and capecitabine in a phase II study. Patients and methods: Fifty-two patients (median age, 60 years) with MBC received the combination consisting of oral vinorelbine 60 mg/m2 on days 1, 8 and 15 plus capecitabine 1,000 mg/m2 bid given from day 1 to day 14 in an open-label, multicentre phase II study [the recommended doses were established in a phase I study (Nol\ue9 et al. in Ann Oncol 17:332-339, 2006)]. Cycles were repeated every 3 weeks. Results: Seventy-nine percent of the patients had received prior adjuvant chemotherapy and 81% presented with visceral involvement. The median number of administered cycles per patient was 7 (range 1-18). Twenty-three responses were documented and validated by an independent panel review, yielding response rates of 44.2% (95% CI, 30.5-58.7) in the 52 enrolled patients and 54.8% (95% CI, 38.7-70.2) in the 42 evaluable patients. Median progression-free survival and median overall survival were 8.4 and 25.8 months, respectively. Neutropenia was the main dose-limiting toxicity but complications were uncommon, only one patient having experienced febrile neutropenia. Other frequently reported adverse events included, fatigue, nausea, vomiting, diarrhoea and constipation, stomatitis and hand-foot syndrome, which were rarely severe. Conclusions: This regimen combining oral vinorelbine with capecitabine is effective and manageable in the first-line treatment of MBC. Oral vinorelbine on days 1, 8 and 15 with capecitabine from days 1 to 14 every 3 weeks represents a convenient option which offers an all-oral treatment to the patients and prolongs their infusion-free survival

Regulation of hepatokine gene expression in response to fasting and feeding: Influence of PPAR-α and insulin-dependent signalling in hepatocytes

International audienc

First-line trifluridine/tipiracil + bevacizumab in patients with unresectable metastatic colorectal cancer: final survival analysis in the TASCO1 study

Background: Therapeutic options are limited in patients with unresectable metastatic colorectal cancer (mCRC) ineligible for intensive chemotherapy. The use of trifluridine/tipiracil plus bevacizumab (TT-B) in this setting was evaluated in the TASCO1 trial; here, we present the final overall survival (OS) results. Methods: TASCO1 was an open-label, non-comparative phase II trial. Patients (n = 153) were randomised 1:1 to TT-B (trifluridine/tipiracil 35 mg/m2 orally twice daily on days 1–5 and 8–12, and bevacizumab intravenously 5 mg/kg on days 1 and 15 of each 28-day cycle) or capecitabine plus bevacizumab (C-B; capecitabine, 1250 mg/m2 orally twice daily on days 1–14 and bevacizumab 7.5 mg/kg intravenously on day 1 of each 21-day cycle). Final OS was analysed when all patients had either died or withdrawn from the study. Adjusted multivariate regression was used to investigate the effects of pre-specified variables on OS. Results: At 1 September 2020, median OS was 22.3 months (95% CI: 18.0–23.7) with TT-B and 17.7 months (95% CI: 12.6–19.8) with C-B (adjusted HR 0.78; 95% CI: 0.55–1.10). No variables negatively affected OS with TT-B. Safety results were consistent with prior findings. Conclusions: TT-B is a promising therapeutic regimen in mCRC patients ineligible for intensive chemotherapy. Clinical trial information: NCT02743221 (clinicaltrials.gov

Phase II study evaluating trifluridine/tipiracil + bevacizumab and capecitabine + bevacizumab in first-line unresectable metastatic colorectal cancer (mCRC) patients who are non-eligible for intensive therapy (TASCO1): Results of the primary analysis.

status: publishe

The hepatocyte insulin receptor is required to program the liver clock and rhythmic gene expression.

Liver physiology is circadian and sensitive to feeding and insulin. Food intake regulates insulin secretion and is a dominant signal for the liver clock. However, how much insulin contributes to the effect of feeding on the liver clock and rhythmic gene expression remains to be investigated. Insulin action partly depends on changes in insulin receptor (IR)-dependent gene expression. Here, we use hepatocyte-restricted gene deletion of IR to evaluate its role in the regulation and oscillation of gene expression as well as in the programming of the circadian clock in the adult mouse liver. We find that, in the absence of IR, the rhythmicity of core-clock gene expression is altered in response to day-restricted feeding. This change in core-clock gene expression is associated with defective reprogramming of liver gene expression. Our data show that an intact hepatocyte insulin receptor is required to program the liver clock and associated rhythmic gene expression

The Labour Party conference verbatim report 20 September - 4 October 1996

SIGLEAvailable from British Library Document Supply Centre-DSC:7638.253(1996) / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Integrative study of diet-induced mouse models of NAFLD identifies PPARα as a sexually dimorphic drug target.

We evaluated the influence of sex on the pathophysiology of non-alcoholic fatty liver disease (NAFLD). We investigated diet-induced phenotypic responses to define sex-specific regulation between healthy liver and NAFLD to identify influential pathways in different preclinical murine models and their relevance in humans. Different models of diet-induced NAFLD (high-fat diet, choline-deficient high-fat diet, Western diet or Western diet supplemented with fructose and glucose in drinking water) were compared with a control diet in male and female mice. We performed metabolic phenotyping, including plasma biochemistry and liver histology, untargeted large-scale approaches (liver metabolome, lipidome and transcriptome), gene expression profiling and network analysis to identify sex-specific pathways in the mouse liver. The different diets induced sex-specific responses that illustrated an increased susceptibility to NAFLD in male mice. The most severe lipid accumulation and inflammation/fibrosis occurred in males receiving the high-fat diet and Western diet, respectively. Sex-biased hepatic gene signatures were identified for these different dietary challenges. The peroxisome proliferator-activated receptor α (PPARα) co-expression network was identified as sexually dimorphic, and in vivo experiments in mice demonstrated that hepatocyte PPARα determines a sex-specific response to fasting and treatment with pemafibrate, a selective PPARα agonist. Liver molecular signatures in humans also provided evidence of sexually dimorphic gene expression profiles and the sex-specific co-expression network for PPARα. These findings underscore the sex specificity of NAFLD pathophysiology in preclinical studies and identify PPARα as a pivotal, sexually dimorphic, pharmacological target. NCT02390232