Stroudebsen9699

66, 95% CI 0.49-0.89), patients with tumour stage III or IV (HR 0.71, 95% CI 0.58-0.88), and those with the least comorbidity (HR 0.71, 95% CI 0.57-0.89).

Metformin use may improve survival in gastric adenocarcinoma among diabetes patients.

Metformin use may improve survival in gastric adenocarcinoma among diabetes patients.

This open-label, Phase 1b/2 study evaluated the highly selective MET inhibitor tepotinib in systemic anticancer treatment (SACT)-naive Asian patients with advanced hepatocellular carcinoma (aHCC) with MET overexpression.

In Phase 2b, tepotinib was orally administered once daily (300, 500 or 1,000 mg) to Asian adults with aHCC. The primary endpoints were dose-limiting toxicities (DLTs) and adverse events (AEs). Phase 2 randomised SACT-naive Asian adults with aHCC with MET overexpression to tepotinib (recommended Phase 2 dose [RP2D]) or sorafenib 400 mg twice daily. The primary endpoint was independently assessed time to progression (TTP).

In Phase 1b (n = 27), no DLTs occurred; the RP2D was 500 mg. In Phase 2 (n = 90, 45 patients per arm), the primary endpoint was met independently assessed TTP was significantly longer with tepotinib versus sorafenib (median 2.9 versus 1.4 months, HR = 0.42, 90% confidence interval 0.26-0.70, P = 0.0043). Progression-free survival and objective response also favoured tepotinib. Treatment-related Grade ≥3 AE rates were 28.9% with tepotinib and 45.5% with sorafenib.

Tepotinib improved TTP versus sorafenib and was generally well tolerated in SACT-naive Asian patients with aHCC with MET overexpression.

ClinicalTrials.gov NCT01988493.

ClinicalTrials.gov NCT01988493.The NLRP3 inflammasome plays a crucial role in innate immune-mediated inflammation and contributes to the pathogenesis of multiple autoinflammatory, metabolic and neurodegenerative diseases, but medications targeting the NLRP3 inflammasome are not available for clinical use. RRx-001 is a well-tolerated anticancer agent currently being investigated in phase III clinical trials, but its effects on inflammatory diseases are not known. Here, we show that RRx-001 is a highly selective and potent NLRP3 inhibitor that has strong beneficial effects on NLRP3-driven inflammatory diseases. RRx-001 inhibits the activation of the canonical, noncanonical, and alternative NLRP3 inflammasomes but not the AIM2, NLRC4 or Pyrin inflammasomes. Mechanistically, RRx-001 covalently binds to cysteine 409 of NLRP3 via its bromoacetyl group and therefore blocks the NLRP3-NEK7 interaction, which is critical for the assembly and activation of the NLRP3 inflammasome. More importantly, RRx-001 treatment attenuates the symptoms of lipopolysaccharide (LPS)-induced systemic inflammation, dextran sulfate sodium (DSS)-induced colitis and experimental autoimmune encephalomyelitis (EAE) in mice. Thus, our study identifies RRx-001 as a new potential therapeutic agent for NLRP3-driven diseases.The 2019-20 wildfires in eastern Australia presented a globally important opportunity to evaluate the respective roles of climatic drivers and natural and anthropogenic disturbances in causing high-severity fires. Here, we show the overwhelming dominance of fire weather in causing complete scorch or consumption of forest canopies in natural and plantation forests in three regions across the geographic range of these fires. Sampling 32% (2.35 Mha) of the area burnt we found that >44% of the native forests suffered severe canopy damage. Past logging and wildfire disturbance in natural forests had a very low effect on severe canopy damage, reflecting the limited extent logged in the last 25 years (4.5% in eastern Victoria, 5.3% in southern New South Wales (NSW) and 7.8% in northern NSW). The most important variables determining severe canopy damage were broad spatial factors (mostly topographic) followed by fire weather. Timber plantations affected by fire were concentrated in NSW and 26% were burnt by the fires and >70% of the NSW plantations suffered severe canopy damage showing that this intensive means of wood production is extremely vulnerable to wildfire. learn more The massive geographic scale and severity of these Australian fires is best explained by extrinsic factors an historically anomalous drought coupled with strong, hot dry westerly winds that caused uninterrupted, and often dangerous, fire weather over the entire fire season.Economic activities in the ocean (that is, the 'blue economy') provide value to society, yet also jeopardize marine ecosystems. For example, fisheries are an essential source of income and food security for billions of people, yet bycatch poses a major threat to marine biodiversity, creating trade-offs between economic growth and biodiversity conservation. This Perspective explores bycatch levies as a market-based instrument for reconciling these trade-offs. We outline the theory and practice of bycatch levies to demonstrate how they could incentivize bycatch prevention and raise revenue for compensatory conservation, provided they are well designed, as part of a policy mix for sustainable and equitable ocean governance. We then explore ways forward for mainstreaming bycatch levies into the blue economy. While compensatory bycatch mitigation has been controversial, increasing adoption of net outcome approaches to biodiversity conservation suggests they could become mainstreamed within the next decade. Bycatch levies could raise billions of dollars towards closing global biodiversity financing gaps, delivering net outcomes for biodiversity under the United Nations Post-2020 Global Biodiversity Framework while enabling blue growth, and moving towards win-wins for economic welfare and biodiversity conservation.Nautilus is the sole surviving externally shelled cephalopod from the Palaeozoic. It is unique within cephalopod genealogy and critical to understanding the evolutionary novelties of cephalopods. Here, we present a complete Nautilus pompilius genome as a fundamental genomic reference on cephalopod innovations, such as the pinhole eye and biomineralization. Nautilus shows a compact, minimalist genome with few encoding genes and slow evolutionary rates in both non-coding and coding regions among known cephalopods. Importantly, multiple genomic innovations including gene losses, independent contraction and expansion of specific gene families and their associated regulatory networks likely moulded the evolution of the nautilus pinhole eye. The conserved molluscan biomineralization toolkit and lineage-specific repetitive low-complexity domains are essential to the construction of the nautilus shell. The nautilus genome constitutes a valuable resource for reconstructing the evolutionary scenarios and genomic innovations that shape the extant cephalopods.