No abstract

Mutations in the KRAS oncogene are found in more than 90% of patients with pancreatic ductal adenocarcinoma (PDAC), with Gly-to-Asp mutations (KRASG12D) being most common. Here, we tested the efficacy of a small molecule KRASG12D inhibitor, MRTX1133, in implantable and autochthonous PDAC models with an intact immune system. In vitro studies validated the specificity and potency of MRTX1133. In vivo, MRTX1133 prompted deep tumor regressions in all models tested, including complete or near-complete remissions after 14d. Concomitant with tumor cell apoptosis and proliferative arrest, drug treatment led to marked shifts in the tumor microenvironment (TME), including changes in fibroblasts, matrix, and macrophages. T cells were necessary for MRTX1133’s full anti-tumor effect, and T cell depletion accelerated tumor regrowth after therapy. These results validate the specificity, potency, and efficacy of MRTX1133 in immunocompetent KRASG12D-mutant PDAC models, providing a rationale for clinical testing and a platform for further investigation of combination therapies.

No abstract

The social structure of female sperm whales (Physeter macrocephalus) was examined from data collected during studies of identified individuals off the Galápagos Islands in 1985, 1987, and 1989, off the Seychelles Islands in 1990, and off mainland Ecuador in 1991. Three levels of social organization were examined in the Galápagos Islands studies. "Units," permanent associations between individuals, showed no significant deviation from a mean size of 13 individuals. "Groups," temporary associations between units lasting a few days, had a mean size of 24 individuals. Group size was lower in 1987 (an "El Niño" year) than in 1985 or 1989, but this difference was not statistically significant. "Aggregations" of groups in the same general area lasting periods of hours were significantly larger in 1985 (mean of 77 individuals) than in 1987 (mean of 47 individuals). There are significant differences between areas in aggregation sizes but not in group sizes. Groups appear to aggregate frequently off the Galápagos Islands, occasionally off mainland Ecuador, and very rarely off the Seychelles Islands. These temporal and geographic differences in sizes of groups and aggregations in sperm whales are probably caused by variations in the distribution and abundance of their food, but responses to recent exploitation may also be a factor.

Standardized studies of living sperm whales Physeter macrocephalus were carried out in 3 areas with very different recent whaling intensities. These were off the Galapagos Islands, where there seems to have been little recent whaling, off the Seychelles and Amirantes Islands, where animals were regularly caught by passing Soviet whalers, and off mainland Ecuador, adjacent to the area whaled very heavily from Paita, Peru. Sperm whale densities off the Galapagos were about 4. 2 times higher than off the Seychelles and 2.4 times higher than off mainland Ecuador. Feeding success, as indicated by defecation rates, was significantly higher off the Seychelles than in the other 2 areas. Calving rates showed the same trend, but differences between areas were not significant. Length distributions of females and immatures were similar off the Galapagos and Seychelles but rather larger animals were found off mainland Ecuador. There were very low densities of large, mature males in all areas. Our results, with the exception of the low feeding success and calving rate found off mainland Ecuador, are consistent with general models of density-dependent processes. The discrepancies may be due to migration of whales to mainland Ecuador from less exploited regions.

Tumors depend on a blood supply to deliver oxygen and nutrients, making tumor vasculature an attractive anti-cancer target. However, only a fraction of cancer patients benefits from angiogenesis inhibitors. Whether anti-angiogenic therapy would be more effective if targeted to individuals with specific tumor characteristics is unknown. To better characterize the tumor vascular environment both within and between cancer types, we developed a standardized metricthe Endothelial Index (EI)to estimate vascular density in over 10,000 human tumors, corresponding to 31 solid tumor types, from transcriptome data. We then used this index to compare hyper-and hypo-vascular tumors, enabling the classification of human tumors into six vascular microenvironment signatures (VMSs) based on the expression of a panel of 24 vascular hub genes. EI and VMS correlated with known tumor vascular features and were independently associated with prognosis in certain cancer types. Retrospective testing of clinical trial data identified VMS2 classification as a powerful biomarker for response to bevacizumab. Our studies thus provide an unbiased picture of human tumor vasculature which may enable more precise deployment of anti-angiogenesis therapy.

Septo-optic dysplasia (SOD) is a congenital disorder characterized by optic nerve, pituitary and midline brain malformations. The clinical presentation of SOD is highly variable with a poorly understood etiology. The majority of SOD cases are sporadic, but in rare instances inherited mutations have been identified in a small number of transcription factors, some of which regulate the expression of Sonic hedgehog (Shh) during mouse forebrain development. SOD is also associated with young maternal age, suggesting that environmental factors, including alcohol consumption at early stages of pregnancy, might increase the risk of developing this condition. Here, we address the hypothesis that SOD is a multifactorial disorder stemming from interactions between mutations in Shh pathway genes and prenatal ethanol exposure. Mouse embryos with mutations in the Shh co-receptor, Cdon, were treated in utero with ethanol or saline at embryonic day 8 (E8.0) and evaluated for optic nerve hypoplasia (ONH), a prominent feature of SOD. We show that both Cdon−/− mutation and prenatal ethanol exposure independently cause ONH through a similar pathogenic mechanism that involves selective inhibition of Shh signaling in retinal progenitor cells, resulting in their premature cell-cycle arrest, precocious differentiation and failure to properly extend axons to the optic nerve. The ONH phenotype was not exacerbated in Cdon−/− embryos treated with ethanol, suggesting that an intact Shh signaling pathway is required for ethanol to exert its teratogenic effects. These results support a model whereby mutations in Cdon and prenatal ethanol exposure increase SOD risk through spatiotemporal perturbations in Shh signaling activity.

BACKGROUND:The U.S. Food and Drug Administration has to date granted approval or emergency use authorization to three vaccines against severe acute respiratory syndrome coronavirus 2 and coronavirus disease 2019. In clinical trials and real-use observational studies, the Pfizer-BioNTech BNT162b2 messenger RNA coronavirus disease 2019 vaccine, as well as the Moderna mRNA-1273 messenger RNA coronavirus disease 2019 vaccine, have demonstrated high efficacy and few adverse events.