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Investigating therapeutic "outliers" that show exceptional responses to anti-cancer treatment can uncover biomarkers of drug sensitivity. We performed preclinical trials investigating primary murine acute myeloid leukemias (AMLs) generated by retroviral insertional mutagenesis in KrasG12D "knockin" mice with the MEK inhibitor PD0325901 (PD901). One outlier AML responded and exhibited intrinsic drug resistance at relapse. Loss of wild-type (WT) Kras enhanced the fitness of the dominant clone and rendered it sensitive to MEK inhibition. Similarly, human colorectal cancer cell lines with increased KRAS mutant allele frequency were more sensitive to MAP kinase inhibition, and CRISPR-Cas9-mediated replacement of WT KRAS with a mutant allele sensitized heterozygous mutant HCT116 cells to treatment. In a prospectively characterized cohort of patients with advanced cancer, 642 of 1,168 (55%) with KRAS mutations exhibited allelic imbalance. These studies demonstrate that serial genetic changes at the Kras/KRAS locus are frequent in cancer and modulate competitive fitness and MEK dependency.

Objective: This study aims to evaluate ChatGPT's performance in addressing real-world otolaryngology patient questions, focusing on accuracy, comprehensiveness, and patient safety, to assess its suitability for integration into healthcare. Methods: A cross-sectional study was conducted using patient questions from the public online forum Reddit's r/AskDocs, where medical advice is sought from healthcare professionals. Patient questions were input into ChatGPT (GPT-3.5), and responses were reviewed by 5 board-certified otolaryngologists. The evaluation criteria included difficulty, accuracy, comprehensiveness, and bedside manner/empathy. Statistical analysis explored the relationship between patient question characteristics and ChatGPT response scores. Potentially dangerous responses were also identified. Results: Patient questions averaged 224.93 words, while ChatGPT responses were longer at 414.93 words. The accuracy scores for ChatGPT responses were 3.76/5, comprehensiveness scores were 3.59/5, and bedside manner/empathy scores were 4.28/5. Longer patient questions did not correlate with higher response ratings. However, longer ChatGPT responses scored higher in bedside manner/empathy. Higher question difficulty correlated with lower comprehensiveness. Five responses were flagged as potentially dangerous. Conclusion: While ChatGPT exhibits promise in addressing otolaryngology patient questions, this study demonstrates its limitations, particularly in accuracy and comprehensiveness. The identification of potentially dangerous responses underscores the need for a cautious approach to AI in medical advice. Responsible integration of AI into healthcare necessitates thorough assessments of model performance and ethical considerations for patient safety. [ABSTRACT FROM AUTHOR]

The influence of health and socioeconomic status on perceptions of aging and adaptation strategies of older African/Caribbean-American women was examined. Responses of 38 women (average age = 77.3 years) to: 'What do you like and dislike about growing old?' and 'To what would you attribute your long life?' were analyzed. Respondents were classified as: financially independent/healthy, financially dependent/healthy, financially independent/not healthy and financially dependent/not healthy. Narratives revealed declining health and restricted financial resources limited perceptions of opportunities for well-being. Despite differences in health and financial status, groups had some common strategies: avoiding risk behaviors, holding moral beliefs, optimism, altruism and spirituality. It was concluded that health and socioeconomic status had some influence on perceptions of aging and adaptation strategies. Keywords: African-American; Caribbean-American; Older Adult; Aging Perspectives

Three drivers of subsidence are recognized in the Western Interior Basin: Mesozoic–early Cenozoic flexure adjacent to the thin‐skinned, eastward propagating Sevier Orogeny, Late Cretaceous–Eocene flexure associated with thick‐skinned Laramide Uplifts and Late Cretaceous dynamic subsidence. This study combines outcrop lithofacies, palaeocurrent measurements, detrital zircon geochronology, biostratigraphy, stratigraphic correlations and isopach maps of Coniacian–Maastrichtian (89–66 Ma) units to identify these subsidence mechanisms impact on basin geometry and stratigraphic architecture in the northern Utah to southwestern Wyoming segment of the North American Cordillera. Detrital zircon maximum depositional ages and biostratigraphy support that the Maastrichtian Hams Fork Conglomerate was deposited above the Moxa unconformity in the wedgetop and foredeep depozones. The Moxa unconformity underlies the progradational Ericson Formation in the distal foredeep. The Hams Fork, however, is younger than the Ericson Formation, and instead equivalent to upper Almond Formation. Therefore, the hiatus associated with the Moxa unconformity continued for several million years longer in the fold belt and proximal basin than in the distal foredeep, with Ericson Formation‐equivalent strata onlapping the Moxa unconformity towards the west. Regional thickness patterns record and constrain the timing of the transition from Sevier to Laramide‐style tectonic regimes. From 88 to 83 Ma (upper Baxter Formation) a westward‐thickening stratigraphic wedge characterized the foredeep developed by lithospheric flexure by thrust‐belt loading. Nevertheless, the presence of >500 m of subsidence >200 km from the thrust front suggests a long‐wavelength subsidence mechanism consistent with dynamic subsidence. By 83 Ma (Blair Formation) the long‐wavelength depocentre shifted away from the thrust belt, with no evidence of a Sevier foredeep. This depocentre continued migrating eastward during the early‐mid Campanian (ca. 81–77 Ma). The late Campanian–Maastrichtian (ca. 74–66 Ma) is marked by narrow sedimentary wedges adjacent to the Wind River, Granite and Uinta Mountain uplifts and attributed to flexural loading by Laramide deformation. [ABSTRACT FROM AUTHOR]

Research was conducted to examine the relationship between cellular DNA damage response and double-strand break (DSB) repair in Nijmegen breakage syndrome. This involved the isolation of the p95 gene encoder from the hMre11/hRad50 protein complex. Results revealed similarities between NBS1 and the p95 gene. A direct relationship was established between DSB repair and cell cycle functions.