Metabolic compensation activates pro-survival mTORC1 signaling upon 3-phosphoglycerate dehydrogenase inhibition in osteosarcoma

Osteosarcoma is the most common pediatric and adult primary malignant bone cancer. Curative regimens target the folate pathway, downstream of serine metabolism, with high-dose methotrexate. Here, the rate-limiting enzyme in the biosynthesis of serine from glucose, 3-phosphoglycerate dehydrogenase (PHGDH), is examined, and an inverse correlation between PHGDH expression and relapse-free and overall survival in osteosarcoma patients is found. PHGDH inhibition in osteosarcoma cell lines attenuated cellular proliferation without causing cell death, prompting a robust metabolic analysis to characterize pro-survival compensation. Using metabolomic and lipidomic profiling, cellular response to PHGDH inhibition is identified as accumulation of unsaturated lipids, branched chain amino acids, and methionine cycle intermediates, leading to activation of pro-survival mammalian target of rapamycin complex 1 (mTORC1) signaling. Increased mTORC1 activation sensitizes cells to mTORC1 pathway inhibition, resulting in significant, synergistic cell death in vitro and in vivo. Identifying a therapeutic combination for PHGDH-high cancers offers preclinical justification for a dual metabolism-based combination therapy for osteosarcoma

Atmospheric sources of trace element contamination in cultivated urban areas: A review

Producing food in cities has garnered increasing attention over the past decade. Although there are ecological and social benefits, cultivated urban areas (CUAs) also bear contamination hazards, including from trace elements (TEs). Trace element contamination has been studied extensively in CUAs, but atmospheric sources remain understudied and poorly understood. A brief discussion is offered on atmospheric particulate deposition processes in cities and their implications for urban food production. Available findings are discussed and contrasted. Existing research assesses atmospheric deposition indirectly or otherwise lacks controls for other TE contaminants. There is little to no engagement with methodological guidelines from the atmospheric sciences, which reduces confidence in the findings so far attained. Suggestions are delineated to combine techniques used in the atmospheric sciences with the robust methodologies already generated by studies on TE contamination in CUAs, such as isotope and TE ratios analyses

USP6 activation in nodular fasciitis by promoter-swapping gene fusions

Molecular tumour pathology - and tumour geneticsMTG

Associations of social cohesion and quality of life with objective and perceived built environments : A latent profile analysis among seniors

Background Healthy aging requires support from local built and social environments. Using latent profile analysis, this study captured the multidimensionality of the built environment and examined relations between objective and perceived built environment profiles, neighborhood social cohesion and quality of life among seniors. Methods In total, 693 participants aged 66–97 were sampled from two US locales in 2005–2008 as part of the Senior Neighborhood Quality of Life Study (SNQLS). Perceived social cohesion and quality of life were assessed using validated surveys. Six objective (geographic information system (GIS)-based) and seven perceived built environment latent profiles generated in previous SNQLS publications were used for analyses. Mixed-effects models estimated social cohesion and quality of life separately as a function of the built environment profiles. Results More walkable and destination-rich perceived built environment profiles were associated with higher social cohesion and quality of life. Objective built environment profiles were not associated with social cohesion and only positively associated with quality of life in only one locale (Baltimore/DC). Conclusions Latent profile analysis offered a comprehensive approach to assessing the built environment. Seniors who perceived their neighborhoods to be highly walkable and recreationally dense experienced higher neighborhood social cohesion and quality of life, which may set the stage for healthier aging

Neighborhood Socioeconomic Status, Green Space, and Walkability and Risk for Falls Among Postmenopausal Women: The Women's Health Initiative

PurposeThis study estimated associations between neighborhood socioeconomic status (NSES), walkability, green space, and incident falls among postmenopausal women and evaluated modifiers of these associations, including study arm, race and ethnicity, baseline household income, baseline walking, age at enrollment, baseline low physical functioning, baseline fall history, climate region, and urban-rural residence.MethodsThe Women's Health Initiative recruited a national sample of postmenopausal women (50-79 years) across 40 U.S. clinical centers and conducted yearly assessments from 1993 to 2005 (n = 161,808). Women reporting a history of hip fracture or walking limitations were excluded, yielding a final sample of 157,583 participants. Falling was reported annually. NSES (income/wealth, education, occupation), walkability (population density, diversity of land cover, nearby high-traffic roadways), and green space (exposure to vegetation) were calculated annually and categorized into tertiles (low, intermediate, high). Generalized estimating equations assessed longitudinal relationships.ResultsNSES was associated with falling before adjustment (high vs. low, odds ratio, 1.01; 95% confidence interval, 1.00-1.01). Walkability was significantly associated with falls after adjustment (high vs. low, odds ratio, 0.99; 95% confidence interval, 0.98-0.99). Green space was not associated with falling before or after adjustment. Study arm, race and ethnicity, household income, age, low physical functioning, fall history, and climate region modified the relationship between NSES and falling. Race and ethnicity, age, fall history, and climate region modified relationships between walkability and green space and falling.ConclusionsOur results did not show strong associations of NSES, walkability, or green space with falling. Future research should incorporate granular environmental measures that may directly relate to physical activity and outdoor engagement