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Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations ( PTPN11 , BRAF ) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles. Our study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor’s clonal evolution during treatment. Genomic, transcriptomic, and microenvironmental analyses of samples from patients with glioblastoma treated with nivolumab or pembrolizumab identifies features associated with treatment response that may help in refining patient stratification.

Large-scale cancer genomic studies enable the systematic identification of mutations that lead to the genesis and progression of tumors, uncovering the underlying molecular mechanisms and potential therapies. While some such mutations are recurrently found in many tumors, many others exist solely within a few samples, precluding detection by conventional recurrence-based statistical approaches. Integrated analysis of somatic mutations and RNA expression data across 12 tumor types reveals that mutations of cancer genes are usually accompanied by substantial changes in expression. We use topological data analysis to leverage this observation and uncover 38 elusive candidate cancer-associated genes, including inactivating mutations of the metalloproteinase ADAMTS12 in lung adenocarcinoma. We show that ADAMTS12 −/− mice have a five-fold increase in the susceptibility to develop lung tumors, confirming the role of ADAMTS12 as a tumor suppressor gene. Our results demonstrate that data integration through topological techniques can increase our ability to identify previously unreported cancer-related alterations. Rare cancer mutations are often missed using recurrence-based statistical approaches, but are usually accompanied by changes in expression. Here the authors leverage this information to uncover several elusive candidate cancer-associated genes using topological data analysis.

Environmental temperature and an organism’s ability to respond to it are critical determinants of the geographic distribution of species. Nematostella vectensis is a burrowing sea anemone that inhabits estuaries along the Atlantic coast of North America from Nova Scotia (45° N) to Georgia (31° N). Like other estuarine species, N. vectensis is exposed to large daily (>20°C) and seasonal (>25°C) fluctuations in temperature, requiring wide temperature tolerances. At the same time, the natural distribution of this species spans a pronounced thermal cline, which may promote the evolution of different temperature optima and tolerances in populations. We tested the thermal tolerance of N. vectensis adult and developmental stages, which showed all life cycle stages had critical temperatures within 1°C (lethal temperature 39.5 to 40.5°C). When temperature tolerance values were compared with recorded field data, N. vectensis is living in environments very close to their physiological limit. We utilized common garden experiments (13, 21, and 29°C) to test for temperature-specific growth and regeneration rates in N. vectensis from different portions of this species’ range. Temperature had a significant effect on growth and regeneration rate in all clonal lines, with a significant negative relationship between latitude of origin and growth rate at 29°C. Individuals from higher latitudes did not exhibit higher growth rates at cooler temperatures. Together, our results show a combination of broad thermal tolerances for developmental and adult stages and evidence for local adaptation to higher temperatures in populations living in lower latitude locations that would be physiologically compromised with future warming.

In the version of this article originally published, the graph in Extended Data Fig. 2c was a duplication of Extended Data Fig. 2b. The correct version of Extended Data Fig. 2c is now available online.

Endometrial cancer (EC) exhibits one of the most striking racial disparities in oncology with black women disproportionately affected by aggressive high-grade subtypes that have poorer outcomes. While social and environmental factors undoubtedly contribute, the molecular underpinnings of these disparities remain critically understudied. To bridge this knowledge gap, we performed matched tumor-normal whole-genome sequencing and tumor transcriptome sequencing on 71 predominantly high-grade EC patient samples from an ancestrally diverse cohort of women recruited at a large hospital system in the New York metropolitan area. Our analysis characterized the germline and somatic mutation landscape, identifying ancestry-associated molecular differences. Notably, focal amplification of the EVI1 transcription factor (encoded at the MECOM locus) was significantly more frequent in African ancestry patients and associated with poorer clinical outcomes in an external validation cohort. Additionally transcriptome analysis revealed decreased CD8+ T cell infiltration with increasing African ancestry, suggesting tumor immune microenvironment differences with potential therapeutic implications.

This release is the first complete recording of all of Cage's works for organ, plus 4'33. The organ is ideally suited to Cage’s aesthetic — its multitude of stops make it the ultimate prepared instrument. The fact that sound emanates from a number of pipes placed at discrete locations in space nicely accords with Cage's idea of the separation of sounds in space. And it represents vast possibilities that could be released as sound through the use of chance operations. For this reason Cage's organ music occupies a small but quite important place within his output.