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Advanced bladder cancer patients show very variable responses to immune checkpoint inhibitors (ICIs) and effective strategies to predict response are still lacking. Here we integrate mutation and gene expression data from 707 advanced bladder cancer patients treated with anti-PD-1/anti-PD-L1 to build highly accurate predictive models. We find that, in addition to tumor mutational burden (TMB), enrichment in the APOBEC mutational signature, and the abundance of pro-inflammatory macrophages, are major factors associated with the response. Paradoxically, patients with high immune infiltration do not show an overall better response. We show that this can be explained by the activation of immune suppressive mechanisms in a large portion of these patients. In the case of non-immune-infiltrated cancer subtypes, we uncover specific variables likely to be involved in the response. Our findings provide information for advancing precision medicine in patients with advanced bladder cancer treated with immunotherapy., Competing Interests: Competing interests: Potential conflicts of interest: J.B. has served in consulting or advisory roles for Astellas Pharma, AstraZeneca/MedImmune, Bristol Myers Squibb, Genentech, Novartis, Pfizer, Pierre Fabre, and the healthcare business of Merck KGaA, Darmstadt, Germany; has received travel and accommodation expenses from Ipsen, Merck & Co., Kenilworth, NJ, and Pfizer; reports patents, royalties, other intellectual property from UpToDate; reports stock and other ownership interests in Rainier Therapeutics; has received honoraria from UpToDate; and has received institutional research funding from Millennium, Pfizer, Sanofi, and the healthcare business of Merck KGaA, Darmstadt, Germany. The remaining authors declare no competing interests., (© 2025. The Author(s).)

Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment and can result in complete remissions even at advanced stages of the disease. However, only a small fraction of patients respond to the treatment. To better understand which factors drive clinical benefit, we have generated whole exome and RNA sequencing data from 27 advanced urothelial carcinoma patients treated with anti-PD-(L)1 monoclonal antibodies. We assessed the influence on the response of non-synonymous mutations (tumor mutational burden or TMB), clonal and subclonal mutations, neoantigen load and various gene expression markers. We found that although TMB is significantly associated with response, this effect can be mostly explained by clonal mutations, present in all cancer cells. This trend was validated in an additional cohort. Additionally, we found that responders with few clonal mutations had abnormally high levels of T and B cell immune markers, suggesting that a high immune cell infiltration signature could be a better predictive biomarker for this subset of patients. Our results support the idea that highly clonal cancers are more likely to respond to ICI and suggest that non-additive effects of different signatures should be considered for predictive models., (© 2023. Springer Nature Limited.)

We systematically reviewed the existing evidence (until end of November 2021) on the association between long-term exposure to greenspace and behavioral problems in children according to the PRISMA 2020. The review finally reached 29 relevant studies of which, 17 were cross-sectional, 11 were cohort, and one was a case-control. Most of the studies were conducted in Europe (n = 14), followed by the USA (n = 8), and mainly (n = 21) from 2015 onwards. The overall quality of the studies in terms of risk of bias was "fair" (mean quality score = 5.4 out of 9) according to the Newcastle-Ottawa Scale. Thirteen studies (45%) had good or very good quality in terms of risk of bias. The strength and difficulty questionnaire was the most common outcome assessment instrument. Exposure to the greenspace in the reviewed studies was characterized based on different indices (availability, accessibility, and quality), mostly at residential address locations. Association of exposure to different types of greenspace were reported for nine different behavioral outcomes including total behavioral difficulties (n = 16), attention deficit hyperactivity disorder (ADHD) symptoms and severity (n = 15), ADHD diagnosis (n = 10), conduct problems (n = 10), prosocial behavior (n = 10), emotional symptoms (n = 8), peer-relationship problems (n = 8), externalizing disorders (n = 6), and internalizing disorders (n = 5). Most of the reported associations (except for conduct problems) were suggestive of beneficial association of greenspace exposure with children's behaviors; however, the studies were heterogeneous in terms of their exposure indicators, study design, and the outcome definition., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Exposure to greenspace has been associated with reduced stress; however, the available evidence on such an association for the fetus is still very scarce. We, for the first time, investigated the association between maternal greenspace exposure and the level of cortisol, a stress hormone, in the cord blood. Our study was based on a cohort of 150 pregnant women in Sabzevar, Iran (2018). We comprehensively assessed greenspace exposure for each participant through (i) residential surrounding greenspace (using two satellite-derived vegetation indices), (ii) residential proximity to green spaces, (iii) maternal visual access to greenspace, (iv) use of public and private green spaces, (v) having a private garden, and (vi) the number of plant pots at home. Linear regression models were developed to assess the association of each indicator of greenspace exposure with cord blood cortisol levels, controlled for the relevant covariates. We observed that a higher residential surrounding greenspace (100 m buffer), having a window with greenspace view, window greenspace coverage of more than 50%, frequently looking at greenspace through window, residential proximity to large green spaces, and more time spent in green spaces were associated with lower cortisol levels in the cord blood. The findings for residential surrounding greenspace at 300 m and 500 m buffers, residential proximity to any green space regardless of its size, having a private garden, and number of plant pots at home were not conclusive. While about one-third of the association between residential surrounding greenspace (100 m buffer) could be mediated through reduction in exposure to air pollution, we did not observe any strong evidence for such a mediatory role for the visual access to greenspace. The findings stratified for parental education and housing type showed mixed patterns. Our findings suggest that more greenspace exposure might reduce cortisol level in the cord blood., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)