Functional variomics provides the foundation for personalized medicine by linking genetic variation to disease expression, outcome and treatment, yet its utility is dependent on appropriate assays to evaluate mutation impact on protein function. To fully assess the effects of 106 missense and nonsense variants of PTEN associated with autism spectrum disorder, somatic cancer and PTEN hamartoma syndrome (PHTS), we take a deep phenotypic profiling approach using 18 assays in 5 model systems spanning diverse cellular environments ranging from molecular function to neuronal morphogenesis and behavior. Variants inducing instability occur across the protein, resulting in partial-to-complete loss-of-function (LoF), which is well correlated across models. However, assays are selectively sensitive to variants located in substrate binding and catalytic domains, which exhibit complete LoF or dominant negativity independent of effects on stability. Our results indicate that full characterization of variant impact requires assays sensitive to instability and a range of protein functions.

ObjectivesAtmospheric fine particulate matter (PM2.5) has multiple adverse effects on human health. Global atmospheric levels of PM2.5 increased by 0.55 μg/m3/year (2.1%/year) from 1998 through 2012. There is evidence of a causal relationship between atmospheric PM2.5 and breast cancer (BC) incidence, but few studies have investigated BC mortality and atmospheric PM2.5. We investigated BC mortality in relation to atmospheric PM2.5 levels among patients living in Varese Province, northern Italy.MethodsWe selected female BC cases, archived in the local population-based cancer registry, diagnosed at age 50–69 years, between 2003 and 2009. The geographic coordinates of each woman's place of residence were identified, and individual PM2.5 exposures were assessed from satellite data. Grade, stage, age at diagnosis, period of diagnosis and participation in BC screening were potential confounders. Kaplan-Meir and Nelson-Aalen methods were used to test for mortality differences in relation to PM2.5 quartiles. Multivariable Cox proportional hazards modelling estimated HRs and 95% CIs of BC death in relation to PM2.5 exposure.ResultsOf 2021 BC cases, 325 died during follow-up to 31 December 2013, 246 for BC. Risk of BC death was significantly higher for all three upper quartiles of PM2.5 exposure compared to the lowest, with HRs of death: 1.82 (95% CI 1.15 to 2.89), 1.73 (95% CI 1.12 to 2.67) and 1.72 (95% CI 1.08 to 2.75).ConclusionsOur study indicates that the risk of BC mortality increases with PM2.5 exposure. Although additional research is required to confirm these findings, they are further evidence that PM2.5 exposure is harmful and indicate an urgent need to improve global air quality.

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OBJECTIVES: Severe acute respiratory syndrome–related coronavirus-2 binds and inhibits angiotensin-converting enzyme-2. The frequency of acute cardiac injury in patients with coronavirus disease 2019 is unknown. The objective was to compare the rates of cardiac injury by angiotensin-converting enzyme-2–binding viruses from viruses that do not bind to angiotensin-converting enzyme-2. DATA SOURCES: We performed a systematic review of coronavirus disease 2019 literature on PubMed and EMBASE. STUDY SELECTION: We included studies with ten or more hospitalized adults with confirmed coronavirus disease 2019 or other viral pathogens that described the occurrence of acute cardiac injury. This was defined by the original publication authors or by: 1) myocardial ischemia, 2) new cardiac arrhythmia on echocardiogram, or 3) new or worsening heart failure on echocardiogram. DATA EXTRACTION: We compared the rates of cardiac injury among patients with respiratory infections with viruses that down-regulate angiotensin-converting enzyme-2, including H1N1, H5N1, H7N9, and severe acute respiratory syndrome–related coronavirus-1, to those with respiratory infections from other influenza viruses that do not bind angiotensin-converting enzyme-2, including Influenza H3N2 and influenza B. DATA SYNTHESIS: Of 57 studies including 34,072 patients, acute cardiac injury occurred in 50% (95% CI, 44–57%) of critically ill patients with coronavirus disease 2019. The overall risk of acute cardiac injury was 21% (95% CI, 18–26%) among hospitalized patients with coronavirus disease 2019. In comparison, 37% (95% CI, 26–49%) of critically ill patients with other respiratory viruses that bind angiotensin-converting enzyme-2 (p = 0.061) and 12% (95% CI, 7–22%) of critically ill patients with other respiratory viruses that do not bind angiotensin-converting enzyme-2 (p < 0.001) experienced a cardiac injury. CONCLUSIONS: Acute cardiac injury may be associated with whether the virus binds angiotensin-converting enzyme-2. Acute cardiac injury occurs in half of critically ill coronavirus disease 2019 patients, but only 12% of patients infected by viruses that do not bind to angiotensin-converting enzyme-2.