Papillary Renal Cell Carcinomas Rewire Glutathione Metabolism and Are Deficient in Both Anabolic Glucose Synthesis and Oxidative Phosphorylation

Papillary renal cell carcinoma (pRCC) is a malignant kidney cancer with a prevalence of 7–20% of all renal tumors. Proteome and metabolome profiles of 19 pRCC and patient-matched healthy kidney controls were used to elucidate the regulation of metabolic pathways and the underlying molecular mechanisms. Glutathione (GSH), a main reactive oxygen species (ROS) scavenger, was highly increased and can be regarded as a new hallmark in this malignancy. Isotope tracing of pRCC derived cell lines revealed an increased de novo synthesis rate of GSH, based on glutamine consumption. Furthermore, profound downregulation of gluconeogenesis and oxidative phosphorylation was observed at the protein level. In contrast, analysis of the The Cancer Genome Atlas (TCGA) papillary RCC cohort revealed no significant change in transcripts encoding oxidative phosphorylation compared to normal kidney tissue, highlighting the importance of proteomic profiling. The molecular characteristics of pRCC are increased GSH synthesis to cope with ROS stress, deficient anabolic glucose synthesis, and compromised oxidative phosphorylation, which could potentially be exploited in innovative anti-cancer strategies

Mutations in ELAC2 associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3'-end processing

Mutations in either the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial respiration. Within this group, an increasing number of mutations have been identified in nuclear genes involved in mitochondrial RNA metabolism, including ELAC2. The ELAC2 gene codes for the mitochondrial RNase Z, responsible for endonucleolytic cleavage of the 3' ends of mitochondrial pre-tRNAs. Here, we report the identification of sixteen novel ELAC2 variants in individuals presenting with mitochondrial respiratory chain deficiency, hypertrophic cardiomyopathy and lactic acidosis. We provide evidence for the pathogenicity of the novel missense variants by studying the RNase Z activity in an in vitro system. We also modelled the residues affected by missense mutation in solved RNase Z structures, providing insight into enzyme structure and function. Finally, we show that primary fibroblasts from the affected individuals have elevated levels of unprocessed mitochondrial RNA precursors. Our study thus broadly confirms the correlation of ELAC2 variants with severe infantile-onset forms of hypertrophic cardiomyopathy and mitochondrial respiratory chain dysfunction. One rare missense variant associated with the occurrence of prostate cancer (p.Arg781His) impairs the mitochondrial RNase Z activity of ELAC2, suggesting a functional link between tumorigenesis and mitochondrial RNA metabolism

Associations between extreme temperatures and cardiovascular cause-specific mortality: results from 27 countries

BACKGROUND: Cardiovascular disease is the leading cause of death worldwide. Existing studies on the association between temperatures and cardiovascular deaths have been limited in geographic zones and have generally considered associations with total cardiovascular deaths rather than cause-speci fi c cardiovascular deaths. METHODS: We used uni fi ed data collection protocols within the Multi-Country Multi-City Collaborative Network to assemble a database of daily counts of speci fi c cardiovascular causes of death from 567 cities in 27 countries across 5 continents in overlapping periods ranging from 1979 to 2019. City-speci fi c daily ambient temperatures were obtained from weather stations and climate reanalysis models. To investigate cardiovascular mortality associations with extreme hot and cold temperatures, we fi t case-crossover models in each city and then used a mixed-effects meta-analytic framework to pool individual city estimates. Extreme temperature percentiles were compared with the minimum mortality temperature in each location. Excess deaths were calculated for a range of extreme temperature days. RESULTS: The analyses included deaths from any cardiovascular cause (32 154 935), ischemic heart disease (11 745 880), stroke (9 351 312), heart failure (3 673 723), and arrhythmia (670 859). At extreme temperature percentiles, heat (99th percentile) and cold (1st percentile) were associated with higher risk of dying from any cardiovascular cause, ischemic heart disease, stroke, and heart failure as compared to the minimum mortality temperature, which is the temperature associated with least mortality. Across a range of extreme temperatures, hot days (above 97.5th percentile) and cold days (below 2.5th percentile) accounted for 2.2 (95% empirical CI [eCI], 2.1-2.3) and 9.1 (95% eCI, 8.9-9.2) excess deaths for every 1000 cardiovascular deaths, respectively. Heart failure was associated with the highest excess deaths proportion from extreme hot and cold days with 2.6 (95% eCI, 2.4-2.8) and 12.8 (95% eCI, 12.2-13.1) for every 1000 heart failure deaths, respectively. CONCLUSIONS: Across a large, multinational sample, exposure to extreme hot and cold temperatures was associated with a greater risk of mortality from multiple common cardiovascular conditions. The intersections between extreme temperatures and cardiovascular health need to be thoroughly characterized in the present day-and especially under a changing climate

Heat-related cardiorespiratory mortality: effect modification by air pollution across 482 cities from 24 countries

Background Evidence on the potential interactive effects of heat and ambient air pollution on cause-specific mortality is inconclusive and limited to selected locations. Objectives We investigated the effects of heat on cardiovascular and respiratory mortality and its modification by air pollution during summer months (six consecutive hottest months) in 482 locations across 24 countries. Methods Location-specific daily death counts and exposure data (e.g., particulate matter with diameters ≤ 2.5 µm [PM2.5]) were obtained from 2000 to 2018. We used location-specific confounder-adjusted Quasi-Poisson regression with a tensor product between air temperature and the air pollutant. We extracted heat effects at low, medium, and high levels of pollutants, defined as the 5th, 50th, and 95th percentile of the location-specific pollutant concentrations. Country-specific and overall estimates were derived using a random-effects multilevel meta-analytical model. Results Heat was associated with increased cardiorespiratory mortality. Moreover, the heat effects were modified by elevated levels of all air pollutants in most locations, with stronger effects for respiratory than cardiovascular mortality. For example, the percent increase in respiratory mortality per increase in the 2-day average summer temperature from the 75th to the 99th percentile was 7.7% (95% Confidence Interval [CI] 7.6-7.7), 11.3% (95%CI 11.2-11.3), and 14.3% (95% CI 14.1-14.5) at low, medium, and high levels of PM2.5, respectively. Similarly, cardiovascular mortality increased by 1.6 (95%CI 1.5-1.6), 5.1 (95%CI 5.1-5.2), and 8.7 (95%CI 8.7-8.8) at low, medium, and high levels of O3, respectively. Discussion We observed considerable modification of the heat effects on cardiovascular and respiratory mortality by elevated levels of air pollutants. Therefore, mitigation measures following the new WHO Air Quality Guidelines are crucial to enhance better health and promote sustainable development

Fluctuating temperature modifies heat-mortality association around the globe

Studies have investigated the effects of heat and temperature variability (TV) on mortality. However, few assessed whether TV modifies the heat-mortality association. Data on daily temperature and mortality in the warm season were collected from 717 locations across 36 countries. TV was calculated as the standard deviation of the average of the same and previous days’ minimum and maximum temperatures. We used location-specific quasi-Poisson regression models with an interaction term between the cross-basis term for mean temperature and quartiles of TV to obtain heat-mortality associations under each quartile of TV, and then pooled estimates at the country, regional, and global levels. Results show the increased risk in heat-related mortality with increments in TV, accounting for 0.70% (95% confidence interval [CI]: −0.33 to 1.69), 1.34% (95% CI: −0.14 to 2.73), 1.99% (95% CI: 0.29–3.57), and 2.73% (95% CI: 0.76–4.50) of total deaths for Q1–Q4 (first quartile–fourth quartile) of TV. The modification effects of TV varied geographically. Central Europe had the highest attributable fractions (AFs), corresponding to 7.68% (95% CI: 5.25–9.89) of total deaths for Q4 of TV, while the lowest AFs were observed in North America, with the values for Q4 of 1.74% (95% CI: −0.09 to 3.39). TV had a significant modification effect on the heat-mortality association, causing a higher heat-related mortality burden with increments of TV. Implementing targeted strategies against heat exposure and fluctuant temperatures simultaneously would benefit public health. © 2022 The Author(s)Funding text 1: This study was supported by the Australian Research Council (DP210102076) and the Australian National Health and Medical Research Council (APP2000581). Y.W and B.W. were supported by the China Scholarship Council (nos. 202006010044 and 202006010043); S.L. was supported by an Emerging Leader Fellowship of the Australian National Health and Medical Research Council (no. APP2009866); Y.G. was supported by Career Development Fellowship (no. APP1163693) and Leader Fellowship (no. APP2008813) of the Australian National Health and Medical Research Council; J.K. and A.U. were supported by the Czech Science Foundation (project no. 20–28560S); N.S. was supported by the National Institute of Environmental Health Sciences-funded HERCULES Center (no. P30ES019776); Y.H. was supported by the Environment Research and Technology Development Fund (JPMEERF15S11412) of the Environmental Restoration and Conservation Agency; M.d.S.Z.S.C. and P.H.N.S. were supported by the São Paulo Research Foundation (FAPESP); H.O. and E.I. were supported by the Estonian Ministry of Education and Research (IUT34–17); J.M. was supported by a fellowship of Fundação para a Ciência e a Tecnlogia (SFRH/BPD/115112/2016); A.G. and F.S. were supported by the Medical Research Council UK (grant ID MR/R013349/1), the Natural Environment Research Council UK (grant ID NE/R009384/1), and the EU's Horizon 2020 project, Exhaustion (grant ID 820655); A.S. and F.d.D. were supported by the EU's Horizon 2020 project, Exhaustion (grant ID 820655); V.H. was supported by the Spanish Ministry of Economy, Industry and Competitiveness (grant ID PCIN-2017–046); and A.T. by MCIN/AEI/10.13039/501100011033 (grant CEX2018-000794-S). Statistics South Africa kindly provided the mortality data, but had no other role in the study. Y.G. A.G. M.H. and B. Armstrong set up the collaborative network. Y.G. S.L. and Y.W. designed the study. Y.G. S.L. and A.G. developed the statistical methods. Y.W. B.W. S.L. and Y.G. took the lead in drafting the manuscript and interpreting the results. Y.W. B.W. Y.G. A.G. S.T. A.O. A.U. A.S. A.E. A.M.V.-C. A. Zanobetti, A.A. A. Zeka, A.T. B. Alahmad, B. Armstrong, B.F. C.Í. C. Ameling, C.D.l.C.V. C. Åström, D.H. D.V.D. D.R. E.I. E.L. F.M. F.A. F.D. F.S. G.C.-E. H. Kan, H.O. H. Kim, I.-H.H. J.K. J.M. J.S. K.K. M.H.-D. M.S.R. M.H. M.P. M.d.S.Z.S.C. N.S. P.M. P.G. P.H.N.S. R.A. S.O. T.N.D. V.C. V.H. W.L. X.S. Y.H. M.L.B. and S.L. provided the data and contributed to the interpretation of the results and the submitted version of the manuscript. Y.G. S.L. and Y.W. accessed and verified the data. All of the authors had full access to all of the data in the study and had final responsibility for the decision to submit for publication. The authors declare no competing interests.; Funding text 2: This study was supported by the Australian Research Council ( DP210102076 ) and the Australian National Health and Medical Research Council ( APP2000581 ). Y.W and B.W. were supported by the China Scholarship Council (nos. 202006010044 and 202006010043 ); S.L. was supported by an Emerging Leader Fellowship of the Australian National Health and Medical Research Council (no. APP2009866 ); Y.G. was supported by Career Development Fellowship (no. APP1163693) and Leader Fellowship (no. APP2008813) of the Australian National Health and Medical Research Council ; J.K. and A.U. were supported by the Czech Science Foundation (project no. 20–28560S ); N.S. was supported by the National Institute of Environmental Health Sciences -funded HERCULES Center (no. P30ES019776 ); Y.H. was supported by the Environment Research and Technology Development Fund ( JPMEERF15S11412 ) of the Environmental Restoration and Conservation Agency; M.d.S.Z.S.C. and P.H.N.S. were supported by the São Paulo Research Foundation (FAPESP); H.O. and E.I. were supported by the Estonian Ministry of Education and Research ( IUT34–17 ); J.M. was supported by a fellowship of Fundação para a Ciência e a Tecnlogia ( SFRH/BPD/115112/2016 ); A.G. and F.S. were supported by the Medical Research Council UK (grant ID MR/R013349/1 ), the Natural Environment Research Council UK (grant ID NE/R009384/1 ), and the EU’s Horizon 2020 project, Exhaustion (grant ID 820655 ); A.S. and F.d.D. were supported by the EU’s Horizon 2020 project, Exhaustion (grant ID 820655 ); V.H. was supported by the Spanish Ministry of Economy, Industry and Competitiveness (grant ID PCIN-2017–046 ); and A.T. by MCIN/AEI/10.13039/501100011033 (grant CEX2018-000794-S). Statistics South Africa kindly provided the mortality data, but had no other role in the study

Comparison of weather station and climate reanalysis data for modelling temperature-related mortality

Epidemiological analyses of health risks associated with non-optimal temperature are traditionally based on ground observations from weather stations that offer limited spatial and temporal coverage. Climate reanalysis represents an alternative option that provide complete spatio-temporal exposure coverage, and yet are to be systematically explored for their suitability in assessing temperature-related health risks at a global scale. Here we provide the first comprehensive analysis over multiple regions to assess the suitability of the most recent generation of reanalysis datasets for health impact assessments and evaluate their comparative performance against traditional station-based data. Our findings show that reanalysis temperature from the last ERA5 products generally compare well to station observations, with similar non-optimal temperature-related risk estimates. However, the analysis offers some indication of lower performance in tropical regions, with a likely underestimation of heat-related excess mortality. Reanalysis data represent a valid alternative source of exposure variables in epidemiological analyses of temperature-related risk. © 2022, The Author(s).The original version of this Article contained an error in Affiliation 25, which was incorrectly given as ‘Faculty of Medicine ArqFuturo INSPER, University of São Paulo, São Paulo, Brazil’. The correct affiliation is listed below. Faculty of Medicine, University of São Paulo, São Paulo, Brazil The original Article has been corrected. © The Author(s) 2022.The study was primarily supported by Grants from the European Commission’s Joint Research Centre Seville (Research Contract ID: JRC/SVQ/2020/MVP/1654), Medical Research Council-UK (Grant ID: MR/R013349/1), Natural Environment Research Council UK (Grant ID: NE/R009384/1), European Union’s Horizon 2020 Project Exhaustion (Grant ID: 820655). The following individual Grants also supported this work: J.K and A.U were supported by the Czech Science Foundation, project 20-28560S. A.T was supported by MCIN/AEI/10.13039/501100011033, Grant CEX2018-000794-S. V.H was supported by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie Grant agreement No 101032087. This work was generated using Copernicus Climate Change Service (C3S) information [1985–2019]

Joint effect of heat and air pollution on mortality in 620 cities of 36 countries

Background The epidemiological evidence on the interaction between heat and ambient air pollution on mortality is still inconsistent. Objectives To investigate the interaction between heat and ambient air pollution on daily mortality in a large dataset of 620 cities from 36 countries. Methods We used daily data on all-cause mortality, air temperature, particulate matter ≤ 10 μm (PM10), PM ≤ 2.5 μm (PM2.5), nitrogen dioxide (NO2), and ozone (O3) from 620 cities in 36 countries in the period 1995–2020. We restricted the analysis to the six consecutive warmest months in each city. City-specific data were analysed with over-dispersed Poisson regression models, followed by a multilevel random-effects meta-analysis. The joint association between air temperature and air pollutants was modelled with product terms between non-linear functions for air temperature and linear functions for air pollutants. Results We analyzed 22,630,598 deaths. An increase in mean temperature from the 75th to the 99th percentile of city-specific distributions was associated with an average 8.9 % (95 % confidence interval: 7.1 %, 10.7 %) mortality increment, ranging between 5.3 % (3.8 %, 6.9 %) and 12.8 % (8.7 %, 17.0 %), when daily PM10 was equal to 10 or 90 μg/m3, respectively. Corresponding estimates when daily O3 concentrations were 40 or 160 μg/m3 were 2.9 % (1.1 %, 4.7 %) and 12.5 % (6.9 %, 18.5 %), respectively. Similarly, a 10 μg/m3 increment in PM10 was associated with a 0.54 % (0.10 %, 0.98 %) and 1.21 % (0.69 %, 1.72 %) increase in mortality when daily air temperature was set to the 1st and 99th city-specific percentiles, respectively. Corresponding mortality estimate for O3 across these temperature percentiles were 0.00 % (-0.44 %, 0.44 %) and 0.53 % (0.38 %, 0.68 %). Similar effect modification results, although slightly weaker, were found for PM2.5 and NO2. Conclusions Suggestive evidence of effect modification between air temperature and air pollutants on mortality during the warm period was found in a global dataset of 620 cities.Massimo Stafoggia, Francesca K. de’ Donato, Masna Rai and Alexandra Schneider were partially supported by the European Union’s Horizon 2020 Project Exhaustion (Grant ID: 820655). Jan Kyselý and Aleš Urban were supported by the Czech Science Foundation project (22-24920S). Joana Madureira was supported by the Fundação para a Ciência e a Tecnologia (FCT) (grant SFRH/BPD/115112/2016). Masahiro Hashizume was supported by the Japan Science and Technology Agency (JST) as part of SICORP, Grant Number JPMJSC20E4. Noah Scovronick was supported by the NIEHS-funded HERCULES Center (P30ES019776). South African Data were provided by Statistics South Africa, which did not have any role in conducting the study. Antonio Gasparrini was supported by the Medical Research Council-UK (Grants ID: MR/V034162/1 and MR/R013349/1), the Natural Environment Research Council UK (Grant ID: NE/R009384/1), and the European Union’s Horizon 2020 Project Exhaustion (Grant ID: 820655)

Global, regional, and national burden of mortality associated with short-term temperature variability from 2000-19: a three-stage modelling study

BACKGROUND: Increased mortality risk is associated with short-term temperature variability. However, to our knowledge, there has been no comprehensive assessment of the temperature variability-related mortality burden worldwide. In this study, using data from the MCC Collaborative Research Network, we first explored the association between temperature variability and mortality across 43 countries or regions. Then, to provide a more comprehensive picture of the global burden of mortality associated with temperature variability, global gridded temperature data with a resolution of 0.5 degrees x 0.5 degrees were used to assess the temperature variability-related mortality burden at the global, regional, and national levels. Furthermore, temporal trends in temperature variability-related mortality burden were also explored from 2000-19. METHODS: In this modelling study, we applied a three-stage meta-analytical approach to assess the global temperature variability-related mortality burden at a spatial resolution of 0.5 degrees x 0.5 degrees from 2000-19. Temperature variability was calculated as the SD of the average of the same and previous days' minimum and maximum temperatures. We first obtained location-specific temperature variability related-mortality associations based on a daily time series of 750 locations from the Multi-country Multi-city Collaborative Research Network. We subsequently constructed a multivariable meta-regression model with five predictors to estimate grid-specific temperature variability related-mortality associations across the globe. Finally, percentage excess in mortality and excess mortality rate were calculated to quantify the temperature variability-related mortality burden and to further explore its temporal trend over two decades. FINDINGS: An increasing trend in temperature variability was identified at the global level from 2000 to 2019. Globally, 1 753 392 deaths (95% CI 1 159 901-2 357 718) were associated with temperature variability per year, accounting for 3.4% (2.2-4.6) of all deaths. Most of Asia, Australia, and New Zealand were observed to have a higher percentage excess in mortality than the global mean. Globally, the percentage excess in mortality increased by about 4.6% (3.7-5.3) per decade. The largest increase occurred in Australia and New Zealand (7.3%, 95% CI 4.3-10.4), followed by Europe (4.4%, 2.2-5.6) and Africa (3.3, 1.9-4.6). INTERPRETATION: Globally, a substantial mortality burden was associated with temperature variability, showing geographical heterogeneity and a slightly increasing temporal trend. Our findings could assist in raising public awareness and improving the understanding of the health impacts of temperature variability. FUNDING: Australian Research Council, Australian National Health & Medical Research Council

Expanding the clinical phenotype of IARS2-related mitochondrial disease.

BACKGROUND: IARS2 encodes a mitochondrial isoleucyl-tRNA synthetase, a highly conserved nuclear-encoded enzyme required for the charging of tRNAs with their cognate amino acid for translation. Recently, pathogenic IARS2 variants have been identified in a number of patients presenting broad clinical phenotypes with autosomal recessive inheritance. These phenotypes range from Leigh and West syndrome to a new syndrome abbreviated CAGSSS that is characterised by cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia, as well as cataract with no additional anomalies. METHODS: Genomic DNA from Iranian probands from two families with consanguineous parental background and overlapping CAGSSS features were subjected to exome sequencing and bioinformatics analysis. RESULTS: Exome sequencing and data analysis revealed a novel homozygous missense variant (c.2625C > T, p.Pro909Ser, NM_018060.3) within a 14.3 Mb run of homozygosity in proband 1 and a novel homozygous missense variant (c.2282A > G, p.His761Arg) residing in an ~ 8 Mb region of homozygosity in a proband of the second family. Patient-derived fibroblasts from proband 1 showed normal respiratory chain enzyme activity, as well as unchanged oxidative phosphorylation protein subunits and IARS2 levels. Homology modelling of the known and novel amino acid residue substitutions in IARS2 provided insight into the possible consequence of these variants on function and structure of the protein. CONCLUSIONS: This study further expands the phenotypic spectrum of IARS2 pathogenic variants to include two patients (patients 2 and 3) with cataract and skeletal dysplasia and no other features of CAGSSS to the possible presentation of the defects in IARS2. Additionally, this study suggests that adult patients with CAGSSS may manifest central adrenal insufficiency and type II esophageal achalasia and proposes that a variable sensorineural hearing loss onset, proportionate short stature, polyneuropathy, and mild dysmorphic features are possible, as seen in patient 1. Our findings support that even though biallelic IARS2 pathogenic variants can result in a distinctive, clinically recognisable phenotype in humans, it can also show a wide range of clinical presentation from severe pediatric neurological disorders of Leigh and West syndrome to both non-syndromic cataract and cataract accompanied by skeletal dysplasia

Association between pre-biologic T2-biomaker combinations and response to biologics in patients with severe asthma

Funding This study was conducted by the Observational and Pragmatic Research Institute (OPRI) Pte Ltd and was partially funded by Optimum Patient Care Global (OPCG) and AstraZeneca Ltd. No funding was received by the OPRI for its contribution. The International Severe Asthma Registry (ISAR) is operated by OPCG and co-funded by OPCG and AstraZenecaPeer reviewe