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Peroxisomal biogenesis disorders (PBDs) are genetic disorders of peroxisome biogenesis and metabolism that are characterized by profound developmental and neurological phenotypes. The most severe class of PBDs—Zellweger spectrum disorder (ZSD)—is caused by mutations in peroxin genes that result in both non‐functional peroxisomes and mitochondrial dysfunction. It is unclear, however, how defective peroxisomes contribute to mitochondrial impairment. In order to understand the molecular basis of this inter‐organellar relationship, we investigated the fate of peroxisomal mRNAs and proteins in ZSD model systems. We found that peroxins were still expressed and a subset of them accumulated on the mitochondrial membrane, which resulted in gross mitochondrial abnormalities and impaired mitochondrial metabolic function. We showed that overexpression of ATAD1, a mitochondrial quality control factor, was sufficient to rescue several aspects of mitochondrial function in human ZSD fibroblasts. Together, these data suggest that aberrant peroxisomal protein localization is necessary and sufficient for the devastating mitochondrial morphological and metabolic phenotypes in ZSDs. Synopsis: How peroxisomal biogenesis disorders lead to mitochondrial dysfunction is not well understood. This study reveals that peroxisomal proteins mislocalize to the mitochondria, thereby disrupting mitochondrial function. The mitochondrial quality control protein ATAD1 can rescue this defect. Peroxin transcription and translation is unperturbed by loss of peroxisomes.Several peroxins (Pex13, Pex11, Pex14, Pex2, Pex17, Pex25) mislocalize to the mitochondrial outer membrane.Mislocalized peroxins are able to form a subassembly of the peroxisomal importomer on mitochondria, which interferes with mitochondrial function.The mitochondrial extractase ATAD1 can remove peroxins from the mitochondrial membrane, which is sufficient to restore mitochondrial morphology, respiration, and metabolism in cells derived from ZSD patients. [ABSTRACT FROM AUTHOR]

Objective: To assess the association between occupational exposures and knee osteoarthritis (OA).Methods: We systematically searched for observational studies that examined the relationship between occupational exposures and knee OA and total knee replacement. Four databases were searched up to October 1, 2019. Two reviewers independently assessed study quality using the Newcastle-Ottawa Scale and evidence quality using the Grading of Recommendations Assessment, Development and Evaluation approach. Subgroup meta-analyses were conducted for important study characteristics and each type of occupational exposure. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated for the meta-analysis using random-effects models.Results: Eighty eligible studies were identified including 25 case-control (n = 20,505 total participants), 36 cross-sectional (n = 139,463 total participants), and 19 cohort studies (n = 16,824,492 total participants). A synthesis of 71 studies suggested increased odds of knee OA (OR 1.52 [95% CI 1.37-1.69]) by combining different physically demanding jobs and occupational activities as compared to sedentary occupations and/or low-exposure groups. Odds of knee OA were greater in males and in industry-based studies and studies assessing lifetime occupational exposures. There were 9 specific job titles that were associated with knee OA, including farmer, builder, metal worker, and floor layer. Occupational lifting, kneeling, climbing, squatting, and standing were all associated with higher odds of knee OA as compared to the odds of knee OA in sedentary workers.Conclusion: Strenuous, physically demanding occupations and occupational activities were associated with increased odds of knee OA as supported by moderate-quality evidence. Specifically, agricultural and construction sectors, which typically involve heavy lifting, frequent climbing, prolonged kneeling, squatting, and standing, carried increased odds of knee OA. [ABSTRACT FROM AUTHOR]

Background The safety of front-line chemotherapies for the treatment of extensive stage small-cell lung cancer ( ED-SCLC) is uncertain. We carried out a network meta-analysis to compare the toxicity of different therapies for ED-SCLC. Methods We searched EMBASE, PubMed, CENTRAL and . We performed network meta-analysis on hematological (anemia, leukopenia, neutropenia, and thrombocytopenia) and non-hematological toxicities (diarrhea, infection, and nausea and vomiting). Results Nine studies with 2317 patients were included. Etoposide with carboplatin ( EC) was associated with a higher incidence of anemia (odds ratio [ OR] 2.02, 95% confidence interval [ CI] 1.13-3.63), leukopenia ( OR 2.67, 95% CI 1.25-5.72), neutropenia ( OR 12.08, 95% CI 2.13-68.66), and thrombocytopenia ( OR 2.73, 95% CI 1.27-5.85) compared with irinotecan with carboplatin ( IC). Similarly, etoposide with cisplatin ( EP) was associated with a higher incidence of anemia ( OR 1.70, 95% CI 1.13-2.56), leukopenia ( OR 2.65, 95% CI 1.34-5.28), neutropenia ( OR 5.70, 95% CI 2.93-11.10), and thrombocytopenia ( OR 3.26, 95% CI 1.66-6.38) compared with irinotecan with cisplatin ( IP). EC was associated with a lower incidence of diarrhea ( OR 0.26, 95% CI 0.10-0.68) compared with IC, and EP was associated with a lower incidence of diarrhea ( OR 0.09, 95% CI 0.03-0.25) and nausea and vomiting ( OR 0.53, 95% CI 0.33-0.84) than IP. Conclusions Hematological toxicities were most common in EC-treated patients, while the lowest incidence occurred with IP treatment. The IP regimen was associated with the highest incidence of toxicities of the digestive tract, while the lowest incidence occurred with EC treatment. [ABSTRACT FROM AUTHOR]