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Abstract Background Twenty-five germline variants are associated with adult diffuse glioma, and some of these variants have been shown to be associated with particular subtypes of glioma. We hypothesized that additional germline variants could be identified if a genome-wide association study (GWAS) were performed by molecular subtype. Methods A total of 1320 glioma cases and 1889 controls were used in the discovery set and 799 glioma cases and 808 controls in the validation set. Glioma cases were classified into molecular subtypes based on combinations of isocitrate dehydrogenase (IDH) mutation, telomerase reverse transcriptase (TERT) promoter mutation, and 1p/19q codeletion. Logistic regression was applied to the discovery and validation sets to test for associations of variants with each of the subtypes. A meta-analysis was subsequently performed using a genome-wide P-value threshold of 5 × 10−8. Results Nine variants in or near D-2-hydroxyglutarate dehydrogenase (D2HGDH) on chromosome 2 were genome-wide significant in IDH-mutated glioma (most significant was rs5839764, meta P = 2.82 × 10−10). Further stratifying by 1p/19q codeletion status, one variant in D2HGDH was genome-wide significant in IDH-mutated non-codeleted glioma (rs1106639, meta P = 4.96 × 10−8). Further stratifying by TERT mutation, one variant near FAM20C (family with sequence similarity 20, member C) on chromosome 7 was genome-wide significant in gliomas that have IDH mutation, TERT mutation, and 1p/19q codeletion (rs111976262, meta P = 9.56 × 10−9). Thirty-six variants in or near GMEB2 on chromosome 20 near regulator of telomere elongation helicase 1 (RTEL1) were genome-wide significant in IDH wild-type glioma (most significant was rs4809313, meta P = 2.60 × 10−10). Conclusions Performing a GWAS by molecular subtype identified 2 new regions and a candidate independent region near RTEL1, which were associated with specific glioma molecular subtypes.

Objectives: Survival benefit of combination over single-agent chemotherapy for metastatic pancreatic ductal adenocarcinoma (PDAC) was demonstrated in younger patients in clinical trials. The authors aimed to evaluate whether this survival benefit of combination chemotherapy is present in elderly patients with metastatic PDAC. Materials and Methods: The authors identified elderly patients (age 65 y or older) with stage IV PDAC and extracted available clinical information from a prospectively maintained institutional pancreatic cancer registry from 2007 to 2016. The primary endpoint was overall survival. Cox proportional hazards regression was used for multivariable survival analyses. Survival outcomes for the entire cohort and by age group I (elderly, 65 to 75 y) and age group II (very elderly, older than 75 y) were assessed. Results: A total of 606 patients were included with a median age of 73.8 years. Among them, 239 patients (39%) received combination chemotherapy and 152 patients (25.1%) received single-agent chemotherapy as first-line treatment. Combination chemotherapy was associated with significantly longer median overall survival compared with single-agent chemotherapy (10.9 vs. 7.5 mo, P<0.001) with hazard ratio 0.62 (95% confidence interval, 0.47-0.81; P=0.001) after adjusting for age, sex, comorbidity, Eastern Cooperative Oncology Group (ECOG) performance status, and carbohydrate antigen 19-9 level. Analyses by age groups indicated that very elderly patients (age group II) benefited from combination chemotherapy compared with single-agent chemotherapy with hazard ratio 0.56 (95% confidence interval, 0.31-1; P=0.049), comparable with the age group I (P age-treatment interaction=0.81). Conclusion: Elderly patients, even those older than 75 years, with metastatic PDAC benefited from combination chemotherapy.

Background Past research in population health trends has shown that injuries form a substantial burden of population health loss. Regular updates to injury burden assessments are critical. We report Global Burden of Disease (GBD) 2017 Study estimates on morbidity and mortality for all injuries. Methods We reviewed results for injuries from the GBD 2017 study. GBD 2017 measured injury-specific mortality and years of life lost (YLLs) using the Cause of Death Ensemble model. To measure non-fatal injuries, GBD 2017 modelled injury-specific incidence and converted this to prevalence and years lived with disability (YLDs). YLLs and YLDs were summed to calculate disability-adjusted life years (DALYs). Findings In 1990, there were 4 260 493 (4 085 700 to 4 396 138) injury deaths, which increased to 4 484 722 (4 332 010 to 4 585 554) deaths in 2017, while age-standardised mortality decreased from 1079 (1073 to 1086) to 738 (730 to 745) per 100 000. In 1990, there were 354 064 302 (95% uncertainty interval: 338 174 876 to 371 610 802) new cases of injury globally, which increased to 520 710 288 (493 430 247 to 547 988 635) new cases in 2017. During this time, age-standardised incidence decreased non-significantly from 6824 (6534 to 7147) to 6763 (6412 to 7118) per 100 000. Between 1990 and 2017, age-standardised DALYs decreased from 4947 (4655 to 5233) per 100 000 to 3267 (3058 to 3505). Interpretation Injuries are an important cause of health loss globally, though mortality has declined between 1990 and 2017. Future research in injury burden should focus on prevention in high-burden populations, improving data collection and ensuring access to medical care.

Nonalcoholic steatohepatitis (NASH) is an advanced form of nonalcoholic fatty liver disease (NAFLD), resulting from the complex interplay of genetic and environmental risk factors, e.g. diet. The development of novel therapies has been hampered by the lack of a preclinical animal model with high physiologic fidelity to the human condition. A single mutation (I148M) in the patatin‐like phospholipase domain‐containing 3 ( PNPLA3 ) gene is significantly associated with liver fat content and has been identified as the strongest genetic risk factor for NAFLD/NASH, cirrhosis, and hepatocellular carcinoma. We hypothesized that editing PNPLA3 I148M mutation into a genome of Ossabaw, a miniature pig that already has a natural propensity to develop metabolic syndrome, will develop phenotypes that hallmark NAFLD/NASH, and improve preclinical modeling over existing rodent models. PNPLA3 I148M/I148M founders were developed using TALEN‐stimulated homology directed repair in fibroblasts, followed by somatic cell nuclear transfer. Mutant pigs with age/gender‐matched wildtype controls, reared on standard (SD) and specialized western diet (WD), were clinically and histopathologically characterized. No significant differences in circulating triglyceride and liver enzyme levels was observed in our initial cohort on SD of a female mutant pig relative to the wildtype control. However, this mutant female exhibited increased ALP level and a more atherogenic lipoprotein profile with LDL particle concentration than the levels of the respective control. Histopathologically, the mutant female fed on the WD for 3 months exhibited augmented interlobular inflammation, ballooning, as well lipid and collagen buildup in the liver relative to the wildtype counterparts on the same WD or SD. Longitudinal studies in second larger cohort of barrows over six‐months period revealed significantly elevated liver enzymes (ALP, ALT, GGT), bile acids, and lipid profiles (cholesterol, triglyceride, triglyceride‐rich lipoprotein and vLDL) among the mutant versus wildtypes on western diet, substantiating liver pathology and the associated comorbidity of dyslipidemia. Liver histopathology from these barrows on WD over 6‐months did not reveal as significant difference as in the females of the initial cohort, implying gender differences and variances in western diet formulation in susceptibility to NAFLD/NASH that warrant future large‐scale studies. Levels of circulating extracellular vesicles (EVs) were significantly elevated in the sera of mutant pigs relative to wildtypes on the WD, validating this as an important biomarker in NAFLD/NASH pathology. Additionally, the mutant pigs on the WD had significantly greater coronary artery plaque burden than the control groups, in line with the predicted higher comorbidity level in mutants and reinforces the relevance to human clinical medicine. Support or Funding Information NIH (1R43OD023257‐01A1 to TM) and internal funds from Recombinetics Inc., Drs. Chalasani, Sturek, and Malhi.

AbstractMuch of the similarities of the tissue characteristics, pathologies and mechanisms of heterotopic ossification (HO) formation are shared between HO of tendon and ligament (HOTL). Unmet need and no effective treatment has been developed for HOTL, primarily attributable to poor understanding of cellular and molecular mechanisms. HOTL forms via endochondral ossification, a common process of most kinds of HO. HOTL is a dynamic pathologic process that includes trauma/injury, inflammation, mesenchymal stromal cell (MSC) recruitment, chondrogenic differentiation and, finally, ossification. A variety of signal pathways involve HOTL with multiple roles in different stages of HO formation, and here in this review, we summarize the progress and provide an up‐to‐date understanding of HOTL.

Abstract Acute renal depletion of sorting nexin 1 (SNX1) in mice results in blunted natriuretic response and hypertension due to impaired dopamine D 5 receptor (D 5 R) activity. We elucidated the molecular mechanisms for these phenotypes in Snx1 −/− mice. These mice had increased renal expressions of angiotensin II type 1 receptor (AT 1 R), NADPH oxidase (NOX) subunits, D 5 R, and NaCl cotransporter. Basal reactive oxygen species (ROS), NOX activity, and blood pressure (BP) were also higher in Snx1 ‐/‐ mice, which were normalized by apocynin, a drug that prevents NOX assembly. Renal proximal tubule (RPT) cells from hypertensive (HT) Euro‐American males had deficient SNX1 activity, impaired D 5 R endocytosis, and increased ROS compared with cells from normotensive (NT) Euro‐American males. siRNA‐mediated depletion of SNX1 in RPT cells from NT subjects led to a blunting of D 5 R agonist‐induced increase in cAMP production and decrease in Na + transport, effects that were normalized by over‐expression of SNX1. Among HT African‐Americans, three of the 12 single nucleotide polymorphisms interrogated for the SNX1 gene were associated with a decrease in systolic BP in response to hydrochlorothiazide (HCTZ). The results illustrate a new paradigm for the development of hypertension and imply that the trafficking protein SNX1 may be a crucial determinant for hypertension and response to antihypertensive therapy.

Endothelial progenitor cells (EPCs) patrols the circulation and contributes to endothelial cell regeneration. Atherosclerotic renal artery stenosis (ARAS) induces microvascular loss in the stenotic kidney (STK). Low-energy shockwave therapy (SW) can induce angiogenesis and restore the STK microcirculation, but the underlying mechanism remains unclear. We tested the hypothesis that SW increases EPC homing to the swine STK, associated with capillary regeneration. Normal pigs and pigs after 3 wk of renal artery stenosis were treated with six sessions of low-energy SW (biweekly for three consecutive weeks) or left untreated. Four weeks after completion of treatment, we assessed EPC (CD34+/KDR+) numbers and levels of the homing-factor stromal cell-derived factor (SDF)-1 in the inferior vena cava and the STK vein and artery, as well as urinary levels of vascular endothelial growth factor (VEGF) and integrin-1β. Subsequently, we assessed STK morphology, capillary count, and expression of the proangiogenic growth factors angiopoietin-1, VEGF, and endothelial nitric oxide synthase ex vivo. A 3-wk low-energy SW regimen improved STK structure, capillary count, and function in ARAS+SW, and EPC numbers and gradients across the STK decreased. Plasma SDF-1 and renal expression of angiogenic factors were increased in ARAS+SW, and urinary levels of VEGF and integrin-1β tended to rise during the SW regimen. In conclusion, SW improves ischemic kidney capillary density, which is associated with, and may be at least in part mediated by, promoting EPCs mobilization and homing to the stenotic kidney.