Citations

Abstract Background: Epigenetic disturbances are crucial in cancer initiation, potentially with pleiotropic effects, and may be influenced by the genetic background. Methods: In a subsets (ASSET) meta-analytic approach, we investigated associations of genetic variants related to epigenetic mechanisms with risks of breast, lung, colorectal, ovarian and prostate carcinomas using 51,724 cases and 52,001 controls. False discovery rate–corrected P values (q values < 0.05) were considered statistically significant. Results: Among 162,887 imputed or genotyped variants in 555 candidate genes, SNPs in eight genes were associated with risk of more than one cancer type. For example, variants in BABAM1 were confirmed as a susceptibility locus for squamous cell lung, overall breast, estrogen receptor (ER)–negative breast, and overall prostate, and overall serous ovarian cancer; the most significant variant was rs4808076 [OR = 1.14; 95% confidence interval (CI) = 1.10–1.19; q = 6.87 × 10−5]. DPF1 rs12611084 was inversely associated with ER-negative breast, endometrioid ovarian, and overall and aggressive prostate cancer risk (OR = 0.93; 95% CI = 0.91–0.96; q = 0.005). Variants in L3MBTL3 were associated with colorectal, overall breast, ER-negative breast, clear cell ovarian, and overall and aggressive prostate cancer risk (e.g., rs9388766: OR = 1.06; 95% CI = 1.03–1.08; q = 0.02). Variants in TET2 were significantly associated with overall breast, overall prostate, overall ovarian, and endometrioid ovarian cancer risk, with rs62331150 showing bidirectional effects. Analyses of subpathways did not reveal gene subsets that contributed disproportionately to susceptibility. Conclusions: Functional and correlative studies are now needed to elucidate the potential links between germline genotype, epigenetic function, and cancer etiology. Impact: This approach provides novel insight into possible pleiotropic effects of genes involved in epigenetic processes. Cancer Epidemiol Biomarkers Prev; 26(6); 816–25. ©2017 AACR.

Steatohepatitis-like change has not been described in focal nodular hyperplasia (FNH). Steatohepatitis-like change in FNH may show overlapping features with steatohepatitic variant of hepatocellular carcinoma (HCC). This problem can be compounded if seen in FNH with widened cell plates or hepatocyte rosettes, other features that can also be seen in HCC. This study examined steatotic FNHs for the frequency of steatohepatitis-like change, especially in the setting of FNH with rosettes and/or widened cell plates. Thirty-three resection specimens of steatotic FNH from 3 institutions were evaluated for degree of steatosis, background liver steatosis, ductular reaction, and lymphocytic infiltrate, as well as presence of thick fibrous bands, thick-walled vessels, ballooned hepatocytes, Mallory-Denk bodies, dilated sinusoids, hepatocyte rosettes, and thick hepatic plates. Steatosis was distributed along fibrous septa as well as diffusely throughout the FNH. Steatohepatitis-like changes were focally present in 54% (18 cases). Thick plates>3 cells were focally found in 14 cases (42%); rosettes were common (70%). All cases showed at least 2 of the histologic features highly suggestive for the diagnosis of FNH such as thick bands of fibrosis, thick-walled vessels and/or ductular reaction and the typical map-like pattern of glutamine synthetase immunostaining. More than half of fatty FNH examined for this study had features of at least focal steatohepatitis-like changes. This finding should not be confused with steatohepatitic variant of HCC. Common typical features of FNH including thick-walled vessels, ductular reaction and thick fibrous bands are helpful for discrimination of FNH from HCC.

AbstractBackgroundAnimal studies have increasingly highlighted the role of macrophages in the development of delayed gastric emptying. However, their role in the pathophysiology of human gastroparesis is unclear. Our aim was to determine changes in macrophages and other cell types in the gastric antrum muscularis propria of patients with diabetic and idiopathic gastroparesis.MethodsFull thickness gastric antrum biopsies were obtained from patients enrolled in the Gastroparesis Clinical Research Consortium (11 diabetic, 6 idiopathic) and 5 controls. Immunolabeling and quantitative assessment was done for interstitial cells of Cajal (ICC) (Kit), enteric nerves protein gene product 9.5, neuronal nitric oxide synthase, vasoactive intestinal peptide, substance P, tyrosine hydroxylase), overall immune cells (CD45) and anti‐inflammatory macrophages (CD206). Gastric emptying was assessed using nuclear medicine scintigraphy and symptom severity using the Gastroparesis Cardinal Symptom Index.ResultsBoth diabetic and idiopathic gastroparesis patients showed loss of ICC as compared to controls (Mean [standard error of mean]/hpf: diabetic, 2.28 [0.16]; idiopathic, 2.53 [0.47]; controls, 6.05 [0.62]; P=.004). Overall immune cell population (CD45) was unchanged but there was a loss of anti‐inflammatory macrophages (CD206) in circular muscle (diabetic, 3.87 [0.32]; idiopathic, 4.16 [0.52]; controls, 6.59 [1.09]; P=.04) and myenteric plexus (diabetic, 3.83 [0.27]; idiopathic, 3.59 [0.68]; controls, 7.46 [0.51]; P=.004). There was correlation between the number of ICC and CD206‐positive cells (r=.55, P=.008). Enteric nerves (PGP9.5) were unchanged: diabetic, 33.64 (3.45); idiopathic, 41.26 (6.40); controls, 46.80 (6.04).ConclusionLoss of antral CD206‐positive anti‐inflammatory macrophages is a key feature in human gastroparesis and it is associates with ICC loss.

AbstractObjectiveThe aim of this study was to examine the relative contributions of body mass index (BMI) and pubertal measures for risk and age of onset of pediatric MS.MethodsCase–control study of 254 (63% female) MS cases (onset<18 years of age) and 420 (49% female) controls conducted at 14 U.S. Pediatric MS Centers. Sex‐ and age‐stratified BMI percentiles were calculated using CDC growth charts from height and weight measured at enrollment for controls, and within 1 year of onset for MS cases. Sex‐stratified associations between MS risk and age at symptom onset with both BMI and pubertal factors were estimated controlling for race and ethnicity.ResultsOnly 11% of girls and 15% of boys were prepubertal (Tanner stage I) at MS onset. 80% of girls had onset of MS after menarche. BMI percentiles were higher in MS cases versus controls (girls: P < 0.001; boys: P = 0.018). BMI was associated with odds of MS in multivariate models in postpubertal girls (OR = 1.60, 95% confidence interval [CI]: 1.12, 2.27, P = 0.009) and boys (OR = 1.43, 95% CI: 1.08, 1.88, P = 0.011). In girls with MS onset after menarche, higher BMI was associated with younger age at first symptoms (P = 0.031). Younger menarche was associated with stronger effects of BMI through mediation and interaction analysis. In pubertal/postpubertal boys, 89% of whom were obese/overweight, earlier sexual maturity was associated with earlier onset of MS (P < 0.001).InterpretationHigher BMI in early adolescence is a risk factor for MS in girls and boys. Earlier age at sexual maturity contributes to earlier age at MS onset, particularly in association with obesity.

Background Platelet polyphosphate is an inorganic procoagulant polymer of orthophosphate units that is stored in dense granules and is released upon platelet activation. Here, we describe an assay to measure polyphosphate on the surface of procoagulant human platelets. Methods and Results Recombinant Escherichia coli ‐expressed exopolyphosphatase deletion mutant PPX_Δ12 labeled with fluorescent Alexa488 dye was used as a polyphosphate probe in flow cytometry. PPX_Δ12‐Alexa488‐signal dose‐dependently increased with long‐chain polyphosphate binding to platelets. In contrast, short‐chain polyphosphate that is found in the supernatant of activated platelets, did not bind to the platelet surface. Both exopolyphosphatase treatment and polyphosphate pre‐incubation abolished PPX_Δ12‐Alexa488 binding to polyphosphate on platelets. Stimulation of platelets with thrombin receptor agonist Trap6, and P2Y 12 receptor activator ADP increased polyphosphate accumulation on platelet surfaces and PPX_Δ12‐Alexa488 signal in a dose‐dependent manner. Conclusion This study indicates that long‐chain polyphosphate binds to platelet plasma membranes and presents a promising diagnostic assay to measure this interaction on human platelets in platelet‐rich plasma. Future investigations will aim to determine if polyphosphate can be used as a novel biomarker of thrombosis. © 2016 International Clinical Cytometry Society

AbstractBackgroundEarly satiety (ES) and postprandial fullness (PPF) are often present in gastroparesis, but the importance of these symptoms in gastroparesis has not been well‐described. The aims were: (i) Characterize ES and PPF in patients with gastroparesis. (ii) Assess relationships of ES and PPF with etiology of gastroparesis, quality of life, body weight, gastric emptying, and water load testing.MethodsGastroparetic patients filled out questionnaires assessing symptoms (PAGI‐SYM) and quality of life (PAGI‐QOL, SF‐36v2). Patients underwent gastric emptying scintigraphy and water load testing.Key Results198 patients with gastroparesis (134 IG, 64 DG) were evaluated. Early satiety was severe or very severe in 50% of patients. Postprandial fullness was severe or very severe in 60% of patients. Severity scores for ES and PPF were similar between idiopathic and diabetic gastroparesis. Increasing severity of ES and PPF were associated with other gastroparesis symptoms including nausea/vomiting, satiety/early fullness, bloating, and upper abdominal pain and GERD subscores. Increasing severity of ES and PPF were associated with increasing gastroparesis severity, decreased BMI, decreased quality of life from PAGI‐QOL and SF‐36 physical health. Increasing severity of ES and PPF were associated with increasing gastric retention of a solid meal and decreased volume during water load test.Conclusions & InferencesEarly satiety and PPF are commonly severe symptoms in both diabetic and idiopathic gastroparesis. Early satiety and PPF severity are associated with other gastroparesis symptom severities, body weight, quality of life, gastric emptying, and water load testing. Thus, ES and PPF are important symptoms characterizing gastroparesis. ClinicalTrials.gov number: NCT NCT01696747.

Introduction: Racial and ethnic groups are under-represented among research subjects who assent to brain donation in Alzheimer disease research studies. There has been little research on this important topic. Although there are some studies that have investigated the barriers to brain donation among African American study volunteers, there is no known research on the factors that influence whether or not Asians or Latinos are willing to donate their brains for research. Methods: African American, Caucasian, Asian, and Latino research volunteers were surveyed at 15 Alzheimer Disease Centers to identify predictors of willingness to assent to brain donation. Results: Positive predictors included older age, Latino ethnicity, understanding of how the brain is used by researchers, and understanding of what participants need to do to ensure that their brain will be donated. Negative predictors included African/African American race, belief that the body should remain whole at burial, and concern that researchers might not be respectful of the body during autopsy. Discussion: The predictive factors identified in this study may be useful for researchers seeking to increase participation of diverse ethnic groups in brain donation.