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  • 1
    Publication Date: 2018-02-09
    Description: Objective To identify modifiable factors associated with sessile serrated polyps (SSPs) and compare the association of these factors with conventional adenomas (ADs) and hyperplastic polyps (HPs). Design We used data from the Tennessee Colorectal Polyp Study, a colonoscopy-based case–control study. Included were 214 SSP cases, 1779 AD cases, 560 HP cases and 3851 polyp-free controls. Results Cigarette smoking was associated with increased risk for all polyps and was stronger for SSPs than for ADs (OR 1.74, 95% CI 1.16 to 2.62, for current vs never, p trend =0.008). Current regular use of non-steroidal anti-inflammatory drugs was associated with a 40% reduction in SSP risk in comparison with never users (OR 0.68, 95% CI 0.48 to 0.96, p trend =0.03), similar to the association with AD. Red meat intake was strongly associated with SSP risk (OR 2.59, 95% CI 1.41 to 4.74 for highest vs lowest intake, p trend 〈0.001) and the association with SSP was stronger than with AD (p trend =0.003). Obesity, folate intake, fibre intake and fat intake were not associated with SSP risk after adjustment for other factors. Exercise, alcohol use and calcium intake were not associated with risk for SSPs. Conclusions SSPs share some modifiable risk factors for ADs, some of which are more strongly associated with SSPs than ADs. Thus, preventive efforts to reduce risk for ADs may also be applicable to SSPs. Additionally, SSPs have some distinctive risk factors. Future studies should evaluate the preventive strategies for these factors. The findings from this study also contribute to an understanding of the aetiology and biology of SSPs.
    Print ISSN: 0017-5749
    Electronic ISSN: 1468-3288
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 2
    Publication Date: 2018-09-06
    Description: Deep-UV light detection has important application in surveillance and homeland security regions. CH 3 NH 3 PbX 3 (X = Cl, Br, I) materials have outstanding optical absorption and electronic transport properties suitable for obtaining excellent deep-UV photoresponse. In this work, we have grown high-quality CH 3 NH 3 PbX 3 (X = Cl, Br, I) bulk crystals and used them to fabricate photodetectors. We found that they all have high-sensitive and fast-speed response to 255 nm deep-UV light. Their responsivities are 10–10 3 times higher than MgZnO and Ga 2 O 3 detectors, and their response speeds are 10 3 times faster than Ga 2 O 3 and ZnO detectors. These results indicate a new promising route for deep-UV detection.
    Keywords: materials science
    Electronic ISSN: 2054-5703
    Topics: Natural Sciences in General
    Published by Royal Society
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  • 3
    Publication Date: 2018-11-09
    Description: The maintenance of autoreactive B cells in a quiescent state is crucial for preventing autoimmunity. Here we identify a variant of human immunoglobulin G1 (IgG1) with a Gly 396 -〉Arg substitution (hIgG1-G396R), which positively correlates with systemic lupus erythematosus. In induced lupus models, murine homolog Gly 390 -〉Arg (G390R) knockin mice generate excessive numbers of plasma cells, leading to a burst of broad-spectrum autoantibodies. This enhanced production of antibodies is also observed in hapten-immunized G390R mice, as well as in influenza-vaccinated human G396R homozygous carriers. This variant potentiates the phosphorylation of the IgG1 immunoglobulin tail tyrosine (ITT) motif. This, in turn, alters the availability of phospho-ITT to trigger longer adaptor protein Grb2 dwell times in immunological synapses, leading to hyper–Grb2–Bruton’s tyrosine kinase (Btk) signaling upon antigen binding. Thus, the hIgG1-G396R variant is important for both lupus pathogenesis and antibody responses after vaccination.
    Keywords: Immunology, Medicine, Diseases
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2018-04-04
    Description: Background: Associations between physical activity and pancreatic cancer risk are unclear. Methods: In two prospective cohort studies, the Shanghai Women's Health Study and Shanghai Men's Health Study, physical activity and other information were collected at the baseline interview of 72,451 women and 60,037 men. Participants were followed up through annual linkage with a cancer registry in combination with in-person interviews taking place every 2 to 4 years. Results: We identified 225 female and 159 male cases during a median follow up of 16.1 and 10.3 years, respectively. Adult exercise participation was significantly associated with a decreased pancreatic cancer risk in men [hazard ratio (HR), 95% confidence interval (CI): 0.71 (0.50–1.00)]. Meeting the recommended minimum exercise threshold to achieve health benefits of 150 min/week of moderate-intensity or 75 min/week of vigorous-intensity exercise was associated with further decreased pancreatic cancer risk [HR (95% CI): 0.59 (0.40–0.87)]. We also observed an inverse association between adolescent physical activity and pancreatic cancer risk in men [HR (95% CI): 0.54 (0.33–0.90)]. Exercise throughout one's lifetime was associated with a 68% decrease in pancreatic cancer risk [HR (95% CI): 0.32 (0.16–0.66)]. No significant association was found in women. Adult non-exercise daily activity and occupational activity were not associated with pancreatic cancer risk in either men or women. Conclusions: Adult exercise and adolescent physical activity were significantly associated with a decreased pancreatic cancer risk in men but not in women. Impact: These findings underscore the importance of investigating the possible modification by sex on the exercise and pancreatic cancer risk association. Cancer Epidemiol Biomarkers Prev; 27(4); 479–87. ©2018 AACR .
    Print ISSN: 1055-9965
    Electronic ISSN: 1538-7755
    Topics: Medicine
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  • 5
    Publication Date: 2018-03-06
    Description: Background: Infection with Helicobacter pylori is the leading risk factor for noncardia gastric cancer, yet its influence on prognosis of gastric cancer is largely unknown. Thus, exploring the role of Helicobacter pylori ( H. pylori ) in survival could lead to a greater understanding of the high mortality associated with gastric cancer. Methods: Seropositivity to 15 H. pylori antigens was assessed using a multiplex assay in two prospective cohorts, the Shanghai Men's Health Study and the Shanghai Women's Health Study. Multivariable-adjusted Cox proportional hazards regression was used to examine the association between prediagnostic H. pylori antigen levels and gastric cancer–specific survival. Results: Prediagnostic levels of H. pylori serum antibodies that were previously associated with gastric cancer incidence in this population were not associated with gastric cancer survival, whether assessed in a 6-antigen panel [HR = 1.29; 95% confidence interval (CI), 0.78–2.13 for men; HR = 0.93; 95% CI, 0.57–1.52 for women], focused on CagA + H. pylori (HR = 0.73; 95% CI, 0.44–1.20 forwomen; HR = 1.27; 95% CI, 0.70–2.31 for men) or on the high-risk biomarkers of dual Omp and HP 0305 seropositivity (HR = 0.97; 95% CI, 0.72–1.30 for women; HR = 1.37; 95% CI, 0.97–1.94 for men). Conclusions: Prediagnostic H. pylori antigen levels are not associated with gastric cancer survival in East Asian populations. Impact: Identification of additional factors associated with gastric cancer survival would further our understanding of the high mortality associated with this malignancy. Cancer Epidemiol Biomarkers Prev; 27(3); 342–4. ©2017 AACR .
    Print ISSN: 1055-9965
    Electronic ISSN: 1538-7755
    Topics: Medicine
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  • 6
    Publication Date: 2018-03-09
    Description: Systemic lupus erythematosus (SLE) is a common prototypic autoimmune disease with substantial genetic predispositions. It is more prevalent in Asians than in Caucasians. Genome wide association studies (GWAS) have discovered more than 80 genetic loci for the risk of SLE 1 , which improve the understanding of SLE etiology and provide potential therapeutic targets. However, each GWAS finding only confers a relatively small effect, and they in total cannot fully explain SLE heritability, suggesting more genetic variants are yet to be discovered. This article is protected by copyright. All rights reserved.
    Print ISSN: 0007-0963
    Electronic ISSN: 1365-2133
    Topics: Medicine
    Published by Wiley-Blackwell
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  • 7
    Publication Date: 2018-01-09
    Description: Background: Pancreatic cancer mutation signatures closely resemble breast cancer, suggesting that both cancers may have common predisposition mechanisms that may include commonly inherited SNPs. Methods: We examined 23 genetic variants known to be associated with pancreatic cancer as breast cancer risk factors in the Root genome-wide association study (GWAS; 1,657 cases and 2,029 controls of African diaspora) and GAME-ON/DRIVE GWAS (16,003 cases and 41,335 controls of European ancestry). Results: None of the pancreatic cancer susceptibility variants were individually associated with breast cancer risk after adjustment for multiple testing (at α = 0.002) in the two populations. In Root GWAS, a change by one SD in the polygenic risk score (PRS) was not significantly associated with breast cancer. In addition, we did not observe a trend in the relationship between PRS percentiles and breast cancer risk. Conclusions: The association between reported pancreatic cancer genetic susceptibility variants and breast cancer development in women of African or European ancestry is likely weak, if it does exist. Impact: Known GWAS-derived susceptibility variants of pancreatic cancer do not explain its shared genetic etiology with breast cancer. Cancer Epidemiol Biomarkers Prev; 27(1); 116–8. ©2017 AACR .
    Print ISSN: 1055-9965
    Electronic ISSN: 1538-7755
    Topics: Medicine
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  • 8
    Publication Date: 2018-11-02
    Description: Background: Pathogenic germline mutations in the CDKN2A tumor suppressor gene are rare and associated with highly penetrant familial melanoma and pancreatic cancer in non-Hispanic whites (NHW). To date, the prevalence and impact of CDKN2A rare coding variants (RCV) in racial minority groups remain poorly characterized. We examined the role of CDKN2A RCVs on the risk of pancreatic cancer among minority subjects. Methods: We sequenced CDKN2A in 220 African American (AA) pancreatic cancer cases, 900 noncancer AA controls, and 183 Nigerian controls. RCV frequencies were determined for each group and compared with that of 1,537 NHW patients with pancreatic cancer. Odds ratios (OR) and 95% confidence intervals (CI) were calculated for both a case–case comparison of RCV frequencies in AAs versus NHWs, and case–control comparison between AA cases versus noncancer AA controls plus Nigerian controls. Smaller sets of Hispanic and Native American cases and controls also were sequenced. Results: One novel missense RCV and one novel frameshift RCV were found among AA patients: 400G〉A and 258_278del. RCV carrier status was associated with increased risk of pancreatic cancer among AA cases (11/220; OR, 3.3; 95% CI, 1.5–7.1; P = 0.004) compared with AA and Nigerian controls (17/1,083). Further, AA cases had higher frequency of RCVs: 5.0% (OR, 13.4; 95% CI, 4.9–36.7; P 〈 0.001) compared with NHW cases (0.4%). Conclusions: CDKN2A RCVs are more common in AA than in NHW patients with pancreatic cancer and associated with moderately increased pancreatic cancer risk among AAs. Impact: RCVs in CDKN2A are frequent in AAs and are associated with risk for pancreatic cancer. Cancer Epidemiol Biomarkers Prev; 27(11); 1364–70. ©2018 AACR.
    Print ISSN: 1055-9965
    Electronic ISSN: 1538-7755
    Topics: Medicine
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  • 9
    Publication Date: 2018-05-15
    Description: The spike glycoprotein (S) of murine coronavirus mouse hepatitis virus (MHV) strain A59 uses murine carcinoembryonic antigen-related cell adhesion molecule 1a as its receptor for cell entry, but S protein can also be triggered in the absence of receptor by pH 8.0 alone at 37°C. The mechanism by which conformational changes of this S glycoprotein can be triggered by pH 8.0 has not yet been determined. Here, we show that MHV-A59 S protein is triggered by pH 8.0 at 37°C to induce receptor-independent syncytium (RIS) formation on 293T cells, and that the conformational changes in S proteins triggered by pH 8.0 are very similar to those triggered by receptor binding. We systemically mutated each of 15 histidine residues in S protein and found that H209 is essential for pH 8.0-triggered RIS formation, while H179, H441, H643, and H759 also play important roles in this process. Replacement of H209 with Ala had no effect on receptor binding, but in murine 17Cl.1 cells mutant H209A MHV-A59 showed delayed growth kinetics and was readily outcompeted by wild-type virus when mixed together, indicating that the H209A mutation caused a defect in virus fitness. Finally, the H209A mutation significantly increased the thermostability of S protein in its prefusion conformation, which may raise the energy barrier for conformational change of S protein required for membrane fusion and lead to a decrease in virus fitness in cell culture. Thus, MHV-A59 may have evolved to lower the stability of its S protein in order to increase virus fitness. IMPORTANCE Enveloped viruses enter cells through fusion of viral and cellular membranes, and the process is mediated by interactions between viral envelope proteins and their host receptors. In the prefusion conformation, viral envelope proteins are metastable, and activation to the fusion conformation is tightly regulated, since premature activation would lead to loss of viral infectivity. The stability of viral envelope proteins greatly influences their activation and virus fitness. Here, we report that, similar to the A82V mutation in Ebola glycoprotein, in the S glycoprotein of murine coronavirus MHV-A59, the histidine residue at position of 209 significantly affects the thermal stability of the S protein, determines whether S protein can be activated at 37°C by either pH 8.0 alone or by receptor binding, and affects viral fitness in cell culture. Thus, the spike glycoprotein of MHV-A59 has evolved to retain histidine at position 209 to optimize virus fitness.
    Print ISSN: 0022-538X
    Electronic ISSN: 1098-5514
    Topics: Medicine
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  • 10
    Publication Date: 2018-08-08
    Description: B lymphocytes use B cell receptors (BCRs) to recognize membrane-bound antigens to further initiate cell spreading and contraction responses during B cell activation. We combined traction force microscopy and live-cell imaging to profile the origin, dynamics, and function of traction force generation in these responses. We showed that B cell activation required the generation of 10 to 20 nN of traction force when encountering antigens presented by substrates with stiffness values from 0.5 to 1 kPa, which mimic the rigidity of antigen-presenting cells in vivo. Perturbation experiments revealed that F-actin remodeling and myosin- and dynein-mediated contractility contributed to traction force generation and B cell activation. Moreover, membrane-proximal BCR signaling molecules (including Lyn, Syk, Btk, PLC-2, BLNK, and Vav3) and adaptor molecules (Grb2, Cbl, and Dok-3) linking BCR microclusters and motor proteins were also required for the sustained generation of these traction forces. We found a positive correlation between the strength of the traction force and the mean fluorescence intensity of the BCR microclusters. Furthermore, we demonstrated that isotype-switched memory B cells expressing immunoglobulin G (IgG)–BCRs generated greater traction forces than did mature naïve B cells expressing IgM-BCRs during B cell activation. Last, we observed that primary B cells from patients with rheumatoid arthritis generated greater traction forces than did B cells from healthy donors in response to antigen stimulation. Together, these data delineate the origin, dynamics, and function of traction force during B cell activation.
    Print ISSN: 1945-0877
    Topics: Medicine
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