Publications by authors named "Chu Chen"

490 Publications

An improved lentiviral system for efficient expression and purification of β-defensins in mammalian cells.

Biotechnol J 2021 May 30:e2100023. Epub 2021 May 30.

Department of Endocrinology and Metabolism, School of Medicine, Shanghai Tenth People's Hospital of Tongji University, No. 301 Middle Yanchang Road, Shanghai, 200072, China.

β-defensins are a family of conserved small cationic antimicrobial peptides with different significant biological functions. The majority of mammalian β-defensins are expressed in epididymis, and many of them are predicted to have post-translational modifications. However, only a few of its members have been well studied due to the limitations of expressing and purifying bioactive proteins with correct post-translational modifications efficiently. Here we developed a novel Fc tagged lentiviral system and Fc tagged prokaryotic expression systems provided new options for β-defensins expression and purification. The novel lentiviral system contains a secretive signal peptide, a N-terminal IgG Fc tag, a green fluorescent protein (GFP), and a puromycin selection marker to facilitate efficient expression and fast purification of β-defensins by protein A magnetic or agarose beads. It also enables stable and large-scale expression of β-defensins with regular biological activities and post-translational modification. Purified β-defensins such as Bin1b and a novel human β-defensin hBD129 showed antimicrobial activity, immuno-regulatory activity, and expected post-translational phosphorylation, which were not found in Escherichia coli (E. coli) expressed form. Furthermore, we successfully applied the novel system to identify mBin1b interacting proteins, explaining Bin1b in a better way. These results suggest that the novel lentiviral system is a powerful approach to produce correct post-translational processed β-defensins with bioactivities and is useful to identify their interacting proteins. This study has laid the foundation for future studies to characterize function and mechanism of novel β-defensins. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/biot.202100023DOI Listing
May 2021

Cyclin E in normal physiology and disease states.

Trends Cell Biol 2021 May 27. Epub 2021 May 27.

Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA. Electronic address:

E-type cyclins, collectively called cyclin E, represent key components of the core cell cycle machinery. In mammalian cells, two E-type cyclins, E1 and E2, activate cyclin-dependent kinase 2 (CDK2) and drive cell cycle progression by phosphorylating several cellular proteins. Abnormally elevated activity of cyclin E-CDK2 has been documented in many human tumor types. Moreover, cyclin E overexpression mediates resistance of tumor cells to various therapeutic agents. Recent work has revealed that the role of cyclin E extends well beyond cell proliferation and tumorigenesis, and it may regulate a diverse array of physiological and pathological processes. In this review, we discuss these various cyclin E functions and the potential for therapeutic targeting of cyclin E and cyclin E-CDK2 kinase.
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http://dx.doi.org/10.1016/j.tcb.2021.05.001DOI Listing
May 2021

A multi-omics study links TNS3 and SEPT7 to long-term former smoking NSCLC survival.

NPJ Precis Oncol 2021 May 17;5(1):39. Epub 2021 May 17.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, 02115, USA.

The genetic architecture of non-small cell lung cancer (NSCLC) is relevant to smoking status. However, the genetic contribution of long-term smoking cessation to the prognosis of NSCLC patients remains largely unknown. We conducted a genome-wide association study primarily on the prognosis of 1299 NSCLC patients of long-term former smokers from independent discovery (n = 566) and validation (n = 733) sets, and used in-silico function prediction and multi-omics analysis to identify single nucleotide polymorphisms (SNPs) on prognostics with NSCLC. We further detected SNPs with at least moderate association strength on survival within each group of never, short-term former, long-term former, and current smokers, and compared their genetic similarity at the SNP, gene, expression quantitative trait loci (eQTL), enhancer, and pathway levels. We identified two SNPs, rs34211819 at 7p12.3 (P = 3.90 × 10) and rs1143149 at 7p14.2 (P = 9.75 × 10), were significantly associated with survival of NSCLC patients who were long-term former smokers. Both SNPs had significant interaction effects with years of smoking cessation (rs34211819: P = 8.0 × 10; rs1143149: P = 0.003). In addition, in silico function prediction and multi-omics analysis provided evidence that these QTLs were associated with survival. Moreover, comparison analysis found higher genetic similarity between long-term former smokers and never-smokers, compared to short-term former smokers or current smokers. Pathway enrichment analysis indicated a unique pattern among long-term former smokers that was related to immune pathways. This study provides important insights into the genetic architecture associated with long-term former smoking NSCLC.
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http://dx.doi.org/10.1038/s41698-021-00182-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128887PMC
May 2021

Dairy foods, calcium, and risk of breast cancer overall and for subtypes defined by estrogen receptor status: a pooled analysis of 21 cohort studies.

Am J Clin Nutr 2021 May 8. Epub 2021 May 8.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.

Background: Epidemiologic studies examining the relations between dairy product and calcium intakes and breast cancer have been inconclusive, especially for tumor subtypes.

Objective: To evaluate the associations between intakes of specific dairy products and calcium and risk of breast cancer overall and for subtypes defined by estrogen receptor (ER) status.

Method: We pooled the individual-level data of over 1 million women who were followed for a maximum of 8-20 years across studies. Associations were evaluated for dairy product and calcium intakes and risk of incident invasive breast cancer overall (n = 37,861 cases) and by subtypes defined by ER status. Study-specific multivariable hazard ratios (HRs) were estimated and then combined using random-effects models.

Results: Overall, no clear association was observed between the consumption of specific dairy foods, dietary (from foods only) calcium, and total (from foods and supplements) calcium, and risk of overall breast cancer. Although each dairy product showed a null or very weak inverse association with risk of overall breast cancer (P, test for trend >0.05 for all), differences by ER status were suggested for yogurt and cottage/ricotta cheese with associations observed for ER-negative tumors only (pooled HR = 0.90, 95% CI: 0.83, 0.98 comparing ≥60 g/d with <1 g/d of yogurt and 0.85, 95% CI: 0.76, 0.95 comparing ≥25 g/d with <1 g/d of cottage/ricotta cheese). Dietary calcium intake was only weakly associated with breast cancer risk (pooled HR = 0.98, 95% CI: 0.97, 0.99 per 350 mg/d).

Conclusion: Our study shows that adult dairy or calcium consumption is unlikely to associate with a higher risk of breast cancer and that higher yogurt and cottage/ricotta cheese intakes were inversely associated with the risk of ER-negative breast cancer, a less hormonally dependent subtype with poor prognosis. Future studies on fermented dairy products, earlier life exposures, ER-negative breast cancer, and different racial/ethnic populations may further elucidate the relation.
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http://dx.doi.org/10.1093/ajcn/nqab097DOI Listing
May 2021

Inhibition of 2-Arachidonoylglycerol Metabolism Alleviates Neuropathology and Improves Cognitive Function in a Tau Mouse Model of Alzheimer's Disease.

Mol Neurobiol 2021 May 3. Epub 2021 May 3.

Department of Cellular and Integrative Physiology, School of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA.

Alzheimer's disease (AD) is the most common cause of dementia, which affects more than 5 million individuals in the USA. Unfortunately, no effective therapies are currently available to prevent development of AD or to halt progression of the disease. It has been proposed that monoacylglycerol lipase (MAGL), the key enzyme degrading the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain, is a therapeutic target for AD based on the studies using the APP transgenic models of AD. While inhibition of 2-AG metabolism mitigates β-amyloid (Aβ) neuropathology, it is still not clear whether inactivation of MAGL alleviates tauopathies as accumulation and deposition of intracellular hyperphosphorylated tau protein are the neuropathological hallmark of AD. Here we show that JZL184, a potent MAGL inhibitor, significantly reduced proinflammatory cytokines, astrogliosis, phosphorylated GSK3β and tau, cleaved caspase-3, and phosphorylated NF-kB while it elevated PPARγ in P301S/PS19 mice, a tau mouse model of AD. Importantly, tau transgenic mice treated with JZL184 displayed improvements in spatial learning and memory retention. In addition, inactivation of MAGL ameliorates deteriorations in expression of synaptic proteins in P301S/PS19 mice. Our results provide further evidence that MAGL is a promising therapeutic target for AD.
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http://dx.doi.org/10.1007/s12035-021-02400-2DOI Listing
May 2021

Dataset of testicular germ cell tumors (TGCT) risk associated with serum polychlorinated biphenyl (PCB) by age at diagnosis and histologic types.

Data Brief 2021 Jun 27;36:107014. Epub 2021 Mar 27.

School of Public Health, Brown University, Providence, RI 02903, USA.

In a population-based case control study of testicular germ cell tumors (TGCT), we reported a strong positive association between serum levels of Wolff's Group 1 (potentially estrogenic) polychlorinated biphenyl (PCBs) and risk of TGCT, and the observed associations were similar for both seminoma and non-seminoma. While the observed specific associations between TGCT and Wolff's Group 1 PCBs cannot be easily explained by bias or confounding, a question can still be asked, that is, could the relationship between PCBs and TGCT differ by age at diagnosis? PCBs tend to bioaccumulate, with more heavily chlorinated PCB congeners tending to have longer half-lives. Half-lives of PCB congeners were reported ranging from 4.6 years for PCB-28 to 41.0 years for PCB-156. The half-life for the heavy PCB congeners (17.8 years) was found to be approximately twice that for the light PCBs (9.6 years) in early studies. Therefore, the same PCB concentration measured in a 20-year-old vs. a 55-year-old is unlikely to represent the same lifetime PCB exposure or type of PCB exposure. In this analysis, we stratified the data by median age of diagnosis of TGCT and further stratified by histologic type of TGCT (seminoma vs non-seminoma) to explore if the risk of TGCT associated with PCB exposures differs by age.
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http://dx.doi.org/10.1016/j.dib.2021.107014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076715PMC
June 2021

Associations between Genetically Predicted Circulating Protein Concentrations and Endometrial Cancer Risk.

Cancers (Basel) 2021 Apr 26;13(9). Epub 2021 Apr 26.

Population Sciences in the Pacific Program, Cancer Epidemiology Division, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI 96813, USA.

Endometrial cancer (EC) is the leading female reproductive tract malignancy in developed countries. Currently, genome-wide association studies (GWAS) have identified 17 risk loci for EC. To identify novel EC-associated proteins, we used previously reported protein quantitative trait loci for 1434 plasma proteins as instruments to evaluate associations between genetically predicted circulating protein concentrations and EC risk. We studied 12,906 cases and 108,979 controls of European descent included in the Endometrial Cancer Association Consortium, the Epidemiology of Endometrial Cancer Consortium, and the UK Biobank. We observed associations between genetically predicted concentrations of nine proteins and EC risk at a false discovery rate of <0.05 (-values range from 1.14 × 10 to 3.04 × 10). Except for vascular cell adhesion protein 1, all other identified proteins were independent from known EC risk variants identified in EC GWAS. The respective odds ratios (95% confidence intervals) per one standard deviation increase in genetically predicted circulating protein concentrations were 1.21 (1.13, 1.30) for DNA repair protein RAD51 homolog 4, 1.27 (1.14, 1.42) for desmoglein-2, 1.14 (1.07, 1.22) for MHC class I polypeptide-related sequence B, 1.05 (1.02, 1.08) for histo-blood group ABO system transferase, 0.77 (0.68, 0.89) for intestinal-type alkaline phosphatase, 0.82 (0.74, 0.91) for carbohydrate sulfotransferase 15, 1.07 (1.03, 1.11) for D-glucuronyl C5-epimerase, and 1.07 (1.03, 1.10) for CD209 antigen. In conclusion, we identified nine potential EC-associated proteins. If validated by additional studies, our findings may contribute to understanding the pathogenesis of endometrial tumor development and identifying women at high risk of EC along with other EC risk factors and biomarkers.
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http://dx.doi.org/10.3390/cancers13092088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123478PMC
April 2021

Strategies and applications of covalent organic frameworks as promising nanoplatforms in cancer therapy.

J Mater Chem B 2021 04;9(16):3450-3483

Department of Polymer Science and Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China. and Tianjin Key Laboratory of Membrane Science and Desalination Technology, Tianjin University, Tianjin 300350, China.

Cancer nanomedicine is the best option to face the limits of conventional chemotherapy and phototherapy methods, and thus the intensive quest for new nanomaterials to improve therapeutic efficacy and safety is still underway. Owing to their low density, well-defined structures, large surface area, finely tunable pore size, and metal ion free features, covalent organic frameworks (COFs) have been extensively studied in many research fields. The recent great interest in nanoscale COFs to improve the properties of bulk COFs has led to broadening of their applicability in the biomedical field, such as nanocarriers with an outstanding loading capacity and efficient delivery of therapeutic agents, smart theranostic nanoplatforms with excellent stability, high ROS generation, light-to-heat conversion capabilities, and different response and diagnostic characteristics. The COFs and related nanoplatforms with a wide variety of designability and functionalization have opened up a new avenue for exciting opportunities in cancer therapy. Herein we review the state-of-the-art technical and scientific developments in this emerging field, focusing on the overall progress addressed so far in building versatile COF-based nanoplatforms to enhance chemotherapy, photodynamic/photothermal therapy, and combination. Future perspectives for achieving the synergistic effect of cancer elimination and clinical translation are further discussed to motivate future contributions and explore new possibilities.
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http://dx.doi.org/10.1039/d1tb00041aDOI Listing
April 2021

Non-destructive laser-ultrasonic Synthetic Aperture Focusing Technique (SAFT) for 3D visualization of defects.

Photoacoustics 2021 Jun 27;22:100248. Epub 2021 Feb 27.

School of Science, Nanjing University of Science and Technology, Nanjing 210094, China.

The Laser Ultrasonic (LU) technique has been widely studied. Detected ultrasonic signals can be further processed using Synthetic Aperture Focusing Techniques (SAFTs), to detect and image internal defects. LU-based SAFT in frequency-domain (F-SAFT) is developed to visualize horizontal hole-type defects in aluminum. Bulk acoustic waves are non-destructively generated by irradiating a laser line-source, and detected using a laser Doppler vibrometer at a point away from the generation. The influence of this non-coincident generation-detection on the equivalent acoustic velocity used in the algorithm is studied via velocity mappings. Because the wide-band generation characteristic of the LU technique, frequency range selections in acoustic wave signals are implemented to increase Signal-to-Noise Ratio (SNR) and reconstruction speed. Results indicate that by using the LU F-SAFT algorithm, and incorporating optimizations such as velocity mapping and frequency range selection, small defects can be visualized in 3D with corrected locations and improved image quality.
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http://dx.doi.org/10.1016/j.pacs.2021.100248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937565PMC
June 2021

A reply to "Lung cancer outcomes: Are BMI and race clinically relevant?"

Lung Cancer 2021 04 26;154:225-226. Epub 2021 Feb 26.

Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, ON, Canada; Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.

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http://dx.doi.org/10.1016/j.lungcan.2021.02.019DOI Listing
April 2021

Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers.

PLoS Genet 2021 Mar 5;17(3):e1009254. Epub 2021 Mar 5.

University of Salzburg, Department of Biosciences and Cancer Cluster Salzburg, Salzburg, Austria.

Squamous cell carcinomas (SqCC) of the aerodigestive tract have similar etiological risk factors. Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of GWAS data on lung SqCC (LuSqCC), oro/pharyngeal SqCC (OSqCC), laryngeal SqCC (LaSqCC) and esophageal SqCC (ESqCC) cancers, totaling 13,887 cases and 61,961 controls of European ancestry. We identified one novel genome-wide significant (Pmeta<5x10-8) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273). Additionally, three previously unknown loci reached suggestive significance (Pmeta<5x10-7): 1q32.1 (rs12133735, near MDM4), 5q31.2 (rs13181561, TMEM173) and 19p13.11 (rs61494113, ABHD8). Multiple previously identified loci for aerodigestive SqCC also showed evidence of pleiotropy in at least another SqCC site, these include: 4q23 (ADH1B), 6p21.33 (STK19), 6p21.32 (HLA-DQB1), 9p21.33 (CDKN2B-AS1) and 13q13.1(BRCA2). Gene-based association and gene set enrichment identified a set of 48 SqCC-related genes rel to DNA damage and epigenetic regulation pathways. Our study highlights the importance of cross-cancer analyses to identify pleiotropic risk loci of histology-related cancers arising at distinct anatomical sites.
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http://dx.doi.org/10.1371/journal.pgen.1009254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968735PMC
March 2021

Randomized Trial of Different initial IVIG Regimens in Kawasaki Disease.

Pediatr Int 2021 Feb 18. Epub 2021 Feb 18.

Pediatric Heart Center, Children's Hospital of Fudan University, Shanghai, China.

Background: We aimed to assess the efficacy of different initial intravenous immunoglobulin (IVIG) regimens in Kawasaki disease (KD) patients to find more cost-effective therapy options.

Methods: A multicentre, open-label, blind-endpoint randomized controlled trial was conducted from January 2014 to December 2015. KD Patients within 10 days of illness were randomly assigned to receive different IVIG regimens (Group A, 2 g/kg once; Group B, 1 g/kg for 2 consecutive days; Group C, 1 g/kg once) and aspirin 30mg/kg/d. Primary outcomes included hours to defervescence and development of coronary artery lesions (CAL) during the study period. Major secondary outcomes included total fever days, total dose of IVIG, changes of laboratory data, length of stay, and hospitalization expenses. (ClinicalTrials.gov: NCT02439996).

Results: A total of 404 patients underwent randomization. No difference was found in the outcomes of defervescence among three groups at 6, 12, 24, and 36 hours after completion of initial IVIG infusion. There were no differences in the incidence of CAL during the study period (at week 2, month 1, month 3, and month 6 of illness), changes of laboratory data, total fever days and length of stay. Group C patients had the lowest total dose of IVIG (mean: 1.2 vs 2.2 vs 2.1 g/kg; P<0.001) and hospitalization expenses (mean: 8443.8 vs 10798.4 vs 11011.4 RMB; P<0.001) than other two groups.

Conclusions: A single dose of 1g/kg IVIG is a low-cost treatment with the same efficacy as 2 g/kg IVIG and can be an option for the initial therapy of KD patients.
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http://dx.doi.org/10.1111/ped.14656DOI Listing
February 2021

Long-term Functional Outcomes and Relapse of Anti-NMDA Receptor Encephalitis: A Cohort Study in Western China.

Neurol Neuroimmunol Neuroinflamm 2021 03 15;8(2). Epub 2021 Feb 15.

From the Department of Neurology (X.G., C.C., X.L., J.L., A.L., K.G., D.Z., Z.H.), West China Hospital, Sichuan University, Chengdu; and Department of Neurology (Z.H.), Chengdu Shangjin Nanfu Hospital, Sichuan, China.

Objective: To study the factors associated with relapse and functional outcomes in patients with anti-NMDA receptor encephalitis in Western China.

Methods: The Outcome of the anti-NMDA receptor Encephalitis Study in Western China was initiated in October 2011 to collect prospective observational data from consecutively enrolled patients with anti-NMDA receptor encephalitis.

Results: We consecutively enrolled 244 patients (median age: 26 years, range: 9-78 years; females: 128 [52.45%]) between October 2011 and September 2019. Fatality occurred in 17 (6.96%) patients, and tumors were found in 38 (15.57%) patients. The median follow-up duration was 40 (6-96) months. Of these patients, 84.8% showed clinical improvements within 4 weeks after immunotherapy, with a median modified Rankin Scale of 2 (interquartile range [IQR]: 2-3), and 80.7% (median: 1, IQR: 0-2) and 85.7% (median: 0, IQR: 0-1) had substantial recovery (i.e., mild or no residual symptoms) at 12 and 24 months, respectively. The overall prognosis was still improving at 42 months after onset. Disturbance of consciousness during the first month was the only independent predictor (OR: 2.91, 95% CI: 1.27-6.65; = 0.01) of a poor functional neurologic outcome. Overall, 15.9% of the patients had one or multiple relapses, with 82.0% experiencing the first relapse within 24 months and 76.9% experiencing relapses that were less severe than the initial episodes. Relapse-related risk factors included the female sex and delayed treatment ( < 0.05).

Conclusions: Most patients achieved favorable long-term functional outcomes. Some patients experienced one or multiple relapses, especially female patients. Timely immunotherapy at onset may reduce the risk of relapse.
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http://dx.doi.org/10.1212/NXI.0000000000000958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105891PMC
March 2021

Knockdown of TRAF6 inhibits chondrocytes apoptosis and inflammation by suppressing the NF-κB pathway in lumbar facet joint osteoarthritis.

Mol Cell Biochem 2021 Apr 27;476(4):1929-1938. Epub 2021 Jan 27.

Department of Spine Surgery, Affiliated Hospital 2 of Nantong University, Nantong, 226001, Jiangsu, China.

Tumor necrosis factor receptor-associated factor 6 (TRAF6), a regulator of NF-κB signaling, has been discovered recently to be probably related to osteoarthritis, while the function of TRAF6 in lumbar facet joint osteoarthritis(FJOA)still remains unknown. The aim of this study was to probe the specific function of TRAF6 in chondrocytes and its connection with the pathophysiology of FJOA. We found upregulation of TRAF6 in FJOA cartilage by western blot analysis. In vitro, we stimulated immortalized human chondrocytes by LPS to establish the cells apoptosis model. Western blot analysis demonstrated that levels of TRAF6 and cleaved caspase-3/8 in the chondrocyte injury model increased significantly. Knockdown of TRAF6 suppressed the expression of matrix metallopeptidase-13 (MMP-13) and interleukin-6 (IL-6) induced by LPS, and alleviated cell apoptosis. Meanwhile, western blot and immunofluorescent staining demonstrated that IκBα degradation and p65 nuclear transportation were also inhibited, revealing that knockdown of TRAF6 suppressed activation of the NF-κB pathway in LPS-induced chondrocytes apoptosis model. Collectively, our findings suggest that TRAF6 plays a crucial role in FJOA development by regulating NF-κB signaling pathway. Knockdown of TRAF6 may supply a potential therapeutic strategy for FJOA.
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http://dx.doi.org/10.1007/s11010-021-04048-xDOI Listing
April 2021

Serum polychlorinated biphenyl (PCB) levels and risk of testicular germ cell tumors: A population-based case-control study in Connecticut and Massachusetts.

Environ Pollut 2021 Jan 11;273:116458. Epub 2021 Jan 11.

School of Public Health, Brown University, Providence, RI, USA, 02903. Electronic address:

The incidence rate of testicular germ cell tumors (TGCT) has continuously increased in Western countries over the last several decades. Some epidemiologic studies have reported that the endocrine disrupting polychlorinated biphenyls (PCBs) in serum may be associated with TGCT risk, but the evidence is inconsistent. Our goal was to investigate whether serum levels of PCBs are associated with the increase of TGCT risk. We conducted a population-based case-control study of 308 TGCT cases and 323 controls, all residents of Connecticut and Massachusetts. Serum levels of 56 PCBs congeners were measured using gas chromatography and unconditional logistic regression model was used to evaluate the risk of TGCT associated with total PCBs exposure, groups of PCBs categorized by Wolff's functional groups, and individual PCB congeners. The results showed that there was no association between total serum levels of PCBs and risk of TGCT overall (quartile 4 (Q4) vs. quartile 1 (Q1) odds ratio (OR) and 95% confidence interval (C.I.) = 1.0 (0.6-1.9), ρ trend = 0.9). However, strong positive association was observed between total serum levels of Wolff's Group 1 (potentially estrogenic) PCBs and risk of overall TGCT (Q4 vs. Q1 OR = 2.5, 95% CI = 1.3-4.7, ρ trend <0.05) as well as seminoma and non-seminoma subtypes. Wolff's Group 1 PCB congeners that showed an increased risk of TGCT included: 25, 44, 49, 52, 70, 101, 174, and 201/177. Considering the continuing increase of TGCT, these associations should be replicated in different populations with larger sample size.
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http://dx.doi.org/10.1016/j.envpol.2021.116458DOI Listing
January 2021

Assessing Lung Cancer Absolute Risk Trajectory Based on a Polygenic Risk Model.

Cancer Res 2021 Mar 20;81(6):1607-1615. Epub 2021 Jan 20.

Institute for Clinical and Translational Research, Baylor Medical College, Houston, Texas.

Lung cancer is the leading cause of cancer-related death globally. An improved risk stratification strategy can increase efficiency of low-dose CT (LDCT) screening. Here we assessed whether individual's genetic background has clinical utility for risk stratification in the context of LDCT screening. On the basis of 13,119 patients with lung cancer and 10,008 controls with European ancestry in the International Lung Cancer Consortium, we constructed a polygenic risk score (PRS) via 10-fold cross-validation with regularized penalized regression. The performance of risk model integrating PRS, including calibration and ability to discriminate, was assessed using UK Biobank data ( = 335,931). Absolute risk was estimated on the basis of age-specific lung cancer incidence and all-cause mortality as competing risk. To evaluate its potential clinical utility, the PRS distribution was simulated in the National Lung Screening Trial ( = 50,772 participants). The lung cancer ORs for individuals at the top decile of the PRS distribution versus those at bottom 10% was 2.39 [95% confidence interval (CI) = 1.92-3.00; = 1.80 × 10] in the validation set ( = 5.26 × 10). The OR per SD of PRS increase was 1.26 (95% CI = 1.20-1.32; = 9.69 × 10) for overall lung cancer risk in the validation set. When considering absolute risks, individuals at different PRS deciles showed differential trajectories of 5-year and cumulative absolute risk. The age reaching the LDCT screening recommendation threshold can vary by 4 to 8 years, depending on the individual's genetic background, smoking status, and family history. Collectively, these results suggest that individual's genetic background may inform the optimal lung cancer LDCT screening strategy. SIGNIFICANCE: Three large-scale datasets reveal that, after accounting for risk factors, an individual's genetics can affect their lung cancer risk trajectory, thus may inform the optimal timing for LDCT screening.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969419PMC
March 2021

Stable Expression of a Hepatitis E Virus (HEV) RNA Replicon in Two Mammalian Cell Lines to Assess Mechanism of Innate Immunity and Antiviral Response.

Front Microbiol 2020 3;11:603699. Epub 2020 Dec 3.

Institute of Preventive Veterinary Science and Key Laboratory of Animal Virology of Ministry of Agriculture, Department of Veterinary Medicine, Zhejiang University, Hangzhou, China.

Hepatitis E virus (HEV) is one of the major etiological agents responsible for acute hepatitis. Hepatitis E virus does not replicate efficiently in mammalian cell cultures, thus a useful model that mimics persistent HEV replication is needed to dissect the molecular mechanism of pathogenesis. Here we report a genotype-3 HEV RNA replicon expressing an EGFP-Zeocin (EZ) resistant gene (p6-EZ) that persistently self-replicated in cell lines of human (Huh-7-S10-3) or hamster (BHK-21) origin after transfection with RNA transcripts and subsequent drug screening. Two cell lines, S10-3-EZ and BHK-21-EZ, stably expressed EGFP in the presence of Zeocin during continuous passages. Both genomic and subgenomic HEV RNAs and viral replicase proteins were stably expressed in persistent HEV replicon cells. The values of the cell models in antiviral testing, innate immune RNA sensing and type I IFN in host defense were further demonstrated. We revealed a role of RIG-I like receptor-interferon regulatory factor 3 in host antiviral innate immune sensing during HEV replication. We further demonstrated that treatment with interferon (IFN-α) or ribavirin significantly reduced expression of replicon RNA in a dose-dependent manner. The availability of the models will greatly facilitate HEV-specific antiviral development, and delineate mechanisms of HEV replication.
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http://dx.doi.org/10.3389/fmicb.2020.603699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793998PMC
December 2020

Long-term cognitive and neuropsychiatric outcomes of anti-GABAR encephalitis patients: A prospective study.

J Neuroimmunol 2021 02 29;351:577471. Epub 2020 Dec 29.

Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, China. Electronic address:

Long-term cognitive and neuropsychiatric outcomes of anti-gamma-aminobutyric-acid B receptor (anti-GABAR) encephalitis are unclear. In this prospective study, 31 patients with anti-GABAR encephalitis were underwent cognitive and neuropsychiatric evaluations every 6 months. At 24 months' follow-up, cognitive impairments were observed in 80% of patients that mainly included deficits in memory, executive functions and nonverbal reasoning; and neuropsychiatric symptoms were observed in 50% of patients that mainly included depressive symptoms and irritation. The risk factors associated with cognitive deficits was age > 45 years. This study demonstrated that most patients with anti-GABAR encephalitis had persistent cognitive deficits and neuropsychiatric symptoms.
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http://dx.doi.org/10.1016/j.jneuroim.2020.577471DOI Listing
February 2021

Overexpression of RgPAL family genes involved in phenolic biosynthesis promotes the replanting disease development in Rehmannia glutinosa.

J Plant Physiol 2021 Feb 15;257:153339. Epub 2020 Dec 15.

College of Bioengineering, Henan University of Technology, Lianhua Street 100, Zhengzhou High-technology Zero, Henan Province, 450001, China. Electronic address:

Rehmannia glutinosa production is affected by the replanting disease, which involves autotoxic harm mediated by specific endogenous allelochemicals in root exudates. Many phenolics that act as allelochemical agents are mostly phenylpropanoid products of secondary metabolism in plants. Phenylalanine ammonia-lyase (PAL) is the first enzyme that catalyses the deamination of l-phenylalanine for entrance into the phenylpropanoid pathway. PAL family genes have been isolated and functionally characterized in many plant species. However, PAL family genes involved in phenolic biosynthesis remain largely uncharacterized in R. glutinosa. Here, we identified and characterized four PAL family genes (RgPAL2 to RgPAL5) in the species whose sequences exhibited highly conserved domains of PALs according to in silico analysis, implying their potential function in phenolic biosynthesis. Overexpression of RgPALs in R. glutinosa enhanced phenolic production, verifying that RgPAL family genes participate in phenolic biosynthesis pathways. Moreover, we found that the release of several allelopathic phenolics from the roots of RgPAL-overexpressing transgenic R. glutinosa increased, implying that the RgPALs positively promote their release. Importantly, under continuous monoculture stress, we found that the RgPAL transgenic plants exhibited more significant autotoxic harm than did non-transgenic (WT) plants by activating the phenolics/phenylpropanoid pathway, indicating that RgPAL family genes function as positive regulators of the replanting disease development in R. glutinosa. This study revealed that RgPAL family genes are involved in the biosynthesis and release of several phenolics and positively control the replanting disease development in R. glutinosa, laying a foundation for further clarification of the molecular mechanisms underlying the disease formation.
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http://dx.doi.org/10.1016/j.jplph.2020.153339DOI Listing
February 2021

Ultrasonic thyroid nodule detection method based on U-Net network.

Comput Methods Programs Biomed 2021 Feb 17;199:105906. Epub 2020 Dec 17.

Department of General Surgery, Fourth Affiliated Hospital of China Medical University, No. 4, Chongshan East Road, Huanggu District, Shenyang City, Liaoning Province, 110032, China. Electronic address:

Objective: Aiming at the time consuming processing of existing thyroid nodule detection and difficulty in feature extraction, U-Net-based thyroid nodule detection is proposed to perform computed aided diagnosis.

Method: This paper proposes a mark-guided ultrasound deep network segmentation model of thyroid nodules. By comparing with VGG19, Inception V3, DenseNet 161, segmentation accuracy, segmentation edge and network operation time, it is found that the algorithm in this paper has relative advantages.

Results: U-Net network-based ultrasound thyroid nodules segmented the nodule area overlapped with the manually depicted nodule area close to 100%, the segmentation accuracy rate was as high as 0.9785, and the U-Net segmentation result was closer to the manually depicted nodule. The accuracy of U-Net segmentation of the thyroid is about 3% higher than the other three networks.

Conclusion: The segmentation of nodules based on U-Net proposed in this paper significantly improves the segmentation accuracy of thyroid nodules with a small training data set, and provides a comprehensive reference for clinical diagnosis and treatment.
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http://dx.doi.org/10.1016/j.cmpb.2020.105906DOI Listing
February 2021

The relationship between body-mass index and overall survival in non-small cell lung cancer by sex, smoking status, and race: A pooled analysis of 20,937 International lung Cancer consortium (ILCCO) patients.

Lung Cancer 2021 02 4;152:58-65. Epub 2020 Dec 4.

Cancer Prevention Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Introduction: The relationship between Body-Mass-Index (BMI) and lung cancer prognosis is heterogeneous. We evaluated the impact of sex, smoking and race on the relationship between BMI and overall survival (OS) in non-small-cell-lung-cancer (NSCLC).

Methods: Data from 16 individual ILCCO studies were pooled to assess interactions between BMI and the following factors on OS: self-reported race, smoking status and sex, using Cox models (adjusted hazard ratios; aHR) with interaction terms and adjusted penalized smoothing spline plots in stratified analyses.

Results: Among 20,937 NSCLC patients with BMI values, females = 47 %; never-smokers = 14 %; White-patients = 76 %. BMI showed differential survival according to race whereby compared to normal-BMI patients, being underweight was associated with poor survival among white patients (OS, aHR = 1.66) but not among black patients (aHR = 1.06; p = 0.02). Comparing overweight/obese to normal weight patients, Black NSCLC patients who were overweight/obese also had relatively better OS (p = 0.06) when compared to White-patients. BMI was least associated with survival in Asian-patients and never-smokers. The outcomes of female ever-smokers at the extremes of BMI were associated with worse outcomes in both the underweight (p<0.001) and obese categories (p = 0.004) relative to the normal-BMI category, when compared to male ever-smokers.

Conclusion: Underweight and obese female ever-smokers were associated with worse outcomes in White-patients. These BMI associations were not observed in Asian-patients and never-smokers. Black-patients had more favorable outcomes in the extremes of BMI when compared to White-patients. Body composition in Black-patients, and NSCLC subtypes more commonly seen in Asian-patients and never-smokers, may account for differences in these BMI-OS relationships.
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http://dx.doi.org/10.1016/j.lungcan.2020.11.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042597PMC
February 2021

Associations of long-term exposure to traffic-related air pollution with risk of valvular heart disease based on a cross-sectional study.

Ecotoxicol Environ Saf 2021 Feb 18;209:111753. Epub 2020 Dec 18.

Deportment occupational Health and Environmental Health, Hebei Medical University, Shijiazhuang 050017, People's Republic of China; Hebei Province Key Laboratory of Environment and Human Health, Shijiazhuang 050017, People's Republic of China.

Emerging evidence demonstrated that traffic-related air pollution induced adverse effects on cardiovascular system. We designed a population-based cross-sectional study to explore the association between residential proximity to major roadways, traffic density and the prevalence of valvular heart disease (VHD). A total of 34040 subjects from a Rural Health Project between 2013 and 2018 were collected. According to the inclusion and exclusion criteria, 4158 participants were enrolled in the final analysis. And we calculated the subjects' proximity to major roadways and collected the traffic density on the major roadways. Transthoracic echocardiography (TTE) was performed to diagnose the VHD, according to the current AHA/ACC (the American Heart Association and the American College of Cardiology) guidelines. Differences between groups were examined by the one-way ANOVAs for continuous variables and the chi-square tests for categorical variables. A logistic regression models were used to assess the associations. The stratified analysis by age and sex were conducted to further analyze the association. The restricted cubic spline analysis was performed to further evaluate the association between road way distance and VHD. Bonferroni test was used to adjust the significance level. The subjects closer to the major roads had the higher risk of tricuspid regurgitation (TR) (odds risk, OR = 1.519, 95% confidence intervals, 95%CI: 1.058-2.181), especially in female. The risk of VHD was positive (high traffic density VS low traffic density, OR = 1.799, 95%CI: 1.221-2.651), especially in female. In addition, the high traffic density was associated with the risk of mitral regurgitation (MR) (OR = 1.758, 95%CI: 1.085-2.848). The restricted cubic spline analysis found a threshold distance of about 300 m, where had the lowest risk of VHD, aortic regurgitation (AR), MR, TR. Our results found a positive association between traffic-related air pollution and VHD especially in female.
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http://dx.doi.org/10.1016/j.ecoenv.2020.111753DOI Listing
February 2021

Prediction for Intravenous Immunoglobulin Resistance Combining Genetic Risk Loci Identified From Next Generation Sequencing and Laboratory Data in Kawasaki Disease.

Front Pediatr 2020 4;8:462367. Epub 2020 Dec 4.

Department of Cardiology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China.

Kawasaki disease (KD) is the most common cause of acquired heart disease. A proportion of patients were resistant to intravenous immunoglobulin (IVIG), the primary treatment of KD, and the mechanism of IVIG resistance remains unclear. The accuracy of current models predictive of IVIG resistance is insufficient and doesn't meet the clinical expectations. To develop a scoring model predicting IVIG resistance of patients with KD. We recruited 330 KD patients (50 IVIG non-responders, 280 IVIG responders) and 105 healthy children to explore the susceptibility loci of IVIG resistance in Kawasaki disease. A next generation sequencing technology that focused on 4 immune-related pathways and 472 single nucleotide polymorphisms (SNPs) was performed. An R package SNPassoc was used to identify the risk loci, and student's -test was used to identify risk factors associated with IVIG resistance. A random forest-based scoring model of IVIG resistance was built based on the identified specific SNP loci with the laboratory data. A total of 544 significant risk loci were found associated with IVIG resistance, including 27 previous published SNPs. Laboratory test variables, including erythrocyte sedimentation rate (ESR), platelet (PLT), and C reactive protein, were found significantly different between IVIG responders and non-responders. A scoring model was built using the top 9 SNPs and clinical features achieving an area under the ROC curve of 0.974. It is the first study that focused on immune system in KD using high-throughput sequencing technology. Our findings provided a prediction of the IVIG resistance by integrating the genotype and clinical variables. It also suggested a new perspective on the pathogenesis of IVIG resistance.
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http://dx.doi.org/10.3389/fped.2020.462367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746618PMC
December 2020

The gut microbial metabolite phenylacetylglycine protects against cardiac injury caused by ischemia/reperfusion through activating β2AR.

Arch Biochem Biophys 2021 01 8;697:108720. Epub 2020 Dec 8.

Department of Cardiology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China. Electronic address:

Background: Myocardial ischemia/reperfusion (I/R) injury is closely related to cardiomyocyte apoptosis. Stimulating β2 adrenergic receptor (β2AR) can effectively combat cardiomyocyte apoptosis. Previous studies demonstrate that the gut microbial metabolite phenylacetylglycine (PAGly) can stimulate β2AR. However, the effect of PAGly on myocardial I/R injury remains unknown.

Methods: The hypoxia/reoxygenation (H/R) model was established using the neonatal mouse cardiomyocytes (NMCMs). Different doses of PAGly were used to treat NMCMs, and apoptosis was detected by terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) staining. Additionally, the level of cyclic adenosine monophosphate (cAMP) was examined by using a cAMP detection kit. Mouse model of myocardial I/R injury was established in C57BL/6 mice, and different doses of phenylacetic acid were administrated intraperitoneally. Apoptosis of myocardial cells was detected by TUNEL and α-actin staining. The area at risk and the infarct areas were identified by 2,3,5-triphenyltetrazolium chloride (TTC) and Evans blue staining. Western blotting was used to measure the protein expression levels of phosphorylated phosphatidylinositol 3-kinase (p-PI3K), total Akt (t-Akt), phosphorylated Akt (p-AKT), Bcl-2-associated X protein (Bax), B-cell lymphoma-2 (Bcl-2), cleaved caspase-3.

Results: PAGly significantly suppressed H/R injury-induced apoptosis in NMCMs and inhibited apoptosis in myocardial I/R injured mice in vivo. We verified that PAGly activated the anti-apoptotic Gαi/PI3K/AKT signaling cascade in NMCMs via stimulating β2AR signaling. Continuous administration of PAGly at an appropriate dose could inhibit apoptosis and reduce the infarct size resulting from I/R injury in mice. However, high-dose PAGly treatment was associated with a higher mortality rate. Moreover, we demonstrated that Aspirin reduced the infarct size and the high mortality caused by high doses of PAGly in I/R injured mice.

Conclusions: These findings suggest that treatment with the gut microbial metabolite PAGly could suppress cardiomyocyte apoptosis caused by myocardial I/R injury and reduce the infarct size, which provides a novel therapeutic strategy for patients with myocardial infarction.
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http://dx.doi.org/10.1016/j.abb.2020.108720DOI Listing
January 2021

The anaerobic survival mechanism of Schizophyllum commune 20R-7-F01, isolated from deep sediment 2 km below the seafloor.

Environ Microbiol 2021 02 28;23(2):1174-1185. Epub 2020 Nov 28.

State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.

Fungi dominated the eukaryotic group in the anaerobic sedimentary environment below the ocean floor where they play an essential ecological role. However, the adaptive mechanism of fungi to these anaerobic environments is still unclear. Here, we reported the anaerobic adaptive mechanism of Schizophyllum commune 20R-7-F01, isolated from deep coal-bearing sediment down to ~2 km below the seafloor, through biochemical, metabolomic and transcriptome analyses. The fungus grows well, but the morphology changes obviously and the fruit body develops incompletely under complete hypoxia. Compared with aerobic conditions, the fungus has enhanced branched-chain amino acid biosynthesis and ethanol fermentation under anaerobic conditions, and genes related to these metabolisms have been significantly up-regulated. Additionally, the fungus shows novel strategies for synthesizing ethanol by utilizing both glycolysis and ethanol fermentation pathways. These findings suggest that the subseafloor fungi may adopt multiple mechanisms to cope with lack of oxygen.
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http://dx.doi.org/10.1111/1462-2920.15332DOI Listing
February 2021

A Comprehensive Analysis of MicroRNAs in Human Osteoporosis.

Front Endocrinol (Lausanne) 2020 21;11:516213. Epub 2020 Oct 21.

Lab for Bone Metabolism, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China.

MicroRNAs (miRNAs) are single-stranded RNA molecules that control gene expression in various processes, such as cancers, Alzheimer's disease, and bone metabolic diseases. However, the regulatory roles of miRNAs in osteoporosis have not been systematically analyzed. Here, we performed a comprehensive analysis to identify the differentially expressed miRNAs involved in osteoporosis. MiRNAs associated with osteoporosis were collected through literature retrieval and further screened based on specific inclusion and exclusion criteria. The osteoporosis therapeutic targets of miRNAs were obtained by the integration of miRWalk 3.0 database and five human disease therapeutic target databases. Then, the network analysis and functional enrichment analysis of miRNAs and their targets were performed. As a result, 11 eligible miRNAs were identified highly associated with osteoporosis. MiRNA-mRNA network demonstrated there were the complex mutual interactions between miRNAs and their targets. Besides, ADRB2, AR, ESR1, FGFR1, TRAF6, etc., were identified as the top hub genes in protein-protein interaction (PPI) network. Functional enrichment analysis revealed that miRNAs and their targets were mainly mapped on processes associated with bone and immune system, such as bone remolding, bone mineralization, PI3K/AKt, TNF signaling pathways and Th17 cell differentiation. RT-PCR results showed that the expression of miR-335-3p was significantly down-regulated in hind limb unloading (HLU) mice tibia samples compared with controls, the remaining 10 miRNAs were significantly up-regulated after HLU ( < 0.01). In summary, we identified 11 differentially expressed miRNAs and their hub target genes in osteoporosis, which may be novel diagnostic biomarkers for osteoporosis.
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http://dx.doi.org/10.3389/fendo.2020.516213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609919PMC
May 2021

Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers.

Cancer Epidemiol Biomarkers Prev 2021 Jan 3;30(1):217-228. Epub 2020 Nov 3.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.

Background: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers.

Methods: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data.

Results: Genetic correlation analysis revealed significant genetic correlation between the two cancers ( = 0.43, = 2.66 × 10). We found seven loci associated with risk for both cancers ( < 2.4 × 10). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified ( < 5 × 10). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation.

Conclusions: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis.

Impact: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0739DOI Listing
January 2021

Pregnancy outcomes and risk of endometrial cancer: A pooled analysis of individual participant data in the Epidemiology of Endometrial Cancer Consortium.

Int J Cancer 2021 May 17;148(9):2068-2078. Epub 2020 Nov 17.

Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy.

A full-term pregnancy is associated with reduced endometrial cancer risk; however, whether the effect of additional pregnancies is independent of age at last pregnancy is unknown. The associations between other pregnancy-related factors and endometrial cancer risk are less clear. We pooled individual participant data from 11 cohort and 19 case-control studies participating in the Epidemiology of Endometrial Cancer Consortium (E2C2) including 16 986 women with endometrial cancer and 39 538 control women. We used one- and two-stage meta-analytic approaches to estimate pooled odds ratios (ORs) for the association between exposures and endometrial cancer risk. Ever having a full-term pregnancy was associated with a 41% reduction in risk of endometrial cancer compared to never having a full-term pregnancy (OR = 0.59, 95% confidence interval [CI] 0.56-0.63). The risk reduction appeared the greatest for the first full-term pregnancy (OR = 0.78, 95% CI 0.72-0.84), with a further ~15% reduction per pregnancy up to eight pregnancies (OR = 0.20, 95% CI 0.14-0.28) that was independent of age at last full-term pregnancy. Incomplete pregnancy was also associated with decreased endometrial cancer risk (7%-9% reduction per pregnancy). Twin births appeared to have the same effect as singleton pregnancies. Our pooled analysis shows that, while the magnitude of the risk reduction is greater for a full-term pregnancy than an incomplete pregnancy, each additional pregnancy is associated with further reduction in endometrial cancer risk, independent of age at last full-term pregnancy. These results suggest that the very high progesterone level in the last trimester of pregnancy is not the sole explanation for the protective effect of pregnancy.
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http://dx.doi.org/10.1002/ijc.33360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969437PMC
May 2021

Preschool environment and preschool teacher's physical activity and their association with children's activity levels at preschool.

PLoS One 2020 15;15(10):e0239838. Epub 2020 Oct 15.

Centre for Epidemiology and Community Medicine, Region Stockholm, Stockholm, Sweden.

Objective: The aim of this study was to investigate the association between preschool playground size, formalized physical activity (PA) policies, time spent outdoors and preschool teacher's levels of PA and children's objectively assessed levels of PA and sedentary time (ST) during preschool hours.

Methods: In total, 369 children and 84 preschool teachers from 27 preschools in Södermalm municipally, Stockholm Sweden wore an Actigraph GT3X+ accelerometer during 7 consecutive days. Preschool environmental and structural characteristics were measured via the Environment and Policy Evaluation Self-Report (EPAO-SR) instrument and time in- and outdoors was recorded by preschool teachers during the PA measurements. Weight and height of children were measured via validated scales and parents filled out a questionnaire on demographical and descriptive variables. Linear mixed models, nested on preschool level, were used to assess the association between predictors and outcomes.

Results: The mean child age was 4.7 years (SD 0.8) and 45% were girls. We found that children were more active in preschools with a formalized PA policy, compared to preschools without such a policy, but not less sedentary. The association between policy and activity seemed to be more pronounced when accounting for other environmental factors. Similar associations were found in children spent most time outdoors (uppermost quartile) compared with children spent least time outdoors (Lowermost quartile). Preschool teachers' light PA (LPA) (ß = 0.25, P = 0.004) and steps (ß = 0.52, P<0.001) were associated with children's LPA and steps while the preschool playground size showed no association with PA in children, when accounting for other environmental factors.

Conclusion: The current study showed that preschool structural characteristics such as formalized PA policies and more time spent outdoors were positively associated with children's PA. These findings suggest that formalized PA policies and time outdoors may be of importance for promoting children's PA during preschool hours.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239838PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561096PMC
November 2020

Alteration of Gut Microbiota in Patients With Epilepsy and the Potential Index as a Biomarker.

Front Microbiol 2020 18;11:517797. Epub 2020 Sep 18.

Department of Neurology, West China Hospital, Sichuan University, Chengdu, China.

Objective: To explore the structure and composition of the fecal microbiota of patients with epilepsy.

Methods: Variations in the fecal microbiota between patients with epilepsy and healthy controls (HCs) from the same household were investigated and validated by utilizing 16S ribosomal RNA sequencing in two independent cohorts [exploration cohort ( = 55 patients and = 46 HCs) and validation cohort ( = 13 patients and = 10 HCs)].

Results: The alpha diversity indexes of the specimens from patients with epilepsy were much lower than those from the HCs ( < 0.05). The structure and composition of the fecal microbiota differed between patients with different clinical prognoses and between patients and HCs (Adonis: < 0.05). Microbiome alterations in patients with epilepsy included increases in and and decreases in at the phylum level and increases in , , , and others at the genus level [linear discriminant analysis (LDA): 3.5] Patients with drug-resistant epilepsy showed enrichment of bacterial taxa in , , and and the genera , , , , and (Kruskal-Wallis test: < 0.05). Analysis of gut microbiome indicated predictive ability for disease diagnosis, with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.97 (95% CI, 0.84-0.98). Applying the model to our validation cohort resulted in an AUC of 0.96 (95% CI, 0.75-0.97). Notably, the model could distinguish drug-resistant from drug-sensitive epilepsy (AUC = 0.85, 95% CI: 0.69-0.94).

Conclusion: Patients with epilepsy exhibit substantial alterations of fecal microbiota composition, and specific gut commensal strains are altered depending on different clinical phenotypes and thus could serve as potential biomarkers for disease diagnosis.
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http://dx.doi.org/10.3389/fmicb.2020.517797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530173PMC
September 2020