Publications by authors named "Heng He"

39 Publications

Colorectal cancer risk variant rs7017386 modulates two oncogenic lncRNAs expression via ATF1-mediated long-range chromatin loop.

Cancer Lett 2021 Jul 15;518:140-151. Epub 2021 Jul 15.

Department of Epidemiology and Biostatistics, And the Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address:

The activating transcription factor 1 (ATF1) has been identified as a vital pathogenic factor in the progression of colorectal cancer (CRC), whiles, the precise regulatory mechanisms remain elusive. Here, we comprehensively characterized the ATF1 cistrome by RNA-seq and ChIP-seq assays in CRC cell lines. As the results, we identified 358 genes differentially regulated and 15,029 ATF1 binding sites and demonstrated that ATF1 was widely involved in major signaling pathways in CRC, such as Wnt, TNF, Jak-STAT. Subsequently, by the expression quantitative trait loci (eQTL) analyses, we found that rs7017386 was associated with the expression of CCAT1 and PVT1 in the Wnt pathway. By a two-stage population study with 6,131 CRC cases and 10,022 healthy controls, we identified the variant was associated with CRC risk. Mechanistically, we found rs7017386 allele-specifically enhanced the binding affinity of ATF1 and promoted the expressions of PVT1 and CCAT1, via forming a long-range chromatin loop. Moreover, those two lncRNAs could synergistically facilitate c-Myc expression to activate the Wnt pathway in CRC progression. Our findings not only demonstrated the transcriptomic profiling of ATF1 in CRC, but also provided important clues for the etiology of CRC.
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http://dx.doi.org/10.1016/j.canlet.2021.07.021DOI Listing
July 2021

Bisphenol A exposure, interaction with genetic variants and colorectal cancer via mediating oxidative stress biomarkers.

Environ Pollut 2021 Jun 23;287:117630. Epub 2021 Jun 23.

Department of Epidemiology and Biostatistics and Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Bisphenol A (BPA) may induce oxidative stress as well as the toxicity of colon cancer cells. We hypothesized that BPA exposure and interactions with genetic variants might be associated with colorectal cancer (CRC) risk, and the association might be partly mediated by oxidative stress. We measured urinary BPA and three oxidative stress markers [8-iso-prostaglandinF (8-isoPGF), 8-hydroxydeoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA)] in 275 new CRC cases and 538 healthy controls. A set of 25 genetic variations in 12 candidate DNA repair genes and 5 metabolic enzyme genes were genotyped by Sequenom MassARRAY approach. In multivariable logistic regression, significant positive associations of CRC risk with BPA, 8-OHdG and HNE-MA were observed. Additionally, 8-OHdG, HNE-MA and 8-isoPGF were significantly positively associated with BPA (P < 0.05). The mediation analysis showed BPA-associated HNE-MA significantly mediated 11.81% of the effect of BPA on CRC risk. Moreover, BPA was found to interact with ERCC5 rs17655 and rs2296147 (both P < 0.05) to increase CRC risk. In brief, our results suggested BPA was associated with CRC risk and the positive association of BPA with CRC risk might be partly mediated by the oxidative stress HNE-MA. BPA might interact with ERCC5 rs17655 and rs2296147 to increase CRC risk.
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http://dx.doi.org/10.1016/j.envpol.2021.117630DOI Listing
June 2021

Serum concentrations of organochlorine pesticides, biomarkers of oxidative stress, and risk of breast cancer.

Environ Pollut 2021 May 25;286:117386. Epub 2021 May 25.

Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China. Electronic address:

Studies have documented that exposure to organochlorine pesticides (OCPs) is linked with breast cancer, but the underlying biological mechanisms are still unknown. This study included 313 women diagnosed with breast cancer and 313 controls in Wuhan, China, and measured 18 OCPs in serum and 3 oxidative stress biomarkers in urine. Multivariable adjusted regression models were used to evaluate the associations among OCPs, oxidative stress biomarkers, and breast cancer. The mediating effect of oxidative stress was assessed by mediation analysis. We observed that most OCPs were positively associated with risk of breast cancer (all FDR-P values < 0.05 or 0.10). Moreover, we found that p,p'-DDT, p,p'-DDD, dieldrin, heptachlor, and heptachlor epoxide were positively associated with 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA) and 8-iso-prostaglandin F (8-isoPGF), which in turn were positively associated with risk of breast cancer. Mediation analysis indicated that HNE-MA and 8-isoPGF mediated the positive associations between these OCPs and risk of breast cancer, with mediating proportion ranging from 6.23% to 19.9%. Our results suggest that lipid peroxidation may mediate the positive associations between OCP exposures and risk of breast cancer.
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http://dx.doi.org/10.1016/j.envpol.2021.117386DOI Listing
May 2021

Acrylamide exposure and pulmonary function reduction in general population: The mediating effect of systemic inflammation.

Sci Total Environ 2021 Jul 9;778:146304. Epub 2021 Mar 9.

Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. Electronic address:

Acrylamide exposure along with resultant potential adverse health effects have attracted global concern, and the World Health Organization calls for more and urgent studies on the health risks from acrylamide. However, the association and mechanism between acrylamide exposure and pulmonary dysfunction remain unclear. Our goals were to investigate the relationship of internal acrylamide exposure with lung function reduction, and the potential mediating role of systematic inflammation in that relationship. Our study was conducted within the Wuhan-Zhuhai cohort. Urinary biomarkers of acrylamide exposure (N-acetyl-S-(2-carbamoylethyl)-l-cysteine, AAMA; N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-l-cysteine, GAMA) and lung function were determined among 3271 general adults, of whom 2595 had test results of systemic inflammatory marker plasma C-reactive protein (CRP). We employed linear mixed models to assess the relations among urinary acrylamide metabolites, pulmonary function and plasma CRP, and PRODCLIN program to evaluate the mediating role of CRP. We observed that urinary acrylamide metabolites were inversely and dose-dependently related to lung function (P trend<0.05). Each 1-unit increment in log-transformed level of AAMA, GAMA, or AAMA+GAMA (ΣUAAM) was significantly (P < 0.05) related to a 59.9-, 64.2-, or 64.3-mL reduction in FVC, and a 53.9-, 59.7-, or 58.5-mL reduction in FEV, respectively. Such relationships were independent of smoking, and were significant in physically inactive rather than physically active participants. AAMA (β = 0.10), GAMA (β = 0.16) and ΣUAAM (β = 0.12) were significantly (P < 0.05) related to increased CRP, which was significantly (P < 0.05) related to reduced FVC (β = -55.3) and FEV (β = -40.6). We further found that increased CRP significantly (P < 0.05) mediated 6.34-11.1% of the urinary acrylamide metabolites-associated lung function reductions. For the first time, our findings suggested that exposure to acrylamide in daily life was related to reduced lung function and increased systemic inflammation in general population, and systemic inflammation further mediated acrylamide-associated lung function reduction, indicating a potential mechanistic role of systemic inflammation underlying pulmonary dysfunction from acrylamide exposure.
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http://dx.doi.org/10.1016/j.scitotenv.2021.146304DOI Listing
July 2021

Effect of public health interventions on COVID-19 cases: an observational study.

Thorax 2021 Feb 16. Epub 2021 Feb 16.

Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

Background: As the epidemic of COVID-19 is gradually controlled in China, a summary of epidemiological characteristics and interventions may help control its global spread.

Methods: Data for COVID-19 cases in Hubei Province (capital, Wuhan) was extracted until 7 March 2020. The spatiotemporal distribution of the epidemic in four periods (before 10 January, 10-22 January, 23 January-6 February and 7 February-7 March) was evaluated, and the impacts of interventions were observed.

Results: Among 67 706 COVID-19 cases, 52 111 (76.97%) were aged 30-69 years old, and 34 680 (51.22%) were women. The average daily attack rates (95% CI) were 0.5 (0.3 to 0.7), 14.2 (13.2 to 15.1), 45.7 (44.0 to 47.5) and 8.6 (7.8 to 9.3) cases per 10 people in four periods, and the harmonic means (95% CI) of doubling times were 4.28 (4.01 to 4.55), 3.87 (3.78 to 3.98), 5.40 (4.83 to 6.05) and 45.56 (39.70 to 52.80) days. Compared with the first period, daily attack rates rose rapidly in the second period. In the third period, 14 days after 23 January, the daily average attack rate in and outside Wuhan declined by 33.8% and 48.0%; the doubling times increased by 95.0% and 133.2%. In the four periods, 14 days after 7 February, the daily average attack rate in and outside Wuhan decreased by 79.1% and 95.2%; the doubling times increased by 79.2% and 152.0%.

Conclusions: The public health interventions were associated with a reduction in COVID-19 cases in Hubei Province, especially in districts outside of Wuhan.
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http://dx.doi.org/10.1136/thoraxjnl-2020-215086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887867PMC
February 2021

Identification of genetic variants in mA modification genes associated with pancreatic cancer risk in the Chinese population.

Arch Toxicol 2021 03 21;95(3):1117-1128. Epub 2021 Jan 21.

Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.

N6-Methyladenosine (mA) is the most prevalent modification of RNA in eukaryotes, and is associated with many cellular processes and even the development of cancers. We hypothesized that single-nucleotide polymorphisms (SNPs) in mA modification genes, including its "writers", "erasers" and "readers", might affect the mA functions and associate with the susceptibility to pancreatic ductal adenocarcinoma (PDAC). We first conducted a two-stage case-control study in Chinese population to interrogate all SNPs in 22 mA modification genes. In the discovery stage, a total of 2735 SNPs were genotyped in 980 patients and 1991 controls. Then, the promising SNP was replicated in another independent population consisting of 858 cases and 2084 controls. As a result, we found the rs7495 in 3'UTR of hnRNPC was significantly associated with increased risk of PDAC in both stages (combined odds ratio = 1.22, 95% confidence interval = 1.12-1.32, P = 2.39 × 10). To further reveal the biological function of rs7495 and hnRNPC, we performed a series of biochemical experiments. Luciferase reporter assays indicated that rs7495G allele promoted hnRNPC expression through disrupting a putative binding site for has-miR-183-3p. Cell viability assay demonstrated that knockdown of hnRNPC suppressed the proliferation of PDAC cells. RNA-seq analysis suggested that as an mA "reader", hnRNPC played an important role in RNA biological processes. In conclusion, our findings elucidated that rs7495G could confer higher risk of PDAC via promoting the expression of hnRNPC through a miRNA-mediated manner. These results provided a novel insight into the critical role of mA modification in tumorigenesis.
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http://dx.doi.org/10.1007/s00204-021-02978-5DOI Listing
March 2021

Surgical site infection after gastrointestinal surgery in children: an international, multicentre, prospective cohort study.

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BMJ Glob Health 2020 12;5(12)

Introduction: Surgical site infection (SSI) is one of the most common healthcare-associated infections (HAIs). However, there is a lack of data available about SSI in children worldwide, especially from low-income and middle-income countries. This study aimed to estimate the incidence of SSI in children and associations between SSI and morbidity across human development settings.

Methods: A multicentre, international, prospective, validated cohort study of children aged under 16 years undergoing clean-contaminated, contaminated or dirty gastrointestinal surgery. Any hospital in the world providing paediatric surgery was eligible to contribute data between January and July 2016. The primary outcome was the incidence of SSI by 30 days. Relationships between explanatory variables and SSI were examined using multilevel logistic regression. Countries were stratified into high development, middle development and low development groups using the United Nations Human Development Index (HDI).

Results: Of 1159 children across 181 hospitals in 51 countries, 523 (45·1%) children were from high HDI, 397 (34·2%) from middle HDI and 239 (20·6%) from low HDI countries. The 30-day SSI rate was 6.3% (33/523) in high HDI, 12·8% (51/397) in middle HDI and 24·7% (59/239) in low HDI countries. SSI was associated with higher incidence of 30-day mortality, intervention, organ-space infection and other HAIs, with the highest rates seen in low HDI countries. Median length of stay in patients who had an SSI was longer (7.0 days), compared with 3.0 days in patients who did not have an SSI. Use of laparoscopy was associated with significantly lower SSI rates, even after accounting for HDI.

Conclusion: The odds of SSI in children is nearly four times greater in low HDI compared with high HDI countries. Policies to reduce SSI should be prioritised as part of the wider global agenda.
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http://dx.doi.org/10.1136/bmjgh-2020-003429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716674PMC
December 2020

Blockade of CXCR2 suppresses proinflammatory activities of neutrophils in ulcerative colitis.

Am J Transl Res 2020 15;12(9):5237-5251. Epub 2020 Sep 15.

Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University Jining 272000, Shandong, P. R. China.

Ulcerative colitis (UC) is one chronically remittent and progressive inflammatory disorder. Chemokine receptor CXCR2 is reported to be involved in the pathogenesis of several inflammatory diseases. However, how CXCR2 modulate mucosal inflammation in UC is still obscure. In this study, CXCR2 expression was determined in inflamed mucosa and peripheral blood cells from patients with UC by qRT-PCR. Neutrophils isolated from peripheral blood were pretreated with CXCR2 inhibitor (SB225002), and proinflammatory mediators were examined by qRT-PCR, ELISA and IF. The migratory capacity of neutrophils after SB225002 treatment was examined by using Transwell plate. Furthermore, SB225002 was administrated daily in DSS-induced colitis mice. We found that CXCR2 expression was significantly increased in colonic mucosal tissues and peripheral blood cells from patients with active UC. Besides, CXCR2 was highly expressed in neutrophils, and was positively correlated with disease activity. Inhibition of CXCR2 in neutrophils decreased the production of proinflammatory mediators, such as reactive oxygen species (ROS), MPO, S100a8, S100a9, TNF-α, IL-1β, IL-8 and IL-6, and the migratory capacity of neutrophils was markedly impaired after SB225002 treatment. Moreover, blockade of CXCR2 with SB225002 could markedly ameliorate DSS-induced colitis in mice. In summary, CXCR2 plays a critical role in the pathogenesis of UC through modulating immune responses of neutrophils. Blockade of CXCR2 may serve as a new therapeutic approach for treatment of UC.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540107PMC
September 2020

IRF5 Acts as a Potential Therapeutic Marker in Inflammatory Bowel Diseases.

Inflamm Bowel Dis 2021 Feb;27(3):407-417

Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, P.R. China.

Background: Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn's disease (CD), are chronic inflammatory disorders. As is well known, interferon regulatory factor (IRF) 5 is closely associated with the pathogenesis of various inflammatory diseases. But the exact role of IRF5 in IBD remains unclear.

Methods: In this study, we detected IRF5 expression in peripheral blood mononuclear cells (PBMCs) and inflamed mucosa from IBD patients by immunohistochemistry, western blot, and quantitative real-time polymerase chain reaction. Peripheral blood CD4+ T cells were stimulated with inflammatory cytokines and transfected by lentivirus.

Results: In active IBD patients, the expression of IRF5 in PBMCs and inflamed colonic tissues was obviously increased and significantly associated with disease activity. Ectopic overexpression of IRF5 could promote the differentiation of IBD CD4+ T cells into Th1 and Th17 cells by regulating T-bet and RAR related orphan receptor C, whereas knockdown of IRF5 had the opposite effects. Tumor necrosis factor (TNF)-α upregulated expression of IRF5 in CD4+ T cells, but anti-TNF treatment with infliximab could markedly reduce IRF5 expression in CD4+ T cells and intestinal mucosa of CD patients.

Conclusion: Our study reveals a novel mechanism that IRF5 levels are correlated with disease activity in IBD and might function as a possible marker for the management of IBD via regulating Th1 and Th17 immune responses and cytokine production.
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http://dx.doi.org/10.1093/ibd/izaa200DOI Listing
February 2021

Exposure to acrylamide and reduced heart rate variability: The mediating role of transforming growth factor-β.

J Hazard Mater 2020 08 15;395:122677. Epub 2020 Apr 15.

Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China. Electronic address:

The potential adverse health effects of acrylamide have drawn worldwide attention and the World Health Organization has urged further urgent studies on its health threat. Herein we explored the exposure-response relationship and underlying mechanism between internal acrylamide exposure and heart rate variability (HRV) alteration, a marker of cardiac autonomic dysfunction. We measured six HRV indices and two urinary acrylamide metabolites (N-Acetyl-S-(2-carbamoylethyl)-l-cysteine, AAMA; N-Acetyl-S-(2-carbamoyl-2-hydroxyethyl)-l-cysteine, GAMA) for 2997 general Chinese adults from the Wuhan-Zhuhai cohort, of whom 2414 had data on plasma transforming growth factor-β1 (TGF-β1). The associations among urinary acrylamide metabolites, HRV and TGF-β1 were evaluated by linear mixed models and restricted cubic spline models. The mediating role of TGF-β1 was investigated by conducting mediation analysis. We found significantly negative dose-response relationships of all urinary acrylamide metabolites and TGF-β1 with all six HRV indices after adjusting for potential confounders (all P < 0.05). Urinary GAMA (β=0.074, P < 0.05) rather than AAMA (β=0.024, P > 0.05) was positively and dose-dependently associated with TGF-β1, which in turn significantly mediated 5.71-7.41 % of the GAMA-associated HRV reduction. Our findings suggest for the first time that daily exposure of general population to acrylamide is associated with cardiac autonomic dysfunction, where a mechanism involving TGF-β pathway may be involved.
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http://dx.doi.org/10.1016/j.jhazmat.2020.122677DOI Listing
August 2020

LRCH1 suppresses migration of CD4 T cells and refers to disease activity in ulcerative colitis.

Int J Med Sci 2020 17;17(5):599-608. Epub 2020 Feb 17.

Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, P.R. China.

Ulcerative colitis (UC) is a chronically remittent and progressive inflammatory disorder. LRCH1 is reported to be involved in the immune-regulation of several diseases. However, the exact roles of LRCH1 in UC are still obscure. LRCH1 expression was analyzed in the inflamed mucosa and peripheral blood mononuclear cells (PBMCs) from patients with UC by quantitative RT-PCR and immunohistochemistry. Peripheral blood CD4 T cells were transfected with lentivirus-expressing LRCH1 (LV-LRCH1) or LV-sh-LRCH1, and cytokine expression was determined by using flow cytometry, quantitative RT-PCR and ELISA. Transfected CD4 T cells were harvested to examine the capacity of chemotaxis using Transwell plate. LRCH1 expression was highly decreased in colonic mucosa and PBMCs from patients with A-UC, and negatively correlated with disease activity. Up or down regulation of LRCH1 did not affect the differentiation of CD4 T cells, and the related cytokines expression. Moreover, LRCH1 inhibited migratory capacity of CD4 T cells toward CXCL12 by PKCα. LRCH1 plays an important role in the pathogenesis of UC, possibly through modulating the migration of CD4 T cells. Therefore, targeting LRCH1 might serve as a novel therapeutic approach in the management of UC.
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http://dx.doi.org/10.7150/ijms.39106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085219PMC
December 2020

Reply.

Occup Med (Lond) 2019 12;69(8-9):637-638

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http://dx.doi.org/10.1093/occmed/kqz138DOI Listing
December 2019

Systemic Inflammation Mediates the Associations Between Abdominal Obesity Indices and Lung Function Decline in a Chinese General Population.

Diabetes Metab Syndr Obes 2020 20;13:141-150. Epub 2020 Jan 20.

Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of China.

Background: Previous studies reported that obesity indices were inversely associated with lung function. However, the underlying mechanisms remain unclear. We aimed to assess the potential mediating effect of systemic inflammation in the associations between obesity indices and lung function decline among a general population.

Methods: We conducted a cross-sectional study among 3442 participants from the Wuhan-Zhuhai cohort. Plasma C-reactive protein (CRP) was assayed as a marker of systemic inflammation. The relationships among several obesity indices (body mass index, BMI; waist circumference, WC; waist-to-hip ratio, WHR; waist-to-height ratio, WHtR), plasma CRP and lung function were assessed by generalized linear models. The role of CRP in the associations between obesity indices and lung function was analyzed using mediation analysis.

Results: We observed inverse associations between abdominal obesity indices (WC, WHR and WHtR) and lung function parameters, including forced expiratory volume in 1 s (FEV) and forced vital capacity (FVC) (all <0.05). Each 1-unit increase in WC was associated with a 3.39 mL decrease in FEV and a 3.96 mL decrease in FVC (all <0.05). Each 1% increase in WHR and WHtR was associated with a 5.42 mL and a 14.23 mL decrease in FEV, and a 5.70 mL and a 16.92 mL decrease in FVC (all <0.05). Mediation analysis indicated that plasma CRP partly mediated the associations between abdominal obesity and lung function. The mediated proportions of CRP in associations of WC, WHR and WHtR with FEV were 7.96%, 9.59% and 5.76%, respectively. The mediated proportions of CRP in associations of WC and WHR with FVC were 8.33% and 11.40%, respectively.

Conclusion: Abdominal obesity indices were negatively associated with lung function, and the associations may be partly mediated by systemic inflammation.
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http://dx.doi.org/10.2147/DMSO.S229749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980850PMC
January 2020

Global variation in anastomosis and end colostomy formation following left-sided colorectal resection.

Authors:

BJS Open 2019 Jun 28;3(3):403-414. Epub 2019 Feb 28.

Background: End colostomy rates following colorectal resection vary across institutions in high-income settings, being influenced by patient, disease, surgeon and system factors. This study aimed to assess global variation in end colostomy rates after left-sided colorectal resection.

Methods: This study comprised an analysis of GlobalSurg-1 and -2 international, prospective, observational cohort studies (2014, 2016), including consecutive adult patients undergoing elective or emergency left-sided colorectal resection within discrete 2-week windows. Countries were grouped into high-, middle- and low-income tertiles according to the United Nations Human Development Index (HDI). Factors associated with colostomy formation primary anastomosis were explored using a multilevel, multivariable logistic regression model.

Results: In total, 1635 patients from 242 hospitals in 57 countries undergoing left-sided colorectal resection were included: 113 (6·9 per cent) from low-HDI, 254 (15·5 per cent) from middle-HDI and 1268 (77·6 per cent) from high-HDI countries. There was a higher proportion of patients with perforated disease (57·5, 40·9 and 35·4 per cent;  < 0·001) and subsequent use of end colostomy (52·2, 24·8 and 18·9 per cent;  < 0·001) in low- compared with middle- and high-HDI settings. The association with colostomy use in low-HDI settings persisted (odds ratio (OR) 3·20, 95 per cent c.i. 1·35 to 7·57;  = 0·008) after risk adjustment for malignant disease (OR 2·34, 1·65 to 3·32;  < 0·001), emergency surgery (OR 4·08, 2·73 to 6·10;  < 0·001), time to operation at least 48 h (OR 1·99, 1·28 to 3·09;  = 0·002) and disease perforation (OR 4·00, 2·81 to 5·69;  < 0·001).

Conclusion: Global differences existed in the proportion of patients receiving end stomas after left-sided colorectal resection based on income, which went beyond case mix alone.
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http://dx.doi.org/10.1002/bjs5.50138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921967PMC
June 2019

UHRF1 downmodulation enhances antitumor effects of histone deacetylase inhibitors in retinoblastoma by augmenting oxidative stress-mediated apoptosis.

Mol Oncol 2020 02 13;14(2):329-346. Epub 2019 Dec 13.

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.

Identification of new genetic pathways or molecular targets that sensitize cancer cells to chemotherapeutic drugs may improve the efficacy of current chemotherapy. Here, we report that downmodulation of UHRF1 (ubiquitin-like with PHD and RING finger domains 1) in retinoblastoma (RB) cells increases the sensitivity to histone deacetylase (HDAC) inhibitors, augmenting apoptotic cell death. We found that UHRF1 depletion downregulates two redox-responsive genes GSTA4 (glutathione S-transferase α4) and TXN2 (thioredoxin-2) in RB cells, and increases the basal level of intracellular oxidative stress. Antioxidant treatment significantly reduced both basal and HDAC inhibitor-induced DNA damage and apoptosis in UHRF1-depleted cells. Knockdown of GSTA4 or TXN2 sensitized RB cells to HDAC inhibitors, demonstrating that GSTA4 and TXN2 play key roles in redox homeostasis in RB cells and the susceptibility to HDAC inhibitor treatment upon UHRF1 depletion. In human primary RB, GSTA4 and TXN2 proteins were found to be mostly elevated along with high UHRF1 expression. In addition to augmentation of apoptosis in UHRF1-depleted RB cells, we also show that UHRF1 downmodulation derepresses the expression of photoreceptor-specific genes in RB cells in cooperation with a HDAC inhibitor MS-275 and promotes neuron-like differentiation. However, further investigation revealed that the enhanced growth-inhibitory effects of MS-275 in UHRF1-depleted cells were still mainly due to robust apoptosis induction rather than differentiation-mediated growth arrest. Consistent with our findings, UHRF1 depletion in RB cells increased the therapeutic efficacy of MS-275 in murine orthotopic xenografts. These results provide a novel basis for potential benefits of UHRF1 targeting for RB treatment.
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http://dx.doi.org/10.1002/1878-0261.12607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6998393PMC
February 2020

Effects of environmental and lifestyle exposures on urinary levels of polycyclic aromatic hydrocarbon metabolites: A cross-sectional study of urban adults in China.

Chemosphere 2020 Feb 17;240:124898. Epub 2019 Sep 17.

Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China. Electronic address:

Urinary polycyclic aromatic hydrocarbon (PAH) metabolites, biomarkers of internal PAH exposure, are commonly used to explore the effects of PAH on human health. However, the correlation between environmental PAH exposure and the species or levels of urinary PAH metabolites remains unclear. We collected detailed information on PAH exposure sources, including cigarette smoking, cooking, traffic and diet habits via structured questionnaires, and determined 12 urinary monohydroxylated PAH metabolites (OH-PAHs) among 4092 participants from the Wuhan-Zhuhai cohort. Linear mixed models and generalized linear models were conducted to explore the associations of urinary metabolite levels with single or multiple PAH exposure sources. We also calculated the standardized regression coefficients to further compare the contributions of different sources to urinary OH-PAH levels. Our results showed that increasing levels of urinary 1-, 2-hydroxynaphthalene (1-, 2- OHNa) and 2-hydroxyfluorene (2-OHFlu) were significantly correlated with tobacco smoking (all P < 0.01). The concentrations of 1-, 2- OHNa and 9-hydroxyfluorene (9-OHFlu) were positively correlated with dietary intake (all P < 0.05). Individuals who spent a long time in traffic showed elevated levels of 9-OHFlu and 1-hydroxyphenanthrene (1-OHPh) compared with individuals who spent a short time in traffic (all P < 0.05). Self-cooking was associated only with elevated 1-hydroxypyrene (1-OHP) levels. Moreover, good kitchen ventilation resulted in significantly decreased urinary low-molecular-weight OH-PAH levels. These findings suggested that cigarette smoking, self-cooking, high dietary PAH intake and a long time spent in traffic were associated with increased levels of specific urinary PAH metabolites, and good kitchen ventilation effectively reduced the exposure to low-molecular-weight PAHs in self-cooking participants.
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http://dx.doi.org/10.1016/j.chemosphere.2019.124898DOI Listing
February 2020

miR-342 suppresses the proliferation and invasion of acute myeloid leukemia by targeting Naa10p.

Artif Cells Nanomed Biotechnol 2019 Dec;47(1):3671-3676

Department of Hematology, Affiliated Hospital of Jining Medical University , Jining , Shandong , China.

Accumulating studies showed that microRNAs are maintaining a variety of important biological processes but the underlying mechanism in proliferation and tumourigenicity is unclear. In this study we show that miR-342 expression in bone marrow and patients' sera of childhood acute myeloid leukemia (AML) was both significantly higher than those in the corresponding normal controls. Functional assays demonstrated that forced expression of miR-342 significantly suppresses AML cell proliferation and G1/S transition of leukemia cells. Mechanistically, bioinformatics prediction and luciferase reporter assay identified N-a-acetyltransferase 10 protein (Naa10p) as a direct molecular target of miR-342, Naa10p siRNA significantly repressed cell proliferation and increased cell apoptosis. In conclusion, our study confirmed that miR-342/Naa10p plays key roles in AML progression, providing insights into underlying mechanisms of AML pathogenesis and also a potential therapeutic target for this malignancy.
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http://dx.doi.org/10.1080/21691401.2019.1596930DOI Listing
December 2019

Multilocus Mitochondrial Mutations Do Not Directly Affect the Efficacy of Gene Therapy for Leber Hereditary Optic Neuropathy.

J Neuroophthalmol 2020 03;40(1):22-29

Department of Ophthalmology (SY, J-JY, S-SW, XW, HH, S-QM, BL), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Eye Center (SY), Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; and Center of Genetic Diagnosis (CC), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Purpose: Clinical trials of gene therapy for Leber hereditary optic neuropathy (LHON) were conducted in 9 volunteers with the mitochondrial mutation, G11778A in ND4. The purpose of this study was to investigate whether multilocus mitochondrial mutations directly influence the efficacy of gene therapy for LHON.

Methods: Nine volunteers with LHON participated in a clinical trial with intravitreal injection of an adenoviral vector expressing wild-type ND4. Patients were subsequently divided into 2 groups: according to the differences in therapy efficacy and based on improvements in visual acuity. Full mitochondrial DNA sequences of the 2 groups of patients were generated and compared using PubMed, PolyPhen, and PROVEAN. Furthermore, the association between the detected mutations and clinical effects of gene therapy was analyzed.

Results: Best-corrected visual acuity (BCVA) significantly improved (≥0.3 log of minimum angle of resolution [logMAR]) in 7 patients 6 months after gene therapy, whereas there was no significant change in BCVA (<0.3 logMAR) of the remaining 2 patients. All 9 patients carried the G1178A mutation in addition to other nonsynonymous mutations. Among these mutations, some were predicted to be neutral and deleterious. Meanwhile, different mitochondrial mutations in the group in which treatment was ineffective, compared with those in responders, were at nucleotide positions 6569 (CO1; Patient 3), 9641 (CO3; Patient 3), and 4491 (ND2; Patient 5).

Conclusions: Detection of the 3 primary mitochondrial mutations causing LHON is sufficient for screening before gene therapy; sequencing of the entire mitochondrial genome is unnecessary before treatment. Patients with LHON can respond to targeted gene therapy irrespective of additional multilocus mitochondrial mutations.
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http://dx.doi.org/10.1097/WNO.0000000000000797DOI Listing
March 2020

Shift work and ischaemic heart disease: meta-analysis and dose-response relationship.

Occup Med (Lond) 2019 May;69(3):182-188

Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

Background: Shift work is common in many industries. The potential association between shift work and ischaemic heart disease (IHD) remains controversial.

Aims: To conduct a systematic review and meta-analysis of epidemiological evidence and summarize the potential relationship between shift work and IHD.

Methods: We searched all relevant case-control and cohort studies that were published from January 1970 to October 2017 on PubMed, Web of Science and Embase. The random-effects model and the generalized least-squares trend model were, respectively, used to evaluate the pooled relative risk and dose-response relationship between shift work and IHD. Two different authors extracted data and assessed the quality of each study independently.

Results: Twenty-one articles with 31 independent results of 19 782 IHD cases in 320 002 participants were included. The pooled relative risk for the association between shift work and risk of IHD was 1.13 (95% CI 1.08-1.20, I2 = 53%, P < 0.001). Further evaluation of dose-response relationship indicated that each 1-year increase in shift work was associated with 0.9% (RR = 1.009; 95% CI 1.006-1.012) increase of the risk of IHD.

Conclusions: This meta-analysis updated the evidence that shift work was associated with the risk of IHD and supported a positive dose-response relationship between the risk of IHD and increasing duration of shift work.
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http://dx.doi.org/10.1093/occmed/kqz020DOI Listing
May 2019

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy.

Authors:

Br J Surg 2019 Jan;106(2):e103-e112

Background: The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy.

Methods: In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation.

Results: Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89·6 per cent) compared with that in countries with a middle (753 of 1242, 60·6 per cent; odds ratio (OR) 0·17, 95 per cent c.i. 0·14 to 0·21, P < 0·001) or low (363 of 860, 42·2 per cent; OR 0·08, 0·07 to 0·10, P < 0·001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -9·4 (95 per cent c.i. -11·9 to -6·9) per cent; P < 0·001), but the relationship was reversed in low-HDI countries (+12·1 (+7·0 to +17·3) per cent; P < 0·001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0·60, 0·50 to 0·73; P < 0·001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries.

Conclusion: Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.
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http://dx.doi.org/10.1002/bjs.11051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492154PMC
January 2019

Novel adeno‑associated virus‑based genetic vaccines encoding hepatitis C virus E2 glycoprotein elicit humoral immune responses in mice.

Mol Med Rep 2019 Feb 11;19(2):1016-1023. Epub 2018 Dec 11.

Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, P.R. China.

Hepatitis C virus (HCV) infection remains a major public health issue despite the introduction of several direct‑acting antiviral agents (DAAs), with some 185 million individuals infected with HCV worldwide. There is an urgent need for an effective prophylactic HCV vaccine. In the present study, we constructed genetic vaccines based on novel recombinant adeno‑associated viral (rAAV) vectors (AAV2/8 or AAV2/rh32.33) that express the envelope glycoprotein E2 from the HCV genotype 1b. Expression of HCV E2 protein in 293 cells was confirmed by western blot analysis. rAAV2/8.HCV E2 vaccine or rAAV2/rh32.33.HCV E2 vaccine was intramuscularly injected into C57BL/6 mice. HCV E2‑specific antigen was produced, and long‑lasting specific antibody responses remained detectable XVI weeks following immunization. In addition, the rAAV2/rh32.33 vaccine induced higher antigen‑specific antibody levels than the rAAV2/8 vaccine or AAV plasmid. Moreover, both AAV vaccines induced neutralizing antibodies against HCV genotypes 1a and 1b. Finally, it is worth mentioning that neutralizing antibody levels directed against AAV2/rh32.33 were lower than those against AAV2/8 in both mouse and human serum. These results demonstrate that AAV vectors, especially the AAVrh32.33, have particularly favorable immunogenicity for development into an effective HCV vaccine.
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http://dx.doi.org/10.3892/mmr.2018.9739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323296PMC
February 2019

Management and Outcomes Following Surgery for Gastrointestinal Typhoid: An International, Prospective, Multicentre Cohort Study.

Authors:

World J Surg 2018 10;42(10):3179-3188

Background: Gastrointestinal perforation is the most serious complication of typhoid fever, with a high disease burden in low-income countries. Reliable, prospective, contemporary surgical outcome data are scarce in these settings. This study aimed to investigate surgical outcomes following surgery for intestinal typhoid.

Methods: Two multicentre, international prospective cohort studies of consecutive patients undergoing surgery for gastrointestinal typhoid perforation were conducted. Outcomes were measured at 30 days and included mortality, surgical site infection, organ space infection and reintervention rate. Multilevel logistic regression models were used to adjust for clinically plausible explanatory variables. Effect estimates are expressed as odds ratios (ORs) alongside their corresponding 95% confidence intervals.

Results: A total of 88 patients across the GlobalSurg 1 and GlobalSurg 2 studies were included, from 11 countries. Children comprised 38.6% (34/88) of included patients. Most patients (87/88) had intestinal perforation. The 30-day mortality rate was 9.1% (8/88), which was higher in children (14.7 vs. 5.6%). Surgical site infection was common, at 67.0% (59/88). Organ site infection was common, with 10.2% of patients affected. An ASA grade of III and above was a strong predictor of 30-day post-operative mortality, at the univariable level and following adjustment for explanatory variables (OR 15.82, 95% CI 1.53-163.57, p = 0.021).

Conclusions: With high mortality and complication rates, outcomes from surgery for intestinal typhoid remain poor. Future studies in this area should focus on sustainable interventions which can reduce perioperative morbidity. At a policy level, improving these outcomes will require both surgical and public health system advances.
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http://dx.doi.org/10.1007/s00268-018-4624-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132852PMC
October 2018

Proximal penetrating extremity injuries-An opportunity to decrease overtriage?

J Trauma Acute Care Surg 2018 07;85(1):122-127

From the Division of Trauma, Critical Care, and Acute Care Surgery (G.E.M., H.H., A.T.M., T.A.P., J.B.E., J.A.J., M.D.G.), Department of Surgery, College of Medicine, University of Cincinnati, Cincinnati, Ohio.

Background: Penetrating injuries to the extremity proximal to the elbow or knee are anatomic criteria for full trauma team activation (FFTA) by the American College of Surgeon's Committee on Trauma standards. This criterion lacks objective evidence-based support. Overtriage of trauma team activation may result in excessive costs and resource burden at trauma centers. We hypothesized that FFTA for penetrating injuries to the proximal extremities by anatomic criteria alone may lead to significant overtriage.

Methods: A 3-year retrospective review (2013-2015) was completed of all patients evaluated at an urban Level I trauma center with isolated penetrating extremity injuries. Data included the number of full and limited trauma team activations as well as criterion met, Injury Severity Score (ISS), injury, limb characteristics, and disposition. Overtriage was defined as FFTA for an ISS of 15 or less, with a goal rate less than 50%.

Results: We identified 6,335 total trauma team activations with 795 isolated penetrating extremity injuries. Of these injuries, 413 (51.9%) were injuries proximal to the joint. Within this subgroup, 71.2% of patients were discharged from the emergency department with a median ISS of 1 and no additional intervention. Only 5.3% of patients that did not meet additional FFTA criteria underwent immediate operative intervention. By comparison, 21% of FFTAs and 5.8% of limited trauma team activations underwent immediate operative intervention during the 3-year period. Of the 413 isolated penetrating proximal-extremity injuries, only one had an ISS of 15 or greater, resulting in a 99.7% overtriage rate.

Conclusion: Penetrating injuries to the extremities are common in urban trauma centers. Full trauma team activation based on anatomic, rather than physiologic, criteria may lead to a significant overtriage rate. Further distinction in the level of trauma team activation may be made based on hard signs of neurovascular injury.

Level Of Evidence: Epidemiological study, level III; Care Management, level IV.
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http://dx.doi.org/10.1097/TA.0000000000001898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024847PMC
July 2018

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study.

Authors:

Lancet Infect Dis 2018 05 13;18(5):516-525. Epub 2018 Feb 13.

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world.

Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231.

Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p<0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05-2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p<0·001).

Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication.

Funding: DFID-MRC-Wellcome Trust Joint Global Health Trial Development Grant, National Institute of Health Research Global Health Research Unit Grant.
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http://dx.doi.org/10.1016/S1473-3099(18)30101-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910057PMC
May 2018

UHRF1 depletion sensitizes retinoblastoma cells to chemotherapeutic drugs via downregulation of XRCC4.

Cell Death Dis 2018 02 7;9(2):164. Epub 2018 Feb 7.

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, China.

UHRF1 (ubiquitin-like with PHD and ring finger domains 1) is highly expressed in various human cancers including retinoblastoma, and associated with tumor-promoting effects such as inhibition of apoptosis and high proliferation. However, the molecular mechanisms underlying tumor-promoting functions of UHRF1 in retinoblastoma still remain elusive. Here, we show that stable knockdown of UHRF1 renders retinoblastoma cells sensitized to conventional chemotherapeutic drugs such as etoposide and camptothecin, resulting in enhanced DNA damage and apoptotic cell death. We found that UHRF1-depleted retinoblastoma cells can recognize DNA damages normally but have markedly low expression of XRCC4 (X-ray repair cross complementing 4) among the components of nonhomologous end-joining (NHEJ) repair complex. Conversely, overexpression of UHRF1 increased the XRCC4 expression and stable knockdown of XRCC4 sensitized retinoblastoma cells to etoposide treatment, suggesting that XRCC4 is a key mediator for the drug sensitivity upon UHRF1 depletion in retinoblastoma cells. Consistent with the findings, chromatin association of DNA ligase IV in response to acute DNA damage was found to be significantly reduced in UHRF1-depleted retinoblastoma cells and functional complementation for XRCC4 in UHRF1-depleted cells attenuated the drug sensitivity, demonstrating that XRCC4 downregulation in UHRF1-depleted cells impaired DNA repair and consequently induced robust apoptosis upon genotoxic drug treatment. In human primary retinoblastoma, high expression of UHRF1 and XRCC4 could be detected, and elevated XRCC4 expression correlated with reduced apoptosis markers, implying that UHRF1-mediated XRCC4 upregulation under pathophysiological conditions triggered by RB1 gene inactivation may confer protection against endogenous DNA damages that arise during retinoblastoma development. Taken together, these results present a new mechanistic insight into how UHRF1 mediates its tumor-promoting functions in retinoblastoma, and also provide a basis for UHRF1 targeting to improve the efficacy of current chemotherapy for retinoblastoma treatment.
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http://dx.doi.org/10.1038/s41419-017-0203-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833858PMC
February 2018

Functional dissection of the role of UHRF1 in the regulation of retinoblastoma methylome.

Oncotarget 2017 Jun;8(24):39497-39511

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, China.

UHRF1 (ubiquitin-like with PHD and RING finger domains 1) is a critical regulator for DNA methylation, and its frequent overexpression in human cancers has been associated with tumor-promoting effects. However, whether the overexpressed UHRF1 contributes to the establishment and maintenance of tumor methylomes and whether this process can affect the tumorigenesis remain unclear. In this study, we show that UHRF1 is highly expressed in retinoblastoma, and genomes of human primary retinoblastoma and cell lines have differential DNA methylation patterns compared with those of normal retina, characterized by lower global methylation and higher promoter methylation of tumor suppressors. However, our genome-wide DNA methylation study uncovers that UHRF1 down-modulation in retinoblastoma cells exerts minor effects on the existing methylation patterns at both bulk genome and individual gene loci, suggesting that retinoblastoma methylome is primarily maintained by other mechanisms. Furthermore, using two murine retinoblastoma models, we found that high UHRF1 expression does not alter global methylation levels in both premalignant neonatal retina and retinoblastoma tumors, implying that DNA hypomethylation may not be an early mechanism driving retinoblastoma tumorigenesis unlike what has been proposed for other types of cancer. These results suggest that tumor-promoting functions of UHRF1 in retinoblastoma are largely independent of its role in DNA methylation.
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http://dx.doi.org/10.18632/oncotarget.17078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503627PMC
June 2017

Ablation Is Associated With Increased Nitro-Oxidative Stress During Ischemia-Reperfusion Injury: Implications for Human Ischemic Cardiomyopathy.

Circ Heart Fail 2017 Feb;10(2)

From the Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute (B.Z., D.G.W., Z.X., R.H., H.H., S.V., J.L.Z.), Department of Physiology and Cell Biology (B.Z., J.L.Z., M.J.K., M.T.Z.), The Ohio State University, Columbus; Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, HuBei, China (B.Z.); Department of Biostatistics (Y.S., M.X., F.E.H.), Division of Clinical Pharmacology, Department of Medicine (D.M.R., C.M.S.), Division of Cardiac Surgery, Department of Surgery (T.A.), Division of Cardiovascular Medicine (T. N., E. C., Y.R.S., D.R., C.L.G., Q.S.W, R.J.G.), Department of Pharmacology and Department of Pathology, Immunology, and Microbiology (R.J.G.), Vanderbilt University Medical Center, Nashville, TN.

Background: Despite increased secondary cardiovascular events in patients with ischemic cardiomyopathy (ICM), the expression of innate cardiac protective molecules in the hearts of patients with ICM is incompletely characterized. Therefore, we used a nonbiased RNAseq approach to determine whether differences in cardiac protective molecules occur with ICM.

Methods And Results: RNAseq analysis of human control and ICM left ventricular samples demonstrated a significant decrease in expression with ICM. encodes the Kir6.2 subunit of the cardioprotective K channel. Using wild-type mice and -deficient (-null) mice, we examined the effect of expression on cardiac function during ischemia-reperfusion injury. Reactive oxygen species generation increased in -null hearts above that found in wild-type mice hearts after ischemia-reperfusion injury. Continuous left ventricular pressure measurement during ischemia and reperfusion demonstrated a more compromised diastolic function in -null compared with wild-type mice during reperfusion. Analysis of key calcium-regulating proteins revealed significant differences in -null mice. Despite impaired relaxation, -null hearts increased phospholamban Ser16 phosphorylation, a modification that results in the dissociation of phospholamban from sarcoendoplasmic reticulum Ca, thereby increasing sarcoendoplasmic reticulum Ca-mediated calcium reuptake. However, -null mice also had increased 3-nitrotyrosine modification of the sarcoendoplasmic reticulum Ca-ATPase, a modification that irreversibly impairs sarcoendoplasmic reticulum Ca function, thereby contributing to diastolic dysfunction.

Conclusions: expression is decreased in human ICM. Lack of expression increases peroxynitrite-mediated modification of the key calcium-handling protein sarcoendoplasmic reticulum Ca-ATPase after myocardial ischemia-reperfusion injury, contributing to impaired diastolic function. These data suggest a mechanism for ischemia-induced diastolic dysfunction in patients with ICM.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.116.003523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5319711PMC
February 2017

Evaluation of Leber's hereditary optic neuropathy patients prior to a gene therapy clinical trial.

Medicine (Baltimore) 2016 Oct;95(40):e5110

Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong, University of Science and Technology, Wuhan State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of medical Sciences, Qingdao Department of Oncology, Central Hospital, Ezhou, China.

Gene therapy may be a promising approach for the treatment of Leber hereditary optic neuropathy. The aim of this study was to evaluate patients with this condition who were recruited into an upcoming gene therapy clinical trial and to assess any changes in the detection parameters to provide support for the clinical trial. Sixteen patients with Leber hereditary optic neuropathy were evaluated using visual function tests 12 months before the initiation of gene therapy. Then, the results of visual acuity (VA), visual field (VF), RNFL (retinal nerve fiber layer) thickness, and Pattern-reversal Visual evoked potential (PR-VEP) were compared and analyzed. A total of 32 eyes of 16 patients were evaluated. Based on the best-corrected visual acuity (BCVA), 24 eyes were relatively stable compared with the baseline evaluation, and 8 eyes had significant changes, including 5 eyes that showed improvement and 3 eyes that showed impairment. In all eyes, the changes in the best-corrected visual acuity were significantly correlated with the changes in the visual field index (VFI), mean defect (MD), and P100 of the visual evoked potential. In the eyes with relatively stable BCVA and those with an obvious improvement in the BCVA, only the visual mean defect showed a significant change; the other indicators were not significantly different. Aside from the patients showing a tendency of spontaneous improvement, the others were in accordance with the requirement. The effects of Leber hereditary optical neuropathy (LHON) gene therapy should be evaluated primarily based on visual acuity. Additionally, visual field, neural fiber thickness, and electrophysiology should be considered in the evaluation.
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http://dx.doi.org/10.1097/MD.0000000000005110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5059096PMC
October 2016

[Sublethal effects of fenpropathrin and avermectin on Panonychus citri (Acari: Tereanychidae).]

Ying Yong Sheng Tai Xue Bao 2016 Aug;27(8):2629-2635

Chongqing Key Laboratory of Entomology and Pest Control Engineering, College of Plant Protection, Southwest University, Chongqing 400716, China.

A leaf disc bioassay was employed to examine the effects of fenpropathrin and avermectin with a sublethal concentration of LC on the development and reproduction of F, F and F generations by means of life tables. The results showed that after the treatment of fenpropathrin at the sublethal concentration, the number of eggs laid per female significantly increased in F generation, the pre-oviposition duration was significantly shortened and the female ratio of offspring significantly increased both in F and F generations. The intrinsic rate of increase (r) and finite rate of increase (λ) values all increased, and the generation time (T) and population doubling time (Dt) were shortened in F and F generations, with significant difference observed between F generations and the control. After exposure to avermectin, the number of eggs laid per female significantly decreased in F generation, and progeny (F and F) also produced fewer eggs than the control, while the female ratio of offspring increased both in F and F generations and the pre-oviposition period was significantly shortened. The r and λ values all increased, and the T and Dt were shortened in F and F generations. Such effects were more obvious on the F generation than the F generation. Generally, the effects of fenpropathrin and avermectin with a sublethal concentration of LC were not exactly the same on P. citri. Fenpropathrin could promote the development of the contemporary population, while avermectin had certain inhibition on the contemporary population, but both played a certain role in facilitating the development of future populations, which was of significance in developing integrated pest management strategies.
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http://dx.doi.org/10.13287/j.1001-9332.201608.019DOI Listing
August 2016

Long-term outcomes of gene therapy for the treatment of Leber's hereditary optic neuropathy.

EBioMedicine 2016 Aug 6;10:258-68. Epub 2016 Jul 6.

Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China; Wuhan Phoebus Biological Technology Limited Company, Wuhan, People's Republic of China. Electronic address:

Leber's hereditary optic neuropathy (LHON) is a disease that leads to blindness. Gene therapy has been investigated with some success, and could lead to important advancements in treating LHON. This was a prospective, open-label trial involving 9 LHON patients at Tongji Hospital, Wuhan, China, from August 2011 to December 2015. The purpose of this study was to evaluate the long-term outcomes of gene therapy for LHON. Nine LHON patients voluntarily received an intravitreal injection of rAAV2-ND4. Systemic examinations and visual function tests were performed during the 36-month follow-up period to determine the safety and efficacy of this gene therapy. Based on successful experiments in an animal model of LHON, 1 subject also received an rAAV2-ND4 injection in the second eye 12months after gene therapy was administered in the first eye. Recovery of visual acuity was defined as the primary outcome of this study. Changes in the visual field, visual evoked potential (VEP), optical coherence tomography findings, liver and kidney function, and antibodies against AAV2 were defined as secondary endpoints. Eight patients (Patients 2-9) received unilateral gene therapy and visual function improvement was observed in both treated eyes (Patients 4, 6, 7, and 8) and untreated eyes (Patients 2, 3, 4, 6 and 8). Visual regression fluctuations, defined as changes in visual acuity greater than or equal to 0.3 logMAR, were observed in Patients 2 and 9. Age at disease onset, disease duration, and the amount of remaining optic nerve fibers did not have a significant effect on the visual function improvement. The visual field and pattern reversal VEP also improved. The patient (Patient 1) who received gene therapy in both eyes had improved visual acuity in the injected eye after the first treatment. Unfortunately, visual acuity in this eye decreased 3months after he received gene therapy in the second eye. Animal experiments suggested that ND4 expression remains stable in the contralateral eye after intravitreal injections. No serious safety problem was observed in the 3-year follow-up of the 9 participants enrolled in this virus-based gene therapy. Meanwhile, our results support the use of intravitreal rAAV2-ND4 as an aggressive maneuver in our clinical trial. Further study in additional patients and in these 9 subjects is needed to better understand the effects of rAAV2-ND4 gene therapy on LHON and to increase the applications of this technique.
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http://dx.doi.org/10.1016/j.ebiom.2016.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006665PMC
August 2016
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