Publications by authors named "Dongqing Gu"

19 Publications

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Traumatic Brain Injury and Risk of Dementia and Alzheimer's Disease: A Systematic Review and Meta-Analysis.

Neuroepidemiology 2021 Nov 24. Epub 2021 Nov 24.

Introduction: Previous studies have investigated the potential role of traumatic brain injury (TBI) in subsequent development of dementia and Alzheimer's disease (AD) but reported inconsistent results. We aim to determine the association between TBI and subsequent occurrence of dementia and AD.

Methods: We performed a systematic search in PubMed and Web of Science for studies that quantitatively investigated the association between TBI and risk of dementia and AD and were published on or before September 21, 2021. A random-effect model was used to combine the estimates.

Results: Twenty-five eligible articles were included in this meta-analysis. The results suggested that TBI was associated with an increased risk of dementia (pooled odds ratio [OR] = 1.81, 95% confidence interval [CI] = 1.53 - 2.14). However, no association was observed between TBI and Alzheimer's disease (pooled OR = 1.02, 95% CI = 0.91 - 1.15). In the subgroup analysis, TBI with loss of consciousness was not associated with risk of dementia (pooled OR = 0.96, 95% CI = 0.84 - 1.09). Besides, Asian ethnicity, male gender, and mean age of the participants less than 65 were associated with a higher risk of dementia.

Conclusion: Our study suggests an increased risk of dementia among individuals with TBI, highlighting the need for more intensive medical monitoring and health education in individuals with TBI. Biological mechanisms linking TBI and the development of dementia are needed in future studies.
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http://dx.doi.org/10.1159/000520966DOI Listing
November 2021

Head Injury and Amyotrophic Lateral Sclerosis: A Meta-Analysis.

Neuroepidemiology 2021 Feb 23:1-9. Epub 2021 Feb 23.

The Fourth Department, State Key Laboratory of Trauma, Burn and Combined Injuries, Institute for Traffic Medicine, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China,

Background: Prior studies have suggested that head injury might be a potential risk factor of amyotrophic lateral sclerosis (ALS). However, the association has not been well established. We aimed to provide a synopsis of the current understanding of head injury's role in ALS.

Methods: We performed a systematic search in PubMed for observational studies that quantitatively investigated the association between head injury and ALS risk published before April 10, 2020. We used a random-effects model to calculate odds ratios (ORs) and 95% confidence intervals (CIs).

Results: Fourteen eligible articles including 10,703 cases and 2,159,324 controls were selected in current meta-analysis. We found that head injury was associated with an increased risk of ALS (OR = 1.38, 95% CI: 1.20-1.60) and the association was slightly stronger concerning severe head injury and ALS risk (OR = 1.69, 95% CI: 1.27-2.23). Considering the number of head injuries (N) and ALS risk, the association was weak (OR = 1.23, 95% CI: 1.10-1.37, N = 1; OR = 1.29, 95% CI: 0.89-1.86, N ≥ 2). In addition, a strong association with ALS risk was found in individuals who suffered head injury <1 year (OR = 4.05, 95% CI: 2.79-5.89), and when the time lag was set at 1-5, 5-10, and >10 years, the pooled OR was 1.13, 1.35, and 1.10, respectively.

Conclusion: This meta-analysis indicates that head injury, especially severe head injury, could increase ALS risk. Although a strong association is found between head injury <1 year and ALS risk in the current study, this result suggests a possibility of reverse causation.
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http://dx.doi.org/10.1159/000510987DOI Listing
February 2021

Trauma and amyotrophic lateral sclerosis: a systematic review and meta-analysis.

Amyotroph Lateral Scler Frontotemporal Degener 2021 05 11;22(3-4):170-185. Epub 2021 Jan 11.

The Eighth Department, State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China.

: Trauma especially head trauma is considered a potential risk factor of amyotrophic lateral sclerosis (ALS), but their association has not been well established. We aimed to determine the association of prior trauma with ALS risk. This study was performed according to the Meta-Analysis of Observational Studies in Epidemiology guideline to assess related literatures, and a random-effects model was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Twenty-nine eligible articles involving 18,390 cases and 6,519,391 controls were included in this meta-analysis. The results showed that trauma was associated with an increased risk of ALS (pooled OR = 1.51, 95% CI: 1.32-1.73). Besides, patients with trunk trauma, head trauma and lower limb trauma had an increased risk of ALS, whereas no evidence suggested that upper limb trauma and spine trauma could increase ALS risk. Considering the number of traumatic events, the association between trauma and ALS risk was significant for patients with repeated trauma events (pooled OR = 1.21, 95% CI: 1.07-1.38). The results showed that individuals with a history of trauma within 5 years were more likely to be diagnosed with ALS (pooled OR = 1.84, 95% CI: 1.56-2.17). Importantly, both old trauma and very old trauma were found to be associated with an increased risk of ALS (pooled OR = 1.24, 95% CI: 1.12-1.38; pooled OR = 1.28, 95% CI: 1.10-1.49; respectively). This meta-analysis indicated that trauma could increase ALS risk, which may be applied for the clinicians to tailor targeted treatment regimens and make prophylactic strategies for ALS in traumatic patients.
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http://dx.doi.org/10.1080/21678421.2020.1861024DOI Listing
May 2021

Sex Disparities in the Clinical Characteristics, Synchronous Distant Metastasis Occurrence and Prognosis: A Pan-cancer Analysis.

J Cancer 2021 1;12(2):498-507. Epub 2021 Jan 1.

Department of Bone and Soft Tissue Tumours, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China.

This study aims to assess the sex disparities in clinical characteristics and synchronous distant metastasis occurrence at diagnosis, as well as the subsequent prognosis in non-sex-specific cancers. The study included details from patients diagnosed with non-sex-specific cancers, during the period from 2010 to 2016, in the Surveillance, Epidemiology, and End Results (SEER) program. The distant metastasis prevalence and subsequent survival time were summarized in the total population and the population with specific cancers of different systems. The multivariable logistic and the Cox proportional hazards regressions were applied to evaluate the sex effect on distant metastasis occurrence and prognosis. The results were combined using meta-analysis. Across all non-sex-specific cancers, the pooled prevalence of distant metastasis was 15.2% (95% CI: 14.7-15.7%) and 7.1% (95% CI: 6.8-7.3%) for males and females, respectively. The pooled median survival time was 8.40 months (95% CI: 7.99-8.81) for male patients and 9.40 months (95% CI: 8.84-10.02) for female patients. After combining all non-sex-specific cancers, male patients displayed a higher distant metastasis occurrence than females (pooled OR=1.06, 95% CI: 1.04-1.08; 0.01), as well as worse overall survival after distant metastasis (pooled HR=1.08, 95% CI: 1.05-1.10; <0.01). The sex differences were more significant in patients younger than 65 years (0.01). Additionally, the sex influence on prognosis was most predominant amongst patients from Asian or Pacific Islander ethnic groups. Male gender appears to be an independent risk factor associated with the occurrence and prognosis of synchronous distant metastasis. Therefore, sex-specific preventions and treatments should become the focus of future research.
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http://dx.doi.org/10.7150/jca.50536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739003PMC
January 2021

The Injuries and Helmet Use in Bike Share Programs: A Systematic Review.

J Community Health 2021 02;46(1):203-210

State Key Laboratory of Trauma, Burn and Combined Injuries, Eighth Department, Daping Hospital, Research Institute of Surgery, Army Medical University, Chongqing, 400042, People's Republic of China.

To investigate the injury effects of bike share programs and the helmet usage status in bike share programs. We conducted a systematic review of peer reviewed scientific literature. Searches were conducted in three databases (Pubmed, Scopus, and Web of Science) on March 1 2020 to identify all articles on the injury incidence related to bike share programs and the helmet usage status in bike share programs. Titles, abstracts, and full-text articles were screened to identify all articles relevant to the themes by two authors independently, and discrepancies were resolved after discussion with the third author. Standardised data extraction and quality assessment (The Newcastle-Ottawa Scale) were implemented. A sum of 491 records after removing duplicates was identified, 181 fulltext articles were screened, and 13 studies were included in the review. The primary outcome are injuries of bike share users and unhelmeted rate among bike share users as well as the unhelmeted rate among personal bike users. Two studies evaluated the injuries related to bike share users, but have inconclusive results. A total of 11 studies reported the unhelmeted rates in bike share programs ranging from 36.0 to 88.9%. There is a significant change in bike injuries with the implementation of bike share programs. Moreover, the unhelmeted rate of bike share users was generally higher than that of personal bike users, which may result from helmets' accessibility and users' safety perception.
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http://dx.doi.org/10.1007/s10900-020-00836-6DOI Listing
February 2021

Allogeneic Hematopoietic Cell Transplantation Outcomes in Patients Carrying Isocitrate Dehydrogenase Mutations.

Clin Lymphoma Myeloma Leuk 2019 07 26;19(7):e400-e405. Epub 2019 Apr 26.

Department of Hematology and HCT, City of Hope National Medical Center, Duarte, CA.

Background: Mutations in isocitrate dehydrogenase (IDH)1/2 genes result in nicotinamide adenine dinucleotide phosphate-dependent reduction of α-ketoglutarate and formation of 2-hydroxyglutarate, which blocks normal cellular differentiation and promotes leukemogenesis. Nearly 20% of acute myeloid leukemia (AML) patients carry IDH1/2 mutations. Although multiple investigators have described the prognostic implications of IDH mutations in AML patients receiving chemotherapy, the effect of these mutations on outcomes after allogeneic (allo) hematopoietic cell transplantation (HCT) is unknown.

Patients And Methods: We report on the clinical outcome of a cohort of AML patients, who were tested for IDH mutations and underwent alloHCT at City of Hope (2015-2017). Of a total of 317 screened patients, 99 (31%) underwent alloHCT, of whom 23 carried and 76 did not carry IDH mutations (control).

Results: No statistical significance was detected in patient's overall survival (P = .84). With a median follow-up of 7.8 months, 1-year relapse rate of 29% and 13% was seen in the IDH-mutated and control group, respectively (P = .033). IDH1/2 mutation status remained significantly associated with relapse (hazard ratio, 2.8; P = .046) after inclusion of pre-HCT disease status in a multivariable model.

Conclusion: Our results, despite low patient numbers, indicate that IDH mutations are associated with higher relapse rate after alloHCT. Further prospective studies on post transplantation IDH inhibition is required to improve outcomes in AML patients who carry IDH mutations.
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http://dx.doi.org/10.1016/j.clml.2019.04.007DOI Listing
July 2019

Variants in the PSCA gene associated with risk of cancer and nonneoplastic diseases: systematic research synopsis, meta-analysis and epidemiological evidence.

Carcinogenesis 2019 03;40(1):70-83

Department of Epidemiology and Biostatistics, Southwest School of Medicine and First Affiliated Hospital, Army Medical University, Chongqing, China.

Variants in the prostate stem cell antigen (PSCA) gene have been linked with risk of multiple cancers and other diseases. But results have been inconclusive and no systematic research synopsis has been available. We did a comprehensive meta-analysis to investigate associations between variants in this gene and risk of nine cancers and four nonneoplastic diseases based on data from 55 publications including 81 961 cases and 442 932 controls. We graded levels of cumulative epidemiological evidence of a significant association using the Venice criteria and false-positive report probability tests. We performed functional annotation for these variants using data from the Encyclopedia of DNA Elements Project and other public databases. We found that six variants were nominally significantly associated with an increased or reduced risk of three cancers and three nonneoplastic diseases (P < 0.05). Cumulative evidence of an association was graded as strong for rs2294008 [odds ratio (OR) = 1.32, P = 5.1 × 10-33], rs2976392 (OR = 1.29, P = 1.8 × 10-8), rs9297976 (OR = 0.75, P = 1.4 × 10-7), rs2976391 (OR = 1.38, P = 6.1 × 10-5) and rs138377917 (OR = 0.53, P = 0.008) with gastric cancer, rs2294008 with bladder cancer (OR = 1.15, P = 8.0 × 10-19), gastritis (OR = 1.35, P = 1.2 × 10-5), duodenal ulcer (OR = 0.68, P = 2.4 × 10-57) and gastric ulcer (OR = 0.88, P = 1.7 × 10-7). Data from the Encyclopedia of DNA Elements Project and other databases showed that these variants and other variants correlated with them might fall in putative functional regions. In conclusion, this study provides summary evidence that variants in the PSCA gene are associated with risk of gastric and bladder cancer, gastritis, as well as duodenal and gastric ulcer and highlights the significant role of this gene in the pathogenesis of these diseases.
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http://dx.doi.org/10.1093/carcin/bgy151DOI Listing
March 2019

Risk factors for extremely serious road accidents: Results from national Road Accident Statistical Annual Report of China.

PLoS One 2018 1;13(8):e0201587. Epub 2018 Aug 1.

The Fourth Department, State Key Laboratory of Trauma, Burn and Combined Injuries, Institute for Traffic Medicine, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, P.R. China.

Background: In the past decades, extremely serious road accidents with a death toll over ten in each have become a severe public health problem in China. This study investigates risk factors contributing to extremely serious road accidents, which will be crucial for accident prevention.

Methods: Collecting data from The Road Accident Statistical Annual Report openly issued by China's Traffic Management Bureau of the Public Security Ministry for the time period 2004-2015, we used the monthly case number of extreme serious road accidents as the dependent variable. We then selected ten risk factors as primary independent variables: professional driver, driving under influence (alcohol or drug), fatigue, vehicle type, overload, brake problem, weather, road classification, terrain, and region. The method of negative binominal regression was implemented to investigate the association between these risk factors and extremely serious road accidents.

Results: A total of 346 extremely serious road accidents were included in our analysis. On a national scale, we found that professional driver [incidence rate ratio (IRR): 1.10, 95% CI: 1.02-1.19], fatigue (IRR: 1.15, 95% CI: 1.03-1.29), large vehicle type (IRR: 1.11, 95% CI: 1.03-1.21), overload (IRR: 1.09, 95% CI: 1.03-1.16), and terrain (IRR: 1.09, 95% CI: 1.01-1.18) were significantly associated with extremely serious road accidents. Besides, separate analyses on western and non-western region indicated that both regions had shared risk factors as well as distinct factors.

Conclusions: Our study identifies professional driver, fatigue, large vehicle type, overload, and terrain as significant risk factors of extremely serious road accidents in China, and targeted and preventative measures could be taken based on our findings.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201587PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070265PMC
February 2019

Preparation of rice straw-derived biochar for efficient cadmium removal by modification of oxygen-containing functional groups.

Sci Total Environ 2018 Aug 16;631-632:795-802. Epub 2018 Mar 16.

Key Laboratory of Energy Thermal Conversion and Control, Ministry of Education, School of Energy and Environment, Southeast University, Nanjing 210096, PR China.

In order to enhance the adsorption capacity of cadmium (Cd) ion from aqueous solution, the rice straw-derived biochar (BC800) was modified by a mixture of HNO and HO (MHH) with equal volume. Several elemental, chemical and structural characterization methods were used to determine the characteristics of biochars. Batch adsorption experiments were carried out concerning the influences of contact time, initial pH value, and initial concentration. The results indicated that the modified biochar (BCM) was more effective in removing Cd from water than BC800. For 550mgL Cd concentration solution, the adsorption capacity of 93.2mgg was observed for BCM, which was much higher than that of BC800 (69.3mgg). The BCM had a significant increase of acidic functional groups with a rate of 101.6% and the component carboxyl, lacton and phenol groups increased by 124.1%, 29.3% and 111.3% respectively, while the specific surface area increased about 22.0%, compared with BC800. The pseudo-second-order model provided high correlation coefficients for BCM, speculating chemisorption of the Cd onto biochars. Therefore, the rice straw-based biochar treated by MHH is considered to be an efficient adsorbent for Cd removal from aqueous solution, especially for high concentrations of cadmium solution.
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http://dx.doi.org/10.1016/j.scitotenv.2018.03.071DOI Listing
August 2018

Genetic polymorphisms and lung cancer risk: Evidence from meta-analyses and genome-wide association studies.

Lung Cancer 2017 11 1;113:18-29. Epub 2017 Sep 1.

Department of Cardiothoracic Surgery, First Affiliated Hospital of Chongqing Medical University, No.1, Youyi Road, Yuzhong District, Chongqing 400010, China. Electronic address:

A growing number of studies investigating the association between Single Nucleotide Polymorphisms (SNPs) and lung cancer risk have been published since over a decade ago. An updated integrative assessment on the credibility and strength of the associations is required. We searched PubMed, Medline, and Web of Science on or before August 29, 2016. A total of 198 articles were deemed eligible for inclusion, which addressed the associations between 108 variants and lung cancer. Among the 108 variants, 63 were reported to be significantly associated with lung cancer while the remaining 45 were reported non-significant. Further evaluation integrating the Venice Criteria and false-positive report probability (FPRP) was performed to determine the strength of cumulative epidemiological evidence for the 63 significant associations. As a result, 15 SNPs on or near 12 genes and one miRNA with strong evidence of association with lung cancer risk were identified, including TERT (rs2736098), CHRNA3 (rs1051730), AGPHD1 (rs8034191), CLPTM1L (rs401681 and rs402710), BAT3 (rs3117582), TRNAA (rs4324798), ERCC2 (Lys751Gln), miR-146a2 (rs2910164), CYP1B1 (Arg48Gly), GSTM1 (null/present), SOD2 (C47T), IL-10 (-592C/A and -819C/T), and TP53 (intron 6). 19 SNPs were given moderate rating and 17 SNPs were rated as having weak evidence. In addition, all of the 29 SNPs identified in 12 genome-wide association studies (GWAS) were proved to be noteworthy based on FPRP value. This review summarizes and evaluates the cumulative evidence of genetic polymorphisms and lung cancer risk, which can serve as a general and useful reference for further genetic studies.
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http://dx.doi.org/10.1016/j.lungcan.2017.08.026DOI Listing
November 2017

Cumulative evidence for relationships between multiple variants in the VTI1A and TCF7L2 genes and cancer incidence.

Int J Cancer 2018 02 7;142(3):498-513. Epub 2017 Nov 7.

Department of Epidemiology and Biostatistics, First Affiliated Hospital and Southwest School of Medicine, Third Military Medical University, Chongqing, China.

Genetic studies have linked the VTI1A-TCF7L2 region with risk of multiple cancers. However, findings from these studies were generally inconclusive. We aimed to provide a synopsis of current understanding of associations between variants in the VTI1A-TCF7L2 region and cancer susceptibility. We conducted a comprehensive research synopsis and meta-analysis to evaluate associations between 17 variants in this region and risk of seven cancers using data from 32 eligible articles totaling 224,656 cancer cases and 324,845 controls. We graded cumulative evidence of significant associations using Venice criteria and false-positive report probability tests. We also conducted analyses to evaluate potential function of these variants using data from the Encyclopedia of DNA Elements (ENCODE) Project. Eight variants showed a nominally significant association with risk of individual cancer (p < 0.05). Cumulative epidemiological evidence of an association was graded as strong for rs7903146 [odds ratio (OR) = 1.05, p = 4.13 × 10 ] and rs7904519 (OR = 1.07, p = 2.02 × 10 ) in breast cancer, rs11196172 (OR = 1.11, p = 2.22 × 10 ), rs12241008 (OR = 1.13, p = 1.36 × 10 ) and rs10506868 (OR = 1.10, p = 3.98 × 10 ) in colorectal cancer, rs7086803 in lung cancer (OR = 1.30, p = 3.54 × 10 ) and rs11196067 (OR = 1.18, p = 3.59 × 10 ) in glioma, moderate for rs12255372 (OR = 1.12, p = 2.52 × 10 ) in breast cancer and weak for rs7903146 (OR = 1.11, p = 0.007) in colorectal cancer. Data from ENCODE suggested that seven variants with strong evidence and other correlated variants might fall within putative functional regions. Collectively, our study provides summary evidence that common variants in the VTI1A and TCF7L2 genes are associated with risk of breast, colorectal, lung cancer and glioma and highlights the significant role of the VTI1A-TCF7L2 region in the pathogenesis of human cancers.
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http://dx.doi.org/10.1002/ijc.31074DOI Listing
February 2018

Mycobacterium tuberculosis PPE25 and PPE26 proteins expressed in Mycobacterium smegmatis modulate cytokine secretion in mouse macrophages and enhance mycobacterial survival.

Res Microbiol 2017 Apr 25;168(3):234-243. Epub 2016 Jun 25.

Laboratory of Infection and Immunity, West China Center of Medical Sciences, Sichuan University, No. 17, 3rd Section, Ren Min Nan Road, Chengdu, Sichuan 610041, China. Electronic address:

PPE25 and PPE26, the Mycobacterium tuberculosis proline-proline-glutamic acid (PPE) family proteins, are members of the M. tuberculosis ESX-5 system associated with virulence of M. tuberculosis. To investigate the roles of PPE25 and PPE26 during M. tuberculosis infection, we expressed them in non-pathogenic fast-growing Mycobacterium smegmatis, respectively, and used these recombinant strains to infect ANA-1 macrophages and BALB/c mice. We observed that both PPE25 and PPE26 enhanced survival of M. smegmatis in ANA-1 macrophages, and prolonged the persistence of M. smegmatis in mouse tissues. M. smegmatis-expressed PPE25 and PPE26 induced a significantly higher level of TNF-α and a slightly higher amount of IL-1β, which was found to be mediated by the NF-κB, ERK and p38 pathways in ANA-1 macrophages. In addition, M. smegmatis-expressed PPE26 inhibited synthase of inducible nitric oxide and induced stronger cell necrosis. In summary, our data suggest that PPE25 and PPE26 enhance non-pathogenic M. smegmatis to survive in ANA-1 macrophages and persistence in mice, modify expression of multiple cytokines and affect host cell necrosis. Our results could help to understand the complex interactions between the host and M. tuberculosis.
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http://dx.doi.org/10.1016/j.resmic.2016.06.004DOI Listing
April 2017

The Mycobacterium bovis BCG prime-Rv0577 DNA boost vaccination induces a durable Th1 immune response in mice.

Acta Biochim Biophys Sin (Shanghai) 2016 Apr 27;48(4):385-90. Epub 2016 Feb 27.

Laboratory of Infection and Immunity, School of Basic Medical Sciences, West China Center of Medical Science, Sichuan University, Chengdu 610041, China

Tuberculosis remains a major global health problem and effective vaccines are urgently needed. In this study, we used the combined DNA- and protein-based vaccines of immunodominant antigen Rv0577 to boost BCG and evaluated their immunogenicity in BALB/c mice. Our data suggest that the booster vaccine may substantially enhance the immunogenicity of BCG and strengthen both CD4+ T cell-mediated Th1 and CD8+ T cell-mediated cytolytic responses. Compared with the protein-based vaccine, the DNA-based vaccine can induce more durable Th1 immune response, characterized by high levels of antibody response, proliferation response, percentages of CD4+/CD8+ and cytokine secretion in antigen-stimulated splenocyte cultures. In conclusion, we for the first time, developed a protein- and plasmid DNA-based booster vaccine based on Rv0577. Our findings suggest that antigen Rv0577-based DNA vaccine is immunogenic and can efficiently boost BCG, which could be helpful in the design of an efficient vaccination strategy against TB.
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http://dx.doi.org/10.1093/abbs/gmw010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4886249PMC
April 2016

Mycobacterium tuberculosis PE25/PPE41 protein complex induces activation and maturation of dendritic cells and drives Th2-biased immune responses.

Med Microbiol Immunol 2016 Apr 30;205(2):119-31. Epub 2015 Aug 30.

Laboratory of Infection and Immunity, School of Basic Medical Sciences, Sichuan University, Chengdu, 610041, China.

Mycobacterium tuberculosis evades innate host immune responses by parasitizing macrophages and causes significant morbidity and mortality around the world. A mycobacterial antigen that can activate dendritic cells (DCs) and elicit effective host innate immune responses will be vital to the development of an effective TB vaccine. The M. tuberculosis genes PE25/PPE41 encode proteins which have been associated with evasion of the host immune response. We constructed a PE25/PPE41 complex gene via splicing by overlapping extension and expressed it successfully in E. coli. We investigated whether this protein complex could interact with DCs to induce effective host immune responses. The PE25/PPE41 protein complex induced maturation of isolated mouse DCs in vitro, increasing expression of cell surface markers (CD80, CD86 and MHC-II), thereby promoting Th2 polarization via secretion of pro-inflammatory cytokines IL-4 and IL-10. In addition, PE25/PPE41 protein complex-activated DCs induced proliferation of mouse CD4(+) and CD8(+) T cells, and a strong humoral response in immunized mice. The sera of five TB patients were also highly reactive to this antigen. These findings suggest that interaction of the PE25/PPE41 protein complex with DCs may be of great immunological significance.
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http://dx.doi.org/10.1007/s00430-015-0434-xDOI Listing
April 2016

Beyond Li Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations.

J Clin Oncol 2009 Mar 9;27(8):1250-6. Epub 2009 Feb 9.

Departments of Molecular Diagnosis, Molecular Genetics, Clinical Cancer Genetics, and Information Sciences, and the Bioinformatics Group, City of Hope, Duarte, CA 91010-0269 , USA.

Purpose: A clinical testing cohort was used to gain a broader understanding of the spectrum of tumors associated with germline p53 mutations to aid clinicians in identifying high-risk families.

Patients And Methods: Full sequencing of the coding exons (2 to 11) and associated splice junctions of the p53 gene was performed on 525 consecutive patients whose blood samples were submitted for diagnostic testing. Clinical features of p53 germline carriers in this cohort were characterized, clinical referral schemes based on reported p53-associated family phenotypes were evaluated, and practical mutation prevalence tables were generated.

Results: Mutations were identified in 91 (17%) of 525 patients submitted for testing. All families with a p53 mutation had at least one family member with a sarcoma, breast, brain, or adrenocortical carcinoma (ACC). Every individual with a choroid plexus tumor (eight of eight) and 14 of 21 individuals with a childhood ACC had a mutation regardless of family history. Based on reported personal and family history, 95% of patients (71 of 75) with a mutation met either classic Li Fraumeni syndrome (LFS) or Chompret criteria. A simplified prevalence table provides a concise summary of individual and family characteristics associated with p53 mutations.

Conclusion: This is, to our knowledge, the largest single report of diagnostic testing for germline p53 mutations, yielding practical mutation prevalence tables and suggesting clinical utility of classic LFS and Chompret criteria for identifying a subset of cancer-prone families with p53 germline mutations, with important implications for diagnosis and management.
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http://dx.doi.org/10.1200/JCO.2008.16.6959DOI Listing
March 2009

Somatic microindels in human cancer: the insertions are highly error-prone and derive from nearby but not adjacent sense and antisense templates.

Hum Mol Genet 2008 Sep 15;17(18):2910-8. Epub 2008 Jul 15.

Department of Molecular Genetics, City of Hope National Medical Center, 1500 E. Duarte Rd, Duarte, CA 91010, USA.

Somatic microindels (microdeletions with microinsertions) have been studied in normal mouse tissues using the Big Blue lacI transgenic mutation detection system. Here we analyze microindels in human cancers using an endogenous and transcribed gene, the TP53 gene. Microindel frequency, the enhancement of 1-2 microindels and other features are generally similar to that observed in the non-transcribed lacI gene in normal mouse tissues. The current larger sample of somatic microindels reveals recurroids: mutations in which deletions are identical and the co-localized insertion is similar. The data reveal that the inserted sequences derive from nearby but not adjacent sequences in contrast to the slippage that characterizes the great majority of pure microinsertions. The microindel inserted sequences derive from a template on the sense or antisense strand with similar frequency. The estimated error rate of the insertion process of 13% per bp is by far the largest reported in vivo, with the possible exception of somatic hypermutation in the immunoglobulin gene. The data constrain possible mechanisms of microindels and raise the question of whether microindels are 'scars' from the bypass of large DNA adducts by a translesional polymerase, e.g. the 'Tarzan model' presented herein.
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http://dx.doi.org/10.1093/hmg/ddn190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2722894PMC
September 2008

Evidence for mutation showers.

Proc Natl Acad Sci U S A 2007 May 7;104(20):8403-8. Epub 2007 May 7.

Department of Molecular Genetics and Bioinformatics Group, Department of Molecular Genetics, City of Hope National Medical Center, Duarte, CA 91010, USA.

Mutants in the Big Blue transgenic mouse system show spontaneous clustered multiple mutations with unexpectedly high frequency, consistent with chronocoordinate events. We tested the prediction that the multiple mutations seen within the lacI mutation target sometimes occur in the context of chronocoordinate multiple mutations spanning multiple kilobases (mutation showers). Additional sequencing of mutants was performed in regions immediately flanking the lacI region (total of 10.7 kb). Nineteen additional mutations were found outside the lacI region ("ectomutations") from 10 mutants containing two or more lacI mutations, whereas only one ectomutation was found in 130 mutants with a single mutation (P < 0.0001). The mutation showers had an average of approximately one mutation per 3 kb. Four mutants showed closely spaced double mutations in the new sequence, and analysis of the spacing between these mutations revealed significant clustering (P = 0.0098). To determine the extent of the mutation showers, regions (8.5 kb total) remote from the lacI region (approximately 16-17 kb away) were sequenced. Only two additional ectomutations were found in these remote regions, consistent with mutation showers that generally do not extend more than approximately 30 kb. We conclude that mutation showers exist and that they constitute at least 0.2% and possibly 1% or more of mutational events observed in this system. The existence of mutation showers has implications for oncogenesis and evolution, raising the possibilities of "cancer in an instant" and "introns as sponges to reduce the deleterious impact of mutation showers."
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http://dx.doi.org/10.1073/pnas.0610902104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895962PMC
May 2007

Database of somatic mutations in EGFR with analyses revealing indel hotspots but no smoking-associated signature.

Hum Mutat 2007 Aug;28(8):760-70

Clinical Molecular Diagnostic Laboratory (CMDL), Department of Molecular Diagnosis, City of Hope National Medical Center, City of Hope, Duarte, California 91010-0269, USA.

We created an Epidermal Growth Factor Receptor (EGFR) Mutation Database (http://www.cityofhope.org/cmdl/egfr_db) that curates a convenient compilation of somatic EGFR mutations in non-small-cell lung cancer (NSCLC) and associated epidemiological and methodological data, including response to the tyrosine kinase inhibitors Gefitinib and Erlotinib. Herein, we analyze 809 mutations collected from 26 publications. Four super hotspots account for 70% of reported mutations while two-thirds of 131 unique mutations have been reported only once and account for only 11% of reported mutations. Consistent with strong biological selection for gain of function, the reported mutations are virtually all missense substitutions or in-frame microdeletions, microinsertions, or microindels (colocalized insertion and deletion with a net gain or loss of 1-50 nucleotides). Microdeletions and microindels are common in a region of exon 19. Microindels, which account for 8% of mutations, have smaller inserted sequences (95% are 1 to 5 bp) and are elevated 16-fold relative to mouse somatic microindels and to human germline microindels. Microdeletions/microindels are significantly more frequent in responders to Gefitinib or Erlotinib (P = 0.003). In addition, EGFR mutations in smokers do not carry signatures of mutagens in cigarette smoke. Otherwise, the mutation pattern does not differ significantly with respect to gender, age, or tumor histology. The EGFR Mutation Database is a central resource of EGFR sequence variant data for clinicians, geneticists, and other researchers. Authors are encouraged to submit new publications with EGFR sequence variants to be included in the database or to provide direct submissions via The WayStation submission and publication process (http://www.centralmutations.org).
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http://dx.doi.org/10.1002/humu.20512DOI Listing
August 2007

Somatic microindels: analysis in mouse soma and comparison with the human germline.

Hum Mutat 2007 Jan;28(1):69-80

Department of Molecular Genetics, City of Hope National Medical Center, Duarte, California.

Microindels, defined as mutations that result in a colocalized microinsertion and microdeletion with a net gain or loss of between 1 and 50 nucleotides, may be an important contributor to cancer. We report the first comprehensive analysis of somatic microindels. Our large database of mutations in the lacI transgene of Big Blue((R)) mice contains 0.5% microindels, 2.8% pure microinsertions, and 11.5% pure microdeletions. There appears to be no age, gender, or tissue-type specificity in the frequency of microindels. Of the independent somatic mutations that result in a net in-frame insertion or deletion, microindels are responsible for 13% of protein expansions and 6% of protein contractions. These in-frame microindels may play a crucial role in oncogenesis and evolution via "protein tinkering" (i.e., modest expansion or contraction of proteins). Four characteristics suggest that microindels are caused by unique mechanisms, not just simple combinations of the same mechanisms that cause pure microinsertions and pure microdeletions. First, microinsertions and microdeletions commonly occur at hotspots, but none of the 30 microindels are recurrent. Second, the sizes of the deletions and insertions in microindels are larger and more varied than in pure microdeletions and pure microinsertions. Third, microinsertions overwhelmingly repeat the adjacent base (97%) while the insertions in microindels do so only infrequently (17%). Fourth, analysis of the sequence contexts of microindels is consistent with unique mechanisms including recruitment of translesion DNA synthesis polymerases. The mouse somatic microindels have characteristics similar to those of human germline microindels, consistent with similar causative mechanisms in mouse and human, and in soma and germline.
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http://dx.doi.org/10.1002/humu.20416DOI Listing
January 2007
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