ORCID Profile
0000-0001-8503-002X
Current Organisations
Vanderbilt University School of Medicine
,
Vanderbilt University Medical Center
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Hindawi Limited
Date: 2017
DOI: 10.1155/2017/1320241
Abstract: Switching of cellular energy production from oxidative phosphorylation (OXPHOS) by mitochondria to aerobic glycolysis occurs in many types of tumors. However, the significance of this switching for the development of gastric carcinoma and what connection it may have to Helicobacter pylori infection of the gut, a primary cause of gastric cancer, are poorly understood. Therefore, we investigated the expression of OXPHOS complexes in two types of human gastric carcinomas (“intestinal” and “diffuse”), bacterial gastritis with and without metaplasia, and chemically induced gastritis by using immunohistochemistry. Furthermore, we analyzed the effect of HP infection on several key mitochondrial proteins. Complex I expression was significantly reduced in intestinal type (but not diffuse) gastric carcinomas compared to adjacent control tissue, and the reduction was independent of HP infection. Significantly, higher complex I and complex II expression was present in large tumors. Furthermore, higher complex II and complex III protein levels were also obvious in grade 3 versus grade 2. No differences of OXPHOS complexes and markers of mitochondrial biogenesis were found between bacterially caused and chemically induced gastritis. Thus, intestinal gastric carcinomas, but not precancerous stages, are frequently characterized by loss of complex I, and this pathophysiology occurs independently of HP infection.
Publisher: American Association for Cancer Research (AACR)
Date: 18-03-2021
DOI: 10.1158/1055-9965.EPI-20-1471
Abstract: The association between prediagnostic antibody responses to Fusobacterium nucleatum (F. nucleatum) and subsequent risk of colorectal cancer is not established. We conducted a nested case–control study of 8,126 participants in a consortium of 10 prospective cohorts in the United States. Higher seroprevalence of any F. nucleatum antibody was observed among non-White participants (51.1%) compared with White participants (31.2%). We did not find any statistically significant association between seropositivity to any of the eight F. nucleatum proteins and colorectal cancer risk. Prediagnostic antibody responses to F. nucleatum proteins were not associated with the risk of colorectal cancer. Future studies may consider a more specific detection of the immunoglobulin isotypes or focus on examining F. nucleatum in stool or tissue s les.
Publisher: American Society for Microbiology
Date: 12-2015
DOI: 10.1128/IAI.00918-15
Abstract: Helicobacter pylori exhibits a high level of intraspecies genetic ersity. In this study, we investigated whether the ersification of H. pylori is influenced by the composition of the diet. Specifically, we investigated the effect of a high-salt diet (a known risk factor for gastric adenocarcinoma) on H. pylori ersification within a host. We analyzed H. pylori strains isolated from Mongolian gerbils fed either a high-salt diet or a regular diet for 4 months by proteomic and whole-genome sequencing methods. Compared to the input strain and output strains from animals fed a regular diet, the output strains from animals fed a high-salt diet produced higher levels of proteins involved in iron acquisition and oxidative-stress resistance. Several of these changes were attributable to a nonsynonymous mutation in fur ( fur-R88H ). Further experiments indicated that this mutation conferred increased resistance to high-salt conditions and oxidative stress. We propose a model in which a high-salt diet leads to high levels of gastric inflammation and associated oxidative stress in H. pylori -infected animals and that these conditions, along with the high intraluminal concentrations of sodium chloride, lead to selection of H. pylori strains that are most fit for growth in this environment.
Publisher: MDPI AG
Date: 30-10-2020
DOI: 10.3390/MICROORGANISMS8111698
Abstract: Previously, we found that risk of colorectal cancer (CRC) is increased in in iduals with serum antibody response to both Helicobacter pylori (HP) Vacuolating Cytotoxin (VacA) toxin or Streptococcus gallolyticus (SGG) pilus protein Gallo2178. In the present analysis, we tested the hypothesis that combined seropositivity to both antigens is a better indicator of CRC risk than seropositivity to single antigens. We used multiplex serologic assays to analyze pre-diagnostic serum for antibody responses from 4063 incident CRC cases and 4063 matched controls from 10 US cohorts. To examine whether combined SGG Gallo2178 and HP VacA sero-status was associated with CRC risk, we used conditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Compared to dual sero-negative in iduals, there was no increased risk for in iduals sero-positive to SGG Gallo2178 only (OR: 0.93 95% CI: 0.66–1.31) or to HP VacA only (OR: 1.08 95% CI: 0.98–1.19). However, dual sero-positive in iduals had a % increased odds of developing CRC (OR: 1.54 95% CI: 1.16–2.04), suggesting an interaction between antibody responses to these two pathogens and CRC risk (pinteraction = 0.06). In conclusion, this study suggests that dual sero-positivity to HP VacA and SGG Gallo2178 is an indicator of increased risk of CRC.
Publisher: American Association for Cancer Research (AACR)
Date: 10-2020
DOI: 10.1158/1055-9965.EPI-20-0525
Abstract: Prevalence of Helicobacter pylori (H. pylori) infection, the main risk factor for gastric cancer, has been decreasing in the United States however, there remains a substantial racial disparity. Moreover, the time-trends for prevalence of CagA-positive H. pylori infection, the most virulent form, are unknown in the U.S. population. We sought to assess prevalence of CagA-positive H. pylori infection over time by race in the United States. We utilized multiplex serology to quantify antibody responses to H. pylori antigens in 4,476 participants across five cohorts that s led adults from 1985 to 2009. Using log-binomial regression models, we calculated prevalence ratios and 95% confidence intervals for the association between H. pylori–CagA sero-prevalence and birth year by race. African Americans were three times more likely to be H. pylori–CagA sero-positive than Whites. After adjustment, H. pylori–CagA sero-prevalence was lower with increasing birth year among Whites (Ptrend = 0.001), but remained stable for African Americans. When stratified by sex and education separately, the decline in H. pylori–CagA sero-positivity among Whites remained only for females (Ptrend & 0.001) and was independent of educational attainment. Among African Americans, there was no difference by sex furthermore, sero-prevalence increased with increasing birth year among those with a high school education or less (P = 0.006). Among in iduals in the United States born from the 1920s to 1960s, H. pylori–CagA sero-prevalence has declined among Whites, but not among African Americans. Our findings suggest a widening racial disparity in the prevalence of the most virulent form of H. pylori, the main cause of gastric cancer.
Publisher: PeerJ
Date: 18-05-2018
DOI: 10.7717/PEERJ.4803
Abstract: Helicobacter pylori requires genetic agility to infect new hosts and establish long-term colonization of changing gastric environments. In this study, we analyzed H. pylori genetic adaptation in the Mongolian gerbil model. This model is of particular interest because H. pylori -infected gerbils develop a high level of gastric inflammation and often develop gastric adenocarcinoma or gastric ulceration. We analyzed the whole genome sequences of H. pylori strains cultured from experimentally infected gerbils, in comparison to the genome sequence of the input strain. The mean annualized single nucleotide polymorphism (SNP) rate per site was 1.5e −5 , which is similar to the rates detected previously in H. pylori- infected humans. Many of the mutations occurred within or upstream of genes associated with iron-related functions ( fur , tonB1 , fecA2 , fecA3 , and frpB3 ) or encoding outer membrane proteins ( alpA, oipA, fecA2, fecA3, frpB3 and cagY ). Most of the SNPs within coding regions (86%) were non-synonymous mutations. Several deletion or insertion mutations led to disruption of open reading frames, suggesting that the corresponding gene products are not required or are deleterious during chronic H. pylori colonization of the gerbil stomach. Five variants (three SNPs and two deletions) were detected in isolates from multiple animals, which suggests that these mutations conferred a selective advantage. One of the mutations (FurR88H) detected in isolates from multiple animals was previously shown to confer increased resistance to oxidative stress, and we now show that this SNP also confers a survival advantage when H. pylori is co-cultured with neutrophils. Collectively, these analyses allow the identification of mutations that are positively selected during H. pylori colonization of the gerbil model.
Publisher: BMJ
Date: 18-09-2018
DOI: 10.1136/GUTJNL-2017-313863
Abstract: Helicobacter pylori is the strongest risk factor for gastric cancer however, the majority of infected in iduals do not develop disease. Pathological outcomes are mediated by complex interactions among bacterial, host and environmental constituents, and two dietary factors linked with gastric cancer risk are iron deficiency and high salt. We hypothesised that prolonged adaptation of H. pylori to in vivo carcinogenic microenvironments results in genetic modification important for disease. Whole genome sequencing of genetically related H. pylori strains that differ in virulence and targeted H. pylori sequencing following prolonged exposure of bacteria to in vitro carcinogenic conditions were performed. A total of 180 unique single nucleotide polymorphisms (SNPs) were identified among the collective genomes when compared with a reference H. pylori genome. Importantly, common SNPs were identified in isolates harvested from iron-depleted and high salt carcinogenic microenvironments, including an SNP within fur (FurR88H). To investigate the direct role of low iron and/or high salt, H. pylori was continuously cultured in vitro under low iron or high salt conditions to assess fur genetic variation. Exposure to low iron or high salt selected for the FurR88H variant after only 5 days. To extend these results, fur was sequenced in 339 clinical H. pylori strains. Among the isolates examined, 17% (40/232) of strains isolated from patients with premalignant lesions harboured the FurR88H variant, compared with only 6% (6/107) of strains from patients with non-atrophic gastritis alone (p=0.0034). These results indicate that specific genetic variation arises within H. pylori strains during in vivo adaptation to conditions conducive for gastric carcinogenesis.
Publisher: American Society for Microbiology
Date: 21-07-2022
DOI: 10.1128/IAI.00004-22
Abstract: To evaluate potential effects of gastric inflammation on Helicobacter pylori ersification and evolution within the stomach, we experimentally infected Mongolian gerbils with an H. pylori strain in which Cag type IV secretion system (T4SS) activity is controlled by a TetR/ tetO system. Gerbils infected with H. pylori under conditions in which Cag T4SS activity was derepressed had significantly higher levels of gastric inflammation than gerbils infected under conditions with repressed Cag T4SS activity.
Publisher: American Society for Microbiology
Date: 16-02-2023
DOI: 10.1128/IAI.00420-22
Abstract: Both Helicobacter pylori infection and a high-salt diet are risk factors for gastric cancer. We previously showed that a mutation in fur (encoding the ferric uptake regulator variant Fur-R88H) was positively selected in H. pylori strains isolated from experimentally infected Mongolian gerbils receiving a high-salt diet.
Publisher: American Association for Cancer Research (AACR)
Date: 10-2018
DOI: 10.1158/1055-9965.EPI-18-0249
Abstract: Background: Antibody responses to Streptococcus gallolyticus subspecies gallolyticus (SGG) proteins, especially pilus protein Gallo2178, have been consistently associated with colorectal cancer risk. Previous case–control studies and prospective studies with up to 8 years of follow-up, however, were unable to decipher the temporality of antibody responses to SGG in the context of the long-term multistep development of colorectal cancer. In this study, we analyzed a large U.S. colorectal cancer cohort consortium with follow-up beyond 10 years for antibody responses to SGG. Methods: We applied multiplex serology to measure antibody responses to 9 SGG proteins in participants of 10 prospective U.S. cohorts (CLUE, CPSII, HPFS, MEC, NHS, NYUWHS, PHS, PLCO, SCCS, and WHI) including 4,063 incident colorectal cancer cases and 4,063 matched controls. Conditional logistic regression was used to assess whether antibody responses to SGG were associated with colorectal cancer risk, overall and by time between blood draw and diagnosis. Results: Colorectal cancer risk was increased among those with antibody responses to Gallo2178, albeit not statistically significant [OR, 1.23 95% confidence interval (CI), 0.99–1.52]. This association was stronger for cases diagnosed & years after blood draw (OR, 1.40 95% CI, 1.09–1.79), but was not found among cases diagnosed ≥10 years after blood draw (OR, 0.79 95% CI, 0.50–1.24). Conclusions: In a large cohort consortium, we reproduced the association of antibody responses to SGG Gallo2178 with colorectal cancer risk for in iduals diagnosed within 10 years after blood draw. Impact: This timing-specific finding suggests that antibody responses to SGG are associated with increased colorectal cancer risk only after tumorigenesis has begun. Cancer Epidemiol Biomarkers Prev 27(10) 1186–94. ©2018 AACR.
Location: United States of America
Location: United States of America
No related grants have been discovered for Timothy Cover.