Publications by authors named "Jennifer Adams-Haduch"

52 Publications

Association between Pre-Diagnostic Serum Bile Acids and Hepatocellular Carcinoma: The Singapore Chinese Health Study.

Cancers (Basel) 2021 May 28;13(11). Epub 2021 May 28.

Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.

Hepatocellular carcinoma (HCC) is a commonly diagnosed malignancy with poor prognosis. Rising incidence of HCC may be due to rising prevalence of metabolic dysfunction-associated fatty liver disease, where altered bile acid metabolism may be implicated in HCC development. Thirty-five bile acids were quantified using ultra-performance liquid chromatography triple-quadrupole mass spectrometry assays in pre-diagnostic serum of 100 HCC cases and 100 matched controls from the Singapore Chinese Health Study. Conditional logistic regression was used to assess associations for bile acid levels with risk of HCC. Conjugated primary bile acids were significantly elevated whereas the ratios of secondary bile acids over primary bile acids were significantly lower in HCC cases than controls. The respective odds ratios and 95% confidence intervals of HCC were 6.09 (1.75-21.21) for highest vs. lowest tertile of cholic acid species and 30.11 (5.88-154.31) for chenodeoxycholic acid species. Doubling ratio of taurine-over glycine-conjugated chenodeoxycholic acid was associated significantly with 40% increased risk of HCC whereas doubling ratio of secondary over primary bile acid species was associated with 30-40% reduced risk of HCC. In conclusion, elevated primary bile acids and taurine over glycine-conjugated ratios were strongly associated with HCC risk whereas the ratios of secondary bile acids over primary bile acids were inversely associated with HCC risk.
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http://dx.doi.org/10.3390/cancers13112648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198655PMC
May 2021

Low frequency variants associated with leukocyte telomere length in the Singapore Chinese population.

Commun Biol 2021 05 3;4(1):519. Epub 2021 May 3.

Genome Institute of Singapore, Agency for Science, Technology, and Research, Singapore, Singapore.

The role of low frequency variants associated with telomere length homeostasis in chronic diseases and mortalities is relatively understudied in the East-Asian population. Here we evaluated low frequency variants, including 1,915,154 Asian specific variants, for leukocyte telomere length (LTL) associations among 25,533 Singapore Chinese samples. Three East Asian specific variants in/near POT1, TERF1 and STN1 genes are associated with LTL (Meta-analysis P 2.49×10-6.94×10). Rs79314063, a missense variant (p.Asp410His) at POT1, shows effect 5.3 fold higher and independent of a previous common index SNP. TERF1 (rs79617270) and STN1 (rs139620151) are linked to LTL-associated common index SNPs at these loci. Rs79617270 is associated with cancer mortality [HR = 1.544 (1.173, 2.032), P = 0.018] and 4.76% of the association between the rs79617270 and colon cancer is mediated through LTL. Overall, genetically determined LTL is particularly associated with lung adenocarcinoma [HR = 1.123 (1.051, 1.201), P = 0.007]. Ethnicity-specific low frequency variants may affect LTL homeostasis and associate with certain cancers.
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http://dx.doi.org/10.1038/s42003-021-02056-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093266PMC
May 2021

Serum IL27 in Relation to Risk of Hepatocellular Carcinoma in Two Nested Case-Control Studies.

Cancer Epidemiol Biomarkers Prev 2021 Feb 17;30(2):388-395. Epub 2020 Nov 17.

UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.

Background: IL27 mRNA is highly enriched in the tissue of hepatocellular carcinoma. Overexpression of IL27 gene has been found to increase T-cell expression of inhibitory receptors, an immunosuppressive feature in tumor microenvironment, that promotes the development of hepatocellular carcinoma.

Methods: Two parallel case-control studies of hepatocellular carcinoma, each with 100 case-control pairs were conducted in the Singapore Chinese Health Study and the Shanghai Cohort Study to examine the association between serum IL27 levels and risk of developing hepatocellular carcinoma.

Results: The IL27 concentrations were significantly elevated in sera collected from study participants 4 to 5 years prior to the diagnosis of hepatocellular carcinoma in both cohort studies. Compared with the lowest tertile of IL27, odds ratios (OR) of hepatocellular carcinoma for the highest tertile of IL27 was 46.08 [95% confidence interval (CI), 4.68-453.86] in the Singapore Chinese Health Study and 19.09 (95% CI, 3.81-95.57) in the Shanghai Cohort Study (both <0.001). The corresponding ORs in both cohort studies were 42.47 (95% CI, 8.30-217.40) among individuals negative for hepatitis B surface antigen (HBsAg) and 242.46 (95% CI, 38.42-1,529.01) among those positive for HBsAg compared with the lowest tertile of interleukin-27 and negative HBsAg.

Conclusions: Levels of IL27 in prediagnostic sera were significantly associated with increased risk of hepatocellular carcinoma development.

Impact: IL27, through its immunosuppressive property, may play a significant role in the development of hepatocellular carcinoma. Serum levels of IL27 may be used as a biomarker for prediction of hepatocellular carcinoma development.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867592PMC
February 2021

Contribution of a Blood-Based Protein Biomarker Panel to the Classification of Indeterminate Pulmonary Nodules.

J Thorac Oncol 2021 02 31;16(2):228-236. Epub 2020 Oct 31.

McCombs Institute for the Early Detection and Treatment of Cancer, University of Texas MD Anderson Cancer Center, Houston, Texas.

Rationale: The workup and longitudinal monitoring for subjects presenting with pulmonary nodules is a pressing clinical problem. A blood-based biomarker panel potentially has utility for identifying subjects at higher risk for harboring a malignant nodule for whom additional workup would be indicated or subjects at reduced risk for whom imaging-based follow-up would be indicated.

Objectives: To assess whether a previously described four-protein biomarker panel, reported to improve assessment of lung cancer risk compared with a smoking-based lung cancer risk model, can provide discrimination between benign and malignant indeterminate pulmonary nodules.

Methods: A previously validated multiplex enzyme-linked immunoassay was performed on matched case and control samples from each cohort.

Measurements: The biomarker panel was tested in two case-control cohorts of patients presenting with indeterminate pulmonary nodules at the University of Pittsburgh Medical Center and the University of Texas Southwestern.

Main Results: In both cohorts, the biomarker panel resulted in improved prediction of lung cancer risk over a model on the basis of nodule size alone. Of particular note, the addition of the marker panel to nodule size greatly improved sensitivity at a high specificity in both cohorts.

Conclusions: A four-marker biomarker panel, previously validated to improve lung cancer risk prediction, was found to also have utility in distinguishing benign from malignant indeterminate pulmonary nodules. Its performance in improving sensitivity at a high specificity indicates potential utility of the marker panel in assessing likelihood of malignancy in otherwise indeterminate nodules.
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http://dx.doi.org/10.1016/j.jtho.2020.09.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218328PMC
February 2021

Association between Dietary Tomato Intake and the Risk of Hepatocellular Carcinoma: The Singapore Chinese Health Study.

Cancer Epidemiol Biomarkers Prev 2020 07 13;29(7):1430-1435. Epub 2020 Apr 13.

Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.

Background: Intake of tomato and/or lycopene has been associated with reduced risk of several cancers, but there is no report on the association with risk of hepatocellular carcinoma (HCC).

Methods: The associations of tomato and lycopene consumption with risk of HCC were examined in the Singapore Chinese Health Study, a prospective cohort of 63,257 Chinese ages 45 to 74 years at enrollment. Diet was assessed using a validated semiquantitative food frequency questionnaire. Cox proportional hazard regression models were used to estimate HR and its 95% confidence interval (CI) of HCC with the consumption of tomato and lycopene among all cohort participants, and unconditional logistic regression was used to assess the association by hepatitis B surface antigen (HBsAg) positivity in a nested case-control study.

Results: After a mean follow-up of 17.6 years, 561 incident HCC cases were identified. Higher tomato intake was associated with lower risk of HCC after adjustment for potential confounders ( < 0.001). Compared with the lowest quartile, HRs (95% CIs) of HCC for the second, third, and fourth quartile of tomato intake were 0.70 (0.56-0.88), 0.73 (0.58-0.92), and 0.63 (0.49-0.81). Among HBsAg-negative individuals, the inverse association remained ( = 0.03). There was no association between lycopene intake and HCC risk ( = 0.54).

Conclusions: Tomato intake may offer protection against the development of HCC, particularly among individuals without chronic infection with hepatitis B virus.

Impact: Tomato intake is a low-cost preventative measure against HCC that may help reduce risk due to increasing rates of nonalcoholic fatty liver disease.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685773PMC
July 2020

Urinary Cotinine Is as Good a Biomarker as Serum Cotinine for Cigarette Smoking Exposure and Lung Cancer Risk Prediction.

Cancer Epidemiol Biomarkers Prev 2020 01 4;29(1):127-132. Epub 2019 Nov 4.

Division of Cancer Control and Population Sciences, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania.

Background: Cotinine is a metabolite of nicotine. Serum and urinary cotinine are validated biomarkers for cigarette exposure. Their performance for lung cancer risk prediction has not been simultaneously examined in epidemiologic studies.

Methods: A nested case-control study, including 452 incident lung cancer cases and 452 smoking-matched controls in the Shanghai cohort study, was conducted. Mass spectrometry-based methods were used to quantify cotinine in serum and urine samples collected from current smokers at baseline, on average 10 years before cancer diagnosis of cases. Logistic regression was used to estimate ORs, 95% confidence intervals (CI), and AUC ROC for lung cancer associated with higher levels of cotinine.

Results: Serum and urinary cotinine levels were significantly higher in lung cancer cases than controls. Compared with the lowest quartile serum cotinine (≤0.40 nmol/mL), the OR of lung cancer for smokers in the highest quartiles (>1.39 nmol/mL) was 5.46 (95% CI, 3.38-8.81). Similarly, the OR was 5.49 (95% CI, 3.39-8.87) for highest (>16.38 nmol/mg creatinine) relative to the lowest quartile of urinary total cotinine (≤4.11 nmol/mg creatinine). A risk prediction model yielded an AUC of 0.72 (95% CI, 0.69-0.75) for serum cotinine and 0.72 (95% CI, 0.69-0.75) for urinary total cotinine combined with smoking history.

Conclusions: Urinary and serum cotinine have the same performance in prediction of lung cancer risk for current smokers.

Impact: Urinary cotinine is a noninvasive biomarker that can replace serum cotinine in risk prediction of future lung cancer risk for current smokers.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695222PMC
January 2020

Association between leukocyte telomere length and the risk of pancreatic cancer: Findings from a prospective study.

PLoS One 2019 29;14(8):e0221697. Epub 2019 Aug 29.

Division of Cancer Control and Population Sciences, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, United States of America.

Introduction: Telomeres and telomerase play important role in maintaining chromosome integrity and genomic stability. Recent epidemiologic data showed inconsistent findings which suggested that both short and long leukocyte telomeres could be associated with increased risk of pancreatic cancer. We prospectively examined the association between telomere length and pancreatic cancer risk in a population-based cohort study.

Methods: The Singapore Chinese Health Study recruited 63,257 Chinese aged 45 to 74 years from 1993 to 1998 in Singapore. Relative telomere length in peripheral blood leukocytes was quantified using a validated monochrome multiplex quantitative polymerase chain reaction method in 26,540 participants, including 116 participants who later developed pancreatic cancer after an average of 13 years of follow-up. Cox proportional hazard regression method was used to calculate hazard ratio (HR) and its 95% confidence interval (CI) of pancreatic cancer risk associated with telomere length, with adjustment for confounding factors.

Results: Longer telomeres were significantly associated with higher risk of pancreatic cancer (Ptrend = 0.02). Compared with lowest quartile, subjects with highest quartile of telomere length had an HR of 2.18 (95% CI: 1.25-3.80) for developing pancreatic cancer. In stratified analysis, this association remained among pancreatic adenocarcinoma patients but not among pancreatic non-adenocarcinoma patients. In continuous scale, the HRs and 95% CIs were 3.08 (1.17-8.11) for adenocarcinoma patients and 1.47 (0.43-5.06) for non-adenocarcinoma patients. The HRs and 95% CIs of the highest quartile of telomere length, compared with the lowest quartile, for adenocarcinoma and non-adenocarcinoma were 2.50 (1.22-5.13) and 1.63 (0.66-4.03), respectively. The length of follow-up from the collection of blood for the measurement of telomere length to the diagnosis of cancer (median = 8.0, range: from 5.0 months to 16.2 years) had no significant impact on the association between telomere length and pancreatic cancer risk.

Conclusions: The present study demonstrates that longer telomeres are associated with increased risk of overall pancreatic cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221697PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715276PMC
March 2020

Loci for human leukocyte telomere length in the Singaporean Chinese population and trans-ethnic genetic studies.

Nat Commun 2019 06 6;10(1):2491. Epub 2019 Jun 6.

Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore.

Genetic factors underlying leukocyte telomere length (LTL) may provide insights into telomere homeostasis, with direct links to disease susceptibility. Genetic evaluation of 23,096 Singaporean Chinese samples identifies 10 genome-wide loci (P < 5 × 10). Several of these contain candidate genes (TINF2, PARP1, TERF1, ATM and POT1) with potential roles in telomere biology and DNA repair mechanisms. Meta-analyses with additional 37,505 European individuals reveals six more genome-wide loci, including associations at MPHOSPH6, NKX2-3 and TYMS. We demonstrate that longer LTL associates with protection against respiratory disease mortality [HR = 0.854(0.804-0.906), P = 1.88 × 10] in the Singaporean Chinese samples. We further show that the LTL reducing SNP rs7253490 associates with respiratory infections (P = 7.44 × 10) although this effect may not be strongly mediated through LTL. Our data expands on the genetic basis of LTL and may indicate on a potential role of LTL in immune competence.
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http://dx.doi.org/10.1038/s41467-019-10443-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554354PMC
June 2019

Association Between Leukocyte Telomere Length and Colorectal Cancer Risk in the Singapore Chinese Health Study.

Clin Transl Gastroenterol 2019 05;10(5):1-9

Division of Cancer Control and Population Sciences, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Objectives: Telomeres and telomerase play important roles in maintaining chromosome integrity and genomic stability. To address a lack of consensus about the association between leukocyte telomere length and colorectal cancer, we investigated this association in the Singapore Chinese Health Study.

Methods: Relative telomere length in white blood cells was quantified using a validated quantitative polymerase chain reaction method in 26,761 participants, including 776 incident colorectal cancer cases. The Cox proportional hazard regression method was used to calculate the hazard ratio and the corresponding 95% confidence interval (CI) for colorectal cancer associated with longer telomeres.

Results: Longer telomeres were significantly associated with a higher risk of colorectal cancer (Ptrend = 0.02). Compared with the lowest quartile, subjects with the highest quartile of telomere length had a hazard ratio of 1.32 (95% CI: 1.08-1.62) for developing colorectal cancer. The corresponding elevation in rectal cancer risk for the highest quartile of telomere length was 71% (95% CI: 22-140, Ptrend = 0.02). There was no statistically significant association between telomere length and risk of colon cancer.

Discussion: This large cohort study of Singapore Chinese, the first study using a cohort study design with more than 26,000 participants that yielded 776 incidence colorectal cancer cases during 12 years of follow-up, provides evidence in support of longer telomeres being associated with a higher risk of colorectal cancer, particularly rectal cancer.
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http://dx.doi.org/10.14309/ctg.0000000000000043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602767PMC
May 2019

Prediagnostic blood levels of organochlorines and risk of non-Hodgkin lymphoma in three prospective cohorts in China and Singapore.

Int J Cancer 2020 02 9;146(3):839-849. Epub 2019 May 9.

Division of Cancer Epidemiology and Genetics, NCI, NIH, DHHS, Rockville, MD.

Specific organochlorines (OCs) have been associated with non-Hodgkin lymphoma (NHL) with varying degrees of evidence. These associations have not been evaluated in Asia, where the high exposure and historical environmental contamination of certain OC pesticides (e.g., dichlorodiphenyltrichloroethane [DDT], hexachlorocyclohexane [HCH]) are different from Western populations. We evaluated NHL risk and prediagnostic blood levels of OC pesticides/metabolites and polychlorinated biphenyl congeners in a case-control study of 167 NHL cases and 167 controls nested within three prospective cohorts in Shanghai and Singapore. Conditional logistic regression was used to analyze lipid-adjusted OC levels and NHL risk. Median levels of p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE), the primary DDT metabolite, and β-HCH were up to 12 and 65 times higher, respectively, in samples from the Asian cohorts compared to several cohorts in the United States and Norway. An increased risk of NHL was observed among those with higher β-HCH levels both overall (3rd vs. 1st tertile OR = 1.8, 95%CI = 1.0-3.2; p = 0.049) and after excluding cases diagnosed within 2 years of blood collection (3rd vs. 1st tertile OR = 2.0, 95%CI = 1.1-3.9; p = 0.03), and the association was highly consistent across the three cohorts. No significant associations were observed for other OCs, including p,p'-DDE. Our findings provide support for an association between β-HCH blood levels and NHL risk. This is a concern because substantial quantities of persistent, toxic residues of HCH are present in the environment worldwide. Although there is some evidence that DDT is associated with NHL, our findings for p,p'-DDE do not support an association.
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http://dx.doi.org/10.1002/ijc.32350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244652PMC
February 2020

Prediagnostic levels of urinary 8-epi-prostaglandin F2α and prostaglandin E2 metabolite, biomarkers of oxidative damage and inflammation, and risk of hepatocellular carcinoma.

Carcinogenesis 2019 08;40(8):989-997

Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.

Chronic inflammation and oxidative stress play pivotal roles in the pathogenesis of hepatocellular carcinoma (HCC). We conducted a nested case-control study of 347 HCC cases and 691 matched controls within a prospective cohort of 18 244 Chinese men in Shanghai, China. The concentrations of 8-epi-prostaglandin F2α (8-epi-PGF2α), a biomarker of oxidative stress, and prostaglandin E2 (PGE2) metabolite (PGE-M), a biomarker of the inflammation mediator PGE2, were determined in baseline urine samples using validated mass spectrometry assays. 8-epi-PGF2α levels were significantly higher in HCC cases than control subjects (geometric means 0.92 versus 0.80 pmol/mg creatinine, P < 0.001). The relative risks of developing HCC for the highest relative to the lowest quartile of 8-epi-PGF2α were 2.55 (95% confidence interval = 1.62-4.01, Ptrend < 0.001). This positive 8-epi-PGF2α-HCC risk association was independent of smoking status, alcohol consumption and hepatitis B or liver cirrhosis and was present 10 years before the clinical manifestation of HCC. This study did not find any significant association between urinary PEG-M and HCC risk. This study provides direct evidence in support of the critical role of oxidative stress in the development of HCC regardless of its underlying causes.
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http://dx.doi.org/10.1093/carcin/bgy180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967701PMC
August 2019

Nicotine-'-Oxidation by Flavin Monooxygenase Enzymes.

Cancer Epidemiol Biomarkers Prev 2019 02 31;28(2):311-320. Epub 2018 Oct 31.

Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington.

Background: The major mode of metabolism of nicotine is by hydroxylation via cytochrome P450 (CYP) 2A6, but it can also undergo glucuronidation by UDP-glucuronosyltransferases and oxidation by flavin monooxygenases (FMO). The goal of this study was to examine the potential importance of FMOs in nicotine metabolism and assess the potential impact of missense polymorphisms in active FMOs on nicotine-'-oxide (NOX) formation.

Methods: Urine samples from 106 current Chinese smokers were analyzed for nicotine metabolites by mass spectrometry. Wild-type s 1-5 and their most prevalent nonsynonymous variants were cloned and overexpressed in HEK293 cells, and were tested in oxidation reactions against nicotine.

Results: A strong inverse correlation was observed between the ratio of urinary 3'-hydroxycotinine/cotinine, a measure of CYP2A6 activity, and the urinary levels of NOX alone ( = -0.383; < 0.001) or NOX measured as a ratio of total nicotine metabolites ( = -0.414; < 0.001) in smokers. In addition to FMO1 and FMO3, the functional FMO2 isoform was active against nicotine, whereas FMO4 and FMO5 exhibited low activity against nicotine ( > 5.0 mmol/L). Significant ( < 0.05) decreases in '-oxidation activity ( / ) were observed for the FMO1, FMO3, FMO3, FMO3, and FMO3 variants when compared with their respective wild-type isoforms; the truncated FMO2 isoform exhibited no enzyme activity.

Conclusions: These data indicate that increases in nicotine-'-oxidation occur in subjects with deficient CYP2A6 activity, and that several FMO enzymes are active in nicotine-'-oxidation.

Impact: Several common missense FMO variants are associated with altered enzyme activity against nicotine and may play an important role in nicotine metabolism in low-CYP2A6 activity subjects.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-0669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363832PMC
February 2019

Relationship of the oxidative damage biomarker 8-epi-prostaglandin F2α to risk of lung cancer development in the Shanghai Cohort Study.

Carcinogenesis 2018 07;39(7):948-954

Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.

It has been hypothesized that the pathogenesis of lung cancer induced by cigarette smoking involves oxidative damage by free radicals. Epidemiological data on biomarkers of oxidative damage and risk of lung cancer development are sparse. A nested case-control study of 610 lung cancer cases and 610 matched controls was conducted within a prospective cohort of 18 244 Chinese men in Shanghai, China. The concentrations of 8-epi-prostaglandin F2α (8-epiPGF2α), a biomarker of oxidative stress, were determined in baseline urine samples using a validated mass-spectrometry assay. Current smokers had significantly higher level of 8-epiPGF2α than former smokers or never smokers (P < 0.001). 8-epiPGF2α levels were significantly higher in lung cancer cases than their smoking-matched controls in former and current smokers, but not different in never smokers (P for interaction = 0.019). The relative risks of developing lung cancer for former and current smokers in the highest relative to the lowest quartile of 8-epiPGF2α were 5.25 (Ptrend = 0.035) and 1.99 (Ptrend =0.007), respectively. The effect of 8-epiPGF2α and biomarkers of cigarette smoke exposure on lung cancer risk was additive; the relative risk was 5.33 (95% confidence interval = 2.65-7.51) for current smokers with the highest thirds of 8-epiPGF2α and total cotinine compared with their lowest thirds. Smokers with a heightened state of oxidative stress in response to the insults of cigarette smoking may be more susceptible to smoking-induced lung carcinogenesis.
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http://dx.doi.org/10.1093/carcin/bgy060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190890PMC
July 2018

Serologic markers of viral infection and risk of non-Hodgkin lymphoma: A pooled study of three prospective cohorts in China and Singapore.

Int J Cancer 2018 08 6;143(3):570-579. Epub 2018 Apr 6.

Division of Cancer Epidemiology and Genetics, NCI, NIH, DHHS, Rockville, MD.

Incidence rates of non-Hodgkin lymphoma (NHL) and distributions of certain viruses differ between East Asian and Western populations. There are limited data on associations between serologic markers of multiple viral infections in pre-diagnostic blood and NHL risk in East Asians. We conducted a nested case-control study of 214 NHL cases and 214 matched controls from three population-based prospective cohorts in Shanghai and Singapore. Antibodies against antigens from herpesviruses, Hepatitis B (HBV) and C (HCV) virus and polyomaviruses were measured in plasma or serum using fluorescent bead-based multiplex assays. Conditional logistic regression was used to evaluate associations between antibody levels and NHL risk. An increased risk of NHL was observed for higher compared to lower EA-D (Odds Ratio (OR) = 2.04, 95% Confidence Interval (CI) = 1.10-3.81; p  = 0.005) and ZEBRA (OR = 2.17, 95% CI = 0.96-4.89; p  = 0.008) Epstein-Barr Virus (EBV) antibodies, as well as for antibody seropositivity against the IE1A human herpesvirus-6 (HHV-6) antigen (OR = 1.85, 95% CI = 1.04-3.29). An increased NHL risk was also observed for higher compared to lower antibodies against the HBV-HBc and HBe antigens. An increased risk of NHL in relation to EBV and HBV infection in East Asians is consistent with findings in several studies of Western populations, suggesting similar viral risk factors for NHL in these diverse populations with distinct patterns of NHL. The association between HHV-6 antibodies and NHL has not previously been reported in a prospective study in this population and will require replication.
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http://dx.doi.org/10.1002/ijc.31385DOI Listing
August 2018

Leukocyte telomere length in relation to risk of lung adenocarcinoma incidence: Findings from the Singapore Chinese Health Study.

Int J Cancer 2018 06 25;142(11):2234-2243. Epub 2018 Jan 25.

Duke-NUS Medical School Singapore, Singapore, Singapore.

Telomeres are crucial in the maintenance of chromosome integrity and genomic stability. Critically short telomeres can trigger programed cell death while cells with longer telomeres may have increased likelihood of replicative errors, resulting in genetic mutations and chromosomal alterations, and ultimately promoting oncogenesis. Data on telomere length and lung cancer risk from large prospective cohort studies are spare. Relative telomere length in peripheral blood leukocytes was quantified using a validated monochrome multiplex quantitative polymerase chain reaction (qPCR) method in 26,540 participants of the Singapore Chinese Health Study. After a follow-up of 12 years, 654 participants developed lung cancer including 288 adenocarcinoma, 113 squamous cell carcinoma and 253 other/unknown histological type. The Cox proportional hazard regression was used to estimate hazard ratio (HR) and 95% confidence interval (CI). HR of lung adenocarcinoma for individuals in the highest comparing the lowest 20 percentile of telomere length was 2.84 (95% CI 1.94-4.14, p  < 0.0001). This positive association was present in never smokers (p  < 0.0001), ever smokers (p  = 0.0010), men (p  = 0.0003), women (p  < 0.0001), and in shorter (p  = 0.0002) and longer (p  = 0.0001) duration of follow-up. There was no association between telomere length and risk of squamous cell carcinoma or other histological type of lung cancer in all or subgroups of individuals. The agreement of results from this prospective cohort study with those of previous prospective studies and Mendelian randomization studies suggest a possible etiological role of telomere length in the development of lung adenocarcinoma.
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http://dx.doi.org/10.1002/ijc.31251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5893405PMC
June 2018

CYP2A6 genetic polymorphisms and biomarkers of tobacco smoke constituents in relation to risk of lung cancer in the Singapore Chinese Health Study.

Carcinogenesis 2017 04;38(4):411-418

Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.

Cytochrome P450 2A6 (CYP2A6) catalyzes the metabolism of nicotine and the tobacco-specific lung carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Genetic variation in CYP2A6 may affect smoking behavior and contribute to lung cancer risk. A nested case-control study of 197 lung cancer cases and 197 matched controls was conducted within a prospective cohort of 63 257 Chinese men and women in Singapore. Quantified were five genetic variants of CYP2A6 (*1A, *4, *7, *9 and *12) and urinary metabolites of nicotine [total nicotine, total cotinine, total trans-3'-hydroxycotinine (3HC)] and NNK (total NNAL, free NNAL, NNAL-glucuronide, NNAL-N-glucuronide, and NNAL-O-glucuronide). Higher urinary metabolites of nicotine and NNK were significantly associated with a 2- to 3-fold increased risk of lung cancer after adjustment for smoking intensity and duration. Lower CYP2A6-determined nicotine metabolizer status was significantly associated with a lower ratio of total 3HC over total cotinine, lower total nicotine equivalent and reduced risk of developing lung cancer (all Ptrend < 0.001). Compared with normal metabolizers, odds ratios (95% confidence intervals) of developing lung cancer for intermediate, slow and poor metabolizers determined by CYP2A6 genotypes were 0.85 (0.41-1.77), 0.55 (0.28-1.08) and 0.32 (0.15-0.70), respectively, after adjustment for smoking intensity and duration and urinary total nicotine equivalents. Thus the reduced risk of lung cancer in smokers with lower CYP2A6 activity may be explained by lower consumption of cigarettes, less intense smoking and reduced CYP2A6-catalyzed activation of the tobacco-specific lung carcinogen NNK.
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http://dx.doi.org/10.1093/carcin/bgx012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6248819PMC
April 2017

Clinical Trial of 2-Phenethyl Isothiocyanate as an Inhibitor of Metabolic Activation of a Tobacco-Specific Lung Carcinogen in Cigarette Smokers.

Cancer Prev Res (Phila) 2016 05 7;9(5):396-405. Epub 2016 Mar 7.

Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.

2-Phenethyl isothiocyanate (PEITC), a natural product found as a conjugate in watercress and other cruciferous vegetables, is an inhibitor of the metabolic activation and lung carcinogenicity of the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in F344 rats and A/J mice. We carried out a clinical trial to determine whether PEITC also inhibits the metabolic activation of NNK in smokers. Cigarette smokers were recruited and asked to smoke cigarettes containing deuterium-labeled [pyridine-D4]NNK for an acclimation period of at least 1 week. Then subjects were randomly assigned to one of two arms: PEITC followed by placebo, or placebo followed by PEITC. During the 1-week treatment period, each subject took PEITC (10 mg in 1 mL of olive oil, 4 times per day). There was a 1-week washout period between the PEITC and placebo periods. The NNK metabolic activation ratio [pyridine-D4]hydroxy acid/total [pyridine-D4]NNAL was measured in urine samples to test the hypothesis that PEITC treatment modified NNK metabolism. Eighty-two smokers completed the study and were included in the analysis. Overall, the NNK metabolic activation ratio was reduced by 7.7% with PEITC treatment (P = 0.023). The results of this trial, while modest in effect size, provide a basis for further investigation of PEITC as an inhibitor of lung carcinogenesis by NNK in smokers. Cancer Prev Res; 9(5); 396-405. ©2016 AACR.
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http://dx.doi.org/10.1158/1940-6207.CAPR-15-0380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854759PMC
May 2016

Genetic determinants of cytochrome P450 2A6 activity and biomarkers of tobacco smoke exposure in relation to risk of lung cancer development in the Shanghai cohort study.

Int J Cancer 2016 May 21;138(9):2161-71. Epub 2016 Jan 21.

Masonic Cancer Center, University of Minnesota, Minneapolis, MN.

Cytochrome P450 2A6 (CYP2A6) catalyzes nicotine metabolism and contributes to the metabolism of the tobacco-specific lung carcinogen, NNK. Genetic variation in CYP2A6 may affect smoking behavior and contribute to lung cancer risk. A nested case-control study of 325 lung cancer cases and 356 controls was conducted within a prospective cohort of 18,244 Chinese men in Shanghai, China. Quantified were 4 allelic variants of CYP2A6 [*1(+51A), *4, *7, and *9] and urinary total nicotine, total cotinine, total trans-3'-hydroxycotinine (3HC) and total NNAL (an NNK metabolite). Calculated were total nicotine equivalents (TNE), the sum of total nicotine, total cotinine and total 3HC and the total 3HC:total cotinine ratio as a measure of CYP2A6 activity. The nicotine metabolizer status (normal, intermediate, slow and poor) was determined by CYP2A6 genotypes. The smoking-adjusted odds ratios (95% confidence intervals) of lung cancer for the highest vs lowest quartile of total nicotine, total cotinine, total 3HC, TNE and total NNAL were 3.03 (1.80-5.10), 4.70 (2.61-8.46), 4.26 (2.37-7.68), 4.71 (2.61-8.52), and 3.15 (1.86-5.33) (all Ptrend  < 0.001), respectively. Among controls CYP2A6 poor metabolizers had a 78% lower total 3HC:total cotinine ratio and 72% higher total nicotine (Ptrend ≤ 0.002). Poor metabolizers had an odds ratio of 0.64 (95% confidence interval = 0.43-0.97) for lung cancer, which was statistically nonsignificant (odds ratio = 0.74, 95% confidence interval = 0.48-1.15) after adjustment for urinary TNE and smoking intensity and duration. The lower lung cancer risk observed in CYP2A6 poor metabolizers is partially explained by the strong influence of CYP2A6 genetic polymorphisms on nicotine uptake and metabolism.
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http://dx.doi.org/10.1002/ijc.29963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5155585PMC
May 2016

Soluble levels of CD27 and CD30 are associated with risk of non-Hodgkin lymphoma in three Chinese prospective cohorts.

Int J Cancer 2015 Dec 26;137(11):2688-95. Epub 2015 Jun 26.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD.

Prospective studies conducted in Western populations have suggested that alterations in soluble CD27 (sCD27) and soluble CD30 (sCD30), two markers indicative of B-cell activation, are associated with risk of non-Hodgkin lymphoma (NHL). Given that the characteristics of NHL in East Asia differ from the West and mechanistic commonalities between these populations with respect to the role of intermediate endpoint biomarkers in lymphomagenesis have not been explored, we conducted a pooled nested case-control study from three prospective studies of Chinese men and women including 218 NHL cases and 218 individually matched controls. Compared with the lowest quartile, ORs (95% CIs) for the second, third and fourth quartiles of sCD27 were 1.60 (0.83-3.09), 1.94 (0.98-3.83) and 4.45 (2.25-8.81), respectively (p(trend) = 0.000005). The corresponding ORs for sCD30 were 1.74 (0.85-3.58), 1.86 (0.94-3.67) and 5.15 (2.62-10.12; p(trend) = 0.0000002). These associations remained statistically significant in individuals diagnosed with NHL 10 or more years after blood draw. Notably, the magnitude of the associations with NHL risk was very similar to those in Western populations in previous studies. These findings of the similar association between sCD27 or sCD30 and NHL risk across different populations support an important underlying mechanism of B-cell activation in lymphomagenesis.
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http://dx.doi.org/10.1002/ijc.29637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4898881PMC
December 2015

Community-associated extended-spectrum β-lactamase-producing Escherichia coli infection in the United States.

Clin Infect Dis 2013 Mar 13;56(5):641-8. Epub 2012 Nov 13.

Division of Infectious Diseases, University of Pittsburgh Medical Center, PA 15261, USA.

Background. The occurrence of community-associated infections due to extended-spectrum β-lactamase (ESBL)-producing Escherichia coli has been recognized as a major clinical problem in Europe and other regions. Methods. We conducted a prospective observational study to examine the occurrence of community-associated infections due to ESBL-producing E. coli at centers in the United States. Five academic and community hospitals and their affiliated clinics participated in this study in 2009 and 2010. Sites of acquisition of the organisms (community-associated or healthcare-associated), risk factors, and clinical outcome were investigated. Screening for the global epidemic sequence type (ST) 131 and determination of the ESBL types was conducted by polymerase chain reaction and sequencing. Results. Of the 291 patients infected or colonized with ESBL-producing E. coli as outpatients or within 48 hours of hospitalization, 107 (36.8%) had community-associated infection (81.5% of which represented urinary tract infection), while the remainder had healthcare-associated infection. Independent risk factors for healthcare-associated infection over community-associated infection were the presence of cardiovascular disease, chronic renal failure, dementia, solid organ malignancy, and hospitalization within the previous 12 months. Of the community-associated infections, 54.2% were caused by the globally epidemic ST131 strain, and 91.3% of the isolates produced CTX-M-type ESBL. Conclusions. A substantial portion of community-onset, ESBL-producing E. coli infections now occur among patients without discernible healthcare-associated risk factors in the United States. This epidemiologic shift has implications for the empiric management of community-associated infection when involvement of E. coli is suspected.
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http://dx.doi.org/10.1093/cid/cis942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3563390PMC
March 2013

The role of horizontal gene transfer in the dissemination of extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae isolates in an endemic setting.

Diagn Microbiol Infect Dis 2012 Sep 20;74(1):34-8. Epub 2012 Jun 20.

Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

The contribution of horizontal gene transmission (HGT) in the emergence and spread of extended-spectrum beta-lactamase (ESBL)-producing Gram-negative bacteria during periods of endemicity is unclear. Over a 12-month period, rectal colonization with SHV-5- and SHV-12-producing Escherichia coli and Klebsiella pneumoniae was quantified among a cohort of residents in a long-term care facility. Demographic and clinical data were collected on colonized residents. Transferability of SHV-encoding plasmids and pulsed-field gel electrophoresis were performed to quantify the contribution of HGT and cross-transmission, respectively. A total of 25 (12%) of 214 enrolled patients were colonized with 11 SHV-5- and 17 SVH-12-producing E. coli and K. pneumoniae. Clonally related isolates were detected among multiple residents residing on the same and different wards. Among 12 clonally distinct isolates, HGT of SHV-5- and SHV-12-encoding plasmids was identified among 6 (50%) isolates. HGT among clonally distinct strains contributes to the transmission dynamics of these ESBL-producing Gram-negative bacteria and should be considered when evaluating the spread of these pathogens.
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http://dx.doi.org/10.1016/j.diagmicrobio.2012.05.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3427399PMC
September 2012

Features of infections due to Klebsiella pneumoniae carbapenemase-producing Escherichia coli: emergence of sequence type 131.

Clin Infect Dis 2012 Jul 4;55(2):224-31. Epub 2012 Apr 4.

Division of Infectious Diseases, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA.

Background: Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae has become endemic in many US hospitals. On the other hand, KPC-producing Escherichia coli remains rare.

Methods: We studied infection or colonization due to KPC-producing E. coli identified at our hospital between September 2008 and February 2011. A case-control study was conducted to document clinical features associated with this organism. Susceptibility testing, sequencing of β-lactamase genes, pulsed-field gel electrophoresis, multilocus sequence typing, and plasmid analysis were performed for characterization of the isolates.

Results: Thirteen patients with KPC-producing E. coli were identified. The patients had multiple comorbid conditions and were in hospital for variable periods of time before KPC-producing E. coli was identified. The presence of liver diseases was independently associated with recovery of KPC-producing E. coli when compared with extended-spectrum β-lactamase-producing E. coli. The isolates showed variable susceptibility to carbapenems. Seven isolates belonged to sequence type (ST) 131, which is the international epidemic, multidrug-resistant clone, but their plasmid profiles were diverse. KPC-producing organisms other than E. coli were isolated within 1 month from 5 of the patients. The KPC-encoding plasmids were highly related in 3 of them, suggesting the occurrence of their interspecies transfer.

Conclusions: KPC-producing E. coli infections occur in severely ill patients who are admitted to the hospital. Acquisition of the KPC-encoding plasmids by the ST 131 clone, reported here for the first time to our knowledge in the United States, seems to represent multiple independent events. These plasmids are often shared between E. coli and other species.
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http://dx.doi.org/10.1093/cid/cis387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3491773PMC
July 2012

Clinical and microbiologic characteristics of cephalosporin-resistant Escherichia coli at three centers in the United States.

Antimicrob Agents Chemother 2012 Apr 30;56(4):1870-6. Epub 2012 Jan 30.

Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

We investigated the clinical and microbiologic features of 300 cases of cephalosporin-resistant Escherichia coli producing extended-spectrum β-lactamase (ESBL) or plasmid-mediated AmpC β-lactamase (pAmpC) at three medical centers in the United States. Solid-organ malignancy, connective tissue disease, and a recent history of surgery were more common among pAmpC-producing cases (n = 49), whereas urinary catheter at enrollment, diabetes, and hospitalization in the past year were more common among ESBL-producing cases (n = 233). The factors independently associated with clinical outcome were the following: the presence of cardiovascular disease (odds ratio [OR], 2.88; 95% confidence interval [CI], 1.29 to 6.43), intra-abdominal infection (OR, 6.35; 95% CI, 1.51 to 26.7), other or multiples sources of infection (OR, 8.12; 95% CI, 2.3 to 28.6), age of 65 years or greater (OR, 0.43; 95% CI, 0.2 to 0.95), favorable baseline health status (OR, 0.39; 95% CI, 0.16 to 0.95), and appropriate empirical antimicrobial therapy given in the first 72 h (OR, 0.42; 95% CI, 0.20 to 0.88). β-Lactamase genes responsible for cephalosporin resistance were identified in 291 cases. CTX-M-type ESBLs accounted for 72.0%. Of those, 88.0% were CTX-M-15. The next most common type was CMY-type pAmpC (16.7%), followed by SHV- and TEM-type ESBLs (6.3 and 1.3%, respectively). Seven cases (2.3%) had KPC-type β-lactamase. Ertapenem, imipenem, meropenem, doripenem, piperacillin-tazobactam, amikacin, nitrofurantoin, and tigecycline were highly active, with greater than 90% of the isolates being susceptible. Cefepime was less active, with only 74.2% being susceptible due to the predominance of CTX-M-15. These findings have implications in the selection of appropriate empirical therapy when infection due to cephalosporin-resistant E. coli is suspected.
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http://dx.doi.org/10.1128/AAC.05650-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3318325PMC
April 2012

Treatment outcome of bacteremia due to KPC-producing Klebsiella pneumoniae: superiority of combination antimicrobial regimens.

Antimicrob Agents Chemother 2012 Apr 17;56(4):2108-13. Epub 2012 Jan 17.

Division of Infectious Diseases, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

Klebsiella pneumoniae producing Klebsiella pneumoniae carbapenemase (KPC) has been associated with serious infections and high mortality. The optimal antimicrobial therapy for infection due to KPC-producing K. pneumoniae is not well established. We conducted a retrospective cohort study to evaluate the clinical outcome of patients with bacteremia caused by KPC-producing K. pneumoniae. A total of 41 unique patients with blood cultures growing KPC-producing K. pneumoniae were identified at two medical centers in the United States. Most of the infections were hospital acquired (32; 78%), while the rest of the cases were health care associated (9; 22%). The overall 28-day crude mortality rate was 39.0% (16/41). In the multivariate analysis, definitive therapy with a combination regimen was independently associated with survival (odds ratio, 0.07 [95% confidence interval, 0.009 to 0.71], P = 0.02). The 28-day mortality was 13.3% in the combination therapy group compared with 57.8% in the monotherapy group (P = 0.01). The most commonly used combinations were colistin-polymyxin B or tigecycline combined with a carbapenem. The mortality in this group was 12.5% (1/8). Despite in vitro susceptibility, patients who received monotherapy with colistin-polymyxin B or tigecycline had a higher mortality of 66.7% (8/12). The use of combination therapy for definitive therapy appears to be associated with improved survival in bacteremia due to KPC-producing K. pneumoniae.
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http://dx.doi.org/10.1128/AAC.06268-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3318350PMC
April 2012

Molecular epidemiology of carbapenem-nonsusceptible Acinetobacter baumannii in the United States.

J Clin Microbiol 2011 Nov 14;49(11):3849-54. Epub 2011 Sep 14.

Division of Infectious Diseases, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA.

Acinetobacter baumannii is emerging as an important nosocomial pathogen worldwide. We report molecular epidemiology of 65 carbapenem-nonsusceptible A. baumannii isolates identified from hospitals in New York, Pennsylvania, Florida, Missouri, Nevada, and California between 2008 and 2009. All isolates were subjected to pulsed-field gel electrophoresis (PFGE). Select isolates then underwent multilocus sequence typing (MLST). While the PFGE patterns tended to cluster within each hospital, sequence types (STs) belonging to the clonal complex 92 (CC92) and the pan-European clonal lineage II (EUII; worldwide clonal lineage 2) were predominant in all hospitals. Of them, ST122 and ST208 were the most common and were found in four of the six hospitals. Isolates belonging to the pan-European clonal lineages I and III were identified in one hospital each. Carbapenemase-encoding genes bla(OXA-23) and/or ISAba1-bla(OXA-51-like) were present among the majority of isolates. These findings suggest that carbapenem-nonsusceptible A. baumannii isolates found in U.S. hospitals constitute part of the global epidemic driven by CC92, but have unique STs other than ST92, which may be spreading by means of patient transfer between health care facilities within the United States.
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http://dx.doi.org/10.1128/JCM.00619-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3209126PMC
November 2011

Colistin-resistant, Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae belonging to the international epidemic clone ST258.

Clin Infect Dis 2011 Aug;53(4):373-6

Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

Five cases of infection due to colistin-resistant, Klebsiella pneumoniae carbapenemase-producing K. pneumoniae belonging to the international epidemic clone ST258 occurred over a 4-month period. These cases likely represented both emergence of resistance and transmission of resistant organism. The colistin-resistant isolates were able to persist in the absence of selective pressure in vitro.
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http://dx.doi.org/10.1093/cid/cir401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3202324PMC
August 2011

Extended-spectrum AmpC cephalosporinase in Acinetobacter baumannii: ADC-56 confers resistance to cefepime.

Antimicrob Agents Chemother 2011 Oct 25;55(10):4922-5. Epub 2011 Jul 25.

Division of Infectious Diseases, University of Pittsburgh School of Medicine, Scaife Hall S829, 3550 Terrace Street, Pittsburgh, PA 15261, USA.

ADC-56, a novel extended-spectrum AmpC (ESAC) β-lactamase, was identified in an Acinetobacter baumannii clinical isolate. ADC-56 possessed an R148Q change compared with its putative progenitor, ADC-30, which enabled it to hydrolyze cefepime. Molecular modeling suggested that R148 interacted with Q267, E272, and I291 through a hydrogen bond network which constrained the H-10 helix. This permitted cefepime to undergo conformational changes in the active site, with the carboxyl interacting with R340, likely allowing for better binding and turnover.
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http://dx.doi.org/10.1128/AAC.00704-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186995PMC
October 2011

PME-1, an extended-spectrum β-lactamase identified in Pseudomonas aeruginosa.

Antimicrob Agents Chemother 2011 Jun 14;55(6):2710-3. Epub 2011 Mar 14.

Division of Infectious Diseases, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

A novel extended-spectrum β-lactamase (ESBL) was identified in a Pseudomonas aeruginosa clinical isolate obtained from a patient admitted to a hospital in Pennsylvania in 2008. The patient had a prolonged hospitalization in a hospital in Dubai, United Arab Emirates, before being transferred to the United States. The novel ESBL, designated PME-1 (Pseudomonas aeruginosa ESBL 1), is a molecular class A, Bush-Jacoby-Medeiros group 2be enzyme and shared 50, 43, and 41% amino acid identity with the L2 β-lactamase of Stenotrophomonas maltophilia, CTX-M-9, and KPC-2, respectively. PME-1 conferred clinically relevant resistance to ceftazidime, cefotaxime, cefepime, and aztreonam in P. aeruginosa PAO1 but not to carbapenems. Purified PME-1 showed good hydrolytic activity against ceftazidime, cefotaxime, and aztreonam, while activity against carbapenems and cefepime could not be measured. PME-1 was inhibited well by β-lactamase inhibitors, including clavulanic acid, sulbactam, and tazobactam. The bla(PME-1) gene was carried by an approximately 9-kb plasmid and flanked by tandem ISCR24 elements.
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http://dx.doi.org/10.1128/AAC.01660-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3101390PMC
June 2011
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