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Boursi B.,University of Pennsylvania | Boursi B.,The Integrated Cancer Prevention Center | Boursi B.,Tel Aviv University | Haynes K.,University of Pennsylvania | And 2 more authors.
Pharmacoepidemiology and Drug Safety | Year: 2014

Purpose: Cardiac glycosides affect several pathways central for tumor formation. We sought to evaluate the association between digoxin use and colorectal cancer (CRC) risk. Methods: We conducted a nested case-control study using The Health Improvement Network (THIN), a medical record database representative of the broader UK population. Study cases were defined as those with a diagnostic code for CRC. Each case was matched to up to four eligible controls on age, sex, practice site, and duration of follow-up before index date using incidence density sampling. Exposure of interest was digoxin therapy before index date. The odds ratios (ORs) and 95% confidence intervals (CIs) for CRC associated with digoxin use were estimated using conditional logistic regression analysis, adjusted for BMI, alcoholism, smoking history, diabetes mellitus, heart disease, chronic NSAIDs use and previous screening colonoscopies. Results: The case-control analysis included 20990 CRC patients and 82054 controls whose mean follow-up time before index date was 6.5years (SD 4.0). The adjusted OR for CRC among current digoxin users was increased compared with non-users with an adjusted ORs of 1.41 (95%CI 1.25-1.59, p<0.0001), 1.45 (95%CI 1.22-1.72, p<0.0001) and 1.41 (95%CI 1.00-1.99, p=0.049) for first prescriptions 1-5years, 5-10years and more than 10years before index date respectively. Similar results were observed when cumulative duration and number of digoxin prescriptions were analyzed. The risk was not elevated for past digoxin users. Conclusions: Current digoxin use is associated with increased CRC risk. © 2014 John Wiley & Sons, Ltd. Source


Boursi B.,University of Pennsylvania | Boursi B.,The Integrated Cancer Prevention Center | Boursi B.,Tel Aviv University | Haynes K.,University of Pennsylvania | And 2 more authors.
Pharmacoepidemiology and Drug Safety | Year: 2015

Purpose: Gut microbiota has been postulated to serve as a significant promoter of CRC formation, and colonic dysbiosis was previously reported in CRC tissue. Our aim was to evaluate the association between the type and cumulative duration of antibiotic exposure and CRC risk. Methods: We conducted a nested case-control study using a large population-based database from the UK. Cases were defined as those with any medical code of CRC. Subjects with known familial CRC syndromes or IBD were excluded from the study. For every case, four eligible controls matched on age, sex, practice site, and duration of follow-up before index date were selected using incidence-density sampling. Exposure of interest was antibiotic therapy before index date. Adjusted ORs and 95%CIs were estimated using conditional logistic regression analysis. Results: A total of 20990 cases and 82054 controls were identified. The adjusted OR for CRC among subjects first exposed to penicillins >10years prior to index date was 1.11 (95%CI 1.02-1.20). The risk increased significantly with the number of penicillin exposures up to 1.20 (95%CI 1.11-1.31) for >10 courses. The risk also increased with the average number of penicillin treatments per-year (exposure intensity) with an OR of 1.04 (95%CI 1.01-1.08) per one additional treatment per year. Exposure to anti-viral or anti-fungal therapy was not associated with CRC risk. Conclusions: Past exposure to multiple courses of penicillins is related to a modest elevation in CRC risk. © 2015 John Wiley & Sons, Ltd. Source


Shapira A.,Tel Aviv University | Shapira S.,The Integrated Cancer Prevention Center | Shapira S.,Tel Aviv University | Gal-Tanamy M.,Tel Aviv University | And 3 more authors.
PLoS ONE | Year: 2012

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and has become a global health threat. No HCV vaccine is currently available and treatment with antiviral therapy is associated with adverse side effects. Moreover, there is no preventive therapy for recurrent hepatitis C post liver transplantation. The NS3 serine protease is necessary for HCV replication and represents a prime target for developing anti HCV therapies. Recently we described a therapeutic approach for eradication of HCV infected cells that is based on protein delivery of two NS3 protease-activatable recombinant toxins we named "zymoxins". These toxins were inactivated by fusion to rationally designed inhibitory peptides via NS3-cleavable linkers. Once delivered to cells where NS3 protease is present, the inhibitory peptide is removed resulting in re-activation of cytotoxic activity. The zymoxins we described suffered from two limitations: they required high levels of protease for activation and had basal activities in the un-activated form that resulted in a narrow potential therapeutic window. Here, we present a solution that overcame the major limitations of the "first generation zymoxins" by converting MazF ribonuclease, the toxic component of the E. coli chromosomal MazEF toxin-antitoxin system, into an NS3-activated zymoxin that is introduced to cells by means of gene delivery. We constructed an expression cassette that encodes for a single polypeptide that incorporates both the toxin and a fragment of its potent natural antidote, MazE, linked via an NS3-cleavable linker. While covalently paired to its inhibitor, the ribonuclease is well tolerated when expressed in naïve, healthy cells. In contrast, activating proteolysis that is induced by even low levels of NS3, results in an eradication of NS3 expressing model cells and HCV infected cells. Zymoxins may thus become a valuable tool in eradicating cells infected by intracellular pathogens that express intracellular proteases. © 2012 Shapira et al. Source


Boursi B.,University of Pennsylvania | Boursi B.,The Integrated Cancer Prevention Center | Boursi B.,Tel Aviv University | Lurie I.,Tel Aviv University | And 4 more authors.
European Neuropsychopharmacology | Year: 2015

Previous studies demonstrated a possible association between anti-depressant therapy with selective serotonin reuptake inhibitors (SSRI) and tricyclic anti-depressants (TCA), several genetic and hormonal pathways and cancer risk, with inconsistent results. Exposure to serotonin-norepinephrine reuptake inhibitors (SNRI) was not studied extensively. We sought to evaluate the association between exposure to SSRIs, TCAs and SNRIs and the five most common solid tumors. We conducted nested case-control studies using a large UK population-representative database. Cases were those with any medical code for the specific malignancy. For every case, four controls matched on age, sex, practice site, and duration of follow-up before index date were selected using incidence-density sampling. Exposure of interest was SSRI, SNRI or TCA therapy before index date. Odds ratios (ORs) and 95% CIs were estimated for each anti-depressant class using conditional logistic-regression analysis, adjusted for potential confounders, such as obesity, smoking history and alcohol consumption. Results: 109,096 cancer patients and 426,402 matched controls were included. Current SSRI users with treatment initiation>one year before index date had modestly higher risk for lung and breast cancers with ORs of 1.27 (95% CI 1.16-1.38) and 1.12 (95% CI 1.06-1.18), respectively. Among current TCA users, there was a higher risk only for lung cancers with OR of 1.45 (95% CI 1.31-1.6). There was no statistically significant association between current SNRI therapy and cancer risk. Discussion: Treatment with SSRI and TCA might be associated with increased lung cancer risk. SSRI therapy might be associated with modest increase in breast cancer risk. © 2015 Elsevier B.V. and ECNP. Source


Lisiansky V.,The Integrated Cancer Prevention Center | Lisiansky V.,Tel Aviv University | Kraus S.,The Integrated Cancer Prevention Center | Kraus S.,Tel Aviv University | And 17 more authors.
International Journal of Biological Markers | Year: 2014

Background: Inflammatory bowel disease (IBD) results from an inappropriate inflammatory response in which genetic, immune, and environmental factors all play important roles. Recently, single nucleotide polymorphisms (SNPs) in the CD24 gene have been associated with the development of several autoimmune diseases. Aim: To evaluate whether CD24 SNPs, are associated with risk of ulcerative colitis (UC) and Crohn's disease (CD). Methods: The CD24 polymorphisms C170T (rs8734), TG1527del (rs3838646), A1626G (rs1058881), and A1056G (rs1058818) were assessed in a case-control study of an Israeli cohort comprising 117 IBD patients and 105 age and gender-matched healthy controls. Restriction fragment length polymorphism (RFLP) analysis was performed using BstX1, Bsr1, Mfe1, and BstU1 restriction enzymes. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by logistic regression models. Results: Carriers of the C170T SNP were at increased risk of IBD (OR=3.022, 95% CI: 1.748-5.223, p=0.001), UC (OR=3.002, 95% CI: 1.661-5.427, p=0.001) and CD (OR=3.077, 95% CI: 1.334-7.095, p=0.008). Carrying the A1626G and A1056G SNPs was found to be a risk factor for IBD (OR=2.460, 95% CI: 1.420-4.259, p=0.001 and OR=1.856, 95% CI: 1.011- 3.405, p=0.01), UC (OR=2.218, 95% CI: 1.207-4.075, p=0.01 and OR=1.944, 95% CI: 0.995-3.798, p=0.01) but not for CD (p=0.086 and p=0.299). The A1626G and TG1527del were found to be associated with younger age of IBD onset (p=0.022 and p=0.027, respectively). Conclusions: The CD24 C170T polymorphism is associated with IBD risk. The A1626G and A1056G SNPs might be associated only with UC risk. These findings suggest CD24 as a new genetic susceptibility factor, with clinical implications in the prediction of IBD prognosis and therapy. © 2014 Wichtig Publishing. Source

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