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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.

PubMed | The Integrated Cancer Prevention Center, Tel Aviv Sourasky Medical Center, The Institute of Pathology and Tel Aviv University
Type: Journal Article | Journal: PloS one | Year: 2015

Healthy individuals rarely have problems with wound healing. Most skin lesions heal rapidly and efficiently within one to two weeks. However, many medical and surgical complications can be attributed to deficiencies in wound repair. Open wounds have lost the barrier that protects tissues from bacterial invasion and allows the escape of vital fluids. Without expeditious healing, infections become more frequent. The CD24 gene encodes a heavily-glycosylated cell surface protein anchored to the membrane by phosphatidylinositol. CD24 plays an important role in the adaptive immune response and controls an important genetic checkpoint for homeostasis and autoimmune diseases in both mice and humans. We have previously shown that overexpression of CD24 results in increased proliferation and migration rates.To examine the role of CD24 in the wound healing process.An excisional model of wound healing was used and delayed wound healing was studied in genetically modified heat stable antigen (HSA/CD24)-deficient mice (HSA-/-) compared to wild-type (WT) mice.Large full-thickness skin wounds, excised on the back of mice, exhibited a significant delay in the formation of granulation tissue, and in wound closure when compared to their WTHSA+/+ littermates. Wounds were histologically analyzed and scored, based on the degree of cellular invasion, granulation tissue formation, vascularity, and re-epithelialization. Additionally, in stitched wounds, the HSA-/- mice failed to maintain their stitches; they did not hold and fell already 24 hours, revealing erythematous wound fields. Re-expression of HSA, delivered by lentivirus, restored the normal healing phenotype, within 24 hours post-injury, and even improved the healing in WT, and in BalbC mice.Delayed wound-healing in the absence of HSA/CD24 suggests that CD24 plays an important role in this process. Increased expression of CD24, even in the normal state, may be used to enhance wound repair.

PubMed | Karolinska Institutet, Reutlingen University, Addis Ababa Institute of Technology, University of Malaga and 7 more.
Type: Journal Article | Journal: Liver international : official journal of the International Association for the Study of the Liver | Year: 2016

The occurrence of drug-induced liver injury (DILI) is a major issue in all phases of drug development. To identify novel biomarker candidates associated with DILI, we utilised an affinity proteomics strategy, where antibody suspension bead arrays were applied to profile plasma and serum samples from human DILI cases and controls.An initial screening was performed using 4594 randomly selected antibodies, representing 3450 human proteins. Resulting candidate proteins together with proposed DILI biomarker candidates generated a DILI array of 251 proteins for subsequent target analysis and verifications. In total, 1196 samples from 241 individuals across four independent cohorts were profiled: healthy volunteers receiving acetaminophen, patients with human immunodeficiency virus and/or tuberculosis receiving treatment, DILI cases originating from a wide spectrum of drugs, and healthy volunteers receiving heparins.We observed elevated levels of cadherin 5, type 2 (CDH5) and fatty acid-binding protein 1 (FABP1) in DILI cases. In the two longitudinal cohorts, CDH5 was elevated already at baseline. FABP1 was elevated after treatment initiation and seemed to respond more rapidly than alanine aminotransferase (ALT). The elevations were verified in the DILI cases treated with various drugs. In the heparin cohort, CDH5 was stable over time whereas FABP1 was elevated.These results suggest that CDH5 may have value as a susceptibility marker for DILI. FABP1 was identified as a biomarker candidate with superior characteristics regarding tissue distribution and kinetics compared to ALT but likely with limited predictive value for the development of severe DILI. Further studies are needed to determine the clinical utility of the proposed markers.

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.

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.

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.

PubMed | The Integrated Cancer Prevention Center, Tel Aviv University and Tel Aviv Sourasky Medical Center
Type: Journal Article | Journal: PloS one | Year: 2015

There are no validated biomarkers that correlate with the prognosis of pancreatic ductal adenocarcinoma (PDA). The CD24 and adenomatous polyposis coli (APC) genes are important in the malignant transformation of gastrointestinal cells. This study examined APC and CD24 genetic polymorphisms and their possible impact on survival of patients with PDA.Clinical and pathological data as well as blood samples for extracting DNA were obtained for 73 patients with PDA. Real-time PCR assessed genetic variants of APC (I1307K and E1317Q), and four different single nucleotide polymorphisms (SNPs) in the CD24 gene: C170T (rs52812045), TG1527del (rs3838646), A1626G (rs1058881) and A1056G (rs1058818).The median age at diagnosis was 64 (41-90) years. Thirty-one patients (42.5%) were operable, 16 (22%) had locally advanced disease and 26 (35.5%) had disseminated metastatic cancer. The malignancy-related mortality rate was 84%. Median survival was 14 months (11.25-16.74). Survival was similar for wild-type (WT), heterozygous and homozygous variants of the APC or CD24 genes. The three most frequent CD24 SNP combinations were: heterozygote for A1626G and WT for the rest of the alleles (14% of patients), heterozygote for C170T, A1626G, A1056G and WT for the rest (14% of patients), and heterozygote for C170T, A1056G and WT for the rest (10% of patients). All patients were APC WT. The first two groups were significantly younger at diagnosis than the third group.Specific polymorphisms in the APC and CD24 genes may play a role in pancreatic cancer development. Correlation with survival requires a larger cohort.

PubMed | The Integrated Cancer Prevention Center
Type: Journal Article | Journal: Cancer gene therapy | Year: 2012

Ras mutations are present in 95% of pancreatic cancer (PC) cases leading to increased proliferation and apoptosis resistance. The aim of this study is to selectively kill Ras-transformed cells by overexpressing the pro-apoptotic protein, p53 upregulated modulator of apoptosis (PUMA) under a Ras-responsive promoter. Colo357, Panc1 and MiaPaca, PC cell lines harboring K-Ras mutations, normal rat IEC18 enterocytes, and their K-Ras transformed R1 counterparts, were tested. We constructed adenoviral vectors containing the PUMA gene downstream to: (1) Four or five repetitive Ras-responsive elements (Ad-PY4/PY5-PUMA) and (2) a negative control (Ad-SV40-PUMA). Cell viability was estimated by 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and apoptosis was evaluated by FACS. In vivo potency of the adenoviruses was evaluated in athymic nude mice. Infection with Ad-PY4/PY5-PUMA markedly inhibited cell growth (40-50%), and apoptosis was detected in all cells with high Ras activity, whereas IEC18 cells remained unaffected. The control vector, Ad-SV40-PUMA, did not induce any cell death. Selective and high expression of PUMA was detected in Ad-PY4-PUMA-infected cells. In vivo, Ad-PY4-PUMA inhibited by 35% the growth of established tumors compared with the Ad-SV40-PUMA. Selective overexpression of PUMA efficiently inhibits the growth of Ras-transformed cells while sparing the normal ones. This treatment modality may become a useful, effective and safe approach to selectively target Ras-mutated tumor cells.

PubMed | The Integrated Cancer Prevention Center
Type: Journal Article | Journal: Gastroenterology | Year: 2011

Effective and selective treatment options are needed for patients with colorectal cancer (CRC). The CD24 mucin-like glycoprotein is overexpressed in CRCs; monoclonal antibodies (mAbs) against CD24 inhibit tumor cell growth in vitro and in vivo. Based on the tumor-specific expression of CD24, we investigated the potential of anti-CD24 SWA11 mAb, to deliver a cytotoxic agent into CRC cells.We conjugated SWA11 to a Pseudomonas exotoxin derivative (PE38) via an Fc-binding ZZ domain from Staphylococcal protein A (which binds the Fc domain of mouse IgG2a immunoglobulins) to generate the immunotoxin SWA11-ZZ-PE38; IgG-ZZ-PE38 was used as control. Human HT-29 and COLO320 (CD24-positive) and HCT116 (CD24-negative) CRC cell lines were assayed for immunotoxin binding, cytotoxicity, viability, and apoptosis. Toxicity and antitumor efficacy were tested in mice.The immunotoxin preserved the affinity and specificity of SWA11, bound and selectively killed CD24-expressing CRC cells via apoptosis. IC(50) values ranged from 20 to 50 ng/mL-several orders of magnitude lower than that of the mAb alone. The immunotoxins were not toxic to mice at the maximum dose of 0.75 mg/kg. Growth of HT-29 xenograft tumors was significantly reduced in mice given SWA11-ZZ-PE38 (by 78%) compared to untreated mice.Anti-CD24 SWA11 mAb can deliver a PE exotoxin derivative to CRC cells and cause them to undergo apoptosis, without toxicity to normal tissues. This immunotoxin might be developed as a therapeutic treatment for patients with CRC.

PubMed | The Integrated Cancer Prevention Center
Type: Journal Article | Journal: Expert opinion on medical diagnostics | Year: 2013

Gastrointestinal (GI) cancers are frequently associated with high rates of mortality and morbidity, often resulting from late detection, underscoring the need for improved early detection, risk assessment and intervention. Screening approaches available at present are inadequate, and the development of accurate non-invasive biomarkers is needed.A comprehensive review is provided on the current state of blood-based biomarkers for diagnosing GI cancers, with a focus on the next generation of new genetic and epigenetic blood-based tests.It is anticipated that the reader will have a detailed view on the potential of blood-based biomarkers for GI cancers. Although the premise of detecting cancers in blood has been explored previously, recent technological advances have revolutionized the field of non-invasive biomarkers. Consequently, there is unprecedented evidence that it is perhaps the time when a systematic identification of highly specific and sensitive markers may be an essential component in the era of personalized medicine.In spite of the limited success of first-generation tests, data gathered in recent years clearly support the notion that we are on the verge of discovering and optimizing a new generation of non-invasive diagnostic biomarkers for GI neoplasia.

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