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Shapira S.,Integrated Cancer Prevention Center | Shapira S.,Tel Aviv University | Starr A.,Lung and Allergy Institute | Kazanov D.,Integrated Cancer Prevention Center | And 4 more authors.
Gastroenterology | Year: 2011

Background & Aims: 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. Methods: 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. Results: 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/mLseveral 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. Conclusions: 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. © 2011 AGA Institute.


PubMed | Novartis, Pfizer, Firalis SAS, Integrated Cancer Prevention Center and 7 more.
Type: Journal Article | Journal: Toxicologic pathology | Year: 2015

Drug-induced vascular injury (DIVI) is a common preclinical toxicity usually characterized by hemorrhage, vascular endothelial and smooth muscle damage, and inflammation. DIVI findings can cause delays or termination of drug candidates due to low safety margins. The situation is complicated by the absence of sensitive, noninvasive biomarkers for monitoring vascular injury and the uncertain relevance to humans. The Safer And Faster Evidence-based Translation (SAFE-T) consortium is a public-private partnership funded within the European Commissions Innovative Medicines Initiative (IMI) aiming to accelerate drug development by qualifying biomarkers for drug-induced organ injuries, including DIVI. The group is using patients with vascular diseases that have key histomorphologic features (endothelial damage, smooth muscle damage, and inflammation) in common with those observed in DIVI, and has selected candidate biomarkers associated with these features. Studied populations include healthy volunteers, patients with spontaneous vasculitides and other vascular disorders. Initial results from studies with healthy volunteers and patients with vasculitides show that a panel of biomarkers can successfully discriminate the population groups. The SAFE-T group plans to seek endorsement from health authorities (European Medicines Agency and Food and Drug Administration) to qualify the biomarkers for use in regulatory decision-making processes.


Boursi B.,University of Pennsylvania | Boursi B.,Integrated Cancer Prevention Center | Boursi B.,Tel Aviv University | Mamtani R.,University of Pennsylvania | And 2 more authors.
European Journal of Endocrinology | Year: 2015

Objective: Gut microbiota influence metabolic pathways related to the pathogenesis of obesity, insulin-resistance and diabetes. Antibiotic therapy can alter the microbiota, and is commonly used in western countries. We sought to evaluate whether past antibiotic exposure increases diabetes risk. Research design and methods: We conducted a nested case-control study using a large population-based database from the UK. The cases were defined as those with incident diagnosis of diabetes. 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 O1 year before index-date. Odds ratios (ORs) and 95% CIs were estimated using conditional logistic regression. The risk was adjusted for BMI, smoking, last glucose level, and number of infections before index-date, as well as past medical history of coronary artery disease and hyperlipidaemia. Results: The study included 208 002 diabetic cases and 815 576 matched controls. Exposure to a single antibiotic prescription was not associated with higher adjusted diabetes risk. Treatment with two to five antibiotic courses was associated with increase in diabetic risk for penicillin, cephalosporins, macrolides and quinolones with adjusted OR ranging from 1.08 (95% CI 1.05-1.11) for penicillin to 1.15 (95% CI 1.08-1.23) for quinolones. The risk increased with the number of antibiotic courses and reached 1.37 (95% CI 1.19-1.58) for more than 5 courses of quinolones. There was no association between exposure to anti-virals and anti-fungals and diabetes risk. Conclusions: Exposure to certain antibiotic groups increases diabetes risk. © 2015 European Society of Endocrinology.


Boursi B.,University of Pennsylvania | Boursi B.,Integrated Cancer Prevention Center | Haynes K.,University of Pennsylvania | Mamtani R.,University of Pennsylvania | Yang Y.-X.,University of Pennsylvania
Journal of the National Cancer Institute | Year: 2015

Background: Current screening guidelines for colorectal cancer (CRC) do not consider thyroid dysfunction as a risk factor for disease development. We sought to determine the risk of developing CRC in patients with thyroid dysfunction, with and without thyroid hormone replacement (THR). Methods: We conducted a nested case-control study using a large population-based medical records database from the United Kingdom. Study case patients were defined as those with any medical code of CRC. Subjects with familial colorectal cancer syndromes or inflammatory bowel disease (IBD) were excluded. For every case patient, four eligible control patients matched on age, sex, practice site, and duration of follow-up before index date were selected using incidence density sampling. Exposure was THR therapy before index date. We further divided the THR unexposed group into patients with hypothyroidism (TSH > 4mg/dl), patients with hyperthyroidism (TSH < 0.4mg/dl), and subjects without documented thyroid abnormality. The adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for CRC were estimated using conditional logistic regression. All statistical tests were two-sided. Results: We identified 20990 CRC patients and 82054 control patients. The adjusted odds ratio for CRC associated with THR was 0.88 (95% CI = 0.79 to 0.99, P =. 03) and 0.68 (95% CI = 0.55 to 0.83, P <. 001) for treatment initiated five to 10 years and more than 10 years before index date, respectively. This protective association increased with cumulative duration of therapy. In contrast, hyperthyroidism (adjusted OR = 1.21, 95% CI = 1.08 to 1.36, P =. 001) or untreated hypothyroidism (adjusted OR = 1.16, 95% CI = 1.08 to 1.24, P <. 001) were associated with increased risk of CRC. Conclusion: Long-term THR is associated with a decreased risk of CRC. Hyperthyroidism and untreated hypothyroidism are associated with modestly elevated risk of CRC. © 2015 The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.


Lurie I.,Tel Aviv University | Lurie I.,Shalvata Mental Health Center | Yang Y.-X.,University of Pennsylvania | Yang Y.-X.,Center for Clinical Epidemiology and Biostatistics | And 7 more authors.
Journal of Clinical Psychiatry | Year: 2015

Objective: Changes in the microbiota (dysbiosis) were suggested to increase the risk of several psychiatric conditions through neurologic, metabolic, and immunologic pathways. Our aim was to assess whether exposure to specific antibiotic groups increases the risk for depression, anxiety, or psychosis. Method: We conducted 3 nested case-control studies during the years 1995-2013 using a large population-based medical record database from the United Kingdom. The study included 202,974 patients with depression, 14,570 with anxiety, and 2,690 with psychosis and 803,961, 57,862, and 10,644 matched controls, respectively. Cases were defined as individuals aged 15-65 years with any medical Read code for depression, anxiety, or psychosis. Subjects with diagnosis-specific psychotropic prescriptions > 90 days before index date were excluded. For every case, 4 controls were selected using incidence density sampling, matching on age, sex, practice site, calendar time, and duration of follow-up before index date. The primary exposure of interest was therapy with 1 of 7 antibiotic classes > 1 year before index date. Odds ratios (ORs) and 95% CIs were calculated for the association between each psychiatric disorder and exposure to individual classes of antibiotics using conditional logistic regression analysis. The risk was adjusted for obesity, smoking history, alcohol consumption, socioeconomic status, and number of infectious events before diagnosis. Results: Treatment with a single antibiotic course was associated with higher risk for depression with all antibiotic groups, with an adjusted OR (AOR) of 1.23 for penicillins (95% CI, 1.18-1.29) and 1.25 (95% CI, 1.15-1.35) for quinolones. The risk increased with recurrent antibiotic exposures to 1.40 (95% CI, 1.35-1.46) and 1.56 (95% CI, 1.46-1.65) for 2-5 and > 5 courses of penicillin, respectively. Similar association was observed for anxiety and was most prominent with exposures to penicillins and sulfonamides, with an AOR of 1.17 (95% CI, 1.01-1.36) for a single course of penicillin and 1.44 (95% CI, 1.18-1.75) for > 5 courses. There was no change in risk for psychosis with any antibiotic group. There was a mild increase in the risk of depression and anxiety with a single course of antifungals; however, there was no increase in risk with repeated exposures. Conclusion: Recurrent antibiotic exposure is associated with increased risk for depression and anxiety but not for psychosis. © 2015 Physicians Postgraduate Press, Inc.


Shapira S.,Integrated Cancer Prevention Center | Shapira S.,Tel Aviv University | Lisiansky V.,Integrated Cancer Prevention Center | Lisiansky V.,Tel Aviv University | And 4 more authors.
Expert Opinion on Investigational Drugs | Year: 2010

Colorectal cancer (CRC) is a major health concern worldwide. It is the third most frequently diagnosed cancer and the second leading cause of cancer death. There currently are a number of treatment options for CRC, however many of them have failed to demonstrate desired therapeutic benefit. Therefore, significant efforts are being directed towards the development of new biological therapies with improved efficacy. Immunotherapy is an emerging treatment modality for a variety of cancers. Several promising treatments have already been approved by the US FDA and are being tested in clinical trials. Antibodies have been proved to be useful in cancer therapy due to their ability to recognize tumor-associated antigens expressed at higher density on malignant cells in comparison with those that are normal. Antibodies can be used as a single therapy or in combination with other therapies. A large variety of monoclonal antibodies have been developed. However, only a very few are able to kill a sufficient number of malignant cells and cause tumor regression. Hence, it is often necessary to arm the antibody with a cytotoxic agent to enhance the efficacy of the anti-tumor activity. This review provides a brief overview of some of the current agents being employed in targeted immunotherapy for CRC. © 2010 Informa UK Ltd.


Shapira S.,Integrated Cancer Prevention Center | Shapira S.,Tel Aviv University | Fokra A.,Integrated Cancer Prevention Center | Fokra A.,Tel Aviv University | And 5 more authors.
Current Medicinal Chemistry | Year: 2014

Colorectal cancer (CRC) is a major health concern worldwide, as it is the third most frequently diagnosed cancer and the second leading cause of cancer-related death. There are a number of treatment options for CRC, however many of them are disappointing. Therefore, significant efforts are directed towards the development of new biological therapies with improved efficacy. The use of peptides in CRC treatment holds promise as emerging novel anti-cancer agents. Targeted therapy based on the use of peptides that can directly target tumor cells without affecting normal cells is evolving as an alternative strategy to conventional therapies and particularly, chemotherapy. The main advantages of peptides are their relatively easy and rapid synthesis process, and the vast possibilities for chemical modifications that can be exploited for novel peptide design and improved delivery. Peptides can be utilized directly as cytotoxic agents or indirectly as they can act as carriers of cytotoxic agents, drugs, or radioisotopes by specifically targeting tumor cells. They can also be used for diagnostic purposes. Current research focuses on developing peptides that can serve as tumor targeting moieties, permeabilize membranes to induce cytotoxicy, radiolabeled peptides, and peptide vaccines. In addition, improving targeting to tumors, reducing side effects, due to non-specific toxicity, and unraveling the pharmacokinetic characteristics of potential peptides, for either therapeutic or diagnostic use, are also subjects of intensive investigation. This review provides a brief overview on the role of peptides in CRC diagnosis and therapy that are currently being investigated, and their potential applications in the clinical setting. © 2014 Bentham Science Publishers.


Hahn E.,University of Toronto | Kraus S.,Integrated Cancer Prevention Center | Kraus S.,Tel Aviv University | Arber N.,Integrated Cancer Prevention Center | Arber N.,Tel Aviv University
Digestive Diseases | Year: 2010

Chemoprevention of colorectal cancer is a promising science that has particular importance due to the limited success of current treatments for most advanced common malignancies. Many chemopreventive agents have been studied including cyclooxygenase (COX) inhibitors. Two isoforms of the COX enzymes are COX-1 and COX-2. COX-1 is constitutively expressed in normal tissue, serving an important role in tissue homeostasis, whereas COX-2 is an inducible enzyme, which is markedly overexpressed at sites of inflammation and colorectal neoplasms. The preventive efficacy of traditional nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit COX-1 and/or COX-2, has considerable support from animal and epidemiological studies; however, there are well-documented toxicities associated with NSAID use. These adverse effects are attributed to NSAIDs' inhibition of COX-1. The development of COX-2 specific inhibitors gave hopes of bypassing the associated traditional NSAID toxicities while better targeting tissues sustaining inflammation and neoplasia. The PrsSAP, APC and APPROVe trials demonstrated the efficacy of COX-2 specific inhibitors in preventing the recurrence of sporadic colorectal polyps. However, the trials were terminated early due to discovery of significant cardiovascular toxicity, although the exact extent of this toxicity remains unclear. The exact mechanisms through which NSAIDs exert their cancer preventing effects are currently unknown; inhibition of COX-2 is of great importance, but COX-2 independent pathways exist as well. In addition, the efficacy of NSAID use for cancer prevention can differ significantly between individuals. Personalized medicine in this field is also greatly anticipated. Combination therapy is under extensive research in order to improve efficacy while reducing toxicity profiles. Chemoprevention of colorectal cancer is largely possible, but the ultimate drug and proper patient selection, among other elements of the cancer prevention equation, are still needed. © 2010 S. Karger AG, Basel.


Arber N.,Integrated Cancer Prevention Center | Moshkowitz M.,Integrated Cancer Prevention Center
Current Gastroenterology Reports | Year: 2011

Intestinal polyposis syndromes are relatively rare. However, it is important for clinicians to recognize the potential risks of these syndromes. Based on histology, these syndromes can be classified mainly into hamartomatous polyposis syndromes and familial adenomatous polyposis (FAP), which affects mainly the large intestine. This review discusses the clinical manifestations and underlying genetics of the most common small intestinal polyposis syndromes: Peutz-Jeghers syndrome (PJS), juvenile polyposis (JP), PTEN hamartoma tumor syndrome (PHTS), and the small intestinal implications of familial adenomatous polyposis (FAP). © Springer Science+Business Media, LLC 2011.


PubMed | Integrated Cancer Prevention Center
Type: Journal Article | Journal: Current medicinal chemistry | Year: 2014

Colorectal cancer (CRC) is a major health concern worldwide, as it is the third most frequently diagnosed cancer and the second leading cause of cancer-related death. There are a number of treatment options for CRC, however many of them are disappointing. Therefore, significant efforts are directed towards the development of new biological therapies with improved efficacy. The use of peptides in CRC treatment holds promise as emerging novel anti-cancer agents. Targeted therapy based on the use of peptides that can directly target tumor cells without affecting normal cells is evolving as an alternative strategy to conventional therapies and particularly, chemotherapy. The main advantages of peptides are their relatively easy and rapid synthesis process, and the vast possibilities for chemical modifications that can be exploited for novel peptide design and improved delivery. Peptides can be utilized directly as cytotoxic agents or indirectly as they can act as carriers of cytotoxic agents, drugs, or radioisotopes by specifically targeting tumor cells. They can also be used for diagnostic purposes. Current research focuses on developing peptides that can serve as tumor targeting moieties, permeabilize membranes to induce cytotoxicy, radiolabeled peptides, and peptide vaccines. In addition, improving targeting to tumors, reducing side effects, due to non-specific toxicity, and unraveling the pharmacokinetic characteristics of potential peptides, for either therapeutic or diagnostic use, are also subjects of intensive investigation. This review provides a brief overview on the role of peptides in CRC diagnosis and therapy that are currently being investigated, and their potential applications in the clinical setting.

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