Dan Farbstein

Technion - Israel Institute of Technology, H̱efa, Haifa, Israel

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Publications (11)43.45 Total impact

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    ABSTRACT: Haptoglobin (Hp) genotype 2-2 increases cardiovascular diabetes complications. In type 2 diabetes, α-tocopherol was shown to lower cardiovascular risk in Hp 2-2, potentially through HDL function improvements. Similar type 1 diabetes data are lacking. We conducted a randomized crossover pilot of α-tocopherol supplementation on HDL function [i.e., cholesterol efflux (CE) and HDL-associated lipid peroxides (LP)] and lipoprotein subfractions in type 1 diabetes. Hp genotype was assessed in members of two Allegheny County, PA, type 1 diabetes registries and the CACTI cohort; 30 were randomly selected within Hp genotype, and 28 Hp 1-1, 31 Hp 2-1 and 30 Hp 2-2 were allocated to daily α-tocopherol or placebo for 8 weeks with a 4-week washout. Baseline CE decreased with the number of Hp 2 alleles (p-trend = 0.003). There were no differences in LP or lipoprotein subfractions. In intention-to-treat analysis stratified by Hp, α-tocopherol increased CE in Hp 2-2 (β = 0.79, p = 0.03) and LP in Hp 1 allele carriers (β Hp 1-1 = 0.18, p = 0.05; β Hp 2-1 = 0.21, p = 0.07); reduced HDL particle size (β = -0.07, p = 0.03) in Hp 1-1 carriers; increased LDL particle concentration in Hp 1-1; and decreased it in Hp 2-2 carriers. However, no significant interactions were observed by Hp. In this type 1 diabetes study, HDL function worsened with the number of Hp 2 alleles. α-Tocopherol improved HDL function in Hp 2-2 carriers and appeared to adversely affect lipid peroxides and lipoprotein subfractions among Hp 1 allele carriers. As no significant interactions were observed, findings require replication in larger studies.
    Acta Diabetologica 05/2015; DOI:10.1007/s00592-015-0770-8 · 3.68 Impact Factor
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    ABSTRACT: Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) often present with systemic symptoms such as fatigue, shortness of breath and night sweats, mimicking pregnancy-related features which may result in delayed disease diagnosis. Furthermore, the wish to avoid investigational imaging, aiming to protect the fetus from radiation exposure, may lead to a further delay, which does not often result in significant changes in HL clinical nature and patient outcome. In contrast, a more aggressive behavior (i.e., advanced disease stage and reproductive organ involvement) of most NHL types diagnosed in pregnancy may require urgent therapeutic intervention to prevent disease progression. Current management of pregnancy-associated NHL depends on histological subtype of the disease, gestational stage at diagnosis and the urgency of treatment for a specific patient. Patients diagnosed with indolent lymphoma may often be just followed, whereas those presenting with aggressive or highly aggressive disease need to be urgently treated with chemoimmunotherapy, either after undergoing an elective pregnancy termination if diagnosed at an early gestational stage, or with pregnancy preservation, if diagnosed later. Supportive care of NHL is also important; however, granulocyte colony stimulating factor (G-CSF) which is commonly used outside of pregnancy, should be cautiously employed, considering its established teratogenicity in animals, though this is less proven in humans. In conclusion, given the paucity of studies prospectively evaluating the outcome of pregnant women with NHL, international efforts are warranted to elucidate critical issues and develop guidelines for the management of such patients.
    Blood Reviews 09/2014; 28(5). DOI:10.1016/j.blre.2014.06.004 · 5.45 Impact Factor
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    ABSTRACT: Abstract Introduction Surveillance FDG PET, commonly employed in patients with diffuse large B cell lymphoma (DLBCL) who achieve remission following induction, is very sensitive but not sufficiently specific, and is associated with a high false positive (FP) rate. The current study was aimed to investigate whether the employment of specific CT morphologic measurements could reduce FP incidence and improve the positive predictive value (PPV) and clinical applicability of surveillance FDG PET/CT in detecting DLBCL relapse. Methods The study was approved by the Institutional Review Board (IRB) of the Rambam Health Care Campus (Haifa, Israel). The study population included patients with DLBCL who participated in the previous surveillance PET study (n=119) (Avivi I, Am J Hematol, 2013), and had at least one positive PET scan, suggestive of disease relapse (n=83). A PET scan was defined as positive in the presence of increased FDG uptake unrelated to physiological bio-distribution of the tracer or to a known benign process. CT-derived features of PET positive sites, including long and short diameters (mm), the presence of calcification and fatty hilum within lymph nodes, were assessed. Patient's outcome, focusing on relapse development, confirmed either by tissue biopsy or by consecutive imaging demonstrating progression in the presence of compatible clinical symptoms, was recorded. The performance of surveillance PET scans, with and without concurrent employment of CT-derived measurements, was compared, focusing on FP rate and PPV of these two approaches to relapse detection. Results Eighty three follow-up PETs (FU-PETs) interpreted as positive for relapse, were reviewed. Seventy studies performed in 51 patients were included in final analysis, 13 studies were excluded as CT quality did not allow adequate morphologic evaluation. Twenty five of 70 FU-PET studies (36%) were true positive (TP) and 45 (64%) false positive, which is compatible with a PPV of 36%. Evaluation of CT-related parameters of PET positive sites showed that the employment of either long axis ≥15 mm or short axis ≥10 mm, significantly improved the prediction of relapse by PET (Table 1). The ratio between long and short axis measurements was not found to efficiently discriminate between FP and TP scans. Likewise, the presence of calcification or fatty hilum did not affect this discrimination. Multivariate analysis found IPI ≥2, lack of prior rituximab therapy and long or short axis measurements ≥15 and 10 mm, respectively, to be independent predictors of true positivity of FU-PET scans (odds ratio=9.84 ,8.5, and 7.67, P< 0.05, respectively).
    Blood 11/2013; · 10.43 Impact Factor
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    ABSTRACT: The haptoglobin (Hp) genotype is a major determinant of progression of nephropathy in individuals with diabetes mellitus (DM). The major function of the Hp protein is to bind and modulate the fate of extracorpuscular hemoglobin and its iron cargo. We have previously demonstrated an interaction between the Hp genotype and the DM on the accumulation of iron in renal proximal tubule cells. The primary objective of this study was to determine the intracellular localization of this iron in the proximal tubule cell and to assess its potential toxicity. Transmission electron microscopy demonstrated a marked accumulation of electron-dense deposits in the lysosomes of proximal tubules cells in Hp 2-2 DM mice. Energy-dispersive X-ray spectroscopy and electron energy loss spectroscopy were used to perform elemental analysis of these deposits and demonstrated that these deposits were iron rich. These deposits were associated with lysosomal membrane lipid peroxidation and loss of lysosomal membrane integrity. Vitamin E administration to Hp 2-2 DM mice resulted in a significant decrease in both intralysosomal iron-induced oxidation and lysosomal destabilization. Iron-induced renal tubular injury may play a major role in the development of diabetic nephropathy and may be a target for slowing the progression of renal disease.
    Free Radical Biology and Medicine 06/2012; 53(4):779-86. DOI:10.1016/j.freeradbiomed.2012.06.015 · 5.71 Impact Factor
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    Dan Farbstein · Andrew P Levy
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    ABSTRACT: HDL is known to be inversely correlated with cardiovascular disease due to its diverse antiatherogenic functions. These functions include cholesterol efflux and reverse cholesterol transport, antioxidative and anti-inflammatory activities. However, HDL has been shown to undergo a loss of function in several pathophysiological states, as in the acute phase response, obesity and chronic inflammatory diseases. Some of these diseases were also shown to be associated with increased risk for cardiovascular disease. One such disease that is associated with HDL dysfunction and accelerated atherosclerosis is diabetes mellitus, a disease in which the HDL particle undergoes diverse structural modifications that result in significant changes in its function. This review will summarize the changes that occur in HDL in diabetes mellitus and how these changes lead to HDL dysfunction. Possible treatments for HDL dysfunction are also briefly described.
    Expert Review of Cardiovascular Therapy 03/2012; 10(3):353-61. DOI:10.1586/erc.11.182
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    ABSTRACT: Vitamin E provides cardiovascular protection to individuals with diabetes and the haptoglobin 2-2 genotype but appears to increase cardiovascular risk in individuals with diabetes and the haptoglobin 2-1 genotype. We have previously demonstrated that the haptoglobin protein is associated with HDL and that HDL function and its oxidative modification are haptoglobin genotype dependent. We set out to test the hypothesis that the pharmacogenetic interaction between the haptoglobin genotype on cardiovascular risk might be secondary to a parallel interaction between the haptoglobin genotype and vitamin E on HDL function. Fifty-nine individuals with diabetes and the haptoglobin 2-1 or 2-2 genotypes were studied in a double-blind placebo controlled crossover design. Participants were treated with either vitamin E (400IU) or placebo for 3 months and crossed over for an equivalent duration. Serum was collected at baseline and after the completion of each treatment. HDL functionality as well as HDL associated markers of oxidation and inflammation were measured after each interval in HDL purified from the cohort. Compared to placebo, vitamin E significantly increased HDL function in haptoglobin 2-2 but significantly decreased HDL function in haptoglobin 2-1. This pharmacogenetic interaction was paralleled by similar non-significant trends in HDL associated lipid peroxides, glutathione peroxidase, and inflammatory cargo. There exists a pharmacogenetic interaction between the haptoglobin genotype and vitamin E on HDL function (clinicaltrials.gov NCT01113671).
    Atherosclerosis 06/2011; 219(1):240-4. DOI:10.1016/j.atherosclerosis.2011.06.005 · 3.97 Impact Factor
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    ABSTRACT: As atherosclerosis is still one of the major causes of death in Western populations, it is important to identify those individuals who are at increased risk for the disease so that aggressive treatment may be administered as early as possible. Following the understanding that oxidative stress has a pivotal role in the development and progression of atherosclerosis, many polymorphisms in genes that are related to redox systems were examined for their association with increased risk for cardiovascular disease (CVD). Although many polymorphisms were studied, only a handful showed consistent relevance to CVD in different trials. This article focuses on six of these polymorphisms, examining their effect on the risk for CVD as well as their effect on protein expression and function. Reports regarding pharmacogenetic implications of these polymorphisms, where such exist, are discussed as well.
    Current Atherosclerosis Reports 03/2011; 13(3):215-24. DOI:10.1007/s11883-011-0170-7 · 3.06 Impact Factor
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    ABSTRACT: Atherosclerosis remains one of the leading causes of death in Western populations. Subsequent to the discovery that oxidative stress plays a pivotal role in the development and progression of atherosclerosis, vitamins C and E, along with other antioxidants, were studied as potential therapies for the disease. However, while in vitro and in vivo studies showed promising antiatherogenic effects for vitamins C and E, clinical trials in which patients were given high doses of vitamin E or C showed no benefit and even possible harm. This review will attempt to summarize the known mechanistic data regarding the biochemical effects of vitamins C and E and their relevance to atherosclerosis, and offer an explanation for the failure of clinical trials to show that supplementation with these vitamins provides any benefit when given indiscriminately. We provide one example of how pharmacogenomics may be used to identify a sub-population which may indeed benefit from antioxidant supplementation.
    Molecules 11/2010; 15(11):8098-110. DOI:10.3390/molecules15118098 · 2.42 Impact Factor
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    Dan Farbstein · Andrew P Levy
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    ABSTRACT: Prospective identification of which individuals with diabetes mellitus (DM) are at greatest risk for developing cardiovascular disease (CVD) complications would have considerable public health importance by allowing the allocation of limited resources to be focused on those individuals who would most benefit from aggressive intervention. Over the past 20 years genetic disease association studies have demonstrated that polymorphisms at specific genetic loci may identify those individuals at greatest risk for developing CVD in the setting of DM. This article reviews the evidence accumulated to date on four polymorphic loci with the aim of explaining how these polymorphisms modify the risk for CVD in DM by modifying the functional activity of a specific gene. Use of the knowledge of these genetic differences among individuals in targeting drug therapy (pharmacogenomics) is also discussed.
    Cardiology clinics 08/2010; 28(3):477-96. DOI:10.1016/j.ccl.2010.04.005 · 1.06 Impact Factor
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    ABSTRACT: Haptoglobin is an abundant hemoglobin-binding protein present in the plasma. The function of haptoglobin is primarily to determine the fate of hemoglobin released from red blood cells after either intravascular or extravascular hemolysis. There are two common alleles at the Hp genetic locus denoted 1 and 2. There are functional differences between the Hp 1 and Hp 2 protein products in protecting against hemoglobin-driven oxidative stress that appear to have important clinical significance. In particular, individuals with the Hp 2-2 genotype and diabetes mellitus appear to be at significantly higher risk of microvascular and macrovascular complications. A pharmacogenomic strategy of administering high dose antioxidants specifically to Hp 2-2 DM individuals may be clinically effective.
    Antioxidants & Redox Signaling 09/2009; 12(2):293-304. DOI:10.1089/ars.2009.2793 · 7.67 Impact Factor
  • Dan Farbstein · Andrew P Levy
    Therapy 07/2009; 6(4):531-538. DOI:10.2217/thy.09.23