Institute of Endocrinology and Metabolism

Petah Tikva, Israel

Institute of Endocrinology and Metabolism

Petah Tikva, Israel

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Levit S.,Institute of Endocrinology and Metabolism | Philippov Y.I.,Endocrinology Research Center | Gorelyshev A.S.,Endocrinology Research Center
Diabetes Mellitus | Year: 2013

Diabetes mellitus is a heterogeneous group of diseases that, although unified by a number of characteristics, require a differential therapeutic approach. Current review discusses key pathogenic features of type 2 diabetes mellitus that determine therapy goals and options in management. We further enunciate and pathogenetically substantiate a new «gravicentric» concept for treatment of type 2 diabetes mellitus that differs in many ways from the common contemporary approach.


Stein L.,Roswell Park Cancer Institute | Rothschild J.,Roswell Park Cancer Institute | Luce J.,Roswell Park Cancer Institute | Cowell J.K.,Georgia Regents University | And 4 more authors.
Thyroid | Year: 2010

Background: Following exposure to radiation during the Chernobyl fallout tragedy, papillary thyroid carcinoma (PTC) increased significantly in individuals who were children at the time of the accident. We have used two high-throughput, whole genome platforms to analyze radiation-induced PTCs from pediatric patients from the Chernobyl region. Methods: We performed comparative genomic hybridization using Affymetrix 50K Mapping arrays and gene expression profiling on 10 pediatric post-Chernobyl PTCs obtained from patients living in the region. We performed an overlay analysis of these two data sets. Results: Many regions of copy number alterations (CNAs) were detected including novel regions that had never been associated with PTCs. Increases in copy numbers were consistently found on chromosomes 1p, 5p, 9q, 12q, 13q, 16p, 21q, and 22q. Deletions were observed less frequently and were mapped to 1q, 6q, 9q, 10q, 13q, 14q, 21q, and 22q. Gene expression analysis revealed that most of the altered genes were also perturbed in sporadic adult PTC; however, 141 gene expression changes were found to be unique to the post-Chernobyl tumors. The genes with the highest increases in expression that were novel to the pediatric post-Chernobyl tumors were TESC, PDZRN4, TRAa/TRDa, GABBR2, and CA12. The genes showing the largest expression decreases included PAPSS2, PDLIM3, BEXI, ANK2, SORBS2, and PPARGCIA. An overlay analysis of the gene expression and CNA profiles was then performed. This analysis identified genes showing both CNAs and concurrent gene expression alterations. Many of these are commonly seen in sporadic PTC such as SERPINA, COL8A, and PDX, while others were unique to the radiation-induced profiles including CAMK2N1, AK1, DHRS3, and PDE9A. Conclusions: This type of analysis allows an assessment of gene expression changes that are associated with a physical mechanism. These genes and chromosomal regions are potential markers for radiation-induced PTC. © 2010 Mary Ann Liebert, Inc.


Brenner A.V.,U.S. National Institutes of Health | Tronko M.D.,Institute of Endocrinology and Metabolism | Hatch M.,U.S. National Institutes of Health | Bogdanova T.I.,Institute of Endocrinology and Metabolism | And 13 more authors.
Environmental Health Perspectives | Year: 2011

Background: Current knowledge about Chornobyl-related thyroid cancer risks comes from ecological studies based on grouped doses, case-control studies, and studies of prevalent cancers. Objective: To address this limitation, we evaluated the dose-response relationship for incident thyroid cancers using measurement-based individual iodine-131 (I-131) thyroid dose estimates in a prospective analytic cohort study. Methods: The cohort consists of individuals < 18 years of age on 26 April 1986 who resided in three contaminated oblasts (states) of Ukraine and underwent up to four thyroid screening examinations between 1998 and 2007 (n = 12,514). Thyroid doses of I-131 were estimated based on individual radioactivity measurements taken within 2 months after the accident, environmental transport models, and interview data. Excess radiation risks were estimated using Poisson regression models. Results: Sixty-five incident thyroid cancers were diagnosed during the second through fourth screenings and 73,004 person-years (PY) of observation. The dose-response relationship was consistent with linearity on relative and absolute scales, although the excess relative risk (ERR) model described data better than did the excess absolute risk (EAR) model. The ERR per gray was 1.91 [95% confidence interval (CI), 0.43-6.34], and the EAR per 104 PY/Gy was 2.21 (95% CI, 0.04-5.78). The ERR per gray varied significantly by oblast of residence but not by time since exposure, use of iodine prophylaxis, iodine status, sex, age, or tumor size. Conclusions: I-131-related thyroid cancer risks persisted for two decades after exposure, with no evidence of decrease during the observation period. The radiation risks, although smaller, are compatible with those of retrospective and ecological post-Chornobyl studies.


PubMed | Institute of Endocrinology and Metabolism, National Cancer Institute and U.S. National Cancer Institute
Type: Journal Article | Journal: Cancer epidemiology | Year: 2015

The Chernobyl nuclear power plant accident in Ukraine in 1986 led to widespread radioactive releases into the environment - primarily of radioiodines and cesium - heavily affecting the northern portions of the country, with settlement-averaged thyroid doses estimated to range from 10 mGy to more than 10 Gy. The increased risk of thyroid cancer among exposed children and adolescents is well established but the impact of radioactive contamination on the risk of other types of cancer is much less certain. To provide data on a public health issue of major importance, we have analyzed the incidence of non-thyroid cancers during the post-Chernobyl period in a well-defined cohort of 13,203 individuals who were <18 years of age at the time of the accident. The report is based on standardized incidence ratio (SIR) analysis of 43 non-thyroid cancers identified through linkage with the National Cancer Registry of Ukraine for the period 1998 through 2009. We compared the observed and expected number of cases in three cancer groupings: all solid cancers excluding thyroid, leukemia, and lymphoma. Our analyses found no evidence of a statistically significant elevation in cancer risks in this cohort exposed at radiosensitive ages, although the cancer trends, particularly for leukemia (SIR=1.92, 95% confidence interval: 0.69; 4.13), should continue to be monitored.


Landau Z.,Diabetes Unit | Klonoff D.,Diabetes Research Institute | Nayberg I.,Diabetes Research Institute | Feldman D.,Diabetes Unit | And 5 more authors.
Diabetes/Metabolism Research and Reviews | Year: 2014

Background: Previous studies have shown that heating the insulin injection site may accelerate insulin absorption. We investigated the pharmacological profile of insulin administered with InsuPatch, a local skin-heating device. Methods: In this randomized, crossover study carried out in 56 subjects with type 1 diabetes treated with insulin pump [mean age 32±13.5 years; 23 women; HbA1c:7.8±0.9% (62±10 mmol/mol) (mean+/-standard deviation)]. Euglycemic glucose clamps were performed after administration of 0.15 units/kg of short-acting insulin analogues. Each subject underwent three clamp procedures: two with the InsuPatch device (day 1 and day 3) and one without the device (day 1 control). The primary endpoints were the following: (1) the change in the area under the curve (AUC) of insulin during the first 60 min post-insulin bolus on day 1 with the InsuPatch device versus day 1 control and (2) parameters to assess the safety of using the device. Results: The area under the curve of insulin during the initial 60 min (insulin AUC0-60) after insulin bolus was increased by 29.7±7% on day 1 InsuPatch versus day 1 control (p<0.01). Maximal post-insulin bolus concentration was 57 mU/L on day 1 InsuPatch versus 47.6 mU/L on day 1 control (p<0.01). On day 3 InsuPatch, insulin AUC0-60 was increased by 27.9±72% versus day 1 InsuPatch (p<0.01). Maximal insulin concentration was 70.4 mU/L versus 57 mU/L, respectively (p=0.05). Conclusions: The use of the heating device upon administration of short-acting insulin analogues in pump-treated type 1 diabetic patients was found to enhance insulin absorption. This heating device may therefore serve to achieve better meal insulin coverage. © 2014 John Wiley & Sons, Ltd.


PubMed | Ukrainian Academy of Sciences, Silesian University of Technology, Center of Oncology of Poland, Imperial College London and 2 more.
Type: Journal Article | Journal: European journal of nuclear medicine and molecular imaging | Year: 2016

Following the nuclear accidents in Chernobyl and later in Fukushima, the nuclear community has been faced with important issues concerning how to search for and diagnose biological consequences of low-dose internal radiation contamination. Although after the Chernobyl accident an increase in childhood papillary thyroid cancer (PTC) was observed, it is still not clear whether the molecular biology of PTCs associated with low-dose radiation exposure differs from that of sporadic PTC.We investigated tissue samples from 65 children/young adults with PTC using DNA microarray (Affymetrix, Human Genome U133 2.0 Plus) with the aim of identifying molecular differences between radiation-induced (exposed to Chernobyl radiation, ECR) and sporadic PTC. All participants were resident in the same region so that confounding factors related to genetics or environment were minimized.There were small but significant differences in the gene expression profiles between ECR and non-ECR PTC (global test, p<0.01), with 300 differently expressed probe sets (p<0.001) corresponding to 239 genes. Multifactorial analysis of variance showed that besides radiation exposure history, the BRAF mutation exhibited independent effects on the PTC expression profile; the histological subset and patient age at diagnosis had negligible effects. Ten genes (PPME1, HDAC11, SOCS7, CIC, THRA, ERBB2, PPP1R9A, HDGF, RAD51AP1, and CDK1) from the 19 investigated with quantitative RT-PCR were confirmed as being associated with radiation exposure in an independent, validation set of samples.Significant, but subtle, differences in gene expression in the post-Chernobyl PTC are associated with previous low-dose radiation exposure.


PubMed | Imperial College London, Medical Radiological Research Center, Integrated Biobank of Luxembourg and Institute of Endocrinology and Metabolism
Type: Journal Article | Journal: Journal of clinical pathology | Year: 2016

To establish whether RNA degrades in long-term storage at -80C and whether RNA integrity numbers (RINs) determine fitness for purpose in severely degraded RNA.RNA was extracted from 549 thyroid biospecimens stored at -80C for 0.1-10.9years then their RINs correlated with storage time. RT-PCR for 65, 265, 534 and 942 base pair amplicons of hydroxymethylbilane synthase was used to measure amplicon length in RNA from cryopreserved and FFPE biospecimens that were equally degraded according to RIN.Storage time did not correlate with RIN. Longer amplicons were obtained from cryopreserved samples than FFPE samples with equal RINs.RNA does not degrade in thyroid biospecimens stored for long periods of time at -80C. Although RINs are known to predict amenability to analytical platforms in good quality samples, this prediction is unreliable in severely degraded samples.


Baradaran H.R.,Tehran University of Medical Sciences | Mirghorbani S.-M.,Institute of Endocrinology and Metabolism | Javanbakht A.,Institute of Endocrinology and Metabolism | Yadollahi Z.,Tehran University of Medical Sciences | Khamseh M.E.,Institute of Endocrinology and Metabolism
International Journal of Preventive Medicine | Year: 2013

Background: Patients with diabetes experience some level of emotional distress varying from disease-specific distress to general symptoms of anxiety and depression. Since empirical data about symptom distress in relation to diabetes are sparse in Iran, this study was designed to assess the diabetes-specific distress in Iranian population. Methods: Persian version of Diabetes Distress Scale (DDS) questionnaire was completed by volunteer outpatients on a consecutive basis between February 2009 and July 2010, in Endocrine Research Center (Firouzgar Hospital). Then, scheduled appointments were made with a psychiatrist in the same week following completion of the questionnaire. The psychiatrist was not aware about the results of this questionnaire and patients were interviewed based on DSM-IV criteria. Results: One hundred and eighty-five patients completed the questionnaire and were interviewed by a psychiatrist. Fifty-two percent of the patients were females. The mean age was 56.06 (SD=9.5) years and the mean of duration of diabetes was 9.7 (SD=7.3) years. Sixty-five (35%) had distress. Among the patients with distress, 55% were females and 64% had lower grade of education. Eighty patients were diagnosed as having Major Depressive Disorder. There was a relation between Emotional Burden subscale and age (P=0.004), employment status (P=0.03), and also diabetes duration (P=0.02). The physician-related distress subscale was also related to the type of medication (P=0.009) and marital status (P=0.01). It has been shown that the regimen-related distress subscale was also related to age (P=0.003) and duration of diabetes (P=0.005). Conclusions: High prevalence rate of distress in the study highlights the significance of the need for identifying distress and also other mental health conditions in patients with diabetes in order to take collaborative care approaches.


Nikonenko A.G.,Bogomoletz Institute of Physiology | Bozhok Y.M.,Institute of Endocrinology and Metabolism
Cytometry Part A | Year: 2015

The nucleus of an eukaryotic cell is a membrane-bound organelle containing a major part of the cellular genome. Nuclear shape is controlled by forces generated in the cytoskeleton, nuclear envelope and matrix of the nucleus and may change when the balance of these forces is disturbed. In certain cases, such changes may be indicative of cell pathology. Nuclear shape feature is being commonly addressed in both experimental research and diagnostics; nevertheless its symmetry-related aspects receive little attention. This article introduces a technique allowing to estimate nuclear shape asymmetry in digital images captured from cyto- or histological preparations. Implemented in a software package, this technique quantifies the asymmetry using two scenarios. The first one presumes the identification of nuclear pixels laying outside the largest inscribed circle. According to the second scenario, the algorithm searches for nuclear pixels lacking pixel-partners symmetric with respect to the nuclear area's centroid. In both cases, the proportion of "asymmetric" pixels is used to estimate the feature of interest. The technique was validated on images of cell nuclei having distinctive shape phenotypes. A conclusion was made that shape asymmetry feature may be useful accessory to the toolbox of nuclear morphometry. © 2014 International Society for Advancement of Cytometry.


Nikonenko A.G.,Bogomoletz Institute of Physiology | Bozhok Y.M.,Institute of Endocrinology and Metabolism
Diagnostic Cytopathology | Year: 2012

Fine-needle aspiration (FNA) cytology is widely used to examine thyroid lesions. However, its diagnostic accuracy is limited by the narrow choice of cytopathologic markers indicative of invasive/metastatic powers of a tumor. The aim of this study was to identify features that may serve as such indicators. We have examined FNA smears of 50 histologically proven papillary thyroid carcinoma (PTC) cases applying computer-assisted morphometry to assess patterns formed by PTC cells. Cytokeratine (CK) 8 immunocytochemistry was used to verify the epithelial origin of cells under study. All analyzed smears contained blood, histiocyte-like cells and CK8-positive follicular cells occurring both as single cells and in monolayer cell sheets. In 60% of cases we revealed cell sheets displaying two distinct cell patterns. The first one (pattern R) consisted of moderately pleomorphic, rather regularly arranged cells having an amphophilic cytoplasm. The second one (pattern I) was formed by highly pleomorphic cells with a basophilic cytoplasm. Patterns R and I were clearly different in cell size and shape as well as in nuclear size and shape. These patterns were never observed within the same cell sheet indicating that they may be formed by different subclones of tumor cells. Thus, it can be concluded that PTC frequently displays two definitely different cell patterns. We think that these patterns have a potential to serve as indicators for early events of an invasive/metastatic process. It remains to be seen whether the simultaneous occurrence of these patterns is a PTC-specific feature. Diagn. Cytopathol. 2012;40:E55-E61. © 2011 Wiley Periodicals, Inc. Copyright © 2011 Wiley Periodicals, Inc.

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