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Paulsson K.,Lund University | Forestier E.,Umeå University | Andersen M.K.,Copenhagen University | Autio K.,Helsinki and Uusimaa Hospital Group | And 12 more authors.
Haematologica | Year: 2013

Between 1992 and 2008, 713 high hyperdiploid acute lymphoblastic leukemias in children aged 1-15 years were diagnosed and treated according to the Nordic Society for Pediatric Hematology and Oncology acute lymphoblastic leukemia 1992/2000 protocols. Twenty (2.8%) harbored t(1;19), t(9;22), der(11q23), or t(12;21). The median age of patients with "classic" high hyperdiploidy was lower than that of patients with translocation-positive high hyperdiploidy (P<0.001). Cases with triple trisomies (+4, +10, +17), comprising 50%, had higher modal numbers than the triple trisomy-negative cases (P<0.0001). The probabilities of event-free survival and overall survival were lower for those with white blood cell counts ≥50 ×109/L (P=0.017/P=0.009), ≥5% bone marrow blasts at day 29 (P=0.001/0.002), and for high-risk patients (P<0.001/P=0.003), whereas event-free, but not overall, survival, was higher for cases with gains of chromosomes 4 (P<0.0001), 6 (P<0.003), 17 (P=0.010), 18 (P=0.049), and 22 (P=0.040), triple trisomies (P=0.002), and modal numbers >53/55 (P=0.020/0.024). In multivariate analyses, modal number and triple trisomies were significantly associated with superior event-free survival in separate analyses with age and white blood cell counts. When including both modal numbers and triple trisomies, only low white blood cell counts were significantly associated with superior event-free survival (P=0.009). We conclude that high modal chromosome numbers and triple trisomies are highly correlated prognostic factors and that these two parameters identify the same subgroup of patients characterized by a particularly favorable outcome. © 2013 Ferrata Storti Foundation.


Lundin C.,Lund University | Forestier E.,Umeå University | Klarskov Andersen M.,Copenhagen University | Autio K.,Helsinki and Uusimaa Hospital Group | And 11 more authors.
Journal of Hematology and Oncology | Year: 2014

Background: Children with Down syndrome (DS) have an increased risk for acute lymphoblastic leukemia (ALL). Although previous studies have shown that DS-ALL differs clinically and genetically from non-DS-ALL, much remains to be elucidated as regards genetic and prognostic factors in DS-ALL. Methods. To address clinical and genetic differences between DS-ALL and non-DS-ALL and to identify prognostic factors in DS-ALL, we ascertained and reviewed all 128 pediatric DS-ALL diagnosed in the Nordic countries between 1981 and 2010. Their clinical and genetic features were compared with those of the 4,647 B-cell precursor (BCP) ALL cases diagnosed during the same time period. Results: All 128 DS-ALL were BCP ALL, comprising 2.7% of all such cases. The 5-year event-free survival (EFS) and overall survival (OS) were significantly (P = 0.026 and P = 0.003, respectively) worse for DS-ALL patients with white blood cell counts ≥50 × 109/l. The age distributions varied between the DS and non-DS cases, with age peaks at 2 and 3 years, respectively; none of the DS patients had infant ALL (P = 0.029). The platelet counts were lower in the DS-ALL group (P = 0.005). Abnormal karyotypes were more common in non-DS-ALL (P < 0.0001), and there was a significant difference in the modal number distribution, with only 2% high hyperdiploid DS-ALL cases (P < 0.0001). The 5-year EFS and 5-year OS were significantly worse for DS-ALL (0.574 and 0.691, respectively) compared with non-DS-ALL (0.783 and 0.894, respectively) in the NOPHO ALL-1992/2000 protocols (P < 0.001). Conclusions: The present study adds further support for genetic and clinical differences between DS-ALL and non-DS-ALL. © 2014 Lundin et al.; licensee BioMed Central Ltd.


Kerkhof H.J.M.,Genetic Laboratory | Kerkhof H.J.M.,The Netherlands Genomics Initiative Sponsored Netherlands Consortium for Healthy Aging | Bierma-Zeinstra S.M.A.,Erasmus University Rotterdam | Arden N.K.,University of Oxford | And 18 more authors.
Annals of the Rheumatic Diseases | Year: 2014

Objective: To develop and validate a prognostic model for incident knee osteoarthritis (KOA) in a general population and determine the value of different risk factor groups to prediction. Methods: The prognostic model was developed in 2628 individuals from the Rotterdam Study-I (RS-I). Univariate and multivariate analyses were performed for questionnaire/easily obtainable variables, imaging variables, genetic and biochemical markers. The extended multivariate model was tested on discrimination (receiver operating characteristic curve and area under the curve (AUC)) in two other populationbased cohorts: Rotterdam Study-II and Chingford Study. Results: In RS-I, there was moderate predictive value for incident KOA based on the genetic score alone in subjects aged <65 years (AUC 0.65), while it was only 0.55 for subjects aged ≥65 years. The AUC for gender, age and body mass index (BMI) in prediction for KOA was 0.66. Addition of the questionnaire variables, genetic score or biochemical marker urinary C-terminal cross-linked telopeptide of type II collagen to the model did not change the AUC. However, when adding the knee baseline KL score to the model the AUC increased to 0.79. Applying external validation, similar results were observed in the Rotterdam Study-II and the Chingford Study. Conclusions: Easy obtainable 'Questionnaire' variables, genetic markers, OA at other joint sites and biochemical markers add only modestly to the prediction of KOA incidence using age, gender and BMI in an elderly population. Doubtful minor radiographic degenerative features in the knee, however, are a very strong predictor of future KOA. This is an important finding, as many radiologists do not report minor degenerative changes in the knee. © 2014, BMJ Publishing Group. All rights reserved.


Igenomix has recently been rewarded accreditation by College of American Pathologists (CAP) in Dubai (UAE), given its state-of-the-art facilities and cutting-edge products in the space of advanced reproductive genetics. The U.S. federal government recognizes the CAP Laboratory Accreditation Program, begun in the early 1960s, as being equal to or more stringent than the government's own inspection program. The process is designed to ensure the highest standard of care for all laboratory patients. "The CAP Laboratory Accreditation Program's goal is to improve patient safety by advancing the quality of pathology and laboratory services through education, standard setting, and ensuring laboratories meet or exceed regulatory requirements. Igenomix is now the first Private Genetic Laboratory to be accredited by CAP in Middle East, which demonstrates the quality of the genetic testing services Igenomix delivers," said Dr. Rupali Chopra, Lab Director, Igenomix Dubai. Francisco Rodríguez, General Manager Igenomix, Middle East & India, upon learning of the laboratory's accreditation, said, "Igenomix becoming accredited by CAP is a great achievement and milestone, but most important is that doctors and patients can now be completely sure about Igenomix commitment and conviction of providing the best quality genetic services." Igenomix is one of the world's leading providers of advanced services in reproductive genetics. Currently operating from eight laboratories worldwide, has aggressive expansion plans to set foot in many new geographies including Canada and Turkey which will be operational soon. The global team of experts led by Prof. Dr. Carlos Simon, Professor of Obstetrics and Gynaecology at Valencia University and Stanford School of Medicine, Chief Scientific Officer and also a key shareholder of Igenomix, has come up with some path-breaking genetics services to support the specialists in the field of reproductive medicine over last few years. Specialist services offered by IGENOMIX include PGS (PreImplantation Genetic Screening) with the added advantage of MitoScore, NACE (Non invasive Analysis of Chromosomal Examination); CGT (Carrier Genetic Test); PGD (Preimplantation Genetic Diagnosis) and ERA (Endometrial Receptivity Analysis). Igenomix is a biotechnology company that provides advanced services in reproductive genetics. Our broad experience and advanced research ability make us one of the global leaders in this field, and we make sure we offer effective solutions adapted to different infertility problems. For further information about the company visit: http://www.igenomix.com


PubMed | Genetic Laboratory and Biomedical University of Rome
Type: | Journal: Epilepsia | Year: 2016

Unverricht-Lundborg disease or progressive myoclonic epilepsy type 1 (EPM1) is an autosomal recessive disease caused by mutation of the cystatin B gene (CSTB), located on chromosome 21q22.3. The most common mutation is an expansion of unstable dodecamer repetition (CCCCGCCCCGCG), whereas other types of mutations are rare. Among these, heterozygous compound mutations are described to induce a more severe phenotype than that of homozygous dodecameric repetition. We report two siblings affected by heterozygous compound mutations carrying a novel mutation of the deletion of three nucleotides in exon 2 of the gene in position 132-134 of the coding sequence (c.132-134del) in the allele not including the dodecamer repetition. This mutation results in the loss of two amino acid residues and insertion of an asparagine in position 44 (p.Lys44_Ser45delinsAsn). Our patients presented a very different clinical picture. The male patient had a severe myoclonus, drug-resistant epilepsy and psychiatric comorbidity, while his affected sister had only very rare seizures and sporadic myoclonic jerks at awakening. The revision of literature about heterozygous compound EPM1 patients confirms this gender phenotypic expressivity, with female patients carrying less severe symptoms than male patients. These data lead to the hypothesis of complex gender-specific factors interacting with CSTB expressivity in EPM1 patients.


Ogino J.,Sapporo Medical University | Asanuma H.,Sapporo Medical University | Hatanaka Y.,Hokkaido University | Matsuno Y.,Hokkaido University | And 9 more authors.
Pathology International | Year: 2013

With the aim of standardizing Ki-67 immunohistochemistry, we assessed interobserver and interlaboratory variability of the Ki-67 labeling index and Ki-67 score among eight general pathologists for 24 gastrointestinal stromal tumors (GISTs) and 12 leiomyosarcomas, which were predominantly of the gastrointestinal (GI) tract, mesentery and retroperitoneum, based on a review of a tissue microarrays subjected to immunohistochemistry with antibodies for Ki-67. For Ki-67 immunostaining of mesenchymal tumors of the GI tract, including GISTs, differences were seen in the scores given by regional hospitals. Conversely, for two categories of the Ki-67 labeling index, namely <10% and ≥10%, concordance of the Ki-67 score between microscopic observation and image analysis, and between the observers, was good, but it was not good for the other four categories of the index for <5%, 5-9%, 10-29%, and ≥30%. The concordance of the Ki-67 scores between the observers in two categories was higher using the Ki-67 pre-stained tissue microarrays (TMAs) within each participating institute than that using the Ki-67 stained TMAs between the participating institutes. The reproducibility of a 10% cut-off value for the Ki-67 labeling index to predict the prognosis of GISTs was relatively high, but there is an urgent need to standardize the staining technique. © 2013 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.


Dragomir C.,Genetic Laboratory | Stan A.,Genetic Laboratory | Stefanescu D.T.,Genetic Laboratory | Savu L.,Genetic Laboratory | Severin E.,Carol Davila University of Medicine and Pharmacy
Genetic Testing and Molecular Biomarkers | Year: 2011

Objective: In this study, the aim of prenatal screening was to estimate the carrier frequency of the three mutations 35delG, del (GJB6-D13S1830), and del (GJB6-D13S1854), which are known to be the leading mutations of hereditary hearing loss in European populations. Methods: We performed a prenatal screening to assess the carrier frequency of the most common mutations at the DFNB1 gene locus in the general population. Samples of amniotic fluid (n=339) and chorionic villi (n=11) were taken from an unselected group of 350 unrelated pregnant women with normal hearing. Genomic fetal DNA was extracted and analyzed by PCR multiplex assays. Results: The rate of carriers for the 35delG GJB2 mutation was 3.14%, comparable to that of most Southeastern European populations. All samples were negative for GJB6-D13S1830 and GJB6-D13S1854 deletions. The genetic tests were considered for carrier detection and early diagnosis rather than termination of pregnancy. Conclusions: Our study suggests a need for detecting the carriers. This is the first step for the construction of a national database and provides information for health planners and policy makers to help them in planning programs and allocation resources. The molecular testing was well received by pregnant women and appears to be feasible and highly acceptable. © 2011, Mary Ann Liebert, Inc.


Prasad V.,University of Cincinnati | Lorenz J.N.,University of Cincinnati | Lasko V.M.,University of Cincinnati | Nieman M.L.,University of Cincinnati | And 2 more authors.
Frontiers in Physiology | Year: 2013

Cl-/HCO-3 exchangers are expressed abundantly in cardiac muscle, suggesting that HCO-3 extrusion serves an important function in heart. Mice lacking Anion Exchanger Isoform 3 (AE3), a major cardiac Cl-/HCO-3 exchanger, appear healthy, but loss of AE3 causes decompensation in a hypertrophic cardiomyopathy (HCM) model. Using intra-ventricular pressure analysis, in vivo pacing, and molecular studies we identified physiological and biochemical changes caused by loss of AE3 that may contribute to decompensation in HCM. AE3-null mice had normal cardiac contractility under basal conditions and after ß-adrenergic stimulation, but pacing of hearts revealed that frequency-dependent inotropy was blunted, suggesting that AE3-mediated HCO-3 extrusion is required for a robust force-frequency response (FFR) during acute biomechanical stress in vivo. Modest changes in expression of proteins that affect Ca2+-handling were observed, but Ca2+-transient analysis of AE3-null myocytes showed normal twitch-amplitude and Ca2+-clearance. Phosphorylation and expression of several proteins implicated in HCM and FFR, including phospholamban (PLN), myosin binding protein C, and troponin I were not altered in hearts of paced AE3-null mice; however, phosphorylation of Akt, which plays a central role in mechanosensory signaling, was significantly higher in paced AE3-null hearts than in wild-type controls and phosphorylation of AMPK, which is affected by Akt and is involved in energy metabolism and some cases of HCM, was reduced. These data show loss of AE3 leads to impaired rate-dependent inotropy, appears to affect mechanical stress-responsive signaling, and reduces activation of AMPK, which may contribute to decompensation in heart failure. © 2013 Prasad, Lorenz, Lasko, Nieman, Al Moamen and Shull.


PubMed | Genetic Laboratory
Type: Clinical Trial | Journal: Genetic testing and molecular biomarkers | Year: 2011

In this study, the aim of prenatal screening was to estimate the carrier frequency of the three mutations 35delG, del (GJB6-D13S1830), and del (GJB6-D13S1854), which are known to be the leading mutations of hereditary hearing loss in European populations.We performed a prenatal screening to assess the carrier frequency of the most common mutations at the DFNB1 gene locus in the general population. Samples of amniotic fluid (n=339) and chorionic villi (n=11) were taken from an unselected group of 350 unrelated pregnant women with normal hearing. Genomic fetal DNA was extracted and analyzed by PCR multiplex assays.The rate of carriers for the 35delG GJB2 mutation was 3.14%, comparable to that of most Southeastern European populations. All samples were negative for GJB6-D13S1830 and GJB6-D13S1854 deletions. The genetic tests were considered for carrier detection and early diagnosis rather than termination of pregnancy.Our study suggests a need for detecting the carriers. This is the first step for the construction of a national database and provides information for health planners and policy makers to help them in planning programs and allocation resources. The molecular testing was well received by pregnant women and appears to be feasible and highly acceptable.


PubMed | Genetic Laboratory and Carol Davila University of Medicine and Pharmacy
Type: Journal Article | Journal: Journal of medicine and life | Year: 2015

DNA damage and chromosomal alterations in peripheral lymphocytes parallels DNA mutations in tumor tissues.The aim of our study was to predict the presence of neoplastic colorectal lesions by specific biomarkers in medium risk individuals (age 50 to 75, with no personal or family of any colorectal neoplasia).We designed a prospective cohort observational study including patients undergoing diagnostic or opportunistic screening colonoscopy. Specific biomarkers were analyzed for each patient in peripheral lymphocytes - presence of micronuclei (MN), nucleoplasmic bridges (NPB) and the Nuclear Division Index (NDI) by the cytokinesis-blocked micronucleus assay (CBMN). Of 98 patients included, 57 were medium risk individuals. MN frequency and NPB presence were not significantly different in patients with neoplastic lesions compared to controls. In medium risk individuals, mean NDI was significantly lower for patients with any neoplastic lesions (adenomas and adenocarcinomas, AUROC 0.668, p 00.5), for patients with advanced neoplasia (advanced adenoma and adenocarcinoma, AUROC 0.636 p 0.029) as well as for patients with adenocarcinoma (AUROC 0.650, p 0.048), for each comparison with the rest of the population. For a cut-off of 1.8, in medium risk individuals, an NDI inferior to that value may predict any neoplastic lesion with a sensitivity of 97.7%, an advanced neoplastic lesion with a sensitivity of 97% and adenocarcinoma with a sensitivity of 94.4%.NDI score may have a role as a colorectal cancer-screening test in medium risk individuals.DNA = deoxyribonucleic acid; CRC = colorectal cancer; EU = European Union; WHO = World Health Organization; FOBT = fecal occult blood test; CBMN = cytokinesis-blocked micronucleus assay; MN = micronuclei; NPB = nucleoplasmic bridges; NDI = Nuclear Division Index; FAP = familial adenomatous polyposis; HNPCC = hereditary non-polypoid colorectal cancer; IBD = inflammatory bowel diseases; ROC = receiver operating characteristics; AUROC = area under the receiver operating characteristics curve.

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