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PubMed | Brest University Hospital Center, Nancy University Hospital Center, Cytogenetics Laboratory, Medecine Legale and 25 more.
Type: Journal Article | Journal: Clinical genetics | Year: 2016

Microarray-based comparative genomic hybridization (aCGH) is commonly used in diagnosing patients with intellectual disability (ID) with or without congenital malformation. Because aCGH interrogates with the whole genome, there is a risk of being confronted with incidental findings (IF). In order to anticipate the ethical issues of IF with the generalization of new genome-wide analysis technologies, we questioned French clinicians and cytogeneticists about the situations they have faced regarding IF from aCGH. Sixty-five IF were reported. Forty corresponded to autosomal dominant diseases with incomplete penetrance, 7 to autosomal dominant diseases with complete penetrance, 14 to X-linked diseases, and 4 were heterozygotes for autosomal recessive diseases with a high prevalence of heterozygotes in the population. Therapeutic/preventive measures or genetic counselling could be argued for all cases except four. These four IF were intentionally not returned to the patients. Clinicians reported difficulties in returning the results in 29% of the cases, mainly when the question of IF had not been anticipated. Indeed, at the time of the investigation, only 48% of the clinicians used consents mentioning the risk of IF. With the emergence of new technologies, there is a need to report such national experiences; they show the importance of pre-test information on IF.

PubMed | Cytogenetics Laboratory, Federal University of Vales do Jequitinhonha and Mucuri, Federal University of Säo João del Rei and Federal University of Viçosa
Type: Journal Article | Journal: Genetics and molecular research : GMR | Year: 2016

When evaluating plants, in particular perennial species, it is common to obtain repeated measures of a given trait from the same individual to evaluate the traits repeatability in successive harvests. The degree of correlation among these measures defines the coefficient of repeatability, which has been widely utilized in the study of forage traits of interest for breeding. The objective of the present study was to evaluate the repeatability of agronomic traits in Panicum maximum hybrids. Hybrids from three progenies totaling 320 hybrids were evaluated in an incomplete-block design, with consideration of production and morpho-agronomic traits. Of the production traits, total dry matter and leaf dry matter showed the highest repeatability and varied from 0.540 to 0.769, whereas stem dry matter had lower coefficients (0.265-0.632). Among the morpho-agronomic traits, plant height and incidence of Bipolaris maydis had higher coefficients (0.118-0.460). The repeatability values of the agronomic traits were low-to-moderate, and six evaluations were sufficient to provide accuracy in the selection of hybrids regarding total dry matter, leaf dry matter, plant height, and incidence of B. maydis, whereas the other traits require more repeated measures to increase reliability in the prediction of their response.

Rea I.M.,Queen's University of Belfast | Maxwell L.D.,Immunology and Microbiology Laboratory | McNerlan S.E.,Cytogenetics Laboratory | Alexander H.D.,University of Ulster | And 3 more authors.
Immunity and Ageing | Year: 2013

Background: Natural Killer Cells (NK) play an important role in detection and elimination of virus-infected, damaged or cancer cells. NK cell function is guided by expression of Killer Immunoglobulin-like Receptors (KIRs) and contributed to by the cytokine milieu. KIR molecules are grouped on NK cells into stimulatory and inhibitory KIR haplotypes A and B, through which NKs sense and tolerate HLA self-antigens or up-regulate the NK-cytotoxic response to cells with altered HLA self-antigens, damaged by viruses or tumours. We have previously described increased numbers of NK and NK-related subsets in association with sIL-2R cytokine serum levels in BELFAST octo/nonagenarians. We hypothesised that changes in KIR A and B haplotype gene frequencies could explain the increased cytokine profiles and NK compartments previously described in Belfast Elderly Longitudinal Free-living Aging STudy (BELFAST) octo/nonagenarians, who show evidence of ageing well.Results: In the BELFAST study, 24% of octo/nonagenarians carried the KIR A haplotype and 76% KIR B haplotype with no differences for KIR A haplogroup frequency between male or female subjects (23% v 24%; p=0.88) or for KIR B haplogroup (77% v 76%; p=0.99). Octo/nonagenarian KIR A haplotype carriers showed increased NK numbers and percentage compared to Group B KIR subjects (p=0.003; p=0.016 respectively). There were no KIR A/ B haplogroup-associated changes for related CD57+CD8 (high or low) subsets. Using logistic regression, KIR B carriers were predicted to have higher IL-12 cytokine levels compared to KIR A carriers by about 3% (OR 1.03, confidence limits CI 0.99-1.09; p=0.027) and 14% higher levels for TGF-β (active), a cytokine with an anti-inflammatory role, (OR 1.14, confidence limits CI 0.99-1.09; p=0.002).Conclusion: In this observational study, BELFAST octo/nonagenarians carrying KIR A haplotype showed higher NK cell numbers and percentage compared to KIR B carriers. Conversely, KIR B haplotype carriers, with genes encoding for activating KIRs, showed a tendency for higher serum pro-inflammatory cytokines compared to KIR A carriers. While the findings in this study should be considered exploratory they may serve to stimulate debate about the immune signatures of those who appear to age slowly and who represent a model for good quality survivor-hood. © 2013 Rea et al.; licensee BioMed Central Ltd.

Sawyer J.R.,University of Arkansas for Medical Sciences | Sawyer J.R.,Cytogenetics Laboratory | Tian E.,University of Arkansas for Medical Sciences | Heuck C.J.,University of Arkansas for Medical Sciences | And 12 more authors.
Blood | Year: 2015

Multiple myeloma is a B-cell malignancy stratified in part by cytogenetic abnormalities, including the high-risk copy number aberrations (CNAs) of 11q21 and 17p- . To investigate the relationship between 1q21 CNAs and DNA hypomethylation of the 1q12 pericentromeric heterochromatin, we treated in vitro peripheral blood cultures of 5 patients with balanced constitutional rearrangements of 1q12 and 5 controls with the hypomethylating agent 5-azacytidine. Using G-banding, fluorescence in situ hybridization, and spectral karyotyping, we identified structural aberrations and copy number gains of 1q21 in the treated cells similar to those found in patients with cytogenetically defined high-risk disease. Aberrations included 1q12 triradials, amplifications of regions juxtaposed to 1q12, and jumping translocations 1q12. Strikingly, all 5 patients with constitutional 1q12 rearrangements showed amplifications on the derivative chromosomes distal to the inverted or translocated 1q12 region, including MYCN in 1 case. At the same time, no amplification of the 1q21 region was found when the 1q12 region was inverted or absent. These findings provide evidence that the hypomethylation of the 1q12 region can potentially amplify any genomic region juxtaposed to it and mimic CNAs found in the bone marrow of patients with high-risk disease. © 2015 by The American Society of Hematology.

Rocha C.M.,University of Aveiro | Carrola J.,University of Aveiro | Barros A.S.,University of Aveiro | Gil A.M.,University of Aveiro | And 12 more authors.
Journal of Proteome Research | Year: 2011

In this work, the variations in the metabolic profile of blood plasma from lung cancer patients and healthy controls were investigated through NMR-based metabonomics, to assess the potential of this approach for lung cancer screening and diagnosis. PLS-DA modeling of CPMG spectra from plasma, subjected to Monte Carlo Cross Validation, allowed cancer patients to be discriminated from controls with sensitivity and specificity levels of about 90%. Relatively lower HDL and higher VLDL + LDL in the patients' plasma, together with increased lactate and pyruvate and decreased levels of glucose, citrate, formate, acetate, several amino acids (alanine, glutamine, histidine, tyrosine, valine), and methanol, could be detected. These changes were found to be present at initial disease stages and could be related to known cancer biochemical hallmarks, such as enhanced glycolysis, glutaminolysis, and gluconeogenesis, together with suppressed Krebs cycle and reduced lipid catabolism, thus supporting the hypothesis of a systemic metabolic signature for lung cancer. Despite the possible confounding influence of age, smoking habits, and other uncontrolled factors, these results indicate that NMR-based metabonomics of blood plasma can be useful as a screening tool to identify suspicious cases for subsequent, more specific radiological tests, thus contributing to improved disease management. © 2011 American Chemical Society.

Dawson A.J.,Cytogenetics Laboratory | Chernos J.,Alberta Childrens Hospital | McGowan-Jordan J.,Childrens Hospital of Eastern Ontario | Lavoie J.,Montreal Childrens Hospital | And 4 more authors.
Clinical Genetics | Year: 2011

The aim of this statement is to provide clinicians, cytogeneticists and molecular geneticists of the Canadian College of Medical Geneticists (CCMG) a comprehensive review of the role of UPD in constitutional genetic diagnosis and to provide a guideline as to when investigation for UPD is recommended. Members of the CCMG Cytogenetics, Molecular Genetics, Clinical Practice, and Prenatal Diagnosis committees reviewed the relevant literature on uniparental disomy (UPD) in constitutional genetic diagnosis (May 2010). Guidelines were developed for UPD testing in Canada. The guidelines were circulated for comment to the CCMG members at large and following appropriate modification, approved by the CCMG Board of Directors (July 2010). © 2010 John Wiley & Sons A/S.

Ricci M.,University of Miami | Mohapatra B.,Cytogenetics Laboratory | Urbiztondo A.,University of Miami | Birusingh R.J.,University of Miami | And 4 more authors.
Journal of Cardiac Failure | Year: 2010

Background: Hypoplastic left heart syndrome (HLHS) is characterized by underdevelopment of the left ventricle (LV) and increased biomechanical stress on the right ventricle (RV) from single ventricle physiology. Despite the clinical significance, the signaling pathways active during RV remodeling and disease progression are not known. To address this, we examined differential changes in expression of genes associated with transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) signaling in RV tissue isolated from HLHS patients relative to RV and LV tissue from control subjects. Methods and Results: Quantitative real-time polymerase chain reaction was used to detect changes in expression of 84 genes involved in TGF-β/BMP-mediated cardiac development, cell growth, and differentiation in RV tissue collected from 6 neonates with HLHS undergoing stage 1 Norwood procedure (age, 1-7 days; mean, 4 days) and RV and LV tissue obtained from 5 infants with noncardiac pathology (age range, 1-135 days: mean, 85 days) that served as controls. Analysis of gene expression profiles between control-LV and control-RV revealed significant depression of TGF-β/BMP signaling in RV compared with LV. Of the 84 genes analyzed, 38 were differentially expressed between HLHS-RV and control-RV, whereas only 22 compared with control-LV. Significant changes were observed in: tissue remodeling genes including Activin receptor type IIA (ACVR2A) (+2.13) and Activin receptor-like kinase 1 (ACVRL1) (+2.22); and cell survival, growth, and differentiation genes including CDC25A (+2.18), p21 (-3.64), p15 (+2.15), BMP5 (+4.58), BMP3 (+2.16), GDF3 (+8.59), NODAL (+2.32), and BMP binding endothelial regulator (BMPER) (+4.58). The most significant changes common to HLHS-RV versus control-RV and control-LV sample groups is observed for Anti müllerian hormone receptor 2 (AMHR2) (+18.79 control-RV, +3.38 control-LV), and the BMP antagonist Inhibin alpha (INHA) (+11.47 control-RV, +5.73 control-LV). Conclusions: Although this descriptive study does not allow cause-effect inferences, our results suggest changes in cardiac development pathways and upregulation of genes associated with cell growth and differentiation in the neonatal RV of children with HLHS. These molecular profiles are more closely related to those observed in the normal LV rather than normal RV at similar maturational age. This work provides the basis for future mechanistic studies to elucidate the molecular mechanisms regulating RV remodeling in HLHS. © 2010 Elsevier Inc. All rights reserved.

Slovak M.L.,Cytogenetics Laboratory | Slovak M.L.,Quest Diagnostics | Bedell V.,Cytogenetics Laboratory | Hsu Y.-A.,Cytogenetics Laboratory | And 6 more authors.
Clinical Cancer Research | Year: 2011

Purpose: To determine the recurring DNA copy number alterations (CNA) in classical Hodgkin lymphoma (HL) by microarray-based comparative genomic hybridization (aCGH) using laser capture microdissected CD30+ Hodgkin and Reed-Sternberg (HRS) cells. Experimental Design: Archived tissues from 27 CD30+ HL plus control samples were analyzed by DNA microarrays. The HL molecular karyotypes were compared with the genomic profiles of germinal center B cells and treatment outcome (chemotherapy responsive vs. primary refractory disease). Results: Gains and losses observed in more than 35% of HL samples were localized to 22 and 12 chromosomal regions, respectively. Frequent gains (>65%) were associated with growth and proliferation, NF-kB activation, cell-cycle control, apoptosis, and immune and lymphoid development. Frequent losses (>40%) observed encompassed tumor suppressor genes (SPRY1, NELL1, and ID4, inhibitor of DNA binding 4), transcriptional repressors (TXNIP, thioredoxin interacting protein), SKP2 (S-phase kinase-associated protein 2; ubiquitin ligase component), and an antagonist of NF-kB activation (PPARGC1A). In comparison to the germinal center profiles, the most frequent imbalances in HL were losses in 5p13 (AMACR, GDNF, and SKP2), and gains in 7q36 (SHH, sonic hedgehog homolog) and 9q34 (ABL1, CDK9, LCN2, and PTGES). Gains (>35%) in theHLchemoresponsive patients housed genes known to regulate T-cell trafficking or NF-κB activation (CCL22, CX3CL1, CCL17, DOK4, and IL10), whereas the refractory samples showed frequent loss of 4q27 (interleukin; IL21/IL2) and 17p12, and gain of 19q13.3 (BCL3/RELB). Conclusion: We identified nonrandom CNAs in the molecular karyotypes of classical HL. Several recurring genetic lesions correlated with disease outcome. These findings may be useful prognostic markers in the counseling and management of patients and for the development of novel therapeutic approaches in primary refractory HL. ©2011 AACR.

PubMed | Cytogenetics Laboratory and Childrens Hospital at Erlanger
Type: | Journal: Current protocols in toxicology | Year: 2016

Cultured mammalian cells are used extensively in cell biology studies. It requires a number of special skills in order to be able to preserve the structure, function, behavior, and biology of the cells in culture. This unit describes the basic skills required to maintain and preserve cell cultures: maintaining aseptic technique, preparing media with the appropriate characteristics, passaging, freezing and storage, recovering frozen stocks, and counting viable cells. 2016 by John Wiley & Sons, Inc.

PubMed | Sloan Kettering Cancer Center, Cytogenetics Laboratory, NeoGenomic Laboratories, Leukemia Service and New York University
Type: | Journal: Leukemia research | Year: 2016

In patients with chronic myelogenous leukemia (CML), point mutations in the BCR-ABL1 kinase domain are the most common cause of treatment failure with a tyrosine kinase inhibitor (TKI). It is not clear whether the splice variant BCR-ABL1(35INS) is also associated with treatment failure.We reviewed all CML patients who had BCR-ABL1 kinase mutation analysis performed between August 1, 2007, and January 15, 2014. Patients who had BCR-ABL1(35INS) detected had their medical records reviewed to determine response to TKI therapy.Two hundred and eighty four patients had kinase mutation testing performed; of these, 64 patients (23%) had BCR-ABL1(35INS) detected. Forty-five patients were in chronic phase (70%), 10 were in accelerated phase (16%), 6 were in blastic phase (9%), and 3 were in other settings (5%). Of the 34 chronic phase patients who began therapy with imatinib, 23 patients (68%) failed therapy: 8 patients (24%) had primary refractory disease, 11 patients (32%) progressed, and 4 patients (12%) had disease progression after dose interruption. In contrast to the patients with disease progression or lack of response, none of 23 patients who were responding to imatinib had BCR-ABL1(35INS) detected. DNA sequencing of commonly mutated spliceosomal genes SF3B1, U2AF1, SRSF2, ZRSR2, SFA31, PRPF408, U2A565, and SF1 did not reveal mutations in seven BCR-ABL1(35INS) -positive patients tested.The splice variant BCR-ABL1(35INS) is frequently found in patients who are resistant to imatinib. Mutations in the commonly mutated spliceosomal proteins do not contribute to this association.

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