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Haematology genetics

Bruno Buecher, Marine Le Mentec, François Doz, Franck Bourdeaut, Marion Gauthier-Villars, Dominique Stoppa Lyonnet, Chrystelle Colas
Inherited mono-allelic mutation in one of the 4 major MMR genes results in Lynch syndrome which predisposes, in adulthood, mainly to colorectal and endometrial tumors characterized by microsatellite instability (MSI phenotype). Individuals with bi-allelic mutations of one of these genes developed early and multiple malignancies, most often in childhood. This recessively inherited condition is named CMMRD for Constitutional Mismatch Repair Deficiency. The spectrum of tumors is distinct from Lynch syndrome. Malignant brain tumors are at least as frequent as gastrointestinal tumors and in more than a third of cases haematological malignancies were also reported...
December 11, 2018: Bulletin du Cancer
Amit Gupta, Karan Shah, Manisha J Oza, Tapan Behl
Cancer is an uncontrolled and abnormal growth of cells in the body. Gene that guards the cell cycle and function as tumor suppressor is p53 (also called as the guardian of the genome) which is encoded by the TP53 gene. Various events like DNA damage, heat shock, hypoxia and oncogene over expression, results in activation of p53.Thus, it plays a major role as a regulatory protein which regulates various diverse biological responses, responsible for genetic stability by preventing genome mutation. More than 50% mutations in human cancers along with the increase in expression of murine double minute 2 gene (mdm2), has been found as one of the reason for cancer progression...
January 2019: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Johanna P van Geffen, Sanne L N Brouns, Joana Batista, Harriet McKinney, Carly Kempster, Magdolna Nagy, Suthesh Sivapalaratnam, Constance C F M J Baaten, Nikki Bourry, Mattia Frontini, Kerstin Jurk, Manuela Krause, Daniele Pillitteri, Frauke Swieringa, Remco Verdoold, Rachel Cavill, Marijke J E Kuijpers, Willem H Ouwehand, Kate Downes, Johan W M Heemskerk
In combination with microspotting, whole-blood microfluidics can provide high-throughput information on multiple platelet functions in thrombus formation. Based on assessment of the inter- and intra-subject variability in parameters of microspot-based thrombus formation, we aimed to determine the platelet factors contributing to this variation. Blood samples from 94 genotyped healthy subjects were analysed for conventional platelet phenotyping: i.e. haematological parameters, platelet glycoprotein expression levels and activation markers (24 parameters)...
December 13, 2018: Haematologica
Alassane Thiam, Sabrina Baaklini, Babacar Mbengue, Samia Nisar, Maryam Diarra, Sandrine Marquet, Mouhamadou Mansour Fall, Michel Sanka, Fatou Thiam, Rokhaya Ndiaye Diallo, Magali Torres, Alioune Dieye, Pascal Rihet
Background: Host factors, including host genetic variation, have been shown to influence the outcome of Plasmodium falciparum infection. Genome-wide linkage studies have mapped mild malaria resistance genes on chromosome 6p21, whereas NCR3-412 polymorphism (rs2736191) lying within this region was found to be associated with mild malaria. Methods: Blood samples were taken from 188 Plasmodium falciparum malaria patients (76 mild malaria patients, 85 cerebral malaria patients, and 27 severe non-cerebral malaria patients)...
2018: PeerJ
Harinder Gill, Ho-Wan Ip, Rita Yim, Wing-Fai Tang, Herbert H Pang, Paul Lee, Garret M K Leung, Jamilla Li, Karen Tang, Jason C C So, Rock Y Y Leung, Jun Li, Gianni Panagioutou, Clarence C K Lam, Yok-Lam Kwong
Current prognostication in myelofibrosis (MF) is based on clinicopathological features and mutations in a limited number of driver genes. The impact of other genetic mutations remains unclear. We evaluated for mutations in a myeloid panel of 54 genes using next-generation sequencing. Multivariate Cox regression analysis was used to determine prognostic factors for overall survival (OS) and leukaemia-free survival (LFS), based on mutations of these genes and relevant clinical and haematological features. One hundred and one patients (primary MF, N = 70; secondary MF, N = 31) with a median follow-up of 49 (1-256) months were studied...
December 4, 2018: Annals of Hematology
Nelson Leung, Frank Bridoux, Vecihi Batuman, Aristeidis Chaidos, Paul Cockwell, Vivette D D'Agati, Angela Dispenzieri, Fernando C Fervenza, Jean-Paul Fermand, Simon Gibbs, Julian D Gillmore, Guillermo A Herrera, Arnaud Jaccard, Dragan Jevremovic, Efstathios Kastritis, Vishal Kukreti, Robert A Kyle, Helen J Lachmann, Christopher P Larsen, Heinz Ludwig, Glen S Markowitz, Giampaolo Merlini, Peter Mollee, Maria M Picken, Vincent S Rajkumar, Virginie Royal, Paul W Sanders, Sanjeev Sethi, Christopher P Venner, Peter M Voorhees, Ashutosh D Wechalekar, Brendan M Weiss, Samih H Nasr
The term monoclonal gammopathy of renal significance (MGRS) was introduced by the International Kidney and Monoclonal Gammopathy Research Group (IKMG) in 2012. The IKMG met in April 2017 to refine the definition of MGRS and to update the diagnostic criteria for MGRS-related diseases. Accordingly, in this Expert Consensus Document, the IKMG redefines MGRS as a clonal proliferative disorder that produces a nephrotoxic monoclonal immunoglobulin and does not meet previously defined haematological criteria for treatment of a specific malignancy...
December 3, 2018: Nature Reviews. Nephrology
İlker Karacan, Reyhan Diz Küçükkaya, Fatma Nur Karakuş, Seyhun Solakoğlu, Aslıhan Tolun, Veysel Sabri Hançer, Eda Tahir Turanlı
OBJECTIVE: Autosomal recessive cutis laxa type IIA (ARCL2A) is a rare congenital disorder characterized by loose and elastic skin, growth and developmental delay, and skeletal anomalies. It is caused by biallelic mutations in ATP6V0A2 . Those mutations lead to increased pH in secretory vesicles and thereby to impaired glycosyltransferase activity and organelle trafficking. We aimed to identify the genetic and molecular cause of the unexpected haematological findings in a Turkish family...
November 26, 2018: Turkish Journal of Haematology: Official Journal of Turkish Society of Haematology
Aoula Al-Zebeeby, Meike Vogler, Mateus Milani, Caitlin Richards, Ahoud Alotibi, Georgia Greaves, Martin J S Dyer, Gerald M Cohen, Shankar Varadarajan
BH3 mimetics are novel targeted drugs with remarkable specificity and potency and enormous potential to improve cancer therapy. However, acquired resistance is an emerging problem. We report the rapid development of resistance in chronic lymphocytic leukemia cells isolated from patients exposed to increasing doses of Navitoclax (ABT-263), a BH3 mimetic. To mimic such rapid development of chemoresistance, we have developed simple resistance models to three different BH3 mimetics, targeting BCL-2 (ABT-199), BCL-XL (A-1331852) or MCL-1 (A-1210477), in relevant haematological cancer cell lines...
November 22, 2018: Haematologica
Sofie G Højfeldt, Benjamin O Wolthers, Morten Tulstrup, Jonas Abrahamsson, Ramneek Gupta, Arja Harila-Saari, Mats Heyman, Louise T Henriksen, Òlafur G Jónsson, Päivi M Lähteenmäki, Bendik Lund, Kaie Pruunsild, Goda Vaitkeviciene, Kjeld Schmiegelow, Birgitte K Albertsen
Asparaginase is essential in childhood acute lymphoblastic leukaemia (ALL) treatment, however hypersensitivity reactions to pegylated asparaginase (PEG-asparaginase) hampers anti-neoplastic efficacy. Patients with PEG-asparaginase hypersensitivity have been shown to possess zero asparaginase enzyme activity. Using this measurement to define the phenotype, we investigated genetic predisposition to PEG-asparaginase hypersensitivity in a genome-wide association study (GWAS). From July 2008 to March 2016, 1494 children were treated on the Nordic Society of Paediatric Haematology and Oncology ALL2008 protocol...
November 18, 2018: British Journal of Haematology
Ninna Bager, Kristian L Juul-Dam, Julie D Sandahl, Jonas Abrahamsson, Berna Beverloo, Eveline S J M de Bont, Shau-Yin Ha, Kirsi Jahnukainen, Ólafur G Jónsson, Gertjan L Kaspers, Zhanna Kovalova, Birgitte Lausen, Barbara De Moerloose, Ulrika Noren-Nyström, Josefine Palle, Kadri Saks, Bernward Zeller, Eigil Kjeldsen, Henrik Hasle
Data on occurrence, genetic characteristics and prognostic impact of complex and monosomal karyotype (CK/MK) in children with acute myeloid leukaemia (AML) are scarce. We studied CK and MK in a large unselected cohort of childhood AML patients diagnosed and treated according to Nordic Society for Paediatric Haematology and Oncology (NOPHO)-AML protocols 1993-2015. In total, 800 patients with de novo AML were included. CK was found in 122 (15%) and MK in 41 (5%) patients. CK and MK patients were young (median age 2·1 and 3·3 years, respectively) and frequently had FAB M7 morphology (24% and 22%, respectively)...
November 8, 2018: British Journal of Haematology
Kei Sato, Azusa Uehara, Sayaka Kinoshita, Ikki Nomura, Minami Yagi, Yuta Tanizaki, Yu Matsuda-Shoji, Atsushi Matsubayashi, Nobuyasu Endo, Yutaka Nagai, Takashi Kato
Automated blood cell counters can distinguish cells based on their size and the presence or absence of a nucleus. However, most vertebrates have nucleated blood cells that cannot be counted automatically. We established an alternative automatic method for counting peripheral blood cells by staining cells with the fluorescent dye acridine orange (AO) and analysing cell populations using flow cytometry (FCM). As promising new animal models, we chose Xenopus laevis and three inbred strains of X. tropicalis. We compared the haematological phenotypes, including blood cell types, cell sizes, cellular structure, and erythrocyte lifespans/turnover rate among X...
November 2, 2018: Scientific Reports
Tian Xue, Wei-Ge Wang, Xiao-Yan Zhou, Xiao-Qiu Li
Programmed cell death ligand 1 (PD-L1) is upregulated in various types of haematological malignancies and is associated with immunosuppression. This study aimed to investigate the expression pattern of PD-L1 in Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL). We retrospectively analysed clinicopathological characteristics in 30 cases of EBV-positive DLBCL and immunohistochemically evaluated the level of membrane bound PD-L1 protein. Twenty-eight cases expressed PD-L1 protein 15 of which showed an intense positive staining...
October 30, 2018: Pathology
Ibrahim Bala Salisu, Ahmad Ali Shahid, Amina Yaqoob, Abdul Qayyum Rao, Tayyab Husnain
Genetically modified (GM) crops expressing insect resistance and herbicide tolerance provide a novel approach for improved crop production but their advent at the same time presents serious challenges in terms of food safety. Although prevailing scientific proof has suggested that transgenic crops are analogous to their conventional counterparts, their use in human and animal diet gave rise to emotional public discussion. A number of studies had been conducted to evaluate the potential unintended effects of transgenic crops expressing single transgene, but very few studies for those with multiple transgenes...
October 29, 2018: Journal of Animal Physiology and Animal Nutrition
Nicoletta Staropoli, Domenico Ciliberto, Teresa Del Giudice, Eleonora Iuliano, Maria Cucè, Francesco Grillone, Angela Salvino, Vito Barbieri, Antonio Russo, Pierfrancesco Tassone, Pierosandro Tagliaferri
INTRODUCTION: Carboplatin is the milestone of epithelial ovarian cancer (EOC) treatment, thus response to platinum is the major prognostic factor. Among platinum-sensitive patients, 40% carry a germline or somatic BRCA1/2 mutation. In this scenario a new class of drugs, the PARP inhibitors (PARPis), produced a significant improvement in long-term disease control. In order to make an aggregate evaluation of the impact of these agents, we performed a systematic review and meta-analysis...
November 2018: Critical Reviews in Oncology/hematology
Jennifer E May, Craig Donaldson, Liana Gynn, H Ruth Morse
Mesenchymal stem/stromal cells (MSCs) within the bone marrow (BM) are vitally important in forming the micro-environment supporting haematopoiesis after myeloablative chemotherapy. MSCs are known to be damaged phenotypically and functionally by chemotherapy; however, to the best our knowledge, the persistence of genotoxic effects of chemotherapy on the BM micro-environment has not been studied. We therefore aimed to evaluate genotoxic effects of chemotherapy on the BM both in vitro and in vivo, using the comet and micronucleus assays, focussing on the persistence of DNA lesions that may contribute to complications in the patient...
September 17, 2018: Mutagenesis
Santiago Montes-Moreno, Mark J Routbort, Elijah J Lohman, Bedia A Barkoh, Rashmi Kanagal-Shamanna, Carlos E Bueso-Ramos, Rajesh R Singh, L Jeffrey Medeiros, Raja Luthra, Keyur P Patel
ASXL1 (additional sex combs like 1) is a gene that is mutated in a number of hematological neoplasms. The most common genetic alteration is c.1934dupG p.Gly646fs. Previous publications have shown that ASXL1 mutations have a negative prognostic impact in patients with MDS and AML, however, controversy exists regarding the molecular testing of ASXL1 c.1934dupG as polymerase splippage over the adjacent homopolymer could lead to a false-positive result. Here, we report the first study to systematically test different targeted next generation sequencing (NGS) approaches for this mutation in patients with hematologic neoplasms...
2018: PloS One
Mario Sabatelli, Luca Laurenti, Marco Luigetti
Peripheral neuropathies are a vast group of diseases with heterogeneous aetiologies, including genetic and acquired causes. Several haematological disorders may cause an impairment of the peripheral nervous system, with diverse mechanisms and variable clinical, electrophysiological and pathological manifestations. In this practical review, we considered the main phenotypes of peripheral nervous system diseases associated with lymphoproliferative disorders. The area of intersection of neurological and haematological fields is of particular complexity and raises specific problems in the clinical practice of lymphoproliferative disorders...
2018: Mediterranean Journal of Hematology and Infectious Diseases
Shenmiao Yang, Robert Peter Gale, Hongxia Shi, Yanrong Liu, Yueyun Lai, Jin Lu, Xiaojun Huang
BACKGROUND: Chronic lymphocytic leukaemia (CLL) is 10- to 20-fold less common in Asians (including Han Chinese) compared with persons of predominately European descent. Why is unknown but seems predominately genetic. We observed an increasing frequency of new cases of CLL at our Haematology Centre beginning 2011 and wondered why. OBJECTIVE: Determine the cause(s) for this increased frequency. METHOD: We interrogated the context of CLL diagnosis in 483 consecutive subjects seen at the Institute of Haematology of a large referral hospital in Beijing...
October 2018: Leukemia Research
Donatella Poz, Elena De Falco, Calogera Pisano, Rosalinda Madonna, Peter Ferdinandy, Carmela Rita Balistreri
Evidence suggests association of red blood cell distribution width (RDW) with cardiovascular diseases (CVDs). On the contrary, we underline that the sole RDW values cannot represent a valid CVD biomarker. High RDW values are expression of biological effects of a lot of both endogenous and exogenous factors (i.e., age, sex, genetic background, inflammation, hormones, drugs, diet, exercise, hematological analyzers, and ranges of values), modulating the biology and physiology of erythrocytes. Thus, the singular monitoring of RDW cannot be used to predict cardiovascular disorders...
October 13, 2018: Rejuvenation Research
Luca Trotta, Anna Norberg, Mervi Taskinen, Vivien Béziat, Sofie Degerman, Ulla Wartiovaara-Kautto, Hannamari Välimaa, Kirsi Jahnukainen, Jean-Laurent Casanova, Mikko Seppänen, Janna Saarela, Minna Koskenvuo, Timi Martelius
BACKGROUND: The telomere biology disorders (TBDs) include a range of multisystem diseases characterized by mucocutaneous symptoms and bone marrow failure. In dyskeratosis congenita (DKC), the clinical features of TBDs stem from the depletion of crucial stem cell populations in highly proliferative tissues, resulting from abnormal telomerase function. Due to the wide spectrum of clinical presentations and lack of a conclusive laboratory test it may be challenging to reach a clinical diagnosis, especially if patients lack the pathognomonic clinical features of TBDs...
August 17, 2018: Orphanet Journal of Rare Diseases
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