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Haematology genetics

Trine I Jensen, Esben Axelgaard, Rasmus O Bak
The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated (Cas)9 platform offers an efficient way of making precise genetic changes to the human genome. This can be employed for disruption, addition and correction of genes, thereby enabling a new class of genetic therapies that can be applied to haematological disorders. Here we review recent technological advances in the CRISPR/Cas9 methodology and applications in haematology for curing monogenic genetic disorders and for engineering novel chimeric antigen receptor (CAR) T cells to treat haematological malignancies...
March 12, 2019: British Journal of Haematology
Gisela Barbany, Cecilia Arthur, Agne Liedén, Magnus Nordenskjöld, Richard Rosenquist, Bianca Tesi, Karin Wallander, Emma Tham
In recent years, detection of cell free tumour DNA (ctDNA) or liquid biopsy has emerged as an attractive non-invasive methodology to detect cancer-specific genetic aberrations in plasma, and numerous studies have reported on the feasibility of ctDNA in advanced cancer. In particular, ctDNA assays can capture a more 'global' portrait of tumour heterogeneity, monitor therapy response and lead to early detection of resistance mutations. More recently, ctDNA analysis has also been proposed as a promising future tool for detection of early cancer and/or cancer screening...
March 12, 2019: Journal of Internal Medicine
Marina Cavazzana, Frederic D Bushman, Annarita Miccio, Isabelle André-Schmutz, Emmanuelle Six
Pioneering gene therapy trials have shown that the genetic engineering of haematopoietic stem and progenitor cells can be an alternative to allogeneic transplantation in the treatment of primary immunodeficiencies. Early trials also highlighted the risk of insertional mutagenesis and oncogene transactivation associated with the first generation of gammaretroviral vectors. These events prompted the development of safer, self-inactivating lentiviral or gammaretroviral vectors. These lentiviral vectors have been successfully used to treat over 200 patients with 10 different haematological disorders (including primary immunodeficiencies, haemoglobinopathies and metabolic disorders) and for the generation of chimeric antigen receptor-T cells for cancer therapy...
March 11, 2019: Nature Reviews. Drug Discovery
Takayoshi Matsumura, Ayako Nakamura-Ishizu, Kensuke Takaoka, Hiroaki Maki, Siva S N A Muddineni, Chelsia Q Wang, Hitoshi Suzushima, Makoto Kawakita, Norio Asou, Masao Matsuoka, Mineo Kurokawa, Motomi Osato, Toshio Suda
Inherited thrombocytopenia is a genetically heterogeneous disease characterized by varying degrees of thrombocytopenia and risk of haematological malignancy, and the genetic cause of many cases remains unknown. We performed whole-exome sequencing of a family with thrombocytopenia and myeloid malignancy and identified a novel TUBB1 variant, T149P. Screening of other thrombocytopenia pedigrees identified another TUBB1 variant, R251H. TUBB1 encodes the tubulin β-1 chain, a major component of microtubules abundant in megakaryocytes...
March 10, 2019: British Journal of Haematology
Catherine Ludden, Danesh Moradigaravand, Dorota Jamrozy, Theodore Gouliouris, Beth Blane, Plamena Naydenova, Juan Hernandez-Garcia, Paul Wood, Nazreen Hadjirin, Milorad Radakovic, Charles Crawley, Nicholas M Brown, Mark Holmes, Julian Parkhill, Sharon J Peacock
Klebsiella pneumoniae is a human, animal and environmental commensal and a leading cause of nosocomial infections, which are often caused by multi-resistant strains that are challenging to treat. We conducted a One Health evaluation of putative sources of K. pneumoniae that are carried by, and infect hospital patients. This combined data from a six-month study on two haematology wards at Addenbrooke's Hospital, Cambridge, in 2015 to isolate K. pneumoniae from stool, blood and the environment, and a cross-sectional survey of K...
March 7, 2019: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Benjamin Chin-Yee, Bekim Sadikovic, Ian H Chin-Yee
Genomic technologies are revolutionizing the practice of haematology-oncology, leading to improved disease detection, more accurate prognostication and targeted treatment decisions. These advances, however, have also introduced new clinical challenges, which include problems of prognostic underdetermination and its attendant risks of over- and undertreatment. Genomic data is generated from different technologies, from cytogenetics to next-generation sequencing, which are often interpreted interchangeably and in a binary fashion-as the presence or absence of a given chromosomal deletion or mutation-an oversimplification which may lead to mistaken prognosis...
March 5, 2019: British Journal of Haematology
Robert M Herd, Jose I Velazco, Helen Smith, Paul F Arthur, Brad Hine, Hutton Oddy, Robin C Dobos, Roger S Hegarty
This experiment was to evaluate a suite of biological traits likely to be associated with genetic variation in residual feed intake (RFI) in Angus cattle. Twenty nine steers and 30 heifers bred to be divergent in postweaning RFI (RFIp) and that differed in mid-parent RFIp-EBV (RFIp-EBVmp) by more than 2 kg DMI/d were used in this study. A 1-unit (1 kg DM/d) decrease in RFIp-EBVmp was accompanied by a 0.08 kg (SE = 0.03; P < 0.05) increase in ADG, a 0.58 kg/d (0.17; P < 0.01) decrease in DMI, a 0.89 kg/kg (0...
February 20, 2019: Journal of Animal Science
Z Pavelka, K Zitterbart, H Nosková, V Bajčiová, O Slabý, J Štěrba
BACKGROUND: Individuals with constitutional mismatch repair-deficiency syndrome (CMMR-D) are characterised by early occurrence of colon cancer, haematological malignancies, and brain tumors (malignant gliomas, high-grade gliomas) in childhood, adolescence, and early adulthood. High mutational tumor burden is typical of glioblastoma in CMMR-D patients and could be a reason why this type of glioblastoma responds well to immunotherapies, including those that employ checkpoint inhibitors...
2019: Klinická Onkologie: Casopis Ceské a Slovenské Onkologické Spolecnosti
Hilko van der Voet, Paul W Goedhart, Esteban García-Ruiz, Concepción Escorial, Jana Tulinská
Safety assessments guard against unintended effects for human health and the environment. When new products are compared with accepted reference products by broad arrays of measurements, statistical analyses are usually summarised by significance tests or confidence intervals per endpoint. The traditional approach is to test for statistical significance of differences. However, absence or presence of significant differences is not a statement about safety. Equivalence limits are essential for safety assessment...
February 5, 2019: Food and Chemical Toxicology
Mojgan Djavaheri-Mergny, Sylvie Giuriato, Mario P Tschan, Magali Humbert
Haematopoiesis is a tightly orchestrated process where a pool of hematopoietic stem and progenitor cells (HSPCs) with high self-renewal potential can give rise to both lymphoid and myeloid lineages. The HSPCs pool is reduced with ageing resulting in few HSPC clones maintaining haematopoiesis thereby reducing blood cell diversity, a phenomenon called clonal haematopoiesis. Clonal expansion of HSPCs carrying specific genetic mutations leads to increased risk for haematological malignancies. Therefore, it comes as no surprise that hematopoietic tumours develop in higher frequency in elderly people...
January 30, 2019: Cells
K A Rack, E van den Berg, C Haferlach, H B Beverloo, D Costa, B Espinet, N Foot, S Jeffries, K Martin, S O'Connor, J Schoumans, P Talley, N Telford, S Stioui, Z Zemanova, R J Hastings
Cytogenomic investigations of haematological neoplasms, including chromosome banding analysis, fluorescence in situ hybridisation (FISH) and microarray analyses have become increasingly important in the clinical management of patients with haematological neoplasms. The widespread implementation of these techniques in genetic diagnostics has highlighted the need for guidance on the essential criteria to follow when providing cytogenomic testing, regardless of choice of methodology. These recommendations provide an updated, practical and easily available document that will assist laboratories in the choice of testing and methodology enabling them to operate within acceptable standards and maintain a quality service...
January 29, 2019: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Fardad T Afshari, Dhruv Parikh, Vladimir Petrik
Spontaneous spinal epidural haematoma is a rare entity associated with high morbidity. Although there are previous reports of spinal haematoma secondary to X-linked genetic haemophilia, there are no such cases secondary to acquired autoimmune haemophilia. We report the case of a 71-year-old patient who presented with sudden quadriplegia secondary to cervical (C2 to T1) epidural haematoma as a result of undiagnosed autoimmune acquired haemophilia A. She underwent emergency cervical laminectomy and evacuation of spinal haematoma with significant recovery in upper limb function...
September 2018: Case Reports in Neurology
Valeria Spina, Davide Rossi
In the era of personalised medicine, genetic information is critical to directing therapeutic options, aiding risk stratification and disease monitoring of lymphomas. Liquid biopsy is a novel noninvasive, real-time and tumour-specific technique, reliably reflecting the comprehensive tumour genetic profile, and thus holds great promise for the genetic assessment, response monitoring and relapse detection of lymphomas. Standard methods for disease response assessment in patients with lymphoma, including positron emission tomography, are imperfect...
January 14, 2019: Swiss Medical Weekly
Abby P Douglas, Caroline Marshall, Sarah L Baines, David Ritchie, Jeff Szer, Victoria Madigan, Hiu Tat Chan, Susan A Ballard, Benjamin P Howden, Kirsty Buising, Monica A Slavin
INTRODUCTION: The majority of vancomycin-resistant Enterococcus faecium (VREfm) in Australia is of the vanB genotype. An outbreak of vanA VREfm emerged in our haematology/oncology unit between November 2014 and May 2015. The first case of daptomycin non-susceptible E. faecium (DNSEfm) detected was a patient with vanA VREfm bacteraemia who showed clinical failure of daptomycin therapy, prompting microbiologic testing confirming daptomycin non-susceptibility. OBJECTIVES: To describe the patient profiles, antibiotic susceptibility and genetic relatedness of vanA VREfm isolates in the outbreak...
January 21, 2019: Journal of Medical Microbiology
Jonathan Spoor, Hamid Farajifard, Nima Rezaei
Neutropenia is a dangerous and potentially fatal condition that renders patients vulnerable to recurrent infections. Its severity is commensurate with the absolute count of neutrophil granulocytes in the circulation. In paediatric patients, neutropenia can have many different aetiologies. Primary causes make up but a small portion of the whole and are relatively unknown. In the past decades, a number of genes has been discovered that are responsible for congenital neutropenia. By perturbation of mitochondrial energy metabolism, vesicle trafficking or synthesis of functional proteins, these mutations cause a maturation arrest in myeloid precursor cells in the bone marrow...
January 2019: Critical Reviews in Oncology/hematology
Aruna Pal, Abantika Pal, Samiddha Banerjee, S Batobyal, P N Chatterjee
Cytochrome B is the mitochondrial protein, which functions as part of the electron transport chain and is the main subunit of transmembrane cytochrome bc1 and b6f complexes affecting energy metabolism through oxidative phosphorylation. The present study was conducted to study the effect of mutation of Cytochrome B gene on the health condition of sheep, which the first report of association of mitochondrial gene with disease traits in livestock species. Non-synonymous substitutions (F33 L and D171N) and Indel mutations were observed for Cytochrome B gene, leading to a truncated protein, where anemia, malfunctioning of most of the vital organs as liver, kidney and mineral status was observed and debility with exercise intolerance and cardiomyopathy in extreme cases were depicted...
January 17, 2019: Mitochondrion
Jitwadee Inthagard, Joanne Edwards, Antonia K Roseweir
Cancer treatments often reach a refractory period leading to treatment failure and patients developing disease recurrence. This can be due to tumour cells escaping the immune response and creating an immunosuppressive microenvironment enhancing cancer progression. Immunotherapy has become a promising tool for cancer treatment as it restores the anti-tumour response of the patient's immune system. Immune checkpoint inhibitors are the most widely studied immunotherapies worldwide and are now approved for multiple cancers...
January 31, 2019: Clinical Science (1979-)
Ana Sofia Quina, Ana Filipa Durão, Francesc Muñoz-Muñoz, Jacint Ventura, Maria da Luz Mathias
Heavy metal mining is one of the largest sources of environmental pollution. The analysis of different types of biomarkers in sentinel species living in contaminated areas provides a measure of the degree of the ecological impact of pollution and is thus a valuable tool for human and environmental risk assessments. In previous studies we found that specimens from two populations of the Algerian mice (Mus spretus) living in two abandoned heavy metal mines (Aljustrel and Preguiça, Portugal) had higher body burdens of heavy metals, which led to alterations in enzymatic activities and in haematological, histological and genotoxic parameters, than mice from a nearby reference population...
January 8, 2019: Ecotoxicology and Environmental Safety
Andrea Ballini, Luigi Santacroce, Stefania Cantore, Lucrezia Bottalico, Gianna Dipalma, Skender Topi, Rajiv Saini, Danila De Vito, Francesco Inchingolo
BACKGROUND: Inflammatory bowel diseases (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), are described as a chronic inflammation of the small intestine and colon, caused by a dysregulated immune response to host intestinal microbiota in genetically susceptible subjects. OBJECTIVE: The aim of this study was to compare probiotic therapy versus placebo in Oxidative Stress Values and clinical features in patients affected by IBD. METHOD: Forty (40) patients previously diagnosed for IBD were recruited and randomized to receive probiotics (test group, n=20) or placebo (control group, n=20) administered for 90 days...
December 21, 2018: Endocrine, Metabolic & Immune Disorders Drug Targets
Reena Kumari Sharma, Mudita Gupta, Samriti Sood, Archit Gupta
Dyskeratosis congenita (DKC) also known as Zinsser-Cole-Engman syndrome is a progressive genetic disease with a classical presentation characterised by a triad of reticulate pigmentation of skin, nail dystrophy and leukoplakia. It may be a multisystem disease with the involvement of haematological, gastrointestinal, genitourinary, neurological, ophthalmic, pulmonary and skeletal system. We report a sporadic case of DKC presenting with poikiloderma, nail dystrophy and oral leukoplakia.
November 28, 2018: BMJ Case Reports
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