Catalogue Search | MBRL
Are you sure you want to remove the book from the shelf?
{{itemTitle}}
345
result(s) for
"Cross, Nicholas"
Sort by:
النظريات العلمية ومكتشفوها
يتناول هذا الكتاب كوبرنيكوس وعلم الفلك الحديثJosh Sakolsky وكبلر وقوانين الحركة الكوكبيةHeather Hasan ونيوتن وقوانين الحركة الثلاث Nicholas Crossنيكولاس كوبرنيكوس هو عالم الفلك البولندي الذي قاد الطريق أثناء الأيام الأولى للثورة العلمية ونظام كوبرنيكوس الكوني شمسي المركز والذي هز به الأرض وطرح فيه أن الشمس هي مركز الكون وليست الأرض وكان من المعتقد لمئات السنين أن الأرض هي مركز الكون وظل بحث كوبرنيكوس الذي تحدى به المعتقدات يلهم لزمن طويل عقولا عظيمة غيرت العالم وهناك سلسلة من العقول العظيمة تبدأ بكوبرنيكوس مرورا بجاليليو وصولا إلى إسحاق نيوتن وألبرت أينشتاين قد أسهموا كلهم في العلم وأتاحوا للبشر الوصول إلى فهم أفضل للكون.
Book
Clonal myelopoiesis in the UK Biobank cohort: ASXL1 mutations are strongly associated with smoking
We sought to determine the significance of myeloid clonal hematopoiesis (CH) in the UK Biobank cohort (n = 502,524, median age = 58 years). Utilizing SNP array (n = 486,941) and whole exome sequencing data (n = 49,956), we identified 1166 participants with myeloid CH, defined by myeloid-associated mosaic chromosome abnormalities (mCA) and/or likely somatic driver mutations in DNMT3A, TET2, ASXL1, JAK2, SRSF2, or PPM1D. Myeloid CH increased by 1.1-fold per annum (myeloid mCA, P = 1.57 × 10−38; driver mutations, P = 5.89 × 10−47). Genome-wide association analysis identified two distinct signals within TERT that predisposed to myeloid CH, plus a weaker signal corresponding to the JAK2 46/1 haplotype. Specific subtypes of myeloid CH were associated with several blood features and clinical phenotypes, including TET2 mutations and chronic obstructive pulmonary disease. Smoking history was significantly associated with myeloid CH: 53% of myeloid CH cases were smokers compared to 44% of controls (P = 3.38 × 10−6), a difference principally due to current (OR = 1.10; P = 6.14 × 10−6) rather than past smoking (P = 0.08). Breakdown of CH by specific mutation type revealed that ASXL1 loss of function mutations were most strongly associated with current smoking status (OR = 1.07; P = 1.92 × 10−5), and the only abnormality associated with past smoking (OR = 1.04; P = 0.0026). We suggest that the inflammatory environment induced by smoking may promote the outgrowth of ASXL1-mutant clones.
Journal Article
Clonal myelopoiesis promotes adverse outcomes in chronic kidney disease
We sought to determine the relationship between age-related clonal hematopoiesis (CH) and chronic kidney disease (CKD). CH, defined as mosaic chromosome abnormalities (mCA) and/or driver mutations was identified in 5449 (2.9%) eligible UK Biobank participants (n = 190,487 median age = 58 years). CH was negatively associated with glomerular filtration rate estimated from cystatin-C (eGFR.cys; β = −0.75, P = 2.37 × 10–4), but not with eGFR estimated from creatinine, and was specifically associated with CKD defined by eGFR.cys < 60 (OR = 1.02, P = 8.44 × 10–8). In participants without prevalent myeloid neoplasms, eGFR.cys was associated with myeloid mCA (n = 148, β = −3.36, P = 0.01) and somatic driver mutations (n = 3241, β = −1.08, P = 6.25 × 10–5) associated with myeloid neoplasia (myeloid CH), specifically mutations in CBL, TET2, JAK2, PPM1D and GNB1 but not DNMT3A or ASXL1. In participants with no history of cardiovascular disease or myeloid neoplasms, myeloid CH increased the risk of adverse outcomes in CKD (HR = 1.6, P = 0.002) compared to those without myeloid CH. Mendelian randomisation analysis provided suggestive evidence for a causal relationship between CH and CKD (P = 0.03). We conclude that CH, and specifically myeloid CH, is associated with CKD defined by eGFR.cys. Myeloid CH promotes adverse outcomes in CKD, highlighting the importance of the interaction between intrinsic and extrinsic factors to define the health risk associated with CH.
Journal Article
European LeukemiaNet laboratory recommendations for the diagnosis and management of chronic myeloid leukemia
From the laboratory perspective, effective management of patients with chronic myeloid leukemia (CML) requires accurate diagnosis, assessment of prognostic markers, sequential assessment of levels of residual disease and investigation of possible reasons for resistance, relapse or progression. Our scientific and clinical knowledge underpinning these requirements continues to evolve, as do laboratory methods and technologies. The European LeukemiaNet convened an expert panel to critically consider the current status of genetic laboratory approaches to help diagnose and manage CML patients. Our recommendations focus on current best practice and highlight the strengths and pitfalls of commonly used laboratory tests.
Journal Article
Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders
Nicholas Cross and colleagues report the identification of somatic mutations altering the histone methyltransferase EZH2 in myeloid disorders. They identify monoallelic and biallelic EZH2 mutations in 7% of myeloid disorders, most commonly myelodysplastic and/or myeloproliferative neoplasms and myelofibrosis.
Abnormalities of chromosome 7q are common in myeloid malignancies, but no specific target genes have yet been identified. Here, we describe the finding of homozygous
EZH2
mutations in 9 of 12 individuals with 7q acquired uniparental disomy. Screening of a total of 614 individuals with myeloid disorders revealed 49 monoallelic or biallelic
EZH2
mutations in 42 individuals; the mutations were found most commonly in those with myelodysplastic/myeloproliferative neoplasms (27 out of 219 individuals, or 12%) and in those with myelofibrosis (4 out of 30 individuals, or 13%).
EZH2
encodes the catalytic subunit of the polycomb repressive complex 2 (PRC2), a highly conserved histone H3 lysine 27 (H3K27) methyltransferase that influences stem cell renewal by epigenetic repression of genes involved in cell fate decisions. EZH2 has oncogenic activity, and its overexpression has previously been causally linked to differentiation blocks in epithelial tumors. Notably, the mutations we identified resulted in premature chain termination or direct abrogation of histone methyltransferase activity, suggesting that
EZH2
acts as a tumor suppressor for myeloid malignancies.
Journal Article
HUGO Gene Nomenclature Committee (HGNC) recommendations for the designation of gene fusions
Gene fusions have been discussed in the scientific literature since they were first detected in cancer cells in the early 1980s. There is currently no standardized way to denote the genes involved in fusions, but in the majority of publications the gene symbols in question are listed either separated by a hyphen (-) or by a forward slash (/). Both types of designation suffer from important shortcomings. HGNC has worked with the scientific community to determine a new, instantly recognizable and unique separator—a double colon (::)—to be used in the description of fusion genes, and advocates its usage in all databases and articles describing gene fusions.
Journal Article
The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms
The upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours is part of an effort to hierarchically catalogue human cancers arising in various organ systems within a single relational database. This paper summarizes the new WHO classification scheme for myeloid and histiocytic/dendritic neoplasms and provides an overview of the principles and rationale underpinning changes from the prior edition. The definition and diagnosis of disease types continues to be based on multiple clinicopathologic parameters, but with refinement of diagnostic criteria and emphasis on therapeutically and/or prognostically actionable biomarkers. While a genetic basis for defining diseases is sought where possible, the classification strives to keep practical worldwide applicability in perspective. The result is an enhanced, contemporary, evidence-based classification of myeloid and histiocytic/dendritic neoplasms, rooted in molecular biology and an organizational structure that permits future scalability as new discoveries continue to inexorably inform future editions.
Journal Article
JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms
Nick Cross and colleagues report that the
JAK2
V617F
somatic mutation that drives the development of chronic myeloproliferative neoplasms is associated with the presence of a specific inherited haplotype in
JAK2
.
Chronic myeloproliferative neoplasms (MPNs) are a group of related conditions characterized by the overproduction of cells from one or more myeloid lineages. More than 95% of cases of polycythemia vera, and roughly half of essential thrombocythemia and primary myelofibrosis acquire a unique somatic 1849G>T
JAK2
mutation (encoding V617F) that is believed to be a critical driver of excess proliferation
1
,
2
,
3
,
4
. We report here that
JAK2
V617F
-associated disease is strongly associated with a specific constitutional
JAK2
haplotype, designated 46/1, in all three disease entities compared to healthy controls (polycythemia vera,
n
= 192,
P
= 2.9 × 10
−16
; essential thrombocythemia,
n
= 78,
P
= 8.2 × 10
−9
and myelofibrosis,
n
= 41,
P
= 8.0 × 10
−5
). Furthermore,
JAK2
V617F
specifically arises on the 46/1 allele in most cases. The 46/1
JAK2
haplotype thus predisposes to the development of
JAK2
V617F
-associated MPNs (OR = 3.7; 95% CI = 3.1–4.3) and provides a model whereby a constitutional genetic factor is associated with an increased risk of acquiring a specific somatic mutation.
Journal Article
Recurrent SETBP1 mutations in atypical chronic myeloid leukemia
Carlo Gambacorti-Passerini and colleagues identify recurrent
SETBP1
mutations in atypical chronic myeloid leukemia. The mutations, which cluster in a small region of
SETBP1
, are associated with high white blood cell counts and poor prognosis.
Atypical chronic myeloid leukemia (aCML) shares clinical and laboratory features with CML, but it lacks the
BCR
-
ABL1
fusion. We performed exome sequencing of eight aCMLs and identified somatic alterations of
SETBP1
(encoding a p.Gly870Ser alteration) in two cases. Targeted resequencing of 70 aCMLs, 574 diverse hematological malignancies and 344 cancer cell lines identified
SETBP1
mutations in 24 cases, including 17 of 70 aCMLs (24.3%; 95% confidence interval (CI) = 16–35%). Most mutations (92%) were located between codons 858 and 871 and were identical to changes seen in individuals with Schinzel-Giedion syndrome. Individuals with mutations had higher white blood cell counts (
P
= 0.008) and worse prognosis (
P
= 0.01). The p.Gly870Ser alteration abrogated a site for ubiquitination, and cells exogenously expressing this mutant exhibited higher amounts of SETBP1 and SET protein, lower PP2A activity and higher proliferation rates relative to those expressing the wild-type protein. In summary, mutated
SETBP1
represents a newly discovered oncogene present in aCML and closely related diseases.
Journal Article
Mosaic loss of chromosome Y in peripheral blood is associated with shorter survival and higher risk of cancer
Lars Forsberg, Jan Dumanski and colleagues report that age-related loss of chromosome Y in peripheral blood is associated with increased risks of all-cause mortality, cancer mortality and non-hematological cancer mortality.
Incidence and mortality for sex-unspecific cancers are higher among men, a fact that is largely unexplained
1
,
2
. Furthermore, age-related loss of chromosome Y (LOY) is frequent in normal hematopoietic cells
3
,
4
, but the phenotypic consequences of LOY have been elusive
5
,
6
,
7
,
8
,
9
,
10
. From analysis of 1,153 elderly men, we report that LOY in peripheral blood was associated with risks of all-cause mortality (hazards ratio (HR) = 1.91, 95% confidence interval (CI) = 1.17–3.13; 637 events) and non-hematological cancer mortality (HR = 3.62, 95% CI = 1.56–8.41; 132 events). LOY affected at least 8.2% of the subjects in this cohort, and median survival times among men with LOY were 5.5 years shorter. Association of LOY with risk of all-cause mortality was validated in an independent cohort (HR = 3.66) in which 20.5% of subjects showed LOY. These results illustrate the impact of post-zygotic mosaicism on disease risk, could explain why males are more frequently affected by cancer and suggest that chromosome Y is important in processes beyond sex determination. LOY in blood could become a predictive biomarker of male carcinogenesis.
Journal Article