204 research outputs found

    South Atlantic intermediate water advances into the North-east Atlantic with reduced Atlantic meridional overturning circulation during the last glacial period

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    The Nd isotopic composition (epsilon Nd) of seawater and cold-water coral (CWC) samples from the Gulf of Cadiz and the Alboran Sea, at a depth of 280-827 m were investigated in order to constrain middepth water mass dynamics within the Gulf of Cadiz over the past 40 ka. epsilon Nd of glacial and Holocene CWC from the Alboran Sea and the northern Gulf of Cadiz reveals relatively constant values (-8.6 to -9.0 and -9.5 to -10.4, respectively). Such values are similar to those of the surrounding present-day middepth waters from the Mediterranean Outflow Water (MOW; epsilon Nd approximate to -9.4) and Mediterranean Sea Water (MSW; epsilon Nd approximate to -9.9). In contrast, glacial epsilon Nd values for CWC collected at thermocline depth (550-827 m) in the southern Gulf of Cadiz display a higher average value (-8.90.4) compared to the present-day value (-11.70.3). This implies a higher relative contribution of water masses of Mediterranean (MSW) or South Atlantic origin (East Antarctic Intermediate Water, EAAIW). Our study has produced the first evidence of significant radiogenic epsilon Nd values (approximate to -8) at 19, 23-24, and 27 ka, which are coeval with increasing iceberg discharges and a weakening of Atlantic Meridional Overturning Circulation (AMOC). Since MOW epsilon Nd values remained stable during the last glacial period, it is suggested that these radiogenic epsilon Nd values most likely reflect an enhanced northward propagation of glacial EAAIW into the eastern Atlantic Basin

    Molecular and phenotypic diversity of <I>CBL</I>-mutated juvenile myelomonocytic leukemia

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    Mutations in the CBL gene were first identified in adults with various myeloid malignancies. Some patients with juvenile myelomonocytic leukemia (JMML) were also noted to harbor mutations in CBL, but were found to have generally less aggressive disease courses compared to patients with other forms of Ras pathway-mutant JMML. Importantly, and in contrast to most reports in adults, the majority of CBL mutations in JMML patients are germline with acquired uniparental disomy occurring in affected marrow cells. Here, we systematically studied a large cohort of 33 JMML patients with CBL mutations and found that this disease is highly diverse in presentation and overall outcome. Moreover, we discovered somatically acquired CBL mutations in 15% of pediatric patients who presented with more aggressive disease. Neither clinical features nor methylation profiling were able to distinguish patients with somatic CBL mutations from those with germline CBL mutations, highlighting the need for germline testing. Overall, we demonstrate that disease courses are quite heterogeneous even among patients with germline CBL mutations. Prospective clinical trials are warranted to find ideal treatment strategies for this diverse cohort of patients

    The genomic landscape of juvenile myelomonocytic leukemia

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    Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative neoplasm (MPN) of childhood with a poor prognosis. Mutations in NF1, NRAS, KRAS, PTPN11 and CBL occur in 85% of patients, yet there are currently no risk stratification algorithms capable of predicting which patients will be refractory to conventional treatment and therefore be candidates for experimental therapies. In addition, there have been few other molecular pathways identified aside from the Ras/MAPK pathway to serve as the basis for such novel therapeutic strategies. We therefore sought to genomically characterize serial samples from patients at diagnosis through relapse and transformation to acute myeloid leukemia in order to expand our knowledge of the mutational spectrum in JMML. We identified recurrent mutations in genes involved in signal transduction, gene splicing, the polycomb repressive complex 2 (PRC2) and transcription. Importantly, the number of somatic alterations present at diagnosis appears to be the major determinant of outcome

    Genetic predispositions to childhood leukemia.

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    Targeting the Ras pathway in pediatric hematologic malignancies.

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    Purpose of reviewRas pathway mutations are one of the most common type of alterations in pediatric hematologic malignancies and are frequently associated with adverse outcomes. Despite ongoing efforts to use targeted treatments, there remain no Food and Drug Administration (FDA)-approved medications specifically for children with Ras pathway-mutated leukemia. This review will summarize the role of Ras pathway mutations in pediatric leukemia, discuss the current state of Ras pathway inhibitors and highlight the most promising agents currently being evaluated in clinical trials.Recent findingsEfficacy using RAF and MEK inhibitors has been demonstrated across multiple solid and brain tumors, and these are now considered standard-of-care for certain tumor types in adults and children. Clinical trials are now testing these medications for the first time in pediatric hematologic disorders, such as acute lymphoblastic leukemia, juvenile myelomonocytic leukemia, and histiocytic disorders. Novel inhibitors of the Ras pathway, including direct RAS inhibitors, are also being tested in clinical trials across a spectrum of pediatric and adult malignancies.SummaryActivation of the Ras pathway is a common finding in pediatric hematologic neoplasms. Implementation of precision medicine with a goal of improving outcomes for these patients will require testing of Ras pathway inhibitors in combination with other drugs in the context of current and future clinical trials

    Genetic predispositions to childhood leukemia

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    While the majority of leukemia cases occur in the absence of any known predisposing factor, there are germline mutations that significantly increase the risk of developing hematopoietic malignancies in childhood. In this review article, we describe a number of these mutations and their clinical features. These predispositions can be broadly classified as those leading to bone marrow failure, those involving tumor suppressor genes, DNA repair defects, immunodeficiencies or other congenital syndromes associated with transient myeloid disorders. While leukemia can develop as a secondary event in the aforementioned syndromes, there are also several syndromes that specifically lead to the development of leukemia as their primary phenotype. Many of the genes discussed in this review can also be somatically mutated in other cancers, highlighting the importance of understanding shared alterations and mechanisms underpinning syndromic and sporadic leukemia

    Juvenile myelomonocytic leukemia in the molecular era: a clinician's guide to diagnosis, risk stratification, and treatment.

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    Juvenile myelomonocytic leukemia is an overlapping myeloproliferative and myelodysplastic disorder of early childhood . It is associated with a spectrum of diverse outcomes ranging from spontaneous resolution in rare patients to transformation to acute myeloid leukemia in others that is generally fatal. This unpredictable clinical course, along with initially descriptive diagnostic criteria, led to decades of productive international research. Next-generation sequencing now permits more accurate molecular diagnoses in nearly all patients. However, curative treatment is still reliant on allogeneic hematopoietic cell transplantation for most patients, and additional advances will be required to improve risk stratification algorithms that distinguish those that can be observed expectantly from others who require swift hematopoietic cell transplantation
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