The JAK2 V617F mutation was found in most patients with myeloproliferative disorders (MPDs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. We have generated transgenic mice expressing the mutated enzyme in the hematopoietic system driven by a vav gene promoter. The mice are viable and fertile. One line of the transgenic mice, which expressed a lower level of JAK2 V617F , showed moderate elevations of blood cell counts, whereas another line with a higher level of JAK2 V617F expression displayed marked increases in blood counts and developed phenotypes that closely resembled human essential thrombocythemia and polycythemia vera. The latter line of mice also developed primary myelofibrosis-like symptoms as they aged. The transgenic mice showed erythroid, megakaryocytic, and granulocytic hyperplasia in the bone marrow and spleen, displayed splenomegaly, and had reduced levels of plasma erythropoietin and thrombopoietin. They possessed an increased number of hema- IntroductionMyeloproliferative disorders are a group of conditions characterized by chronic increases in some or all of the blood cells (platelets, white blood cells, and red blood cells). [1][2][3] This group of blood disorders includes polycythemia vera (PV), essential (or primary) thrombocythemia (ET), primary myelofibrosis (PMF), and chronic myeloid leukemia (CML). PV is characterized by increased production of all 3 types of cells, whereas ET is manifest in the elevation of platelets. PMF is a disease in which fibrous (scar-like) tissues form in the marrow as a result of abnormal production of red cells, white cells, and platelets. CML is characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the peripheral blood. It is generally thought that MPDs arise from a transformation in a hematopoietic stem cell. Indeed, CML is now defined by its causative molecular lesion, the BCR-ABL fusion gene, which most commonly results from the Philadelphia translocation (Ph). Because of this defined molecular defect, a highly effective drug, namely, imatinib mesylate (Gleevec; Novartis, Basel, Switzerland), has been developed to treat CML. 4 So far, there is no effective cure for the 3 Ph-negative MPDs. Recently, 5 groups have identified a gain-of-function mutation of tyrosine kinase JAK2, which likely represents a major molecular defect in approximately 90% patients with PV and in approximately 50% of patients with ET or PMF. [5][6][7][8][9][10] The JAK2 mutant displays deregulated kinase activity and generates a PV-like phenotype in mouse bone marrow transplant models. [11][12][13][14] Studies also demonstrated infrequent occurrence of this mutation in chronic myelomonocytic leukemia, atypical myeloproliferative disorders, myelodysplastic syndrome, systemic mastocytosis, chronic neutrophilic leukemia, and acute myeloid leukemia. [15][16][17][18][19] Interestingly, our recent studies also demonstrated that nearly 1% of blood samples collected fr...

Background Red blood cell distribution width (RDW) is a clinical index used to make early diagnosis and to monitor treatment effects in iron deficiency anemia. Recently, several studies have suggested that RDW was associated with mortality from various cancers; however, there has been little evidence regarding RDW and cancer as a whole. Therefore, the purpose of our study was to investigate the relationship of RDW and overall cancer mortality in hospital. Methods We extracted patient data from the Multiparameter Intelligent Monitoring in Intensive Care Database III version 1.3 (MIMICIII.1.3). RDW was measured prior to hospital admission. Patients older than 18 who were diagnosed with malignant tumors were included. The primary outcome was cancer mortality in hospital. Logistic regression and multivariate analysis were used to assess the association between the RDW and hospital mortality. Result A total of 3384 eligible patients were enrolled. A positive correlation was observed between RDW and overall cancer mortality. Patients with higher RDW (14.4-16.3%, 16.4-30.5%) were at greater risk of death than the patients with RDW in the reference range (11.5-14.3%). On multivariate analysis, when adjusted for age and gender, the adjusted OR (95% CIs) in the mid-RDW group and high-RDW group were 1.61 (1.28, 2.03) and 2.52 (2.03, 3.13), respectively, with the low-RDW group set as the baseline. Similar trends were also observed in the model adjusted for other clinical characteristics. This suggested that elevated RDW was related to increased risk of cancer mortality, and RDW may play an important role in the prediction of short-term mortality after hospitalization in cancer patients. Conclusion Elevated RDW was associated with overall cancer mortality. To a certain extent, RDW may predict the risk of mortality in patients with cancers; it was an independent prognostic indicator of short-term mortality after hospitalization in cancer patients.

Acute kidney injury (AKI) is a common complication in cancer patients. Kidney function is closely related to patients' quality of life and tumor prognosis. Cisplatin is a highly effective anti-tumor drug. However, the use of cisplatin is limited by its nephrotoxicity. It has been reported that FGF21 has a renal-protective function, but the mechanisms by which it does so remain unclear. In this study, we show that the expression of FGF21 is significantly upregulated in both in vitro and in vivo cisplatin-induced AKI models. Administration of recombinant FGF21 to cisplatin-induced AKI mice resulted in significantly decreased blood urea nitrogen (BUN) and serum creatinine levels, as well as significantly reduced protein levels of kidney injury molecule-1 (TIM-1), C-caspase 3, and Bax. H&E-stained kidney sections from cisplatin-induced AKI mice treated with recombinant FGF21 showed a relatively normal renal tissue structure, a reduced number of necrotic sites and vacuolar changes, and decreased casts, suggesting alleviated renal tubular injury. Experiments with an AKI cell model (cisplatin-treated HK-2 cells) yielded similar results as the mouse model; recombinant FGF21 significantly downregulated protein expression levels of TIM-1, C-caspase 3, and Bax. Furthermore, administration of recombinant FGF21 to cisplatin-treated AKI models significantly increased SIRT1 expression, and the beneficial effects of FGF21 on kidney injury were reversed by SIRT1 knockdown. Collectively, our results suggest that SIRT1 mediates the protective effect of FGF21 on cisplatin-induced kidney injury.

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