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Therapy-related leukemia carries a poor prognosis, and leukemia after chemotherapy is a growing risk in clinic, whose mechanism is still not well understood. Ikaros transcription factor is an important regulator in hematopoietic cells development and differentiation. In the absence of Ikaros, lymphoid cell differentiation is blocked at an extremely early stage, and myeloid cell differentiation is also significantly affected. In this work, we showed that chemotherapeutic drug etoposide reduced the protein levels of several isoforms of Ikaros including IK1, IK2 and IK4, but not IK6 or IK7, by accelerating protein degradation, in leukemic cells. To investigate the molecular mechanism of Ikaros degradation induced by etoposide, immunoprecipitation coupled with LC-MS/MS analysis was conducted to identify changes in protein interaction with Ikaros before and after etoposide treatment, which uncovered KCTD5 protein. Our further study demonstrates that KCTD5 is the key stabilizing factor of Ikaros and chemotherapeutic drug etoposide induces Ikaros protein degradation through decreasing the interaction of Ikaros with KCTD5. These results suggest that etoposide may induce leukemic transformation by downregulating Ikaros via KCTD5, and our work may provide insights to attenuate the negative impact of chemotherapy on hematopoiesis. [ABSTRACT FROM AUTHOR]

Background: The incidence of acute pancreatitis caused by hyperlipidaemia is increasing. A quick and easy diagnosis of the severity of hyperlipidaemic acute pancreatitis (HTGP) is important to improve patient prognosis and reduce mortality. Previous studies reported that insulin resistance (IR) is associated with acute pancreatitis. Our study aimed to investigate the correlation between the triglycerides to high‐density lipoprotein cholesterol (TG/HDL‐C) ratio and HTGP. Methods: Patients' laboratory and clinical parameters were obtained from the institutional pancreatitis database. Univariate and multivariate logistic regression analyses were applied to evaluate the risk factors for the severity of HTGP and the efficacy of four clinical scoring systems: Ranson's Criteria, Acute Physiology and Chronic Health Evaluation II (APACHE II), the Bedside Index for Severity in Acute Pancreatitis (BISAP), and Marshall. Results: Of 290 patients, 134 (46.2%) were diagnosed with moderately severe to severe HTGP. The TG/HDL‐C ratio was higher in the moderately severe to severe HTGP subgroup than in the mild HTGP subgroup. Among the independent risk factors, such as amylase, albumin, aspartate transaminase (AST), systemic inflammatory response syndrome (SIRS), and TG/HDL‐C ratio, the TG/HDL‐C ratio had the highest area under the curve (AUC) (0.727, 95% CI, 0.571–0.701). In comparison with other clinical scoring systems, the TG/HDL‐C ratio has a relatively preferable predictive ability. Conclusion: Our findings suggest that the TG/HDL‐C ratio is positively correlated with HTGP severity and could be used as a simple indicator of severe HTGP. [ABSTRACT FROM AUTHOR]

Background: Body composition parameters are associated with hypertriglyceridemia‐induced pancreatitis (HTGP). This study investigated the association between the quantity of muscle assessed using computed tomography (CT) and the severity of HTGP. Methods: The modified CT severity index (MCTSI) was calculated from admission examination data. Patients' characteristics and body composition parameters were collected. Univariate and multivariate logistic regression analyses were also performed. The receiver operating characteristic curves and corresponding area under the curves (AUC) were calculated to test the efficiency of the model. A nomogram was then constructed. Results: Of the 175 included patients, 138 were male, of which 85 had moderately severe to severe HTGP. Patients with low skeletal muscle mass (LSMM) and high MCTSI were significantly more likely to have moderately severe to severe HTGP. Patients with LSMM had lower body mass index, lower HDL‐C level, higher amylase level, prevalence of surgery, shorter umbilical waist circumference, and longer length of hospital stay. Univariate and multivariate logistic regression analyses confirmed that female sex, lipase, total cholesterol, LSMM‐MCTSI (P =.004, odds ratio = 23.105), and albumin were risk factors. The TOTAL model that combined LSMM‐MCTSI and clinical risk parameters performed best (AUCs = 0.875), followed by other models (LSMM‐MCTSI: AUCs = 0.762, MCTSI: AUCs = 0.728). The Delong test revealed significant difference. Finally, a nomogram was developed to predict the severity of HTGP. Conclusion: The performance of MCTSI in predicting severity can be improved by considering LSMM, which is a promising strategy for the treatment of HTGP. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a hematologic malignant disease largely affecting older adults with poor outcomes. Lack of effective targeted treatment is a major challenge in managing the disease in the clinic. Scaffolding adaptor Gab2 is amplified in a subset of AML. However, the causative role of Gab2 in AML remains to be explored. In this study, it was found that Gab2 was expressed at high levels in AML patient samples and AML cell lines. Experiments by knocking down Gab2 expression using shRNA showed that Gab2 promoted AML cell growth and migration in vitro and in vivo. Further studies using Gab2 mutants and pharmacological inhibitors revealed that Gab2 increased CREB phosphorylation via the SHP‐2/Erk signaling pathway. CREB phosphorylation contributed to Gab2‐induced cell migration by increasing MMP2 and MMP9 expression. This research indicates that high Gab2 expression promotes AML progression through the SHP2‐Erk‐CREB signaling pathway. CREB suppression may help treat AML with high Gab2 expression. [ABSTRACT FROM AUTHOR]

Background: Analytic morphometric assessment has recently been proposed to be applied to the study of acute pancreatitis (AP). However, the relationship between body composition and the outcomes of hypertriglyceridemic pancreatitis (HTGP) is still unclear. The aim of this study was to evaluate body composition in relation to the length of hospital stay (LOS) and recurrence of HTGP. Methods: Patient characteristics, admission examination data, body composition parameters, LOS, and recurrence within 1 year were collected from the institutional pancreatitis database and follow-up records. Logistic regression analysis was used to identify risk factors for LOS and recurrence of HTGP. Results: Of the 196 included patients, 158 (80.6%) were men and 53 (27.0%) were sarcopenic. The average LOS was 15.83± 10.02 days. The recurrence rate of HTGP was 36.7%. Multivariate analysis with multiple linear regression suggested that subcutaneous adipose tissue (SAT) area (p=0.019) and high-density lipoprotein-cholesterol (HDL-C) (p=0.001) were independently associated with the LOS for HTGP after adjusting for age and sex. The multivariate adjusted hazard ratios for SAT area and HDL-C, with respect to the relationship between body parameters and LOS, were 1.008 (95% confidence interval [CI], 1.001– 1.015) and 0.090 (95% CI, 0.022– 0.361), respectively. No significant differences were observed between the AP and recurrent AP (RAP) groups in terms of characteristics, admission examination data, and body composition parameters. Conclusion: SAT area and HDL-C are associated with LOS in patients with HTGP. The body composition of patients at the first symptom onset of HTGP cannot predict recurrence. [ABSTRACT FROM AUTHOR]

As a subtype of acute myeloid leukemia (AML), acute promyelocytic leukemia (APL) is characterized by a chromosomal translocation, most of which result in the production of a PML‐RAR alpha fusion protein. Although the overall survival rate of APL patients has improved dramatically due to all‐trans retinoic acid (ATRA) treatment, ATRA‐resistance remains a clinical challenge in the management of APL. Therefore, alternative agents should be considered for ATRA‐resistant APL patients. Here, we report that antimalaria drug primaquine phosphate (PRQ) exhibits an anti‐leukemia effect on both ATRA‐sensitive cell line NB4 and ATRA‐resistant APL cell lines, NB4‐LR2, NB4‐LR1, and NB4‐MR2. Moreover, PRQ significantly inhibited primary colony formation of untreated or relapsed APL patients. Further study showed that PRQ could induce the apoptosis of APL cells by inhibiting NF‐κB signaling pathway. The in vivo study showed that PRQ significantly inhibited NB4‐LR2 xenograft tumors growth. These results suggest that PRQ is a potential therapeutic agent for ATRA‐resistant APL patients. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is one of the most common types of acute leukemia in adults with the lowest survival rate of all leukemia. Resistance to cytarabine and anthracycline-based chemotherapy is a major cause of treatment failure. Thus, finding new drugs with anti-leukemia activities and minimal side effect is urgently needed. Here through screening more than 1000 drugs approved by the Food and Drug Administration (FDA) of United States, the anthelmintic drug mebendazole (MBZ) was found to inhibit the growth of AML cell lines (THP-1, U937, NB4 and K562) and bone marrow mononuclear cells (BM-MNCs) from AML patients at pharmacologically achievable concentrations. In contrast, similar concentration of MBZ had little inhibitory effect on the growth of normal peripheral blood mononuclear cells (PBMC) or human umbilical vein endothelial cells (HUVEC). In addition, MBZ induced mitotic arrest and mitotic catastrophe in AML cells based on nuclear morphology, cell cycle distribution, mitotic marker analyses and the number of multinucleated cells and apoptotic cells. Furthermore, MBZ treatment inhibited activation of Akt and Erk in AML leukemic cells. Finally, MBZ repressed the progression of leukemic cells in vivo and prolonged survival in AML xenograft mouse model. Taken together, our results suggest that MBZ could be a potential new therapeutic agent for the treatment of AML patients. [ABSTRACT FROM AUTHOR]

IK4 is an isoform of IKAROS gene which plays a key role in the hematopoiesis, in this work, the construction of retro-virus vector of IK4 mutation and its expression in leukemic cells was investigated. PCR site-directed mutagenesis method based on overlap extension was used to construct four IK4 gene mutants of single- or multi-site mutations, which were then cloned into the retrovirus vector Pmscv-puro to form recombinant expression vector. The point mutations were verified by DNA sequencing. The recombinant expression vectors were co-transfected with packaging plasmids VSVG and Gag-Pol into 293T cells to produce retroviruses. Supernatants containing retroviruses were collected and were used to infect NB4 cells. Puromycin was used to select stable cell lines. The expression of mutants was verified by Western blotting analysis. Four IK4 gene mutants of single- or multi-site mutations were successfully constructed by overlap extension PCR, and the mutants were expressed in leukemic cells, which will provide basis for subsequent function and mechanism research. [ABSTRACT FROM AUTHOR]