Novel PIKfyve/Tubulin Dual-target Inhibitor as a Promising Therapeutic Strategy for B-cell Acute Lymphoblastic Leukemia

Objective:In B-cell acute lymphoblastic leukemia(B-ALL),current intensive chemotherapies for adult patients fail to achieve durable responses in more than 50%of cases,underscoring the urgent need for new therapeutic regimens for this patient population.The present study aimed to determine whether HZX-02-059,a novel dual-target inhibitor targeting both phosphatidylinositol-3-phosphate 5-kinase(PIKfyve)and tubulin,is lethal to B-ALL cells and is a potential therapeutic for B-ALL patients.Methods:Cell proliferation,vacuolization,apoptosis,cell cycle,and in-vivo tumor growth were evaluated.In addition,Genome-wide RNA-sequencing studies were conducted to elucidate the mechanisms of action underlying the anti-leukemia activity of HZX-02-059 in B-ALL.Results:HZX-02-059 was found to inhibit cell proliferation,induce vacuolization,promote apoptosis,block the cell cycle,and reduce in-vivo tumor growth.Downregulation of the p53 pathway and suppression of the phosphoinositide 3-kinase(PI3K)/AKT pathway and the downstream transcription factors c-Myc and NF-κB were responsible for these observations.Conclusion:Overall,these findings suggest that HZX-02-059 is a promising agent for the treatment of B-ALL patients resistant to conventional therapies.

Mortality Trend and Predictors of Mortality in Dysphagic Stroke Patients Postpercutaneous Endoscopic Gastrostomy

Background：Percutaneous endoscopic gastrostomy （PEG） feeding is widely used in stroke patients suffering from persistent dysphagia;however,predicting the risks and benefits of PEG insertion in the individual patient is difficult.The aim of our study was to investigate if candidate risk factors could predict short-term mortality risk in poststroke patients who had PEG tube insertion for persistent dysphagia.Methods：This was a retrospective study of 3504 consecutive stroke patients admitted to two metropolitan hospitals during the period January 2005 to December 2013 and who also underwent PEG insertion for feeding due to persistent dysphagia.Results：A total of 102 patients were included in the study.There were 22 deaths in 6 months after insertion of PEG tubes and 20 deaths of those occurred within 3 months post PEG.Those who survived beyond 6 months showed significantly lower mean age （75.9 ± 9.0 years vs.83.0 ± 4.9 years,P 〈 0.001）,a lower mean American Society of Anesthesia （ASA） score （3.04 ± 0.63 vs.3.64 ± 0.58,P 〈 0.001） compared to nonsurvivors.In multiple Logistic,age （P =0.004,odds ratio [OR] =1.144;95% confidence interval [CI]：1.044-1.255）;ASA （P =0.002,OR =5.065;95% CI：1.815-14.133） and albumin level pre-PEG insertion （P =0.033,OR =0.869;95% CI：0.764-0.988）were the independent determinants of mortality respectively.Conclusions：We propose that age,ASA score and albumin level pre-PEG insertion to be included as factors to assist in the selection of patients who are likely to survive more than 3 months post PEG insertion.