Platelet-derived growth factor-B (PDGF-B) induced by hypoxia promotes the survival of pulmonary arterial endothelial cells through the PI3K/Akt/Stat3 pathway.

BACKGROUND/AIMS: Pulmonary arterial endothelial plexiform lesions are a basic pathological change associated with pulmonary vascular remodeling and are characterized by the formation of tumorlets as a result of over-growth of endothelial cells. Accumulating evidence suggests that platelet-derived growth factor (PDGF) participates in regulating the progression of pulmonary arterial hypertension. However, whether PDGF promotes the survival of pulmonary arterial endothelial cells (PAECs), as well as the specific molecular mechanisms that underlie its actions, remains unknown. METHODS: MTT assays, caspase-3 and caspase-9 activity assays and western blot analysis were performed. RESULTS: We found that both the mRNA and protein expression of PDGF-B was induced by hypoxia and that the inhibitory effects exerted by hypoxia on apoptosis were attenuated by inhibitors of PDGF beta. Moreover, PDGF-B inhibited apoptosis in a dose-dependent manner by stimulating the phosphorylation of both Akt and Stat3, and the PI3K/AKT pathway serves as an up-stream participant in the Stat3 activation stimulated by PDGF-B. Additionally, the anti-apoptotic effects of PDGF-B were abolished when PAECs were treated with either an inhibitor or small interfering RNA targeting Stat3. CONCLUSIONS: These observations suggest that PDGF-B is induced by hypoxia and protects against apoptosis via the PI3K/Akt/Stat3 signaling pathway.

CD19 chimeric antigen receptor-T cells as bridging therapy to allogeneic hematopoietic cell transplantation improves outcome in patients with refractory/relapsed B-cell acute lymphoblastic leukemia.

Chimeric antigen receptor (CAR)-T cell therapy has been confirmed improving remission rates in refractory patients or relapsed B-cell acute lymphoblastic leukemia (R/R B-ALL). However, the added benefits of undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) following CAR-T therapy remain a subject of debate. In this research we investigated the efficiency and long-term outcomes of CD19 CAR-T bridging with allo-HSCT in R/R B-ALL patients. A total of 42 patients were brought into the cohort studies. Our findings revealed that patients who appected CAR-T followed by HSCT had a 1-year overall survival (OS) rate of 70 % and a 1-year leukemia-free survival (LFS) rate of 95 %. Moreover, patients who underwent this combined treatment had higher OS and LFS rates compared to those who received CAR-T therapy alone. In conclusion, the results of this clinical trial provide compelling evidence for the safety and efficacy of using CAR-T therapy as a bridging strategy to allo-HSCT in patients with R/R B-ALL.

miR-139-5p Regulates the Proliferation of Acute Promyelocytic Leukemia Cells by Targeting MNT.

Acute promyelocytic leukemia (APL) patients with progressive leukocytosis are more likely to have various complications and poor outcomes. However, the regulatory roles of microRNAs in the leukocytosis of APL have not been clarified. Our study aims to evaluate the effects of miRNAs on leukocytosis during induction therapy of APL patients and explore its potential mechanisms. During induction treatment, patients with white blood cell count higher than 10 × 109/L were divided into leukocytosis group and others were nonleukocytosis group. Using microarray assays, we found that miR-139-5p was significantly downregulated in the leukocytosis group. Elevated expression of miR-139-5p inhibited the proliferation of NB4 cells by arresting the cell cycle and inducing apoptosis. We further identified that MNT was a target of miR-139-5p. miR-139-5p significantly inhibited the proliferation, invasion, and migration function of NB4 cells through targeting MNT. Strategies for regulating miR-139-5p or MNT expression might provide new therapeutic approaches for progressive leukocytosis in APL.

Predicting mortality from intracranial hemorrhage in patients who undergo allogeneic hematopoietic stem cell transplantation.

Intracranial hemorrhage (ICH) is a rare but fatal central nervous system complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, factors that are predictive of early mortality in patients who develop ICH after undergoing allo-HSCT have not been systemically investigated. From January 2008 to June 2020, a total of 70 allo-HSCT patients with an ICH diagnosis formed the derivation cohort. Forty-one allo-HSCT patients with an ICH diagnosis were collected from 12 other medical centers during the same period, and they comprised the external validation cohort. These 2 cohorts were used to develop and validate a grading scale that enables the prediction of 30-day mortality from ICH in all-HSCT patients. Four predictors (lactate dehydrogenase level, albumin level, white blood cell count, and disease status) were retained in the multivariable logistic regression model, and a simplified grading scale (termed the LAWS score) was developed. The LAWS score was adequately calibrated (Hosmer-Lemeshow test, P > .05) in both cohorts. It had good discrimination power in both the derivation cohort (C-statistic, 0.859; 95% confidence interval, 0.776-0.945) and the external validation cohort (C-statistic, 0.795; 95% confidence interval, 0.645-0.945). The LAWS score is the first scoring system capable of predicting 30-day mortality from ICH in allo-HSCT patients. It showed good performance in identifying allo-HSCT patients at increased risk of early mortality after ICH diagnosis. We anticipate that it would help risk stratify allo-HSCT patients with ICH and facilitate future studies on developing individualized and novel interventions for patients within different LAWS risk groups.

Treatment response, survival, safety, and predictive factors to chimeric antigen receptor T cell therapy in Chinese relapsed or refractory B cell acute lymphoblast leukemia patients.

This study aimed to evaluate treatment response, survival, safety profiles, and predictive factors to chimeric antigen receptor T cell (CAR-T) therapy in Chinese patients with relapsed or refractory B cell acute lymphoblast leukemia (R/R B-ALL). 39R/R B-ALL patients who underwent CAR-T therapy were included. Baseline data were collected from patients' electronic medical records. Patients' peripheral bloods, bone marrow aspirates, and biopsies were obtained for routine examination, and treatment response and survival profiles as well as adverse events were evaluated. The rates of complete remission (CR), CR with minimal residual disease (MRD) negative/positive, and bridging to hematopoietic stem-cell transplantation (HSCT) were 92.3%, 76.9%, 15.4%, and 43.6%, respectively. The median event-free survival (EFS) was 11.6 months (95% confidence interval (CI): 4.0-19.2 months) and median overall survival (OS) was 14.0 months (95% CI: 10.9-17.1 months). Bridging to HSCT independently predicted better EFS and OS, while high bone marrow blasts level independently predicted worse EFS. The incidence of cytokine release syndrome (CRS) was 97.4%, and refractory disease as well as decreased white blood cell independently predicted higher risk of severe CRS. Other common adverse events included hematologic toxicities (grade I: 5.1%, grade II: 7.7%, grade III: 17.9%, grade IV: 69.2%), neurotoxicity (28.2%), infection (38.5%), and admission for intensive care unit (10.3%). In conclusion, CAR-T therapy presents with promising treatment response, survival and safety profiles, and higher disease burden predicts worse survival as well as increased risk of severe CRS in Chinese R/R B-ALL patients.

Low-dose hypomethylating agent decitabine in combination with aclacinomycin and cytarabine achieves a better outcome than standard FLAG chemotherapy in refractory/relapsed acute myeloid leukemia patients with poor-risk cytogenetics and mutations.

BACKGROUND: Relapsed and refractory acute myeloid leukemia (RR-AML) still poses major treatment concerns. Current treatments include high doses of cytarabine or fludarabine in combination with cytarabine and G-CSF (FLAG), but provide mixed results. Low-dose decitabine, a hypomethylating drug, in combination with aclarubicin and cytarabine (DAC) has shown safety and efficacy in the treatment of AML; however, clinical data are limited for the treatment of RR-AML. METHODS: In this study, we retrospectively compared the response and safety of DAC vs FLAG for RR-AML patients. RESULTS: For the 35 patients with RR-AML enrolled in this study, the overall response rates reached 100% and 55.6% in the DAC group and FLAG group, respectively (P=0.002). Complete response rates after DAC and FLAG treatment were 64.7% and 33.3%, respectively (P=0.002). Median overall survival (95% CI) of the DAC treatment group was significantly higher than for the FLAG group (median not achieved vs 16.8 months, P=0.021). CONCLUSION: DAC treatment was also more effective in those patients with poor prognosis, suggesting that DAC resulted in a better outcome for RR-AML treatment. In conclusion, in our study, DAC therapy provided more safety and effectiveness and lower toxicity in the treatment of RR-AML compared to FLAG therapy.

TGF-ß1 inhibits the apoptosis of pulmonary arterial smooth muscle cells and contributes to pulmonary vascular medial thickening via the PI3K/Akt pathway.

Previous studies have highlighted that the transforming growth factor­ß1 (TGF­ß1) pathway may be activated by hypoxic conditions. TGF­ß1 also participates in the regulation of proliferation, differentiation, migration and apoptosis of various cell types. Furthermore, TGF­ß1 has been reported to participate in the regulation of the progression of pulmonary arterial hypertension (PAH). However, the effect of TGF­ß1 on pulmonary arterial smooth muscle cells (PASMCs) and the corresponding molecular mechanisms remain unclear. The present study aimed to determine whether TGF­ß1 protects against cell apoptosis in PASMCs, and identify the underlying molecular mechanisms. Western blotting, MTT and lactate dehydrogenase activity assays were performed, and the activity of caspase­3 and caspase­9 was detected in order to investigate the hypothesis. It was determined that TGF­ß1 may facilitate cell growth in a dose­dependent manner in serum­starved PASMCs. Furthermore, it was observed that apoptosis in serum­starved PASMCs was inhibited by TGF­ß1 via regulation of the expression levels of mitochondrial membrane proteins. Additionally, the phosphatidylinositol 3­kinase/protein kinase B (PI3K/Akt) pathway was found to be activated by TGF­ß1 in PASMCs, while the inhibition of PI3K/Akt signaling also prevented the apoptosis­limiting effects of TGF­ß1. These observations suggest that TGF­ß1 protects PASMCs from apoptosis and contributes to pulmonary vascular medial thickening via the PI3K/Akt pathway.

Determination of arsenic metabolites in patients with newly diagnosed acute promyelocytic leukemia treated with arsenic trioxide.

The efficacy of arsenic trioxide (ATO) in the treatment of acute promyelocytic leukemia (APL) is widely accepted. It is necessary to determine the concentration of arsenic due to its toxicity. The profiles of arsenic speciation in patients with relapsed or refractory APL have been demonstrated in few reports. Arsenic metabolite concentrations in the plasma of patients with newly diagnosed APL during the first course of arsenic remission induction therapy were determined, and the complicated change pattern of these metabolite concentrations in this phase is described for the first time in this study. We demonstrated that the concentration of trivalent inorganic arsenic (As(III)), which is regarded as the most effective and toxic, was much lower than those of other metabolites. Concentrations of the same arsenic metabolites were obviously distinct among various individuals. We infer that determination of the metabolites separately is necessary, and cannot be replaced by total arsenic determination. In addition, the amount of methylated metabolites of arsenic increased during the first course of ATO therapy, and these metabolites might therefore play an increasingly important role. Further research should be carried out to study the relationship between arsenic metabolite concentrations and efficacy, as well as side effects in patients with APL treated with ATO.