Chlorogenic Acid as a Potential Therapeutic Agent for Cholangiocarcinoma.

Chlorogenic acid (CGA) has demonstrated anti-tumor effects across various cancers, but its role in cholangiocarcinoma (CCA) remains unclear. Our study revealed CGA's potent anti-tumor effects on CCA, significantly suppressing cell proliferation, migration, colony formation, and invasion while inhibiting the epithelial-mesenchymal transition. CGA induced apoptosis, modulated cell cycle progression, and exhibited a stable binding affinity to AKR1B10 in CCA. AKR1B10 was highly expressed in RBE cells, and CGA treatment reduced AKR1B10 expression. Knocking out AKR1B10 inhibited the proliferation of RBE cells, whereas the overexpression of AKR1B10 promoted their proliferation. Additionally, CGA suppressed the proliferation of RBE cells with AKR1B10 overexpression. Mechanistically, AKR1B10 activated AKT, and CGA exerted its inhibitory effect by reducing AKR1B10 levels, thereby suppressing AKT activation. Furthermore, CGA facilitated the polarization of tumor-associated macrophages towards an anti-tumor phenotype and enhanced T-cell cytotoxicity. These findings underscore CGA's potential as a promising therapeutic agent for CCA treatment.

Neutrophil CD64: a potential biomarker for the diagnosis of infection in patients with haematological malignancies.

METHODS: The clinical data of 76 patients with haematological malignancies and infection who were treated in our department between January 2014 and October 2019 were retrospectively analysed. To evaluate the diagnostic value of some biomarkers, infection indexes such as white blood cell count (WBC), neutrophil count (NEUT), neutrophil CD64 and procalcitonin (PCT) were compared across the patients with confirmed infection status and infection-control status. Sensitivity, specificity and area under the receiver operating characteristic curve (AUC) were also determined. RESULTS: The WBC and NEUT did not differ significantly, whereas the neutrophil CD64 and PCT levels were significantly elevated in patients with a confirmed infection status (p < 0.05), with sensitivity of 31.0%, 45.2%, 76.2% and 50%, respectively, and specificity of 90.5%, 69%, 71.4% and 64.3%, respectively. The AUC of WBC, NEUT, neutrophil CD64 and PCT was 0.528, 0.517, 0.844 and 0.599, respectively. Further highlighting their diagnostic value, the neutrophil CD64 and PCT levels in neutropenia patients were significantly upregulated in patients with infection status (p < 0.05) but the WBC and NEUT were unchanged, with sensitivity of 73.7%, 63.2%, 68% and 68.4%, respectively, and specificity of 68.4%, 52.6%, 57.9% and 63.2%, respectively. The AUC of neutrophil CD64, PCT, WBC and NEUT was 0.864, 0.593, 0.419 and 0.403, respectively. CONCLUSION: These results indicate that neutrophil CD64 is a promising biomarker with superior sensitivity and specificity for diagnosing infection in patients with haematological malignancies, especially neutropenia patients.

Prognostic nomogram predicting survival of patients with unresectable hepatocellular carcinoma after hepatic arterial infusion chemotherapy.

BACKGROUND AND AIM: Hepatic arterial infusion chemotherapy (HAIC) has shown encouraging efficacy in the treatment of hepatocellular carcinoma (HCC). This study aims to establish and validate a novel nomogram to predict individualized survival outcomes for patients with unresectable HCC after HAIC. METHODS: Between January 2016 and December 2018, 463 patients diagnosed with HCC who initially received HAIC were included in this study (training cohort: n = 308; validation cohort: n = 153). The prognostic nomogram was constructed based on the training cohort using the independent predictors assessed by the multivariate Cox proportional hazards model. The predictive accuracy and discriminative ability of the model were evaluated by the concordance index (C-index), calibration curve and area under the time-dependent receiver operating characteristic (tdAUC) curve. RESULTS: After a median follow-up of 35.4 months, 358 patients had died. Six factors, including C-reactive protein, albumin-bilirubin grade, alpha fetoprotein, extrahepatic metastasis, portal vein invasion and tumor size, were selected to establish the nomogram. In the training cohort, the C-index of the nomogram was 0.710, which was significantly better than that of six conventional staging systems (P < 0.001), and the nomogram had a higher tdAUC over time. The calibration curve showed good agreement between the predicted probability and actual outcome. According to specified values, the nomogram stratified patients into three or four risk groups (P < 0.001). Similar findings could be observed in the validation cohort. CONCLUSION: The nomogram in this study accurately predicted the OS of patients with unresectable HCC after HAIC.

Rituximab for the treatment of idiopathic membranous nephropathy with nephrotic syndrome: a systematic review and meta-analysis

Background/aim: This meta-analysis comprehensively investigated the efficacy and safety of rituximab (RTX) in patients with idiopathic membranous nephropathy (IMN). Materials and methods: We searched the MEDLINE, EMBASE and Cochrane Registry of Controlled Trials databases from January 2000 to January 2020. Studies evaluating the efficacy and safety of RTX in the treatment of IMN with nephrotic syndrome (NS) were included. Results: Nine studies (total of 357 patients) were included in the meta-analysis. The pooled complete response and overall response (OR) rates at 12 months were 13.2% [95% con fidence interval (CI), 0.09­0.18] and 60% (95% CI, 0.48­0.72), and those at 24 months were 27.8% (95% CI, 0.22­0.34) and 66% (95% CI, 0.6­0.72), respectively. The pooled OR rates for the low-, standard-, and high-dose groups were 39.3%, 64%, and 60%, respectively, and those for the first-line and second-line groups were 58% and 54%, respectively. Conclusion: Treatment of IMN with RTX has comparable efficacy to other immunosuppressive treatments (ISTs). RTX has the advantages of no requirement for steroids and lower rates adverse event and relapse rates. Patients who relapse or are resistant to other IST agents also respond to RTX. RTX-based regimens and other B-cell-targeted therapies may represent the future of IMN therapy.

MicroRNA-486-5p targeting PTEN Protects Against Coronary Microembolization-Induced Cardiomyocyte Apoptosis in Rats by activating the PI3K/AKT pathway.

Coronary microembolization (CME) is responsible for a substantial fraction of microvascular obstruction (MVO), which are strongly associated with mortality and hospitalization for heart failure within 1 year after primary percutaneous coronary intervention (PCI) in ST-segment elevation myocardial infarction (STEMI). However, the effect of miRNA on cardiomyocyte apoptosis in a CME model has been less well-studied. miRNA sequencing analysis was performed to examine differentially expressed miRNAs induced by CME in rats. Phosphatase and tensin homologue (PTEN) 3 'RACE and dual-luciferase reporter assays were performed to confirm that PTEN is a direct target gene of miR-486-5p. miRNA-486-5p overexpression was established by injecting AAV into rats via the tail vein. The CME model was established by injecting microspheres into the left ventricle of rats. 6h after surgery, cardiac function, microinfarct area, and the apoptotic index were determined. RT-PCR was used to evaluate mRNA level and Western blotting was used to evaluate protein expression. miRNA sequencing data showed that there were 5 upregulated and 8 downregulated miRNAs, and the relative expression of miRNA-486-5p was significantly downregulated. PTEN 3'RACE and dual-luciferase reporter assays confirmed that miR-486-5p directly targets the rat PTEN gene. The expression of miR-486-5p gradually declined, however, the expression of PTEN mRNA rapidly increased at early time points after CME. Overexpression of miR-486-5p reduced cardiomyocyte apoptosis and improved cardiac function through inhibition of PTEN and activation of the PI3K/Akt pathway in rat CME models. Overexpression of miR-486-5p, which targets PTEN, protects against CME-induced cardiomyocyte apoptosis and improves cardiac function in rats by activating the PI3K/Akt pathway.

Egr-1 is involved in coronary microembolization-induced myocardial injury via Bim/Beclin-1 pathway-mediated autophagy inhibition and apoptosis activation.

Coronary microembolization (CME) substantially reduces the clinical benefits of myocardial reperfusion therapy. Autophagy and apoptosis participate in the pathophysiological processes of almost all cardiovascular diseases, including CME-induced myocardial injury, but the precise underlying mechanisms remain unclear. In the present study, we observed that Egr-1 expression was substantially increased after CME modeling. Inhibition of Egr-1 expression through the targeted delivery of rAAV9-Egr-1-shRNA improved cardiac function and reduced myocardial injury. The microinfarct size was also significantly smaller in the Egr-1 inhibitor group than in the CME group. These benefits were partially reversed by the autophagy inhibitor 3-MA. As shown in our previous study, autophagy in the myocardium was impaired after CME. Inhibition of Egr-1 expression in vivo restored the autophagy flux and reduced myocardial apoptosis, at least partially, by inhibiting the Egr-1/Bim/Beclin-1 pathway, as evidenced by the results of the western blot, RT-qPCR, and TUNEL staining. At the same time, TEM showed a dramatic increase in the number of typical autophagic vacuoles in the Egr-1 inhibitor group compared to the CME group. Based on these findings, the Egr-1/Bim/Beclin-1 pathway may be involved in CME-induced myocardial injury by regulating myocardial autophagy and apoptosis, and this pathway represents a potential therapeutic target in CME.

Pim1 Overexpression Prevents Apoptosis in Cardiomyocytes After Exposure to Hypoxia and Oxidative Stress via Upregulating Cell Autophagy.

BACKGROUND/AIMS: Microvascular obstruction (MVO), an undesirable complication of percutaneous coronary intervention, is independently associated with adverse left ventricle remodeling and poor prognosis after acute myocardial infarction. Hypoxia and oxidative stress major roles in the pathophysiology of MVO. Pim1 serves an important protective role in the ischemic myocardium, but the underlying mechanisms remain poorly defined. Autophagy in early hypoxia or during moderate oxidative stress has been demonstrated to protect the myocardium. In this study, we investigated the association between the protective effect of Pim1 and autophagy after hypoxia and oxidative stress. METHODS: Ventricular myocytes from neonatal rat heart (NRVMs) were isolated. NRVMs were exposed to hypoxia and H2O2. Rapamycin and 3-methyladenine (3-MA) were used as an activator and inhibitor of autophagy, respectively. pHBAd-Pim1 was transfected into NRVMs. We assessed cardiomyocyte apoptosis by Annexin V-FITC/PI flow cytometry. Autophagy was evaluated by mRFP-GFP-LC3 adenovirus infection by confocal microscopy. Western blotting was used to quantify apoptosis or autophagy protein (caspase-3, LC3, P62, AMPK, mTOR, ATG5) concentrations. RESULTS: Autophagy and apoptosis in NRVMs significantly increased and peaked at 3 h and 6 h, respectively, after exposure to hypoxia and H2O2. The mTOR inhibitor rapamycin induced autophagy and decreased cardiomyocyte apoptosis, but the autophagy inhibitor 3-MA decreased autophagy and increased apoptosis at 3 h after exposure to hypoxia and H2O2. Pim1 levels in NRVMs increased at 3 h and decreased gradually after exposure to hypoxia and H2O2. Pim1 overexpression enhanced autophagy and decreased apoptosis. Pim1-induced promotion of autophagy is partly the result of activation of the AMPK/mTOR/ATG5 pathway after exposure to hypoxia and H2O2. CONCLUSION: Our results revealed that Pim1 overexpression prevented NRVMs from apoptosis via upregulating autophagy after exposure to hypoxia and oxidative stress, partly through activation of the AMPK/mTOR/ATG5 autophagy pathway.

A retrospective comparison of Escherichia coli and polyethylene glycol-conjugated asparaginase for the treatment of adolescents and adults with newly diagnosed acute lymphoblastic leukemia.

Data from clinical trials suggest that polyethylene glycol-conjugated asparaginase (PEG asparaginase) should be recommended as a replacement for Escherichia coli (E. coli) asparaginase in the treatment of pediatric acute lymphoblastic leukemia (ALL) due to its prolonged effect, similar safety profile and convenience. The present study investigated the efficacy and safety of PEG asparaginase in adolescents and adults with newly diagnosed ALL. The clinical data of 122 patients, ≥14 years old with de novo ALL, who received either PEG asparaginase or E. coli asparaginase as part of an induction regimen, were retrospectively analyzed. The results revealed that PEG asparaginase had a comparable complete remission rate (95.65 vs. 90.79%), median overall survival time (14.07 vs. 16.29 months) and median relapse-free survival time (10.00 vs. 8.57 months) with E. coli asparaginase. In addition, patients <35 years old receiving PEG asparaginase obtained a higher median RFS time compared with those receiving E. coli asparaginase (10.93 vs. 8.97 months; P=0.037). Patients treated with E. coli asparaginase exhibited a significantly higher incidence of central nervous system leukemia (CNSL) compared with those treated with PEG asparaginase (27.63 vs. 10.87%; P=0.028) during the consolidation phase. Toxic events, including allergy, grade III-IV liver dysfunction, renal function damage and pancreatic lesions were similar between the two groups. A longer duration of coagulation dysfunction (9.80±5.51 vs. 6.80±4.21 days; P=0.002) and agranulocytosis (18.89±8.79 vs. 12.03±8.34 days; P<0.01), and a higher incidence of grade IV-V infections (22.73 vs. 7.25%; P=0.018) were observed in the PEG asparaginase group. However, these did not increase bleeding events or infection-associated mortalities. When taking the convenience and superior efficacy in preventing CNSL into consideration, PEG asparaginase is a candidate for first-line treatment of adolescent and adult ALL. A larger prospective clinical trial is required to further confirm this point of view.

The protective effect of nicorandil on cardiomyocyte apoptosis after coronary microembolization by activating Nrf2/HO-1 signaling pathway in rats.

BACKGROUND: Myocardial apoptosis is considered to be the chief cause of progressive cardiac dysfunction induced by coronary microembolization (CME), and the Nrf2/HO-1 signaling pathway is involved in CME-induced myocardial apoptosis. Nicorandil (NIC) has multiple beneficial cardiovascular effects on myocardial injury. Therefore, this study was undertaken to analyze the role of NIC pretreatment in the inhibiting myocardial apoptosis after CME in rats. METHODS: Forty rats were divided into Sham group, CME group, CME plus NIC (NIC) group, and CME plus AAV9-Nrf2 (AAV9-Nrf2) group (n = 10 per group). CME-induced myocardial apoptosis model was established through injecting plastic microspheres (42 µM) into the left ventricle except the Sham group. NIC group received nicorandil 3 mg/(kg.d) for 7 days before the operation. Cardiac function was assessed by echocardiography. The mRNA expression level of Nrf2 was detected by RT-PCR. The protein expression levels of Nrf2, HO-1, Bcl-2, Bax and cleaved caspase-3 were detected by Western blot. The size of the microinfarction area was measured by HBFP staining; myocardial apoptosis was analyzed by TUNEL staining. RESULTS: Compared with the sham group, the cardiac function and the expression level of Nrf2, HO-1 and Bcl-2were decreased, while myocardial apoptosis and the expression of Bax and cleaved caspase-3 were increased in the CME group. Compared with the CME group, cardiac function was significantly improved, the expression levels of Nrf2, HO-1, and Bcl-2 were increased, the expression of Bax and cleaved caspase-3 were decreased, and the myocardial apoptosis was attenuated in the NIC group and AAV9-Nrf2 group. CONCLUSION: NIC pretreatment effectively inhibit CME-induced myocardial apoptosis and improve cardiac function. The protective effects are mediated through the activation of the Nrf2/HO-1 signaling in cardiomyocytes.

Potential Involvement of MiR-30e-3p in Myocardial Injury Induced by Coronary Microembolization via Autophagy Activation.

BACKGROUND/AIMS: Coronary microembolization (CME) can lead to no-reflow or slow reflow, which is one of the important reasons for loss of clinical benefit from myocardial reperfusion therapy. MicroRNAs and autophagy are heavily implicated in the occurrence and development of almost all cardiovascular diseases. Therefore, the present study was designed to investigate the role of miR-30e-3p and autophagy in CME-induced myocardial injury rat model. METHODS: Sixty rats were randomly divided into six groups: sham, CME 1h,3h,6h,9h, and 12h (n = 10 per group). Our CME rat model was created by injecting polyethylene microspheres (42mm) into the left ventricle of the heart; the sham group was injected with same volume of normal saline. The cardiac function and serum cardiac troponin I (cTnI) level of each group was measured. HE staining and HBFP staining were used to evaluate the myocardial micro-infarction area of myocardium tissue samples. Then RT-qPCR and western blot were used to detect the expression of miR-30e-3p and, autophagy related protein LC3-II and p62, respectively. Transmission electron microscope (TEM) was used to identify autophagic vacuoles in tissue samples. RESULTS: The cardiac function of the CME 6h,9h, and 12h groups were significantly decreased compared to the sham group (P < 0.05) and the cTnI level in each group were also significantly increased (P < 0.05). The expression of miR-30e-3p in the CME 6h, 9h and 12h group were decreased significantly compared with the sham group (P < 0.05). Meanwhile, the expression of autophagy related protein LC3-II decreased significantly and p62 increased significantly in the CME 9h and 12h group (P < 0.05). TEM images showed typical autophagic vacuoles for each of the CME groups. CONCLUSIONS: Myocardial miR-30e-3p is down regulated after CME and is accompanied by inhibited autophagy and decreased cardiac function. Therefore, miR-30e-3p may be involved in CME-induced cardiac dysfunction by regulating myocardial autophagy.

The protective effect of activating Nrf2 / HO-1 signaling pathway on cardiomyocyte apoptosis after coronary microembolization in rats.

BACKGROUND: Myocardial apoptosis is closely related to myocardial injury caused by coronary microembolization (CME).Nuclear factor erythroid 2-like (Nrf2) has been taken into account as an inhibitor of apoptosis in various tissues. Thus, this research aims to investigate which part Nrf2/HO-1 signaling pathway plays in myocardial apoptosis process following the effect of CME on rats. METHODS: Separate 40 rats then form them into a group of shame, a group of CME, a group of CME plus AAV-Nrf2(AAV-Nrf2 (CME) group) and a group of CME plus AAV-control (AAV-control (CME) group) stochastically and averagely. Rat CME was established by injecting into the left ventricular chamber, with or without pretreatment of adeno-associated virus Nrf2 (AAV-Nrf2). Echocardiological measurements, using Terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling (TUNEL) to stain, conducting Quantitative PCR in real time (RT-PCR) as well as Western blotting to evaluate the impacts of them functionally, morphologically and molecularly in CME. RESULTS: Nrf2 decreased in cardiomyocytes after CME. Upregulation of Nrf2 inside an organism through AAV connect to improving the function of heart as well as attenuating myocardial apoptosis, following the restrain of proapoptotic mRNAs and proteins like caspase-3, caspase-9 and bax expressing as well as the increase of antiapoptotic mRNA and proteins like HO-1 and bcl-2 expressing. CONCLUSION: Activation of Nrf2/HO-1 pathway can improve CME-induced cardiac dysfunction effectively and also reduce the myocardial apoptosis.

Expression of p53 in myocardium following coronary microembolization in rats and its significance.

BACKGROUND: Cardiomyocyte apoptosis is a primary cause for coronary microembolization (CME)-induced cardiac dysfunction. p53 induces cell growth retardation and apoptosis through stress pathway. The present study investigated the mechanism of p53-induced myocardial apoptosis and cardiac dysfunction by activating the mitochondrion apoptotic pathway following CME. METHODS: Forty SD rats were equally divided into microembolization (CME), sham operation (sham), CME+siRNA-p53, and CME+control-p53 groups. The CME rat model was established by injecting microembolization spheres via the left ventricle. Cardiac ultrasound, TUNEL, fluorescence quantitative PCR, and Western blot were used to assess the cardiac function indicators, cardiomyocyte apoptosis, and the expressions of mRNA and protein in myocardial tissues, respectively. RESULTS: Echocardiography revealed a significantly reduced cardiac function of the CME group than the sham group while the CME-induced cardiac dysfunction was improved in the CME+siRNA-p53 group. The indicators of myocardial apoptosis in the CME group increased significantly than the sham group; those of the CME+siRNA-p53 group decreased significantly than the CME group. Fluorescence quantitative PCR and Western blot demonstrated that p53, Bbc3 (PUMA), and cleaved caspase-3 expressions were significantly increased, and BCL-2 expression was declined in myocardial tissues of the CME group compared to the sham group. A contrasting result was observed in the CME+siRNA-p53 group as compared to the CME group. CONCLUSIONS: P53 is involved in the CME-induced cardiac dysfunction, which may up-regulate Bbc3 to activate BCL-2/caspase3 mitochondrial apoptotic pathway and induce myocardial apoptosis. Inhibiting the p53 expression can effectively suppress this pathway, thereby reducing myocardial apoptosis and cardiac dysfunction.

MiR-486 regulates cardiomyocyte apoptosis by p53-mediated BCL-2 associated mitochondrial apoptotic pathway.

BACKGROUND: Cardiomyocyte apoptosis is a common pathological manifestation that occurs in several heart diseases. This study aimed to explore the mechanism of microRNA-486 (miR-486) in cardiomyocyte apoptosis by interfering with the p53-activated BCL-2 associated mitochondrial pathway. METHODS: miR-486 mimics and inhibitors were transfected into the primary cardiomyocytes of suckling Sprague-Dawley rat pups, and H2O2 was used to induce apoptosis. Flow cytometry and TUNEL were both used to detect cardiomyocyte apoptosis, while the relative mRNA transcript and protein levels of miR-486, p53, Bbc3, BCL-2, and cleaved caspase-3 were detected using RT-PCR and western blot analysis, respectively. RESULTS: miR-486 overexpression significantly decreased the expressions of p53, Bbc3 and cleaved caspase-3 (P < 0.05), and BCL-2 expression was significantly increased (P < 0.05), which in turn caused a significant decrease in the rate of cardiomyocyte apoptosis (P < 0.05). In contrast, miR-486 silencing resulted in an elevated rate of cardiomyocyte apoptosis (P < 0.05). CONCLUSION: miR-486 may regulate cardiomyocyte apoptosis via p53-mediated BCL-2 associated mitochondrial apoptotic pathway. Therefore, up-regulating miR-486 expression in cardiomyocytes can effectively reduce the activation of the BCL-2 associated mitochondrial apoptotic pathway, consequently protecting cardiomyocytes.

TAK-242 Protects Against Apoptosis in Coronary Microembolization-Induced Myocardial Injury in Rats by Suppressing TLR4/NF-κB Signaling Pathway.

BACKGROUND/AIMS: Myocardial apoptosis is heavily implicated in the myocardial injury caused by coronary microembolization (CME), and toll-like receptor 4 (TLR4) is considered to be involved in this apoptotic cascade. Therefore, the present study was designed to investigate the role of TLR4/NF-κB signaling pathway regulated by TAK-242, a selective TLR4 signal transduction inhibitor, in the myocardial apoptosis after CME in rats. METHODS: Forty-five rats were randomized (random number) into three groups: sham, CME and CME + TAK-242 (n = 15 per group).CME was induced by injecting polyethylene microspheres (42µm) into the left ventricular except the sham group. CME + TAK-242 group was treated with TAK-242 (2mg/kg) via the tail vein 30 minutes before CME modeling. Cardiac function was evaluated 6 hours after operation. Tissue biopsy was stained with HBFP to measure the size of micro-infarction area. TUNEL staining was used to detect myocardial apoptosis. Western blot and qPCR were used to evaluate the expression of TLR4, MyD88, NF-κB p65, p-IκBα and Cleaved caspase-3. RESULTS: Cardiac function in the CME group and CME + TAK-242 group were significantly decreased compared with the sham group (P < 0.05) and the micro-infarction area, the apoptotic index, the expression of TLR4, NF-κB p65, p-IκBα and Cleaved caspase-3 were increased significantly (P < 0.05). Cardiac function in the CME + TAK-242 group was significantly improved compared with the CME group (P < 0.05) and the micro-infarction area, the apoptotic index, the expression of TLR4, MyD88, NF-κB p65, p-IκBα and Cleaved caspase-3 were decreased significantly (P < 0.05). CONCLUSIONS: TAK-242 can effectively improve CME-induced cardiac dysfunction by regulating TLR4/NF-κB signaling pathway and then reducing the myocardial apoptosis.

Allogeneic hematopoietic stem cell transplantation improves the prognosis of p16-deleted adult patients with acute lymphoblastic leukemia.

AIM: The prognostic value of CDKN2A inactivation in adult patients with acute lymphoblastic leukemia (ALL) is still under debate, and the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for adult ALL with p16 deletion remains to be evaluated. MATERIALS & METHODS: This study analyzed the clinical implications of p16 deletion in adult ALL and investigated the efficacy of allo-HSCT in patients with p16 deletion. RESULTS: Deletion of p16 was identified in 38.4% of the adult ALL patients, and the prevalences of hemizygous deletion, homozygous deletion and mixed hemi/homozygous of p16 were 22.1, 11.6 and 5.5%, respectively. The prevalence of p16 deletion was 39.7% in B-lineage ALL and 33.3% in T-lineage ALL. Deletion of p16 was significantly associated with higher white blood cell count (p = 0.032) and lower platelets (p = 0.023) but was not related to age, sex, percentage of bone marrow blasts, hepatosplenomegaly, CNS leukemia rate, first complete remission and relapse rate (p > 0.05). Deletion of p16 was significantly correlated with poor outcome in terms of event-free survival (EFS; p = 0.028) and overall survival (OS; p = 0.033). Twenty-two of the 33 patients with p16 deletion received allo-HSCT treatment. Patients with p16 deletion after allo-HSCT experienced higher EFS and OS than those without (52.9 vs 0%, p < 0.001; 46.8 vs 29.1%, p = 0.01, respectively). Multivariate analysis found CNS leukemia and poor response to induction chemotherapy to be the risk factors for EFS and OS, whereas no deletions of p16 and allo-HSCT were favorable factors. CONCLUSION: Deletion of p16 is a strong adverse prognostic factor in adult ALL. Testing for p16 alterations at diagnosis may help in risk stratification, and we propose to implement testing for p16 deletion in future treatment protocols.

A New Strategy to Target Acute Myeloid Leukemia Stem and Progenitor Cells Using Chidamide, a Histone Deacetylase Inhibitor.

Leukemia stem cells (LSCs) are responsible for treatment failure and relapse in acute myeloid leukemia (AML). Therefore, development of novel LSCs-targeting therapeutic strategies is of crucial clinical importance to improve the treatment outcomes of AML. Histone deacetylase (HDAC) inhibitors have shown potent and specific anticancer stem cell activities in preclinical studies. Chidamide, a novel benzamide-type selectively HDAC inhibitor, has been reported to induce G1 arrest and apoptosis in the relatively mature progenitor population, whereas its effect on primitive LSCs has not been clarified. In this study, we demonstrated that chidamide specifically induces apoptosis in LSC-like cells and primary AML CD34(+) cells in a concentration- and time-dependent manner. Our further molecular mechanistic study uncovered that chidamide induces LSCs death by activation of reactive oxygen species (ROS). It compromises the mitochondria membrane potential, modulates antiapoptotic and pro-apoptotic proteins in BCL2 family and activates caspase-3 leading to PARP degradation. Meanwhile, chidamide activates CD40 and modulates its downstream signaling pathways, JNK and NFκB. The results of this study suggest that chidamide may be a novel LSC-targeting agent for AML therapeutics.