Protective effects of COVID-19 vaccination in splenectomized patients with immune thrombocytopenia.

Splenectomy is an effective treatment for immune thrombocytopenia (ITP). The effect of COVID-19 vaccination on splenectomized patients with ITP during the COVID-19 pandemic has not been reported. Therefore, this study aimed to investigate the effect of COVID-19 vaccination on clinical outcomes in these patients. This was a longitudinal study of splenectomized patients with ITP. A total of 191 splenectomized patients were included in this study. After a median follow-up of 114 months, 146 (76.4%) patients had a sustained response to splenectomy. During COVID-19 infection, vaccinated patients showed a lower risk of severe infections (odds ratio [OR], 0.13; 95% confidence interval [CI]: 0.05-0.36; p < 0.001), hospitalization (OR, 0.13; 95% CI, 0.04-0.48; p = 0.002), and ITP exacerbation (OR, 0.16; 95% CI, 0.04-0.67; p = 0.012). These findings indicate that COVID-19 vaccination plays a protective role in splenectomized patients with ITP.

Advances in Drug Delivery Systems for the Treatment of Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a common and catastrophic hematological neoplasm with high mortality rates. Conventional therapies, including chemotherapy, hematopoietic stem cell transplantation (HSCT), immune therapy, and targeted agents, have unsatisfactory outcomes for AML patients due to drug toxicity, off-target effects, drug resistance, drug side effects, and AML relapse and refractoriness. These intrinsic limitations of current treatments have promoted the development and application of nanomedicine for more effective and safer leukemia therapy. In this review, the classification of nanoparticles applied in AML therapy, including liposomes, polymersomes, micelles, dendrimers, and inorganic nanoparticles, is reviewed. In addition, various strategies for enhancing therapeutic targetability in nanomedicine, including the use of conjugating ligands, biomimetic-nanotechnology, and bone marrow targeting, which indicates the potential to reverse drug resistance, are discussed. The application of nanomedicine for assisting immunotherapy is also involved. Finally, the advantages and possible challenges of nanomedicine for the transition from the preclinical phase to the clinical phase are discussed.

Myelomonocytic and monocytic acute myeloid leukemia demonstrate comparable poor outcomes with venetoclax-based treatment: a monocentric real-world study.

Venetoclax (VEN), a BCL-2 inhibitor, has transformed treatment strategies for elderly and unfit acute myeloid leukemia (AML) patients by significantly improving response rates and survival. However, the predictive factors for VEN efficacy differ from traditional chemotherapy. The clinical relevance of the FAB (French-American-British) monocytic subtype, including M4 and M5, has been debated as a marker for VEN resistance. This real-world study examined 162 newly diagnosed (ND) and 85 relapsed/refractory (R/R) AML patients who received VEN-based therapy at West China Hospital, Sichuan University, from January 2019 to January 2023. We retrospectively collected clinical and treatment data from electronic medical records. The median age of the cohort was 55.5 years (range: 16.5-83.5). The composite complete remission (cCR) rate in the entire cohort was 60.7%. Specifically, among newly diagnosed (ND) patients, FAB monocytic subtypes exhibited lower cCR compared to non-monocytic subtypes (55.1% vs. 76.3%, P = 0.007). Additionally, there were no significant differences observed between M4 and M5 subtypes, both in the ND group (61.7% vs. 40.9%, p = 0.17) and the R/R group (38.2% vs. 40%, p > 0.9). Furthermore, the median follow-up was 238 (range: 7-1120) days. ND patients with monocytic subtypes had shorter overall survival compared to non-monocytic subtypes (295 days vs. not reached, p = 0.0017). Conversely, R/R patients showed no such difference (204 vs. 266 days, p = 0.72). In summary, our study suggests that the FAB monocytic subtype can predict VEN resistance and shorter survival in ND AML patients. Moreover, there is no significant distinction between M4 and M5 subtypes.

Literature review on genotype-phenotype correlation in patients with hereditary spherocytosis.

Hereditary spherocytosis (HS) is a prevalent inherited hemolytic disorder primarily reported in Caucasians. Recently, next-generation sequencing (NGS) techniques have shown tremendous potential in the diagnosis of HS. HS commonly originates from variants in ANK1, SPTB, SLC4A1, SPTA1, and EPB42. This review is focused on 13 previous clinical studies on genotype-phenotype correlation, which might promote the role of causative variants in the diagnosis and prognosis of HS. Most studies have focused on the pediatric population and Asian countries. The occurrence of novel variants was common in each cohort, and variants with a high frequency of causative genes were demonstrated. In conclusion, patients with variants in SPTA1 and SLC4A1 were reported to have more severe and milder anemia, respectively. ANK1 and SPTB are the most common variants in patients with HS, and no significant difference in phenotypes was observed between patients with variants in ANK1 versus SPTB. The types and locations of variants might influence the phenotype of each genotype, whereas the roles of concomitant pathogenic genes and the source of variants deserve further investigation.

Pedigree investigation, clinical characteristics, and prognosis analysis of haematological disease patients with germline TET2 mutation.

BACKGROUND: Increasing germline gene mutations have been discovered in haematological malignancies with the development of next-generation sequencing (NGS), which is critical for proper clinical management and long-term follow-up of affected individuals. Tet methylcytosine dioxygenase 2 (TET2) is one of the most common mutations in haematological neoplasms. We aimed to compare the clinical characteristics of patients with germline and somatic TET2 mutations in haematological diseases and to analyse whether germline TET2 mutations have a family aggregation and tumour predisposition. METHODS: Out of 612 patients who underwent NGS of 34 recurrently mutated genes in haematological diseases, 100 haematological patients with TET2 mutations were selected for further study. Somatic mutations were detected by NGS in bone marrow/peripheral blood genomic DNA (gDNA). Germline TET2 mutations were validated in nail/hair gDNA by Sanger sequencing. Digital data were extracted from the haematology department of the West China Hospital of Sichuan University. TET2 mutation results were analysed by referencing online public databases (COSMIC and ClinVar). RESULTS: One hundred patients were studied, including 33 patients with germline and 67 patients with somatic TET2 mutations. For germline TET2 mutations, the variant allele frequency (VAF) was more stable (50.58% [40.5-55], P < 0.0001), and mutation sites recurrently occurred in three sites, unlike somatic TET2 mutations. Patients with germline TET2 mutations were younger (median age 48, 16-82 years) (P = 0.0058) and mainly suffered from myelodysplastic syndromes (MDS) (n = 13, 39.4%), while patients with somatic TET2 mutations were mainly affected by acute myeloid leukemia (AML) (n = 26, 38.8%) (P = 0.0004). Germline TET2 mutation affected the distribution of cell counts in the peripheral blood and bone marrow (P < 0.05); it was a poor prognostic factor for MDS patients via univariate analysis (HR = 5.3, 95% CI: 0.89-32.2, P = 0.0209) but not in multivariate analysis using the Cox regression model (P = 0.062). CONCLUSIONS: Germline TET2 mutation might have a family aggregation, and TET2 may be a predisposition gene for haematological malignancy under the other gene mutations as the second hit. Germline TET2 mutation may play a role in the proportion of blood and bone marrow cells and, most importantly, may be an adverse factor for MDS patients.

Pneumatosis cystoides intestinalis associated with etoposide in hematological malignancies: a case report and a literature review.

Pneumatosis cystoides intestinalis (PCI) is a rare condition characterized by the presence of air collection within the subserosa and/or submucosa of the gastrointestinal wall. Due to the lack of specific symptoms, PCI is likely to be misdiagnosed or missed without the use of imaging techniques or gastrointestinal endoscopy. Here, we report a patient who complained of abdominal distention and constipation after chemotherapy for hematological malignancies, and was diagnosed with secondary PCI via computed tomography (CT) and exploratory laparotomy. Pneumoperitoneum was no longer observed after two weeks of conservative treatments. Notably, the possibility of intra-abdominal pressure (IAP) as a predictor for surgical intervention was proposed. Furthermore, we conducted a literature review on PCI after chemotherapy in hematological malignancies to raise awareness of etoposide-related PCI, while whether PCI could be identified as an adverse event of etoposide requires more evidence.

Comparison of monoclonal antibodies targeting CD38, SLAMF7 and PD-1/PD-L1 in combination with Bortezomib/Immunomodulators plus dexamethasone/prednisone for the treatment of multiple myeloma: an indirect-comparison Meta-analysis of randomised controlled trials.

BACKGROUND: Many clinical trials have assessed the effect and safety of monoclonal antibodies (MAbs) in combination with proteasome inhibitors or immunomodulators plus dexamethasone/prednisone for the treatment of multiple myeloma (MM). The treatment outcomes of comparing different MAbs in combination with the above-mentioned agents remained unclear. We performed the meta-analysis to indirectly compare the effect and safety of MAbs targeting CD38, SLAMF7, and PD-1/PD-L1 in combination with bortezomib/immunomodulators plus dexamethasone/prednisone for patients with MM. METHODS: We searched thoroughly in the databases for randomised controlled trials (RCTs) in which at least one of the three MAbs were included. We included eleven eligible RCTs with 5367 patients in the meta-analysis. Statistical analysis was carried out using StataMP14 and Indirect Treatment Comparisons software. RESULTS: We calculated hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) and relative risk (RR) for overall response rate, complete response (CR) or better, very good partial response (VGPR) or better, VGPR, partial response, stable disease, and grade 3 or higher adverse events among the three groups. The HRs for PFS of the CD38 group vs SLAMF7 group, CD38 group vs PD-1/PD-L1 group, and SLAMF7 group vs PD-1/PD-L1 group were 0.662 (95%CI 0.543-0.806), 0.317 (95%CI 0.221-0.454), and 0.479 (95%CI 0.328-0.699), respectively. The HR for OS of the CD38 group vs SLAMF7 group was 0.812 (95%CI 0.584-1.127). The RR for CR or better in the CD38 group vs SLAMF7 group was 2.253 (95%CI 1.284-3.955). The RR for neutropenia of the CD38 group vs SLAMF7 group was 1.818 (95%CI 1.41-2.344). CONCLUSIONS: Treatment with the CD38 group had longer PFS and better treatment response than that with the SLAMF7 or PD-1/PD-L1 group. In addition, the SLAMF7 group prolonged PFS compared with the PD-1/PD-L1 group and was associated with a lower incidence of grade 3 or higher neutropenia than the CD38 and PD-1/PD-L1 group. In conclusion, MAbs targeting CD38 are the best, followed by those targeting SLAMF7; MAbs targeting PD-1/PD-L1 are the worst when in combination with bortezomib/immunomodulators plus dexamethasone/prednisone for the treatment of MM.

Inhibition of long noncoding RNA MALAT1 suppresses high glucose-induced apoptosis and inflammation in human umbilical vein endothelial cells by suppressing the NF-κB signaling pathway.

The study investigated the expression of long noncoding RNA (lncRNA) MALAT1 in high glucose (HG)-induced human vascular endothelial cells (HUVECs) and the role of MALAT1 in the apoptosis of HG-induced HUVECs. The HUVECs were cultured and induced with 25 mmol/L HG. After that, the HUVECs were transfected with MALAT1 siRNA. The expression levels of MALAT1 were detected with qPCR, whereas the expression levels of Bax, Bcl-2, cleaved-caspase-3, cleaved-caspase-9, p-65, and p-p65 were detected using Western blot. The roles of MALAT1 in cell activities, including apoptosis, were evaluated using the CCK-8 assay, TUNEL staining, and flow cytometry. The expression levels of inflammatory factors (TNF-α and IL-6) were measured using ELISA. The expression levels of MALAT1, TNF-α, and IL-6 in HUVECs were increased in the HG environment; however, when MALAT1 was silenced in the HUVECs, cell proliferation increased significantly, the expression levels of TNF-α, IL-6, Bax, cleaved-caspase-3, and cleaved-caspase-9 decreased, and the rate of apoptosis also decreased. Silencing MALAT1 inhibited the expression of p-p65 in HG-induced HUVECs. In conclusion, our study demonstrated that MALAT1 is upregulated in HG-induced HUVECs, and inhibition of MALAT1 inhibits HG-induced apoptosis and inflammation in HUVECs by suppression of the NF-κB signaling pathway.

The prognostic impact of variant allele frequency (VAF) in TP53 mutant patients with MDS: A systematic review and meta-analysis.

Tumor protein p53 (TP53) is frequently expressed in patients with myelodysplastic syndromes (MDS). Studies have already reported the poor prognostic impact of TP53 gene mutations in MDS patients. However, parts of this subgroup of patients with low-risk MDS still have relatively better survival and longer remission times. Therefore, we performed a meta-analysis to evaluate the prognostic difference intra-gene of variant allele frequency (VAF). The primary endpoint was overall survival (OS), and event-free survival (EFS) was selected as the secondary endpoint. We extracted the hazard ratio (HR) and 95% confidence interval (CI) for OS and EFS from univariate and multivariate Cox proportional hazard models. A total of 4003 MDS patients and 1278 TP53-mutated patients from 13 cohorts of 11 studies up to February 24, 2020, were included in our meta-analysis. Pooled HRs suggested that a high mutant VAF had an adverse impact on OS (HR = 2.11, 95% CI: 1.48-3.01, P < .0001) but no impact on EFS (HR = 15.57, 95% CI: 0.75-324.44, P = .003) in MDS patients. Twenty percent is a proper threshold to set (HR = 2.02, 95% CI: 1.31-3.13, P = .001) and is a rough line between high clone burden and low clone burden, while 40% is an exact cutoff point (HR = 2.11, 95% CI: 1.26-3.55, P < .0001) to guide diagnosis and treatment. Beyond the traditional binary classification of gene mutation, we aimed to find a way to divide mutant molecular markers more specifically by VAF to provide clinical therapeutic values. Our meta-analysis indicates that a high VAF is an independent, adverse prognostic factor for OS in TP53 mutant MDS patients. Patients with mediate/low-frequency parts who could be treated like wide-type patients have relatively better survival and may choose allogeneic hematopoietic stem cell transplantation as conditions permitting. Further prospective studies are needed in the future, and a large subgroup analysis of the same cutoff point subgroups is needed to obtain a more reliable basis for the impact of other mutant gene VAFs on the prognosis of MDS.

Continuous thrombocytopenia after SARS-CoV-2 nucleic acid negative in a non-severe COVID-19 patient for several months.

BACKGROUND: Thrombocytopenia was common in the coronavirus disease (Covid-19) patients during the infection, especially in severe COVID-19 patients, but was less in the non-severe Covid-19 patients. However, the platelet count would be restored after antivirus treatment. In this paper, we report continuous thrombocytopenia in a non-severe Covid-19 case after a negative nucleic acid test for Covid-19. CASE PRESENTATION: A non-severe COVID-19 patient had the platelet continuous decrease for several months after the SARS-CoV-2 nucleic acid turning negative, and without well response to the glucocorticoid. The dynamic change of platelet count followed that of the lymphocyte count. After excluding the medicines possibility, immune system disorders, other specific virus infection and specific antibody of platelet, the thrombocytopenia continuously lasted for several months. The upward trend did not begin until June 2020 and she took the tapering dose of prednisone under the instruction of the hematologist. CONCLUSION: Excluding other potentialities inducing thrombocytopenia, we highly hypothesized the SARS-CoV-2 may cause thrombocytopenia by disturbing the immune system to induce the thrombocytopenia in our report,, which needs longer time to restore the immune system and platelet count via the glucocorticoid. We firstly reported this case in order to contribute the clinician to better deal with the patients like this.

Prognostic significance of the EVI1 gene expression in patients with acute myeloid leukemia: a meta-analysis.

Ecotropic virus integration site-1 (EVI1) is frequently expressed in patients with acute myeloid leukemia (AML). Many studies have reported the potential poor prognostic impact of EVI1 higher expression (EVI1H) in the AML patients; however, the conclusions previously reported have not been fully assessed and are still controversial. Therefore, we performed a meta-analysis to evaluate the prognostic significance of EVI1H in patients with AML. The primary endpoint was overall survival (OS), and the event-free survival (EFS) was selected as the secondary endpoint. We extracted the hazard ratio (HR) and their 95% confidence interval (CI) for the OS and EFS from the multivariate COX proportional hazard models. A total of 4767 AML patients from 11 studies up to 23 February 2019 were subjected to our meta-analysis. Pooled HRs suggested that EVI1H had an adverse impact on OS (HR = 1.52, 95%CI 1.24-1.86) and EFS (HR = 1.41, 95%CI 1.14-1.74) in AML patients. EVI1H was also associated with a shorter OS (HR = 1.73, 95%CI 1.43-2.11) and EFS (HR = 1.17, 95%CI 1.05-1.31) in AML patients with the intermediate cytogenetic risk (ICR) according to the National Comprehensive Cancer Network (NCCN), European leukemia network (ELN), or International System for Human Cytogenetic Nomenclature (ISCN). Furthermore, EVI1H appeared to be a poor prognosis indicator in patients with normal cytogenetics (NC) (HR for OS:2.01, 95%CI 1.32-3.05; HR for EFS 1.54, 95%CI 1.09-2.17) and young patients (HR for OS 1.30, 95%CI 1.09-1.55), respectively. This meta-analysis indicates EVI1H has an independent and significantly adverse prognostic impact on AML patients in the entire population, and this conclusion same applies to some subgroups like AML patients with ICR, NC, and young AML patients.

Prognostic value of U2AF1 mutant in patients with de novo myelodysplastic syndromes: a meta-analysis.

U2 small nuclear RNA auxiliary factor 1 (U2AF1) mutant is the most common molecular biological abnormality in patients with myelodysplastic syndromes. Some studies have reported the prognostic impact of U2AF1 mutant in patients with de novo MDS, with discrepant results, so we do a meta-analysis about the relevant literatures to further investigate their prognostic impact on patients with de novo MDS. We conducted a literature search on databases such as PubMed, Embase, and the Cochrane Library to obtain studies on the prognosis of U2AF1 mutant in patients with de novo MDS published up to August 9, 2018. The primary endpoint was overall survival (OS), and the secondary endpoint was acute myeloid leukemia (AML) transformation. We extracted the hazard ratios (HRs) of OS and AML transformation and their 95% confidence intervals (CIs). Meta-analysis was performed by selecting a fixed-effect model or a random-effects model based on the heterogeneity between studies. A total of 14 cohort studies were included in the final meta-analysis, including 3322 patients with de no MDS, in which 390 patients were associated with U2AF1 mutant. The results showed that U2AF1 mutant had an adverse prognostic impact on OS (HR = 1.84, 95% CI: 1.45-2.33, P < 0.00001) and AML transformation (HR = 2.47, 95% CI: 1.50-4.06, P = 0.0004). U2AF1 mutant was associated with shorter OS in subgroup analyses of low- or intermediate-1-IPSS, U2AF1S34 and U2AF1Q157/R156. Out meta-analysis indicates that U2AF1 mutants are independent, detrimental prognostic factors for OS and AML transformation in patients with de novo MDS, as well as associating with shorter OS in subgroups of low- or intermediate-1-IPSS, U2AF1S34 and U2AF1Q157/R156. Further prospective studies are needed in the future, and subgroup analysis of U2AF1 subgroups is needed to obtain a more reliable basis for the impact of U2AF1 mutant on the prognosis of de novo MDS.

[Relationship of Cystic Fibrosis Transmembrane Conductance Regulator Expression with Clinical Features and Prognosis in Patients with Acute Leukemia].

OBJECTIVE: To investigate the expression of cystic fibrosis transmembrane conductance regulator (CFTR) protein in patients with acute leukemia and its relationship to clinical features and prognosis of acute leukemia. METHODS: A total of115 patients with acute leukemia were enrolled in the experimental group and 20 healthy individuals were used as control. Peripheral blood or bone marrow samples were collected, and mononuclear cells were isolated. The expression of CFTR protein was detected by Western blot. The relationships of CFTR protein expression to clinical features and prognosis was analyzed. RESULTS: The expression of CFTR protein was not detected in peripheral blood mononuclear cells of normal control, while it was positive in more than half of acute leukemias including acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), but negative in the patients with acute promyelocytic leukemia (M3). In the patients with AML, there was no difference in peripheral white blood cells (WBC), peripheral blast cells, platelet and hemoglobin (HGB) between CFTR-positive and CFTR-negative patients. There was no relationship between the expression of CFTR protein and gene mutations such as NPM1, CEBPA, FLT3-ITD, and C-Kit. Complete remission (CR) rate after two course in CFTR-negative patients was slightly higher than that in positive patients. The survival time of CFTR-negative patients was little longer than that of positive patients, but the difference was not statistically significant. CONCLUSIONS: The expression of CFTR protein seems not associated with clinical features, treatment response and prognosis in the patients with acute leukemia.

Nutlin-3 plus tanshinone IIA exhibits synergetic anti-leukemia effect with imatinib by reactivating p53 and inhibiting the AKT/mTOR pathway in Ph+ ALL.

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is triggered by BCR/ABL kinase. Recent efforts focused on the development of more potent tyrosine kinase inhibitors (TKIs) that also inhibit mutant tyrosine kinases such as nilotinib and dasatinib. Although major advances in the treatment of this aggressive disease with potent inhibitors of the BCR/ABL kinases, patients in remission frequently relapse due to drug resistance possibly mediated, at least in part, by compensatory activation of growth-signaling pathways and protective feedback signaling of leukemia cells in response to TKI treatment. Continuous activation of AKT/mTOR signaling and inactivation of p53 pathway were two mechanisms of TKI resistance. Here, we reported that nutlin-3 plus tanshinone IIA significantly potentiated the cytotoxic and apoptotic induction effects of imatinib by down-regulation of the AKT/mTOR pathway and reactivating the p53 pathway deeply in Ph+ ALL cell line. In primary samples from Ph+ ALL patients, nutlin-3 plus tanshinone IIA also exhibited synergetic cytotoxic effects with imatinib. Of note, three samples from Ph+ ALL patients harboring T315I mutation also showed sensitivity to the combined treatment of imatinib, nutlin-3 plus tanshinone IIA. In Ph+ ALL mouse models, imatinib combined with nutlin-3 plus tanshinone IIA also exhibited synergetic effects on reduction in leukemia burden. These results demonstrated that nutlin-3 plus tanshinone IIA combined TKI might be a promising treatment strategy for Ph+ ALL patients.

[The Roles of Glut5 in Imatinib Resistance in the Ph+ Acute Lymphoblastic Leukemia Cell].

OBJECTIVES: To explore the possible roles of glucose transport 5 (Glut5) in imatinib resistance in the Ph+ acute lymphoblastic leukemia cell (Ph+ ALL). METHODS: The gene chip technique was used to detect different gene expression between Ph+ ALL cell line SUP-B15/R (imatinib resistant cell line) and SUP-B15/S (imatinib sensitive cell line), the gene of solute carrier family 2 member 5 (SLC2A5) and its coded protein Glut5 were screened out and were reconfirmed by qPCR and Western blot assay. The imatinib half maximal inhibitory concentration (IC50) to SUP-B15/S cells with or without fructose treatment was further detected by MTT assay, simultaneously signal pathway gene was detected by qPCR assay. RESULTS: Metabolism related gene SLC2A5 was screened out with gene chip technique and the Western blot assay and qPCR confirmed the high expression of SLC2A5 gene and its coded protein Glut5 in SUP-B15/R cells. IC50 values of imatinib to SUP-B15/S cells after treatment with 25 µmol/L fructose were increased from (44.50±2.38) µmol/L to (64.71±1.69) µmol/L, in the meanwhile, PI3K and AKT mRNA level also increased in fructose treated SUP-B15/S cells compared to the control. CONCLUSIONS: High expression of SLC2A5 and Glut5 protein in SUP-B15/R cells leads to increased fructose absorption, and further activates PI3K/AKT pathway which cause the SUP-B15 cell resistance to imatinib.

[The Mechanism of Combination using mTORC1/2 Inhibitor and Imatinib to Suppress Cell Proliferation of Ph +ALL Cell Line].

OBJECTIVES: To investigate the anti-leukemia effect and mechanism of mTORC1/2 inhibitor PP242 combined with imatinib (IM) on the proliferation of Ph+ acute lymphoblastic leukemia (ALL) cell line SUP-B15. METHODS: SUP-B15 cell line was treated with PP242, imatinib (IM), or PP242 plus IM for 72 h, IC50 values (the concentration of drug required to kill 50% of the cells) and the combination index (CI ) of synergistic cytotoxicity was determined using MTT methods. The expressions of PI3K/Akt/mTOR and apoptosis associated proteins were examined by Western blot test. RESULTS: The IC50 value of IM alone was (1.50±0.09) µmol/L, however, the IC50 values were (0.81±0.030) µmol/L, (0.36±0.140) µmol/L and (0.02±0.002) µmol/L combined with 20 nmol/L, 30 nmol/L and 50 nmol/L of PP242, and the CI values were 0.764, 0.545 and 0.507, indicating two drugs had highly synergistic effect on anti-proliferation in the SUP-B15 cell line. The expressions of p-Akt, p-4EBP1, p-elF4E, p-cAbl, p-mTOR and p-P70 were down-regulated significantly in a dose-dependent and time-dependent manner after PP242 treatment#.Compared with PP242 or IM alone, the down-regulation of PI3K/Akt/mTOR signaling pathway and the up-regulation of the apoptosis associated proteins (bax and cleaved caspase-3) were more significant in the combination of two drugs. CONCLUSION: The combination of IM and PP242 could increase the inhibition of PI3K/Akt/mTOR signaling pathway and apoptosis mediated by bax and caspase-3 in SUP-B15 cell line.

The efficacy of pelvic floor muscle training for pelvic organ prolapse: a systematic review and meta-analysis.

INTRODUCTION AND HYPOTHESIS: Our objective was to assess the effectiveness of pelvic floor muscle training (PFMT) as a treatment for women with pelvic organ prolapse (POP) or as an adjunct to prolapse surgery. METHODS: Relevant literature sources were searched using databases including PubMed, Ovid, Web of Science, Scopus, ClinicalTrials.gov, EBSCO, CINAHL, the Cochrane Central Register of Controlled Trials, CNKI, VIP, Wanfang, and CBM until 5 July 2015. Eligible studies were restricted to randomized controlled trials (RCT). The available data were pooled using Review Manager version 5.2. For data deemed not appropriate for synthesis, a narrative overview was conducted. RESULTS: In total, 13 studies with 2,340 patients were included. Our results indicated women receiving PFMT gained a greater improvement than controls in prolapse symptom score [mean difference (MD) -3.07, 95 % confidence interval (CI) -3.91 to -2.23] and POP stages [risk ratio (RR) 1.70, 95 % CI 1.19-2.44]. The number of women who said their prolapse was getting better was higher (RR 5.48, 95 % CI 2.19-13.72) and other discomfort syndromes, such as vaginal, bladder, and rectum, were lower in the PFMT groups than in controls. Meanwhile, women after PFMT had greater improvement in muscle strength and endurance but did not show a significant difference for further treatment needs. In addition, the results evaluating PFMT as an adjunct to prolapse surgery were inconclusive because of the variability in methods of measuring outcome. CONCLUSIONS: Our meta-analysis demonstrated women who received PFMT showed a greater subjective improvement in prolapse symptoms and an objective improvement in POP severity.

The antileukemia effect of metformin in the Philadelphia chromosome-positive leukemia cell line and patient primary leukemia cell.

In recent years, there have been considerable research advances on the antileukemic mechanisms of the antidiabetic drug metformin. Our current studies have shown that metformin suppresses cell viability, induces apoptosis, and downregulates the mTORC1 signaling pathway both in the Ph+ALL cell line and primary blasts from Ph+ ALL patients, as well as the CML cell lines K562 (imatinib-sensitive) and K562R (imatinib-resistance). We have also shown that metformin activates the ERK pathway in Ph+ALL cells, SUP-B15, a side effect that can be overcome by U0126 (MEK1/2 inhibitor) or imatinib. Moreover, this activation of ERK signaling in SUP-B15 induces autophagy. Inhibition of the autophagic process by 3-MA, promoting the death of these cells, suggests that autophagy may be a cytoprotective factor in cell survival after metformin treatment. Finally, metformin is shown to potentiate the anticancer efficacy of imatinib in Ph+ALL and CML cells, resensitizing the CML imatinib-resistance cells to imatinib. Overall, our data suggest that metformin represents a promising and attractive agent for Ph+ALL or CML therapy.

The antileukemia roles of PP242 alone or in combination with daunorubicin in acute leukemia.

PP242 is a novel dual mammalian target of rapamycin (mTOR) inhibitor that simultaneously inhibits mTORC1 and mTORC2, and its antileukemia effect has been sufficiently investigated here. The human acute leukemia cell lines and primary blasts were treated with PP242 alone or in combination with daunorubicin (DNR). Cell proliferation was examined using an MTT assay. The phosphorylation expression of the Akt/mTORC1/eIF4E signaling pathway was assessed by western blot analysis. The assembly of the eIF4F translation initiation complex was examined using a 7-methyl-guanosine cap affinity assay. PP242 significantly induced cytotoxicity in human acute leukemia cells, especially in combination with DNR. The phosphorylation levels of eIF4E (p-eIF4E) at Ser209 influence the antileukemia roles of PP242. As expected, the antiproliferative effects of PP242 on leukemia cells with low p-eIF4E expression, such as the acute promyelocytic leukemia NB4 cell line and AML-M3 primary blasts, were poor. Surprisingly, the effects of PP242 in leukemia cells with high p-eIF4E expression, such as the acute myelomonocytic leukemia THP-1 cell line and M4-M5 primary blasts, were also weak. In contrast, PP242 exerted a significant antiproliferative effect in the Ph+ acute lymphoblastic leukemia SUP-B15 cell line and the mantle cell lymphoma JEKO-1 cell line, which had intermediate p-eIF4E levels. PP242 inhibited the translation of the antiapoptotic protein Mcl-1 by downregulating the Akt/mTORC1/eIF4E signaling pathway. More importantly, DNR activated the Akt/mTORC1/eIF4E signaling pathway, whereas PP242 effectively eliminated this deleterious side effect of DNR and synergistically enhanced the anticancer ability of DNR treatment. PP242, especially in combination with DNR, exerts significant antileukemia effects.