Long-Term Remission in T315I+ Relapsed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia with Blinatumomab and Allogeneic Stem Cell Transplantation: Two Case Studies.

BACKGROUND Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in adults has a poor prognosis with conventional chemotherapy. Treatment with tyrosine kinase inhibitors (TKIs) followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) has improved clinical outcomes; however, the relapse rate is still high. Therapeutic options for patients with relapsed/refractory (R/R) Ph+ ALL are scarce, with very few studies focusing on these patients. Blinatumomab is a novel bispecific T-cell engager antibody construct showing promising efficacy in R/R Ph+ ALL. CASE REPORT Here, we present 2 cases of relapsed Ph+ ALL with T315I mutation refractory to multiple TKIs and chemotherapy. Patient 1 was a 48-year-old woman who had increased leukocytes in her peripheral blood cells, with 90% abnormal cells and decreased platelets. Bone marrow (BM) smear showed 95% blasts. Patient 2 was a 20-year-old man who had leukocytosis with thrombocytopenia, while all other parameters were normal. BM aspirate showed 98% immature granulocytes/blasts. The immunophenotypic observations of both the patients on BM were consistent with the presence of ALL. Both patients were effectively treated with a combination of blinatumomab and allo-HSCT and achieved complete remission in 1 month with minimal residual disease negativity and remained in remission for a long period. CONCLUSIONS The findings suggest, that for patients with R/R Ph+ ALL with T315I mutation who respond poorly to TKIs, salvage therapy with blinatumomab is a potentially effective treatment for improving clinical outcomes. The treatment with blinatumomab can further act as a bridge to HSCT in these patients, helping them to attain deeper remission.

MT1E in AML: A Gateway to Understanding Regulatory Cell Death and Immunotherapeutic Responses.

Regulated cell death (RCD) plays a crucial role in the initiation and progression of tumors, particularly in acute myeloid leukemia (AML). This study investigates the prognostic importance of RCD-related genes in AML and their correlation with immune infiltration.We combined TCGA and GTEx data, analyzing 1488 RCD-related genes, to develop a predictive model using LASSO regression and survival analysis. The model's accuracy was validated against multiple databases, examining immune cell infiltration, therapy responses, and drug sensitivity among risk groups. RT-qPCR confirmed MT1E expression in AML patients and healthy bone marrow. CCK8 and Transwell assays measured cell proliferation, adhesion, migration, and invasion, while flow cytometry and Western blotting assessed apoptosis and protein expression.We developed a prognostic model using 10 RCD methods, which demonstrated strong predictive ability, showing an inverse correlation between age and risk scores with survival in AML patients. Functional enrichment analysis of the model is linked to immune modulation pathways. RT-qPCR revealed significantly lower MT1E expression in AML versus healthy bone marrow (p<0.05). Consequently, experiments were designed to assess the function of MT1E overexpression.Findings indicated that MT1E overexpression showed it significantly reduced THP-1 cell proliferation and adhesion(p<0.001), decreased migration(p<0.001) and invasiveness(p<0.05), and increased apoptosis(p<0.05), with a notable rise in Caspase3 expression.A novel AML RCD risk model was developed, showing promise as a prognostic marker for evaluating outcomes and immune therapy effectiveness. Insights into MT1E's impact on AML cell proliferation and apoptosis open possibilities for improving patient outcomes and devising personalized treatment strategies.

A novel 10-gene ferroptosis-related prognostic signature in acute myeloid leukemia.

Acute myeloid leukemia (AML) is one of the most common hematopoietic malignancies and exhibits a high rate of relapse and unfavorable outcomes. Ferroptosis, a relatively recently described type of cell death, has been reported to be involved in cancer development. However, the prognostic value of ferroptosis-related genes (FRGs) in AML remains unclear. In this study, we found 54 differentially expressed ferroptosis-related genes (DEFRGs) between AML and normal marrow tissues. 18 of 54 DEFRGs were correlated with overall survival (OS) (P<0.05). Using the least absolute shrinkage and selection operator (LASSO) Cox regression analysis, we selected 10 DEFRGs that were associated with OS to build a prognostic signature. Data from AML patients from the International Cancer Genome Consortium (ICGC) cohort as well as the First Affiliated Hospital of Wenzhou Medical University (FAHWMU) cohort were used for validation. Notably, the prognostic survival analyses of this signature passed with a significant margin, and the riskscore was identified as an independent prognostic marker using Cox regression analyses. Then we used a machine learning method (SHAP) to judge the importance of each feature in this 10-gene signature. Riskscore was shown to have the highest correlation with this 10-gene signature compared with each gene in this signature. Further studies showed that AML was significantly associated with immune cell infiltration. In addition, drug-sensitive analysis showed that 8 drugs may be beneficial for treatment of AML. Finally, the expressions of 10 genes in this signature were verified by real-time quantitative polymerase chain reaction. In conclusion, our study establishes a novel 10-gene prognostic risk signature based on ferroptosis-related genes for AML patients and FRGs may be novel therapeutic targets for AML.

Multi-omics data identified TP53 and LRP1B as key regulatory gene related to immune phenotypes via EPCAM in HCC.

BACKGROUND: Many studies showed that the prognosis of hepatocellular carcinoma (HCC) was significantly associated with the expressions of TP53 and LRP1B. However, the potential influence of the two genes on the malignant progression of HCC is still to be expounded. METHODS: According to the correlation analysis between immune cells and expression levels of TP53 and LRP1B, we filtered the immune cells to perform unsupervised clustering analysis. Integration of multi-omic data analysis identified genetic alteration and epigenetic alteration. In addition, pathway analysis was used to explore the potential function of the differentially expressed mRNAs. According to the differentially expressed genes, we established an interaction network to seek the hub gene. Least absolute shrinkage and selection operator (LASSO) regression analysis was used to build a prognosis model. RESULTS: The unsupervised clustering analysis showed that the cluster A1 showed the highest immune cell levels and the cluster B2 showed the lowest immune cell levels. Multi-omics data analysis identified that somatic mutations, copy number variations, and DNA methylation levels had significant differences between cluster A1 and cluster B2. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis found that the upregulated mRNAs in the cluster A1 were mainly concentrated in T cell activation, external side of plasma membrane, receptor ligand activity, and cytokine-cytokine receptor interaction. Importantly, the EPCAM was identified as a critical node in the lncRNAs-miRNAs-mRNAs regulatory network correlated with the immune phenotypes. In addition, based on differentially expressed genes between cluster A1 and cluster B2, the prognostic model established by LASSO could predict the overall survival (OS) of HCC accurately. CONCLUSIONS: The results indicated that the TP53 and LRP1B acted as the key genes in regulating the immune phenotypes of HCC via EPCAM.

Interaction between CD9 and PI3K­p85 activates the PI3K/AKT signaling pathway in B­lineage acute lymphoblastic leukemia.

Our previous study has shown that CD9 knockdown could suppress cell proliferation, adhesion, migration and invasion, and promote apoptosis and the cytotoxicity of chemotherapeutic drugs in the B­lineage acute lymphoblastic leukemia (B­ALL) cell line SUP­B15. In this study, we further investigated the molecular mechanism underlying the effects of CD9 on leukemic cell progression and the efficacy of chemotherapeutic agents in B­ALL cells. Using the CD9­knockdown SUP­B15 cells, we demonstrated that the silencing of the CD9 gene significantly reduced the expression of phosphorylated­phosphatidylinositol­3 kinase (p­PI3K), phosphorylated­protein kinase B (p­AKT), P­glycoprotein (P­gp), multidrug resistance­associated protein 1 (MRP1), breast cancer resistance protein (BCRP), matrix metalloproteinase 2 (MMP2) and phosphorylated­focal adhesion kinase (p­FAK). In addition, glutathione S­transferase (GST) pull­down assay showed the binding between CD9 and both PI3K­p85α and PI3K­p85ß in vitro, while co­immunoprecipitation assay showed the binding between CD9 and both PI3K­p85α and PI3K­p85ß in vivo. Furthermore, the PI3K/AKT inhibitor LY294002 mirrored the effects of CD9 knockdown in SUP­B15 cells. Taken together, these findings demonstrated that CD9 activates the PI3K/AKT signaling pathway through direct interaction with PI3K­p85 in B­ALL cells. Our data provide evidence for the inhibition of the PI3K/AKT pathway as a novel therapeutic option in CD9 antigen­positive B­ALL.

Long non-coding RNA-based signature for predicting prognosis of hepatocellular carcinoma.

Long non-coding RNAs (lncRNAs), as one common type of non-coding RNAs, play a critical role in the tumorigenesis and development of hepatocellular carcinoma (HCC). In the current study, we aimed to assess the correlation between lncRNAs expression levels and prognosis of HCC patients. A lncRNA-based signature was also developed to predict the prognosis of HCC in this work. The lncRNAs expression profiles in tissues of tumor and para-carcinoma were obtained from The Cancer Genome Atlas (TCGA) database. The lncRNA-based prognostic model was established by least absolute shrinkage and selection operator (LASSO). The multivariate Cox-regression analysis was applied to identify the independent risk factors and subsequently developed a prognostic nomogram. Based on the co-expression analyses, we identified the lncRNA-related mRNAs and performed the biological function analysis. Between HCC and para-carcinoma tissues, 220 differentially expressed lncRNAs were filtered. Among these lncRNAs, 19 lncRNAs were identified as prognostic factors and were used to build a prognostic signature of overall survival (OS). Furthermore, a nomogram with high performance for predicting the OS of HCC patients (C-index: 0.779) by combining the 19-lncRNA signature (P < 0.001) and clinicopathologic factors including HBV (P = 0.005) and stage (P =0.017) was established. Functional enrichment analysis revealed that 19 lncRNAs had potential effects on tumor cell proliferation in HCC. In summary, we established a 19-lncRNA signature to predict the prognosis of HCC patients, which may perform a crucial role in guiding the management of HCC.

Iron overload adversely effects bone marrow haematogenesis via SIRT-SOD2-mROS in a process ameliorated by curcumin.

BACKGROUND: Iron overload, which is common in patients with haematological disorders, is known to have a suppressive effect on haematogenesis. However, the mechanism for this effect is still unclear. The antioxidant curcumin has been reported to protect against iron overload-induced bone marrow damage through an as-yet-unknown mechanism. METHODS: We established iron overload cell and mouse models. Mitochondrial reactive oxygen species (mROS) levels, autophagy levels and the SIRT3/SOD2 pathway were examined in the models and in the bone marrow of patients with iron overload. RESULTS: Iron overload was shown to depress haematogenesis and induce mitochondrion-derived superoxide anion-dependent autophagic cell death. Iron loading decreased SIRT3 protein expression, promoted an increase in SOD2, and led to the elevation of mROS. Overexpression of SIRT3 reversed these effects. Curcumin treatment ameliorated peripheral blood cells generation, enhanced SIRT3 activity, decreased SOD2 acetylation, inhibited mROS production, and suppressed iron loading-induced autophagy. CONCLUSIONS: Our results suggest that curcumin exerts a protective effect on bone marrow by reducing mROS-stimulated autophagic cell death in a manner dependent on the SIRT3/SOD2 pathway.

CD9 knockdown suppresses cell proliferation, adhesion, migration and invasion, while promoting apoptosis and the efficacy of chemotherapeutic drugs and imatinib in Ph+ ALL SUP­B15 cells.

Philadelphia chromosome­positive acute lymphoblastic leukemia (Ph+ ALL) is regarded as a prognostically unfavorable subgroup, as this ALL subgroup has an increased risk of relapse/refractory disease. CD9, which belongs to the tetraspanin membrane proteins, is implicated in several pathological processes, including tumor progression. However, the role of CD9 in the pathogenesis of Ph+ ALL and the potential benefit of applying CD9­targeted RNA interference strategies for treatment of Ph+ ALL require further investigation. The aim of the present study was to determine the effects of CD9 on leukemic cell progression and the efficacy of therapeutic agents in Ph+ ALL cells, in addition to assessing the in vitro anti­leukemia activity of CD9­targeted RNA interference in Ph+ ALL cells. In the present study, a lentiviral short hairpin RNA (shRNA) expression vector targeting CD9 gene in Ph+ ALL SUP­B15 cells was constructed. The present results demonstrated that treatment of SUP­B15 cells with lentiviral­mediated shRNA against CD9 decreased CD9 mRNA and protein expression compared with the shControl cells transduced with a blank vector. In addition, CD9 knockdown could suppress cell proliferation, adhesion, migration and invasion, and promote apoptosis and the efficacy of chemotherapeutic drugs (such as vincristine, daunorubicin, cyclophosphamide and dexamethasone) and the tyrosine kinase inhibitor imatinib in SUP­B15 cells. Furthermore, CD9 knockdown suppressed cell proliferation and promoted apoptosis in SUP­B15 cells via a p53­dependent pathway. These findings suggested that gene silencing of CD9 using a shRNA­expressing lentivirus vector may provide a promising treatment for Ph+ ALL.

High-dose rituximab in combination with autologous stem cell transplantation for relapsed or refractory diffuse large B cell lymphoma / Combinación de altas dosis de rituximab y autotrasplante de progenitores hematopoyéticos en pacientes de linfoma B difuso de células grandes en recaída o refractario

OBJECTIVES: The aim of this study was to evaluate the efficacy and toxicity of high-dose rituximab (HD-R) in combination with autologous stem cell transplantation (auto-SCT) in patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL). METHODS: There were 22 patients in the HD-R group, to whom rituximab was administered during stem cell mobilization (375mg/m2 1 day before and 7 days after chemotherapy) and after transplantation (1000mg/m2 on days +1 and +8). In the control group, the procedure was the same as that in the HD-R group but without rituximab. We observed the safety, tolerability, adverse effects and immune reconstitution of HD-R therapy. The log-rank test, univariate analysis and multivariate Cox regression analysis were used to evaluate the effect of HD-R on survival. RESULTS: In total, 22 relapsed or refractory DLBCL patients were treated with HD-R. No dose-limiting toxicities were observed except for CD19+ B cell reconstruction in the first 6 months after SCT. There were 20 relapsed or refractory DLBCL patients in the control group. The 3-year progression-free survival (PFS) and overall survival (OS) greatly improved in the HD-R group compared to that in the control group (63.8% vs. 35.0%, P=0.028 and 80.1% vs. 50.0%, P=0.035, respectively). The univariate and multivariate analyses demonstrated that HD-R and the time to relapse were independent prognostic factors for OS and PFS. CONCLUSION: HD-R in combination with auto-SCT is a feasible and promising treatment for patients with relapsed or refractory DLBCL

OBJETIVOS: El objetivo de este estudio fue evaluar la eficacia y la toxicidad de la combinación de altas dosis de rituximab (HD-R) y el trasplante de células madre autólogas (auto-SCT) en pacientes con linfoma B difuso de células grandes (LBDCG) en recaída o refractario. MÉTODOS: El grupo HD-R incluyó 22 pacientes a quienes se les administró rituximab durante la movilización de células madre (375mg/m2 un día antes y 7 días después de la quimioterapia) y tras el trasplante (1000mg/m2 los días +1 y +8). En el grupo control, el procedimiento fue el mismo que en el grupo HD-R, aunque sin rituximab. Observamos la seguridad, la tolerabilidad, los efectos adversos y la reconstitución inmune de la terapia HD-R. Utilizamos la prueba log-rank, el análisis univariante y el análisis de regresión de Cox multivariante para evaluar el efecto de HD-R en la supervivencia. RESULTADOS: En total, 22 pacientes de LBDCG en recaída o refractario fueron tratados con HD-R. No se observaron toxicidades limitantes de dosis excepto para la reconstrucción de células CD19+ B en los primeros 6 meses tras SCT. El grupo control incluyó 20 pacientes de LBDCG en recaída o refractario. La supervivencia libre de progresión (SLP) a 3 años y la supervivencia general (SG) mejoró significativamente en el grupo HD-R en comparación con el grupo control (63,8 vs. 35%; p = 0,028 y el 80,1 vs. 50%; p = 0,035, respectivamente). Los análisis univariante y multivariante demostraron que HD-R y tiempo de recaída eran factores pronósticos independientes para SG y SLP. CONCLUSIÓN: La combinación de HD-R y auto-SCT es un tratamiento factible y prometedor para pacientes con LBDCG en recaída o refractario

Activation-induced cytidine deaminase overexpression in double-hit lymphoma: potential target for novel anticancer therapy.

Activation-induced cytidine deaminase (AID) is one kind of the mutant enzymes, which target regulating the immunoglobulin (Ig) gene in Burkitt's lymphoma to initiate class switch recombination (CSR), resulting in c-Myc chromosomal translocation. However, it is not clear that whether AID induces c-Myc/IgH translocation in double-hit lymphoma (DHL) with c-Myc gene translocation. In this study, the AID in DHL tissues and classical diffuse large b-cell lymphoma (DLBCL) tissues were compared. The results suggested that AID is of important value in predicting DHL, stronger CSR of AID was observed in DHL patients, which exhibited AID overexpression and c-Myc gene translocation of DHL after CSR induction. It is concluded that AID directly induces CSR in DHL and may result in c-Myc gene translocation. Targeting AID may be a good treatment regimen for DHL.

Normal Absolute Monocyte Count at the Time of Relapse is Associated with Improved Survival After First Salvage Therapy in Adult Patients with Early Relapsed B-Lineage Acute Lymphoblastic Leukemia.

BACKGROUND: Peripheral monocytes, a key cell type for innate immunity, have been shown to be associated with survival in various types of hematological malignancies. However, no previous studies regarding the prognostic impact of peripheral absolute monocyte count (AMC) in early relapsed B-lineage acute lymphoblastic leukemia (B-ALL) have been reported. METHODS: Forty-nine cases of early relapsed adult B-ALL were reviewed. The upper (0.80 × 109/L) and lower limits (0.12 × 109/L) of the normal value for AMC were used as cut-off points. Kaplan-Meier curves and Log rank test were used for comparison of overall survival (OS). The univariate and multivariate Cox proportional hazards models were used for investigating the factors associated with OS. RESULTS: More than half (59.2%) of all patients showed a normal AMC (0.12-0.80 × 109/L). The median follow-up was 5.3 months from the start of first salvage therapy. Univariate analysis revealed that normal AMC (versus low/high AMC) at the time of relapse was a prognostic factor for improved OS (P = 0.021). On multivariate analysis, normal AMC (versus low/high AMC) at the time of relapse remained an independent prognostic factor for improved OS (hazard ratio = 0.43, P = 0.030). CONCLUSION: AMC at the time of relapse, which can be easily derived from routine clinical laboratory testing of complete blood count, might be used as a prognostic marker for survival outcomes in adult patients with early relapsed B-ALL.

High-dose rituximab in combination with autologous stem cell transplantation for relapsed or refractory diffuse large B cell lymphoma.

OBJECTIVES: The aim of this study was to evaluate the efficacy and toxicity of high-dose rituximab (HD-R) in combination with autologous stem cell transplantation (auto-SCT) in patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL). METHODS: There were 22 patients in the HD-R group, to whom rituximab was administered during stem cell mobilization (375mg/m2 1 day before and 7 days after chemotherapy) and after transplantation (1000mg/m2 on days +1 and +8). In the control group, the procedure was the same as that in the HD-R group but without rituximab. We observed the safety, tolerability, adverse effects and immune reconstitution of HD-R therapy. The log-rank test, univariate analysis and multivariate Cox regression analysis were used to evaluate the effect of HD-R on survival. RESULTS: In total, 22 relapsed or refractory DLBCL patients were treated with HD-R. No dose-limiting toxicities were observed except for CD19+ B cell reconstruction in the first 6 months after SCT. There were 20 relapsed or refractory DLBCL patients in the control group. The 3-year progression-free survival (PFS) and overall survival (OS) greatly improved in the HD-R group compared to that in the control group (63.8% vs. 35.0%, P=0.028 and 80.1% vs. 50.0%, P=0.035, respectively). The univariate and multivariate analyses demonstrated that HD-R and the time to relapse were independent prognostic factors for OS and PFS. CONCLUSION: HD-R in combination with auto-SCT is a feasible and promising treatment for patients with relapsed or refractory DLBCL.

Peptide-immobilized starch/PEG sponge with rapid shape recovery and dual-function for both uncontrolled and noncompressible hemorrhage.

It is challenging for traditional hemostatic sponges to meet the clinic demand for both uncontrolled and noncompressible hemorrhage. With the aim to develop a rapid shape recovery material with both active and passive hemostatic performance, a dual-functional hemostatic sponge (TRAP-Sp) with a macroporous structure and good mechanical properties for controlling massive and noncompressible hemorrhage was prepared by chemically immobilizing thrombin-receptor-agonist-peptide (TRAP) onto a starch/polyethylene glycol (PEG) sponge. The TRAP2-Sp1 showed the best hemostatic performance among all samples in both rat artery uncontrollable hemorrhage and liver defect noncompressible hemorrhage models. When analyzing the hemostatic mechanism of TRAP-Sp, the high water absorption capacity of the sponge contributed to absorbing plasma, concentrating blood cells, and enhancing blood coagulation. After absorbing water, the shape-fixed TRAP-Sp with sufficient mechanical strength and high resilience can rapidly expand and apply pressure to the wound. TRAP immobilized on the sponge could activate the adhered platelets in an active pathway. Additionally, evaluation of cytotoxicity, hemolysis, and histology further highlighted the adequate biocompatibility of TRAP-Sp. With excellent hemostatic performance and biosafety, this sponge could be a potential candidate as a topical hemostatic agent for uncontrolled and noncompressible hemorrhage. STATEMENT OF SIGNIFICANCE: There is a need for innovative hemostatic materials for both uncontrolled and noncompressible hemorrhage. This manuscript describes a rapid shape recovery hemostatic sponge with both active and passive hemostatic performances synthesized by foaming technique, cross-linking reaction, and chemical immobilization of thrombin-receptor-agonist-peptide (TRAP). On contact with blood, the shape-fixed sponge can not only rapidly recover its original shape and concentrate platelets and RBCs but also activate the adhered platelets efficiently. The dual-functional sponge has excellent hemostatic efficacy in rat femoral artery hemorrhage and can control noncompressible hemorrhage in penetrating liver wound. Thus, we believe that this sponge could be a potential candidate as a topical hemostatic agent for uncontrolled and noncompressible hemorrhage.

Fabricating antimicrobial peptide-immobilized starch sponges for hemorrhage control and antibacterial treatment.

It is important to control immediate hemorrhage and prevent infection simultaneously in the wound management. However, most of hemostatic materials are associated with low efficiency of hemostasis, poor biocompatibility and lack of antimicrobial properties. A kind of starch-based macroporous sponges (KR-Sps) immobilized covalently with antimicrobial peptide KR12 using highly efficient thiol-ene photo click reaction were developed. The physical properties of these sponges could be fine-tuned by varying the ratio of modified starch/HS-PEG-SH and the polymer concentration. The in vitro and vivo results demonstrated that KR-Sps induced thrombosis, shortened clotting time and reduced the blood loss at bleeding site. Besides, KR12 immobilized sponge exhibited inherent antimicrobial properties against Gram (+) and (-) bacteria and methicillin-resistant Staphylococcus aureus (MRSA), which could maintain at least 5 days. Therefore, KR-Sps were believed to be an excellent candidate as hemostatic and antimicrobial product for the intraoperative wound management.

Unrelated Donor Peripheral Blood Stem Cell Transplantation for Patients with ß-Thalassemia Major Based on a Novel Conditioning Regimen.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only available curative treatment for patients with ß-thalassemia major (ß-TM). However, the problem of finding a suitable sibling donor with well-matched human leukocyte antigens is still a major obstacle to curing these patients. With the progress in high-resolution HLA typing technology and supportive care, outcomes after allogeneic HSCT from an HLA well-matched unrelated donor (UD) now approach those of well-matched sibling donors. However, UD HSCT is hampered by an increased risk of graft-versus-host disease and transplant-related mortality. Here we report the outcome of transplantation in patients with ß-TM using a novel WZ-14-TM transplant protocol, based on cyclophosphamide, intravenous busulfan, fludarabine, and antithymocyte globulin, in our center. Forty-eight patients between 2 and 11 years of age with ß-TM received HLA well-matched UD peripheral blood stem cell transplantation following the WZ-14-TM protocol. All of the transplanted patients achieved donor engraftment. The incidences of grade II to IV acute and chronic graft-versus-host disease were 8.3% and 8.3%, respectively. The overall survival and thalassemia-free survival rates were both 100%. This encouraging result suggests that the WZ-14-TM protocol is a feasible and safe conditioning regime for patients with ß-TM undergoing UD HSCT.

Exosome secreted from adipose-derived stem cells attenuates diabetic nephropathy by promoting autophagy flux and inhibiting apoptosis in podocyte.

BACKGROUND: It is confirmed that adipose-derived stem cells (ADSCs) transplantation effectively relieves kidney fibrosis and type 2 diabetes disease in mice. Currently, exosome from urine-derived stem cells (USCs) can protect type 1 diabetes-mediated kidney injury and attenuate podocyte damage in diabetic nephropathy (DN). Exosome derived from USCs has evolved into the strategy for DN treatment, but the role of ADSCs-derived exosome (ADSCs-Exo) in DN remains unclear. The present study is aimed to investigate the therapeutic action and molecular mechanism of ADSCs-derived exosome on DN. METHODS: ADSCs and exosome were authenticated by immunofluorescence and flow cytometry. Morphology and the number of exosome were evaluated by electron microscope and Nanosight Tracking Analysis (NTA), respectively. Cell apoptosis was assessed using flow cytometry. Podocyte autophagy and signaling transduction were measured by immunofluorescence and immunoblotting. Dual Luciferase Reporter assay was employed to detect the regulatory relationship between miR-486 and Smad1. RESULTS: ADSCs-Exo attenuated spontaneous diabetes by reducing levels of urine protein, serum creatinine (Scr), blood urea nitrogen (BUN), and podocyte apoptosis in mice. In in vitro experiment, ADSCs-Exo also reversed high glucose-induced decrease of cell viability and the increase of cell apoptosis in MPC5 cells. In terms of mechanism, ADSCs-Exo could enhance autophagy flux and reduce podocyte injury by inhibiting the activation of mTOR signaling in MPC5 and spontaneous diabetic mice. Eventually, we found that miR-486 was the key factors in ADSCs and in the process of ADSCs-Exo-mediated improvement of DN symptom in vivo and in vitro. miR-486 reduced Smad1 expression by target regulating Smad1 whose reduction could inhibit mTOR activation, leading to the increase of autophagy and the reduction of podocyte apoptosis. CONCLUSIONS: In conclusion, we illustrated that ADSCs-Exo vividly ameliorated DN symptom by enhancing the expression of miR-486 which led to the inhibition of Smad1/mTOR signaling pathway in podocyte. Possibly, ADSCs-Exo was used as a main therapeutic strategy for DN in future.

Benzene induces haematotoxicity by promoting deacetylation and autophagy.

Chronic exposure to benzene is known to be associated with haematotoxicity and the development of aplastic anaemia and leukaemia. However, the mechanism underlying benzene-induced haematotoxicity, especially at low concentrations of chronic benzene exposure has not been well-elucidated. Here, we found that increased autophagy and decreased acetylation occurred in bone marrow mononuclear cells (BMMNCs) isolated from patients with chronic benzene exposure. We further showed in vitro that benzene metabolite, hydroquinone (HQ) could directly induce autophagy without apoptosis in BMMNCs and CD34+ cells. This was mediated by reduction in acetylation of autophagy components through inhibiting the activity of acetyltransferase, p300. Furthermore, elevation of p300 expression by Momordica Antiviral Protein 30 Kd (MAP30) or chloroquine reduced HQ-induced autophagy. We further demonstrated that in vivo, MAP30 and chloroquine reversed benzene-induced autophagy and haematotoxicity in a mouse model. Taken together, these findings highlight increased autophagy as a novel mechanism for benzene-induced haematotoxicity and provide potential strategies to reverse this process for therapeutic benefits.

lncRNA KRAL reverses 5-fluorouracil resistance in hepatocellular carcinoma cells by acting as a ceRNA against miR-141.

BACKGROUND: 5-Fluorouracil (5-FU) has been widely applied to treat various types of cancers, including hepatocellular carcinoma (HCC). However, primary or acquired 5-FU resistance prevents the clinical application of this drug in cancer therapy. Herein, our study is the first to demonstrate that lower expression of KRAL, a long non-coding RNA (lncRNA), mediates 5-FU resistance in HCC via the miR-141/Keap1 axis. METHODS: Cell proliferation assays, western blot analysis, qRT-PCR, the dual-luciferase reporter assay and RNA immunoprecipitation were performed to investigate the mechanisms by which KRAL mediates 5-fluorouracil resistance in HCC cell lines. RESULTS: The quantitative analysis indicated that KRAL and Keap1 were significantly decreased and that Nrf2 was increased in HepG2/5-FU and SMMC-7721/5-FU cells compared with the corresponding expression levels in the respective parental cells. Overexpression of KRAL increased Keap1 expression, and inactivating the Nrf2-dependent antioxidant pathway could reverse the resistance of HepG2/5-FU and SMMC-7721/5-FU cells to 5-FU. Moreover, KRAL functioned as a competitive endogenous RNA (ceRNA) by effectively binding to the common miR-141 and then restoring Keap1 expression. These findings demonstrated that KRAL is an important regulator of Keap1; furthermore, the ceRNA network involving KRAL may serve as a treatment strategy against 5-FU resistance in hepatocellular carcinoma cells. CONCLUSIONS: KRAL/miR-141/Keap1 axis mediates 5-fluorouracil resistance in HCC cell lines.

Mean platelet volume predicts prognosis in patients with diffuse large B-cell lymphoma.

To determine the prognostic value of baseline mean platelet volume (MPV) in diffuse large B-cell lymphoma (DLBCL) patients. We retrospectively analyzed 161 DLBCL patients who received R-CHOP chemotherapy. The associations between MPV and clinicopathological factors were assessed. A low MPV (MPV ≤ 9.1 fl, cut-off was calculated by receiver operating characteristics) was not associated with any other clinicopathological factors. Patients with MPV ≤ 9.1 fl experienced a shorter progression-free survival (PFS) (2-year PFS rate, 60.6% vs 84.0%, P = 0.003) and overall survival (OS) (2-year OS rate, 70.4% vs 87.9%, P = 0.030), compared with those with MPV > 9.1 fl. The multivariate analysis demonstrated that MPV ≤ 9.1 fl was an independent prognostic factor of OS (Hazard Ratio [HR] = 0.588, P = 0.045) and PFS (HR = 0.456, P = 0.010). Therefore, we demonstrated that low baseline MPV is an independent prognostic marker of poor outcome in patients with DLBCL.

Benzene metabolite hydroquinone induces apoptosis of bone marrow mononuclear cells through inhibition of ß-catenin signaling.

The Akt/glycogen synthase kinase-3ß (GSK-3ß)/ß-catenin signaling pathway has been shown to play an important role in hematopoiesis, and hematopoietic cells are sensitive targets for benzene-induced hematotoxicity. We therefore hypothesized that dysregulation of the Akt/GSK-3ß/ß-catenin signaling was associated with benzene-induced hematotoxicity. Here, we showed that hydroquinone (HQ), a major metabolite of benzene in humans, significantly inhibited cell viability and colony formation while inducing apoptosis of human bone marrow mononuclear cells in vitro. Interestingly, we found that HQ inhibited the Akt affected ß-catenin signaling by activation of GSK-3ß, resulting in downregulation of ß-catenin and its targets Cyclin D1 and Survivin. HQ blocked nuclear translocation of ß-catenin and lymphoid enhancer-binding factor 1 (LEF-1), and importantly, HQ also reduced the interaction of ß-catenin and LEF-1 in the nucleus. As expected, blockage of GSK-3ß activity with a GSK-3ß inhibitor lithium chloride (LiCl) or activation of Akt signaling with an Akt agonist insulin-like growth factor-1 (IGF-1) could inhibit HQ-induced activation of GSK-3ß as well as hematotoxicity. Taken together, our results suggest that HQ-induced hematotoxicity in bone marrow mononuclear cells is associated with dysregulation of Akt/GSK-3ß/ß-catenin signaling due to the dissociation of ß-catenin/LEF-1 complex, and LiCl and IGF-1 may be two potential agents to ameliorate HQ-induced hematotoxicity.