Novel miR-490-3p/hnRNPA1-b/PKM2 axis mediates the Warburg effect and proliferation of colon cancer cells via the PI3K/AKT pathway

BACKGROUND Heterogeneous ribonucleoprotein A1(hnRNPA1)has been reported to enhance the Warburg effect and promote colon cancer(CC)cell proliferation,but the role and mechanism of the miR-490-3p/hnRNPA1-b/PKM2 axis in CC have not yet been elucidated.AIM To investigate the role and mechanism of a novel miR-490-3p/hnRNPA1-b/PKM2 axis in enhancing the Warburg effect and promoting CC cell proliferation through the PI3K/AKT pathway.METHODS Paraffin-embedded pathological sections from 220 CC patients were collected and subjected to immunohistochemical analysis to determine the expression of hnRNPA1-b.The relationship between the expression values and the clinicopathological features of the patients was investigated.Differences in mRNA expression were analyzed using quantitative real-time polymerase chain reaction,while differences in protein expression were analyzed using western blot.Cell proliferation was evaluated using the cell counting kit-8 and 5-ethynyl-2’-deoxyuridine assays,and cell cycle and apoptosis were detected using flow cytometric assays.The targeted binding of miR-490-3p to hnRNPA1-b was validated using a dual luciferase reporter assay.The Warburg effect was evaluated by glucose uptake and lactic acid production assays.RESULTS The expression of hnRNPA1-b was significantly increased in CC tissues and cells compared to normal controls(P<0.05).Immunohistochemical results demonstrated significant variations in the expression of the hnRNPA1-b antigen in different stages of CC,including stage I,II-III,and IV.Furthermore,the clinicopathologic characterization revealed a significant correlation between hnRNPA1-b expression and clinical stage as well as T classification.HnRNPA1-b was found to enhance the Warburg effect through the PI3K/AKT pathway,thereby promoting proliferation of HCT116 and SW620 cells.However,the proliferation of HCT116 and SW620 cells was inhibited when miR-490-3p targeted and bound to hnRNPA1-b,effectively blocking the Warburg effect.CONCLUSION These findings suggest that the novel miR-490-3p/hnRNPA1-b/PKM2 axis could provide a new strategy for the diagnosis and treatment of CC.

Lactate Decreases Bortezomib Sensitivity and Predicts Poor Clinical Outcomes of Multiple Myeloma

Objective:Metabolic disorders are regarded as hallmarks of multiple myeloma(MM)and are responsible for rapid cancer cell proliferation and tumor growth.However,the exact biological roles of metabolites in MM cells have not been fully explored.This study aimed to explore the feasibility and clinical significance of lactate for MM and investigate the molecular mechanism of lactic acid(Lac)in the proliferation of myeloma cells and cell sensitivity to bortezomib(BTZ).Methods:Metabolomic analysis of the serum was carried out to obtain metabolites expression and clinical characteristics in MM patients.The CCK8 assay and flow cytometry were used to detect cell proliferation,apoptosis,and cell cycle changes.Western blotting was used to detect the potential mechanism and apoptosis-and cycle-related protein changes.Results:Lactate was highly expressed in both the peripheral blood and bone marrow of MM patients.It was significantly correlated with Durie-Salmon Staging(DS Staging)and the International Staging System(ISS Staging)and the serum and urinary involved/uninvolved free light chain ratios.Patients with relatively high lactate levels had a poor treatment response.Moreover,in vitro experiments showed that Lac could promote the proliferation of tumor cells and decrease the proportion of G0/G1-phase cells,which was accompanied by an increased proportion of S-phase cells.In addition,Lac could decrease tumor sensitivity to BTZ by disrupting the expression of nuclear factor kappa B subunit 2(NFκB2)and Re1B.Conclusion:Metabolic changes are important in MM cell proliferation and treatment response;lactate could be used as a biomarker in MM and as a therapeutic target to overcome cell resistance to BTZ.

Research on Reactive Power Optimization of Offshore Wind Farms Based on Improved Particle Swarm Optimization

The lack of reactive power in offshore wind farms will affect the voltage stability and power transmission quality of wind farms.To improve the voltage stability and reactive power economy of wind farms,the improved particle swarmoptimization is used to optimize the reactive power planning in wind farms.First,the power flow of offshore wind farms is modeled,analyzed and calculated.To improve the global search ability and local optimization ability of particle swarm optimization,the improved particle swarm optimization adopts the adaptive inertia weight and asynchronous learning factor.Taking the minimum active power loss of the offshore wind farms as the objective function,the installation location of the reactive power compensation device is compared according to the node voltage amplitude and the actual engineering needs.Finally,a reactive power optimizationmodel based on Static Var Compensator is established inMATLAB to consider the optimal compensation capacity,network loss,convergence speed and voltage amplitude enhancement effect of SVC.Comparing the compensation methods in several different locations,the compensation scheme with the best reactive power optimization effect is determined.Meanwhile,the optimization results of the standard particle swarm optimization and the improved particle swarm optimization are compared to verify the superiority of the proposed improved algorithm.

针灸治疗干眼的代谢组学分析

目的:探讨干眼(DED)发病及其有效治疗的分子机制。方法:采用超高效液相色谱-四极杆飞行时间质谱(UHPLC-Q-TOF-MS)非靶向技术对18例经药物或针灸治疗的DED患者的泪液样本进行代谢组学研究。结果:在待测样品中共鉴定出190种代谢物,是迄今为止最广泛的泪液代谢组学研究。结果表明,所有患者的代谢组学特征明显不同,但药物或针灸治疗后的代谢组学差异非常细微。药物治疗后只有6种代谢物发生显著变化,其中肌苷、单胺四乙酸、尿酸盐、丙酰胆碱、烟酰胺等5种代谢物的含量均增加并参与炎症反应。针刺治疗后只有4种代谢物,其中丙氨酸、丝氨酸和高丝氨酸的含量有显著差异。对上述显著变化的代谢物的代谢途径进一步分析表明,针灸治疗的患者只有1种代谢途径,即氨酰tRNA生物合成受到显著影响,这与疾病的病因高度相关,表明针灸疗法可以解决干眼的病因,而不是症状,与药物治疗相比,在一定程度上显示出更好的疗效。结论:代谢组学分析有助于明确有效治疗干眼的潜在机制中涉及到的关键调控因素或途径,并将有助于为DED治疗提供新的潜在靶点和策略。

High-dose Chemotherapy Combined with Autologous Hematopoietic Stem Cell Transplantation as Frontline Therapy for Intermediate/High-risk Diffuse Large B Cell Lymphoma

The role of autologous hematopoietic stem cell transplantation(auto-HSCT)following high-dose chemotherapy has been validated and accepted as a standard treatment for patients with relapsed diffuse large B-cell lymphoma(DLBCL).However,its clinical efficacy as frontline therapy remains to be elucidated.This study aimed to examine the feasibility of frontline auto-HSCT for newly diagnosed intermediate/high-risk DLBCL patients.We retrospectively reviewed the data of 223 patients treated with frontline auto-HSCT or chemotherapy alone(year 2008-2014)from four hospitals.The median follow-up time was 29.4 months.Between the two treatment arms among the intermediate/high-risk DLBCL patients,the 3-year overall survival(OS)and progression-free survival(PFS)rates of patients given frontline auto-HSCT were 87.6%and 81.9%,respectively,and the chemotherapy-alone group showed 3-year OS and PFS rates of 64.9%and 59.59%,respectively.Compared with the chemotherapy-alone group,the frontline auto-HSCT could eliminate the adverse impact of non-germinal center B-cell(GCB)type.In addition,in the frontline auto-HSCT group,patients who achieved complete response(CR)at auto-HSCT had a longer survival time than those who did not achieve CR.Our results suggested that frontline auto-HSCT could improve the prognosis of intennediate/high-risk DLBCL patients.

Facile Approach for Preparation of Xylan-based Double-network Hydrogels

In this study,xylan-based double-network(DN)hydrogels(xylanbased DN gels)with excellent mechanical properties were prepared using acrylic acid and acrylamide(AM)based on a DN approach.The first layer network was obtained by grafting and crosslinking polyacrylic acid(PAA)molecular chains onto xylan with ammonium persulfate(APS)as the initiator and N,N'-methylenebisacrylamide(MBA)as the crosslinking agent;this network was subsequently immersed into an aqueous AM monomer in the presence of APS and MBA for the preparation of the second layer network.The results showed that the double networks were crosslinked by covalent bonds and that the mechanical properties of the xylan-based DN gels were enhanced.Thus,the xylan-based DN gels exhibited a maximum compression stress of 24.9 MPa.The xylan-based DN gels could also recover 97%of their original height after 15 repeated compression cycles;this indicates that the xylan-based DN gels possessed high resistance to friction and wear.Therefore,the prepared xylan-based DN gels have considerable potential for tissue engineering applications.

Connexin 43-modified bone marrow stromal cells reverse the imatinib resistance of K562 cells via Ca^(2+)-dependent gap junction intercellular communication

Background: Imatinib mesylate (IM) resistance is an emerging problem for chronic myeloid leukemia (CML). Previous studies found that connexin 43 (Cx43) deficiency in the hematopoietic microenvironment (HM) protects minimal residual disease (MRD), but the mechanism remains unknown. Methods: Immunohistochemistry assays were employed to compare the expression of Cx43 and hypoxia-inducible factor 1α (HIF-1α) in bone marrow (BM) biopsies of CML patients and healthy donors. A coculture system of K562 cells and several Cx43-modified bone marrow stromal cells (BMSCs) was established under IM treatment. Proliferation, cell cycle, apoptosis, and other indicators of K562 cells in different groups were detected to investigate the function and possible mechanism of Cx43. We assessed the Ca^(2+)-related pathway by Western blotting. Tumor-bearing models were also established to validate the causal role of Cx43 in reversing IM resistance. Results: Low levels of Cx43 in BMs were observed in CML patients, and Cx43 expression was negatively correlated with HIF-1α. We also observed that K562 cells cocultured with BMSCs transfected with adenovirus-short hairpin RNA of Cx43 (BMSCs-shCx43) had a lower apoptosis rate and that their cell cycle was blocked in G0/G1 phase, while the result was the opposite in the Cx43-overexpression setting. Cx43 mediates gap junction intercellular communication (GJIC) through direct contact, and Ca ^(2+ )is the key factor mediating the downstream apoptotic pathway. In animal experiments, mice bearing K562, and BMSCs-Cx43 had the smallest tumor volume and spleen, which was consistent with the in vitro experiments. Conclusions: Cx43 deficiency exists in CML patients, promoting the generation of MRD and inducing drug resistance. Enhancing Cx43 expression and GJIC function in the HM may be a novel strategy to reverse drug resistance and promote IM efficacy.

Corrigendum:Connexin 43-modified bone marrow stromal cells reverse the imatinib resistance of K562 cells via Ca^(2+)-dependent gap junction intercellular communication

Following the original article’s publication,[1]the authors declared that the affiliation of the first author Xiaoping Li was submitted incorrectly,while correct author affiliations should be as follows.The authors apologize for any inconvenience caused.

Reverse effect of Semaphorin-3F on rituximab resistance in diffuse large B-cell lymphoma via the Hippo pathway

Background:Exploring the underlying mechanism of rituximab resistance is critical to improve the outcomes of patients with diffuse large B-cell lymphoma(DLBCL).Here,we tried to identify the effects of the axon guidance factor semaphorin-3F(SEMA3F)on rituximab resistance as well as its therapeutic value in DLBCL.Methods:The effects of SEMA3F on the treatment response to rituximab were investigated by gain-or loss-of-function experiments.The role of the Hippo pathway in SEMA3F-mediated activity was explored.A xenograft mouse model generated by SEMA3F knockdown in cells was used to evaluate rituximab sensitivity and combined therapeutic effects.The prognostic value of SEMA3F and TAZ(WW domain-containing transcription regulator protein 1)was examined in the Gene Expression Omnibus(GEO)database and human DLBCL specimens.Results:We found that loss of SEMA3F was related to a poor prognosis in patients who received rituximab-based immunochemotherapy instead of chemotherapy regimen.Knockdown of SEMA3F significantly repressed the expression of CD20 and reduced the proapoptotic activity and complement-dependent cytotoxicity(CDC)activity induced by rituximab.We further demonstrated that the Hippo pathway was involved in the SEMA3F-mediated regulation of CD20.Knockdown of SEMA3F expression induced the nuclear accumulation of TAZ and inhibited CD20 transcriptional levels via direct binding of the transcription factor TEAD2 and the CD20 promoter.Moreover,in patients with DLBCL,SEMA3F expression was negatively correlated with TAZ,and patients with SEMA3F^(low)TAZ^(high)had a limited benefit from a rituximab-based strategy.Specifically,treatment of DLBCL cells with rituximab and a YAP/TAZ inhibitor showed promising therapeutic effects in vitro and in vivo.Conclusion:Our study thus defined a previously unknown mechanism of SEMA3F-mediated rituximab resistance through TAZ activation in DLBCL and identified potential therapeutic targets in patients.

Strip width spread prediction in rough rolling process based on mechanism modeling and optimization

Aiming at the problems of low accuracy and poor robustness that existed in the current hot rolling strip width spread model,an improved strip spread prediction model based on a material forming mechanism and Bayesian optimized adaptive differential evolution algorithm(BADE)was proposed.At first,we improved the original spread mechanism model by adding the weight and bias term to enhance the model robustness based on rolling temperature.Then,the BADE algorithm was proposed to optimize the improved spread mechanism model.The optimization algorithm is based on a novel adaptive differential evolution algorithm,which can effectively achieve the global optimal solution.Finally,the prediction performances of five machine learning algorithms were compared in experiments.The results show that the prediction accuracy of the improved spread model is obviously better than that of the machine learning algorithms,which proves the effectiveness of the proposed method.

Seed metabolomic study reveals significant metabolite variations and correlations among different soybean cultivars

Soybean[Glycine max（L.） Merr.]is one of the world＇s major crops,and soybean seeds are a rich and important resource for proteins and oils.While ＂omics＂ studies,such as genomics,transcriptomics,and proteomics,have been widely applied in soybean molecular research,fewer metabolomic studies have been conducted for largescale detection of low molecular weight metabolites,especially in soybean seeds.In this study,we investigated the seed metabolomes of 29 common soybean cultivars through combined gas chromatography-mass spectrometry and ultra-performance liquid chromatography-tandem mass spectrometry.One hundred sixty-nine named metabolites were identified and subsequently used to construct a metabolic network of mature soybean seed.Among the 169 detected metabolites,104 were found to be significantly variable in their levels across tested cultivars.Metabolite markers that could be used to distinguish genetically related soybean cultivars were also identified,and metabolitemetabolite correlation analysis revealed some significant associations within the same or among different metabolite groups.Findings from this work may potentially provide the basis for further studies on both soybean seed metabolism and metabolic engineering to improve soybean seed quality and yield.

Biocompatible and antibacterial soy protein isolate/quaternized chitosan composite sponges for acute upper gastrointestinal hemostasis

Innovative biomedical applications have high requirements for biomedical materials.Herein,a series of biocompatible,antibacterial and hemostatic sponges were successfully fabricated for the treatment of acute upper gastrointestinal bleeding(AUGB).Quaternized chitosan(QC)and soy protein isolate(SPI)were chemically cross-linked to obtain porous SPI/QC sponges(named SQS-n,with n¼30,40,50 or 60 corresponding to the weight percentage of the QC content).The chemical composition,physical properties and biological activity of SQS-n were investigated.SQS-n could support the adhesion and proliferation of L929 cells while triggering no obvious blood toxicity.Meanwhile,SQS-n exhibited good broad-spectrum antibacterial activity against both grampositive bacteria(Staphylococcus aureus)and gram-negative bacteria(Escherichia coli).The in vivo hemostatic effect of SQS-n was evaluated using three different bleeding models.The results revealed that SQS-50 performed best in reducing blood loss and hemostatic time.The overall hemostatic effect of SQS-50 was comparable to that of a commercial gelatin sponge.The enhanced antibacterial and hemostatic activities of SQS-n were mainly attributed to the QC component.In conclusion,this work developed a QC-functionalized hemostatic sponge that is highly desirable for innovative biomedical applications,such as AUGB.