Silencing of Jumonji domain-containing 1C inhibits the osteogenic differentiation of bone marrow mesenchymal stem cells via nuclear factor-κB signaling

BACKGROUND Osteoporosis is a common metabolic bone disorder induced by an imbalance between osteoclastic activity and osteogenic activity.During osteoporosis,bone mesenchymal stem cells(BMSCs)exhibit an increased ability to differentiate into adipocytes and a decreased ability to differentiate into osteoblasts,resulting in bone loss.Jumonji domain-containing 1C(JMJD1C)has been demonstrated to suppress osteoclastogenesis.AIM To examine the effect of JMJD1C on the osteogenesis of BMSCs and the potential underlying mechanism.METHODS BMSCs were isolated from mouse bone marrow tissues.Oil Red O staining,Alizarin red staining,alkaline phosphatase staining and the expression of adipo-genic and osteogenic-associated genes were assessed to determine the differen-tiation of BMSCs.Bone marrow-derived macrophages(BMMs)were incubated with receptor activator of nuclear factor-kappaΒligand to induce osteoclast differentiation,and osteoclast differen-tiation was confirmed by tartrate-resistant acid phosphatase staining.Other related genes were measured via reverse transcription coupled to the quantitative polymerase chain reaction and western blotting.Enzyme-linked immunosorbent assays were used to measure the levels of inflammatory cytokines,including tumor necrosis factor alpha,interleukin-6 and interleukin-1 beta.RESULTS The osteogenic and adipogenic differentiation potential of BMSCs isolated from mouse bone marrow samples was evaluated.JMJD1C mRNA and protein expression was upregulated in BMSCs after osteoblast induction,while p-nuclear factor-κB(NF-κB)and inflammatory cytokines were not significantly altered.Knockdown of JMJD1C repressed osteogenic differentiation and enhanced NF-κB activation and inflammatory cytokine release in BMSCs.Moreover,JMJD1C expression decreased during BMM osteoclast differentiation.CONCLUSION The JMJD1C/NF-κB signaling pathway is potentially involved in BMSC osteogenic differentiation and may play vital roles in the pathogenesis of osteoporosis.

Hemoperfusion and continuous veno-venous hemodiafiltration for eliminating chlorfenapyr in poisoning patients

Chlorfenapyr is a liposoluble insecticide belonging to the pyrrole family.Chlorfenapyr is activated when the N-ethoxymethyl side chain breaks,forming a toxic metabolite,which uncouples oxidative phosphorylation in the mitochondria,inhibits the production of adenosine triphosphate (ATP),and leads to the death of cells and targe organisms.[1] Symptoms of chlorfenapyr poisoning in patients are mild and atypical in the early stage,especially in patients receiving low dose exposure;however,such cases are rare and may be ignored by physicians,often leading to delayed treatment.[2,3].

Chlorine poisoning caused by improper mixing of household disinfectants during the COVID-19 pandemic:Case series

BACKGROUND Misuse of disinfectants during the coronavirus disease 2019 pandemic has led to several poisoning incidents.However,there are few clinical case reports on poisoning caused by improper mixing of household disinfectants.AIM To summarize the clinical characteristics and treatment effects of chlorine poisoning caused by improper mixing of hypochlorite bleach with acidic cleaning agents.METHODS We retrospectively analyzed baseline and clinical data,clinical symptoms,and treatment methods of seven patients with chlorine poisoning who were admitted to the National Army Poisoning Treatment Center.RESULTS Among the seven patients,the average poisoning time(exposure to admission)was 57 h(4-240 h).All patients were involved in cleaning bathrooms.Chest computed tomography scans revealed bilateral lung effusions or inflammatory changes in five patients.The partial pressure of oxygen decreased in six patients,and respiratory failure occurred in one.Five patients had different degrees of increase in white blood cell count.Humidified oxygen therapy,non-invasive mechanical ventilation,anti-inflammatory corticosteroids,antioxidants,and antibiotics were administered for treatment.The average length of hospital stay was 7 d(4-9 d).All seven patients recovered and were discharged.CONCLUSION Improper mixing of household disinfectants may cause damage to the respiratory system due to chlorine poisoning.Corticosteroids may improve lung exudation in severe cases,and symptomatic supportive treatment should be performed early.

Phase II study of novel orally PI3Kα/δinhibitor TQ-B3525 in relapsed and/or refractory follicular lymphoma

This registration study assessed clinical outcomes of TQ-B3525,the dual phosphatidylinositol-3-kinase(PI3K)α/δinhibitor,in relapsed and/or refractory follicular lymphoma(R/R FL).This phase II study(ClinicalTrials.gov NCT04324879.Registered March 27,2020)comprised run-in stage and stage 2.R/R FL patients after≥2 lines therapies received oral 20 mg TQ-B3525 once daily in a 28-day cycle until intolerable toxicity or disease progression.Primary endpoint was independent review committee(IRC)-assessed objective response rate(ORR).Based on results(ORR,88.0%;duration of response[DOR],11.8 months;progression-free survival[PFS],12.0 months)in 25 patients at run-in stage,second stage study was initiated and included 82 patients for efficacy/safety analysis.Patients received prior-line(median,3)therapies,with 56.1%refractory to previous last therapies;73.2%experienced POD24 at baseline.At stage 2,ORR was 86.6%(71/82;95%CI,77.3-93.1%),with 28(34.2%)complete responses.Disease control rate was 95.1%due to 7(8.5%)stable diseases.Median time to response was 1.8 months.Among 71 responders,median DOR was not reached;18-month DOR rate was 51.6%.with median follow-up of 13.3 months,median PFS was 18.5(95%CI,10.2-not estimable)months.Median overall survival(OS)was not reached by cutoff date;24-month OS rate was estimated as 86.1%.Response rates and survival data were consistent across all subgroups.Grade 3 or higher treatment-related adverse events were observed in 63(76.8%)cases,with neutropenia(22.0%),hyperglycemia(19.5%),and diarrhea(13.4%)being common.TQ-B3525 showed favorable efficacy and safety for R/R FL patients after≥2 lines prior therapies.

Clinical features and prognostic analysis of the blastoid variant of mantle cell lymphoma: An analysis of 20 patients from two centers

Managing Editor:Peng Lyu Mantle cell lymphoma(MCL),a relatively uncommon subtype of non-Hodgkin's lymphoma(NHL),constitutes approximately 2%-10%of NHL cases.Characterized by its inertness,aggressiveness,and incurability,MCL has a median overall survival(OS)of approximately 3-5 years.

Next-generation sequencing revealed factors associated with cumulative incidence of relapse and leukemia-free survival in patients with newly diagnosed acute myeloid leukemia

BackgroundSeveral prognostic biomarkers have been validated for acute myeloid leukemia(AML),a heterogeneous hematopoietic malignancy.However,the factors associated with the cumulative incidence of relapse(CIR)and leukemia-free survival(LFS)in real-world patients with AML have not been well defined.MethodsThis study examined clinical and mutational data of 246 patients with newly diagnosed AML who received the traditional“3+7”regimen in PLA General Hospital from January 2008 to August 2020.Factors associated with CIR and LFS in patients newly diagnosed with AML were analyzed using next-generation sequencing.ResultsAdditional sex combs-like 1(ASXL1)and Serine/arginine-rich splicing factor 2(SRSF2)mutations were found to be associated with an increased risk of CIR and a reduced LFS in univariate analysis,while only SRSF2 mutations were associated with these factors in the multivariate analysis.Hyperleukocytosis maintained an independent effect on LFS in the multivariate analysis.Hematopoietic stem cell transplantation conferred a significant prognostic benefit on both CIR and LFS in our cohort.Furthermore,we validated the risk classification of patients with AML receiving traditional induction regimens across a broad age range.Based on next-generation sequencing results,we concluded that SRSF2 mutations were predictive of an increased risk of relapse,inferior LFS rates,and non-relapse mortality in patients with newly diagnosed AML.ConclusionThese findings indicate that patients with SRSF2 mutations might not benefit from the conventional“3+7”regimen.Our results may help in developing molecular stratification strategies and could guide treatment decisions for patients with newly diagnosed AML.

Divergent expression of Neurl3 from hemogenic endothelial cells to hematopoietic stem progenitor cells during development

Prior to the generation of hematopoietic stem cells(HSCs)from the hemogenic endothelial cells(HECs)mainly in the dorsal aorta in midgestational mouse embryos,multiple hematopoietic progenitors including erythro-myeloid progenitors and lymphoid progenitors are generated from yolk sac HECs.These HSCindependent hematopoietic progenitors have recently been identified as major contributors to functional blood cell production until birth.However,little is known about yolk sac HECs.Here,combining integrative analyses of multiple single-cell RNA-sequencing datasets and functional assays,we reveal that Neurl3-EGFP,in addition to marking the continuum throughout the ontogeny of HSCs from HECs,can also serve as a single enrichment marker for yolk sac HECs.Moreover,while yolk sac HECs have much weaker arterial characteristics than either arterial endothelial cells in the yolk sac or HECs within the embryo proper,the lymphoid potential of yolk sac HECs is largely confined to the arterial-biased subpopulation featured by the Unc5b expression.Interestingly,the B lymphoid potential of hematopoietic progenitors,but not for myeloid potentials,is exclusively detected in Neurl3-negative subpopulations in midgestational embryos.Taken together,these findings enhance our understanding of blood birth from yolk sac HECs and provide theoretical basis and candidate reporters for monitoring step-wise hematopoietic differentiation.

Next-generation sequencing reveals relapse and leukemia-free survival risks in newly diagnosed acute myeloid leukemia treated with CAG regimen combined with decitabine

Background:Acute myeloid leukemia(AML)is a heterogeneous hematopoietic malignancy whose prognosis is associated with several biomarkers.Decitabine,a deoxyribonucleic acid(DNA)methyltransferase(DNMT)in-hibitor,combined with cytarabine,aclarubicin hydrochloride,and granulocyte colony-stimulating factor(DCAG),has been used in patients newly diagnosed with AML.This regimen has been especially used in older and fragile patients who are immunocompromised or have co-morbidities,as well as those with specific gene mutations.However,the integration of molecular risk stratification and treatment guidance for the DCAG regimen has not been well defined.Therefore,this study aimed to investigate the genetic mutations associated with AML and establish appropriate treatment strategies for patients newly diagnosed with AML.Methods:This study analyzed the clinical data and genetic mutations based on next-generation sequencing(NGS)in 124 newly diagnosed patients with AML who received the DCAG regimen at the People's Liberation Army(PLA)General Hospital from January 2008 to August 2020.Factors associated with the cumulative incidence of relapse(CIR)and leukemia-free survival(LFS)in patients newly diagnosed with AML were analyzed.Results:The most adverse prognosis of DCAG-treated patients was observed in those with FLT3-ITD,KIT,PTPN11,GATA2,or IDH1 mutations during univariable analysis,whereas PTPN11 mutation was solely significant in multivariable analysis,with an increased likelihood of CIR(P=0.001)and reduced LFS duration(P=0.077).Hyperleukocytosis was maintained as an independent risk factor for increased CIR risk(P=0.044)and decreased LFS duration(P=0.042)in multivariable analysis.In this study,we validated the risk classification of patients with AML receiving an epigenetic modifier-based induction regimen across a broad age range.Conclusion:NGS demonstrated a dismal overall outcome in patients with the rare PTPN11 mutations,indicating the need for new therapies that target this high-risk subtype of AML.These results offer a potential molecular stratification and treatment guidance for patients with AML.

基于个体化机器学习的原发性免疫性血小板减少症危重出血预测模型:一项全国前瞻性队列研究

原发性免疫性血小板减少症(ITP)中少见但至关重要的危重出血事件,给患者的预后、生活质量和治疗决策带来严重影响。尽管有一些研究探讨了ITP中与危重出血相关的风险因素,但目前尚缺乏大样本数据、大规模多中心研究结果以及针对ITP患者致命出血事件的预测模型。本研究首次采用国际血栓与止血学会新提出的ITP致命出血标准,利用大样本数据开发了首个基于机器学习的在线应用,用于预测ITP患者的致命出血.研究中,我们使用中国各地大型多中心数据进行开发,并对全国39家医疗中心进行为期一年的外部测试,得到了较好的训练、验证和测试数据集预测能力该基于新算法的便捷网络工具能够快速识别ITP患者的出血风险,辅助临床决策,有望未来降低不良事件的发生。