Simplified algorithm for genetic subtyping in diffuse large B-cell lymphoma

Genetic classification helps to disclose molecular heterogeneity and therapeutic implications in diffuse large B-cell lymphoma(DLBCL).Using whole exome/genome sequencing,RNA-sequencing,and fluorescence in situ hybridization in 337 newly diagnosed DLBCL patients,we established a simplified 38-gene algorithm(termed‘LymphPlex’)based on the information on mutations of 35 genes and rearrangements of three genes(BCL2,BCL6,and MYC),identifying seven distinct genetic subtypes:TP53Mut(TP53 mutations),MCD-like(MYD88,CD79B,PIM1,MPEG1,BTG1,TBL1XR1,PRDM1,IRF4 mutations),BN2-like(BCL6 fusion,NOTCH2,CD70,DTX1,BTG2,TNFAIP3,CCND3 mutations),N1-like(NOTCH1 mutations),EZB-like(BCL2 fusion,EZH2,TNFRSF14,KMT2D,B2M,FAS,CREBBP,ARID1A,EP300,CIITA,STAT6,GNA13 mutations,with or without MYC rearrangement),and ST2-like(SGK1,TET2,SOCS1,DDX3X,ZFP36L1,DUSP2,STAT3,IRF8 mutations).Extended validation of 1001 DLBCL patients revealed clinical relevance and biological signature of each genetic subtype.TP53Mut subtype showed poor prognosis,characterized by p53 signaling dysregulation,immune deficiency,and PI3K activation.MCD-like subtype was associated with poor prognosis,activated B-cell(ABC)origin,BCL2/MYC double-expression,and NF-κB activation.BN2-like subtype showed favorable outcome within ABC-DLBCL and featured with NF-κB activation.N1-like and EZB-like subtypes were predominated by ABC-DLBCL and germinal center B-cell(GCB)-DLBCL,respectively.EZB-like-MYC+subtype was characterized by an immunosuppressive tumor microenvironment,while EZB-like-MYC-subtype by NOTCH activation.ST2-like subtype showed favorable outcome within GCB-DLBCL and featured with stromal-1 modulation.Genetic subtype-guided targeted agents achieved encouraging clinical response when combined with immunochemotherapy.Collectively,LymphPlex provided high efficacy and feasibility,representing a step forward to the mechanism-based targeted therapy in DLBCL.

Immunosuppressive tumor microenvironment contributes to tumor progression in diffuse large B-cell lymphoma upon anti-CD19 chimeric antigen receptor T therapy

Anti-CD19 chimeric antigen receptor(CAR)-T cell therapy has achieved 40%–50%long-term complete response in relapsed or refractory diffuse large B-cell lymphoma(DLBCL)patients.However,the underlying mechanism of alterations in the tumor microenvironments resulting in CAR-T cell therapy failure needs further investigation.A multi-center phase I/II trial of anti-CD19 CD28z CAR-T(FKC876,ChiCTR1800019661)was conducted.Among 22 evaluable DLBCL patients,seven achieved complete remission,10 experienced partial remissions,while four had stable disease by day 29.Single-cell RNA sequencing results were obtained from core needle biopsy tumor samples collected from long-term complete remission and early-progressed patients,and compared at different stages of treatment.M2-subtype macrophages were significantly involved in both in vivo and in vitro anti-tumor functions of CAR-T cells,leading to CAR-T cell therapy failure and disease progression in DLBCL.Immunosuppressive tumor microenvironments persisted before CAR-T cell therapy,during both cell expansion and disease progression,which could not be altered by infiltrating CAR-T cells.Aberrant metabolism profile of M2-subtype macrophages and those of dysfunctional T cells also contributed to the immunosuppressive tumor microenvironments.Thus,our findings provided a clinical rationale for targeting tumor microenvironments and reprogramming immune cell metabolism as effective therapeutic strategies to prevent lymphoma relapse in future designs of CAR-T cell therapy.

Positron emission tomography-adapted therapy in low-risk diffuse large B-cell lymphoma:results of a randomized,phase Ⅲ,non-inferiority trial

Background:The current standard of care for non-bulky diffuse large B-cell lymphoma(DLBCL)patients with an International Prognostic Index(IPI)of 0 is four cycles of rituximab plus cyclophosphamide,doxorubicin,vincristine and prednisone(R-CHOP)but whether the same efficacy can be achieved with reduced chemotherapy regimen of four cycles for non-bulky DLBCL patients with an IPI of 1 remains unclear.This study compared four cycles versus six cycles of chemotherapy in non-bulky low-risk DLBCL patients with negative interim positron emission tomography with computed tomography(PET-CT,Deauville 1-3),irrespective of age and other IPI risk factors(IPI 0-1).Methods:This was an open-label,randomized,phaseⅢ,non-inferiority trial.Patients aged 14-75 years with newly diagnosed low-risk DLBCL,according to IPI,achieving PET-CT confirmed complete response(CR)after four cycles of R-CHOPwere randomized(1:1)between four cycles of rituximab(4R-CHOP+4R arm)or two cycles of R-CHOP plus two cycles of rituximab(6R-CHOP+2R arm).The primary endpoint was 2-year progression-free survival(PFS),conducted in the intention-to-treat population.Safety was assessed in patients with at least one cycle of assigned treatment.The non-inferiority margin was-8%.Results:A total of 287 patients were included in the intention-to-treat analysis,the median follow-up was 47.3 months,and the 2-year PFS rate was 95%(95%confidence interval[CI],92%to 99%)and 94%(95%CI,91%to 98%)for the 4R-CHOP+4R and 6R-CHOP+2R arm.The absolute difference in 2-year PFS between the two arms was 1%(95%CI,-5%to 7%),supporting the non-inferiority of 4R-CHOP+4R.Grade 3-4 neutropenia was lower in the last four cycles of rituximab alone in the 4R-CHOP+4R arm(16.7%versus 76.9%),with decreased risk of febrile neutropenia(0.0%versus 8.4%)and infection(2.1%versus 14.0%).Conclusions:For newly diagnosed low-risk DLBCL patients,interim PET-CT after four cycles of R-CHOP was effective in identifying patients with Deauville 1-3 who would have a good response and Deauville 4-5 patients who might have high-risk biological features or develop resistance.Reducing the standard six cycles to four cycles of chemotherapy had comparable clinical efficacy and fewer adverse events in low-risk,non-bulky DLBCL with interim PET-CT confirmed CR.

Dependence of interferogram phase on incident wavenumber and phase stability of Doppler asymmetric spatial heterodyne spectroscopy

Instrument drifts introduce additional phase errors into atmospheric wind measurement of Doppler asymmetric spatial heterodyne spectroscopy (DASH). Aiming at the phase sensitivity of DASH to instrument drifts, in this paper we calculate the optical path difference (OPD) and present an accurate formula of DASH interferogram. By controlling variables in computational ray-tracing simulations and laboratory experiments, it is indicated that initial phase is directly determined by incident wavenumber, OPD offset and field of view (FOV). Accordingly, it is indicated that retrieved phase of DASH is sensitive to slight structural change caused by instrument drift, which provides the proof of necessary-to-track and -correct phase errors from instrument drifts.

Therapeutic targeting miR130b counteracts diffuse large B-cell lymphoma progression via OX40/OX40L-mediated interaction with Th17 cells

MicroRNAs(miRNAs)are involved in lymphoma progression by regulating the tumor microenvironment.Serum miR130b is overexpressed in diffuse large B-cell lymphoma(DLBCL),inducing Th17 cell alterations.To further illustrate its biological significance and therapeutic rationale,miR130b was detected by quantitative real-time PCR in the serum samples of 532 newly diagnosed DLBCL patients.The mechanism of miR130b on lymphoma progression and the tumor microenvironment was investigated both in vitro and in vivo.Therapeutic targeting miR130b was also evaluated,including OX40 agonistic antibody and lipid nanoparticles(LNPs)-miR130b antagomir.The results showed that serum miR130b significantly correlated with tumor miR130b and serum interleukin-17,indicating lymphoma relapse and inferior survival of DLBCL patients.MiR130b overexpression altered tumor microenvironment signaling pathways and increased Th17 cell activity.As mechanism of action,miR130b downregulated tumor OX40L expression by directly targeting IFNAR1/p-STAT1 axis,recruiting Th17 cells via OX40/OX40L interaction,thereby promoting immunosuppressive function of Th17 cells.In co-culture systems of B-lymphoma cells with immune cells,miR130b inhibited lymphoma cell autophagy,which could be counteracted by OX40 agonistic antibody and LNPs-miR130b antagomir.In murine xenograft model established with subcutaneous injection of A20 cells,both OX40 agonistic antibody and LNPs-miR130b antagomir remarkably inhibited Th17 cells and retarded miR130b-overexpressing tumor growth.In conclusion,as an oncogenic biomarker of DLBCL,miR130b was related to lymphoma progression through modulating OX40/OX40L-mediated lymphoma cell interaction with Th17 cells,attributing to B-cell lymphoma sensitivity towards OX40 agonistic antibody.Targeting miR130b using LNPs-miR130b antagomir could also be a potential immunotherapeutic strategy in treating OX40-altered lymphoid malignancies.

Citrate-promoted dissolution of nanostructured manganese oxides:Implications for nano-enabled sustainable agriculture

Nanostructured manganese oxides (nano-MnO_(x)) have shown great promises as versatile agrochemicals in nano-enabled sustainable agriculture,owing to the coupled benefits of controlled release of dissolved Mn2+,an essential nutrient needed by plants,and oxidative destruction of environmental organic pollutants.Here,we show that three δ-MnO_(2)nanomaterials consisting of nanosheet-assembled flower-like nanospheres not only exhibit greater kinetics in citrate-promoted dissolution,but also are less prone to passivation,compared with three α-MnO_(2)nanowire materials.The better performance of the δ-MnO_(2)nanomaterials can be attributed to their higher abundance of surface unsaturated Mn atoms–particularly Mn(Ⅲ)–that is originated from their specific exposed facets and higher abundance of surface defects sites.Our results underline the great potential of modulating nanomaterial surface atomic configuration to improve their performance in sustainable agricultural applications.

Effectiveness of COVID-19 Vaccination Against SARS-CoV-2 Omicron Variant Infection and Symptoms—China,December 2022–February 2023

Summary What is already known about this topic?A considerable percentage of the population has received both primary and booster vaccinations,which could potentially provide protection against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)Omicron infections and related symptoms.What is added by this report?The self-reported infection rate,as determined from an online survey,reached its peak(15.5%)between December 19 and 21,2022,with an estimated 82.4%of individuals in China being infected as of February 7,2023.During the epidemic,the effectiveness of booster vaccinations against SARS-CoV-2 Omicron infection was found to be 49.0%within three months of vaccination and 37.9%between 3 and 6 months following vaccination.Furthermore,the vaccine effectiveness of the booster vaccination in relation to symptom prevention varied from 48.7%to 83.2%within three months and from 25.9%to 69.0%between 3 and 6 months post-booster vaccination.

A statistical analysis of conjugate equatorial plasma bubbles based on 630 nm airglow observations

Using the observations of the 630-nm all-sky imagers(ASIs)located in the geomagnetic conjugate points in the American sector from 2014 to 2017,this study statistically analyzed the features of conjugate equatorial plasma bubbles(EPBs),including their occurrence rate,zonal width,location and zonal drift velocity.The results show that the occurrence rate of the EPBs that occur simultaneously at geomagnetic conjugate points is~84%.The zonal widths of the EPBs are mainly~100 km,and the width differences of EPBs between the northern and southern hemispheres are mainly within±30 km.The zonal displacements of the center locations of the northern and southern EPBs are within±50 km.The zonal drift velocities of the northern and southern EPBs are nearly equal.However,it should be noted that the velocity of the EPBs in the northern hemisphere is 10%faster than that in the southern hemisphere.The results suggest that conjugate EPBs are common.Moreover,the non-conjugate EPBs in the northern and southern hemisphere can occur occasionally,which is probably associated with the different ionospheric backgrounds between the two hemispheres.The features of the conjugate EPBs as shown in this study provides support for the nowcasting of EPBs in the conjugate hemispheres.

惠州市气温与湿疹门诊人次关联的时间序列研究

目的探讨惠州市气温对湿疹门诊人次的影响。方法从惠州市皮肤病防治所收集2016年1月1日至2019年12月31日湿疹门诊数据, 同期气象因素(日均气温、相对湿度)数据源自广东省气候中心的86个气象站点。采用分布滞后非线性模型评估环境温度暴露对湿疹的滞后效应, 采用自然平滑样条函数控制湿度的非线性混杂。结果惠州市皮肤病防治所4年内共报告湿疹门诊254 053人次, 日均就诊173.89人次。日均气温与湿疹日就诊人次呈"U"型关联。低温段温度每降低1 ℃, 湿疹发病风险上升2.20%(1.19%~3.21%), 高温段温度每升高1 ℃, 湿疹发病风险上升2.35%(1.24%~3.5%)。全人群中有1.60%(0.44%~2.68%)的湿疹门诊次归因于低温天气, 即归因人次为4 065(1 128~6 798);6.33%(1.40%~10.87%)的湿疹门诊人次归因于高温天气, 即归因人次为16 082(3 557~27 616)。结论高温和低温暴露均与湿疹就诊风险增加有关。

Association Between COVID-19 Vaccination Coverage and Case Fatality Ratio:a Comparative Study—Hong Kong SAR,China and Singapore,December 2021–March 2022

Summary What is already known about this topic?Hong Kong Special Administrative Region(SAR),China and Singapore are both facing considerable Omicron variant epidemic.However,the overwhelmed medical system and high case fatality ratio(CFR)just occurred in Hong Kong SAR,China but not in Singapore.What is added by this report?The low vaccination coverage in Hong Kong SAR,China,especially among the older adults,is shown to be a primary reason of its recent high CFR.What are the implications for public health practice?Facing the potential epidemic risk,non-vaccinated,non-fully-vaccinated,and non-booster-vaccinated people in China,especially the elderly,should get any type of accessible vaccine,which could save lives when the infection unfortunately befalls.