IQGAP3 promotes the progression of glioma as an immune and prognostic marker

Background:IQGAP3 plays a crucial role in regulating cell proliferation,division,and cytoskeletal organization.Abnormal expression of IQGAP3 has been linked to various tumors,but its function in glioma is not well understood.Methods:Various methods,including genetic differential analysis,single-cell analysis,ROC curve analysis,Cox regression,Kaplan-Meier analysis,and enrichment analysis,were employed to analyze the expression patterns,diagnostic potential,prognostic implications,and biological processes involving IQGAP3 in normal and tumor tissues.The impact of IQGAP3 on immune infiltration and the immune microenvironment in gliomas was evaluated using immunofluorescence.Additionally,the cBioPortal database was used to analyze copy number variations and mutation sites of IQGAP3.Experimental validation was also performed to assess the effects of IQGAP3 on glioma cells and explore underlying mechanisms.Results:High IQGAP3 expression in gliomas is associated with an unfavorable prognosis,particularly in wild-type IDH and 1p/19q non-codeleted gliomas.Enrichment analysis revealed that IQGAP3 is involved in regulating the cell cycle,PI3K/AKT signaling,p53 signaling,and PLK1-related pathways.Furthermore,IQGAP3 expression may be closely related to the immunosuppressive microenvironment of glioblastoma.BRD-K88742110 and LY-303511 are potential drugs for targeting IQGAP3 in anti-glioma therapy.In vitro experiments showed that downregulation of IQGAP3 inhibits the proliferation and migration of glioma cells,with the PLK1/PI3K/AKT pathway potentially playing a crucial role in IQGAP3-mediated glioma progression.Conclusion:IQGAP3 shows promise as a valuable biomarker for diagnosis,prognosis,and immunotherapeutic strategies in gliomas.

2022 Chinese expert consensus and guidelines on clinical management of toxicity in anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma

Adoptive cellular immunotherapy with chimeric antigen receptor(CAR)T cells has emerged as a novel modality for treating relapsed and/or refractory B-cell non-Hodgkin lymphoma(B-NHL).With increasing approval of CAR T-cell products and advances in CAR T cell therapy,CAR T cells are expected to be used in a growing number of cases.However,CAR T-cell-associated toxicities can be severe or even fatal,thus compromising the survival benefit from this therapy.Standardizing and studying the clinical management of these toxicities are imperative.In contrast to other hematological malignancies,such as acute lymphoblastic leukemia and multiple myeloma,anti-CD19 CAR T-cell-associated toxicities in B-NHL have several distinctive features,most notably local cytokine-release syndrome(CRS).However,previously published guidelines have provided few specific recommendations for the grading and management of toxicities associated with CAR T-cell treatment for B-NHL.Consequently,we developed this consensus for the prevention,recognition,and management of these toxicities,on the basis of published literature regarding the management of anti-CD19 CAR T-cell-associated toxicities and the clinical experience of multiple Chinese institutions.This consensus refines a grading system and classification of CRS in B-NHL and corresponding measures for CRS management,and delineates comprehensive principles and exploratory recommendations for managing anti-CD19 CAR T-cell-associated toxicities in addition to CRS.

Preclinical and clinical trials of oncolytic vaccinia virus in cancer immunotherapy:a comprehensive review

Oncolytic virotherapy has emerged as a promising treatment for human cancers owing to an ability to elicit curative effects via systemic administration.Tumor cells often create an unfavorable immunosuppressive microenvironment that degrade viral structures and impede viral replication;however,recent studies have established that viruses altered via genetic modifications can serve as effective oncolytic agents to combat hostile tumor environments.Specifically,oncolytic vaccinia virus(OVV)has gained popularity owing to its safety,potential for systemic delivery,and large gene insertion capacity.This review highlights current research on the use of engineered mutated viruses and gene-armed OVVs to reverse the tumor microenvironment and enhance antitumor activity in vitro and in vivo,and provides an overview of ongoing clinical trials and combination therapies.In addition,we discuss the potential benefits and drawbacks of OVV as a cancer therapy,and explore different perspectives in this field.

Tumor-derived exosomes induce initial activation by exosomal CD19 antigen but impair the function of CD19-specific CAR T-cells via TGF-βsignaling

Tumor-derived exosomes (TEXs) enriched in immune suppressive molecules predominantly drive T-cell dysfunction and impair antitumor immunity. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment for refractory and relapsed hematological malignancies, but whether lymphoma TEXs have the same impact on CAR T-cell remains unclear. Here, we demonstrated that B-cell lymphoma-derived exosomes induce the initial activation of CD19-CAR T-cells upon stimulation with exosomal CD19. However, lymphoma TEXs might subsequently induce CAR T-cell apoptosis and impair the tumor cytotoxicity of the cells because of the upregulated expression of the inhibitory receptors PD-1, TIM3, and LAG3 upon prolonged exposure. Similar results were observed in the CAR T-cells exposed to plasma exosomes from patients with lymphoma. More importantly, single-cell RNA sequencing revealed that CAR T-cells typically showed differentiated phenotypes and regulatory T-cell (Treg) phenotype conversion. By blocking transforming growth factor β (TGF-β)-Smad3 signaling with TGF-β inhibitor LY2109761, the negative effects of TEXs on Treg conversion, terminal differentiation, and immune checkpoint expression were rescued. Collectively, although TEXs lead to the initial activation of CAR T-cells, the effect of TEXs suppressed CAR T-cells, which can be rescued by LY2109761. A treatment regimen combining CAR T-cell therapy and TGF-β inhibitors might be a novel therapeutic strategy for refractory and relapsed B-cell lymphoma.

Challenges and optimal strategies of CAR T therapy for hematological malignancies

Remarkable improvement relative to traditional approaches in the treatment of hematological malignancies by chimeric antigen receptor (CAR) T-cell therapy has promoted sequential approvals of eight commercial CAR T products within last 5 years. Although CAR T cells’ productization is now rapidly boosting their extensive clinical application in real-world patients, the limitation of their clinical efficacy and related toxicities inspire further optimization of CAR structure and substantial development of innovative trials in various scenarios. Herein, we first summarized the current status and major progress in CAR T therapy for hematological malignancies, then described crucial factors which possibly compromise the clinical efficacies of CAR T cells, such as CAR T cell exhaustion and loss of antigen, and finally, we discussed the potential optimization strategies to tackle the challenges in the field of CAR T therapy.

Analysis of the genomic landscape of primary central nervous system lymphoma using whole-genome sequencing in Chinese patients

Primary central nervous system lymphoma(PCNSL)is an uncommon non-Hodgkin’s lymphoma with poor prognosis.This study aimed to depict the genetic landscape of Chinese PCNSLs.Whole-genome sequencing was performed on 68 newly diagnosed Chinese PCNSL samples,whose genomic characteristics and clinicopathologic features were also analyzed.Structural variations were identified in all patients with a mean of 349,which did not significantly influence prognosis.Copy loss occurred in all samples,while gains were detected in 77.9%of the samples.The high level of copy number variations was significantly associated with poor progression-free survival(PFS)and overall survival(OS).A total of 263 genes mutated in coding regions were identified,including 6 newly discovered genes(ROBO2,KMT2C,CXCR4,MYOM2,BCLAF1,and NRXN3)detected in≥10%of the cases.CD79B mutation was significantly associated with lower PFS,TMSB4X mutation and high expression of TMSB4X protein was associated with lower OS.A prognostic risk scoring system was also established for PCNSL,which included Karnofsky performance status and six mutated genes(BRD4,EBF1,BTG1,CCND3,STAG2,and TMSB4X).Collectively,this study comprehensively reveals the genomic landscape of newly diagnosed Chinese PCNSLs,thereby enriching the present understanding of the genetic mechanisms of PCNSL.

Etoposide,dexamethasone,and pegaspargase with sandwiched radiotherapy in early-stage natural killer/T-cell lymphoma:A randomized phase III study

Methotrexate,etoposide,dexamethasone,and pegaspargase(MESA)with sandwiched radiotherapy is known to be effective for early-stage extranodal natural killer/T-cell lymphoma,nasal type(NKTCL).We explored the efficacy and safety of reduced-intensity,non-intravenous etoposide,dexamethasone,and pegaspargase(ESA)with sandwiched radiotherapy.This multicenter,randomized,phase III trial enrolled patients aged between 14 and 70 years with newly diagnosed early-stage nasal NKTCL from 27 centers in China.Patients were randomly assigned(1:1)to receive ESA(pegaspargase 2,500 IU/m^(2)intramuscularly on day 1,etoposide 200 mg orally,and dexamethasone 40 mg orally on days 2–4)or MESA(methotrexate 1 g/m^(2)intravenously on day 1,etoposide 200 mg orally,and dexamethasone 40 mg orally on days 2–4,and pegaspargase 2,500 IU/m^(2)intramuscularly on day 5)regimen(four cycles),combined with sandwiched radiotherapy.

Heavy flavour physics and CP violation at LHCb:Aten-year review

Heavy flavour physics provides excellent opportunities to indirectly search for new physics at very high energy scales and to study hadron properties for deep understanding of the strong interaction.The LHCb experiment has been playing a leading role in the study of heavy flavour physics since the start of the LHC operations about ten years ago,and made a range of high-precision measurements and unexpected discoveries,which may have far-reaching implications on the field of particle physics.This review highlights a selection of the most influential physics results on CP violation,rare decays,and heavy flavour production and spectroscopy obtained by LHCb using the data collected during the first two operation periods of the LHC.The upgrade plan of LHCb and the physics prospects are also briefly discussed.

Outcomes in refractory diffuse large B-cell lymphoma:results fromamulticenter real-world study in China

Background:Diffuse large B-cell lymphoma(DLBCL)patients refractory to rituximab-based immunochemotherapy have a dismal prognosis.However,the definition of refractory DLBCL remains inconsistent and no large cohort study data is available from Asian countries.To validate the definition and outcomes of refractory DLBCL in China,we conducted a multicenter,retrospective cohort study.Methods:The REtrospective AnaLysis of Treatment REspoNse of refractory DLBCL(REAL-TREND)study was performed using real-world data from 8 centers in China.DLBCL patients with curative intent were included in the REAL-TREND dataset.Overall survival(OS)was estimated using the Kaplan-Meier method and compared by the log-rank test.Due to heterogeneity in response rates among different centers,the response rates of refractory patients were pooled using random-effect models.Multivariate survival analysis was performed using the Cox regression model.Results:A total of 2778 DLBCL patients diagnosed between January,2010 and December,2015 were enrolled to this study.After validating previous definitions,the SCHOLAR-1 study was most suitable to define refractory DLBCL.The estimated 5-year cumulative incidence of refractory patients was 20%(95% confidence Interval[CI]=18%-22%).After the determination of refractory disease,overall response rate and complete remission rate were 30%(95%CI=22%-38%)and 9%(95%CI=4%-15%),respectively.Patients with either no response to immunochemotherapy or relapse within 12 months after stem-cell transplantation had inferior survival with a median OS of 5.9 months(95%CI=5.5-7.1 months)and 2-year OS rate of 16%(95%CI=12%-20%).International prognostic index score 4-5(hazard ratio[HR]=2.22;95%CI=1.47-3.35),central nervous systemrelapse(HR=1.43;95%CI=1.04-1.97),and best response status(HR=2.68;95%CI=1.42-5.03 for partial remission.HR=5.97,95%CI=3.21-11.11 for stable disease/progressive disease)were independent unfavorable prognostic factors.Conclusions:This is the first large-scale Asian cohort study focusing on outcomes of refractory DLBCL.The definition of the SCHOLAR-1 study identifies patients with homogenously inferior survival,thus is appropriate to select refractory DLBCL.Due to poor clinical outcomes in the rituximab era,patients with refractory DLBCL may be potential candidates for novel treatment modalities.

The model of cytokine release syndrome in CAR T-cell treatment for B-cell non-Hodgkin lymphoma

Chimeric antigen receptor T(CAR T)cell therapy has demonstrated efficacy in the treatment of haematologic malignancies.However,the accompanying adverse events,the most common of which is cytokine release syndrome(CRS),substantially limit its wide application.Due to its unique physiological characteristics,CRS in CAR T-cell treatment for B-cell non-Hodgkin lymphoma(BNHL)may exhibit some special features.Although existing guidelines had greatly promoted the recognition and management of CRS,many recommendations are not fully applicable to B-NHL.Therefore,it is imperative to identify responses that are specific to CRS observed following CAR T treatment for B-NHL.Based on underlying biological processes and known pathophysiological mechanisms,we tentatively propose a new model to illustrate the occurrence and evolution of CAR T-cell-therapy-related CRS in BNHL.In this model,tumour burden and bone marrow suppression are considered determinants of CRS.Novel phenomena after CAR T-cell infusion(such as local inflammatory response)are further identified.The proposed model will help us better understand the basic biology of CRS and recognize and manage it more rationally.

Chinese expert consensus on the management of chimeric antigen receptor T cell therapy-associated coagulopathy

Chimeric antigen receptor T-cell(CAR-T)therapy has greatly improved the disease remission rate and long-term survival rate of patients with relapsed/refractory hematological malignancies.[1-3]Currently,several commercial CAR-T products are available in the market and numerous CAR-T clinical trials have been conducted.Attention should be paid to the safety of CAR-T therapy.The main adverse effects of CAR-T therapy are cytokine release syndrome(CRS)and immune effector cell-associated neurotoxicity syndrome(ICANS).[4]

Efficacy and prognostic factors of imatinib plus CALLG2008 protocol in adult patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia

A CALLG2008 protocol was developed by the Chinese Acute Lymphoblastic Leukemia Cooperative Group for adult acute lymphoblastic leukemia （ALL）. We retrospectively analyzed 153 newly diagnosed adult patients with Philadelphia chromosome （Ph）-positive ALL enrolled into imatinib （400 mg/d） plus CALLG2008 regimen between 2009 and 2015. The median age was 40 years （range, 18-68 years）, with 81 （52.3%） males. The overall hematologic complete remission （CR） rate was 96.7% after induction. With a median follow-up of 24.2 months, the estimated 3-year overall survival （OS） and event-free survival （EFS） rates were 49.5% （95% confidence interval （CI）： 38.5%-59.5%） and 49.2% （95% CI： 38.3%-59.2%）, respectively. Fifty-eight （36 with haploidentical donor） patients underwent allogeneic hematopoietic stem call transplantation （allo-HSCT） in first CR. Among the patients in CR1 after induction, both the 3-year OS and EFS were significantly better in the allo-HSCT group than in the without alIo-HSCT group （73.2%, 95% CI： 58.3%-83.5% vs. 22.2%, 95% CI： 8.7%-39.6% and 66.5%, 95% CI： 50.7%-78.2% vs. 16.1%, 95% CI： 5.1%-32.7%, respectively）. Multivariate analysis showed that alIo-HSCT and achievement of major molecular response were associated with favorable OS or EFS independently. Interestingly, in the alIo-HSCT cohort, the donor type （haploidentical versus matched donors） had no significant impact on EFS or OS. All these results suggested that imatinib plus CALLG2008 was an effective protocol for Ph-positive ALL. Haploidentical donors can also be a reasonable alternative expedient donor pool.

CD70-targeting CAR-T cells have potential activity against CD19-negative B-cell Lymphoma

To the Editor:CD19-targeting chimeric antigen receptor T(CAR-T)cell therapy is a revolutionary immunotherapy in treating relapsed or refractory B lineage malignancies.However,relapse with CD19-negative tumor after treatment with anti-CD19 CAR-T cells has been reported in different types of B-cell lymphoid malignancies,with a percentage exceeding 10% in patients with acute lymphoblastic leukemia[1]and up to 38% in patients with non-Hodgkin lymphoma(NHL)[2].

Optimal model establishment of whole-process management data for CAR-T therapy in China—how should this be done?

Chimeric antigen receptor(CAR)T-cell therapy utilizes patients’own T lymphocytes that are engineered to attack cancer cells[1,2,3].With the US Food and Drug Administration(FDA)approval of four CD19-and one BCMA-targeted CAR therapy for B cell malignancies[4,5],CAR T-cell therapy has finally reached the status of a medicinal product.

Somatic Mutations Confer Severe Peripheral Neuropathy in POEMS Syndrome-Associated Multicentric Castleman Disease

Dear Editor,POEMS-associated multicentric Castleman disease(POEMS-MCD)is a subtype of MCD that presents POEMS symptoms(polyneuropathy,organomegaly,endocrinopathy,M protein,and skin changes)as well as the manifestations of MCD.Among these symptoms,polyneuropathy is a critical feature.However,its mechanism remains poorly understood.The present study presents a case of severe peripheral neuropathy in a POEMSMCD patient.Whole-exome sequencing(WES),threedimensional modeling,and protein stability analysis demonstrated that the mutation V49G in PDLIM5 resulted in instability of the protein,which may play a key role in the pathogenesis of peripheral neuropathy in POEMSMCD.

Diagnosis and management of acquired thrombotic thrombocy- topenic purpura in southeast China： a single center experience of 60 cases

Acquired thrombotic thrombocytopenic purpura （TTP） is a rare life-threatening thrombotic microangiopathy. This study aimed to provide a profile of the diagnosis and management of patients with acquired TTP collected in 10 years in a single center in southeast China. A total of 60 patients diagnosed with acute acquired TTP from March 2005 to August 2015 were enrolled. Among the 60 patients, 52 patients presented with their first episodes, and eight patients had two or more episodes. The median age at presentation was 49 （range, 17 to 78） years with a female predominance （male：female ratio, 1：1.60）. ADAMTS 13 activity were analyzed in 43 patients, among whom 33 （76.7%） patients had a baseline level of 〈 5%. Mortality was 30%. Plasma exchange （PEX） was performed in 62 of 69 （89.9%） episodes. Corticosteroids were administered in 54 of 69 （78.3%） episodes. Other immunosuppressants （e.g., vincristine, cyclosporine, and cyclosporin） were used in 7 of 69 （10.1%） episodes. Rituximab was documented in 4 patients with refractory/relapsed TTP for 5 episodes, showing encouraging results. In conclusion, the diagnosis of TTP depended on a comprehensive analysis of clinical data. Plasma ADAMTS13 activity assay helped confirm a diagnosis. PEX was the mainstay of the therapy, and rituximab can be used in relapsed/refractory disease.

Epi-immunotherapy for cancers:rationales of epi-drugs in combination with immunotherapy and advances in clinical trials

Over the last two decades,several epi-drugs,immune checkpoint inhibitors(ICIs)and adoptive cell therapies have received clinical approval for use in certain types of cancer.However,monotherapy with epi-drugs or ICIs has shown limited efficacy in most cancer patients.Epigenetic agents have been shown to regulate the crosstalk between the tumor and host immunity to alleviate immune evasion,suggesting that epi-drugs can potentially synergize with immunotherapy.In this review,we discuss recent insights into the rationales of incorporating epigenetic therapy into immunotherapy,called epi-immunotherapy,and focus on an update of current clinical trials in both hematological and solid malignancies.Furthermore,we outline the future challenges and strategies in the field of cancer epi-immunotherapy.

A novel method to test particle ordering and final state alignment in helicity formalism

In this study,the non-trival effect of the selection of reference particles for decay angle definitions is demonstrated when constructing the partial-wave amplitude of multi-body decays using helicity formalism.This issue is often ignored in the standard use case of helicity formalism.A new technique is proposed to test the selection of the particle ordering,and it can also be used as a generalized method to calculate the rotation operators that are used for the final-state alignment between different decay chains.Moreover,numerical validations are performed to support the arguments and to verify the effectiveness of the proposed technique.

A protocol to develop T helper and Treg cells in vivo

An understanding of the development and function of T helper(Th)1,Th17 and regulatory T(Treg)cells is critical toward revealing pro-inflammatory immune responses,especially in autoimmune diseases.However,there is no standard protocol to monitor the development of these cells over time in vivo.This protocol details a method to generate Th1,Th17,and Treg cells in a T cell-induced colitis model in vivo and monitor their dynamic changes,which can be used for further investigations in their development from naive CD4+T cells in specific gene knockouts and background strains.

The DDB1-DCAF2 complex is essential for B cell development because it regulates cell cycle progression

B cell development in the bone marrow is critical for producing numerous B cells that play an essential role in the adaptive immune response.B cells develop from common lymphoid progenitors(CLPs),which then differentiate through a series of stages,which include prepro-B cells,pro-B cells,pre-B cells,immature B cells,and mature B cells.