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.

Combined effects of high temperature and waterlogging on yield and stem development of summer maize

The purpose of this study was to identify the physiological mechanism underlying the effects of high temperature and waterlogging on summer maize.The stem development and yield of the maize hybrid Denghai 605 in response to high-temperature stress,waterlogging stress,and their combination applied for six days at the third-leaf,sixth-leaf,and tasseling stages were recorded.The combined stresses reduced lignin biosynthetic enzyme activity and lignin accumulation,leading to abnormal stem development.Reduction of the area and number of vascular bundles in stems led to reduced dry matter accumulation and allocation.Decreased grain dry weight at all three stages reduced grain yield relative to a control.In summary,high temperature,waterlogging,and their combined stress impaired stem development and grain yield of summer maize.The combined stresses were more damaging than either stress alone.

SlMYB1 regulates the accumulation of lycopene, fruit shape, and resistance to Botrytis cinerea in tomato

Fruit lycopene,shape,and resistance are essential traits in vegetables whose final product is fruit,and they are also closely related to and strictly regulated by multiple transcription factors.Lycopene,which cannot be synthesized by the human body and can only be ingested from the outside,was important in maintaining human health.During fruit ripening and post-harvest,tomato plants face a variety of biotic or abiotic stresses,which might inf lict great damage to fruit quality due to its f lat shape and pointed tip during storage and transportation.Therefore,there is an urgent need for key molecular switches to simultaneously improve fruit lycopene and resistance to biotic stress during ripening.Here,we identified the MYB transcription factor SlMYB1 in tomato plants which could bind to the promoters of lycopene synthesis-related genes,SlLCY1,SlPSY2,and the pathogen-related gene SlPR5 directly,to regulate the fruit lycopene and resistance to Botrytis cinerea in tomato.In addition to regulating lycopene synthesis,SlMYB1 also regulates the content of soluble sugar,soluble protein and f lavonoid in tomato.What’s more,SlMYB1 could regulate the tomato fruit shape,making it smoother or f latter to prevent skin damage caused by vibration on fruits.RNA sequencing(RNA-seq)further showed that SlMYB1 fruit-specific expression lines had multiple differentially expressed genes compared with those from wild-type plants,suggesting that SlMYB1 might have multiple roles in fruit nutritional quality control and resistance to stresses,which is a rare occurrence in previous studies.In summary,our results revealed that SlMYB1 was an essential multi-functional transcription factor that could regulate the lycopene and resistance to Botrytis cinerea,and change the shape of fruit in tomato plants.

Knowledge-Based Efficient N-1 Analysis Calculation Method for Urban Distribution Networks with CIM File Data

The N-1 criterion is a critical factor for ensuring the reliable and resilient operation of electric power distribution networks.However,the increasing complexity of distribution networks and the associated growth in data size have created a significant challenge for distribution network planners.To address this issue,we propose a fast N-1 verification procedure for urban distribution networks that combines CIM file data analysis with MILP-based mathematical modeling.Our proposed method leverages the principles of CIM file analysis for distribution network N-1 analysis.We develop a mathematical model of distribution networks based on CIM data and transfer it into MILP.We also take into account the characteristics of medium voltage distribution networks after a line failure and select the feeder section at the exit of each substation with a high load rate to improve the efficiency of N-1 analysis.We validate our approach through a series of case studies and demonstrate its scalability and superiority over traditional N-1 analysis and heuristic optimization algorithms.By enabling online N-1 analysis,our approach significantly improves the work efficiency of distribution network planners.In summary,our proposed method provides a valuable tool for distribution network planners to enhance the accuracy and efficiency of their N-1 analyses.By leveraging the advantages of CIM file data analysis and MILP-based mathematical modeling,our approach contributes to the development of more resilient and reliable electric power distribution networks.

Donor-Derived CD19-Targeted T Cell Infusion Eliminates B Cell Acute Lymphoblastic Leukemia Minimal Residual Disease with No Response to Donor Lymphocytes after Allogeneic Hematopoietic Stem Cell Transplantation

Leukemia relapse is still the leading cause of treatment failure after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for B cell acute lymphoblastic leukemia (B-ALL). Relapsed patients with BALL after allo-HSCT have a very short median survival. Minimal residual disease (MRD) is predictive of forthcoming hematological relapse after hematopoietic stem cell transplantation (HSCT);furthermore, eliminating MRD effectively prevents relapse. Donor lymphoblastic infusion (DLI) is the main established approach to treat B-ALL with MRD after allo-HSCT. However, about one-third of patients with MRD are non-responsive to DLI and their prognosis worsens. Although donor-derived cluster of differentiation (CD)19-directed chimeric antigen receptor-modified (CAR) T cells (CART19s) can potentially cure leukemia, the efficiency and safety of infusions with these cells have not yet been investigated in patients with MRD after HSCT. Between September 2014 and February 2018, six patients each received one or more infusions of CART19s from HSCT donors. Five (83.33%) achieved MRD-negative remission, and one case was not responsive to the administration of CAR T cells. Three of the six patients are currently alive without leukemia. No patient developed acute graft-versus-host disease (aGVHD), and no patient died of cytokine release syndrome. Donor-derived CAR T cell infusions seem to be an effective and safe intervention for patients with MRD in B-ALL after allo-HSCT and for those who were not responsive to DLI.

Halogen Storage Electrode Materials for Rechargeable Batteries

The ever-increasing demand for rechargeable batteries with high energy density,abundant resources,and high safety has pushed the development of various battery technologies based on cation,anion,or dual-ion transfer.The use of halogen storage electrode materials has led to new concept battery systems such as halide-ion batteries(HIB)and dual-ion batteries(DIB).This review highlights the recent progress on these electrode materials,including metal(oxy)halides,layered double hydroxides,MXenes,graphite-based materials,and organic materials with carbon or nitrogen redox centers.The reversible electrochemical halogen storage of halide ions(e.g.,F^(−),Cl^(−),and Br^(−)),dual halogen(e.g.,Br_(m)Cl_(n) and [ICl_(2)]^(−)),or binary halide anions(e.g.,PF_(6)^(−),AlCl_(4)^(−),[ZnCl_(x)]^(2−x),and [MgCl_(x)]^(2−x)) in the electrodes is covered.The challenges and mechanisms of halogen storage in various electrode materials in HIBs and DIBs are summarized and analyzed,providing insights into the development of high-performance halogen storage electrode materials for rechargeable batteries.

Hormones Regulate in Vitro Organ Regeneration from Leaf-Derived Explants in <i>Arabidopsis</i>

Plant in vitro organogenesis is well-controlled and thus provides an ideal system for plant propagation and studying mechanisms of plant development. However, the data on systematic in vitro organogenesis from leaf explant with various concentrations and combinations of hormones are limited. Arabidopsis is a very useful model plant species for many aspects of plant biological study. Here, we reported a simple, fast and efficient one-step process for evaluating leaf explant-derived in vitro Arabidopsis organogenesis involving the application of various concentrations and combinations of exogenous hormones. The central portion of the fourth rosette leaf was harvested from the 21-days-old seedling and cultured in vitro on the media containing 216 combinations of exogenous hormones. Different types of organs, including roots, shoots, inflorescences, and leaf-like organs were initiated from leaf explants. Several optimal experimental combinations were selected. A hormone combination, 1.00 μM NAA + 10.00 μM ZT, was considered as the most efficient one for adventitious shoot regeneration. And for adventitious root regeneration, six hormone combinations, [(NAA + ZT: 1.00 + 0.10 μM;10.00 + 0.01 μM;20.00 + 0.10 μM;20.00 + 1.00 μM) and (NAA + 6-BA: 10.00 + 0.10 μM;20.00 + 10.00 μM)], were thought to be the best ones. Further, both auxin and cytokinin ratios and concentrations were crucial for efficient in vitro organogenesis. Our study provides the important information for hormone-regulated organogenesis.

Productivity in the Southern Ocean Antarctic Zone during the Northern Hemisphere Glaciation(NHG)and its link to atmospheric pCO_(2)

A decrease in atmospheric CO_(2)partial pressure(pCO_(2))is considered an important prerequisite for the onset and intensification of Northern Hemisphere Glaciation(NHG).However,how the ocean sequestered missing CO_(2)during the NHG is still uncertain.Changes in surface productivity and deep ventilation in the Southern Ocean(SO)have been proposed to explain the variations in atmospheric pCO_(2)over the last eight glacial cycles,but it is unclear whether these mechanisms contributed to the decrease in atmospheric pCO_(2)during the NHG.Using titanium-normalized contents and mass accumulation rates of biogenic opal and total organic carbon from the International Ocean Discovery Program(IODP)Expedition 374 Site U1524A,we reconstruct the productivity in the Ross Sea,Antarctica,from 3.3 Ma to 2.4 Ma.The productivity records exhibit a long-term decreasing trend and several distinct phased evolutionary features.Specifically,the local productivity fluctuated dramatically during 3.3-3.0 Ma,decreased gradually during 3.0-2.6 Ma,and remained relatively constant during 2.6-2.4 Ma.By comparing productivity with its potential influences,we infer that the phased and long-term evolutions of productivity were mainly controlled by changes in deep ocean ventilation.Sea ice expansion might have decreased productivity during 3.3-3.0 Ma by light attenuation.Changes in eolian dust input have little effect on productivity.Further analysis revealed no coupling linkage between productivity and atmospheric pCO_(2),indicating that the productivity in the SO Antarctic Zone(AZ)was not the main factor controlling the atmospheric CO_(2)decrease during the NHG.To improve our understanding of the role of SO processes in the NHG,further studies should focus on the potential influences of deep ocean ventilation on atmospheric pCO_(2)in the AZ,and similar studies should also be extended to the sea area in the Subantarctic Zone.

Current assessment and management of measurable residual disease in patients with acute lymphoblastic leukemia in the setting of CAR-T-cell therapy

Chimeric antigen receptor(CAR)-modified T-cell therapy has achieved remarkable success in the treatment of acute lymphoblastic leukemia(ALL).Measurable/minimal residual disease(MRD)monitoring plays a significant role in the prognostication and management of patients undergoing CAR-T-cell therapy.Common MRD detection methods include flow cytometry(FCM),polymerase chain reaction(PCR),and next-generation sequencing(NGS),and each method has advantages and limitations.It has been well documented that MRD positivity predicts a poor prognosis and even disease relapse.Thus,how to perform prognostic evaluations,stratify risk based on MRD status,and apply MRD monitoring to guide individual therapeutic decisions have important implications in clinical practice.This review assesses the common and novel MRD assessment methods.In addition,we emphasize the critical role of MRD as a prognostic biomarker and summarize the latest studies regarding MRD-directed combination therapy with CAR-T-cell therapy and allogeneic hematopoietic stem cell transplantation(allo-HSCT),as well as other therapeutic strategies to improve treatment effect.Furthermore,this review discusses current challenges and strategies for MRD detection in the setting of disease relapse after targeted therapy.

Immune-related genetic prognostic index to predict prognosis and immune checkpoint inhibitor therapy efficiency in acute myeloid leukemia

To the Editor:Acute myeloid leukemia(AML)is a heterogeneous disease characterized by proliferation of abnormal myeloblasts in the bone marrow.Traditional treatment,such as chemotherapy with or without hematopoietic stem cell transplantation(HSCT),has been used as the first-line therapy in AML.However,the clinical outcome of patients with AML varies greatly due to several factors,such as the tumor immune microenvironment(TME).

Dual MOFs composites:MIL-53 coated with amorphous UiO-66 for enhanced photocatalytic oxidation of tetracycline and methylene blue

In this work,we proposed a novel strategy for the photocatalytic degradation of the target pollutants tetracycline(TC)and methylene blue(MB)using core–shell dual metal-organic frameworks(MOFs)composites.A series of mesoporous composites MIL-53@UiO-66 were synthesized by solvent-thermal synthesis via coating UiO-66 on the surface of MIL-53.The results show that under the same degradation conditions,only 30 and 15 min are needed to degrade 93%of TC and 96%of MB in the photo-Fenton reaction system,respectively.The amorphous shell layer brings stronger adsorption to the catalyst.MIL-53@UiO-66 composites with equalizing Fermi level are formed to promote photon absorption and electron transfer.Meanwhile,the MIL-53@UiO-66 composites with excellent stability will be a promising catalyst for environmental remediation.

Accurate prediction of pan-cancer types using machine learning with minimal number of DNA methylation sites

DNA methylation analysis has been applied to determine the primary site of cancer;however, robust and accurate prediction of cancer types with a minimum number of sites is still a significant scientific challenge. To build an accurate and robust cancer type prediction tool with a minimum number of DNA methylation sites, we internally benchmarked different DNA methylation site selection and ranking procedures, as well as different classification models. We used The Cancer Genome Atlas dataset (26 cancer types with 8296 samples) to train and test models and used an independent dataset (17 cancer types with 2738 samples) for model validation. A deep neural network model using a combined feature selection procedure (named MethyDeep) can predict 26 cancer types using 30 methylation sites with superior performance compared with the known methods for both primary and metastatic cancers in independent validation datasets. In conclusion, MethyDeep is an accurate and robust cancer type predictor with the minimum number of DNA methylation sites;it could help the cost-effective clarification of cancer of unknown primary patients and the liquid biopsy-based early screening of cancers.

Bridging chimeric antigen receptor T-cell before transplantation improves prognosis of relapsed/refractory B-cell acute lymphoblastic leukemia

To the Editor:For recipients with relapsed/refractory(R/R)B-cell acute lymphoblastic leukemia(B-ALL),allogeneic hematopoietic stem cell transplantation(allo-HSCT)often fails to provide them with a satisfactory prognosis.The chimeric antigen receptor T(CAR-T)cells are proven to be safe and effective for these patients.[1]But there are few published studies assessing the advantages of CAR-T compared to traditional chemotherapy as a bridging treatment followed by HSCT.Consequently,we conducted this study to confirm whether children and young adult R/R B-ALL patients with CAR-T therapy could expect a better post-HSCT prognosis,compared to R/R patients only receiving traditional chemotherapy before transplantation.

Current status and future perspective of natural killer cell therapy for cancer

Natural killer(NK)cells possess innate abilities to effectively eliminate cancer cells.However,because of difficulties of proliferation and easy to be induced dysfunction in the setting of cancer post NK cell therapy,the curative effect of NK cell infusion has been constrained and not been widely applicable in clinical practice.The rapid development of biotechnology has promoted the development of NK cell therapy for cancer treatment.In this review,we will provide a comprehensive analysis of the current status and future prospects of NK cell therapy for cancer,focusing on the biological characteristics of NK cells,as well as strategies to enhance their targeting capabilities and overcome tumor immune suppression within the microenvironment.

秦岭中段野生动物多样性的红外相机监测数据库平台介绍

秦岭地处我国中西部,生物地理位置重要,拥有丰富的生物多样性,有大熊猫(Ailuropoda melanoleuca)、秦岭羚牛(Budorcas bedfordi)、金丝猴(Rhinopithecus roxellana)和朱鹮(Nipponia nippon)等4个秦岭森林旗舰物种,被称为"秦岭四宝"。利用红外相机技术开展秦岭野生动物的非损伤性监测不仅可以为秦岭山系提供物种名录信息,还可以为了解秦岭野生动物的行为和活动格局提供科学数据。清华大学环境学院生态团队自2009–2020年在秦岭中段南坡先后实施了7个项目,对秦岭南坡的4个保护区进行了野生动物监测,面积达1,113 km2(26.5 km×42 km),红外相机位点数267个,相机日数152,160天,共获取红外相机照片855,260张。共鉴定出27种野生兽类和63种野生鸟类,并应用这些照片数据开展了信息挖掘工作,对野生动物行为、稀有物种、与生境的关系,以及人为活动对野生动物的影响等领域进行了研究,已取得部分成果。在此基础上建立了"秦岭中段野生动物多样性的红外相机监测数据库平台",供团队内部及合作者使用。通过10年的监测,我们提出未来研究建议:(1)对于非常偶见的物种,还需要更长的时间并在更多样化的生境布设相机,以获取更多影像数据评估其现状;(2)数据库需要在更大程度和深度上进行信息挖掘,尤其在种间关系、物种–生境关系、种群动态等方面;(3)对典型大种群数量的物种(如秦岭羚牛和野猪Sus scrofa)及食物链顶端大型捕食动物(如金钱豹Panthera pardus)进行种群动态研究,为整个秦岭生态系统的健康持续提供科学支撑;(4)利用数据库的数据及今后红外相机监测数据进行野生动物疾病的发生发展监测研究。

Rapid reconstitution of NK1 cells after allogeneic transplantation is associated with a reduced incidence of graft-versus-host disease

The balance between immunostimulation and immunoregulation in T cell immunity is achieved by maintaining specific ratios of Th1, Th2, Th3 and Tr1 cells. Here, we investigate levels of type 1(IFN-gamma; NK1), type 2(IL-13; NK2), type 3(TGF-beta;NK3) and regulatory(IL-10; NKr) cytokines in peripheral blood to assess the cytokine profiles of natural killer(NK) cells following human allogeneic hematopoietic stem cell transplantation(allo-HSCT). NK2 and NK3 cell expansion was observed after allo-HSCT; levels of NKr cells reached donor levels at day 15, though levels of NK1 cells were consistently lower than donor levels until day 60 after allo-HSCT. Multivariate analysis showed that a higher level of NK1 cells by day 15 was associated with a lower overall risk of acute graft-versus-host disease(GVHD)(HR 0.157, P=0.010) as well as II-IV acute GVHD(HR0.260, P=0.059). Furthermore, higher levels of NK1 cells by day 15 were correlated with lower rates of cytomegalovirus(CMV)reactivation(HR 0.040, 0.005–0.348, P=0.003). These results indicate that rapid reconstitution of NK cells, especially NK1 cells,can help prevent the development of GVHD as well as CMV reactivation after allogeneic transplantation.

Improved clinical outcomes of rhG-CSF-mobilized blood and marrow haploidentical transplantation compared to propensity score-matched rhG-CSF-primed peripheral blood stem cell haploidentical transplantation:a multicenter study

The effects of haploidentical rhG-CSF-mobilized blood and marrow transplantation(HBMT) on hematological malignances are well established. Previous prospective single-center studies have demonstrated better survival after HBMT versus haploidentical rhG-CSF-mobilized peripheral blood stem cell transplantation(HPBSCT) for acute leukemia(AL) not in remission(NR) or in more than the second complete remission(>CR2). To test the hypothesis that HBMT is still superior to HPBSCT for patients with AL, multiple myeloma(MM), or non-Hodgkin lymphoma(NHL) in CR1/CR2 and for patients with chronic myeloid leukemia in the first and second chronic phase lacking a matched donor, we designed a propensity score method-based multicenter study.Hematopoietic recovery, acute graft-versus-host disease(aGVHD), and chronic GVHD were comparable between the HBMT group(n=168) and the HPBSCT group(n=42). No significant differences were found in non-relapse mortality rate(20.17%±3.58%and 27.24%±7.16%, P=0.18) or relapse rate(19.96%±3.72% and 28.49%±8.25%, P=0.32) between the HBMT group and the HPBSCT group. HBMT recipients had better overall survival(65.0%±4.2% and 54.2%±8.3%, P=0.037) and disease-free survival(59.9%±4.6% and 44.3%±8.7%, P=0.051). Multivariate analysis showed that HPBSCT was associated with poorer DFS(HR(95%CI), 1.639(0.995–2.699), P=0.052). Our comparisons showed that HBMT was superior to HPBSCT as a post-remission treatment for patients lacking an identical donor.

Gut microbiome alterations and its link to corticosteroid resistance in immune thrombocytopenia

Quantitative metagenomic studies have linked the gut microbiota to autoimmune disorders.Here,we performed deep shotgun metagenomic sequencing of fecal samples from 99 immune thrombocytopenia(ITP)patients and 52 healthy controls.Dysbiosis in the gut microbiome of ITP was detected phylogenetically and functionally,and classifier based on species markers distinguished individuals with ITP from healthy controls.In particular,the abundance of Ruminococcus gnavus,Bifidobacterium longum and Akkermansia muciniphila was markedly increased in treatment-na?ve ITP patients,and the alterations of microbial species were correlated with clinical indices.Functionally,the secondary bile acid biosynthesis and flagellar assembly were depleted in the gut microbiota of ITP,which may contribute to the onset of ITP by affecting the immune system.Furthermore,we found that corticosteroid treatment affected the gut microbiome of ITP.Compared with corticosteroid-sensitive ITP patients,we identified that the corticosteroid-resistant ITP patients displayed a distinct gut microbiome,which was different from that of the treatment-na?ve ITP patients.Together,we provided support for the critical role of gut microbiota in the development of ITP and established a foundation for further research characterizing gut microbiota in relation to corticosteroid resistance of ITP.

Genome-Wide Analysis and Expression Patterns of the YUCCA Genes in Maize

Auxin plays important roles in various aspects of plant growth and development （Zhao, 2010）. In Arabidopsis, a number of YUCCA （YUC） genes, which are involved in auxin biosyn- thesis, have been identified （Zhao et al., 2001; Woodward et al., 2005; Cheng et al., 2006, 2007; Kim et al., 2007; Chen et al., 2014）. YUC genes encode flavin monooxygenases （FMOs） that convert indole-3-pyruvate （IPA） to indole-3-acetic acid （IAA） （Zhao, 2012）. The Arabidopsis YUC family is comprised of 11 members （Zhao et al., 2001;

Bismuth chloride@mesocellular carbon foam nanocomposite cathode materials for rechargeable chloride ion batteries

Chloride ion batteries(CIB) are considered to be one of the most promising energy storage devices. As cathode materials for CIBs, metal chlorides have many advantages, such as high theoretical energy density, abundant elemental resources and ideal discharge voltage plateau. However, the dissolution and huge volume change of metal chlorides during cycling lead to considerable short lifespan, which limits their potential application for CIBs. Herein, the bismuth chloride nanocrystal is confined in mesocellular carbon foam matrix by a new vacuum impregnation approach. The mesocellular carbon foam with large interconnected pores(15.7 or 23.2 nm) may buffer the large volume variation of bismuth chloride during charge and discharge, giving rise to significantly enhanced electrochemical performance. The as-prepared bismuth chloride@mesocellular carbon foam cathode delivered an initial discharge capacity of 298 m Ah/g and a reversible capacity of 91 m Ah/g after 60 cycles. In contrast, the pure bismuth chloride cathode almost cannot discharge after 30 cycles. This is the first report that the metal chloride cathode can achieve a prolonged cycling in CIBs.