Application of HACCP in Producting Process of Tartary Buckwheat

Food safely has always been the focus of consumer＇s attention since the successful accession of China to the WTO ,and many Chinese food processing enterprises have transformed from small workshop into a large-scale modern enterprises capable of processing continuously ,which requires us to constantly update and improve a series of food safety control system,In this paper,we studied the application of HACCP system in the manufacturing process of tartary buchwheat tea and analyzed hazards in the process of bitter buckwheat tea,and concluded that purchase of raw material,screening and grading ,soaking,cooking ,drying and sterilization ,shelling,packaging and storage of ginished product are eight links as critical control points ,Based on this,corrective measures were proposed,and a detailed HACCP plan was developed.

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.

Culturing adequate CAR-T cells from less peripheral blood to treat B-cell malignancies

Objective:Chimeric antigen receptor-modified T(CAR-T)cells have shown impressive results against relapsed/refractory B cell malignancies.However,the traditional manufacture of CAR-T cells requires leukapheresis to isolate large amounts of peripheral blood T cells,thus making some patients ineligible for the procedure.Methods:We developed a simple method for CAR-T cell preparation requiring small volumes of peripheral blood.First,CD3+T cells isolated from 50 mL peripheral blood from patients(B-cell malignancies)were stimulated with immobilized anti-CD3/RetroNectin in 6-well plates and then transduced with CAR-expressing lentiviral vector.After 4 d,the T cells were transferred to culture bags for large-scale CAR-T cell expansion.In vitro and animal experiments were performed to evaluate the activity of the manufactured CAR-T cells.Finally,29 patients with B-cell acute lymphoblastic leukemia(B-ALL)and 9 patients with B-cell lymphoma were treated with the CAR-T cells.Results:The CAR-T cells were expanded to 1–3×10^(8) cells in 8–10 d and successfully killed B cell-derived malignant tumor cells in vitro and in vivo.For patients with B-ALL,the complete remission rate was 93%1 month after CAR-T cell infusion;after 12 months,the overall survival(OS)and leukemia-free survival rates were 69%and 31%,respectively.For patients with lymphoma,the objective response rate(including complete and partial remission)was 78%2 months after CAR-T cell infusion,and after 12 months,the OS and progression-free survival rates were 71%and 43%,respectively.Cytokine-release syndrome(CRS)occurred in 65.51%and 55.56%of patients with B-ALL and B-cell lymphoma,respectively;severe CRS developed in 20.69%of patients with B-ALL and in no patients with lymphoma.Conclusions:Our novel method can generate sufficient numbers of CAR-T cells for clinical use from 50–100 mL peripheral blood,thus providing an alternative means of CAR-T cell generation for patients ineligible for leukapheresis.

A Novel Dominant Allele from 93-11, ES(4), Represses Reactive Oxygen Species Scavenging and Leads to Early-Senescence in Rice

Senescence is the last developmental process in plant,which has an important impact on crop yield and quality.In this study,a stable hereditary early-senescence line BC64 was isolated from the high-generation recombinant inbred lines of 93-11 and Wuyunjing7(W7).Genetic analysis showed that the premature aging phenotype was controlled by a dominant gene derived from 93-11.By linkage analysis,the gene was primarily mapped in the region between marker B4 and B5 near the centromere of chromosome 4,described as ES(4).Through multiple backcrossing with W7,the near-isogenic line of ES(4)(NIL-ES(4))was obtained.Compared with wild-type W7,NIL-ES(4)plants showed more sever senescence phenotype in both nature and dark conditions.In NIL plants,leaves turned yellow at the fully tillering stage;photosynthetic rate,pollen fertility and seed setting rate were decreased.Moreover,the malondialdehyde,proline content and relative conductivity in NIL-ES(4)were significantly higher than those in W7;both transcript level and activities of reactive oxygen species scavenging enzymes were repressed;H2O2 and O^(2−)were significantly accumulated.This study provides a basis for further cloning and function identification of ES(4).

Relationship between the expression of ERCC-1,survivin and both efficiency and prognosis of cisplatin contained first-line chemotherapy in advanced lung adenocarcinoma

Objective:We analyzed the relationship between the expression of ERCC-1(excisition repair cross complement-1), survivin and sensitivity and prognosis of cisplatin contained regimens first-line chemotherapy in advanced lung adenocarcinoma.Methods:Immunohistochemical(IHC) method was used to evaluate the expression of ERCC-1 and survivin in 80 pathologically confirmed advanced lung adenocarcinoma patients given cisplatin-contained regimens first-line chemotherapy.The response rate and survival time were analyzed according to the expression of ERCC-1 and survivin.Results:Only 77 patients could be reviewed by IHC staining.The expression rates of ERCC-1 and survivin were 33.77% and 53.25 % respectively.The worse response rate and shorter TTP/ PFS could be identified in ERCC-1 positive group.Patients with positive expression of survivin had worse survival time.Conclusion:Expression of ERCC-1 may be a molecular marker of cisplatincontained regimens first-line chemotherapy resistance and poor prognosis in advanced lung adenocarcinoma patients.Positive expression of survivin predicates poor prognosis for patients with advanced lung adenocarcinoma.

Chimeric antigen receptor-immune cells against solid tumors:Structures,mechanisms,recent advances,and future developments

The advent of chimeric antigen receptor(CAR)-T cell immunotherapies has led to breakthroughs in the treatment of hematological malignancies.However,their success in treating solid tumors has been limited.CAR-natural killer(NK)cells have several advantages over CAR-T cells because NK cells can be made from pre-existing cell lines or allogeneic NK cells with a mismatched major histocompatibility complex(MHC),which means they are more likely to become an"off-the-shelf"product.Moreover,they can kill cancer cells via CAR-dependent/independent pathways and have limited toxicity.Macrophages are the most malleable immune cells in the body.These cells can efficiently infiltrate into tumors and are present in large numbers in tumor microenvironments(TMEs).Importantly,CAR-macrophages(CAR-Ms)have recently yielded exciting preclinical results in several solid tumors.Nevertheless,CAR-T,CAR-NK,and CAR-M all have their own advantages and limitations.In this review,we systematically discuss the current status,progress,and the major hurdles of CAR-T cells,CAR-NK cells,and CAR-M as they relate to five aspects:CAR structure,therapeutic mechanisms,the latest research progress,current challenges and solutions,and comparison according to the existing research in order to provide a reasonable option for treating solid tumors in the future.

Identification of potential immune-related mechanisms related to the development of multiple myeloma

Background:Although significant advances have been made in the treatment of multiple myeloma(MM),leading to unprecedented response and survival rates among patients,the majority eventually relapse,and a cure remains elusive.This situation is closely related to an incomplete understanding of the immune microenvironment,especially monocytes/macrophages in patients with treatment-naïve MM.The aim of this study was to provide insight into the immune microenvironment,especially monocytes/macrophages,in patients with treatment-naïve MM.Methods:This study used the single-cell RNA sequencing(scRNA-seq)data of both patients with MM and heathy donors to identify immune cells,including natural killer(NK)cells,T cells,dendritic cells(DCs),and monocytes/macrophages.Transcriptomic data and flow cytometry analysis of monocytes/macrophages were used to further examine the effect of monocytes/macrophages in treatment-naïve MM patients.Results:A significant difference was observed between the bone marrow(BM)immune cells of the healthy controls and treatment-naïve MM patients through scRNA-seq.It is noteworthy that,through an scRNA-seq data analysis,this study found that interferon(IFN)-induced NK/T cells,terminally differentiated effector memory(TEMRA)cells,T-helper cells characterized by expression of IFN-stimulated genes(ISG^(+)Th cells),IFN-responding exhausted T cells,mannose receptor C-type 1(MRC1)^(+)DCs,IFN-responding DCs,MHCII^(+)DCs,and immunosuppressive monocytes/macrophages were enriched in patients with treatment-naïve MM.Significantly,transcriptomic data of monocytes/macrophages demonstrated that"don’t eat me"-related genes and IFN-induced genes increase in treatment-naïve MM patients.Furthermore,scRNA-seq,transcriptomic data,and flow cytometry also showed an increased proportion of CD16^(+)monocytes/macrophages and expression level of CD16.Cell-cell communication analysis indicated that monocytes/macrophages,whose related important signaling pathways include migration inhibitory factor(MIF)and interleukin 16(IL-16)signaling pathway,are key players in treatment-naïve MM patients.Conclusions:Our findings provide a comprehensive and in-depth molecular characterization of BM immune cell census in MM patients,especially for monocytes/macrophages.Targeting macrophages may be a novel treatment strategy for patients with MM.

Immune cells in the B-cell lymphoma microenvironment:From basic research to clinical applications

B-cell lymphoma is a group of hematological malignancies characterized by variable genetic and biological features and clinical behaviors.The tumor microenvironment(TME)is a complex network in tumors,which consists of surrounding blood vessels,extracellular matrix,immune and non-immune cells,and signaling molecules.Increasing evidence has shown that the TME,especially immune cells within,is a double-edged sword,acting either as a tumor killer or as a promoter of tumor progression.These pro-tumor activities are driven by subpopulations of immune cells that express typical markers but have unique transcriptional characteristics,making tumor-associated immune cells good targets for human anti-cancer therapy by ablating immunosuppressive cells or enhancing immune-activated cells.Thus,exploring the role of immune cells in the TME provides distinct insights for immunotherapy in B-cell lymphoma.In this review,we elucidated the interaction between immune cells and tumor cells and their function in the initiation,progression,and prognosis of B-cell lymphoma,from preclinical experiments to clinical trials.Furthermore,we outlined potential therapeutic approaches and discussed the potential clinical value and future perspectives of targeting immune cells in patients with B-cell lymphoma.

Exploiting the potential of the ubiquitin-proteasome system in overcoming tyrosine kinase inhibitor resistance in chronic myeloid leukemia

The advent of tyrosine kinase inhibitors(TKI)targeting BCR-ABL has drastically changed the treatment approach of chronic myeloid leukemia(CML),greatly prolonged the life of CML patients,and improved their prognosis.However,TKI resistance is still a major problem with CML patients,reducing the efficacy of treatment and their quality of life.TKI resistance is mainly divided into BCR-ABL-dependent and BCR-ABL-independent resistance.Now,the main clinical strategy addressing TKI resistance is to switch to newly developed TKIs.However,data have shown that these new drugs may cause serious adverse reactions and intolerance and cannot address all resistance mutations.Therefore,finding new therapeutic targets to overcome TKI resistance is crucial and the ubiquitin-proteasome system(UPS)has emerged as a focus.The UPS mediates the degradation of most proteins in organisms and controls a wide range of physiological processes.In recent years,the study of UPS in hematological malignant tumors has resulted in effective treatments,such as bortezomib in the treatment of multiple myeloma and mantle cell lymphoma.In CML,the components of UPS cooperate or antagonize the efficacy of TKI by directly or indirectly affecting the ubiquitination of BCR-ABL,interfering with CML-related signaling pathways,and negatively or positively affecting leukemia stem cells.Some of these molecules may help overcome TKI resistance and treat CML.In this review,the mechanism of TKI resistance is briefly described,the components of UPS are introduced,existing studies on UPS participating in TKI resistance are listed,and UPS as the therapeutic target and strategies are discussed.

Mechanisms of resistance to third-generation EGFR tyrosine kinase inhibitors

The tyrosine kinase inhibitors （TKI） of the epidermal growth factor receptor （EGFR） are becoming the first line of therapy for advanced non-small cell lung cancer （NSCLC）. Acquired mutations in EGFR account for one of the major mechanisms of resistance to the TKIs. Three generations of EGFR TKIs have been used in clinical applications. AZD9291 （osimertinib; Tagrisso） is the first and only FDA approved third-generation EGFR TKI for T790M-positive advanced NSCLC patients. However, resistance to AZD9291 arises after 9-13 months of therapy. The mechanisms of resistance to third-generation inhibitors reported to date include the EGFR C797S mutation, EGFR L718Q mutation, and amplifications of HER-2, MET, or ERBB2. To overcome the acquired resistance to AZD9291, EAI045 was discovered and recently reported to be an allosteric EGFR inhibitor that overcomes T790M- and C797S-mediated resistance. This review summarizes recent investigations on the mechanisms of resistance to the EGFR TKIs, as well as the latest development of EAI045 as a fourth-generation EGFR inhibitor.

Sintilimab for relapsed/refractory extranodal NK/T cell lymphoma: a multicenter, single-arm, phase 2 trial (ORIENT-4)

This study(ORIENT-4)aimed to assess the efficacy and safety of sintilimab,a humanized anti-PD-1 antibody,in patients with relapsed/refractory extranodal NK/T cell lymphoma(r/r ENKTL).ORIENT-4 is a multicenter,single-arm,phase 2 clinical trial(NCT03228836).Patients with r/r ENKTL who failed to at least one asparaginase-based regimen were enrolled to receive sintilimab 200 mg intravenously every 3 weeks for up to 24 months.The primary endpoint was the objective response rate(ORR)based on Lugano 2014 criteria.Twenty-eight patients with r/r ENKTL were enrolled from August 31,2017 to February 7,2018.Twenty-one patients(75.0%,95%CI:55.1–89.3%)achieved an objective response.With a median follow-up of 30.4 months,the median overall survival(OS)was not reached.The 24-month OS rate was 78.6%(95%CI,58.4–89.8%).Most treatment-related adverse events(TRAEs)were grade 1–2(71.4%),and the most common TRAE was decreased lymphocyte count(42.9%).Serious adverse events(SAEs)occurred in 7(25.0%)patients,and no patient died of adverse events.Sintilimab is effective and well tolerated in patients with r/r ENKTL and could be a novel therapeutic approach for the control of ENKTL in patients.

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]

Ferroptosis in acute leukemia

Ferroptosis is an iron-dependent cell death pathway that is different from apoptosis,pyroptosis,and necrosis.The main characteristics of ferroptosis are the Fenton reaction mediated by intracellular free divalent iron ions,lipid peroxidation of cell membrane lipids,and inhibition of the anti-lipid peroxidation activity of intracellular glutathione peroxidase 4(GPX4).Recent studies have shown that ferroptosis can be involved in the pathological processes of many disorders,such as ischemia-reperfusion injury,nervous system diseases,and blood diseases.However,the specific mechanisms by which ferroptosis participates in the occurrence and development of acute leukemia still need to be more fully and deeply studied.This article reviews the characteristics of ferroptosis and the regulatory mechanisms promoting or inhibiting ferroptosis.More importantly,it further discusses the role of ferroptosis in acute leukemia and predicts a change in treatment strategy brought about by increased knowledge of the role of ferroptosis in acute leukemia.

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.

China Anti‑Cancer Association(CACA)guidelines for holistic integrative management of lymphoma(version 2022)Lymphoma,Guideline,Diagnosis,Treatment,Holistic integrative medicine

Purpose Lymphoma has become a major threat to human health.Fortunately,the diagnosis and treatment of lymphoma have developed rapidly,and research progress has emerged in an endless stream,with new drugs emerging one after another.These results are constantly rewriting guidelines changing clinical practice,need to be popularized and applied more widely.Methods This guideline has integrated consensuses reached by the Lymphoma Committee of China Anti-Cancer Association(CACA),based on China’s practice,tracking previous results of the most advanced clinical researches,absorbing the latest clinical evidence,and referring to domestic and international lymphoma guidelines.Results This holistic integrative guideline of lymphoma introduces the latest progress in the diagnosis and treatment of different subtypes of lymphoma,guide the clinical application of new drugs,standardized and precise management for lymphoma patients.Conclusions CACA guidelines for holistic integrative management of lymphoma(version 2022)enhance standardization and precision of the management for lymphoma patients in China.