Research progress and potential medical applications of anaplastic lymphoma kinase in treatment of non-small cell lung cancer / 中国药理学通报

During the treatment of non-small cell lung cancer ( NSCLC) , many patients have developed drug resistance due to the use of targeted EGFR inhibitors. The main reasons for drug resistance are EGFR site mutations and bypass activation. Activation of ALK pathway is one of the major types of bypass activation. A recent authoritative study indicates that ALK is closely related to immunotherapy. This article reviews the treatment of ALK in tumors from three aspects: the structure and physiological function of ALK, the small molecule inhibitor of ALK, the biological function of ALK and its related treatment methods for NSCLC, and prospects future directions for better application of ALK in the treatment of NSCLC.

Application of immunotherapy in relapsed/refractory B-cell acute lymphoblastic leukemia / 中国药房

Immunotherapy， as an emerging treatment method， has been proven to improve the prognosis of patients with relapsed/refractory B-cell acute lymphoblastic leukemia （B-ALL） and has good application prospects. Immunotherapy， including chimeric antigen receptor T cell immunotherapy （CAR-T） and monoclonal antibodies， has shown great potential for application， and has been approved for marketing. This article summarizes the application of the above two therapies in the treatment of relapsed/ refractory B-ALL， and concludes that CAR-T is a kind of personalized immunotherapy， and the selection of ideal targets is an important part of its action. Currently， the ideal targets in clinical studies include CD19， CD22 and CD19/CD22. Monoclonal antibodies， including blinatumomab and inotuzumab ozogamicin， have shown superior therapeutic efficacy for relapsed/refractory B- ALL. Immunotherapy has shown superior therapeutic effects compared to conventional chemotherapy， expanding the selection of treatment options for relapsed/refractory B-ALL.

Cuidado de Enfermagem à Pessoa com Paraplegia à Luz de Betty Neuman / Nursing Care for the Person with Paraplegia in the Light of Betty Neuman / Cuidados de enfermería a la persona con paraplejia a la luz de Betty Neuman

Objetivo: Relatar e compreender o cuidado de enfermagem à pessoa com paraplegia secundária a acidente automobilístico. Método:Estudo qualitativo descritivo, tipo relato de caso, realizado em hospital público de Feira de Santana/BA. Procedeu-se à entrevista, com uma participante em situação de paraplegia. Utilizou-se a elaboração da SAE e suas etapas considerando os aspectos da Teoria de Betty Neuman. Resultados:O relato da paciente e informações obtidas em prontuário demonstraram desinformações e condutas soltas que dificultam o cuidado, alimentavam sentimento de angústia e tristeza à paciente. Conclusão:proporcionou o entendimento acerca do indivíduo vítima de politrauma e suas necessidades, entendendo o adoecer com transcurso multifatorial onde segundo a teoria de Betty Neuman o ambiente e o indivíduo dialogam entre si surtindo efeito positivo e negativo sob o equilíbrio do corpo humano

Objective: To report and understand nursing care for individuals with paraplegia secondary to car accidents. Method:Descriptive qualitative study, in the form of a case report, conducted at a public hospital in Feira de Santana/BA. An interview was conducted with a participant in a paraplegic situation. The Nursing Process (NP) was developed, and its stages were considered, taking into account aspects of Betty Neuman's Theory. Results:The patient's account and information obtained from medical records revealed misinformation and disjointed behaviors that hindered care, fostering feelings of anguish and sadness in the patient. Conclusion:This study provided an understanding of individuals suffering from polytrauma and their needs, understanding illness as a multifactorial process where, according to Betty Neuman's theory, the environment and the individual interact, having both positive and negative effects on the balance of the human body.

Objetivo: Informar y comprender el cuidado de enfermería para personas con paraplejia secundaria a accidentes automovilísticos. Método:Estudio cualitativo descriptivo, tipo informe de caso, llevado a cabo en un hospital público en Feira de Santana/BA. Se realizó una entrevista con una participante en situación de paraplejia. Se utilizó el desarrollo del Proceso de Enfermería (PE) y sus etapas considerando los aspectos de la Teoría de Betty Neuman. Resultados:El relato de la paciente y la información obtenida de los registros médicos revelaron desinformación y conductas desarticuladas que dificultaron el cuidado, fomentando sentimientos de angustia y tristeza en la paciente. Conclusión:Este estudio proporcionó una comprensión de las necesidades de individuos que sufren politraumatismos, entendiendo la enfermedad como un proceso multifactorial donde, según la teoría de Betty Neuman, el entorno y el individuo interactúan, teniendo efectos tanto positivos como negativos en el equilibrio del cuerpo humano.

Análisis de mutaciones BRAF y NRAS de tumores tiroideos en pacientes de Argentina / Analysis of BRAF and NRAS mutations in thyroid tumors in patients from Argentina

Resumen Introducción : Se ha descrito que alteraciones molecu lares de las células foliculares tiroideas en el gen BRAF o en NRAS están asociadas con el proceso de carcinogé nesis. Nuestro objetivo fue conocer la frecuencia muta cional de BRAF y NRAS a partir de muestras de punción aspirativa con aguja fina (PAAF) en nuestra población. Métodos : Se analizó por qPCR el estado mutacional de BRAF (codón 600) y NRAS (codón 61) de 193 mues tras obtenidas por PAAF de nódulos sospechosos y se comparó con los datos de la anatomía patológica de 115 pacientes. Resultados : La mutación BRAF se identificó en 40 muestras (74.1%) de las punciones categorizadas como Bethesda VI (n = 54). En las muestras que se correspon dieron con carcinoma papilar de tiroides (CPT) variante clásica por histología (n = 47), el 70% presentó la muta ción, mientras que en los otros subtipos la prevalencia fue más baja (p = 0.013). En muestras de lesión folicular (n = 36), el 50% de los carcinomas foliculares resultaron positivos para NRAS pero solo el 6.7% de los adenomas presentaron esta variación. La presencia de mutación BRAF y CPT se asociaron con metástasis en los gan glios linfáticos (p = 0.014) y mayor riesgo relativo de recurrencia según el Consenso Argentino Intersocietario (RR = 6.77, p = 0.022). No hubo diferencias significativas entre la mutación de BRAF y otras características de agresividad en CPT. Conclusión : La mutación de BRAF y NRAS se observa en un número significativo de CPT y carcinoma folicular, respectivamente, en nuestra población. La mutación BRAF se correlaciona significativamente con metástasis en los ganglios linfáticos.

Abstract Introduction : Molecular alterations in follicular cells in the BRAF or NRAS genes have been reported to be associated with the process of carcinogenesis. Our aim was to determine the mutational frequency of BRAF and NRAS in fine-needle aspiration (FNA) specimens in our population. Methods : The mutational status of BRAF (codon 600) and NRAS (codon 61) was analysed by qPCR in 193 FNA specimens from suspicious nodules and compared with pathological data of 115 patients. Results : BRAF mutation was identified in 40 samples (74.1%) of FNAs classified as Bethesda VI (n = 54). In samples histologically diagnosed as classic papillary thyroid carcinoma (cPTC, n = 47), mutation was observed in 70% of cases, while in other subtypes the prevalence was lower (p = 0.013). In FNA specimens of follicular lesions (n = 36), positivity for NRAS was found in 50% of the follicular carcinomas (FTCs), but only in 6.7% of adenomas. Finally, there was a significant correlation between BRAF and PTC with lymph-node metastasis (p = 0.014) and increased relative risk of recurrence based on the Argentine Intersociety Consensus (RR = 6.77, p = 0.022). No significant differences were found between BRAF mutation and other features of aggressiveness in PTC. Conclusion : BRAF and NRAS mutations are observed in a significant number of PTCs and FTCs, in our popu lation. There is a significant correlation between BRAF mutation and lymph-node metastasis.

Progress of Chimeric Antigen Receptor Gene Modified-T Cell Immunotherapy for Thoracic Malignancies / 肿瘤防治研究

With a deepened understanding of the pathophysiology and pathogenesis of thoracic malignancies, the treatment has been transited from traditional treatment on the basis of surgery, radiotherapy, and chemotherapy to individualized and precise targeted therapy and immunotherapy. As an antitumor immunotherapy, chimeric antigen receptor gene-modified T (CAR-T) cells have been approved by the FDA for the treatment of hematological malignancies in five CAR-T products. They have also achieved good therapeutic effects in solid tumors. However, significant challenges remain in the clinical application of CAR-T cell immunotherapy in thoracic malignancies. In this review, the latest research progress of CAR-T cell immunotherapy in the treatment of thoracic malignancies were summarized, including the basic characteristics of CAR-T cells, the popular target antigens, and the existing problems and challenges, to provide new ideas and strategies for clinical immunotherapy of thoracic malignancies.

Advance in chimeric antigen receptor-T cell immunotherapy for multiple myeloma / 中国生物制品学杂志

@#In recent years,considerable progress has been made in the treatment of multiple myeloma(MM).However,despite the current improved prognosis of this malignancy,it always ends in relapse and therefore new therapeutic approaches are urgently needed to overcome it.The chimeric antigen receptor(CAR)-T cells targeting B cell maturation antigen(BCMA),cluster of differentiation 19(CD19),cluster of differentiation 38(CD38) and kappa light chains have been evaluated,and have achieved remarkable results in clinical trials.However,even when MM is treated with CAR-T cell therapy,most patients eventually relapse,which is the greatest limitation of this therapy.This paperreviewedthe research progress,limitations and optimization of CAR-T cell immunotherapy in the treatment of MM.

Establishment and observation of a mouse model of IL-12-CAR-T cell-induced cytokine release syndrome / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：通过构建表达IL-12的小鼠CAR-T细胞，探讨经尾静脉将其输注于小鼠体内建立细胞因子释放综合征（CRS）模型的方法。方法：构建基于靶向鼠源CD19的CAR分子，包装逆转录病毒载体并感染小鼠T细胞构建mCD19-CAR-T、mCD19/IL-12-CAR-T细胞。通过构建小鼠体内胰腺癌Panc02-CD19细胞移植瘤模型，检测mCD19/IL-12-CAR-T细胞的抗肿瘤活性，ELISA法检测两种CAR-T细胞IL-12和IFN-γ分泌水平；经小鼠尾静脉输注mCD19/IL-12-CAR-T 细胞构建CAR-T细胞CRS小鼠模型，流式细胞术检测小鼠血清中IL-6、MCP-1、IL-1、IL-10、TNF-α、IFN-γ等细胞因子的含量，H-E染色法观察荷瘤小鼠肝、脾、肺和肾的病理组织学变化。结果：经过培养扩增的mCD19/IL-12-CAR-T细胞能有效分泌IL-12，CAR阳性率达（56.9±5.4）%；与非靶细胞Panc02或靶细胞Panc02-CD19共培养时，均能高分泌IFN-γ。成功构建小鼠胰腺癌Panc02-CD19细胞移植瘤模型，经小鼠尾静脉注射1×106个mCD19/IL-12-CAR-T细胞能显著抑制移植瘤的生长，但未能诱发严重CRS；输注2×106个mCD19/IL-12-CAR-T细胞后，小鼠出现体质量减轻、血清炎性因子水平升高、组织损伤，最终导致死亡等一系列典型CRS表现。结论：成功构建IL-12-CAR-T细胞诱发的小鼠CRS模型，其稳定性好、重复性高，具有广泛的应用前景。

Research progress of CAR-T immunotherapy in solid tumors combined with new strategies / 中国药科大学学报

@#In recent years, the chimeric antigen receptor T-cell (CAR-T) therapy has achieved breakthrough progress in the treatment of hematologic malignancies. However, when it comes to solid tumors, numerous challenges persist.These include limited CAR-T cell infiltration, susceptibility to T cell exhaustion, off-target effects, and more.Thus, novel therapeutic strategies are imperative to enhance the efficacy of CAR-T therapy for solid tumors. In comparison to standalone CAR-T approaches, the combination of CAR-T with other tumor treatment modalities has demonstrated remarkable effectiveness in both preclinical and clinical research.This review article summarizes the advancements in combining CAR-T with various solid tumor treatments: antibody drugs, oncolytic viruses, tumor vaccines, and nanomedicines.The objective is to furnish a theoretical foundation and novel perspectives for the development of innovative CAR-T combination strategies tailored for solid tumor therapy.

Advances in application of regulatory T cells in transplant immune tolerance: from basic to clinical research / 器官移植

Regulatory T cells (Treg) are important inhibitory immune cells to establish immune tolerance, which play a pivotal role in regulating excessive immune response and autoimmune diseases of the host. Previous studies related to transplant immune tolerance have confirmed that increasing the number of Treg in vivo or enhancing the function of Treg serve as a therapeutic strategy to induce transplant immune tolerance. At present, Treg-based induction methods for transplant immune tolerance include adoptive infusion of Treg, in vivo amplification of Treg and utilization of antigen-specific Treg. In this article, the characteristics and mechanism of Treg, the latest research progress on basic experiments and clinical practice of Treg related to transplant immune tolerance at home and abroad were reviewed, and future challenges and development of Treg therapy were prospected, aiming to unravel the significance and application prospect of Treg in transplant immune tolerance, explore the advantages and limitations of Treg therapeutic strategies, and provide reference and evidence for subsequent research in this field.

Advances in Emerging Therapies for Multiple Myeloma / 肿瘤防治研究

Multiple myeloma (MM) is an incurable plasma cell malignancy with a typical course characterized by response to initial treatment and eventual resistance. Despite major advances in the clinical treatment of multiple myeloma driven by the introduction of new drugs (e.g., proteasome inhibitors and immunomodulators), MM remains incurable. Nevertheless, subsequent cycles of remission and relapse continue as long as new treatments are available to patients. With the development of many new treatments, the approval of 12 new drugs over the past 15 years, and the promising trend of clinical trials, the treatment landscape has dramatically changed and patient survival has improved. This article reviews the progress of new treatments for MM.

Research Progress of Chimeric Antigen Receptor Modified NK Cells in the Treatment of Acute Myeloid Leukemia --Review / 中国实验血液学杂志

Chimeric Antigen Receptor (CAR) is a research hotspot in the field of cellular immunotherapy in recent years, and CAR-T cells therapy are developing rapidly in hematological malignant tumors, but their clinical application is still limited by related risks. It is particularly important to find more optimized immunoreactive cells. Natural killer (NK) cells, as key effector cells of innate immunity, can kill tumor or infected cells quickly without prior sensitization. Autologous or allogeneic NK cell infusion has become an effective cell therapy for acute myeloid leukemia (AML). CAR-NK cells combine the advantages of CAR targeting tumor specific antigens and enhancing immune cells activity with the innate antitumor function of NK cells to enhance the targeting and lytic activity of NK cells to AML primordial cells. At present, most of the CAR-NK treatments for AML are still in the stage of specific target screening and verification. This article reviews the latest research progress of CAR-NK cell therapy in the field of AML therapy.

Progress in Research and Application of CAR-T Cell Therapy in T-Lymphocyte Tumors --Review / 中国实验血液学杂志

T-lymphocyte tumors are a group of diseases containing various types of lymphatic system tumors, with strong heterogeneity and poor clinical outcomes. Chimeric antigen receptor T (CAR-T) cell therapy, as a new immune cell therapy, has made a breakthrough in the field of B-lymphocyte tumors. People are interested in the application prospect of this technique in the field of T-lymphocyte tumors. Some studies have shown that CAR-T cell therapy has made some progress in the treatment of T-lymphocyte tumors, and CAR-T for some targets has entered the stage of clinical trials. However, due to the characteristics of T cells, there are also many challenges. This article reviews the research and application of CAR-T cell therapy in T-lymphocyte tumors.

Universal chimeric Fcγ receptor T cells with appropriate affinity for IgG1 antibody exhibit optimal antitumor efficacy

Developing universal CARs with improved flexible targeting and controllable activities is urgently needed. While several studies have suggested the potential of CD16a in tandem with monoclonal antibodies to construct universal CAR-T cells, the weak affinity between them is one of the limiting factors for efficacy. Herein, we systematically investigated the impact of Fcγ receptor (FcγR) affinity on CAR-T cells properties by constructing universal CARs using Fcγ receptors with different affinities for IgG1 antibodies, namely CD16a, CD32a, and CD64. We demonstrated that the activities of these universal CAR-T cells on tumor cells could be redirected and regulated by IgG1 antibodies. In xenografted mice, 64CAR chimeric Jurkat cells with the highest affinity showed significant antitumor effects in combination with herceptin in the HER2 low expression U251 MG model. However, in the CD20 high expression Raji model, 64CAR caused excessive activation of CAR-T cells, which resulted in cytokine release syndrome (CRS) and the decline of antitumor activity, and 32CAR with a moderate affinity brought the best efficacy. Our work extended the knowledge about FcγR-based universal CAR-T cells and suggested that only the FcγRCAR with an appropriate affinity can offer the optimal antitumor advantages of CAR-T cells.

Relationship of cytokines to adverse reaction of chimeric antigen receptor T cell immunotherapy and targeted drug intervention / 中国生物制品学杂志

@#Chimeric antigen receptor T cell(CAR-T)immunotherapy is the most potential adoptive immunotherapy for malignant tumors,which needs no antigen presenting cells(APC)and is not limited by major histocompatibiliy complex(MHC). CAR-T immunotherapy not only recognizes and kills tumor cells directly,but also forms memory T cells and establishs long-term anti-tumor mechanism,of which the effect in leukemia,multiple myeloma and other non-solid tumors as well as the great potential in solid tumors have been widely verified. However,a variety of adverse reactions such as cytokine release syndrome(CRS),neurotoxicity(NT)and miss target effect are produced during CAR-T immunotherapy,of which the occurrence of CRS and NT may be related to the abnormal level of cytokines. Remarkable increase of cytokine level is a major characteristics of CRS. However,the increase of cytokines is neither the root cause nor the only result of CAR-T adverse reaction. CAR-T immunotherapy has a high incidence of adverse reaction which may even endanger the life of patients. Cytokine targeted drugs such as Anakinra and Tocilizumab may decrease the incidence of adverse reaction and improve the prognosis of patients. This paper reviews the correlation of cytokines with CRS and NT in CAR-T immunotherapy and the effect of cytokine targeting drugs,so as to provide a reference for the basic research,quality control and clinical application of CAR-T immunotherapy.

Research progress of chimeric antigen receptor T cell and T cell antigen coupler modified T cell technology / 中国生物制品学杂志

@#At present,malignant tumor has become one of the public problems that seriously threaten human health. In addition to surgery,radiotherapy,chemotherapy,targeted therapy and other methods,with the development of molecular biology,immunotherapy has also developed rapidly,becoming an emerging method of cancer treatment. The most commonly used immune cells in clinical treatment are DC,NK,CIK,CTL and chimeric antigen receptor T cell(CAR-T). Among them,CAR-T technology is the initial technology for global research,while due to its off-target,neurotoxicity,transfection vector defects and other problems,it also has certain limitations in clinical application. T cell antigen coupler modified T cell(TAC-T)technology is a new technology developed on the basis of CAR-T,which uses natural T cell receptor(TCR)to modify T cells and retarget the antigen of cancer cells. In this paper,the research status of CAR-T technology and the research progress of TAC-T technology are reviewed in order to provide reference for further study on the mechanism of TAC-T technology and its safety of clinical application.

Development strategy and clinical research progress of universal chimeric antigen receptor T-cell drugs / 中国药科大学学报

@#Chimeric antigen receptor T-cell (CAR-T) immunotherapy has made a breakthrough in the clinical treatment of a variety of hematological tumors.However, the CAR-T cell products listed at China and abroad are all autologous CAR-T.Compared with autologous CAR-T treatment, universal CAR-T exhibits significant advantages, which could fulfill the treatment demand of more patients, but also displays high technical barriers.This paper reviews the universal CAR-T, clearly points out the two major challenges faced by the development of universal CAR-T, and then summarizes and analyzes the feasible solutions according to the mechanism causing the two major problems.This paper also summarizes domestic and foreign companies producing universal CAR-T and the latest clinical progress of their superior products, and then discusses the feasibility of the development strategy from another aspect, in order to provide ideas for developing a new generation of universal CAR-T cell therapy products.

Genome editing in cancer biotherapy: strategies, challenges and future directions / 中国肿瘤生物治疗杂志

@#[摘 要] CRISPR等基因编辑技术在多学科、多领域产生了革命性影响，也极大地推动了肿瘤生物治疗研究方法的转变和治疗新策略的形成。在肿瘤研究中，基因编辑加速了肿瘤细胞和免疫细胞中生物治疗新靶点的发现，推动了癌基因、抑癌基因、表观分子、耐药基因等“肿瘤细胞正常化”靶向编辑新策略的提出，促进了CAR-T、TCR-T细胞等过继细胞治疗方法向“通用型”、“即用型”的迭代，也极大地加速了CAR-T细胞等细胞治疗的临床应用。通过更加精准基因编辑系统的研发、基因递送策略的不断进步，以及多靶点编辑、定点插入和体内时空可控编辑的发展，将进一步降低基因编辑的脱靶效应，提高疗效和安全性，同时控制成本，推动基因编辑在肿瘤生物治疗中更加广泛的应用，且有望在实体瘤治疗方面实现新的突破。

Research progress of synthetic biology-based CAR-T cell therapy for solid tumors / 中国肿瘤生物治疗杂志

@#[摘 要] 合成生物学借助工程化技术在人工生物系统的设计与构建方面已经取得了长足进展，尤其在CAR-T细胞的开发和应用中为实体肿瘤治疗带来了深刻变革。在合成生物学技术的支持下，新一代的CAR-T细胞可以在靶向肿瘤后激活细胞因子释放通路，实现CAR-T细胞在肿瘤部位的自我调节；工程化的T细胞在CAR的基础上也可以表达其他受体元件（如正交型IL-2、IL-9受体等），通过人工给药干预可在体内实现多功效、特异性刺激，这对于实现CAR-T细胞在体内的精准刺激和克服抑制性肿瘤微环境等意义非凡。此外，智能化CAR回路系统如synNotch基因回路系统和CAR开关系统等研究结果表明，CAR-T细胞可以通过自身基因回路的反馈或人工给药干预来发挥或终止杀伤功能，可有效保证CAR-T细胞在治疗过程中的安全性。虽然针对实体肿瘤靶点难题的CAR-T细胞开发目前尚未有突破性进展，但对于有明确靶点的肿瘤，Ⅰ期临床试验结果已经显示CAR-T细胞治疗实体肿瘤具有巨大潜力。因此，明确当下CAR-T细胞治疗实体肿瘤的作用机制和应用现状，可以对后续开发高效低毒CAR-T细胞提供新思路。

Advances in the study of the function of CD4+ CAR-T cell subsets in tumor therapy / 中国肿瘤生物治疗杂志

@#[摘 要] 嵌合抗原受体T（CAR-T）细胞疗法是目前治疗癌症最有效的一种免疫治疗方法，但CAR-T细胞功能障碍很大程度限制其自身对癌症治疗的效果。T细胞功能的差异以及记忆和效应T细胞的作用被证明在CAR-T细胞治疗中极为重要。CD8+ T细胞作为发挥抗癌作用的主要效应细胞一直是研究焦点，而对CD4+ T细胞的关注较少。CD4+ T细胞不仅可以通过激活CD8+ T细胞使其杀伤肿瘤细胞，还可以独立发挥抗肿瘤作用。现有研究发现，细胞因子、共刺激域和细胞代谢等因素均可影响CD4+ CAR-T细胞亚群的增殖和分化。本文主要综述了CD4+ CAR-T细胞亚群在治疗肿瘤中的重要性以及影响其增殖分化因素的研究进展，为进一步研发高效的CAR-T细胞提供新思路。

Construction and functional identification of CD19-CAR vector based on PiggyBac transposable system / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：开发基于PiggyBac（PB）转座系统的电转染CAR-T细胞制备方法并鉴定其体外抗肿瘤功能。方法：采用健康人外周血单个核细胞（PBMC）制备T细胞，通过分子克隆技术将CD19基因克隆到PB质粒（转座子）中后经电转染法将转座子和转座酶质粒导入激活的T细胞中，并测定其转染效率，最后运用流式细胞术及荧光素酶发光实验评估其对人Burkitt's淋巴瘤Raji细胞的杀伤能力。结果：电转染制备的CD19 CAR-T细胞转染效率较高（>60%），呈剂量依赖性，且CAR-T细胞相对于Pan-T细胞对Raji细胞杀伤能力显著（P<0.05）。结论：开发的PB转座系统的电转染方法可行，在体外对肿瘤细胞具有显著的杀伤能力，具备临床运用于CD19 CAR-T细胞制备的潜力。