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

Cancer Biology & Medicine 2021年第4期18卷 1066-1079页

作者： Lu Han Jian Zhou Linlin Li Keshu Zhou Lingdi Zhao Xinghu Zhu Qingsong Yin Yufu Li hongqin you Jishuai Zhang Yongping Song Quanli Gao Department of Immunology Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer HospitalZhengzhou 450008China Department of Hematology Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer HospitalZhengzhou 450008China Department of Medical Microbiology School of Basic Medical SciencesXinxiang Medical UniversityXinxiang 453003China The Shenzhen Pregene Biopharma Company Ltd.Shenzhen 518118China

Objective:Chimeric antigen receptor-modified T(CAR-T)cells have shown impressive results against relapsed/refractory B cell ***,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 ***:We developed a simple method for CAR-T cell preparation requiring small volumes of peripheral ***,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 *** 4 d,the T cells were transferred to culture bags for large-scale CAR-T cell *** vitro and animal experiments were performed to evaluate the activity of the manufactured CAR-T ***,29 patients with B-cell acute lymphoblastic leukemia(B-ALL)and 9 patients with B-cell lymphoma were treated with the CAR-T ***: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 *** 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%,*** 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%,***-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 ***: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.

关键词： Fewer initial lymphocytes peripheral blood CAR-T cells B-cell malignancy acute lymphoblastic leukemia

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Distinct phenotype and function of circulating Vδ1+ and Vδ2+ γδT cells in hepatocellular carcinoma

Distinct phenotype and function of circulating Vδ1+ and Vδ...

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第十四届全国免疫学学术大会

作者： hongqin you Xiaokun Wang Henan cancer hospital

Hepatocellular carcinoma(HCC) is one of the leading digestive malignancies,with a high metastasis and *** determine if γδ T cells are altered in HCC,we examined the frequency and phenotype of peripheral blood Vδ1and Vδ2γδ T cells by multi-parameter *** showed that circulating Vδ1γδT cells are increased while the Vδ2γδT cells decreased significantly compared to healthy donors(HDs).The Vδ1/Vδ2γδ T ratios were strictly inverted in patients with HCC indicating that Vδ1and Vδ2γδ T cells are possibly associated with the pathogenesis of *** next investigated the basal activation status of Vδ1 and Vδ2 γδ T cells by analyzing CD69 *** observed that both Vδ1 γδ T and Vδ2 γδ T cells in HCC displayed higher levels of CD69 compared to ***,proportions of activated Vδ1 γδ T cells were higher than Vδ2 γδ T cells in HCC and *** results indicated that Vδ1 γδT cells showed a higher basal activation status than Vδ2 γδ T cells in patients with *** further assessed the differentiation stage based on CD45 RA and CD27 expression.Vδ1 γδ T cells of HCC patients were with an increased terminally differentiated effector memory phenotype(EMRA) compared to HDs,while Vδ2 γδ T cells accumulated in central memory and effector memory stage without differences from *** results suggested that only differentiation of Vδ1γδ T cells were impacted by *** data in another study of ours demonstrated that TIGIT is a marker of anti-tumor activity of γδ T *** this study,we found that TIGIT mainly expressed in Vδ1 γδ T cells,and hardly in Vδ2γδ T cells both in HDs and HCC *** expression of Vδ1 γδ T cells in HCC was significantly higher than *** aforementioned results indicated that Vδ1 γδ T cells participated in the anti-tumor process of HCC *** concluded that circulating Vδ1 γδ T cells,which presented distinct phenotypes to Vδ2 γδ T cells in activation,differentiation and function marker,might be as part of

关键词： Vδ1+γδT Vδ2+γδT Hepatocellular carcinoma

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CDR3δ1-grafted TCRγ4δ1-engineered αβT cells exhibit a broadly effective antitumor activity

CDR3δ1-grafted TCRγ4δ1-engineered αβT cells exhibit a b...

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第十届全国免疫学学术大会

作者： Kangxia He hongqin you Yuxia Li Wei He Department of immunology Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College

Background:The proliferation and function capacity of T cells is seriously impaired in cancer patients,which results in the decrease of T cell number and immunity reaction,and TCR-engineered T cells display obvious antitumor ***,we here propose a promising strategy to redirect peripheral blood-derivedαβT cells by a broadly tumor reactive-CDR3δ1-grafted TCRγ4δ1 gene ***:We employedαβT cells as targets for lentiviral transduction of TCRγ4δ1 to obtain TCRγ4δ1-transducedαβT *** cytotoxicity in vitro,cytotoxic mechanisms,the ability of proliferation and cytokine secretion,autoimmunity and antitumor activity in a human Hep G2 xenograft nude mouse model of TCRγ4δ1-transducedαβT cells were ***:The TCRγ4δ1 genes were transduced to about 36.1%of polyclonallyαβT *** expected,TCRγ4δ1-transducedαβT cells showed evident in-vitro cytotoxicity against Hep G2,BGC-803 and K562 cells by perforin-granzyme pathway,ability of proliferation,and IL-2,IFNγand IL-4 ***,the introduced TCRδ1 or TCRγ4chains couldn`t pair with the endogenous TCRαor TCRβchains,while TCRγ4δ1-transducedαβT cells didn`t produce immune response against a great number of normal cells through TCRγ4δ1 recognition *** importantly,adop-tive transfer of TCRγ4δ1-transducedαβT cells into nude mice bearing a human Hep G2 cell line exhibited significant suppression of tumor ***:In this study,TCRγ4δ1-transducedαβT cells mediate significant antitumor reactivity in vitro and in vivo while ignoring normal cells,thus they might be candidate cells for adoptive T-cell transfer therapy for cancer.

关键词： TCRγ4δ1 adoptive T-cell transfer therapy TCR-engineered T cells

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Combination therapy using low‐dose anlotinib and immune checkpoint inhibitors for extensive‐stage small cell lung cancer

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Cancer Innovation 2024年第6期3卷 76-85页

作者： Han Li Shumin Yuan Han Wu Yajie Wang Yichen Ma Xiance Tang Xiaomin Fu Lingdi Zhao Benling Xu Tiepeng Li Peng Qin hongqin you Lu Han Zibing Wang Department of Immunotherapy The Affiliated Cancer Hospital of Zhengzhou University&Henan Cancer HospitalZhengzhouChina Department of Oncology Qilu Hospital of Shandong UniversityJinanChina Biotherapy Center The First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina Nanchang University Queen Mary School NanchangChina The First Clinical Medical College of Xinjiang Medical University UrumqiChina Department of Medical Affairs The Affiliated Cancer Hospital of Zhengzhou University&Henan Cancer HospitalZhengzhouChina

Background:This study evaluated the efficacy and safety of low‐dose anlotinib combined with immune checkpoint inhibitors as second‐line or later treatment for extensive‐stage small cell lung cancer(ES‐SCLC).Methods:The study included 42 patients with ES‐SCLC who were treated with low‐dose anlotinib combined with programmed cell death protein 1/programmed cell death‐ligand 1 inhibitors at Henan Cancer Hospital between March 2019 and August *** retrospectively analyzed the efficacy and safety data for these *** assessed included progression‐free survival(PFS),overall survival(OS),the overall response rate(ORR),the disease control rate(DCR),and adverse events(AEs).Prognostic factors were identified in univariate and multivariate ***:Median PFS was 11.0 months(95%CI:7.868–14.132)and median OS was 17.3 months(95%CI:11.517–23.083).The ORR was 28.5%and the DCR was 95.2%.Treatment‐related AEs were noted in 27 patients(64.3%),the most common of which was thyroid dysfunction(26.2%).Grade 3/4 treatmentrelated AEs were observed in two patients(4.8%).Conclusions:A combination of low‐dose anlotinib and immune checkpoint inhibitors as second‐line or later treatment for ES‐SCLC may achieve longer PFS and OS and have manageable AEs.

关键词： combination immunotherapy extensive‐stage small cell lung cancer immune checkpoint inhibitors low‐dose antiangiogenic drugs

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Siglec-15在唑来膦酸特异性γδT细胞的表达及与抗原提呈相关分子表达的关系

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中国免疫学杂志 2022年第20期38卷 2438-2442页

作者：游红琴黄正华朱会芳韩露李林霖高全立郑州大学附属肿瘤医院河南省肿瘤医院郑州450008

目的:探讨唾液酸结合免疫球蛋白样凝集素-15(Siglec-15)在唑来膦酸(ZOL)特异性γδT细胞的表达及与抗原提呈相关分子表达的关系。方法:流式细胞术检测ZOL刺激前及刺激后4 d、8 d、12 d和16 d,Siglec-15、CD80、CD86和人类白细胞抗原(HLA... 详细信息

目的:探讨唾液酸结合免疫球蛋白样凝集素-15(Siglec-15)在唑来膦酸(ZOL)特异性γδT细胞的表达及与抗原提呈相关分子表达的关系。方法:流式细胞术检测ZOL刺激前及刺激后4 d、8 d、12 d和16 d,Siglec-15、CD80、CD86和人类白细胞抗原(HLA)-DR在健康对照(HC)和肺癌(LC)患者外周血中的表达及表达水平的相关性。结果:与ZOL刺激前相比,CD80^(+)、CD86^(+)和HLA-DR^(+)γδT细胞水平在HC和LC中均升高(P<0.05);随着ZOL刺激时间延长,Siglec-15在两组γδT细胞中的表达水平均出现先升后降趋势,在刺激后4 d,HC显著高于LC(P<0.05)。LC的Siglec-15^(+)γδT与CD80^(+)γδT细胞比例在刺激前及刺激后的4 d和8 d呈正相关(P<0.05)。结论:Siglec-15在ZOL特异性γδT细胞中的表达水平先升高后降低,表达水平的上调与CD80表达水平的升高有关。

关键词：唾液酸结合免疫球蛋白样凝集素-15 γδT CD80 CD86 人类白细胞抗原-DR

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Glycolytic dysregulation in Alzheimer's disease:unveiling new avenues for understanding pathogenesis and improving therapy

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Neural Regeneration Research 2025年第8期20卷 2264-2278页

作者： you Wu Lijie Yang Wanrong Jiang Xinyuan Zhang Zhaohui Yao Department of Geriatrics Renmin Hospital of Wuhan UniversityWuhanHubei ProvinceChina

Alzheimer's disease poses a significant global health challenge owing to the progressive cognitive decline of patients and absence of curative *** current therapeutic strategies,primarily based on cholinesterase inhibitors and N-methyl-Daspartate receptor antagonists,offer limited symptomatic relief without halting disease progression,highlighting an urgent need for novel research directions that address the key mechanisms underlying Alzheimer's *** studies have provided insights into the critical role of glycolysis,a fundamental energy metabolism pathway in the brain,in the pathogenesis of Alzheimer's *** in glycolytic processes within neurons and glial cells,including microglia,astrocytes,and oligodendrocytes,have been identified as significant contributors to the pathological landscape of Alzheimer's *** changes impact neuronal health and function,thus offering promising targets for therapeutic *** purpose of this review is to consolidate current knowledge on the modifications in glycolysis associated with Alzheimer's disease and explore the mechanisms by which these abnormalities contribute to disease onset and *** focus on the pathways through which glycolytic dysfunction influences Alzheimer's disease pathology should provide insights into potential therapeutic targets and strategies that pave the way for groundbreaking treatments,emphasizing the importance of understanding metabolic processes in the quest for clarification and management of Alzheimer's disease.

关键词： Alzheimer’s disease glial cells glycolysis neuronal metabolism pathogenesis therapeutic targets

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Visualizing traumatic brain injury:ocular clues for diagnosis and assessment

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Neural Regeneration Research 2025年第5期20卷 1399-1400页

作者： Morteza Abyadeh Vivek Gupta Yuyi you Joao A.Paulo Mehdi Mirzaei ProGene Technologies Pty Ltd SydneyNSWAustralia Department of Clinical Medicine Faculty of MedicineHealth and Human SciencesMacquarie Medical SchoolMacquarie UniversityMacquarie ParkNorth RydeSydneyNSWAustralia Department of Cell Biology Harvard Medical SchoolBostonMAUSA

Traumatic brain injury (TBI) is defined as damage to the brain resulting from an external sudden physical force or shock to the *** is considered a silent public health epidemic causing significant death and disability *** were 64,000 TBI related deaths reported in the USA in 2020,with about US$76 billion in direct and indirect medical costs annually.

关键词： diagnosis ocular injury

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Bidirectional regulation of the brain-gut-microbiota axis following traumatic brain injury

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Neural Regeneration Research 2025年第8期20卷 2153-2168页

作者： Xinyu you Lin Niu Jiafeng Fu Shining Ge Jiangwei Shi Yanjun Zhang Pengwei Zhuang National Key Laboratory of Chinese Medicine Modernization Tianjin University of Traditional Chinese MedicineTianjinChina Haihe Laboratory of Modern Chinese Medicine Tianjin University of Traditional Chinese MedicineTianjinChina First Teaching Hospital of Tianjin University of Traditional Chinese Medicine TianjinChina National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion TianjinChina

Traumatic brain injury is a prevalent disorder of the central nervous *** addition to primary brain parenchymal damage,the enduring biological consequences of traumatic brain injury pose long-term risks for patients with traumatic brain injury;however,the underlying pathogenesis remains unclear,and effective intervention methods are *** dysfunction is a significant consequence of traumatic brain *** the most densely innervated peripheral tissue in the body,the gut possesses multiple pathways for the establishment of a bidirectional“brain-gut axis”with the central nervous *** gut harbors a vast microbial community,and alterations of the gut niche contribute to the progression of traumatic brain injury and its unfavorable prognosis through neuronal,hormonal,and immune pathways.A comprehensive understanding of microbiota-mediated peripheral neuroimmunomodulation mechanisms is needed to enhance treatment strategies for traumatic brain injury and its associated *** comprehensively reviewed alterations in the gut microecological environment following traumatic brain injury,with a specific focus on the complex biological processes of peripheral nerves,immunity,and microbes triggered by traumatic brain injury,encompassing autonomic dysfunction,neuroendocrine disturbances,peripheral immunosuppression,increased intestinal barrier permeability,compromised responses of sensory nerves to microorganisms,and potential effector nuclei in the central nervous system influenced by gut ***,we reviewed the mechanisms underlying secondary biological injury and the dynamic pathological responses that occur following injury to enhance our current understanding of how peripheral pathways impact the outcome of patients with traumatic brain *** review aimed to propose a conceptual model for future risk assessment of central nervous system-related diseases while elucidating novel insights into the bidirectional effec

关键词： traumatic brain injury brain-gut-microbiome axis gut microbiota neuroimmune immunosuppression host defense vagal afferents bacterial infection dorsal root ganglia nociception neural circuitry

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Laparoscopic liver resection utilizing the ventral avascular area of the inferior vena cava:A retrospective cohort study

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World Journal of Gastroenterology 2025年第1期31卷 42-57页

作者： Kun Huang Zhu Chen Heng Xiao Hai-Yang Hu Xing-Yu Chen Cheng-you Du Xiang Lan Department of Hepatobiliary Surgery The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400000China Department of General Surgery Mianyang Hospital of Traditional Chinese MedicineMianyang 621000Sichuan ProvinceChina

BACKGROUND Laparoscopic liver resection(LLR)can be challenging due to the difficulty of establishing a retrohepatic tunnel under *** the third hepatic hilum before parenchymal transection often leads to significant liver mobilization,tumor compression,and bleeding from the short hepatic veins(SHVs).This study introduces a novel technique utilizing the ventral avascular area of the inferior vena cava(IVC),allowing SHVs to be addressed after parenchymal transection,thereby reducing surgical complexity and improving outcomes in in situ *** To introduce and evaluate a novel LLR technique using the ventral avascular area of the IVC and compare its short-term outcomes with conventional *** The clinical cohort data of patients with pathologically confirmed hepatocellular carcinoma or intrahepatic cholangiocarcinoma who underwent conventional LLR and novel LLR between July 2021 and July 2023 at the First Affiliated Hospital of Chongqing Medical University were retrospectively *** novel LLR,we initially separated the caudate lobe from the IVC using dissecting forceps along the ventral avascular area of the ***,we transected the parenchyma of the left and right caudate lobes from the caudal side to the cephalic side using the avascular area as a ***,we addressed the SHVs and finally dissected the root of the right hepatic vein or left hepatic *** short-term postoperative outcomes and oncological results of the two approaches were evaluated and *** A total of 256 patients were included,with 150(58.59%)undergoing conventional LLR and 106(41.41%)undergoing novel *** novel technique resulted in significantly larger tumor resections(6.47±2.96 cm vs 4.01±2.33 cm,P<0.001),shorter operative times(199.57±60.37 minutes vs 262.33±83.90 minutes,P<0.001),less intraoperative blood loss(206.92±37.09 mL vs 363.34±131.27 mL,P<0.001),and greater resection volume(345.11±31.40 mL vs 264.38±31.98 mL,P<0.001)comp

关键词： Laparoscopic liver resection Inferior vena cava Retrohepatic tunnel Short hepatic veins Complex liver tumors Intraoperative bleeding control

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Inhibiting SHP2 reduces glycolysis, promotes microglial M1 polarization, and alleviates secondary inflammation following spinal cord injury in a mouse model

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Neural Regeneration Research 2025年第3期20卷 858-872页

作者： Xintian Ding Chun Chen Heng Zhao Bin Dai Lei Ye Tao Song Shuai Huang Jia Wang Tao you Department of Orthopedics The First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhui ProvinceChina Department of Orthopedics Provincial Hospital Affiliated to Anhui Medical UniversityHefeiAnhui ProvinceChina

Reducing the secondary inflammatory response, which is partly mediated by microglia, is a key focus in the treatment of spinal cord injury. Src homology 2-containing protein tyrosine phosphatase 2(SHP2), encoded by PTPN11, is widely expressed in the human body and plays a role in inflammation through various mechanisms. Therefore, SHP2 is considered a potential target for the treatment of inflammation-related diseases. However, its role in secondary inflammation after spinal cord injury remains unclear. In this study, SHP2 was found to be abundantly expressed in microglia at the site of spinal cord injury. Inhibition of SHP2 expression using siRNA and SHP2 inhibitors attenuated the microglial inflammatory response in an in vitro lipopolysaccharide-induced model of inflammation. Notably, after treatment with SHP2 inhibitors, mice with spinal cord injury exhibited significantly improved hind limb locomotor function and reduced residual urine volume in the bladder. Subsequent in vitro experiments showed that, in microglia stimulated with lipopolysaccharide, inhibiting SHP2 expression promoted M2 polarization and inhibited M1 polarization. Finally, a co-culture experiment was conducted to assess the effect of microglia treated with SHP2 inhibitors on neuronal cells. The results demonstrated that inflammatory factors produced by microglia promoted neuronal apoptosis, while inhibiting SHP2 expression mitigated these effects. Collectively, our findings suggest that SHP2 enhances secondary inflammation and neuronal damage subsequent to spinal cord injury by modulating microglial phenotype. Therefore, inhibiting SHP2 alleviates the inflammatory response in mice with spinal cord injury and promotes functional recovery postinjury.

关键词： apoptosis glycolysis inflammatory response microglia neurons polarization spinal cord injury Src homology 2-containing protein tyrosine phosphatase 2

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