Humanized mouse model: a review on preclinical applications for cancer immunotherapy

Due to the refractory and partial sensitive treatments to malignant cancers, immunotherapy has increasingly become a hotspot in effective anti-tumor research. However, at present, existing animal models could not accurately describe the interaction between human tissue and tumor cells for preclinical trials. Furthermore, it is a tough obstacle to reconstitute the immune system and microenvironment in a mouse model identical to humans due to species differences. In the establishment of the humanized mouse model, the co-transplantation of human immunocytes with/without tissues and tumor cells is the key breakthrough to solve this problem. The compelling progress has been investigated in the preclinical drug test for diverse tumor types. This review mainly summarized the development of immunodeficient mice, and the construction and practicability of the humanized mouse model. Furthermore, the investigators also highlight the pros and cons, and recent progress in immunotherapy research for advanced utility of human cancer diseases.     

老年下肢骨折患者行手术室人性化护理的效果

目的评价手术室人性化护理干预对老年下肢骨折患者手术以及术后恢复情况的影响,以加速老年骨折患者康复。方法选择我院近年来收治手术治疗的老年下肢骨折患者,总计100例。结合手术室护理方法进行对照组和研究组随机分组,对照组老年下肢骨折患者采取常规护理,研究组老年下肢骨折患者采取手术室人性化护理干预。比较两组老年下肢骨折患者的手术情况,包括情绪评分、生活质量评分、术后并发症以及护理满意度。结果研究组老年下肢骨折患者SAS、SDS、SF-36评分均明显优于对照组,且安全性和护理满意度均明显高于对照组,观察指标数据差异有统计学意义,P<0.05。结论予以老年下肢骨折患者手术室人性化护理干预满足了患者的护理需求,进一步稳定了患者的情绪、身体,从而提高了患者手术安全性。     

2017年泰州市重点职业病危害因素接触人员职业健康风险评估分析

依据《江苏省重点职业病监测与职业健康风险评估工作实施方案》要求，分析泰州市职业健康检查、职业病诊断与鉴定、职业病患者工伤保险待遇落实及职业病报告信息。结果显示，2017年职业健康检查共16759人，检出职业病10例，疑似职业病23例，职业禁忌证22人。职业病患者均已享受工伤保险待遇。泰州市重点职业病危害因素为电焊烟尘、矽尘和噪声，应进一步加强职业健康监护工作。     

Prediction of human pharmacokinetics of typical compounds by a physiologically based method using chimeric mice with humanized liver

1. In this study, total body clearance (CL_t), volume of distribution at steady state (V_ss) and plasma concentration–time profiles in humans of model compounds were predicted using chimeric mice with humanized livers.

2. On the basis of assumption that unbound intrinsic clearance (CL_Uint) per liver weight in chimeric mice was equal to those in humans, CL_t were predicted by substituting human liver blood flow and liver weights in well-stirred model. V_ss were predicted by Rodgers equation using scaling factors of tissue-plasma concentration ratios (SF_Kp) in chimeric mice estimated from a difference between the observed and predicted V_ss. These physiological approaches showed high prediction accuracy for CL_t and V_ss values in humans.

3. We compared the predictability of CL_t and V_ss determined by the physiologically based predictive approach using chimeric mice with those from predictive methods reported by Pharmaceutical Research Manufacturers of America. The physiological approach using chimeric mice indicated the best prediction accuracy in each predictive method.

4. Simulation of human plasma concentration–time profiles were generally successful with physiologically based pharmacokinetic (PBPK) model incorporating CL_Uint and SF_Kp obtained from chimeric mice.

5. Combined application of chimeric mice and PBPK modeling is effective for prediction of human PK in various compounds.

     

人性化护理模式在手术室护理中的应用价值评价

目的讨论人性化护理模式对手术室患者治疗效果。方法回顾分析我院2018年1月-2018年12月份手术室收治的160例患者,按照患者的个人意愿随机分为常规护理组和人性化护理组,每组各80例。分别采取常规护理和人性化护理,对比两组患者的治疗效果。结果根据数据统计结果显示,人性化护理组患者的护理满意度(73.75%)高于常规护理组(58.75%),P<0.05,具有统计学意义。结论由于手术室患者的病情较重,而且很容易对手术产生明显的恐惧情绪。而人性化护理模式能够照顾患者情绪,有效减少手术时间,增强患者的手术信息,确保整个手术顺利进行,也能够促进术后患者的康复效果。     

人性化护理在轻度脑外伤手术中的患者应用价值

目的分析人性化护理在轻度脑外伤手术中的患者应用价值。方法2018年1月-2019年12月于我科接受手术治疗的72例轻度脑外伤患者为观察对象,奇偶法分组,对照组(常规护理)35例,试验组(人性化护理)37例,分析应用价值。结果护理后,两组患者HAMA、HAMD评分均有所下降,且试验组患者HAMA、HAMD评分更低,有统计学意义(P<0.05)。护理后,试验组患者生活质量评分高于对照组,有统计学意义(P<0.05)。结论轻度脑外伤手术患者行人性化护理可达到理想的应用价值,对于情绪的改善、生活质量的提升价值显著。     

From Immunodeficiency to Humanization: The Contribution of Mouse Models to Explore HTLV-1 Leukemogenesis

The first discovered human retrovirus, Human T-Lymphotropic Virus type 1 (HTLV-1), is responsible for an aggressive form of T cell leukemia/lymphoma. Mouse models recapitulating the leukemogenesis process have been helpful for understanding the mechanisms underlying the pathogenesis of this retroviral-induced disease. This review will focus on the recent advances in the generation of immunodeficient and human hemato-lymphoid system mice with a particular emphasis on the development of mouse models for HTLV-1-mediated pathogenesis, their present limitations and the challenges yet to be addressed.     

Isolation and characterization of human anti-acetylcholine receptor monoclonal antibodies from transgenic mice expressing human immunoglobulin loci

The isolation of human antibodies against muscle acetylcholine receptor (AChR), the autoantigen involved in myasthenia gravis (MG), is important for the development of therapeutically useful reagents. Monovalent antibody fragments from monoclonal antibodies against the main immunogenic region (MIR) of AChR protect the receptor from the destructive activity of MG autoantibodies. Human anti-AChR alpha-subunit antibody fragments with therapeutic potential have been isolated using phage display antibody libraries. An alternative approach for obtaining human mAb has been provided by the development of humanized mice. In this report, we show that immunization of transgenic mouse strains with the extracellular domain of the human AChR alpha-subunit results in antibody responses and isolation of hybridomas producing human mAb. Four specific IgM mAb were isolated and analyzed. mAb170 recognized the native receptor the best and was capable of inducing AChR antigenic modulation, suggesting its specificity for a pathogenic epitope. Moreover, the recombinant antigen-binding (Fab) fragment of this mAb competed with an anti-MIR mAb, revealing that its antigenic determinant lies in or near the MIR. Finally, Fab170 was able to compete with MG autoantibodies and protect the AChR against antigenic modulation induced by MG sera. This approach will be useful for isolating additional mAb with therapeutic potential against the other AChR subunits.     

Broad and Potent Neutralizing Antibodies Recognize the Silent Face of the HIV Envelope

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Patient‐individualized CD8+ cytolytic T‐cell therapy effectively combats minimal residual leukemia in immunodeficient mice

Adoptive transfer of donor‐derived cytolytic T‐lymphocytes (CTL) has evolved as a promising strategy to improve graft‐versus‐leukemia (GvL) effects in allogeneic hematopoietic stem‐cell transplantation. However, durable clinical responses are often hampered by limited capability of transferred T cells to establish effective and sustained antitumor immunity in vivo. We therefore analyzed GvL responses of acute myeloid leukemia (AML)‐reactive CD8⁺ CTL with central and effector memory phenotype in a new allogeneic donor‐patient specific humanized mouse model. CTL lines and clones obtained upon stimulation of naive CD45RA⁺ donor CD8⁺ T cells with either single HLA antigen‐mismatched or HLA‐matched primary AML blasts, respectively, elicited strong leukemia reactivity during cytokine‐optimized short to intermediate (i.e., 2–8 weeks) culture periods. Single doses of CTL were intravenously infused into NOD/scidIL2Rcg^null mice when engraftment with patient AML reached bone marrow infiltration of 1–5%, clinically defining minimal residual disease status. This treatment resulted in complete regression of HLA‐mismatched and strong reduction of HLA‐matched AML infiltration, respectively. Most importantly, mice receiving AML‐reactive CTL showed significantly prolonged survival. Transferred CTL were detectable in murine bone marrow and spleen and demonstrated sustained AML‐reactivity ex vivo. Moreover, injections with human IL‐15 clearly promoted CTL persistence. In summary, we show that naive donor‐derived CD8⁺ CTL effectively combat patient AML blasts in immunodeficient mice. The donor‐patient specific humanized mouse model appears suitable to evaluate therapeutic efficacy of AML‐reactive CTL before adoptive transfer into patients. It may further help to identify powerful leukemia rejection antigens and T‐cell receptors for redirecting immunity to leukemias even in a patient‐individualized manner.