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1. chinaXiv:202104.00020 [pdf]

Bacterial and viral therapies of cancer background, mechanism and perspective

董庆霖
Subjects: Medicine, Pharmacy >> Preclinical Medicine

Bacterial and viral therapies of cancer are highly promising, yet their mechanisms are incompletely understood, hindering their improvement and application. In this paper, We (1) review briefly the genesis and progress of bacterial and viral therapies of cancer, (2) compare and evaluate the proposed mechanisms of bacterial and viral therapies and present the unifying mechanism that bacterial and viral therapies of cancer mainly take advantage of the immune response of cancer cells to bacteria and viruses and the ability of host immune system to recognize and eliminate the responsive cancer cells, and (3) provide a perspective on the exploitation of non-human and non-animal bacteria and viruses, particularly protist-infecting bacteria and viruses and bacterial virus (bacteriophage), for cancer therapy.

submitted time 2021-04-06 Hits147Downloads62 Comment 0

2. chinaXiv:202103.00122 [pdf]

应用改良No-touch技术建立兔颈总动脉-颈外静脉内瘘模型

刘振; 王晓禾; 王加英; 张元元; 侯国存
Subjects: Medicine, Pharmacy >> Preclinical Medicine

目的 探索应用改良No-touch技术建立兔颈总动脉-颈外静脉内瘘模型的可能性。 方法 2021年02月08日至2021年02月22日,将10只雄性新西兰兔随机等分为实验组与假手术组。实验组在内瘘手术时不剥离静脉周围组织,即改良No-touch技术处理颈外静脉,建立颈总动脉-颈外静脉内瘘。假手术组探查到血管后不吻合血管。术后14 d使用CDU评估内瘘血管内径及血流频谱变化、苏木精 - 伊红(H-E)染色观察动静脉内瘘建立后内膜增生情况,并取兔颈外静脉血行血气分析。 结果 实验组兔均顺利成功完成动静脉内瘘手术,成功率100%。术后14 d CDU评估结果显示实验组兔颈外静脉较假手术组明显扩张(P=0.016)、收缩期峰值流速(PSV)明显增加(P=0.015)。在实验组兔内瘘动脉及流出道静脉观察到“双向血流”频谱,提示血流为螺旋层流。H-E染色结果显示,实验组兔颈外静脉内弹力膜破坏、内膜厚度较假手术组明显增加(P<0.001)。实验组兔颈外静脉血PO2较假手术组明显升高(P=0.006)。结论 应用改良No-touch技术可成功建立兔颈总动脉-颈外静脉内瘘,成功率高,重复性好,为进一步研究改良No-touch技术在动静脉内瘘手术中的应用提供理想的动物模型。

submitted time 2021-03-09 Hits576Downloads174 Comment 0

4. chinaXiv:202101.00036 [pdf]

Targeting pan-tumor antigens to activating Fcγ receptors generates a novel dendritic cell tumor vaccine

Sheng, Hui; Wnag, Pan; Zhang, Guoxiu; Zhang, Xiao; Li, Zhongjun; Zhao, Zhihui
Subjects: Medicine, Pharmacy >> Preclinical Medicine

Objective: Therapeutic tumor vaccines are eagerly awaited in clinic by patients with high expectations; however, very few clinically successful tumor vaccine has been developed thus far, and there remains no consensus on the generation of tumor vaccines. We hypothesized that targeted delivery of pan-tumor antigens instead of individual tumor-associated antigen (TAA) to dendritic cells via the activating receptor endocytic pathway (AREP) would provide an alternative avenue to develop potent personalized tumor vaccines. Methods: We first prepared biotin-tagged tumor antigens (B-TAgs) with mouse CT26. WT colorectal cancer cells by exploiting metabolic glycan labeling and bioorthogonal reaction methods; then, we prepared a bifunctional fusion protein containing streptavidin and a mouse IgG2a Fc fragment (SA-Fc), in which streptavidin was used for conjugation with B-TAgs, and Fc for mediating the interaction with the Fcγ receptor. Finally, conjugates (Fc-TAgs) of SA-Fc with B-TAgs were prepared based on affinity-guided noncovalent reaction. The phenotype of Fc-TAgs pulsed bone marrow-derived dendritic cells (BMDCs) was examined by flow cytometry. The therapeutic effects of Fc-TAgs pulsed BMDCs were observed in an established mouse CT26. WT colorectal cancer model. Results: The prepared B-TAgs covers almost all glycosylated tumor antigens. SA-Fc fusion protein exhibits biotin-binding activity as a homodimer. SA-Fc can effectively conjugate with B-TAg at a mixing ratio of 1:96 (w/w). Data of flow cytometry revealed that on Fc-TAgs pulsed BMDCs, the expression levels of surface molecules, such as CD80 and MHC II, were greatly increased. In the established murine colorectal cancer model, combination treatments with Fc-TAgs pulsed BMDCs and PD-1 blockade achieved significant therapeutic effects. Limitations: The strategy we proposed for the preparation of personalized tumor vaccine requires that the tumor be surgically removed from the patient. The rationality and validity of this strategy need to be proven by more preclinical investigations. Conclusions: The novel strategy we proposed circumvents the necessities for neoantigen prediction and provides an alternative pathway to establish a flexible system for the preparation of personalized dendritic cell tumor vaccines. In the setting of checkpoint blockade-based immunotherapy, a novel DCV would improve antitumor immunity and benefit the eradication of tumor residues within the body of the cancer patients.

submitted time 2021-01-07 Hits2782Downloads456 Comment 0

5. chinaXiv:202011.00119 [pdf]

模型引导下免疫检查点抑制剂的研发

郑冠濠; 王琛瑀; 焦正
Subjects: Medicine, Pharmacy >> Pharmacology

免疫检查点抑制剂类药物作为一种新型的抗肿瘤治疗手段,以其对多种肿瘤卓越的疗效及良好的安全性得到广泛认可。基于定量药理学的发展应运而生的模型引导的药物研发(Model-informed Drug Development, MIDD),能加速新药临床试验的进程,提高新药研究过程中决策的正确率,尤其是对研发难度较大而需求甚广的免疫检查点抑制剂类新药取得了成功。本文主要以帕博利珠单抗为例,阐述MIDD方法在免疫检查点抑制剂研发过程中的具体应用,包括研发早期有效给药方案的拟定,研发晚期评估临床疗效和验证给药方案的可行性,再至上市后给药方案的再评估及变更,为MIDD指导抗肿瘤新药的研发提供参考。

submitted time 2020-11-24 Hits2807Downloads430 Comment 0

6. chinaXiv:201907.00014 [pdf]

Remedial dosing recommendations for delayed or missed doses of valproic acid in patients with epilepsy based on Monte Carlo simulations

Chenyu,Wang; Jun-jie Ding; Zheng Jiao; Er-qian Yu; Guo-xing Zhu
Subjects: Medicine, Pharmacy >> Clinical Medicine

Objective: Delayed or missed doses are unavoidable in the pharmacotherapy of epilepsy and significantly compromise the efficacy of antiepileptic drug treatment. An inappropriate remedial regimen can cause seizure relapse or serious adverse events. This study investigated the effect of delayed or missed doses on the pharmacokinetics (PK) of valproic acid (VPA) in patients with epilepsy and established remedial dosing recommendations for nonadherent patients. Methods: Monte Carlo simulations are based on all previous population pharmacokinetic models for pediatric, adult and elderly patients with epilepsy. The following four remedial strategies were investigated for each delayed dose: A) A partial dose or a regular dose is taken immediately; a regular dose is taken at the next scheduled time. B) The delayed dose was administered immediately, followed by a partial dose at the next scheduled time. C) The delayed dose and a partial dose are taken; the next scheduled time is skipped, and the regular regimen is resumed. D) Double doses are taken when missed one dose or two doses, and the regular regimen at the subsequent scheduled time is resumed. Results: The recommended remedial dose was related to the delay duration and daily dose. Remedial dosing strategies A and B were almost equivalent, whereas Strategy C was recommended when the delayed dose was close to the next scheduled dose. Strategy D was only suggested for delayed two doses. Conclusion: Simulations provide quantitative insight into the remedial regimens for nonadherent patients, and clinicians should select the optimal regimen for each patient based on the individual's status.

submitted time 2020-09-07 Hits30557Downloads1502 Comment 1

7. chinaXiv:202007.00041 [pdf]

BRAF mutation predicts survival after immunotherapy across multiple cancer types

Ge, Weiting; Cai, Wen; Wu, Dehao; Hu, Wangxiong; Han, Weidong; Zheng, Shu; Hu, hanguang
Subjects: Medicine, Pharmacy >> Clinical Medicine

Recently studies in selected tumors suggested that BRAF mutation may associates with survival benefit from immune checkpoint inhibitor (ICI) therapy. To broadly investigate this association at a pan-cancer level, we analyzed two independent ICI treatment cohorts (MSKCC: n = 1630, and Dana-Farber: n = 249). BRAF-mutant patients exhibit better overall survival in the MSKCC cohort (Hazard ratio [HR] = 0.55, 95% confidence interval [CI]: 0.43-0.72; P <.001) and the result is validated by the Dana-Farber cohort (HR = 0.68, 95% CI: 0.46-0.99; P = .045). A multivariate analysis adjusting tumor mutational burden, mismatch repair status, cancer type, age and sex confirmed the results (adjusted HR = 0.58, 95% CI = 0.43-0.78; P < .001). Immunogenomic features analysis of TCGA dataset indicated that patients may respond to immunotherapy in various mechanisms. This finding substantially improve the therapeutic prospects for a sizeable fraction of patients who benefit from immunotherapy.

submitted time 2020-07-21 Hits9042Downloads965 Comment 0

8. chinaXiv:202003.00053 [pdf]

胡蜂毒对类风湿关节炎实验模型具有潜在的治疗作用

Gao, Yuan; Yu, Wanxin; Duan, Xiaomei; Ni, Lianli; Liu, Heng; Zhao, Hairong; Xiao, huai; Zhang, Chenggui; Yang, Zhibin
Subjects: Medicine, Pharmacy >> Traditional Chinese Medicine and Chinese Materia Medica

类风湿关节炎(RA)是一种自身免疫性疾病。胡蜂毒被认为是云南景颇族的一种传统民间药物,具有治疗类风湿性关节炎的作用。本研究旨在探讨胡蜂毒对实验性大鼠类风湿性关节炎的改善作用。我们建立了II型胶原(CII)诱导的SD大鼠关节炎(CIA)模型,并检测了炎症抑制作用和自身免疫反应。通过对患肢的肿胀、组织病理学评分及组织病理学改变来评价胡蜂毒(WV)的抗关节炎作用。检测了IL-6、TNF-α和IL-1β的表达水平以及外周血中炎症细胞的数量来。采用流式细胞术检测大鼠脾脏T细胞亚群比例的变化,同时测定脏器指数和免疫血清球蛋白水平。结果表明,不同剂量的WV(0.125、0.25、0.5 mg/kg)对CIA大鼠足肿胀和关节炎评分有显著的缓解作用(P < 0.05)。WV(0.25、0.5 mg/kg)能减轻大鼠踝关节滑膜组织病变,滑膜细胞增生、炎性细胞浸润的组织病理学评分(P < 0.05)。在免疫调节方面,0.5 mg/kg WV可降低免疫血清球蛋白水平(P < 0.05),我们进一步发现,0.5 mg/kg的WV可抑制Th细胞的免疫应答,同时显著增强脾脏细胞中Tc细胞和Treg细胞的功能(P < 0.05)。WV的免疫抑制作用类似于其对大鼠血清中IL-1β、TNF-α、IL-8、IL-6、cox-2和PGE2水平的抑制。综上所述,这些发现表明WV具有抗关节炎的活性,这可能与它们对免疫的调节和抗炎作用有关。

submitted time 2020-05-05 Hits24038Downloads1792 Comment 0

9. chinaXiv:202003.00057 [pdf]

Restoration of brain consciousness ex vivo after circulatory death in pigs

Guo,Zhiyong; Sun,Chengjun; Xu,Guixing; Yin,Meixian; Zhu,Caihui; Zheng,Donghua; Zhang,Yixi; Wang,Linhe; Xie,Rongxing; Zhang,Zhiheng; Gao,Ningxin; Huang,Shanzhou; Yu,Ping; He,Shujiao; Zhao,Qiang; He,Xiaoshun
Subjects: Biology >> Neurobiology

在临床实践中,大脑在心脏停跳数分钟后会出现不可逆的损伤,如果30分钟后患者仍未能成功复苏,将被宣布临床死亡。最新研究显示,在心脏停跳后数小时后,猪的大脑细胞功能仍可在体外得到恢复。然而,在离体状态下意识能否恢复尚不清楚。本研究中,我们建立了用于循环停止后大脑体外复苏的常温机械灌注技术。我们发现大脑单独灌注即能维持大脑循环、细胞结构、代谢活动和脑干功能,但不能恢复大脑意识。而在肝脏的支持下,大脑整体的电活动和意识得以恢复,大脑功能至少可以维持22小时。该技术能够使热缺血50分钟的大脑恢复意识。研究结果表明,肝脏辅助下的大脑常温机械灌注技术可以在循环停止较长时间内恢复和维持大脑的意识。

submitted time 2020-03-23 Hits18460Downloads2282 Comment 0

10. chinaXiv:202003.00054 [pdf]

基于GEO数据库探究RACGAP1表达与膀胱癌患者临床病理和预后的关系.doc

张文杰; 熊巧华; 陈思超; 朱家永; 张冉; 翁鸿; 曾宪涛
Subjects: Medicine, Pharmacy >> Clinical Medicine

[目的] 探究Rac GTP酶活性蛋白1(RACGAP1)基因在膀胱癌组织中的表达情况及临床意义。 [方法] 从NCBI的基因表达汇编(GEO)数据库下载膀胱癌组织RACGAP1的表达数据和临床病理参数。分析RACGAP1基因在膀胱癌组织与正常组织中的表达差异,结合随访信息使用SPSS软件对RACGAP1表达与临床病理特征进行卡方检验,采用Kaplan-Meier法进行生存分析,并利用基因富集分析(GSEA)法分析受RACGAP1调控的相关基因。 [结果] RACGAP1在正常膀胱组织中的表达水平为7.557±0.020,低于膀胱癌组织的7.790±0.028,差异有统计学意义(P<0.05)。膀胱癌组织中RACGAP1表达水平与年龄、侵袭性、T分期、N分期、疾病分级和复发有关(P<0.05)。RACGAP1低表达组和高表达组的5年总生存率分别为73.9%和56.6%(HR=0.47,95%CI:0.29-0.77,P<0.01),肿瘤5年特异生存率分别为91.6%和70.9%(HR=0.33,95%CI:0.17-0.67,P<0.01)。RACGAP1高表达样本富集了MYC信号通路、精子发生、未折叠蛋白反应、G2M检查点、E2F转录因子、MTORC1信号、有丝分裂纺锤体、PI3K/AKT/mTOR途径和DNA修复修复相关的基因集。 [结论] RACGAP1在膀胱癌组织中高表达,与膀胱癌患者的临床病理及预后显著相关,可作为反映膀胱癌患者预后的生物学标志物和潜在的膀胱癌防治靶点。

submitted time 2020-03-16 Hits13652Downloads1548 Comment 0

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