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1. 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 Hits13Downloads5 Comment 0

2. 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 Hits23128Downloads1002 Comment 1

3. 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 Hits5471Downloads457 Comment 0

4. 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 Hits20029Downloads1308 Comment 0

5. 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 Hits14711Downloads1733 Comment 0

6. 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 Hits10756Downloads1076 Comment 0

7. chinaXiv:202003.00008 [pdf]

Germline Polymorphisms and Length of Survival of Nasopharyngeal Carcinoma: An Exome-Wide Association Study in Multiple Cohorts

Yun-Miao Guo; Jie-Rong Chen; Yan-Chun Feng; Chua, Melvin L. K. ; Zeng, Yanni ; Edwin Pun Hui; Allen K. C. Chan; Lin-Quan Tang; Lin Wang; Qian Cui; Hui-Qiong Han; Chun-Ling Luo; Guo-Wang Lin; Yan Liang; Yang Liu; Zhong-Lian He; Yu-Xiang Liu; Pan-Pan Wei; Chu-Jun Liu; Wan Peng
Subjects: Medicine, Pharmacy >> Clinical Medicine

Germline polymorphisms have been linked with differential survival outcomes in cancers but have not been well studied in nasopharyngeal carcinoma (NPC). Here, two-phase association study is conducted to discover germline polymorphisms that are associated with the prognosis of NPC. The discovery phase includes two consecutive hospital cohorts of patients with NPC from Southern China. Exome-wide genotypes at 246,173 single nucleotide polymorphisms (SNPs) are determined, followed by survival analysis for each SNP under Cox proportional hazards regression model. Candidate SNP is replicated in another two independent cohorts from Southern China and Singapore. Meta-analysis of all samples (n = 5,553) confirm that the presence of rs1131636-T, located in the 3′-UTR of RPA1, confers an inferior overall survival (HR = 1.33, 95% CI = 1.20-1.47, P = 6.31 × 10-8). Bioinformatics and biological assays show that rs1131636 has regulatory effects on upstream RPA1. Functional studies further demonstrate that RPA1 promoted the growth, invasion, migration, and radioresistance of NPC cells. Additionally, miR-1253 has been identified as a suppressor for RPA1 expression, likely through regulation of its binding affinity to rs1131636 locus. Collectively, these findings provide a promising biomarker aiding in stratifying patients with poor survival, as well as a potential drug target for NPC.

submitted time 2020-03-06 Hits24507Downloads1460 Comment 0

8. chinaXiv:202003.00026 [pdf]

Effective Treatment of Severe COVID-19 Patients with Tocilizumab

Xu, Xiaoling; Han, Mingfeng; Li, Tiantian; Sun, Wei; Wang, Dongsheng; Fu, Binqing; Zhou, Yonggang; Zheng, Xiaohu; Yang, Yun; Li, Xiuyong; Zhang, Xiaohua; Pan, Aijun; Wei, Haiming
Subjects: Medicine, Pharmacy >> Clinical Medicine

Background: In December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified in Wuhan, China, which spread rapidly and has become a world-wide public health challenge. We aimed to assess the efficacy of tocilizumab in severe patients with Corona Virus Disease-19 (COVID-19) and seek a new therapeutic strategy. Methods: The patients diagnosed as severe or critical COVID-19 in The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital) and Anhui Fuyang Second People’s Hospital were given tocilizumab in addition to routine therapy between February 5 and February 14, 2020. The changes of clinical manifestations, CT scan image, and laboratory examinations were retrospectively analyzed. Findings: Within a few days, the fever returned to normal and all other symptoms improved remarkably. Fifteen of the 20 patients (75.0%) had lowered their oxygen intake and one patient need no oxygen therapy. CT scans manifested that the lung lesion opacity absorbed in 19 patients (90.5%). The percentage of lymphocytes in peripheral blood, which decreased in 85.0% patients (17/20) before treatment (mean, 15.52 ± 8.89%), returned to normal in 52.6% patients (10/19) on the fifth day after treatment. Abnormally elevated C-reactive protein decreased significantly in 84.2% patients (16/19). No obvious adverse reactions were observed. Nineteen patients (90.5%) have been discharged on average 13.5 days after the treatment with tocilizumab and the rest are recovering well. Interpretation: Tocilizumab is an effective treatment in severe patients of COVID-19, which provided a new therapeutic strategy for this fatal infectious disease.

submitted time 2020-03-05 Hits151273Downloads47958 Comment 0

9. chinaXiv:202003.00003 [pdf]

COVID-19 outbreak increased risk of schizophrenia in aged adults

Hu, Wei; Su, Li; Qiao, Juan; Zhu, Jing; Zhou, Yi
Subjects: Psychology >> Clinical and Counseling Psychology

We noticed an unusual increase of first-time patients with schizophrenia (F20) in January 2020 since the outbreak of COVID-19. The aim of this retrospective study is to validate this observation and find potential risk factors, if applicable. A total number of 13,783 records from outpatients in January 2020 were investigated thoroughly. Comparisons between incidence of schizophrenia in outpatients in January 2020 and similar periods of 2017-2019 were made to minimize seasonal influence. Relationship of incidence of schizophrenia and COVID-19 infections in China was calculated. Limited personal information (age, gender, approximate residence) was analyzed to find risk factors.After excluding seasonal factors such as Spring festival, a positive relationship between incidence of schizophrenia in first-time patients and countrywide epidemic situation was found. Statistical results further showed a significant increase of median age from 39 to 50 for first-time patients diagnosed with schizophrenia which is unusual. Meanwhile, a slight but not significant change was found in distribution of gender and approximate residence (urban/suburb). Our data supported that COVID-19 outbreak increased risk of schizophrenia in aged adults which is consistent with the fact that COVID-19 is more lethal to elders. We strongly appeal that public healthcare in countries either with or without infected patients should prepare in advance for potential risks in public mental health.

submitted time 2020-02-29 Hits31263Downloads3969 Comment 0

10. chinaXiv:202002.00078 [pdf]

Confirmed asymptomatic carrier of SARS-CoV-2

Luo, Sihui; Liu, Wei; Liu, Zhenjun; Zheng, Xueying; Ling, Ping; Ding, Yu; Hong, Changxing; Liu, Zhirong; Liu, Jian; Weng, Jianping
Subjects: Medicine, Pharmacy >> Clinical Medicine

Here we reported a case of asymptomatic carrier of SARS-CoV-2 infection. A 50-year old woman, lived with her husband in Anqing(Anhui, China) with no significant past medical history, travel history to Wuhan or adjacent area, or exposure to wild animals. She took throat swab test for SARS-CoV-2 nucleic acid due to her husband’s close contact with patients who had SARS-CoV-2 infection. Her results were confirmed positive on February 6, 2020. But she did not report elevation of temperature measurement, nor respiratory or gastrointestinal symptoms and her chest CT scan showed no significant abnormalities. She was hospitalized on February 6 and treated with antiviral agents. During her hospitalization, apart from a mild elevation of liver enzymes after 10-day treatment of lopinavir/ritonavir, she was asymptomatic, with her blood cell count, live and renal function largely normal. Her subcutaneous oxygen saturation stayed above 97%. Chest CT scan was repeated on February 11 and 20, and both were negative for signs of viral pneumonia. Notably, a second set of throat swabs and anal swabs were sent to test for SARS-CoV-2 on February 19, and the results were still confirmed positive. This is a confirmed case of asymptomatic carrier of SARS-CoV-2 infection. Her persistent positive findings in both throat and anal swabs suggested the possibility of healthy carrier of the virus, which adds to the difficulty in preventing transmission of the disease.

submitted time 2020-02-28 Hits25935Downloads2907 Comment 0

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