Pharmacological research最新文献_第6页

Impact of Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and other antidiabetic agents in Alzheimer’s disease 通讯：钠-葡萄糖共转运体 2 抑制剂（SGLT2i）和其他抗糖尿病药物在阿尔茨海默病中的应用。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-10-18 DOI: 10.1016/j.phrs.2024.107473

Ju-Ching Yen , Jia-Yu Lai , Chi-Ya Yang, Su-Boon Yong, Chin-Yuan Yii

引用次数: 0

Targeted and cytotoxic inhibitors used in the treatment of lung cancers 用于治疗肺癌的靶向和细胞毒性抑制剂。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-10-18 DOI: 10.1016/j.phrs.2024.107465

Robert Roskoski Jr.

Lung cancer is the leading cause of cancer deaths in the United States and the world. It is divided into two major types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). In the tumor-node-metastasis (TNM) cancer-staging classification system (Stages I/II/III/IV), the severity of neoplastic growth is characterized by the size of the tumor (T1 to T4), the extent of lymph node involvement (N0 to N3), and whether (M1) or not (M0) distant metastasis has occurred. Surgery is the treatment of choice for medically fit patients with Stage I/II NSCLC. Combination chemoradiotherapy and immune checkpoint inhibitor therapy are used across all NSCLC types. Oncogene-addicted tumors with sensitizing EGFR or BRAF mutations or activating ALK, ROS1 or NTRK translocations are treated with their cognate orally active small molecule protein kinase blockers. On the order of 20 % of NSCLCs bear activating mutations in EGFR and are treated with osimertinib and other kinase antagonists. SCLC, which accounts for approximately 15 % of lung cancer cases, is a deadly high-grade neuroendocrine carcinoma with a poor prognosis. Limited-stage SCLC is confined to one hemi-thorax and one radiation port and extensive-stage disease signifies those cancers that do not meet the criteria for limited-stage disease. Local treatment options to control thoracic disease include radiotherapy and surgery. In patients with extensive-stage disease, a platinum agent (cisplatin or carboplatin) combined with etoposide and an anti-PDL1 inhibitor (atezolizumab or durvalumab) for four cycles followed by anti-PDL1 maintenance therapy is the recommended first-line regimen.

肺癌是美国乃至全世界癌症死亡的主要原因。它分为两大类型：小细胞肺癌（SCLC）和非小细胞肺癌（NSCLC）。在肿瘤-结节-转移（TNM）癌症分期分类系统（I/II/III/IV 期）中，肿瘤生长的严重程度取决于肿瘤的大小（T1 至 T4）、淋巴结受累的程度（N0 至 N3）以及是否发生（M1）远处转移（M0）。手术是I/II期NSCLC患者的首选治疗方法。化放疗和免疫检查点抑制剂联合疗法适用于所有NSCLC类型。对于具有敏化表皮生长因子受体（EGFR）或BRAF突变或活化ALK、ROS1或NTRK易位的癌基因上瘾肿瘤，可使用与其同源的口服活性小分子蛋白激酶阻断剂进行治疗。约有 20% 的 NSCLC 存在表皮生长因子受体（EGFR）激活突变，可使用奥希替尼和其他激酶拮抗剂进行治疗。SCLC约占肺癌病例的15%，是一种致命的高级别神经内分泌癌，预后较差。局限期SCLC局限于一个半胸腔和一个放射口，广泛期疾病指的是那些不符合局限期疾病标准的癌症。控制胸部疾病的局部治疗方案包括放疗和手术。对于广泛期患者，推荐的一线治疗方案是铂类药物（顺铂或卡铂）联合依托泊苷和抗PDL1抑制剂（atezolizumab或durvalumab）治疗四个周期，然后进行抗PDL1维持治疗。

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引用次数: 0

Therapeutic peptides in the treatment of digestive inflammation: Current advances and future prospects 治疗消化道炎症的治疗肽：当前进展与未来展望》。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-10-17 DOI: 10.1016/j.phrs.2024.107461

Liangliang He , Aijing Li , Ping Yu , Shumin Qin , Hor-Yue Tan , Denglang Zou , Haomeng Wu , Shuai Wang

Digestive inflammation is a widespread global issue that significantly impacts quality of life. Recent advances have highlighted the unique potential of therapeutic peptides for treating this condition, owing to their specific bioactivity and high specificity. By specifically targeting key proteins involved in the pathological process and modulating biomolecular functions, therapeutic peptides offer a novel and promising approach to managing digestive inflammation. This review explores the development history, pharmacological characteristics, clinical applications, and regulatory mechanisms of therapeutic peptides in treating digestive inflammation. Additionally, the review addresses pharmacokinetics and quality control methods of therapeutic peptides, focusing on challenges such as low bioavailability, poor stability, and difficulties in delivery. The role of modern biotechnologies and nanotechnologies in overcoming these challenges is also examined. Finally, future directions for therapeutic peptides and their potential impact on clinical applications are discussed, with emphasis placed on their significant role in advancing medical and therapeutic practices.

消化系统炎症是一个普遍的全球性问题，严重影响着人们的生活质量。由于治疗肽具有特定的生物活性和高度特异性，最近的研究进展凸显了治疗肽在治疗这种疾病方面的独特潜力。通过特异性地靶向参与病理过程的关键蛋白并调节生物分子功能，治疗肽为控制消化系统炎症提供了一种新颖且前景广阔的方法。本综述探讨了治疗肽在治疗消化系统炎症方面的发展历史、药理特性、临床应用和调节机制。此外，综述还探讨了治疗肽的药代动力学和质量控制方法，重点关注生物利用度低、稳定性差和给药困难等挑战。还探讨了现代生物技术和纳米技术在克服这些挑战方面的作用。最后，还讨论了治疗肽的未来发展方向及其对临床应用的潜在影响，重点是其在推动医疗和治疗实践中的重要作用。

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引用次数: 0

The PINK1/Parkin signaling pathway-mediated mitophagy: a forgotten protagonist in myocardial ischemia/reperfusion injury PINK1/Parkin信号通路介导的有丝分裂：心肌缺血/再灌注损伤中被遗忘的主角。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-10-15 DOI: 10.1016/j.phrs.2024.107466

Xiaopeng Zhao , Zheng Wang , Lijie Wang , Tao Jiang , Dan Dong , Mingli Sun

Myocardial ischemia causes extensive damage, further exacerbated by reperfusion, a phenomenon called myocardial ischemia/reperfusion injury (MIRI). Nowadays, the pathological mechanisms of MIRI have received extensive attention. Oxidative stress, multiple programmed cell deaths, inflammation and others are all essential pathological mechanisms contributing to MIRI. Mitochondria are the energy supply centers of cells. Numerous studies have found that abnormal mitochondrial function is an essential "culprit" of MIRI, and mitophagy mediated by the phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1)/Parkin signaling pathway is an integral part of maintaining mitochondrial function. Therefore, exploring the association between the PINK1/Parkin signaling pathway-mediated mitophagy and MIRI is crucial. This review will mainly summarize the crucial role of the PINK1/Parkin signaling pathway-mediated mitophagy in MIR-induced several pathological mechanisms and various potential interventions that affect the PINK1/Parkin signaling pathway-mediated mitophagy, thus ameliorating MIRI.

心肌缺血会造成广泛的损伤，再灌注又会进一步加剧这种损伤，这种现象被称为心肌缺血再灌注损伤（MIRI）。如今，心肌缺血再灌注损伤的病理机制已受到广泛关注。氧化应激、多种程序性细胞死亡、炎症等都是导致 MIRI 的重要病理机制。线粒体是细胞的能量供应中心。大量研究发现，线粒体功能异常是导致 MIRI 的重要 "元凶"，而由磷酸酶和天丝同源物（PTEN）诱导激酶 1（PINK1）/Parkin 信号通路介导的线粒体吞噬作用是维持线粒体功能不可或缺的一部分。因此，探索 PINK1/Parkin 信号通路介导的有丝分裂与 MIRI 之间的关联至关重要。本综述将主要总结 PINK1/Parkin 信号通路介导的有丝分裂在 MIR 诱导的几种病理机制中的关键作用，以及影响 PINK1/Parkin 信号通路介导的有丝分裂从而改善 MIRI 的各种潜在干预措施。

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引用次数: 0

Ex vivo fluorescence-guided resection margin assessment in breast cancer surgery using a topically applied, cathepsin-activatable imaging agent 在乳腺癌手术中使用一种局部涂抹的可激活酪蛋白酶的成像剂，进行体内外荧光引导的切除边缘评估

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-10-12 DOI: 10.1016/j.phrs.2024.107464

Daan G.J. Linders , Okker D. Bijlstra , Ethan Walker , Taryn L. March , Martin Pool , A. Rob P.M. Valentijn , Tom H. Dijkhuis , Jikke N. Woltering , Floor R. Pijl , Gilbert Noordam , Davey van den Burg , Joost R.M. van der Sijp , Onno R. Guicherit , Andreas W.K.S. Marinelli , Jacobus Burggraaf , Robert Rissmann , Matthew Bogyo , Denise E. Hilling , Peter J.K. Kuppen , Brian Straight , Alexander L. Vahrmeijer

Up to 40 % of breast cancer patients have a tumor-positive resection margin (TPRM) – defined as cancer cells at the surface of the resected specimen – after breast-conserving surgery (BCS), necessitating re-resection or boost radiation. To prevent these additional treatments, intraoperative near-infrared (NIR) fluorescence imaging with the topically applied, cathepsin-activatable imaging agent AKRO-6qcICG might be used to detect TPRMs and guide additional resection. Here, to validate its performance, the agent is topically applied to all surfaces of freshly resected breast cancer specimens (n = 11 patients) and to 3–5 mm thick tissue slices of the specimens (n = 26 patients). NIR fluorescence images of the resection surfaces and tissue slices are acquired and correlated to final histopathology. AKRO-6qcICG detects TPRMs with a sensitivity, specificity, PVV, and NPV of 100 %, 67 %, 10 %, and 100 %, respectively. On the tissue slices, the fluorescence signal has a median tumor-to-background ratio of 1.8. These findings indicate that topically applied AKRO-6qcICG can visualize TPRMs ex vivo with a high sensitivity and NPV, with sufficient contrast to adjacent healthy breast tissue.

多达 40% 的乳腺癌患者在接受保乳手术（BCS）后会出现肿瘤阳性切除边缘（TPRM）--即切除标本表面的癌细胞--从而需要再次切除或加强放射治疗。为了避免这些额外的治疗，术中使用局部涂抹的可激活酪蛋白酶的成像剂 AKRO-6qcICG 进行近红外（NIR）荧光成像可用于检测 TPRM 并指导额外的切除手术。在此，为了验证该成像剂的性能，将其局部应用于新鲜切除的乳腺癌标本（n = 11 例患者）的所有表面和 3-5 毫米厚的标本组织切片（n = 26 例患者）。采集切除表面和组织切片的近红外荧光图像，并将其与最终组织病理学相关联。AKRO-6qcICG 检测 TPRM 的灵敏度、特异性、PVV 和 NPV 分别为 100%、67%、10% 和 100%。在组织切片上，荧光信号的肿瘤与背景比中位数为 1.8。这些研究结果表明，局部应用 AKRO-6qcICG 可以在体内以较高的灵敏度和 NPV 显示 TPRM，并与邻近的健康乳腺组织形成足够的对比。

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引用次数: 0

Excessive alcohol intake produces persistent mechanical allodynia and dysregulates the endocannabinoid system in the lumbar dorsal root ganglia of genetically-selected Marchigian Sardinian alcohol-preferring rats 过量摄入酒精会产生持续性机械异感，并使经过基因筛选的马氏撒丁岛酒精偏好大鼠腰部背根神经节的内源性大麻素系统失调

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-10-11 DOI: 10.1016/j.phrs.2024.107462

Vittoria Borgonetti , Valentina Vozella , Tim Ware , Bryan Cruz , Ryan Bullard , Benjamin F. Cravatt , Nicoletta Galeotti , Marisa Roberto

Epidemiological data indicate a strong association between alcohol use disorder (AUD) and neuropathic pain. Genetically-selected Marchigian Sardinian alcohol-preferring (msP) rats exhibit a high preference for alcohol compared with their background strain (Wistar rats), but their sensitivity to mechanical allodynia after chronic alcohol exposure is unknown. The present study compared the development of mechanical allodynia between “low, non-pathological drinker” Wistar rats and “high drinker” msP rats using the two-bottle choice (2BC) free-access procedure. Several studies reported the involvement of endocannabinoids (eCBs) in modulating mechanical allodynia, but there are no data on their role in alcohol-related allodynia. Thus, the present study assessed eCBs and their related lipid species in lumbar dorsal root ganglia (DRG) and correlated them with mechanical allodynia in our model. We found that male and female msP rats developed persistent mechanical allodynia during protracted abstinence from alcohol, presenting no sign of recovery, as opposed to Wistar rats. This effect directly correlated with their total alcohol intake. Notably, we found a correlation between lower lumbar DRG 2-arachidonoylglycerol (2-AG) levels and the development of higher mechanical allodynia during abstinence in msP rats of both sexes but not in Wistar rats. Moreover, alcohol-exposed and abstinent msP and Wistar females but not males exhibited significant alterations of thromboxane B2 and prostaglandin E2/prostaglandin D2 compared with naive rats. These findings demonstrate that DRG 2-AG metabolism is altered in msP rats during prolonged abstinence and represents a potentially interesting pharmacological target for the treatment of mechanical allodynia during alcohol abstinence.

流行病学数据表明，酒精使用障碍（AUD）与神经性疼痛之间存在密切联系。与背景品系（Wistar 大鼠）相比，基因选育的 Marchigian Sardinian 酒精偏好（msP）大鼠表现出较高的酒精偏好，但它们在长期接触酒精后对机械异感的敏感性尚不清楚。本研究采用双瓶选择（2BC）自由进入程序，比较了 "低、非病理性饮酒 "Wistar 大鼠和 "高饮酒 "msP 大鼠机械异感的发展情况。有几项研究报告称，内源性大麻素（eCBs）参与了机械痛觉的调节，但目前还没有关于它们在酒精相关痛觉中作用的数据。因此，本研究评估了腰椎背根神经节（DRG）中的 eCBs 及其相关脂质种类，并将它们与我们模型中的机械痛觉相关联。我们发现，与 Wistar 大鼠相比，雄性和雌性 msP 大鼠在长期戒酒期间会出现持续性机械痛觉，且没有恢复的迹象。这种效应与它们的酒精总摄入量直接相关。值得注意的是，我们发现雌雄msP大鼠较低的腰椎DRG 2-游离酰甘油（2-AG）水平与戒酒期间较高的机械异感之间存在相关性，而Wistar大鼠则不存在这种相关性。此外，与天真大鼠相比，酒精暴露和禁欲的 msP 和 Wistar 雌性大鼠（而非雄性大鼠）的血栓素 B2 和前列腺素 E2/ 前列腺素 D2 有显著变化。这些研究结果表明，msP大鼠在长期戒酒期间DRG 2-AG代谢会发生改变，这可能是治疗戒酒期间机械性痛觉的一个有趣的药理学靶点。

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引用次数: 0

Baseline gut microbiome as a predictive biomarker of response to probiotic adjuvant treatment in gout management 基线肠道微生物组是痛风治疗中益生菌辅助治疗反应的预测性生物标志物

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-10-11 DOI: 10.1016/j.phrs.2024.107445

Feiyan Zhao , Ning Tie , Lai-Yu Kwok , Teng Ma , Jing Wang , Dafu Man , Xiangzheng Yuan , Huiyun Li , Lixia Pang , Hui Shi , Shuiming Ren , Zhongjie Yu , Xin Shen , Hongbin Li , Heping Zhang

Gout is characterized by dysregulation of uric acid (UA) metabolism, and the gut microbiota may serve as a regulatory target. This two-month randomized, double-blind, placebo-controlled trial aimed to investigate the additional benefits of coadministering Probio-X alongside febuxostat. A total of 160 patients with gout were randomly assigned to either the probiotic group (n = 120; Probio-X [1 ×10¹¹ CFU/day] with febuxostat) or the placebo group (n = 40; placebo material with febuxostat). Coadministration of Probio-X significantly decreased serum UA levels and the rate of acute gout attacks (P < 0.05). Based on achieving a target sUA level (360 μmol/L) after the intervention, the probiotic group was further subdivided into probiotic-responsive (ProA; n = 54) and probiotic-unresponsive (ProB; n = 66) subgroups. Post-intervention clinical indicators, metagenomic, and metabolomic changes in the ProB and placebo groups were similar, but differed from those in the ProA group, which exhibited significantly lower levels of acute gout attack, gout impact score, serum indicators (UA, XOD, hypoxanthine, and IL-1β), and fecal gene abundances of UA-producing pathways (KEGG orthologs of K13479 and K01487; gut metabolic modules for formate conversion and lactose and galactose degradation). Additionally, the ProA group showed significantly higher levels (P < 0.05) of gut SCFAs-producing bacteria and UA-related metabolites (xanthine, hypoxanthine, bile acids) after the intervention. Finally, we established a gout metagenomic classifier to predict probiotic responsiveness based on subjects’ baseline gut microbiota composition. Our results indicate that probiotic-driven therapeutic responses are highly individual, with the probiotic-responsive cohort benefitting significantly from probiotic coadministration.

痛风的特点是尿酸（UA）代谢失调，而肠道微生物群可能是一个调节靶点。这项为期两个月的随机、双盲、安慰剂对照试验旨在研究在服用非布索坦的同时服用普罗比奥-X的额外益处。共有160名痛风患者被随机分配到益生菌组（n = 120；Probio-X [1 ×1011 CFU/天] 与非布司他）或安慰剂组（n = 40；安慰剂材料与非布司他）。同时服用 Probio-X 可显著降低血清 UA 水平和痛风急性发作率（P < 0.05）。根据干预后达到目标 sUA 水平（360 μmol/L）的情况，益生菌组又进一步细分为益生菌有反应（ProA；n = 54）和益生菌无反应（ProB；n = 66）两组。ProB组和安慰剂组干预后的临床指标、元基因组和代谢组变化相似，但与ProA组不同，ProA组的痛风急性发作水平、痛风影响评分、血清指标（UA、XOD、次黄嘌呤和IL-1β）以及粪便中产生UA通路的基因丰度（KEGG直向同源物K13479和K01487；甲酸盐转化以及乳糖和半乳糖降解的肠道代谢模块）均显著降低。此外，干预后，ProA 组的肠道 SCFAs 产生菌和 UA 相关代谢物（黄嘌呤、次黄嘌呤、胆汁酸）水平明显更高（P < 0.05）。最后，我们建立了痛风元基因组分类器，根据受试者的基线肠道微生物群组成预测益生菌的反应性。我们的研究结果表明，益生菌驱动的治疗反应具有很强的个体差异性，具有益生菌反应的受试者群可从联合服用益生菌中显著获益。

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引用次数: 0

Efficacy of medications for the treatment of alcohol use disorder (AUD): A systematic review and meta-analysis considering baseline AUD severity 药物治疗酒精使用障碍（AUD）的疗效：考虑到基线 AUD 严重程度的系统回顾和荟萃分析

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-10-11 DOI: 10.1016/j.phrs.2024.107454

Roberta Agabio , Hugo Lopez-Pelayo , Pol Bruguera , San-Yuan Huang , Salvatore Sardo , Marta Pecina , Evgeny M. Krupitsky , Garrett M. Fitzmaurice , Zhicheng Lin

Baseline severity of alcohol use disorder (AUD) is an influencing factor in the response to medications recommended for the treatment of AUD. The scarce efficacy of AUD medications partly justifies their limited uses. We were interested in evaluating the efficacy of approved and recommended AUD medications using generic inverse-variance, an analysis facilitating comparison between medications and placebo both at the end of the study and, concomitantly, to baseline values for the same participants. We conducted a systematic review to include randomized controlled trials (RCTs) comparing any medication to placebo providing, both at baseline and end of treatment, percent heavy drinking days (%HDD), percent drinking days (%DD), and/or drinks per drinking day (DDD). We searched PubMed, Embase, PMC, and three CT registers from inception to April 2023. A total of 79 RCTs (11,737 AUD participants; 30 different medications) were included: 47 RCTs (8465 participants) used AUD medications, and 32 RCTs (3272 participants) used other medications. At baseline, participants consumed on average approximately 12 DDD, and experienced 70 % DD, and 61 % HDD. Placebo halved or reduced these values to a third. Compared to placebo, AUD medications further reduced these outcomes (moderate to high certainty evidence). Other medications reduced the DDD without modifying other alcohol outcomes. AUD medications increased the risk of developing adverse events (high-certainty evidence). Despite the large placebo effects, our results support the benefits of providing AUD medications to people with AUD, helping them reduce alcohol consumption.

酒精使用障碍（AUD）的基线严重程度是影响对推荐用于治疗 AUD 的药物反应的一个因素。治疗酒精中毒性障碍的药物疗效甚微，这在一定程度上证明了这些药物的有限使用是合理的。我们有兴趣使用通用逆方差法评估已获批准和推荐的 AUD 药物的疗效，这种分析方法便于在研究结束时比较药物和安慰剂的疗效，同时也便于比较同一参与者的基线值。我们进行了一项系统性回顾，纳入了在基线值和治疗结束值、大量饮酒天数百分比（%HDD）、饮酒天数百分比（%DDD）和/或每日饮酒量（DDD）方面对任何药物和安慰剂进行比较的随机对照试验（RCT）。我们检索了 PubMed、Embase、PMC 和三个 CT 登记册，检索时间从开始到 2023 年 4 月。共纳入了 79 项 RCT（11737 名 AUD 参与者；30 种不同的药物）：其中 47 项 RCT（8465 名参与者）使用了 AUD 药物，32 项 RCT（3272 名参与者）使用了其他药物。基线时，参与者平均消耗约 12 个 DDD，经历了 70% 的 DD 和 61% 的 HDD。安慰剂可将这些值减半或减至三分之一。与安慰剂相比，抗逆转录病毒药物进一步降低了这些结果（中度至高度确证）。其他药物可降低酗酒致死率，但不会改变其他酗酒结果。AUD 药物增加了发生不良事件的风险（高确定性证据）。尽管存在较大的安慰剂效应，但我们的研究结果支持为 AUD 患者提供 AUD 药物治疗，帮助他们减少饮酒量。

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引用次数: 0

Enhanced drug classification using machine learning with multiplexed cardiac contractility assays 利用多路复用心脏收缩力测定的机器学习增强药物分类。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-10-11 DOI: 10.1016/j.phrs.2024.107459

Reza Aghavali, Erin G. Roberts, Yosuke K. Kurokawa, Erica Mak, Martin Y.C. Chan, Andy O.T. Wong, Ronald A. Li, Kevin D. Costa

Cardiac screening of newly discovered drugs remains a longstanding challenge for the pharmaceutical industry. While therapeutic efficacy and cardiotoxicity are evaluated through preclinical biochemical and animal testing, 90 % of lead compounds fail to meet safety and efficacy benchmarks during human clinical trials. A preclinical model more representative of the human cardiac response is needed; heart tissue engineered from human pluripotent stem cell derived cardiomyocytes offers such a platform. In this study, three functionally distinct and independently validated engineered cardiac tissue assays are exposed to increasing concentrations of known compounds representing 5 classes of mechanistic action, creating a robust electrophysiology and contractility dataset. Combining results from six individual models, the resulting ensemble algorithm can classify the mechanistic action of unknown compounds with 86.2 % predictive accuracy. This outperforms single-assay models and offers a strategy to enhance future clinical trial success aligned with the recent FDA Modernization Act 2.0.

新发现药物的心脏筛选仍然是制药业长期面临的挑战。虽然通过临床前生化和动物试验评估了疗效和心脏毒性，但在人体临床试验中，90% 的先导化合物未能达到安全性和疗效基准。我们需要一个更能代表人类心脏反应的临床前模型；由人类多能干细胞衍生的心肌细胞设计的心脏组织提供了这样一个平台。在这项研究中，三种功能各异且经过独立验证的工程化心脏组织试验暴露于代表 5 类机理作用的已知化合物中，浓度不断增加，从而建立了一个强大的电生理学和收缩力数据集。结合六个单独模型的结果，由此产生的集合算法可以对未知化合物的机理作用进行分类，预测准确率高达 86.2%。这一结果优于单个检测模型，为提高未来临床试验的成功率提供了一种策略，与最近颁布的《FDA 现代化法案 2.0》相一致。

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引用次数: 0

The role of Tim-3 blockade in the tumor immune microenvironment beyond T cells 除 T 细胞外，Tim-3 阻断剂在肿瘤免疫微环境中的作用

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-10-11 DOI: 10.1016/j.phrs.2024.107458

Jie Zhang , Longsheng Wang , Hongjie Guo , Shijia Kong , Wen Li , Qiaojun He , Ling Ding , Bo Yang

Numerous preclinical studies have demonstrated the inhibitory function of T cell immunoglobulin mucin domain-containing protein 3 (Tim-3) on T cells as an inhibitory receptor, leading to the clinical development of anti-Tim-3 blocking antibodies. However, recent studies have shown that Tim-3 is expressed not only on T cells but also on multiple cell types in the tumor microenvironment (TME), including dendritic cells (DCs), natural killer (NK) cells, macrophages, and tumor cells. Therefore, Tim-3 blockade in the immune microenvironment not only affect the function of T cells but also influence the functions of other cells. For example, Tim-3 blockade can enhance the ability of DCs to regulate innate and adaptive immunity. The role of Tim-3 blockade in NK cells function is controversial, as it can enhance the antitumor function of NK cells under certain conditions while having the opposite effect in other situations. Additionally, Tim-3 blockade can promote the reversal of macrophage polarization from the M2 phenotype to the M1 phenotype. Furthermore, Tim-3 blockade can inhibit tumor development by suppressing the proliferation and metastasis of tumor cells. In summary, increasing evidence has shown that Tim-3 in other cell types also plays a critical role in the efficacy of anti-Tim-3 therapy. Understanding the function of anti-Tim-3 therapy in non-T cells can help elucidate the diverse responses observed in clinical patients, leading to better development of relevant therapeutic strategies. This review aims to discuss the role of Tim-3 in the TME and emphasize the impact of Tim-3 blockade in the tumor immune microenvironment beyond T cells.

大量临床前研究表明，T细胞免疫球蛋白粘蛋白结构域含蛋白3（Tim-3）在T细胞上具有抑制功能，是一种抑制性受体，从而导致了抗Tim-3阻断抗体的临床开发。然而，最近的研究表明，Tim-3 不仅在 T 细胞上表达，还在肿瘤微环境（TME）中的多种细胞类型上表达，包括树突状细胞（DC）、自然杀伤细胞（NK）、巨噬细胞和肿瘤细胞。因此，在免疫微环境中阻断 Tim-3 不仅会影响 T 细胞的功能，还会影响其他细胞的功能。例如，阻断 Tim-3 可增强 DCs 调节先天性免疫和适应性免疫的能力。Tim-3阻断在NK细胞功能中的作用存在争议，因为它在某些条件下可以增强NK细胞的抗肿瘤功能，而在另一些情况下则会产生相反的效果。此外，阻断 Tim-3 还能促进巨噬细胞从 M2 表型向 M1 表型的极化逆转。此外，阻断 Tim-3 还能抑制肿瘤细胞的增殖和转移，从而抑制肿瘤的发展。总之，越来越多的证据表明，其他细胞类型中的 Tim-3 也在抗 Tim-3 疗法的疗效中发挥着关键作用。了解抗Tim-3疗法在非T细胞中的功能有助于阐明在临床患者中观察到的不同反应，从而更好地开发相关的治疗策略。本综述旨在讨论 Tim-3 在肿瘤微环境中的作用，并强调阻断 Tim-3 对肿瘤免疫微环境中 T 细胞以外的其他细胞的影响。

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