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关键词： Aurora kinase   alisertib   doxorubicin   hepatotoxicity   fibrosis  

摘要： Background/Objectives: Doxorubicin (DOXO) is effective against various types of cancer;however, it is associated with hepatotoxicity that may eventually lead to liver fibrosis, limiting its clinical use. Aurora kinase A (AURKA) has emerged as a crucial regulator of essential cellular processes and a promising target to overcome tumors resistant to some anticancer drugs, including DOXO. However, the potential beneficial effect of targeting AURKA on DOXO-induced toxicities has not been explored yet. Therefore, the current study aimed to explore the potential protective effect of the AURKA-selective inhibitor alisertib on DOXO-induced hepatotoxicity in mice and address the possible underlying mechanism. Methods: Mice were treated with alisertib (10 and 20 mg/kg) daily for five consecutive days and challenged with DOXO (20 mg/kg, i.p.) once on day two. Results: Our findings revealed that alisertib significantly reduced biomarkers of liver dysfunction and oxidative stress elevated by the DOXO challenge. Interestingly, alisertib suppressed DOXO-induced IL-17A upsurge along with NF-kappa B and STAT3 activation. Alisertib also suppressed the upregulated expression of HIF-1 alpha and VEGF-A as well as PERK activation associated with the DOXO challenge. Moreover, alisertib counteracted DOXO-induced TGF-beta 1 and alpha-SMA overexpression in the liver. These beneficial effects of alisertib were further reflected in the histopathological findings, which indicated the ability of alisertib to ameliorate DOXO-induced hepatic necroinflammation and fibrosis. Conclusions: Alisertib mitigates DOXO-induced hepatotoxicity in mice via targeting the IL-17A/NF-kappa B and IL-17A/STAT3/HIF-1 alpha/VEGF-A signaling pathways, attenuating oxidative stress, inflammation, ER stress, and fibrosis.

关键词： neoplasm   breast   inflammation   cytokines   gene expression  

摘要： Chronic inflammation is associated with several neoplasms. Many studies tried to evaluate the correlation between cytokines and the pathogenesis of various cancer types and IL-2, IL-6, IL-10, and TNF-alpha are often target of these analyses. The aim of the present study was to analyze cytokines mRNA expression in breast cancer samples to better understand pathogenesis and clinical aspects. Patients were selected from the oncology service of Centro Universit & aacute;rio FMABC;tumor RNA was obtained from formalin-fixed paraffin-embedded biopsies of breast cancer tissue. Gene expression was assessed by qPCR. Samples from 95 patients were obtained, presenting tumor stages varying from 0 to IIIB, with most of them in stage IIIA (33.68%). IL-2 and TNF-alpha expression presented a significant correlation with tumor stage. There was no correlation of cytokines expression with Ki-67 and prognostic factors. The study illustrated the pleiotropic role of IL-2, with no expression in early stages of cancer, varying according to "stage worsening". Regarding progesterone receptor (PR), correlation with TNF-alpha and IL-2 can reinforce the role of PR as an indicator of positive prognosis. The findings of this investigation suggest IL-2 and TNF-alpha could be evaluated in a larger study to better understanding pathogenesis and prognosis for this patient profile.

关键词： 猪流行性腹泻病毒   仔猪   免疫器官   病理损伤   免疫相关因子   病毒分布  

摘要： 为探究猪流行性腹泻病毒（porcine epidemic diarrhea virus，PEDV）感染对仔猪免疫器官的影响，选取8头5日龄健康仔猪作为研究对象，随机分为对照组（n=4）和PEDV感染组（n=4）。PEDV感染仔猪后观察并记录临床症状，在病毒感染2 d后实施安乐死并采集胸腺、脾、肠系膜淋巴结、髂下淋巴结、腹股沟淋巴结、肩前淋巴结、下颌淋巴结和肺门淋巴结。利用HE染色观察各免疫器官的病理学变化，通过IHC、Western blot和RT-qPCR分别检测病毒在免疫器官的分布、表达量以及肿瘤坏死因子-α（tumor necrosis factor α，TNF-α）、干扰素-β（interferon β，IFN-β）、白细胞介素-1（interleukin 1，IL-1）与白细胞介素-6（interleukin 6，IL-6）表达量的变化。结果显示：仔猪感染PEDV 1 d后发生水样腹泻。第二天剖检观察到各淋巴结有不同程度的肿大。HE染色发现PEDV主要引起脾脏红髓部分增多，脾索和脾窦界限模糊，脾窦中可见大量的细胞破裂；肠系膜淋巴结中小梁增生变厚，淋巴小结结构模糊不清，数量减少。IHC和RT-qPCR结果显示，PEDV在脾脏、肠系膜淋巴结等免疫器官均有分布，其中肠系膜淋巴结内病毒载量最高；而Western blot未能在以上组织中检测到该病毒。RT-qPCR检测脾脏和肠系膜淋巴结结果表明TNF-α、IFN-β和IL-1均有不同程度的升高，IL-6未发生明显变化。上述结果说明PEDV感染仔猪后部分免疫器官结构受到破坏，且影响了脾脏和肠系膜淋巴结中免疫相关因子TNF-α、IFN-β和IL-1的转录水平，这也为深入研究PEDV的致病机制提供了坚实的基础。

关键词： 慢性阻塞性肺疾病   IL-17A   MMP12   肺气肿   细胞凋亡  

摘要： 探讨补肺汤对慢性阻塞性肺疾病（chronic obstructive pulmonary disease， COPD）肺气肿小鼠Th17细胞免疫反应及细胞凋亡的影响。将C57BL/6小鼠50只随机分为空白组、模型组、补肺汤组、白细胞介素-17A（interleukin-17A， IL-17A）组、甲泼尼龙组。采用烟熏联合腹腔注射弹性蛋白酶方法构建COPD肺气肿小鼠模型，补肺汤及IL-17A单克隆抗体进行干预。小动物肺功能仪检测小鼠肺功能，苏木精-伊红（hematoxylin-eosin，HE）染色观察病理改变，蛋白免疫印迹法检测肺组织B细胞淋巴瘤/白血病-2蛋白（B-cell lymphoma/leukemia-2 protein，Bcl-2）、Bcl-2相关X蛋白（Bcl-2-associated X protein，Bax）、半胱氨酸天冬氨酸蛋白酶-3（cysteine aspartic acid protease-3， caspase-3）、剪切型半胱氨酸天冬氨酸蛋白酶-3（cleaved cysteine aspartic acid protease-3， cleaved caspase-3）表达，酶联免疫吸附测定法（enzyme-linked immunosorbent assay， ELISA）测定肺泡灌洗液基质金属蛋白酶-12（matrix metalloproteinase-12， MMP12）、IL-17A含量及炎症因子白细胞介素-6（interleukin-6， IL-6）、白细胞介素-8（interleukin-8， IL-8）表达，流式细胞术检测细胞凋亡率、CD4+和CD8+T淋巴细胞。结果显示，与空白组比较，模型组小鼠肺组织HE染色符合COPD病理改变，肺功能检测最大呼气后0.2 s的容积与用力呼气容积的比值（FEV0.2/FVC）、呼气量占肺活量25%～75%的平均流速（MMEF）、呼气峰流量（PEF）显著降低，肺泡灌洗液中MMP12、IL-17A、IL-6、IL-8及CD8+T淋巴细胞比例显著升高，肺组织细胞凋亡率、促凋亡蛋白Bax、cleaved caspase-3显著增加，抗凋亡蛋白Bcl-2表达显著减少。与模型组比较，补肺汤组MMP12、IL-17A、Bax、cleaved caspase-3表达显著减少，CD8+T淋巴细胞比例和细胞凋亡率显著降低，抗凋亡蛋白Bcl-2表达显著升高。研究结果揭示补肺汤可能通过调控MMP12及IL-17A介导的免疫炎症反应，减少肺组织细胞凋亡，从而改善COPD肺气肿。

关键词： HLA-C*07:01:130   HLA-genotyping   Illumina   next generation sequencing   novel allele  

摘要： The HLA-C*07:01:130 allele differs from the HLA-C*07:01:01:01 allele by a single nucleotide substitution in exon 3.

摘要： Ankylosing spondylitis (AS) is a chronic and progressive inflammatory arthritis involving disorders of both the immune and skeletal systems. Multiple osteochondromas (MO) is a rare skeletal disorder with a variety of clinical manifestations characterized by multiple benign exostoses. Here, we investigate a Chinese family with HLA-B27-negative AS complicated with MO. Whole-exome sequencing (WES) and Sanger sequencing were used to screen and identify the pathogenic gene. In vitro functional analysis was performed, and a pathogenesis-associated interleukin (IL)-17 receptor C (IL17RC) mutation was analyzed to investigate its effect on phenotypes. WES was used to identify a known missense mutation, NM_000127.3:c.1019 G > A(***340His), in the pathogenic gene EXT1 that is causal for MO. Moreover, a missense mutation, NM_153461.3:c.1067 C > T(***356Met), in the IL17RC gene was identified as potentially responsible for AS or spondyloarthritis symptoms in this family. In vitro over-expression of mutant IL17RC decreased its expression and increased the expression of IL17RA, consistent with the expression of these two genes in patients. Mechanistically, mutant IL17RC enhanced the activation of the NF-kappa B pathway. This study increases our understanding of the pathogenesis and progression of these diseases. Our findings broaden the risk factors in non-HLA-B genes associated with the NF-kappa B pathway in AS.

关键词： HLA-DQA1   next-generation sequencing   novel allele  

摘要： HLA-DQA1*05:06:02 shows one single nucleotide substitution at position 6 C > T in exon 1 compared with HLA-DQA1*05:06:01:01.

关键词： autonomous driving   reinforcement learning   imitation learning  

摘要： Autonomous driving is a complex and fast-evolving domain at the intersection of robotics, machine learning, and control systems. This paper provides a systematic review of recent developments in reinforcement learning (RL) and imitation learning (IL) approaches for autonomous vehicle control, with a dedicated focus on the CARLA simulator, an open-source, high-fidelity platform that has become a standard for learning-based autonomous vehicle (AV) research. We analyze RL-based and IL-based studies, extracting and comparing their formulations of state, action, and reward spaces. Special attention is given to the design of reward functions, control architectures, and integration pipelines. Comparative graphs and diagrams illustrate performance trade-offs. We further highlight gaps in generalization to real-world driving scenarios, robustness under dynamic environments, and scalability of agent architectures. Despite rapid progress, existing autonomous driving systems exhibit significant limitations. For instance, studies show that end-to-end reinforcement learning (RL) models can suffer from performance degradation of up to 35% when exposed to unseen weather or town conditions, and imitation learning (IL) agents trained solely on expert demonstrations exhibit up to 40% higher collision rates in novel environments. Furthermore, reward misspecification remains a critical issue-over 20% of reported failures in simulated environments stem from poorly calibrated reward signals. Generalization gaps, especially in RL, also manifest in task-specific overfitting, with agents failing up to 60% of the time when faced with dynamic obstacles not encountered during training. These persistent shortcomings underscore the need for more robust and sample-efficient learning strategies. Finally, we discuss hybrid paradigms that integrate IL and RL, such as Generative Adversarial IL, and propose future research directions.

关键词： coding change   HLA-A*03:509   HLA-C*05:308   NGS  

摘要： Two novel alleles, HLA-A*03:509 and HLA-C*05:308, were identified during routine next generation sequencing.

关键词： Microglial polarization   Electroacupuncture   Ischemic stroke   Cognitive impairment   IL-33/ST2  

摘要： Post-stroke cognitive impairment (PSCI) is a common and debilitating complication of stroke that significantly hinders rehabilitation. Electroacupuncture (EA), which integrates traditional acupuncture with electrical stimulation, has been widely applied in clinical practice and shown remarkable efficacy in treating PSCI. However, its underlying mechanisms remain largely unexplored. The PSCI rat model was established by middle cerebral artery occlusion/reperfusion (MCAO/R). EA treatment commenced 24 h after reperfusion and was administered daily for two weeks. To investigate the role of the Interleukin-33 (IL-33)/Interleukin 1 Receptor-Like 1 (ST2) signaling pathway in EA's therapeutic effects, the ST2 inhibitor Astegolimab (Anti-ST2) was stereotactically injected into the lateral ventricle prior to EA intervention. Neurological function was evaluated using the Zea-Longa neurological deficit score, while emotional and cognitive behaviors were assessed through the open field test (OFT) and novel object recognition (NOR) test. Cerebral infarct volume was quantified using 2,3,5-triphenyltetrazolium chloride (TTC) staining. Protein expression in the striatum was analyzed by Western blotting and immunofluorescence staining, and structural alterations were examined using hematoxylin-eosin (HE) staining. Microglial polarization in the ischemic penumbra was evaluated via double immunofluorescence staining. Serum levels of inflammatory cytokines, including interleukin (IL)-33, IL-10, IL-4, TNF-alpha, IL-1 beta, and IL-6, were determined using enzyme-linked immunosorbent assay (ELISA). EA markedly enhanced learning and memory in stroke rats, upregulated IL-33 expression, promoted M2 microglial polarization, and preserved the integrity of brain white matter. However, blockade of the IL-33/ST2 pathway with Anti-ST2 diminished the therapeutic benefits of EA, aggravated white matter injury and cerebral infarct volume, and amplified the inflammatory response. EA facilitates microgl