Exercise sustains the hallmarks of health

Exercise has long been known for its active role in improving physical fitness and sustaining health.Regular moderate-intensity exercise improves all aspects of human health and is widely accepted as a preventative and therapeutic strategy for various diseases.It is well-documented that exercise maintains and restores homeostasis at the organismal,tissue,cellular,and molecular levels to stimulate positive physiological adaptations that consequently protect against various pathological conditions.Here we mainly summarize how moderate-intensity exercise affects the major hallmarks of health,including the integrity of barriers,containment of local perturbations,recycling and turnover,integration of circuitries,rhythmic oscillations,homeostatic resilience,hormetic regulation,as well as repair and regeneration.Furthermore,we summarize the current understanding of the mechanisms responsible for beneficial adaptations in response to exercise.This review aimed at providing a comprehensive summary of the vital biological mechanisms through which moderate-intensity exercise maintains health and opens a window for its application in other health interventions.We hope that continuing investigation in this field will further increase our understanding of the processes involved in the positive role of moderate-intensity exercise and thus get us closer to the identification of new therapeutics that improve quality of life.

Effect of oridonin-mediated hallmark changes on inflammatory pathways in human pancreatic cancer(BxPC-3) cells

AIM:To investigate the effect of oridonin on nuclear transcription factors and to study the relationship between biological behavior and inflammatory factors in human pancreatic cancer(BxPC-3)cells.METHODS:BxPC-3 cells were treated with various concentrations of oridonin,and viability curves were generated to test for inhibitory effects of the drug on cells.The expression of cytokines such as interleukin-1β(IL-1β),IL-6,or IL-33 was detected in BxPC-3 cell supernatants using an enzyme-linked immunosorbent assay(ELISA),and the protein expression of nuclear transcription factors including nuclear factorκB,activating protein-1,signal transducer and activator of transcription 3,bone morphogenetic protein 2,trans-forming growth factorβ1 and sma and mad homologues in BxPC-3 cells was detected using Western blot.Carcinoma hallmark-related proteins such as survivin,vascular endothelial growth factor,and matrix metallopeptidase 2 were also detected using immunoblotting,and intra-nuclear IL-33 expression was detected using immunofluorescent staining.RESULTS:Treatment with oridonin reduced the viability of BxPC-3 cells in a dose dependent manner.The cells exhibited reduced growth following treatment with 8μg/mL oridonin(13.05%±3.21%,P<0.01),and the highest inhibitory ratio was 90.64%±0.70%,which was achieved with oridonin at a dose of32μg/mL.The IC50 value of oridonin in BxPC-3 cells was 19.32μg/mL.ELISA analysis revealed that oridonin down-regulated the inflammatory factors IL-1β,IL-6,and IL-33 in a dose-dependent manner.IL-1βexpression was significantly reduced in the 16 and 32μg/mL treatment groups compared to the control group(12.97±0.45 pg/mL,11.17±0.63 pg/mL vs 14.40±0.38pg/mL,P<0.01).Similar trends were observed for IL-6expression,which was significantly reduced in the 16and 32μg/mL treatment groups compared to the control group(4.05±0.14 pg/mL vs 4.45±0.43 pg/mL,P<0.05;3.95±0.13 pg/mL vs 4.45±0.43 pg/mL,P<0.01).IL-33 expression was significantly reduced in the8,16,and 32μg/mL treatment groups compared to the control group(911.05±14.18 pg/mL vs 945.25±12.09 pg/mL,P<0.05;802.70±11.88 pg/mL,768.54±10.98 pg/mL vs 945.25±12.09 pg/mL,P<0.01).Western blot and immunofluorescent staining analyses suggested that oridonin changed the hallmarks and regulated the expression of various nuclear transcription factors.CONCLUSION:The results obtained suggest that oridonin alters the hallmarks of pancreatic cancer cells through the regulation of nuclear transcription factors.

ABC transporters and the hallmarks of cancer:roles in cancer aggressiveness beyond multidrug resistance

The ATP-binding cassette transporters(ABC transporters)have been intensely studied over the past 50 years for their involvement in the multidrug resistance(MDR)phenotype,especially in cancer.They are frequently overexpressed in both naive and post-treatment tumors,and hinder effective chemotherapy by reducing drug accumulation in cancer cells.In the last decade however,several studies have established that ABC transporters have additional,fundamental roles in tumor biology;there is strong evidence that these proteins are involved in transporting tumor-enhancing molecules and/or in protein-protein interactions that impact cancer aggressiveness,progression,and patient prognosis.This review highlights these studies in relation to some well-described cancer hallmarks,in an effort to re-emphasize the need for further investigation into the physiological functions of ABC transporters that are critical for tum or development.Unraveling these new roles offers an opportunity to define new strategies and targets for therapy,which would include endogenous substrates or signaling pathways that regulate these proteins.

A multilevel pan-cancer map links gene mutations to cancer hallmarks

Background:A central challenge in cancer research is to create models that bridge the gap between the molecular level on which interventions can be designed and the cellular and tissue levels on which the disease phenotypes are manifested.This study was undertaken to construct such a model from functional annotations and explore its use when integrated with large-scale cancer genomics data.Methods:We created a map that connects genes to cancer hallmarks via signaling pathways.We projected gene mutation and focal copy number data from various cancer types onto this map.We performed statistical analyses to uncover mutually exclusive and co-occurring oncogenic aberrations within this topology.Results:Our analysis showed that although the genetic fingerprint of tumor types could be very different,there were less variations at the level of hallmarks,consistent with the idea that different genetic alterations have similar functional outcomes.Additionally,we showed how the multilevel map could help to clarify the role of infrequently mutated genes,and we demonstrated that mutually exclusive gene mutations were more prevalent in pathways,whereas many co-occurring gene mutations were associated with hallmark characteristics.Conclusions:Overlaying this map with gene mutation and focal copy number data from various cancer types makes it possible to investigate the similarities and differences between tumor samples systematically at the levels of not only genes but also pathways and hallmarks.

A Hallmark of Information Exchange and Technical Cooperation

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Resistance to apoptosis should not be taken as a hallmark of cancer

In the research community, resistance to apoptosis is often considered a hallmark of cancer. However, pathologists who diagnose cancer via microscope often see the opposite. Indeed, increased apoptosis and mitosis are usually observed simultaneously in cancerous lesions. Studies have shown that increased apoptosis is associated with cancer aggressiveness and poor clinical outcome. Furthermore, overexpression of Bcl-2, an antiapoptotic protein, is linked with better survival of cancer patients. Conversely, Bax, CD95, Caspase-3, and other apoptosis-inducing proteins have been found to promote carcinogenesis. This notion of the role of apoptosis in cancer is not new; cancer cells were found to be short-lived 88 years ago. Given these observations, resistance to apoptosis should not be considered a hallmark of cancer.

基质硬度在肿瘤特征中的生物学意义

肿瘤是全球第二大死亡因素,也是人类关注度最高的疾病之一。在恶性肿瘤的发生、发展过程中,肿瘤细胞通过获得遗传和表观遗传的变异进化出一系列特征,使它们能够生存并适应肿瘤微环境(TME)的应激相关条件。这些特征被认为是“肿瘤的标志”,包括持续的增殖信号、肿瘤转移、血管生成、代谢重编程、抵抗细胞死亡、促肿瘤炎症等。近年来,TME中的力学因素如基质硬度、流体剪切力、门静脉压力等的变化在肿瘤发生发展中的生物学作用越来越受到关注。其中,基质硬度也被称为细胞外基质(ECM)应力,是TME的一个关键物理因素。实体肿瘤中的基质硬度由于胶原蛋白的过度产生、病理性胶原交联和纤维排列而显著增加,而肿瘤细胞能够感知这种异常的ECM应力并通过其力学感受器将力学信号转化为生化信号,加剧疾病症状。然而,基质硬度与肿瘤发生及恶性转化的确切机制尚不完全明确。本文综述了ECM力学信号在调控肿瘤特征方面的研究进展,并讨论了靶向ECM硬度作为治疗肿瘤策略的可能性,为开发基于基质力学的临床肿瘤治疗提供新思路。

象征和标志:党旗制度的发展逻辑、实践功能与实施机制

党章中关于党徽党旗的相关规定是党的根本大法的重要组成部分,具有与党章其他条款同等重要的根本规范性。从党旗及相关制度的产生和发展来看,对其理解应该结合规范文本、历史和现实等要素展开。总体来看,党旗制度的发展和完善呈现出坚持政治性、注重法治性和确保权威性等特点。作为政治选择和党内法规所确定的象征物,党旗具有显化党的光辉历史、证成革命正当性、凝聚全党和全民共识、提升党员和党组织的战斗力、激发党员先锋队意识、指引党领导国家和社会前进方向等诸多实践功能。应通过党旗和国家标志的有序互动、进一步完善规则及强化制度执行等方式,保障党旗的功能和地位。

The systemic hallmarks of cancer

Cancer is not just a lump of cells that divide,invade,and spread randomly,but rather a multi-layered precisely tuned process that requires the participation of the whole organism.There is an urgent need to zoom-out from the cellular and the local stromal view and broaden our perspective by including the whole organism level.Geographically separated cancer tissues communicate between themselves,forming a system that interacts with the rest of the organism through cancer induced systemic pathogenic networks.In the present paper,I introduce six systemic hallmarks of cancer that emerge as a result of these interactions.I also describe several potential therapeutic approaches that can be developed using the cancer system concept.Overall,I argue that the tumoricentric paradigm should be replaced with a broader approach that brings into focus the“cancerized”organism.

解读癌症研究的里程碑:Hallmarks of Cancer

征服癌症是人类永恒的话题。20世纪后半叶,肿瘤研究开始进入分子时代,癌症复杂多样的表型、机制及治疗反应逐渐被认识。2000年,一篇开创性综述“Hallmarks of Cancer”问世,更新至今,已总结出了癌症的14个特征,将肿瘤研究中日益繁杂的概念提炼成一门逻辑科学,有助于更全面地理解癌症发生、发展机制并将这些知识应用于肿瘤的诊断和治疗中,掌握、应用以及继续探索癌症的特征必将有助于在未来更加自信地面对肿瘤疾病带来的挑战。

癌症标志本体构建与应用

目的构建一种可溯源的癌症标志知识本体,支持基因突变、癌症标志和细胞系等相关数据整合、标准化和关联,并基于该本体实现新知识发现。方法基于“七步法”和现阶段本体的构建方法,明确癌症标志本体覆盖范围、框架结构、可复用的术语和新增术语;以结直肠癌为例,利用文本挖掘和文本分类技术对PubMed文献中结直肠癌标志相关知识进行提取,利用癌症标志本体对提取的知识进行规范化表达。结合癌症体细胞突变目录中已有的癌症标志证据和进一步语义检索,实现新知识的发现。结果最终构建癌症标志本体包含类9910个,实例6138个,实现2310篇涉及结直肠癌标志文献摘要和26个结直肠癌标志相关证据的语义表示。与癌症体细胞突变目录数据集相比,本研究发现与结直肠癌相关的多个基因的癌症标志的新证据。结论本研究有助于整合癌症分子层面的致病机制,了解基因突变在癌症发生过程中的具体作用,实现癌症标志知识的快速发现。

大型体育赛事运行理念嬗变——基于新加坡青奥会的亲身体验

以2010年首届新加坡青年奥运会为实证分析,发现青奥会的成功举办使得体育赛事回归本质:全民参与成为赛事举办的目的,竞技比赛成为赛会的展示平台,同时通过组委会一系列文化教育计划培养年轻人积极的生活态度。由此,从青奥会透视出大型体育赛事运行理念的嬗变:全球可持续发展视角下,强调人与社会、自然的和谐发展,其中低碳经济、瘦身规模、城市互动和精英示范是大型体育赛事运行理念的发展方向。

大型体育赛事与城市文化传承的关系研究

大型体育赛事作为一种影响城市精神价值和城市居民生活方式的社会性社会活动,已成为城市政府构建和传承城市文化的重要平台。从规模、形态、效果、生态、传承五个视角透视在推进大型体育赛事与城市体育文化双向驱动过程中应承担的责任和义务,且大型体育赛事在打造城市文化交流平台、展示城市个性靓丽标识、促进城市多元文化融合共生、促成城市文化旅游耦合契机、城市历史脉络的发散延续、城市文化生态的继承演进和形成城市文化功能区的孵化地等方面体现其重要作用和地位。

大型体育赛事与城市发展互动效应研究——以四大网球公开赛为例

依托于现代科技支撑和城市产业化进程,城市作为一种具有聚集效应同时又具有发散效应的人类生存空间,其发展已成为孕育大型体育赛事的驱动力。以四大网球公开赛举办城市墨尔本、巴黎、伦敦和纽约为例,论证大型体育赛事在城市产业发展中所产生的互动效应——聚集与发散效应,通过其互动效应实现两者共生共赢。

系统视野中的上海节庆旅游资源开发

上海节庆旅游资源因其所扮演的促进旅游业和区域经济发展的举足轻重的角色而引起各方关注。本文试以系统论思想为指导，以都市旅游为背景，探讨节庆旅游资源的涵义和上海节庆旅游资源作为系统所具有的整体性、联系性、有序性和动态性等特点。

湖北省旅游节庆系统的构建

根据专家咨询调查资料,在分析湖北省旅游节庆发展现状和开发条件的基础上,从主题定位、形象设计、内容组织、表现手法、时空安排以及类型多样化和时空连续化几个方面,重点阐述建设标志性旅游节庆和旅游节庆系统构建的思想。为使旅游节庆能顺利进行,提出了建设保障体系的四大措施。

7种植物K~＋/H~＋逆向转运蛋白的生物信息学分析

K+/H+逆向转运是普遍存在于几乎所有生物体内的重要离子平衡机制之一。该机制主要由多基因家族KEA(K efflux antiporter)介导。然而,长期以来对KEA的功能特征和生理意义的认识,除了在大肠杆菌中有零星的报道之外,绝大部分尚为空白。本文通过生物信息学分析,比较了7个植物物种KEA的同源和进化关系,发现KEA家族中的部分成员在物种进化过程中具有极高的保守性。以模式植物拟南芥为例,进一步研究了KEA的蛋白质跨膜结构、关键结构域和亚细胞定位预测等。结果表明,AtKEA大多具有10～12个跨膜结构,是典型的膜蛋白,在跨膜区的N端有多个丝氨酸磷酸化调控位点;都含有K+/H+交换结构域和相应的调控域,推测其能够介导K+/H+交换。基因芯片研究表明,AtKEA在根、茎、叶、花和荚果等不同组织器官的表达丰度不同,表明KEA基因家族各成员的生理功能具有时空分异性。上述结果可为进一步深入研究植物K+/H+逆向转运系统的功能提供借鉴。

膝骨性关节炎病程与患侧踇外翻的相关性

目的探究膝骨性关节炎患者病程与患侧踇外翻严重程度的相关性。方法将2011年3月至2017年10月在云南省中医医院骨科住院部(35例)及昆明市中医医院骨科住院部(52例)诊断为踇外翻及同侧KOA并符合纳入标准的87例患者纳入研究。依据KOA分期将87例研究对象分为I期组17例、II期组35例、III期22例、IV期13例;根据正常胫股解剖角得膝内翻组患者33例、膝外翻组患者23例;对比不同KOA分期组及内、外翻2组患者间HVA、IMA、PASA及DASA的差异。结果 4个KOA分期组比较:与I期组、II期组比较III期、IV期组HVA较大,P<0.05;IMA:II期组显著大于I期组,P<0.01,与II期组比较,III期组、IV期组IMA较大,P<0.05; PASA:II期组显著大于I期组,P<0.01,II期组、III期组、IV期组无差异;DASA:II期组显著大于I期组,P<0.01,II期组、III期组、IV期组无差异。膝内翻组与膝外翻组比较:膝内翻组HVA(28.7±2.8) vs (33.5±3.5),平均值显著较小,P<0.01, IMA (12.7±2.5) vs (14.3±2.7)、PASA (10.1±2.5)vs (11.6±2.2)、DASA (11.7±2.1 VS 12.9±2.3)较小,P<0.05。与膝内翻组比较,膝外翻组III、IV期KOA患者比例较高(36.3%vs 56.5%),P<0.05。结论踇外翻与膝骨性关节炎两者之间具有一定的正相关性,而对于膝外翻膝骨性关节炎患者来说,这种相关性更为明显。

Molecular mechanisms of viral hepatitis induced hepatocellular carcinoma

Chronic infection with viral hepatitis affects half a billion individuals worldwide and can lead to cirrhosis,cancer,and liver failure.Liver cancer is the third leading cause of cancer-associated mortality,of which hepatocellular carcinoma(HCC)represents 90%of all primary liver cancers.Solid tumors like HCC are complex and have heterogeneous tumor genomic profiles contributing to complexity in diagnosis and management.Chronic infection with hepatitis B virus(HBV),hepatitis delta virus(HDV),and hepatitis C virus(HCV)are the greatest etiological risk factors for HCC.Due to the significant role of chronic viral infection in HCC development,it is important to investigate direct(viral associated)and indirect(immune-associated)mechanisms involved in the pathogenesis of HCC.Common mechanisms used by HBV,HCV,and HDV that drive hepatocarcinogenesis include persistent liver inflammation with an impaired antiviral immune response,immune and viral protein-mediated oxidative stress,and deregulation of cellular signaling pathways by viral proteins.DNA integration to promote genome instability is a feature of HBV infection,and metabolic reprogramming leading to steatosis is driven by HCV infection.The current review aims to provide a brief overview of HBV,HCV and HDV molecular biology,and highlight specific viral-associated oncogenic mechanisms and common molecular pathways deregulated in HCC,and current as well as emerging treatments for HCC.