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| 1 | Erianin,a novel dibenzyl compound in Dendrobium extract,inhibits lung cancer cell growth and migration via calcium/calmodulin-dependent ferroptosis显示文摘Ferroptosis,a novel form of programmed cell death,is characterized by iron-dependent lipid peroxidation and has been shown to be involved in multiple diseases,including cancer.Stimulating ferroptosis in cancer cells may be a potential strategy for cancer therapy.Therefore,ferroptosis-inducing drugs are attracting more attention for cancer treatment.Here,we showed that erianin,a natural product isolated from Dendrobium chrysotoxum Lindl,exerted its anticancer activity by inducing cell death and inhibiting cell migration in lung cancer cells.Subsequently,we demonstrated for the first time that erianin induced ferroptotic cell death in lung cancer cells,which was accompanied by ROS accumulation,lipid peroxidation,and GSH depletion.The ferroptosis inhibitors Fer-1 and Lip-1 but not Z-VAD-FMK,CQ,or necrostatin-1 rescued erianin-induced cell death,indicating that ferroptosis contributed to erianin-induced cell death.Furthermore,we demonstrated that Ca^(2+)/CaM signaling was a critical mediator of erianin-induced ferroptosis and that blockade of this signaling significantly rescued cell death induced by erianin treatment by suppressing ferroptosis.Taken together,our data suggest that the natural product erianin exerts its anticancer effects by inducing Ca^(2+)/CaMdependent ferroptosis and inhibiting cell migration,and erianin will hopefully serve as a prospective compound for lung cancer treatment. | Peng Chen Qibiao Wu Jiao Feng Lili Yan Yitian Sun Shuiping Liu Yu Xiang Mingming Zhang Ting Pan Xiaying Chen Ting Duan Lijuan Zhai Bingtao Zhai Wengang Wang Ruonan Zhang Bi Chen Xuemeng Han Yicong Li Liuxi Chen Ying Liu Xingxing Huang Ting Jin Wenzheng Zhang Hong Luo Xiaohui Chen Yongqiang Li Qiujie Li Guohua Li Qin Zhang Lvjia Zhuo Zuyi Yang Huifen Tang Tian Xie Xiaoping Ouyang Xinbing Sui | 2020 | Signal Transduction and Targeted Therapy2020，5，1： | 42 |
| 2 | Targeting NF-κB pathway for the therapy of diseases:mechanism and clinical study显示文摘NF-κB pathway consists of canonical and non-canonical pathways.The canonical NF-κB is activated by various stimuli,transducing a quick but transient transcriptional activity,to regulate the expression of various proinflammatory genes and also serve as the critical mediator for inflammatory response.Meanwhile,the activation of the non-canonical NF-κB pathway occurs through a handful of TNF receptor superfamily members.Since the activation of this pathway involves protein synthesis,the kinetics of non-canonical NF-κB activation is slow but persistent,in concordance with its biological functions in the development of immune cell and lymphoid organ,immune homeostasis and immune response.The activation of the canonical and non-canonical NF-κB pathway is tightly controlled,highlighting the vital roles of ubiquitination in these pathways.Emerging studies indicate that dysregulated NF-κB activity causes inflammation-related diseases as well as cancers,and NF-κB has been long proposed as the potential target for therapy of diseases.This review attempts to summarize our current knowledge and updates on the mechanisms of NF-κB pathway regulation and the potential therapeutic application of inhibition of NF-κB signaling in cancer and inflammatory diseases. | Hui Yu Liangbin Lin Zhiqiang Zhang Huiyuan Zhang Hongbo Hu | 2020 | Signal Transduction and Targeted Therapy2020，5，1： | 35 |
| 3 | Wnt/β-catenin signalling:function,biological mechanisms,and therapeutic opportunities显示文摘The Wnt/β-catenin pathway comprises a family of proteins that play critical roles in embryonic development and adult tissue homeostasis.The deregulation of Wnt/β-catenin signalling often leads to various serious diseases,including cancer and non-cancer diseases.Although many articles have reviewed Wnt/β-catenin from various aspects,a systematic review encompassing the origin,composition,function,and clinical trials of the Wnt/β-catenin signalling pathway in tumour and diseases is lacking.In this article,we comprehensively review the Wnt/β-catenin pathway from the above five aspects in combination with the latest research.Finally,we propose challenges and opportunities for the development of small-molecular compounds targeting the Wnt signalling pathway in disease treatment. | Jiaqi Liu Qing Xiao Jiani Xiao Chenxi Niu Yuanyuan Li Xiaojun Zhang Zhengwei Zhou Guang Shu Gang Yin | 2022 | Signal Transduction and Targeted Therapy2022，7，2： | 28 |
| 4 | Pyroptosis: mechanisms and diseases显示文摘Currently,pyroptosis has received more and more attention because of its association with innate immunity and disease.The research scope of pyroptosis has expanded with the discovery of the gasdermin family.A great deal of evidence shows that pyroptosis can affect the development of tumors.The relationship between pyroptosis and tumors is diverse in different tissues and genetic backgrounds.In this review,we provide basic knowledge of pyroptosis,explain the relationship between pyroptosis and tumors,and focus on the significance of pyroptosis in tumor treatment.In addition,we further summarize the possibility of pyroptosis as a potential tumor treatment strategy and describe the side effects of radiotherapy and chemotherapy caused by pyroptosis.In brief,pyroptosis is a double-edged sword for tumors.The rational use of this dual effect will help us further explore the formation and development of tumors,and provide ideas for patients to develop new drugs based on pyroptosis. | Pian Yu Xu Zhang Nian Liu Ling Tang Cong Peng Xiang Chen | 2021 | Signal Transduction and Targeted Therapy2021，6，4： | 26 |
| 5 | HIF-1α-induced expression of m6A reader YTHDF1 drives hypoxia-induced autophagy and malignancy of hepatocellular carcinoma by promoting ATG2A and ATG14 translation显示文摘N6-methyladenosine(m6A),and its reader protein YTHDF1,play a pivotal role in human tumorigenesis by affecting nearly everystage of RNA metabolism.Autophagy activation is one of the ways by which cancer cells survive hypoxia.However,the possibleinvolvement of m6A modification of mRNA in hypoxia-induced autophagy was unexplored in human hepatocellular carcinoma(HCO).In this study,specific variations in YTHDF1 expression were detected in YTHDF1-overexpressing,knockout,and-knockdownHCC cells,HCC organoids,and HCC patient-derived xenograft(PDX)murine models.YTHDF1 expression and hypoxia inducedautophagy were significantly correlated in vitro;signifhcant overexpression of YTHDF1 in HCC tissues was associated with poorprognosis,Multivariate cox regression analysis identihed YTHDF1 expression as an independent prognostic factor in patients withHCC.Multiple HC models conhrmed that YTHDF1 deficiency inhibited HCC autophagy,growth,and metastasis.Luciferase reporterassays and chromatin immunoprecipitation demonstrated that HlIF-1a regulated YTHDF1 transcription by directly binding to itspromoter region under hypoxia.The results of methylated RNA immunoprecipitation sequencing,proteomics,and polysomeprofling indicated that YTHDF1 contibuted to the translation of autophagy-related genes ATG2A and ATG14 by binding to m6A-modifhed ATG2A and ATG14 mRNA,thus facilitating autophagy and autophagy-related malignancy of HCC.Taken together,HlE-1d-induced YTHDF1 expression was associated with hypoxia-induced autophagy and autophagy-related HCC progression via promoting translation of autophagy-related genes ATG2A and ATG14 in a m6A-dependent manner.Our fndings suggest thatYTHDF1 is a potential prognostic biomarker and therapeutic target for patients with HCC. | Qing Li Yong Ni Liren Zhang Runqiu Jiang Jing Xu Hong Yang Yuanchang Hu Jiannan Qiu Liyong Pu Jinhai Tang Xuehao Wang | 2021 | Signal Transduction and Targeted Therapy2021，6，3： | 24 |
| 6 | The JAK/STAT signaling pathway:from bench to clinic显示文摘The Janus kinase/signal transducer and activator of transcription(JAK/STAT)signaling pathway was discovered more than a quarter-century ago.As a fulcrum of many vital cellular processes,the JAK/STAT pathway constitutes a rapid membrane-to-nucleus signaling module and induces the expression of various critical mediators of cancer and inflammation.Growing evidence suggests that dysregulation of the JAK/STAT pathway is associated with various cancers and autoimmune diseases.In this review,we discuss the current knowledge about the composition,activation,and regulation of the JAK/STAT pathway.Moreover,we highlight the role of the JAK/STAT pathway and its inhibitors in various diseases. | Xiaoyi Hu Jing li Maorong Fu Xia Zhao Wei Wang | 2021 | Signal Transduction and Targeted Therapy2021，6，12： | 21 |
| 7 | Inflammation and atherosclerosis: signaling pathways and therapeutic intervention显示文摘Atherosclerosis is a chronic inflammatory vascular disease driven by traditional and nontraditional risk factors.Genome-wide association combined with clonal lineage tracing and clinical trials have demonstrated that innate and adaptive immune responses can promote or quell atherosclerosis.Several signaling pathways,that are associated with the inflammatory response,have been implicated within atherosclerosis such as NLRP3 inflammasome,toll-like receptors,proprotein convertase subtilisin/kexin type 9. | Peng Kong Zi-Yang Cui Xiao-Fu Huang Dan-Dan Zhang Rui-Juan Guo Mei Han | 2022 | Signal Transduction and Targeted Therapy2022，7，5： | 20 |
| 8 | The mechanisms of sorafenib resistance in hepatocellular carcinoma:theoretical basis and therapeutic aspects显示文摘Sorafenib is a multikinase inhibitor capable of facilitating apoptosis,mitigating angiogenesis and suppressing tumor cell proliferation.In late-stage hepatocellular carcinoma(HCC),sorafenib is currently an effective first-line therapy.Unfortunately,the development of drug resistance to sorafenib is becoming increasingly common.This study aims to identify factors contributing to resistance and ways to mitigate resistance.Recent studies have shown that epigenetics,transport processes,regulated cell death,and the tumor microenvironment are involved in the development of sorafenib resistance in HCC and subsequent HCC progression.This study summarizes discoveries achieved recently in terms of the principles of sorafenib resistance and outlines approaches suitable for improving therapeutic outcomes for HCC patients. | Weiwei Tang Ziyi Chen Wenling Zhang Ye Cheng Betty Zhang Fan Wu Qian Wang Shouju Wang Dawei Rong F.P.Reiter E.N.De Toni Xuehao Wang | 2020 | Signal Transduction and Targeted Therapy2020，5，1： | 19 |
| 9 | Oral berberine improves brain dopa/dopamine levels to ameliorate Parkinson’s disease by regulating gut microbiota显示文摘The phenylalanine-tyrosine-dopa-dopamine pathway provides dopamine to the brain.Iin this process,tyrosine hydroxylase(TH)isthe rate-limiting enzyme that hydroxylates tyrosine and generates levodopa(L-dopa)with tetranydrobiopterin(BH_(4))as a coenzyme.Here,we show that oral berberine(BBR)might supply H^(·) through dihydroberberine(reduced BBR produced by bacterial nitroreductase)and promote the production of BHl from dihydrobiopterin;the increased BH,enhances TH activity,which accelerates the production of L-dopa by the gut bacteria.Oral BBR acts in a way similar to vitamins.The L-dopa produced by theintestinal bacteria enters the brain through the circulation and is transformed to dopamine.To verify the gut-brain dialog activatedby BBR's effect,Enterococcus foecalis or Enterococcus faecium was transplanted into Parkinson's disease(PD)mice.The bacteriasignificantly increased brain dopamine and ameliorated PD manifestation in mice;additionally,combination of BBR with bacteriashowed better therapeutic effect than that with bacteria alone.Moreover,2,4,6-trimethy-pyranylium tetrafluoroborate(TMP-TFB)-derivatized matrix-assisted laser desorption mass spectrometry(MALDI-MS)imaging of dopamine identihed elevated striataldopamine levels in mouse brains with oral Enterococcus,and BBR strengthened the imaging intensity of brain dopamine.Theseresults demonstrated that BBR was an agonist of TH in Enterococcus and could lead to the production of L-dopa in the gut.Furthermore,a study of 28 patients with hyperlipidemia conhrmed that oral BBR increased bloodfecal L-dopa by the intestinalbacteria.Hence,BBR might improve the brain function by upregulating the biosynthesis of-dopa in the gut microbiota through avitamin-like effect. | Yan Wang Qian Tong Shu-Rong Ma Zhen-Xiong Zhao Li-Bin Pan Lin Cong Pei Han Ran Peng Hang Yu Yuan Lin Tian-Le Gao Jia-Wen Shou Xiao-Yang Li Xian-Feng Zhang Zheng-Wei Zhang Jie Fu Bao-Ying Wen Jin-Bo Yu Xuetao Cao Jian-Dong Jiang | 2021 | Signal Transduction and Targeted Therapy2021，6，3： | 16 |
| 10 | Human umbilical cord-derived mesenchymal stem cell therapy in patients with COVID-19:a phase 1 clinical trial显示文摘No effective drug treatments are available for coronavirus disease 2019(COVID-19).Host-directed therapies targeting the underlying aberrant immune responses leading to pulmonary tissue damage,death,or long-term functional disability in survivors require clinical evaluation.We performed a parallel assigned controlled,non-randomized,phase 1 clinical trial to evaluate the safety of human umbilical cord-derived mesenchymal stem cells(UC-MSCs)infusions in the treatment of patients with moderate and severe COVID-19 pulmonary disease.The study enrolled 18 hospitalized patients with COVID-19(n=9 for each group).The treatment group received three cycles of intravenous infusion of UC-MSCs(3×107 cells per infusion)on days 0,3,and 6.Both groups received standard COVID-treatment regimens.Adverse events,duration of clinical symptoms,laboratory parameters,length of hospitalization,serial chest computed tomography(CT)images,the PaO2/FiO2 ratio,dynamics of cytokines,and IgG and IgM anti-SARS-CoV-2 antibodies were analyzed.No serious UC-MSCs infusion-associated adverse events were observed.Two patients receiving UC-MSCs developed transient facial flushing and fever,and one patient developed transient hypoxia at 12 h post UC-MSCs transfusion.Mechanical ventilation was required in one patient in the treatment group compared with four in the control group.All patients recovered and were discharged.Our data show that intravenous UC-MSCs infusion in patients with moderate and severe COVID-19 is safe and well tolerated.Phase 2/3 randomized,controlled,double-blinded trials with long-term follow-up are needed to evaluate the therapeutic use of UC-MSCs to reduce deaths and improve long-term treatment outcomes in patients with serious COVID-19. | Fanping Meng Ruonan Xu Siyu Wang Zhe Xu Chao Zhang Yuanyuan Li Tao Yang Lei Shi Junliang Fu Tianjun Jiang Lei Huang Peng Zhao Xin Yuan Xing Fan Ji-Yuan Zhang Jinwen Song Dawei Zhang Yanmei Jiao Limin Liu Chunbao Zhou Markus Maeurer Alimuddin Zumla Ming Shi Fu-Sheng Wang | 2020 | Signal Transduction and Targeted Therapy2020，5，1： | 16 |
| 11 | Ferroptosis:mechanisms and links with diseases显示文摘Ferroptosis is an iron-dependent cell death,which is different from apoptosis,necrosis,autophagy,and other forms of cell death.The process of feroptotic cell death is defined by the accumulation of lethal lipid species derived from the peroxidation of lipids,which can be prevented by iron chelators(e.g.deferiprone,deferoxamine)and small lipophilic antioxidants(e.g,ferrostatin,liproxstatin).This review summarizes current knowledge about the regulatory mechanism of ferroptosis and its association withseveral pathways,including iron,lipid,and cysteine metabolism.We have further discussed the contribution of ferroptosis to thepathogenesis of several diseases such as cancer,ischemia/reperfusion,and various neurodegenerative diseases(e.g.Alzheimersdisease and Parkinson's disease),and evaluated the therapeutic applications of ferroptosis inhibitors in clinics. | Hong-fa Yan Ting Zou Qing-zhang Tuo Shuo Xu Hua Li Abdel Ali Belaidi Peng Lei | 2021 | Signal Transduction and Targeted Therapy2021，6，3： | 16 |
| 12 | The role of m6A modification in the biological functions and diseases显示文摘N6-methyladenosine(m6A)is the most prevalent,abundant and conserved internal cotranscriptional modification in eukaryotic RNAs,especially within higher eukaryotic cells.m6A modification is modified by the m6A methyltransferases,or writers,such as METTL3/14/16,RBM15/15B,ZC3H3,VIRMA,CBLL1,WTAP,and KIAA1429,and,removed by the demethylases,or erasers,including FTO and ALKBH5.It is recognized by m6A-binding proteins YTHDF1/2/3,YTHDC1/2 IGF2BP1/2/3 and HNRNPA2B1,also known as'readers'.Recent studies have shown that m6A RNA modification plays essential role in both physiological and pathological conditions,especially in the initiation and progression of different types of human cancers.In this review,we discuss how m6A RNA methylation influences both the physiological and pathological progressions of hematopoietic,central nervous and reproductive systems.We will mainly focus on recent progress in identifying the biological functions and the underlying molecular mechanisms of m6A RNA methylation,its regulators and downstream target genes,during cancer progression in above systems.We propose that m6A RNA methylation process offer potential targets for cancer therapy in the future. | Xiulin Jiang Baiyang Liu Zhi Nie Lincan Duan Qiuxia Xiong Zhixian Jin Cuiping Yang Yongbin Chen | 2021 | Signal Transduction and Targeted Therapy2021，6，3： | 16 |
| 13 | Impact of mechanical circulatory support and immunomodulation therapy on outcome of patients with fulminant myocarditis: Chinese registry of fulminant myocarditis显示文摘Dear Editor,Patients presenting with acute myocarditis and sudden hemodynamic instability (termed fulminant myocarditis [FM]) still have a high mortality and need for heart transplantation, up to 28% at 60 days.1,2,3 Recent scientific statements and expert opinion consensus suggests early use of temporary mechanical circulatory supports (t-MCS).3,4 Specifically, Chinese scientific statement proposed an extensive use of t-MCS combined with immunoregulatory therapy (IT),4 although formal trials are lacking. We present a multicenter, retrospective study to compare the outcome of patients who were treated with t-MCS and IT vs. patients who didn’t receive these treatments. We included patients with the diagnosis of FM based on the presence of viral prodromal signs/symptoms followed by acute onset of severe heart failure (HF) without other relevant differential diagnosis or pre-existing cardiac disorders. Patients who received both t-MCS and IT during hospitalization were classified as t-MCS+IT group. | Ning Zhou Yuhua Zhao Jiangang Jiang Lan Shen Junming Li Jing Wan Xueping Ma Jing Zhang Enrico Ammirati Dao Wen Wang | 2021 | Signal Transduction and Targeted Therapy2021，6，11： | 14 |
| 14 | Notch signaling pathway:architecture,disease,and therapeutics显示文摘The NOTCH gene was identified approximately 110 years ago.Classical studies have revealed that NOTCH signaling is an evolutionarily conserved pathway.NOTCH receptors undergo three cleavages and translocate into the nucleus to regulate the transcription of target genes.NOTCH signaling deeply participates in the development and homeostasis of multiple tissues and organs,the aberration of which results in cancerous and noncancerous diseases.However,recent studies indicate that the outcomes of NOTCH signaling are changeable and highly dependent on context.In terms of cancers,NOTCH signaling can both promote and inhibit tumor development in various types of cancer.The overall performance of NOTCH-targeted therapies in clinical trials has failed to meet expectations.Additionally,NOTCH mutation has been proposed as a predictive biomarker for immune checkpoint blockade therapy in many cancers.Collectively,the NOTCH pathway needs to be integrally assessed with new perspectives to inspire discoveries and applications.In this review,we focus on both classical and the latest findings related to NOTCH signaling to illustrate the history,architecture,regulatory mechanisms,contributions to physiological development,related diseases,and therapeutic applications of the NOTCH pathway.The contributions of NOTCH signaling to the tumor immune microenvironment and cancer immunotherapy are also highlighted.We hope this review will help not only beginners but also experts to systematically and thoroughly understand the NOTCH signaling pathway. | Binghan Zhou Wanling Lin Yaling Long Yunkai Yang Huan Zhang Kongming Wu Qian Chu | 2022 | Signal Transduction and Targeted Therapy2022，7，4： | 14 |
| 15 | DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer显示文摘Radiotherapy is one of the most common countermeasures for treating a wide range of tumors.However,the radioresistance of cancer cells is still a major limitation for radiotherapy applications.Efforts are continuously ongoing to explore sensitizing targets and develop radiosensitizers for improving the outcomes of radiotherapy.DNA double-strand breaks are the most lethal lesions induced by ionizing radiation and can trigger a series of cellular DNA damage responses(DDRs),including those helping cells recover from radiation injuries,such as the activation of DNA damage sensing and early transduction pathways,cell cycle arrest,and DNA repair.Obviously,these protective DDRs confer tumor radioresistance.Targeting DDR signaling pathways has become an attractive strategy for overcoming tumor radioresistance,and some important advances and breakthroughs have already been achieved in recent years.On the basis of comprehensively reviewing the DDR signal pathways,we provide an update on the novel and promising druggable targets emerging from DDR pathways that can be exploited for radiosensitization.We further discuss recent advances identified from preclinical studies,current clinical trials,and clinical application of chemical inhibitors targeting key DDR proteins,including DNA-PKcs(DNA-dependent protein kinase,catalytic subunit),ATM/ATR(ataxia–telangiectasia mutated and Rad3-related),the MRN(MRE11-RAD50-NBS1)complex,the PARP(poly[ADP-ribose]polymerase)family,MDC1,Wee1,LIG4(ligase IV),CDK1,BRCA1(BRCA1 C terminal),CHK1,and HIF-1(hypoxia-inducible factor-1).Challenges for ionizing radiation-induced signal transduction and targeted therapy are also discussed based on recent achievements in the biological field of radiotherapy. | Rui-Xue Huang Ping-Kun Zhou | 2020 | Signal Transduction and Targeted Therapy2020，5，1： | 14 |
| 16 | Effect of human umbilical cord-derived mesenchymal stem cells on lung damage in severe COVID-19 patients:a randomized,double-blind,placebo-controlled phase 2 trial显示文摘Treatment of severe Coronavirus Disease 2019(COVID-19)is challenging.We performed a phase 2 trial to assess the efficacy andsafety of human umbilical cord-mesenchymal stem cells(UC-MScs)to treat severe coViD-19 patients with lung damage,based onour phase 1 data.In this randomized,double-blind,and placebo-controlled trial,we recruited 101 severe coVID-19 patients withlung damage.They were randomly assigned at a 2:1 ratio to receive either UC-MSCs(4×10^(7)cells per infusion)or placebo on day 0,3,and 6.The primary endpoint was an altered proportion of whole lung lesion volumes from baseline to day 28.Other imagingoutcomes,6-minute walk test(6-MWT),maximum vital capacity,diffusing capacity,and adverse events were recorded and analyzed.In all,100 COVID-19 patients were finally received either UC-MSCs in=65)or placebo(n=35).UC-MSCs administrationexerted numerical improvement in whole lung lesion volume from baseline to day 28 compared with the placebo(the mediandifference was-13.31%,95%Cl-29.14%,2.13%,P=0.08).UC-MSCs significanty reduced the proportions of solid componentlesion volume compared with the placebo(median difference:-15.45%;95%CI-30.82%,-0.39%;P=0.043).The 6-MWT showedan increased distance in patients treated with UC-MSCs(difference:27.00 m;95%CI 0.00,57.00;P=0.057).The incidence of adverseevents was similar in the two groups.These results suggest that UC-MSCs treatment is a safe and potentially effective therapeuticapproach for COVID-19 patients with lung damage.A phase 3 trial is required to evaluate effects on reducing mortality andpreventing long-term pulmonary disability. | Lei Shi Hai Huang Xuechun Lu Xiaoyan Yan Xiaojing Jiang Ruonan Xu Siyu Wang Chao Zhang Xin Yuan Zhe Xu Lei Huang Jun-Liang Fu Yuanyuan Li Yu Zhang Wei-Qi Yao Tianyi Liu Jinwen Song Liangliang Sun Fan Yang Xin Zhang Bo Zhang Ming Shi Fanping Meng Yanning Song Yongpei Yu Jiqiu Wen Qi Li Qing Mao Markus Maeurer Alimuddin Zumla Chen Yao Wei-Fen Xie Fu-Sheng Wang | 2021 | Signal Transduction and Targeted Therapy2021，6，3： | 13 |
| 17 | Toripalimab combined with lenvatinib and GEMOX is a promising regimen as first-line treatment for advanced intrahepatic cholangiocarcinoma:a single-center,single-arm,phase 2 study显示文摘Advanced intrahepatic cholangiocarcinoma(ICC)has a dismal prognosis.Here,we report the efficacy and safety of combining toripalimab,lenvatinib,and gemcitabine plus oxaliplatin(GEMOX)as first-line therapy for advanced ICC.Thirty patients with pathologically confirmed advanced ICC received intravenous gemcitabine(1 g/m2)on Days 1 and 8 and oxaliplatin(85 mg/m2)Q3W for six cycles along with intravenous toripalimab(240 mg)Q3W and oral lenvatinib(8 mg)once daily for one year.The expression of programmed death-ligand 1(PD-L1)and genetic status was investigated in paraffin-embedded tissues using immunohistochemistry and whole-exome sequencing(WES)analysis.The primary endpoint was the objective response rate(ORR).Secondary outcomes included safety,overall survival(OS),progression-free survival(PFS),disease control rate(DCR)and duration of response(DoR).As of July 1,2022,the median follow-up time was 23.5 months,and the ORR was 80%.Twenty-three patients achieved partial response,and one achieved complete response.Patients(21/30)with DNA damage response(DDR)-related gene mutations showed a higher ORR,while patients(14/30)with tumor area positivity≥1(PD-L1 staining)showed a trend of high ORR,but without significant difference.The median OS,PFS,and DoR were 22.5,10.2,and 11.0 months,respectively.The DCR was 93.3%.Further,56.7%of patients experienced manageable grade≥3 adverse events(AEs),commonly neutropenia(40.0%)and leukocytopenia(23.3%).In conclusion,toripalimab plus lenvatinib and GEMOX are promising first-line regimens for the treatment of advanced ICC.A phase-III,multicenter,double-blinded,randomized study to validate our findings was approved by the National Medical Products Administration(NMPA,No.2021LP01825). | Guo-Ming Shi Xiao-Yong Huang Dong Wu Hui-Chuan Sun Fei Liang Yuan Ji Yi Chen Guo-Huan Yang Jia-Cheng Lu Xian-Long Meng Xin-Ying Wang Lei Sun Ning-Ling Ge Xiao-Wu Huang Shuang-Jian Qiu Xin-Rong Yang Qiang Gao Yi-Feng He Yang Xu Jian Sun Zheng-Gang Ren Jia Fan Jian Zhou | 2023 | Signal Transduction and Targeted Therapy2023，8，4： | 12 |
| 18 | Targeting cancer stem cell pathways for cancer therapy显示文摘Since cancer stem cells(CSCs)were first identified in leukemia in 1994,they have been considered promising therapeutic targets for cancer therapy.These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies,such as recurrence,metastasis,heterogeneity,multidrug resistance,and radiation resistance.The biological activities of CSCs are regulated by several pluripotent transcription factors,such as OCT4,Sox2,Nanog,KLF4,and MYC.In addition,many intracellular signaling pathways,such as Wnt,NF-κB(nuclear factor-κB),Notch,Hedgehog,JAK-STAT(Janus kinase/signal transducers and activators of transcription),PI3K/AKT/mTOR(phosphoinositide 3-kinase/AKT/mammalian target of rapamycin),TGF(transforming growth factor)/SMAD,and PPAR(peroxisome proliferator-activated receptor),as well as extracellular factors,such as vascular niches,hypoxia,tumor-associated macrophages,cancer-associated fibroblasts,cancer-associated mesenchymal stem cells,extracellular matrix,and exosomes,have been shown to be very important regulators of CSCs.Molecules,vaccines,antibodies,and CAR-T(chimeric antigen receptor T cell)cells have been developed to specifically target CSCs,and some of these factors are already undergoing clinical trials.This review summarizes the characterization and identification of CSCs,depicts major factors and pathways that regulate CSC development,and discusses potential targeted therapy for CSCs. | Liqun Yang Pengfei Shi Gaichao Zhao Jie Xu Wen Peng Jiayi Zhang Guanghui Zhang Xiaowen Wang Zhen Dong Fei Chen Hongjuan Cui | 2020 | Signal Transduction and Targeted Therapy2020，5，1： | 12 |
| 19 | NF-κB signaling in inflammation显示文摘The transcription factor NF-κB regulates multiple aspects of innate and adaptive immune functions and serves as a pivotal mediator of inflammatory responses.NF-κB induces the expression of various pro-inflammatory genes,including those encoding cytokines and chemokines,and also participates in inflammasome regulation.In addition,NF-κB plays a critical role in regulating the survival,activation and differentiation of innate immune cells and inflammatory T cells.Consequently,deregulated NF-κB activation contributes to the pathogenic processes of various inflammatory diseases.In this review,we will discuss the activation and function of NF-κB in association with inflammatory diseases and highlight the development of therapeutic strategies based on NF-κB inhibition. | Ting Liu Lingyun Zhang Donghyun Joo Shao-Cong Sun | 2017 | Signal Transduction and Targeted Therapy2017，2，1： | 12 |
| 20 | Yes-associated protein(YAP)in pancreatic cancer:at the epicenter of a targetable signaling network associated with patient survival显示文摘Pancreatic ductal adenocarcinoma(PDAC)is generally a fatal disease with no efficacious treatment modalities.Elucidation of signaling mechanisms that will lead to the identification of novel targets for therapy and chemoprevention is urgently needed.Here,we review the role of Yes-associated protein(YAP)and WW-domain-containing Transcriptional co-Activator with a PDZbinding motif(TAZ)in the development of PDAC.These oncogenic proteins are at the center of a signaling network that involves multiple upstream signals and downstream YAP-regulated genes.We also discuss the clinical significance of the YAP signaling network in PDAC using a recently published interactive open-access database(www.proteinatlas.org/pathology)that allows genome-wide exploration of the impact of individual proteins on survival outcomes.Multiple YAP/TEAD-regulated genes,including AJUBA,ANLN,AREG,ARHGAP29,AURKA,BUB1,CCND1,CDK6,CXCL5,EDN2,DKK1,FOSL1,FOXM1,HBEGF,IGFBP2,JAG1,NOTCH2,RHAMM,RRM2,SERP1,and ZWILCH,are associated with unfavorable survival of PDAC patients.Similarly,components of AP-1 that synergize with YAP(FOSL1),growth factors(TGFα,EPEG,and HBEGF),a specific integrin(ITGA2),heptahelical receptors(P2Y2R,GPR87)and an inhibitor of the Hippo pathway(MUC1),all of which stimulate YAP activity,are associated with unfavorable survival of PDAC patients.By contrast,YAP inhibitory pathways(STRAD/LKB-1/AMPK,PKA/LATS,and TSC/mTORC1)indicate a favorable prognosis.These associations emphasize that the YAP signaling network correlates with poor survival of pancreatic cancer patients.We conclude that the YAP pathway is a major determinant of clinical aggressiveness in PDAC patients and a target for therapeutic and preventive strategies in this disease. | Enrique Rozengurt James Sinnett-Smith Guido Eibl | 2018 | Signal Transduction and Targeted Therapy2018，3，1： | 11 |
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