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An unexpected cellular fountain of youth:platelets provide factors rejuvenating brain functions

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Signal Transduction and Targeted Therapy 2024年第1期9卷 16-18页

作者： Harald F.Langer Department of Cardiology AngiologyHaemostaseology and Medical Intensive CareUniversity Medical Centre MannheimMedical Faculty MannheimHeidelberg UniversityMannheimGermany German Centre for Cardiovascular Research(DZHK) Partner Site Heidelberg/MannheimMannheimGermany European center for Angioscience Medical Faculty MannheimHeidelberg UniversityMannheimGermany Cardiovascular systems biology Medical Clinic IUniversity Heart Center LübeckLübeckGermany

In a recent manuscript published in Nature,Schroer et *** that platelets and in particular platelet derived PF-4(CXCL4)are a novel factor,which can rejuvenate the mammalian neuronal system.1 These findings have the potential to trigger an entire new field of research opening new platelet-derived candidate effector molecules for supporting regeneration.

关键词： supporting platelets finding

CD4^(+)T cells produce IFN-I to license cDC1s for induction of cytotoxic T-cell activity in human tumors

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Cellular & Molecular Immunology 2024年第4期21卷 374-392页

作者： Xin Lei Daniël C.de Groot Marij J.P.Welters Tom de Wit Ellen Schrama Hans van Eenennaam Saskia J.Santegoets Timo Oosenbrug Annemarthe van der Veen Joris L.Vos Charlotte L.Zuur Noel F.C.C.de Miranda Heinz Jacobs Sjoerd H.van der Burg Jannie Borst Yanling Xiao Department of Immunology Leiden University Medical CenterLeidenThe Netherlands Oncode institute Leiden University Medical CenterLeidenThe Netherlands Department of Tumor Biology and Immunology The Netherlands Cancer InstituteAmsterdamThe Netherlands Department of medical Oncology Oncode InstituteLeiden University Medical CenterLeidenThe Netherlands IMMIOS B.V. OssThe Netherlands Division of medical Oncology The Netherlands Cancer InstituteAmsterdamThe Netherlands Department of Otorhinolaryngology Leiden university medical center LeidenThe Netherlands Department of Pathology Leiden University Medical CenterLeidenThe Netherlands

CD4^(+)T cells can"help"or"license" conventional type 1 dendritic cells(cDC1s)to induce CD8^(+)cytotoxic T lymphocyte(CTL)anticancer responses,as proven in mouse *** recently identified cDC1s with a transcriptomic imprint of CD4^(+)T-cell help,specifically in T-cell-infiltrated human cancers,and these cells were associated with a good prognosis and response to PD-1-targeting ***,we delineate the mechanism of cDC1 licensing by CD4^(+)T cells in *** CD4^(+)T cells produce IFNβvia the STING pathway,which promotes MHC-I antigen(cross-)presentation by cDC1s and thereby improves their ability to induce CTL anticancer *** cooperation with CD40 ligand(L),IFNβalso optimizes the costimulatory and other functions of cDC1s required for CTL response ***-I-producing CD4^(+)T cells are present in diverse T-cell-infiltrated cancers and likely deliver“help”signals to CTLs locally,according to their transcriptomic profile and colocalization with“helped/licensed”cDCs and tumor-reactive CD8^(+)T *** agreement with this scenario,the presence of IFN-I-producing CD4^(+)T cells in the TME is associated with overall survival and the response to PD-1 checkpoint blockade in cancer patients.

关键词： CD4^(+)T-cell help cDC1 licensing IFN-I signaling CD40 costimulation (cross-)presentation CTL priming Tumor control

Advances in regional nodal management of early-stage breast cancer

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Chinese Journal of cancer Research 2024年第2期36卷 215-225页

作者： Zhao Bi Yongsheng Wang Breast cancer center Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinan 250017China

With the continuous improvement of systemic treatment, reasonable local regional control of early-stage breast cancer can be translated into survival benefits. The optimization of regional nodal management in patients with limited sentinel lymph node(SLN) metastasis needs to be weighed by surgical complications, regional recurrence risk, and lymph node status, as well as other escalating treatment(systemic/radiotherapy) that may result from deescalating surgery. With the effective support and supplementation of systemic therapy and radiotherapy, the management of axillary surgery is developing in a de-escalating trend. The widespread application of neoadjuvant therapy has contributed to optimizing the management of patients with clinically node-negative/imaging nodepositive disease. In clinical practice, it is necessary to consider the residual tumor burden of regional lymph nodes when formulating the optimal irradiation fields in patients with limited positive SLN without axillary lymph node dissection. The combined application of genomic tests and American College of Surgeons Oncology Group Z0011/AMAROS criteria could provide patients with a better strategy of dual de-escalation treatment, which includes the de-escalation of both axillary surgery and systemic treatment. In the era of sentinel lymph node biopsy(SLNB), the regional nodal management of breast cancer should adhere to the concept of “updating ideas, making bold assumptions, and carefully seeking proof”, make full use of the benefits of systemic therapy and radiotherapy to reduce the scope of surgery and complications, and expand the “net benefit” of efficacy and quality of life. This review discusses the optimization of regional nodal management in the era of SLNB, in order to provide reference information for clinicians.

关键词： Breast cancer sentinel lymph node biopsy internal mammary lymph node radiotherapy surgery

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Somatic CDKN2A copy number variations are associated with the prognosis of esophageal squamous cell dysplasia

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Chinese medical Journal 2024年第8期137卷 980-989页

作者： Zhiyuan Fan Jing Zhou Yuan Tian Yu Qin Zhaojun Liu Liankun Gu Sanford M.Dawsey Wenqiang Wei Dajun Deng National Central cancer Registry National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China Key Laboratory of Carcinogenesis and Translational Research(MOE/Beijing) Division of EtiologyPeking University Cancer Hospital and InstituteBeijing 100142China Division of cancer Epidemiology and Genetics National Cancer InstituteBethesdaMDUSA Collaborative Innovation center for cancer Personalized Medicine Nanjing Medical UniversityNanjingJiangsu 211166China

Background:Somatic copy number variations(SCNVs)in the CDKN2A gene are among the most frequent events in the dysplasia-carcinoma sequence of esophageal squamous cell ***,whether CDKN2A SCNVs are useful biomarkers for the risk stratification and management of patients with esophageal squamous cell dysplasia(ESCdys)is *** study aimed to investigate the characteristics and prognostic value of CDKN2A SCNVs in patients with mild or moderate(m/M)***:This study conducted a prospective multicenter study of 205 patients with a baseline diagnosis of m/M ESCdys in five high-risk regions of China(Ci County,Hebei Province;Yanting,Sichuan Province;Linzhou,Henan Province;Yangzhong,Jiangsu Province;and Feicheng,Shandong Province)from 2005 to *** DNA was extracted from paraffin biopsy samples and paired peripheral white blood cells from patients,and a quantitative polymerase chain reaction assay,P16-Light,was used to detect CDKN2A copy *** cumulative regression and progression rates of ESCdys were evaluated using competing risk ***:A total of 205 patients with baseline m/M ESCdys were *** proportion of ESCdys regression was significantly lower in the CDKN2A deletion cohort than in the diploid and amplification cohorts(18.8%[13/69]vs.35.0%[28/80]vs.51.8%[29/56],P<0.001).In the univariable competing risk analysis,the cumulative regression rate was statistically significantly lower(P=0.008),while the cumulative progression rate was higher(P=0.017)in ESCdys patients with CDKN2A deletion than in those without CDKN2A ***2A deletion was also an independent predictor of prognosis in ESCdys(P=0.004)in the multivariable ***:The results indicated that CDKN2A SCNVs are associated with the prognosis of ESCdys and may serve as potential biomarkers for risk stratification.

关键词： Somatic copy number variations Esophageal squamous cell carcinoma Esophageal neoplasms Squamous intraepithelial lesions DNA copy number variations Prognosis Prospective study

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Improving the value of molecular testing:current status and opportunities in colorectal cancer precision medicine

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cancer Biology & Medicine 2024年第1期21卷 21-28页

作者： Haiyun Li Linwei Guo Chenchen Wang Xin Hu Ye Xu Department of Colorectal Surgery Fudan University Shanghai Cancer CenterShanghai 200032China Department of Oncology Shanghai Medical CollegeFudan UniversityShanghai 200032China Department of Gastrointestinal medical Oncology Fudan University Shanghai Cancer CenterShanghai 200032China Precision cancer medical center Affiliated with Fudan university Shanghai cancer center Shanghai 201315China

Colorectal cancer(CRC)is the second leading cause of cancer-related deaths *** radical resection with adjuvant chemotherapy remains the primary treatment choice for CRC,but the 5-year postoperative survival rate is only approximately 60%,and approximately one-third of patients with CRC experience recurrence within 2 years of ***,the transformation of high-throughput sequencing has accelerated the development of precision *** example,KRAS mutations indicate resistance to anti-epidermal growth factor receptor(EGFR)-targeted therapies in ***,molecular-guided individualized therapy has brought new promise in major clinical areas and challenges,such as novel biomarkers predicting sensitivity and resistance to immunotherapy for microsatellite stable(MSS)CRC.

关键词： cancer chemotherapy colorectal

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Gastric cancer secreted miR 214-3p inhibits the anti-angiogenesis effect of apatinib by suppressing ferroptosis in vascular endothelial cells

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Oncology Research 2024年第3期32卷 489-502页

作者： WEIXUE WANG TONGTONG WANG YAN ZHANG TING DENG HAIYANG ZHANG YI BA Department of GI medical Oncology Tanjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerTianjin's Clinical Research Center for CancerTianjin Key Iaboratory of Digestive CancerKey Laboratory of Cancer Prevention and TherapyTianjin300060China

Diferent from necrosis,apoptosis,autophagy and other forms of cell death,ferroptosis is a mechanism that catalyzes lipid peroxidation of polyunsaturated ftty acids under the action of iron divalent or lipoxygenase,leading to cell *** is currently used in the third line standard treatment of advanced gastric cancer,targeting the anti-angiogenesis ***,Apatinib mediated ferroptosis in vascular endothelial cells has not been reported *** exosomes can be taken up into target cells to regulate tumor development,but the mechanism related to vascular endothelial cell ferroptosis has not yet been ***,we show that exosomes secreted by gastric cancer cells carry miR-214.3p into vascular endothelial cells and directdy target zinc finger protein A20 to negatively regulate ACSL4,a key enzyme of lipid peroxidation during frroptosis thereby inhibiting ferroptosis in vascular endothelial cells and reducing the eficiency of *** conclusion,inhibition of miR-214-3p can increase the sensitivity of vascular endothelial cells to Apatinib,thereby promoting the antiangiogenic efect of Apatinib,suggesting a potential combination therapy for advanced gastric cancer.

关键词： Cellular ferroptosis Exosome Tyrosine kinase inhibitor Gastrointestinal tumors miRNA

Rescue of p53 functions by in vitro-transcribed mRNA impedes the growth of high-grade serous ovarian cancer

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cancer Communications 2024年第1期44卷 101-126页

作者： Monika Raab Izabela Kostova Samuel Peña-Llopis Daniela Fietz Monika Kressin Seyed Mohsen Aberoumandi Evelyn Ullrich Sven Becker Mourad Sanhaji Klaus Strebhardt Department of Gynecology Medical SchoolGoethe-UniversityFrankfurt am MainGermany Translational Genomics in Solid Tumors West German Cancer CenterUniversity HospitalEssenGermany German cancer Consortium(DKTK) EssenGermany German cancer Research center(dkfz) HeidelbergGermany Histology and Embryology Institute for Veterinary AnatomyGiessenGermany Franfurt cancer institute(FCI) Goethe UniversityFrankfurt am MainGermany German cancer Consortium(DKTK) Partner site Frankfurt/Mainza partnership between DKFZ and University Hospital FrankfurtFrankfurt am MainGermany Experimental Immunology Department for Children and Adolescents MedicineUniversity Hospital FrankfurtGoethe UniversityFrankfurt am MainGermany

Background:The cellular tumor protein p53(TP53)is a tumor suppressor gene that is frequently mutated in human *** various cancer types,the very aggressive high-grade serous ovarian carcinoma(HGSOC)exhibits the high-est prevalence of TP53 mutations,present in>96%of *** intensive efforts to reactivate p53,no clinical drug has been approved to rescue p53 *** this study,our primary objective was to administer in vitro-transcribed(IVT)wild-type(WT)p53-mRNA to HGSOC cell lines,primary cells,and ortho-topic mouse models,with the aim of exploring its impact on inhibiting tumor growth and dissemination,both in vitro and in ***:To restore the activity of p53,WT p53 was exogenously expressed in HGSOC cell lines using a mammalian vector ***,IVT WT p53 mRNA was delivered into different HGSOC model systems(primary cells and patient-derived organoids)using liposomes and studied for proliferation,cell cycle progression,apoptosis,colony formation,and chromosomal *** alterations induced by p53 mRNA were analyzed using RNA sequencing in OVCAR-8 and primary HGSOC cells,followed by ingenuity path-way *** vivo effects on tumor growth and metastasis were studied using orthotopic xenografts and metastatic intraperitoneal mouse ***:Reactivation of the TP53 tumor suppressor gene was explored in differ-ent HGSOC model systems using newly designed IVT mRNA-based *** introduction of WT p53 mRNA triggered dose-dependent apoptosis,cell cycle arrest,and potent long-lasting inhibition of HGSOC cell *** analysis of OVCAR-8 cells upon mRNA-based p53 reactivation revealed significant alterations in gene expression related to p53 signaling,such as apoptosis,cell cycle regulation,and DNA *** p53 function concurrently reduces chromosomal instability within the HGSOC cells,under-scoring its crucial contribution in safeguarding genomic integrity by moderating the baselin

关键词： apoptosis cell cycle chromosomal instability HGSOC metastatic intraperitoneal mouse model HGSOC orthotopic Xenograft model high-grade serous ovarian cancer in vitro-transcribed p53-mRNA liposomal IVT mRNA delivery system patient-derived organoid patient-derived primary cancer cell

Pyrotinib and chrysin synergistically potentiate autophagy in HER2-positive breast cancer

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Signal Transduction and Targeted Therapy 2024年第1期9卷 295-307页

作者： Xiaoxiao Liu Xing Zhang Zhiying Shao Xiaorong Zhong Xin Ding Liang Wu Jie Chen Ping He Yan Cheng Kunrui Zhu Dan Zheng Jing Jing Ting Luo institute for Breast Health Medicine Cancer CenterBreast CenterWest China HospitalSichuan University610041 ChengduSichuanChina Department of Radiation Oncology Cancer CenterAffiliated Hospital of Xuzhou Medical UniversityJiangsu Center for the Collaboration and Innovation of Cancer BiotherapyCancer InstituteXuzhou Medical University221000 XuzhouChina Department of Orthopedics Trauma and Reconstructive SurgeryUniversity Hospital RWTH AachenAachen 52074Germany cancer institute Xuzhou Medical University221000 XuzhouJiangsuChina Division of Nephrology and Transplantation Department of Internal MedicineUniversity Medical Center Rotterdam Erasmus MCRotterdam 3015 GDThe Netherlands institute for Breast Health Medicine Department of General SurgeryBreast CenterWest China HospitalSichuan University610041 ChengduSichuanChina institute for Breast Health Medicine West China HospitalSichuan University610041 ChengduSichuanChina

Human epidermal growth factor receptor 2(HER2)-positive breast cancer(BC)has been the most challenging subtype of BC,consisting of 20%of BC with an apparent correlation with poor *** that pyrotinib,a new HER2 inhibitor,has led to dramatic improvements in prognosis,the efficacy of pyrotinib monotherapy remains largely restricted due to its acquired ***,identifying a new potential antitumor drug in combination with pyrotinib to amplify therapeutic efficacy is a pressing ***,we reported a novel combination of pyrotinib with chrysin and explored its antitumor efficacy and the underlying mechanism in HER2-positive *** determined that pyrotinib combined with chrysin yielded a potent synergistic effect to induce more evident cell cycle arrest,inhibit the proliferation of BT-474 and SK-BR-3 BC cells,and repress in vivo tumor growth in xenograft mice *** may be attributed to enhanced autophagy induced by endoplasmic reticulum ***,the combined treatment of pyrotinib and chrysin induced ubiquitination and glucose-6-phosphate dehydrogenase(G6PD)degradation by upregulating zinc finger and BTB/POZ domain-containing family protein 16(ZBTB16)in tumorigenesis of ***,we identified that miR-16-5p was a potential upstream regulator of ZBTB16,and it showed a significant inverse correlation with *** of miR-16-5p overexpression by restoring ZBTB16 significantly potentiated the overall antitumor efficacy of pyrotinib combined with chrysin against HER2-positive ***,these findings demonstrate that the combined treatment of pyrotinib and chrysin enhances autophagy in HER2-positive BC through an unrecognized miR-16-5p/ZBTB16/G6PD axis.

关键词： HER2 synergistic Together

Phase Ib study of anti-EGFR antibody(SCT200) in combination with anti-PD-1 antibody(SCT-I10A) for patients with RAS/BRAF wild-type metastatic colorectal cancer

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cancer Biology & Medicine 2024年第7期21卷 636-650页

作者： Ming Bai Yao Lu Chunmei Shi Jianwei Yang Wei Li Xianli Yin Chenghui Huang Lin Shen Liangzhi Xie Yi Ba Department of GI medical Oncology Tianjin Medical University Cancer Institute & Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and TherapyTianjin Tianjin's Clinical Research Center for Cancer Tianjin Key Laboratory of Digestive Cancer Fujian medical university Union Hospital Fujian Provincial cancer Hospital cancer center The First Hospital of Jilin University Department of medical Oncology Gastroenterology and Urology Hunan Cancer Hospital Affiliated Cancer Hospital of Xiangya School of Medicine Central South University Department of Oncology The Third Xiangya Hospital Central South University Department of Gastrointestinal Oncology Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing) Peking University Cancer Hospital and Institute Beijing Engineering Research center of Protein and Antibody Sinocelltech Ltd. Department of cancer center Peking Union Medical College Hospital Chinese Academy of Medical Sciences

Objective: This study evaluated the safety and efficacy of an anti-epidermal growth factor receptor(EGFR) antibody(SCT200) and an anti-programmed cell death 1(PD-1) antibody(SCT-I10A) as third-line or subsequent therapies in patients with rat sarcoma viral oncogene(RAS)/v-raf murine sarcoma viral oncogene homolog B(BRAF) wild-type(wt) metastatic colorectal cancer(mCRC).Methods: We conducted a multicenter, open-label, phase Ib clinical trial. Patients with histologically confirmed RAS/BRAF wt m CRC with more than two lines of treatment were enrolled and treated with SCT-I10A and SCT200. The primary endpoints were the objective response rate(ORR) and safety. The secondary endpoints included disease control rate(DCR), progression-free survival(PFS), and overall survival(OS).Results: Twenty-one patients were enrolled in the study through January 28, 2023. The ORR was 28.57% and the DCR was 85.71%(18/21). The median PFS and OS were 4.14 and 12.84 months, respectively. The treatment-related adverse events(TRAEs) were tolerable. Moreover, compared with the monotherapy cohort from our previous phase I study evaluating SCT200 for RAS/BRAF wt m CRC in a third-line setting, no significant improvements in PFS and OS were observed in the combination ***: SCT200 combined with SCT-I10A demonstrated promising efficacy in previously treated RAS/BRAF wt m CRC patients with an acceptable safety profile. Further head-to-head studies with larger sample sizes are needed to validate whether the efficacy and safety of combined anti-EGFR and anti-PD-1 therapy are superior to anti-EGFR monotherapy in the third-line setting.(Registration No. NCT04229537).

关键词： Colorectal cancer SCT-I10A SCT200 epidermal growth factor receptor programmed cell death 1