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The role of proteasomes in tumorigenesis

Genes & Diseases 2024年第4期11卷 155-169页

作者： Xiangyi Zhou Ruqing Xu Yue Wu Li Zhou Tingxiu Xiang Department of oncology The First Affliated Hospital of Chongqing Medical UniversityChongqing 400016China Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized treatment Chongqing University Cancer HospitalChongqing 400030China

Protein homeostasis is the basis of normal life activities,and the proteasomefamily plays an extremely important function in this process.The proteasome 2os is a concentric circle structure with twoαrings and twoβrings overlapped.The proteasome 2os can perform both ATP-dependent and non-ATP-dependent ubiquitination proteasome degradation by binding to various subunits(such as 19S,11S,and 200 PA),which is performed by its active subunitβ1,β2,andβ5.The proteasome can degrade misfolded,excess proteins tomaintain homeostasis.At the same time,it can be utilized by tumors to degrade over-proliferate and unwanted proteins to support their growth.Proteasomes can affect the development of tumors from several aspects including tumor signaling pathways such as NF-kB and p53,cell cycle,immune regulation,and drug resistance.Proteasome-encoding genes have been found to be overexpressed in a variety of tumors,providing a potential novel target for cancer therapy.In addition,proteasome inhibitors such as bortezomib,carfilzomib,and ixazomib have been put into clinical application as the first-line treatment of multiple myeloma.More and more studies have shown that it also has different therapeutic effects in other tumors such as hepatocellular carcinoma,non-small cell lung cancer,glioblastoma,and neuroblastoma.However,proteasome inhibitors are not much effective due to their tolerance and singleness in other tumors.Therefore,further studies on their mechanisms of action and drug interactions are needed to investigate their therapeutic potential.

关键词： Bortezomib Cancer therapy Immunoproteasome Multiplemyeloma Proteasome 20S Proteasome inhibitor Thymoproteasom

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Lymphatic vessel:origin,heterogeneity,biological functions,and therapeutic targets

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Signal Transduction and Targeted Therapy 2024年第2期9卷 442-478页

作者： Zhaoliang Hu Xushi Zhao Zhonghua Wu Bicheng Qu Minxian Yuan Yanan Xing Yongxi Song Zhenning Wang Department of Surgical oncology and General Surgery The First Hospital of China Medical UniversityKey Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors(China Medical University)Ministry of Education155 North Nanjing StreetHeping DistrictShenyang 110001China

Lymphatic vessels,comprising the secondary circulatory system in human body,play a multifaceted role in maintaining homeostasis among various tissues and organs.They are tasked with a serious of responsibilities,including the regulation of lymph absorption and transport,the orchestration of immune surveillance and responses.Lymphatic vessel development undergoes a series of sophisticated regulatory signaling pathways governing heterogeneous-origin cell populations stepwise to assemble into the highly specialized lymphatic vessel networks.Lymphangiogenesis,as defined by new lymphatic vessels sprouting from preexisting lymphatic vessels/embryonic veins,is the main developmental mechanism underlying the formation and expansion of lymphatic vessel networks in an embryo.However,abnormal lymphangiogenesis could be observed in many pathological conditions and has a close relationship with the development and progression of various diseases.Mechanistic studies have revealed a set of lymphangiogenic factors and cascades that may serve as the potential targets for regulating abnormal lymphangiogenesis,to further modulate the progression of diseases.Actually,an increasing number of clinical trials have demonstrated the promising interventions and showed the feasibility of currently available treatments for future clinical translation.Targeting lymphangiogenic promoters or inhibitors not only directly regulates abnormal lymphangiogenesis,but improves the efficacy of diverse treatments.In conclusion,we present a comprehensive overview of lymphatic vessel development and physiological functions,and describe the critical involvement of abnormal lymphangiogenesis in multiple diseases.Moreover,we summarize the targeting therapeutic values of abnormal lymphangiogenesis,providing novel perspectives for treatment strategy of multiple human diseases.

关键词： therapeutic origin specialized

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Mitochondria-targeted nanoparticles overcome chemoresistance via downregulating BACH1/CD47 axis in ovarian carcinoma

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Chinese Chemical Letters 2024年第5期35卷 344-350页

作者： Ke Gong Jinghan Liao Jiangtao Lin Quan Wang Zhihua Wu Liting Wang Jiali Zhang Yi Dong Yourong Duan Jianhua Chen State Key Laboratory of Systems Medicine for Cancer Shanghai Cancer InstituteRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200032China Department of Ultrasound Xinhua HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200092China Department of oncology Shanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai 200080China

The platinum-based chemotherapy is a routine strategy for the treatment of ovarian cancer,while it is prone to chemoresistance in clinical,which hinders the treatment.Therefore,it is urgently needed to elucidate the underlying mechanism of drug resistance and form the appropriate strategy.The sequencing results showed that cisplatin(DDP)resistant ovarian cancer overexpressed BTB and CNC homology 1(BACH1),and up-regulated the“don’t eat me”signal CD47.We identified that hemin,a BACH1 inhibitor,could effectively down-regulate BACH1 and simultaneously inhibit CD47.Moreover,hemin has a synergistic effect with DDP.We designed a pH-responsive nanoparticle(H/D@FA-CaP-NPs)in which folic acid(FA)ensured targeting of ovarian cancer cells,while hemin inhibited BACH1 as well as down-regulated CD47,achieving the promotion of apoptosis of tumor cells and inducing phagocytosis of tumors by macrophages.Moreover,hemin has a synergistic effect with DDP to promote apoptosis of tumor cells.Structurally,hemin and DDP was encapsulated within hydrophobic 1,2-distearoyl-sn-glycero-3-phosphoethanolamine(DSPE)to form a tight core,and hydrophilic polyethylene glycol 2000(PEG2000)and calcium phosphate(CaP)formed the outside shell,and FA was modified on the surface of nanoparticles.In terms of function,(a)FA enhanced the active targeting of nanoparticles to tumors;(b)NPs targeted mitochondria to induce reactive oxygen species(ROS)production;(c)hemin encapsulated in nanoparticles could specifically target BACH1,thereby down regulating CD47;(d)hemin had a synergistic effect with DDP,thus augmenting the chemotherapy.Altogether,mitochondria-targeted nanoparticles H/D@FA-CaP-NPs promoted tumor apoptosis and mobilized phagocytosis to treat tumor,providing a novel scheme for clinical treatment of cisplatin-resistant ovarian carcinoma.

关键词： Cisplatin-resistant Hemin BACH1 CD47 Phagocytosis ROS Synergistic effect

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Survival Reassessment at Tumor Recurrence in Soft Matter

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Open Journal of Modelling and Simulation 2022年第1期10卷 58-69页

作者： Irina Trifonova Stefan Z. Stefanov specialized hospital for active treatment in oncology Sofia Bulgaria Electricity System Operator (ESO EAD) Sofia Bulgaria

The paper reassesses a survival at tumor recurrence in soft matter. First, the stability of structural motifs under shear in clusters of dipolar spheres is characterized. Next, there are introduced transitions between polymer knots and rhythms of these transitions are obtained. The sensor is built for these rhythms. Treatment, with a tensile force protocol, is modeled, when the tumor in soft matter is observed by the above sensor. Survival probability, at

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Lymphovenous anastomosis and complex decongestive therapy for severe deformed lymphedema with recurrent infection:A case report

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World Journal of Clinical Cases 2024年第22期12卷 5159-5167页

作者： He-Jun Wang Qing-Qing He Chang-Rui Liu Ying-Ying Wang Xun-Wei Liu Department of Thyroid and Breast Surgery The 960th Hospital of People’s Liberation ArmyJinan 250000Shandong ProvinceChina Department of oncology The 960th Hospital of People’s Liberation ArmyJinan 250000Shandong ProvinceChina

BACKGROUND Lower extremity lymphedema is a common complication following treatment for gynecological malignancies.Its incidence rate can reach up to 70%,affecting~20 million people worldwide.However,specialized treatment centers are scarce,and there is a lack of consensus on treatment approaches.Furthermore,there are even fewer reports on the systematic and effective treatment of severe lymphedema with malformations.Effective management of this condition remains a significant challenge for clinicians.CASE SUMMARY A 40-year-old woman developed bilateral leg swelling 6 years after receiving treatment for endometrial cancer.Since August 2018,she experienced>30 episodes of lymphangitis.Upon presentation,she exhibited bilateral leg swelling and deformation,with four large swellings in the posterior thigh that impeded movement,and pain in the limbs.Skin manifestations included lichenoid lesions and features of deep sclerosis.Radionuclide lymphoscintigraphy confirmed the diagnosis of lower limb lymphedema.After 6 mo of complex decongestive therapy(CDT)and three lymphaticovenous anastomosis(LVA)treatments,the patient lost 49 kg in weight.She also experienced a maximum circumference reduction of 35.2 cm in the left lower limb and 37.5 cm in the right lower limb.The leg pain disappeared,her swelling significantly decreased,and she regained the ability to walk,cycle,and run normally.CONCLUSION The combined application of CDT and LVA therapy demonstrates significant positive effects in the treatment of severe,deformed stage III lymphedema.

关键词： Lower extremity lymphedema Endometrial cancer Lymphaticovenous anastomosis Complex decongestive therapy Gynecological malignancies Recurrent infection Case report

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The basic core traditional C hinese medicine for the prevention and treatment of COVID-19 and its active mechanisms

Pharmacology Discovery

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Pharmacology Discovery 2024年第1期4卷 21-30页

作者： Zhe Xu Zi-Xin Li Zi-Yao Geng Rong-Li Shu Hui-Fang Zhou Yu-Hong Bian School of Integrative Medicine Tianjin University of Traditional Chinese MedicineTianjin 301617China Department of oncology First Teaching Hospital of Tianjin University of Traditional Chinese MedicineTianjin 300380China

Background:COVID-19 has had a dramatic impact on human health,economies,societies,and livelihoods around the world.Traditional Chinese medicine(TCM)formulae have played an important role in the prevention and treatment of COVID-19.WHO evaluated the role of TCM in treating of COVID-19 and encouraged other countries to promote the use of TCM formulae.However,the key is to find the basic core traditional Chinese medicine(BC-TCM)among those formulae.Methods:For the first time,we mined the data of TCM formulae in CNIPA and analyzed herb characteristics and association rules.We then determined the BC-TCM and screened main compounds and therapeutic targets.Finally,the potential molecular mechanisms were explored by using enrichment analyses and molecular docking.Results:This study screened 123 patented TCM formulae,including 312 herbs.According to frequency statistics and association rules,nine herbs(Gan Cao,Jin Yinhua,Guang Huoxiang,Fu Ling,Huang Qi,Jie Geng,Lian Qiao,Cang Zhu,Ku Xingren)were selected as the BC-TCM.The BC-TCM involved 166 main compounds and 48 therapeutic targets.The active compounds Hederagenin,Spinasterol,Beta-sitosterol,and Liquiritin had high binding activity to the COVID-19 targets 3CL,ACE2,and core targets RELA,HSP90AA1,STAT3,MAPK3,and TP53 according to molecular docking results.Interestingly,Hederagenin might be a potential compound for the prevention and treatment of COVID-19.Conclusion:Our research predicted and confirmed the preventive therapeutic effect of BC-TCM on COVID-19.This has the potential to broaden the scope of TCM,guide people in using clinical formulae,and provide valuable insights for future TCM discovery research.

关键词： COVID-19 traditional Chinese medicine China national intellectual property administration data mining network pharmacology

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Progress in heavy ion cancer therapy at IMP and future development

Malignancy Spectrum

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Malignancy Spectrum 2024年第2期1卷 91-98页

作者： Qiang Li Xinguo Liu Zhongying Dai Pengbo He Yuanyuan Ma Guosheng Shen Xiaodong Jin Fei Ye Xiaogang Zheng Ting Zhao Hui Zhang Zheng Li Bingwen Zou Yuehu Pu Weiqiang Chen Institute of Modern Physics Chinese Academy of SciencesLanzhouGansuChina Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences LanzhouGansuChina Gansu Provincial Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine LanzhouGansuChina University of Chinese Academy of Sciences BeijingChina Division of Thoracic Tumor Multimodality treatment and Department of Radiation oncology Cancer CenterWest China HospitalSichuan UniversityChengduSichuanChina Medical Equipment Innovation Research Center West China HospitalSichuan UniversityChengduSichuanChina

Basic research on heavy ion cancer therapy such as radiobiology, medicalphysics, and therapeutic technique has been conducted at the Institute ofModern Physics (IMP), Chinese Academy of Sciences since 1995. Based on theachievements acquired in the basic research and the requirements for a heavyion accelerator for radiotherapy purposes, a dedicated heavy ion therapy facilitynamed Heavy Ion Medical Machine (HIMM) was designed at IMP andconstructed in Wuwei, China. The HIMM facility consists of two electroncyclotron resonance ion sources, one cyclotron as the injector and onesynchrotron as the main accelerator, and four different treatment roomsequipped with passive or active beam delivery systems, and accelerates carbonions up to 400 MeV/u. After the performance inspection of HIMM organized bythe National Medical Device Inspection Center, preclinical tests like cell andanimal radiobiological experiments and dosimetric verification using anthropomorphicphantoms for elucidating the biophysical properties of the carbon ionbeams provided by HIMM were carried out. According to the Chinese medicaldevice regulations, a clinical trial in which 46 tumor patients were recruited andtwo hospitals participated was conducted in the HIMM facility, aiming atevaluating the treatment safety and short-term efficacy of the medical device.The success of the clinical trial helped the HIMM facility be authorized by theChinese government as a class III medical device. In this paper, all the aspectsmentioned above are introduced and discussed, and implications for futureimprovements are also given.

关键词： heavy ion cancer therapy clinical trial performance inspection dosimetric verification medical device

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Advances in ATM,ATR,WEE1,and CHK1/2 inhibitors in the treatment of PARP inhibitor-resistant ovarian cancer

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Cancer Biology & Medicine 2023年第12期20卷 915-921页

作者： Qin Tang Xin Wang Haixia Wang Lin Zhong Dongling Zou Department of Gynecologic oncology Chongqing University Cancer Hospital&Chongqing Cancer Institute&Chongqing Cancer HospitalChongqing 400030China Chongqing specialized Medical Research Center of Ovarian Cancer Chongqing 400030China Organoid Transformational Research Center Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized TreatmentChongqing University Cancer HospitalChongqing 400030China

Ovarian cancer(OC)poses a significant challenge in modern gynecologic oncology,both diagnostically and therapeutically.According to the American Cancer Society,an estimated 21,000 new cases of OC were reported in the United States alone in 20211.The most prevalent subtype of OC87,highgrade serous(HGS),is characterized by heightened genomic instability and defects in DNA damage response(DDR)pathways,which contribute to disease development and progression2.Notably,approximately 50%of HGS ovarian cancer(HGSOC)patients exhibit homologous recombination repair(HRR)defects(HRDs)3.

关键词： cancer treatment alone

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New trends in diagnosis and management of gallbladder carcinoma

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World Journal of Gastrointestinal oncology 2024年第1期16卷 13-29页

作者： Efstathios T Pavlidis Ioannis N Galanis Theodoros E Pavlidis ^(nd)Propedeutic Department of Surgery Hippokration General HospitalSchool of MedicineAristotle University of ThessalonikiThessaloniki 54642Greece

Gallbladder(GB)carcinoma,although relatively rare,is the most common biliary tree cholangiocarcinoma with aggressiveness and poor prognosis.It is closely associated with cholelithiasis and long-standing large(>3 cm)gallstones in up to 90%of cases.The other main predisposing factors for GB carcinoma include molecular factors such as mutated genes,GB wall calcification(porcelain)or mainly mucosal microcalcifications,and GB polyps≥1 cm in size.Diagnosis is made by ultrasound,computed tomography(CT),and,more precisely,magnetic resonance imaging(MRI).Preoperative staging is of great importance in decisionmaking regarding therapeutic management.Preoperative staging is based on MRI findings,the leading technique for liver metastasis imaging,enhanced three-phase CT angiography,or magnetic resonance angiography for major vessel assessment.It is also necessary to use positron emission tomography(PET)-CT or ^(18)F-FDG PET-MRI to more accurately detect metastases and any other occult deposits with active metabolic uptake.Staging laparoscopy may detect dissemination not otherwise found in 20%-28.6%of cases.Multimodality treatment is needed,including surgical resection,targeted therapy by biological agents according to molecular testing gene mapping,chemotherapy,radiation therapy,and immunotherapy.It is of great importance to understand the updated guidelines and current treatment options.The extent of surgical intervention depends on the disease stage,ranging from simple cholecystectomy(T1a)to extended resections and including extended cholecystectomy(T1b),with wide lymph node resection in every case or IV-V segmentectomy(T2),hepatic trisegmentectomy or major hepatectomy accompanied by hepaticojejunostomy Roux-Y,and adjacent organ resection if necessary(T3).Laparoscopic or robotic surgery shows fewer postoperative complications and equivalent oncological outcomes when compared to open surgery,but much attention must be paid to avoiding injuries.In addition to surgery,novel targeted treatment along with immunotherapy and recen

关键词： Biliary tract neoplasms Extrahepatic cholangiocarcinoma Gallbladder carcinoma Gallbladder diseases Biliary tree diseases Gastrointestinal malignancies

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Survival at Tumor Recurrence in Soft Matter

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Open Journal of Biophysics 2021年第2期11卷 147-158页

作者： Irina Trifonova Galina Kurteva Stefan Z. Stefanov specialized hospital for active treatment in oncology Sofia Bulgaria ESO EAD Sofia Bulgaria

Survival at tumor recurrence in soft matter, after chemotherapy, is assessed by RNA folding. It is shown that this recurrence is starting with development of a fluidlike globule;it changes the energy of soft matter;it proceeds as a resonant mixing;and at the end it causes diffusion. This diffusion is interpreted as metastasis in soft matter. A tumor memory is designed for its recurrence oscillations. These oscillations are marked as positive or negative according to their influence on life stabilization or destabilization. It is demonstrated that a tumor memorizes two types of recurrences. The intensity of chemotherapy in soft matter for a tumor with such memory is obtained. Survival at tumor recurrence in soft matter, after chemotherapy, is assigned to one of the five regions of the phase diagram of the “thermalized” tumor by microenvironment. To each of these regions is collated a breast cancer survival class. It is found that the survival at tumor recurrence in soft matter, after chemotherapy, well represents actual survival of 32 patients with breast cancer.

关键词： Survival Tumor Recurrence Life Stabilization Chemotherapy Soft Matter

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