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Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies

Signal Transduction and Targeted Therapy 2024年第1期9卷 173-210页

作者： Md Entaz Bahar Hyun Joon Kim Deok Ryong Kim Department of biochemistry and Convergence medical Sciences and Institute of medical Science Gyeongsang National UniversityCollege of MedicineJinjuSouth Korea Department of Anatomy and Convergence medical Sciences and Institute of medical Science Gyeongsang National UniversityCollege of MedicineJinjuSouth Korea

Metastatic dissemination of solid tumors,a leading cause of cancer-related mortality,underscores the urgent need for enhanced insights into the molecular and cellular mechanisms underlying metastasis,chemoresistance,and the mechanistic backgrounds of individuals whose cancers are prone to *** most prevalent signaling cascade governed by multi-kinase inhibitors is the mitogen-activated protein kinase(MAPK)pathway,encompassing the RAS–RAF–MAPK kinase(MEK)–extracellular signal-related kinase(ERK)*** kinase is a primary mediator of the MAPK pathway,responsible for the sequential activation of downstream targets,such as MEK and the transcription factor ERK,which control numerous cellular and physiological processes,including organism development,cell cycle control,cell proliferation and differentiation,cell survival,and *** in this signaling cascade are associated with diseases such as *** inhibitors(RAFi)combined with MEK blockers represent an FDAapproved therapeutic strategy for numerous RAF-mutant cancers,including melanoma,non-small cell lung carcinoma,and thyroid ***,the development of therapy resistance by cancer cells remains an important ***,an intracellular lysosome-dependent catabolic recycling process,plays a critical role in the development of RAFi resistance in ***,targeting RAF and autophagy could be novel treatment strategies for RAF-mutant *** this review,we delve deeper into the mechanistic insights surrounding RAF kinase signaling in tumorigenesis and ***,we explore and discuss the ongoing development of next-generation RAF inhibitors with enhanced therapeutic ***,this review sheds light on the functional interplay between RAF-targeted therapies and autophagy in cancer.

关键词： RAF insight mechanism

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Focal incidental colorectal fluorodeoxyglucose uptake:Should it be spotlighted?

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World Journal of Clinical Cases 2024年第15期12卷 2466-2474页

作者： Haejun Lee Kyung-Hoon Hwang Department of nuclear medicine Gachon University College of MedicineGil Medical CenterIncheon 21565South Korea

Fluorine-18 fluorodeoxyglucose(F-18 FDG)positron emission tomography/computed tomography(PET/CT)has emerged as a cornerstone in cancer evaluation imaging,with a well-established history spanning several *** imaging modality,encompassing the examination of the body from the base of the skull to the upper thighs,comprehensively covers the chest and abdominopelvic regions in a singular scan,allowing for a holistic assessment of nearly the entire body,including areas of marginal *** inherent advantage of this expansive scan range lies in its potential to unveil unexpected incidental abnormal hypermetabolic *** identification of incidental focal FDG uptake within colorectal regions during PET/CT scans is not an uncommon occurrence,albeit fraught with challenges associated with non-specific FDG *** presence of benign colorectal lesions or physiological uptake poses a particular obstacle,as these may manifest with FDG uptake levels that mimic ***,physicians are confronted with a diagnostic dilemma when encountering abnormal FDG uptake in unexpected colorectal *** studies have presented divergent results concerning these *** uptake value and its derivatives have served as pivotal metrics in quantifying FDG uptake in PET *** this article,we aim to succinctly explore the distinctive characteristics of FDG,delve into imaging findings,and elucidate the clinical significance of incidental focal colorectal *** discussion aims to contribute valuable insights into the nuanced interpretation of such findings,fostering a comprehensive understanding.

关键词： Focal Incidental Colorectal Fluorodeoxyglucose Positron emission tomography Hypermetabolism

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Unexpected focal fluorodeoxyglucose uptake in main organs;pass through or pass by?

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World Journal of Clinical Cases 2024年第11期12卷 1885-1899页

作者： Haejun Lee Kyung-Hoon Hwang Department of nuclear medicine Gachon University College of MedicineGil Medical CenterIncheon 21565South Korea

Since the inception of fluorine-18 fluorodeoxyglucose(F-18 FDG),positron emission tomography/computed tomography(PET/CT)utilizing F-18 FDG has become widely accepted as a valuable imaging modality in the field of oncology,with global prevalence in clinical *** that a single Torso PET/CT scan encompasses the anatomical region from the skull base to the upper thigh,the detection of incidental abnormal focal hypermetabolism in areas of limited clinical interest is both feasible and not *** investigations have been undertaken to delineate the distinctive features of these findings,yet the outcomes have proven *** incongruent results of these studies present a challenge for physicians,leaving them uncertain about the appropriate course of *** article provides a succinct overview of the characteristics of fluorodeoxyglucose,followed by a comprehensive discussion of the imaging findings and clinical significance associated with incidental focal abnormal F-18 FDG activity in several representative *** conclusion,while the prevalence of unrecognized malignancy varies across organs,malignancies account for a substantial proportion,ranging from approximately one-third to over half,of incidental focal *** light of these rates,physicians are urged to exercise vigilance in not disregarding unexpected uptake,facilitating more assured clinical decisions,and advocating for further active evaluation.

关键词： Incidental Focal Incidentaloma Fluorodeoxyglucose Positron emission tomography Hypermetabolism

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Self-assembly of tau fragments as a key pathologic event in tauopathies

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Neural Regeneration Research 2024年第12期19卷 2565-2566页

作者： Ly Thi Huong Luu Le Jung Hoon Lee Min Jae Lee Department of biochemistry and Molecular Biology Seoul National University College of MedicineSeoulKorea

Tau protein is encoded by the microtubuleassociated protein tau(MAPT)gene and stabilizes microtubules in the *** has unique biophysical properties that make it both highly water-soluble and positively *** tau is an intrinsically disordered protein lacking defined secondary structures,it can acquire highly organized-sheet structures and stack into a filamentous inclusion such as a paired helical filament(PHF).

关键词： tau pathologic assembly

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Performance of the EDACS-ADP incorporating high-sensitivity troponin assay:Do components of major adverse cardiac events matter?

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World Journal of Emergency medicine 2024年第3期15卷 175-180页

作者： Yedalm Yoo Shin Ahn Bora Chae Won Young Kim Department of Emergency medicine Asan Medical CenterUniversity of Ulsan College of MedicineSeoul 05505Republic of Korea

BACKGROUND:The accelerated diagnostic protocol(ADP)using the Emergency Department Assessment of Chest pain Score(EDACS-ADP),a tool to identify patients at low risk of a major adverse cardiac event(MACE)among patients presenting with chest pain to the emergency department,was developed using a contemporary troponin *** study was performed to validate and compare the performance of the EDACS-ADP incorporating high-sensitivity cardiac troponin I between patients who had a 30-day MACE with and without unstable angina(MACE I and II,respectively).METHODS:A single-center prospective observational study of adult patients presenting with chest pain suggestive of acute coronary syndrome was *** performance of EDACS-ADP in predicting MACE was assessed by calculating the sensitivity and negative predictive ***:Of the 1,304 patients prospectively enrolled,399(30.6%;95%confidence interval[95%CI]:27.7%–33.8%)were considered low-risk using the *** them,the rates of MACE I and II were 1.3%(5/399)and 1.0%(4/399),*** EDACS-ADP showed sensitivities and negative predictive values of 98.8%(95%CI:97.2%–99.6%)and 98.7%(95%CI:97.0%–99.5%)for MACE I and 98.7%(95%CI:96.8%–99.7%)and 99.0%(95%CI:97.4%–99.6%)for MACE II,***:EDACS-ADP could help identify patients as safe for early ***,when unstable angina was added to the outcome,the 30-day MACE rate among the designated lowrisk patients remained above the level acceptable for early discharge without further evaluation.

关键词： Chest pain Major adverse cardiac event Acute coronary syndrome Emergency department

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Prevalence of nonalcoholic fatty liver disease in pediatrics and adolescents:a systematic review and meta-analysis

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World Journal of Pediatrics 2024年第6期20卷 569-580页

作者： Eun Joo Lee Miyoung Choi Sang Bong Ahn Jeong-Ju Yoo Seong Hee Kang Yuri Cho Do Seon Song Hong Koh Dae Won Jeon Hye Won Lee Department of Pediatrics Yonsei University College of MedicineSeoulKorea Clinical Evidence Research National Evidence-Based Healthcare Collaborating Agency(NECA)SeoulKorea Department of Internal medicine Nowon Eulji Medical CenterEulji University College of MedicineSeoulKorea Department of Internal medicine Soonchunhyang University Bucheon HospitalBucheonKorea Department of Internal medicine Sangkye Paek HospitalInje University College of MedicineSeoulKorea Center for Liver and Pancreatobiliary Cancer National Cancer CenterGoyangKorea Department of Internal medicine College of MedicineSt.Vincent's HospitalThe Catholic University of KoreaSuwonKorea Department of Internal medicine Hanyang University College of MedicineSeoulKorea Department of Internal medicine Yonsei University College of MedicineSeoulKorea

Background As childhood obesity escalates worldwide,the prevalence of nonalcoholic fatty liver disease(NAFLD)in pediatric and adolescent populations is also ***,systematic studies and meta-analyses evaluating the prevalence of pediatric NAFLD remain *** The MEDLINE,korean medical Database(KMBASE),Embase,Global Health,and Cochrane Library databases were searched from January 1997 to April *** terms included NAFLD or steatosis;nonalcoholic or steatohepatitis;child(ren),adolescent,or teenager;and prevalence,incidence,or epidemiology.A random-effects meta-analysis model was used to estimate the prevalence of pediatric *** A total of 2116 publications were found,of which 62 were included in the *** them,27 reported the prevalence in the general population and 39 in the obese *** worldwide pooled prevalence of pediatric NAFLD was 13%[95%confidence interval(CI)9-18%]in the general population and 47%(95%CI 41%–53%)in the obese *** 16 studies in the general population and 18 in the obese population,NAFLD prevalence varied by *** the general population,the prevalence of NAFLD was 15%(95%CI 8%–23%)in males and 10%(95%CI 6%–15%)in *** the obese population,it was 54%(95%CI 46%–61%)in males and 39%(95%CI 30%–49%)in *** The global prevalence of pediatric NAFLD is rising in both the general and obese *** the increasing rates of childhood obesity,epidemiological studies on the prevalence and incidence of NAFLD are needed.

关键词： Meta-analysis Nonalcoholic fatty liver disease Pediatric Prevalence

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New insights into ATR inhibition in muscle invasive bladder cancer:The role of apolipoprotein B mRNA editing catalytic subunit 3B

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Oncology Research 2024年第6期32卷 1021-1030页

作者： HYUNHO KIM UIJU CHO SOOK HEE HONG HYUNG SOON PARK IN-HO KIM HO JUNG AN BYOUNG YONG SHIM JIN HYOUNG KANG Division of medical Oncology Department of Internal MedicineSt.Vincent’s HospitalCollege of MedicineThe Catholic University of KoreaSuwonKorea Department of Pathology St.Vincent’s HospitalCollege of MedicineThe Catholic University of KoreaSuwonKorea Division of medical Oncology Department of Internal MedicineSeoul St.Mary’s HospitalCollege of MedicineThe Catholic University of KoreaSeoulKorea

Background:Apolipoprotein B mRNA editing catalytic polypeptide(APOBEC),an endogenous mutator,induces DNA damage and activates the ataxia telangiectasia and Rad3-related(ATR)-checkpoint kinase 1(Chk1)*** cisplatin-based therapy is the mainstay for muscle-invasive bladder cancer(MIBC),it has a poor survival ***,this study aimed to evaluate the efficacy of an ATR inhibitor combined with cisplatin in the treatment of APOBEC catalytic subunit 3B(APOBEC3B)expressing ***:Immunohistochemical staining was performed to analyze an association between APOBEC3B and ATR in patients with *** APOBEC3B expression in MIBC cell lines was assessed using real-time polymerase chain reaction and western blot *** blot analysis was performed to confirm differences in phosphorylated Chk1(pChk1)expression according to the APOBEC3B *** viability and apoptosis analyses were performed to examine the anti-tumor activity of ATR inhibitors combined with ***:There was a significant association between APOBEC3B and ATR expression in the tumor tissues obtained from patients with *** with higher APOBEC3B expression showed higher pChk1 expression than cells expressing low APOBEC3B *** treatment of ATR inhibitor and cisplatin inhibited cell growth in MIBC cells with a higher APOBEC3B *** to cisplatin single treatment,combination treatment induced more apoptotic cell death in the cells with higher APOBEC3B ***:Our study shows that APOBEC3B’s higher expression status can enhance the sensitivity of MIBC to cisplatin upon ATR *** result provides new insight into appropriate patient selection for the effective application of ATR inhibitors in MIBC.

关键词： Apolipoprotein B mRNA editing catalytic polypeptide(APOBEC) Ataxia telangiectasia and Rad3-related(ATR) Bladder cancer DNA damage response DNA replication stress

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Extracellular vesicles for neural regeneration after spinal cord injury

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Neural Regeneration Research 2024年第3期19卷 491-492页

作者： Young-Ju Lim Wook-Tae Park Gun Woo Lee Department of Orthopedic Surgery Yeungnam University Medical CenterYeungnam University College of MedicineDaeguKorea

What is spinal cord injury:Spinal cord injury(SCI)is the damage to the structure of the bundles of cells and nerves that communicate signals from the brain to the body and *** pathology of SCI includes both primary and secondary injuries(Morales et al.,2016).Physical forces such as compression,shearing,contusion,and tearing are major causes of primary injury in *** are two main processes in primary injury:acute and *** acute phase includes traumatic disruption of axons and hemorrhage of the blood vessels around the spinal *** injury to the vessels can lead to increased edema within the neural and cord tissues,susceptibility to infiltration by microglia and astrocytes,excitotoxicity,and ***,disruption of the blood-spinal cord barrier results in the release of inflammatory cytokines from specific cells and vessels.

关键词： acute injuries nerves

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Intracellular zinc signaling via Kruppel-like transcription factor 6 promotes HuD expression in pancreatic β cell

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Genes & Diseases 2024年第4期11卷 24-27页

作者： Seongho Cha Chongtae Kim Myeongwoo Jung Seungyeon Ryu Sukyoung Han Wook Kim Eun Kyung Lee Department of biochemistry Department of Biomedicine&Health SciencesCollege of MedicineThe Catholic University of KoreaSeoul 06591South Korea Catholic Institute for Visual Science College of MedicineThe Catholic University of KoreaSeoul 06591South Korea Department of Molecular Science&Technology Ajou UniversitySuwon 16499South Korea

Dysfunction of pancreaticβcells caused by zinc deficiency is related to the pathogenesis of diabetes.1 Impaired zinc homeostasis in diabetes is associated with reduced zinc transporters.2 Down-regulation of HuD,an es... 详细信息

关键词： βcell homeostasis zinc

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nuclear receptor coactivator 6 is a critical regulator of NLRP3 inflammasome activation and gouty arthritis

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Cellular & Molecular Immunology 2024年第3期21卷 227-244页

作者： Kang-Gu Lee Bong-Ki Hong Saseong Lee Naeun Lee Seung-Whan Kim Donghyun Kim Wan-Uk Kim Center for Integrative Rheumatoid Transcriptomics and Dynamics The Catholic University of KoreaSeoul 06591Republic of Korea Department of Biomedicine&Health Sciences The Catholic University of KoreaSeoul 06591Republic of Korea Department of Pharmacology Asan Medical CenterUniversity of Ulsan College of MedicineSeoul 05505Republic of Korea Bio-medical Institute of Technology University of UlsanSeoul 05505Republic of Korea Department of Microbiology and Immunology Seoul National University College of MedicineSeoul 03080Republic of Korea Institute of Infectious Diseases Seoul National University College of MedicineSeoul 03080Republic of Korea Division of Rheumatology Department of Internal MedicineThe Catholic University of KoreaSeoul 06591Republic of Korea

Transcriptional coactivators regulate the rate of gene expression in the *** receptor coactivator 6(NCOA6),a coactivator,has been implicated in embryonic development,metabolism,and cancer pathogenesis,but its role in innate immunity and inflammatory diseases remains ***,we demonstrated that NCOA6 was expressed in monocytes and macrophages and that its level was increased under proinflammatory ***,nuclear NCOA6 was found to translocate to the cytoplasm in activated monocytes and then become incorporated into the inflammasome with NLRP3 and ASC,forming cytoplasmic ***,NCOA6 associated with the ATP hydrolysis motifs in the NACHT domain of NLRP3,promoting the oligomerization of NLRP3 and ASC and thereby instigating the production of IL-1βand active *** note,Ncoa6 deficiency markedly inhibited NLRP3 hyperactivation caused by the Nlrp3^(R258W) gain-of-function mutation in *** ablation of Ncoa6 substantially attenuated the severity of two NLRP3-dependent diseases,folic-induced acute tubular necrosis and crystal-induced arthritis,in *** with these findings,NCOA6 was highly expressed in macrophages derived from gout patients,and NCOA6-positive macrophages were significantly enriched in gout macrophages according to the transcriptome profiling ***,NCOA6 is a critical regulator of NLRP3 inflammasome activation and is therefore a promising target for NLRP3-dependent diseases,including gout.

关键词： nuclear receptor coactivator 6 nuclear-to-cytoplasmic translocation NLRP3 inflammasome NACHT domain Gouty arthritis

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