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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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Recent trends in the epidemiology and clinical outcomes of inflammatory bowel disease in South Korea,2010-2018

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World Journal of Gastroenterology 2024年第9期30卷 1154-1163页

作者： Seulji Kim Hyun Jung Lee Seung Woo Lee Sanghyun Park Seong-Joon Koh Jong Pil Im Byeong Gwan Kim Kyung-Do Han Joo Sung Kim department of internal medicine Korea Institute of Radiological and Medical SciencesSeoul 01812South Korea department of internal medicine and Liver Research institute Seoul National University College of MedicineSeoul 03080South Korea department of Statistics and Actuarial science Soongsil UniversitySeoul 06978South Korea

BACKGROUND Inflammatory bowel disease(IBD)was previously regarded as a Western disease;however,its incidence is increasing in the *** epidemiology of IBD in Asia differs significantly from the patterns in the *** To comprehensively investigate the epidemiology of IBD in South Korea,inclu-ding its incidence,prevalence,medication trends,and *** We analyzed claims data from the Health Insurance Review and Assessment Service and Rare and Intractable Diseases(RIDs),operated by the National Health Insurance Service of South *** with IBD were identified based on the International Classification of Diseases,Tenth Revision,and RID diagnostic codes for Crohn’s disease(CD)and ulcerative colitis(UC)from 2010 to *** In total,14498 and 31409 patients were newly diagnosed with CD and UC,respectively,between 2010 and *** annual average incidence of CD was 3.11 cases per 105 person-years,and that of UC was 6.74 cases per 10^(5) *** 2014,the incidence rate of CD has been stable,while that of UC has steadily increased,shifting the peak age group from 50-year-olds in 2010 to 20-year-olds in *** CD and UC prevalence increased consistently over the study period;the use of 5-aminosali-cylates and corticosteroids gradually decreased,while that of immunomodulators and biologics steadily increased in both CD and *** clinical outcomes of IBD,such as hospitalization and surgery,decreased during the study *** The CD incidence has been stable since 2014,but that of UC has increased with a shift to a younger age at peak incidence between 2010 and *** clinical outcomes improved over time,with increased use of immunomodu-lators and biologics.

关键词： Inflammatory bowel disease Crohn’s disease Ulcerative colitis Incidence Prevalence

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Impact of lifestyle interventions on pathogenesis of nonalcoholic fatty liver disease

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World Journal of Gastroenterology 2024年第20期30卷 2633-2637页

作者： Wafaa Mohamed Ezzat department of internal medicine Medical Research and Clinical Studies InstituteNational Research CenterGiza 12311Egypt

This editorial builds on the article titled“Establishment and validation of an adherence prediction system for lifestyle interventions in non-alcoholic fatty liver disease”by Zeng et *** carried out a critical examination of nonalcoholic fatty liver disease(NAFLD)pathogenesis and how lifestyle interventions could facilitate disease resolution,particularly highlighting that non-alcoholic steatohepatitis(NASH)is a severe form of *** discussion details that weight loss is a pivotal factor in disease outcomes:A 3%-5%reduction is enough for resolution in 50%of non-obese individuals,while a 7%-10%reduction achieves similar benefits in obese individuals,as demonstrated by magnetic resonance ***,the editorial underscores that such lifestyle changes are instrumental not only in resolving NAFLD but also in reversing hepatic steatosis and *** insights,derived from the research,emphasize the critical role of personalized lifestyle modifications in halting the progression of NAFLD to NASH and even reversing fibrosis,thus offering a template for effective patient management.

关键词： Nonalcoholic fatty liver disease Non-alcoholic steatohepatitis Diet Physical activity Life style

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Trends in colorectal cancer incidence according to an increase in the number of colonoscopy cases in Korea

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World Journal of Gastrointestinal Oncology 2024年第1期16卷 51-60页

作者： Ga Hee Kim Yeong Chan Lee Tae Jun Kim Sung Noh Hong Dong Kyung Chang Young-Ho Kim Dong-Hoon Yang Chang Mo Moon Kyunga Kim Hyun Gun Kim Eun-Ran Kim Division of Gastroenterology Department of Internal MedicineAsan Medical CenterUniversity of Ulsan College of MedicineSeoul 05505South Korea department of Digital Health Samsung Advanced Institute for Health Science and TechnologySungkyunkwan University School of MedicineSeoul 06351South Korea Division of Gastroenterology Department of Internal MedicineSamsung Medical CenterSungkyunkwan University School of MedicineSeoul 06351South Korea Division of Gastroenterology Department of Internal MedicineEwha Womans UniversitySeoul 07985South Korea Biomedical Statistics Center Samsung Medical CenterSeoul 06351South Korea Division of Gastroenterology Department of Internal MedicineSoonchunhyang University College of MedicineSeoul 04401South Korea

BACKGROUND The incidence of colorectal cancer(CRC)and preinvasive CRC(e.g.,early colon cancer and advanced adenoma)is gradually increasing in several *** To evaluate the trend in incidence of CRC and preinvasive CRC according to the increase in the number of colonoscopies performed in *** This retrospective cohort study enrolled Korean patients from 2002 to 2020 to evaluate the incidence of CRC and preinvasive CRC,and assess the numbers of diagnostic colonoscopies and colonoscopic ***-related complications by age group were also *** The incidence of CRC showed a rapid increase,then decreased after 2012 in the 50-75 year-age *** the study period,the rate of incidence of preinvasive CRC increased at a similar level in patients under 50 and 50-75 years of *** 2009,the increase has been rapid,showing a pattern similar to the increase in *** rate of colonoscopic polypectomy in patients aged under 50 was similar to the rate in patients over 75 years of age after *** rate of complications after colonoscopy and related deaths within 3 mo was high for those over 75 years of *** The diagnosis of preinvasive CRC increased with the increase in the number of colonoscopies *** the risk of colonoscopy-related hospitalization and death is high in the elderly,if early lesions at risk of developing CRC are diagnosed and treated under or at the age of 75,colonoscopy-related complications can be reduced for those aged 76 years or over.

关键词： Colorectal cancer Preinvasive colorectal cancer Colorectal polypectomy Colonoscopy

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Epidemiology,therapy and outcome of hepatocellular carcinoma between 2010 and 2019 in Piedmont,Italy

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World Journal of Gastrointestinal Oncology 2024年第3期16卷 761-772页

作者： Christian Bracco Marta Gallarate Marco Badinella Martini Corrado Magnino Salvatore D'Agnano Roberta Canta Giulia Racca Remo Melchio Cristina Serraino Valentina Polla Mattiot Giovanni Gollè Luigi Fenoglio department of internal medicine Santa Croce e Carle General HospitalCuneo 12100Italy department of medical sciences "City of Health and Science"University HospitalTorino 10100Italy

BACKGROUND Hepatocellular carcinoma(HCC)is the most common primary liver malignancy and the second leading cause of cancer deaths *** is often diagnosed at an advanced stage and therefore its prognosis remains poor with a low 5-year survival *** patients have increasingly complex and constantly changing characteristics,thus up-to-date and comprehensive data are *** To analyze the epidemiology and main clinical characteristics of HCC patients in a referral center hospital in the northwest of Italy between 2010 and *** In this retrospective study,we analyzed the clinical data of all consecutive patients with a new diagnosis of HCC recorded at"Santa Croce e Carle"Hospital in Cuneo(Italy)between 1 January 2010 and 31 December *** highlight possible changes in HCC patterns over the 10-year period,we split the population into two 5-year groups,according to the diagnosis period(2010-2014 and 2015-2019).RESULTS Of the 328 HCC patients who were included(M/F 255/73;mean age 68.9±11.3 years),154 in the first period,and 174 in the *** C virus infection was the most common HCC risk factor(41%,135 patients).The alcoholic etiology rate was 18%,the hepatitis B virus infection etiology was 5%,and the non-viral/non-alcoholic etiology rate was 22%.The Child-Pugh score distribution of the patients was:class A 75%,class B 21%and class C 4%.The average Mayo end-stage liver disease score was 10.6±3.7.A total of 55 patients(17%)were affected by portal vein thrombosis and 158(48%)by portal *** average nodule size of the HCC was 4.6±3.1 cm.A total of 204 patients(63%)had more than one nodule<3,and 92%(305 patients)had a non-metastatic stage of the *** Barcelona Clinic Liver Cancer(BCLC)staging distribution of all patients was:4%very early,32%early,23%intermediate,34%advanced,and 7%*** survival rate was 1.6±0.3 *** 20%of the patients underwent ***,presence of ascites,BCLC stage and therapy w

关键词： Hepatocellular carcinoma Hepatitis virus Alcoholic hepatitis Non-alcoholic fatty liver disease Diagnosis Etiology Treatment

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Heterogeneity in the risk of incident liver cirrhosis driven by PNPLA3 genotype and diabetes among different populations

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Hepatobiliary Surgery and Nutrition 2024年第1期13卷 115-118页

作者： Bo Kyung Koo Dong Hyeon Lee Jeong Hwan Park Won Kim Division of Endocrinology Department of Internal MedicineBoramae Medical CenterSeoulRepublic of Korea department of internal medicine Seoul National University College of MedicineSeoulRepublic of Korea Division of Gastroenterology and Hepatology Department of Internal MedicineBoramae Medical CenterSeoulRepublic of Korea department of Pathology Boramae Medical CenterSeoulRepublic of Korea

Advanced fibrosis determines the prognosis of nonalcoholic fatty liver disease(NAFLD);therefore,accurate risk-prediction for advanced fibrosis is fundamental in the management of NAFLD(1).Targeted screening for advanced fibrosis in high-risk populations,such as those with type 2 diabetes,obesity with metabolic complications,a family history of cirrhosis,or significant alcohol use is recommended for implementing early intervention to prevent future adverse hepatic outcomes of NAFLD(2,3).Non-invasive tests including fibrosis-4 index(FIB-4)and liver stiffness measurement(LSM)are recommended to identify individuals at a higher risk of liver-related events(1,2).In addition to clinical classifications,such as FIB-4;genetic information provides further stratification for liver-related outcomes(4).

关键词： Nonalcoholic fatty liver disease(NAFLD) cirrhosis PNPLA3-rs738409

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Real-world utility of serological tests in patients with suspected scrub typhus in the Republic of Korea:A single-center,retrospective,observational study

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Asian Pacific Journal of Tropical medicine 2024年第6期17卷 273-280,I0004,I0005页

作者： Seulki Kim A Reum Kim Seungjin Lim Su Jin Lee Moonsuk Bae Division of Infectious Diseases Department of Internal MedicinePusan National University Yangsan HospitalYangsanRepublic of Korea Research institute for Convergence of Biomedical science and Technology Pusan National University Yangsan HospitalYangsanRepublic of Korea department of internal medicine Pusan National University School of MedicineBusanRepublic of Korea

Objective:Serological tests are widely used for scrub typhus diagnosis;however,their limitations are *** study aims to assess their practical value in clinical ***:We analyzed the data of adult patients with suspected scrub typhus who visited a tertiary care hospital in the Republic of Korea from September to December from 2019 to *** included patients had an acute fever and at least one of the following ten secondary findings:myalgia,skin rash,eschar,headache,thrombocytopenia,increased liver enzyme levels,lymphadenopathy,hepatomegaly,splenomegaly,and pleural *** diagnoses were grouped as scrub typhus or other diseases by two infectious disease ***:Among 136 patients who met the eligibility criteria,109 had scrub typhus and 27 had different *** and paired total antibodies using immunofluorescence assay(IFA),and total antibodies using immunochromatography-based rapid diagnostic testing(ICT)were measured in 98%,22%,and 75%of all patients,*** using paired samples for scrub typhus was established at a median of 11[interquartile range(IQR)10-16]days following the first *** the 82 admitted patients,the median admission time was 9(IQR 7-13)*** to IFA,58(55%)patients with scrub typhus had total immunoglobulin titers≥1:320,while 23(85%)patients with other disease had titers<1:*** ICT results were observed in 64(74%)patients with scrub typhus and 10(67%)patients with other diseases showed negative ICT ***:Serological testing for scrub typhus is currently insufficient for decision-making in clinical practice.

关键词： Scrub typhus Serological test Immunofluorescence assay Immunochromatography Rapid detecting test

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Coronary artery disease and heart failure:Late-breaking trials presented at American Heart Association scientific session 2023

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World Journal of Cardiology 2024年第7期16卷 389-396页

作者： Avilash Mondal Sashwath Srikanth Sanjana Aggarwal Naga R Alle Olufemi Odugbemi Ikechukwu Ogbu Rupak Desai department of internal medicine Nazareth HospitalPhiladelphiaPA 19152United States department of internal medicine East Carolina University GreenvilleGreenvilleNC 27834United States department of internal medicine Hamdard Institute of Medical Sciences and ResearchNew Delhi 110062India department of medicine Narayana Medical CollegeNelloreAndhra Pradesh 524003India department of internal medicine Lincoln Medical CenterBronxNY 10451United States department of internal medicine Mountainview Hospital Sunrise GMELas VegasNV 89108United States Independent Researcher AtlantaGA 30079United States

The late-breaking science presented at the 2023 scientific session of the American Heart Association paves the way for future pragmatic trials and provides meaningful information to guide management strategies in coronary artery disease and heart failure(HF).The dapagliflozin in patient with acute myocardial infarction(DAPA-MI)trial showed that dapagliflozin use among patients with acute MI without a history of diabetes mellitus or chronic HF has better cardiometabolic outcomes compared with placebo,with no difference in cardiovascular *** MINT trial showed that in patients with acute MI and anemia(Hgb<10 g/dL),a liberal transfusion goal(Hgb≥10 g/dL)was not superior to a restrictive strategy(Hgb 7-8 g/dL)with respect to 30-day all-cause death and recurrent *** ORBITA-2 trial showed that among patients with stable angina and coronary stenoses causing ischemia on little or no antianginal therapy,percutaneous coronary intervention results in greater improvements in anginal frequency and exercise times compared with a sham *** ARIES-HM3 trial showed that in patients with advanced HF who received a HeartMate 3 levitated left ventricular assist device and were anticoagulated with a vitamin K antagonist,placebo was noninferior to daily aspirin with respect to the composite endpoint of bleeding and thrombotic events at 1 *** TEAMMATE trial showed that everolimus with low-dose tacrolimus is safe in children and young adults when given≥6 months after cardiac *** patients being treated for HF with reduced ejection fraction(HFrEF)with specific out-of-pocket(OOP)costs for multiple medication options at the time of the clinical encounter may reduce‘contingency planning’and increase the extent to which patients are taking the medications decided *** primary outcome,which was cost-informed decisionmaking,defined as the clinician or patient mentioning costs of HFrEF medication,occurred in 49%of encounters with the checklist only

关键词： Heart failure Coronary artery disease Clinical trials Myocardial infarction Cardiovascular outcome Percutaneous coronary intervention Blood transfusion Cardiac transplant

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Atrial fibrillation and prediabetes:A liaison that merits attention!

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World Journal of Diabetes 2024年第7期15卷 1645-1647页

作者： Akash Batta Juniali Hatwal department of Cardiology Dayanand Medical College and HospitalLudhiana 141001PunjabIndia department of internal medicine Post Graduate Institute of Medical Education&ResearchChandigarh 160012India

Atrial fibrillation(AF)and prediabetes share common pathophysiological mechanisms with endothelial dysfunction and inflammation playing a key *** resultant vicious cycle which sets in culminates in a higher atherogenicity and thermogenicity of the vascular system resulting in increased major adverse cardiac or cerebrovascular event(MACCE)***,the same has not convincingly been verified in real-world *** the recent retrospective study by Desai et al amongst AF patients being admitted to hospitals following MACCE,prediabetes emerged as an independent risk factor for MACCE after adjusting for all confounding ***,certain questions like the role of metformin,quantifying the risk for MACCE amongst prediabetes compared to diabetes,the positive impact of reversion to normoglycemia remain *** provide our insights and give future directions for dedicated research in this area to clarify the exact relationship between the two.

关键词： Atrial fibrillation Major adverse cardiac or cerebrovascular event Prediabetes Diabetes Stroke Heart failure Dysglycemia Metformin

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Promising use of metformin in treating neurological disorders:biomarker-guided therapies

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Neural Regeneration Research 2024年第5期19卷 1045-1055页

作者： Allison Loan Charvi Syal Margarita Lui Ling He Jing Wang Regenerative medicine Program Ottawa Hospital Research InstituteOttawaONCanada department of Biology Faculty of ScienceUniversity of OttawaOttawaONCanada department of Pediatrics and medicine Johns Hopkins Medical SchoolBaltimoreMDUSA department of Cellular and Molecular medicine Faculty of MedicineUniversity of OttawaOttawaONCanada University of Ottawa Brain and Mind Research institute OttawaONCanada

Neurological disorders are a diverse group of conditions that affect the nervous system and include neurodegenerative diseases(Alzheimer’s disease,multiple sclerosis,Parkinson’s disease,Huntington’s disease),cerebrovascular conditions(stroke),and neurodevelopmental disorders(autism spectrum disorder).Although they affect millions of individuals around the world,only a limited number of effective treatment options are available *** most neurological disorders express mitochondria-related metabolic perturbations,metformin,a biguanide type II antidiabetic drug,has attracted a lot of attention to be repurposed to treat neurological disorders by correcting their perturbed energy ***,controversial research emerges regarding the beneficial/detrimental effects of metformin on these neurological *** that most neurological disorders have complex etiology in their pathophysiology and are influenced by various risk factors such as aging,lifestyle,genetics,and environment,it is important to identify perturbed molecular functions that can be targeted by metformin in these neurological *** molecules can then be used as biomarkers to stratify subpopulations of patients who show distinct molecular/pathological properties and can respond to metformin treatment,ultimately developing targeted *** this review,we will discuss mitochondria-related metabolic perturbations and impaired molecular pathways in these neurological disorders and how these can be used as biomarkers to guide metformin-responsive treatment for the targeted therapy to treat neurological disorders.

关键词： Alzheimer’s disease Huntington’s disease metformin mitochondrial perturbation multiple sclerosis neural degenerative diseases Parkinson’s disease stroke targeted therapy

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