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

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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 migration.The 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)pathway.RAF 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 death.Defects in this signaling cascade are associated with diseases such as cancer.RAF 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 cancer.However,the development of therapy resistance by cancer cells remains an important barrier.Autophagy,an intracellular lysosome-dependent catabolic recycling process,plays a critical role in the development of RAFi resistance in cancer.Thus,targeting RAF and autophagy could be novel treatment strategies for RAF-mutant cancers.In this review,we delve deeper into the mechanistic insights surrounding RAF kinase signaling in tumorigenesis and RAFi-resistance.Furthermore,we explore and discuss the ongoing development of next-generation RAF inhibitors with enhanced therapeutic profiles.Additionally,this review sheds light on the functional interplay between RAF-targeted therapies and autophagy in cancer.

关键词： RAF insight mechanism

Unraveling the role of METTL14 in metabolic dysfunction-associated fatty liver disease:insights and therapeutic implications

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Signal Transduction and Targeted Therapy 2024年第5期9卷 1781-1783页

作者： So Jung kim Jeongeun hyun Institute of Tissue Regeneration Engineering(ITREN) Dankook UniversityCheonanRepublic of Korea Department of Nanobiomedical Science and BK21 PLUS NBM Global Research Center for Regenerative Medicine Dankook UniversityCheonanRepublic of Korea Mechanobiology Dental Medicine Research Center College of DentistryDankook UniversityCheonanRepublic of Korea

The recent article published in Signal Transduction and Targeted Therapy sheds light on the significance of N6-methyladenosine(m6A)methyltransferase-like protein METTL14 in mitigating the progression of metabolic dysfunction-associated fatty liver disease(MAFLD).1 In this study,Wang et al.elucidated the downregulation of METTL14 in hepatocytes from both MAFLD patients and high-fat diet(HFD)-induced MAFLD mouse models,underscoring its pivotal role in maintaining hepatic lipid and redox homeostasis in normal livers.

关键词： liver homeostasis al.

Integration of earth-abundant cocatalysts for high-performance photoelectrochemical energy conversion

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Journal of Energy Chemistry 2024年第1期88卷 336-355,I0008页

作者： Joonhee Ma Sang hyun ahn Soo Young kim Department of Materials Science and Engineering Korea UniversitySeoul 02841Republic of Korea School of Chemical Engineering and Materials Science Chung-Ang University84 Heukseok-roDongjak-guSeoul 06974Republic of Korea

Photoelectrochemical(PEC)energy conversion has emerged as a promising and efficient approach to sustainable energy harvesting and storage.By utilizing semiconductor photoelectrodes,PEC devices can harness solar energy and drive electrochemical reactions such as water splitting or carbon dioxide(CO_(2))reduction to generate clean fuels and value-added chemicals.However,PEC energy conversion faces several challenges such as high overpotential,sluggish reaction kinetics,charge carrier recombination,and stability issues,which limit its practical implementation.Recently,significant research has been conducted to improve the overall conversion efficiency of PEC devices.One particularly promising approach is the use of cocatalysts,which involves introducing specific cocatalysts onto the photoelectrode surface to promote charge separation,improve reaction kinetics,and reduce the overpotential,thereby enhancing the overall performance of PEC energy conversion.This review provides a comprehensive overview of the recent developments in the earth-abundant cocatalysts for PEC water splitting and CO_(2) reduction.The main earth-abundant catalysts for the PEC water splitting include transition-metal dichalcogenide(TMD)-based materials,metal phosphides/carbides,and metal oxides/hydroxides.Meanwhile,PEC-CO_(2)RR was divided into C_(1) and C_(2+)based on the final product since various products could be produced,focusing on diverse earth-abundant materials-based cocatalysts.In addition,we provide and highlight key advancements achieved in the very recent reports on novel PEC system design engineering with cocatalysts.Finally,the current problems associated with PEC systems are discussed along with a suggested direction to overcome these obstacles.

关键词： Solar energy Photo-electrochemical Water splitting CO_(2)reduction Cocatalysts

Depolarization mitigated in ferroelectric Hf_(0.5)Zr_(0.5)O_(2)ultrathin films(<5 nm)on Si substrate by interface engineering

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Journal of Advanced Ceramics 2024年第3期13卷 282-292页

作者： Se hyun kim Younghwan Lee Dong hyun Lee Geun Hyeong Park hyun Woo Jeong Kun Yang Yong Hyeon Cho Young Yong kim Min Hyuk Park Department of Materials Science and Engineering College of EngineeringSeoul National UniversitySeoul 08826Republic of Korea Research Institute of Advanced Materials College of EngineeringSeoul National UniversitySeoul 08826Republic of Korea Inter-university Semiconductor Research Center College of EngineeringSeoul National UniversitySeoul 08826Republic of Korea Pohang Accelerator Laboratory Pohang University of Science&TechnologyPohang 790784Republic of Korea

(Hf,Zr)O_(2)offers considerable potential for next-generation semiconductor devices owing to its nonvolatile spontaneous polarization at the nanoscale.However,scaling this material to sub-5 nm thickness poses several challenges,including the formation of an interfacial layer and high trap concentration.In particular,a low-k SiO_(2)interfacial layer is naturally formed when(Hf,Zr)O_(2)films are directly grown on a Si substrate,leading to high depolarization fields and rapid reduction of the remanent polarization.To address these issues,we conducted a study to significantly improve ferroelectricity and switching endurance of(Hf,Zr)O_(2)films with sub-5 nm thicknesses by inserting a TiO_(2)interfacial layer.The deposition of a Ti film prior to Hf_(0.5)Zr_(0.5)O_(2)film deposition resulted in a high-k TiO_(2)interfacial layer and prevented the direct contact of Hf_(0.5)Zr_(0.5)O_(2)with Si.Our findings show that the high-k TiO_(2)interfacial layer can reduce the SiO_(2)/Si interface trap density and the depolarization field,resulting in a switchable polarization of 60.2μC/cm^(2)for a 5 nm thick Hf_(0.5)Zr_(0.5)O_(2)film.Therefore,we propose that inserting a high-k TiO_(2)interfacial layer between the Hf_(0.5)Zr_(0.5)O_(2)film and the Si substrate may offer a promising solution to enhancing the ferroelectricity and reliability of(Hf,Zr)O_(2)grown on the Si substrate and can pave the way for next-generation semiconductor devices with improved performance.

关键词： ferroelectric charge trapping hafnia depolarization

Metabolic relationships between marine red algae and algae‑associated bacteria

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Marine Life Science & Technology 2024年第2期6卷 298-314页

作者： Kyung hyun kim Jeong Min kim Ju Hye Baek Sang Eun Jeong Hocheol kim Hwan Su Yoon Che Ok Jeon Department of Biological Sciences and Biotechnology Hannam UniversityDaejon 34054Republic of Korea Department of Life Science Chung-Ang UniversitySeoul 06974Republic of Korea Department of Biological Sciences Sungkyunkwan UniversitySuwon 16419Republic of Korea

Mutualistic interactions between marine phototrophs and associated bacteria are an important strategy for their success-ful survival in the ocean,but little is known about their metabolic relationships.Here,bacterial communities in the algal sphere(AS)and bulk solution(BS)of nine marine red algal cultures were analyzed,and Roseibium and Phycisphaera were identified significantly more abundantly in AS than in BS.The metabolic features of Roseibium RMAR6-6(isolated and genome-sequenced),Phycisphaera MAG 12(obtained by metagenomic sequencing),and a marine red alga,Porphyridium purpureum CCMP1328(from GenBank),were analyzed bioinformatically.RMAR6-6 has the genetic capability to fix nitrogen and produce B vitamins(B1,B2,B5,B6,B9,and B12),bacterioferritin,dimethylsulfoniopropionate(DMSP),and phenylacetate that may enhance algal growth,whereas MAG 12 may have a limited metabolic capability,not producing vitamins B9 and B12,DMSP,phenylacetate,and siderophores,but with the ability to produce bacitracin,possibly modulating algal microbiome.P.purpureum CCMP1328 lacks the genetic capability to fix nitrogen and produce vitamin B12,DMSP,phenylacetate,and siderophore.It was shown that the nitrogen-fixing ability of RMAR6-6 promoted the growth of P.pur-pureum,and DMSP reduced the oxidative stress of P.purpureum.The metabolic interactions between strain RMAR6-6 and P.purpureum CCMP1328 were also investigated by the transcriptomic analyses of their monoculture and co-culture.Taken together,potential metabolic relationships between Roseibium and P.purpureum were proposed.This study provides a bet-ter understanding of the metabolic relationships between marine algae and algae-associated bacteria for successful growth.

关键词： Metabolic relationship Marine red algae Symbiotic bacteria Roseibium Phycisphaera Porphyridium

Defect Detection Model Using Time Series Data Augmentation and Transformation

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Computers, Materials & Continua 2024年第2期78卷 1713-1730页

作者： Gyu-Il kim hyun Yoo Han-Jin Cho Kyungyong Chung Department of Computer Science Kyonggi UniversitySuwon-si16227Korea Contents Convergence Software Research Institue Kyonggi UniversitySuwon-si16227Korea Department of Energy IT Engineering Far East UniversityEumsung-gun27601Korea Division of AI Computer Science and Engineering Kyonggi UniversitySuwon-si16227Korea

Time-series data provide important information in many fields,and their processing and analysis have been the focus of much research.However,detecting anomalies is very difficult due to data imbalance,temporal dependence,and noise.Therefore,methodologies for data augmentation and conversion of time series data into images for analysis have been studied.This paper proposes a fault detection model that uses time series data augmentation and transformation to address the problems of data imbalance,temporal dependence,and robustness to noise.The method of data augmentation is set as the addition of noise.It involves adding Gaussian noise,with the noise level set to 0.002,to maximize the generalization performance of the model.In addition,we use the Markov Transition Field(MTF)method to effectively visualize the dynamic transitions of the data while converting the time series data into images.It enables the identification of patterns in time series data and assists in capturing the sequential dependencies of the data.For anomaly detection,the PatchCore model is applied to show excellent performance,and the detected anomaly areas are represented as heat maps.It allows for the detection of anomalies,and by applying an anomaly map to the original image,it is possible to capture the areas where anomalies occur.The performance evaluation shows that both F1-score and Accuracy are high when time series data is converted to images.Additionally,when processed as images rather than as time series data,there was a significant reduction in both the size of the data and the training time.The proposed method can provide an important springboard for research in the field of anomaly detection using time series data.Besides,it helps solve problems such as analyzing complex patterns in data lightweight.

关键词： Defect detection time series deep learning data augmentation data transformation

Endoscopic ultrasound-guided tissue sampling induced pancreatic duct leak resolved by the placement of a pancreatic stent:A case report

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World Journal of Clinical Cases 2024年第9期12卷 1677-1684页

作者： Ki-hyun kim Chang Hwan Park Eunae Cho Yohan Lee Department of Internal Medicine Chonnam National University HospitalGwangju 61469South Korea Department of Gastroenterology Chonnam National University HospitalGwangju 61469South Korea

BACKGROUND Pancreatic ductal leaks complicated by endoscopic ultrasonography-guided tissue sampling(EUS-TS)can manifest as acute pancreatitis.CASE SUMMARY A 63-year-old man presented with persistent abdominal pain and weight loss.Diagnosis:Laboratory findings revealed elevated carbohydrate antigen 19-9(5920 U/mL)and carcinoembryonic antigen(23.7 ng/mL)levels.Magnetic resonance imaging of the pancreas revealed an approximately 3 cm ill-defined space-occupying lesion in the inferior aspect of the head,with severe encasement of the superior mesenteric artery.Pancreatic ductal adenocarcinoma was confirmed after pathological examination of specimens obtained by EUS-TS using the fanning method.Interventions and outcomes:The following day,the patient experienced severe abdominal pain with high amylase(265 U/L)and lipase(1173 U/L)levels.Computed tomography of the abdomen revealed edematous wall thickening of the second portion of the duodenum with adjacent fluid collections and a suspicious leak from either the distal common bile duct or the main pancreatic duct in the head.Endoscopic retrograde cholangiopancreatography revealed dye leakage in the head of the main pancreatic duct.Therefore,a 5F 7 cm linear plastic stent was deployed into the pancreatic duct to divert the pancreatic juice.The patient’s abdominal pain improved immediately after pancreatic stent insertion,and amylase and lipase levels normalized within a week.Neoadjuvant chemotherapy was then initiated.CONCLUSION Using the fanning method in EUS-TS can inadvertently cause damage to the pancreatic duct and may lead to clinically significant pancreatitis.Placing a pancreatic stent may immediately resolve acute pancreatitis and shorten the waiting time for curative therapy.When using the fanning method during EUSTS,ductal structures should be excluded to prevent pancreatic ductal leakage.

关键词： Endoscopic ultrasound-guided tissue sampling Pancreatitis Pancreatic duct leak Pancreatic stent Case report

Capsosiphon fulvescens suppresses LPS-stimulated inflammatory responses by suppressing TLR4/NF-κB activation in RAW264.7 murine macrophages

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Asian Pacific Journal of Tropical Biomedicine 2024年第3期14卷 115-126页

作者： Seon Yeong Ji EunJin Bang hyun Hwangbo Min Yeong kim Da Hye kim Su hyun Hong Shin-hyung Park Chang-Young Kwon Gi-Young kim You-Jin Jeon Suengmok Cho Yung hyun Choi Department of Biochemistry Dong-eui University College of Korean MedicineBusan 47227Republic of Korea Basic Research Laboratory for the Regulation of Microplastic-Mediated Diseases and Anti-Aging Research Center Dong-eui UniversityBusan 47227Republic of Korea Department of Pathology Dong-eui University College of Korean MedicineBusan 47227Republic of Korea Department of Oriental Neuropsychiatry Dong-eui University College of Korean MedicineBusan 47227Republic of Korea Department of Marine Life Science Jeju National UniversityJeju 63243Republic of Korea Department of Food Science and Technology/Institute of Food Science Pukyong National UniversityBusan 48513Republic of Korea

Objective:To evaluate the effects of Capsosiphon fulvescens(C.fulvescens)ethanolic extract on inflammation in lipopolysaccharide(LPS)-induced RAW296.7 macrophages.Methods:The protective effects of C.fulvescens ethanolic extract on LPS-induced inflammation in RAW264.7 macrophages were assessed using biochemical analysis,including enzyme-linked immunosorbent assay,quantitative reverse transcription-polymerase chain reaction,and Western blot analysis.To examine reactive oxygen species(ROS)production,flow cytometry analysis,and immunofluorescence staining were used.Furthermore,the modulatory effect of C.fulvescens ethanolic extract on NF-κB activation was investigated.Results:C.fulvescens ethanolic extract significantly attenuated LPS-induced levels of pro-inflammatory cytokines and notably reduced the secretion and mRNA levels of LPS-mediated matrix metalloproteinases.In addition,C.fulvescens ethanolic extract decreased ROS production and suppressed the TLR4/NF-κB signaling pathway.Conclusions:C.fulvescens ethanolic extract alleviates inflammation as well as oxidative stress by modulating the TLR4/NF-κB signaling in LPS-induced RAW264.7 macrophages.C.fulvescens can be used as a potential therapeutic agent to suppress inflammation and oxidative stress-associated diseases.

关键词： Capsosiphon fulvescens Inflammation Oxidative stress NF-κB Nrf2 TLR4

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 countries.AIM To evaluate the trend in incidence of CRC and preinvasive CRC according to the increase in the number of colonoscopies performed in Korea.METHODS 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 polypectomies.Colonoscopy-related complications by age group were also determined.RESULTS The incidence of CRC showed a rapid increase,then decreased after 2012 in the 50-75 year-age group.During the study period,the rate of incidence of preinvasive CRC increased at a similar level in patients under 50 and 50-75 years of age.Since 2009,the increase has been rapid,showing a pattern similar to the increase in colonoscopies.The rate of colonoscopic polypectomy in patients aged under 50 was similar to the rate in patients over 75 years of age after 2007.The rate of complications after colonoscopy and related deaths within 3 mo was high for those over 75 years of age.CONCLUSION The diagnosis of preinvasive CRC increased with the increase in the number of colonoscopies performed.As 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