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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 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

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Emission wavelength selection via anomalous polarized fluorescence in ZnO-C nanowires

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Nano Research 2024年第5期17卷 4489-4497页

作者： joon Kiat Kang kim Yong Lim Chorng Haur Sow Department of Physics National University of SingaporeSingapore 117542Singapore

Defect fluorescence from high aspect ratio semiconductor nanowires typically displays a weak polarization parallel to the nanowire’s long axis due to dielectric mismatch in high aspect ratio media.Instead,anomalous 2.2 eV defect fluorescence distinctly polarized perpendicular to the nanowire is observed and measured from carbon-incorporated zinc oxide nanowires.These observations are significant because polarized defect emissions with consistent polarization on a mesoscopic scale are uncommon.Through a systematic study and comparison of experimental results with density functional theory calculations,an oriented defect complex comprising carbon substituting on an oxygen site and an oxygen vacancy(CO-VO)is deduced to be responsible for the anomalous yellow fluorescence,demonstrating a method for relating atomic-scale defect geometry to mesoscopic properties.The anomalous emission can appear in both green-and red-fluorescing nanowires grown with different carbon concentrations,verifying the independence and uniqueness of the 2.2 eV emission.This allows for polarization-dependent emission wavelength selection from a single nanowire.

关键词： anomalous polarization defects fluorescence zinc oxide carbon

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Neural Wiskott-Aldrich syndrome protein(N-WASP)promotes distant metastasis in pancreatic ductal adenocarcinoma via activation of LOXL2

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Oncology Research 2024年第4期32卷 615-624页

作者： HYUNG SUN kim YUN SUN LEE SEUNG MYUNG DONG HYO JUNG kim DA EUN LEE HYEON WOONG KANG MYEONG JIN kim joon SEONG PARK Department of Surgery Gangnam Severance HospitalYonsei University College of MedicineSeoulKorea Department of Surgery Graduate School of Medical ScienceBrain Korea 21 ProjectYonsei University College of MedicineSeoulKorea Gibiome Co. Ltd.Gyeonggi-doKorea

Pancreatic ductal adenocarcinoma(PDAC)is one of the most aggressive solid malignancies.A specific mechanism of its metastasis has not been established.In this study,we investigated whether Neural Wiskott-Aldrich syndrome protein(N-WASP)plays a role in distant metastasis of PDAC.We found that N-WASP is markedly expressed in clinical patients with PDAC.Clinical analysis showed a notably more distant metastatic pattern in the N-WASP-high group compared to the N-WASP-low group.N-WASP was noted to be a novel mediator of epithelialmesenchymal transition(EMT)via gene expression profile studies.Knockdown of N-WASP in pancreatic cancer cells significantly inhibited cell invasion,migration,and EMT.We also observed positive association of lysyl oxidase-like 2(LOXL2)and focal adhesion kinase(FAK)with the N-WASP-mediated response,wherein EMT and invadopodia function were modulated.Both N-WASP and LOXL2 depletion significantly reduced the incidence of liver and lung metastatic lesions in orthotopic mouse models of pancreatic cancer.These results elucidate a novel role for N-WASP signaling associated with LOXL2 in EMT and invadopodia function,with respect to regulation of intercellular communication in tumor cells for promoting pancreatic cancer metastasis.These findings may aid in the development of therapeutic strategies against pancreatic cancer.

关键词： Pancreatic cancer Neural Wiskott-Aldrich syndrome protein(N-WASP)signaling Metastasis Epithelial-mesenchymal transition(EMT) Lysyl oxidase-like 2(LOXL2)

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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 East.The epidemiology of IBD in Asia differs significantly from the patterns in the West.AIM To comprehensively investigate the epidemiology of IBD in South Korea,inclu-ding its incidence,prevalence,medication trends,and outcomes.METHODS 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 Korea.Patients 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 2018.RESULTS In total,14498 and 31409 patients were newly diagnosed with CD and UC,respectively,between 2010 and 2018.The annual average incidence of CD was 3.11 cases per 105 person-years,and that of UC was 6.74 cases per 10^(5) person-years.Since 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 2018.The 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 UC.The clinical outcomes of IBD,such as hospitalization and surgery,decreased during the study period.CONCLUSION 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 2018.IBD 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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Body-Shaping Membrane to Regenerate Breast Fat by Elastic Structural Holding

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Research 2024年第1期2023卷 165-180页

作者： Hye-Seon kim Jeongeun Park Hyun-Su Ha Sewoom Baek Chan Hee Lee Kyubae Lee Suji Park Jueun kim Se Won Yi Hak-joon Sung Department of Medical Engineering Graduate School of Medical ScienceBrain Korea 21 ProjectYonsei University College of MedicineSeoul 03722Republic of Korea TMD LAB Co.Ltd. 6th Floor31Gwangnaru-ro 8-gilSeongdong-guSeoul 04799Republic of Korea

Tissue regeneration requires structural holding and movement support using tissue-type-specific aids such as bone casts,skin bandages,and joint protectors.Currently,an unmet need exists in aiding breast fat regeneration as the breast moves following continuous body motion by exposing the breast fat to dynamic stresses.Here,the concept of elastic structural holding is applied to develop a shape-fitting moldable membrane for breast fat regeneration(“adipoconductive”)after surgical defects are made.The membrane has the following key characteristics:(a)It contains a panel of honeycomb structures,thereby efficiently handling motion stress through the entire membrane;(b)a strut is added into each honeycomb in a direction perpendicular to gravity,thereby suppressing the deformation and stress concentration upon lying and standing;and(c)thermo-responsive moldable elastomers are used to support structural holding by suppressing large deviations of movement that occur sporadically.The elastomer became moldable upon a temperature shift above T_(m).The structure can then be fixed as the temperature decreases.As a result,the membrane promotes adipogenesis by activating mechanotransduction in a fat miniature model with pre-adipocyte spheroids under continuous shaking in vitro and in a subcutaneous implant placed on the motion-prone back areas of rodents in vivo.

关键词： thereby shaking Elastic

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Two distinct subpopulations of marginal zone B cells exhibit differential antibody-producing capacities and radioresistance

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Cellular & Molecular Immunology 2024年第4期21卷 393-408页

作者： Sujin Lee Yeunjung Ko Hyun Woo Lee Won joon Oh Hun Gi Hong Dinuka Ariyaratne Se Jin Im Tae Jin kim Department of Immunology Graduate School of Basic Medical ScienceSungkyunkwan University School of MedicineSuwon16419Republic of Korea Department of Immunology and Molecular Medicine Faculty of Medical SciencesUniversity of Sri JayewardenepuraNugegodaSri Lanka Present address:Immunology and Microbiology Graduate Program Baylor College of MedicineHoustonTX77030USA

Marginal zone(MZ)B cells,which are splenic innate-like B cells that rapidly secrete antibodies(Abs)against blood-borne pathogens,are composed of heterogeneous subpopulations.Here,we showed that MZ B cells can be divided into two distinct subpopulations according to their CD80 expression levels.CD80^(high)MZ B cells exhibited greater Ab-producing,proliferative,and IL-10-secreting capacities than did CD80^(low)MZ B cells.Notably,CD80^(high)MZ B cells survived 2-Gy whole-body irradiation,whereas CD80^(low)MZ B cells were depleted by irradiation and then repleted with one month after irradiation.Depletion of CD80^(low)MZ B cells led to accelerated development of type II collagen(CII)-induced arthritis upon immunization with bovine CII.CD80^(high)MZ B cells exhibited higher expression of genes involved in proliferation,plasma cell differentiation,and the antioxidant response.CD80^(high)MZ B cells expressed more autoreactive B cell receptors(BCRs)that recognized double-stranded DNA or CII,expressed more immunoglobulin heavy chain sequences with shorter complementarity-determining region 3 sequences,and included more clonotypes with no N-nucleotides or with B-1a BCR sequences than CD80^(low)MZ B cells.Adoptive transfer experiments showed that CD21^(+)CD23^(+)transitional 2 MZ precursors preferentially generated CD80^(low)MZ B cells and that a proportion of CD80^(low)MZ B cells were converted into CD80^(high)MZ B cells;in contrast,CD80^(high)MZ B cells stably remained CD80^(high)MZ B cells.In summary,MZ B cells can be divided into two subpopulations according to their CD80 expression levels,Ab-producing capacity,radioresistance,and autoreactivity,and these findings may suggest a hierarchical composition of MZ B cells with differential stability and BCR specificity.

关键词： Marginal Zone B Cell CD80 Autoreactivity Radioresistance

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Tailoring local structures of atomically dispersed copper sites for highly selective CO2 electroreduction

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Carbon Energy 2024年第4期6卷 79-90页

作者： Kyung‐Jong Noh Byoung joon Park Ying Wang Yejung Choi Sang‐Hoon You Yong‐Tae kim Kug‐Seung Lee Jeong Woo Han Department of Chemical Engineering Pohang University of Science and Technology(POSTECH)PohangGyeongbukRepublic of Korea Department of Materials Science and Engineering Pohang University of Science and Technology(POSTECH)PohangGyeongbukRepublic of Korea Pohang Accelerator Laboratory(PAL) Beamline DivisionPohangGyeongbukRepublic of Korea

Atomically‐dispersed copper sites coordinated with nitrogen‐doped carbon(Cu–N–C)can provide novel possibilities to enable highly selective and active electrochemical CO_(2) reduction reactions.However,the construction of optimal local electronic structures for nitrogen‐coordinated Cu sites(Cu–N_(4))on carbon remains challenging.Here,we synthesized the Cu–N–C catalysts with atomically‐dispersed edge‐hosted Cu–N_(4) sites(Cu–N_(4)C_(8))located in a micropore between two graphitic sheets via a facile method to control the concentration of metal precursor.Edge‐hosted Cu–N_(4)C_(8) catalysts outperformed the previously reported M–N–C catalysts for CO_(2)‐to‐CO conversion,achieving a maximum CO Faradaic efficiency(FECO)of 96%,a CO current density of–8.97 mA cm–2 at–0.8 V versus reversible hydrogen electrode(RHE),and over FECO of 90%from–0.6 to–1.0 V versus RHE.Computational studies revealed that the micropore of the graphitic layer in edge‐hosted Cu–N_(4)C_(8) sites causes the d‐orbital energy level of the Cu atom to shift upward,which in return decreases the occupancy of antibonding states in the*COOH binding.This research suggests new insights into tailoring the locally coordinated structure of the electrocatalyst at the atomic scale to achieve highly selective electrocatalytic reactions.

关键词： atomic local structure density functional theory electrochemical CO_(2)reduction metal nitrogen‐doped carbon single‐atom catalyst

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Regional anesthesia in a patient with primary ciliary dyskinesia:A case report

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World Journal of Clinical Cases 2024年第17期12卷 3183-3187页

作者： Hyung joon Park Ye Hwan kim Young joon Yoon Sang Yun Cho Department of Anesthesiology and Pain Medicine Hanyang University Guri HospitalGuri-si 471-701Gyeonggi-doSouth Korea

BACKGROUND Primary ciliary dyskinesia(PCD)is an inherited autosomal-recessive disorder of impaired mucociliary clearance characterized by chronic respiratory diseases,otolaryngological diseases,central nervous system abnormalities,reproductive system abnormalities,and cardiac function abnormalities.General anesthesia in these patients is associated with a higher incidence of respiratory complications than in patients without the disease.CASE SUMMARY A 16-year-old male patient was referred to the emergency room complaining of right ankle pain due to distal tibiofibular fracture.Three years prior,he had been diagnosed with PCD.At that time,he had experienced several episodes of pneumonia,sinusitis,and chronic middle ear infections,for which he underwent surgical interventions.At the current admission,he presented with cough and sputum but no other respiratory symptoms.A chest computed tomography scan revealed centrilobular ground-glass opacities in both lower lobes and a calcified nodule in the left lower lobe.For the surgical procedure and postoperative pain management,combined spinal-epidural anesthesia was employed.The patient’s postoperative pain score was measured by the numerical rating scale(NRS).On the day of surgery,his NRS was 5 points.By the second postoperative day,the NRS score had decreased to 2–3 points.The epidural catheter was removed on the fourth day following the operation.The patient was subsequently discharged no respiratory complications.CONCLUSION We performed combined spinal-epidural anesthesia in a patient with PCD.The patient experienced no additional respiratory complications and was discharged with a low NRS score for pain.

关键词： Primary ciliary dyskinesia Combined spinal-epidural anesthesia Patient controlled epidural analgesia Lower limb operation Case report

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Prognosis of hepatocellular carcinoma expressing cytokeratin 19:Comparison with other liver cancers

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World Journal of Gastroenterology 2012年第34期18卷 4751-4757页

作者： Jung Il Lee Jin-Woo Lee joon mee kim Ja Kyung kim Hyun Jung Chung Young Soo kim Department of Internal Medicine School of MedicineInha UniversityIncheon 400-711South Korea Department of Pathology School of MedicineInha UniversityIncheon 400-711South Korea Department of Internal Medicine Yonsei University College of MedicineGangnam Severance HospitalSeoul 135-720South Korea

AIM:To investigate whether expressing biliary phenotype predicted poor outcome after the surgical treatment in primary liver cancers. METHODS:Out of 204 patients that underwent liver resection due to hepatocellular carcinoma (HCC), liver specimens of 70 patients with HCC were evaluated for biliary components by cytokeratin (CK) 19 immunostain (CK19 - HCC and CK19 + HCC). CK19 positivity was defined as membranous and/or cytoplasmic expression in ≥ 5% of tumor cells with moderate or strong intensity. Patients with other primary liver cancers, such as com- bined HCC and cholangiocarcinoma (cHCC-CC), intrahe- patic cholangiocarcinoma (ICC) who received curative liver resection, were also included in the study. Clinical characteristics of CK19-HCC and CK19 + HCC patients, including survival outcome after curative liver resection, were compared with that of cHCC-CC and ICC patients. RESULTS: The overall survival (OS) rate of CK19 - HCC(n = 49) after the curative surgical treatment was 90.7%, and 80.4% at 1 and 5 years after the resection. OS rate of CK19 + HCC (n = 21) was 74.3%, 28.9% and OS rate of cHCC-CC (n = 22) was 66.7%, 32.2% at 1 and 5 years after the surgery. For ICC (n = 19), 1 and 5-year-OS rate was 50.2% and 14.3% after the cura-tive resection. The OS rates of CK19 + HCC and cHCC-CC were significantly lower than that of CK19-HCC, but higher than the OS rate of ICC (P = 0.000). There was no statistically significant difference in OS rate between CK19 + HCC and cHCC-CC. The disease free survival (DFS) rate of CK19-HCC was 72.0% and 54.5% at 1 and 3 years after the surgical treatment. DFS rate of CK19 + HCC was 53.3%, 34.3% and DFS rate of cHCC- CC was 51.5%, 39.2% at 1 and 3 years after the resection. For ICC, 1 and 3-year-DFS rate was 28.0% and 14.0% after the curative resection. DFS rate of CK19-HCC was significantly higher than that of ICC (P = 0.017), but marginally higher than DFS rate of either CK19 + HCC or cHCC-CC (P = 0.097, P = 0.089, respec-tively). Predictors of outcome after the surgery of prima

关键词： Cytokeratin 19 Hepatocellular 癌 Intrahepatic cholangiocarcinoma 肝癌症 Hepatectomy

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Vertical plane depth-resolved surface potential and carrier separation characteristics in flexible CZTSSe solar cells with over 12% efficiency

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Carbon Energy 2024年第3期6卷 36-52页

作者： Dae-Ho Son Ha Kyung Park Dae-Hwan kim Jin-Kyu Kang Shi-joon Sung Dae-Kue Hwang Jaebaek Lee Dong-Hwan Jeon Yunae Cho William Jo Taeseon Lee JunHo kim Sang-Hoon Nam Kee-Jeong Yang Division of Energy Technology DGISTDaeguRepublic of Korea Research Center for Thin Film Solar Cells DGISTDaeguRepublic of Korea Department of Physics Ewha Womans UniversitySeoulRepublic of Korea Department of Physics Incheon National UniversityIncheonRepublic of Korea Department of Mechanical Engineering Massachusetts Institute of TechnologyCambridgeMassachusettsUSA

Cu2ZnSn(S,Se)4(CZTSSe)solar cells have resource distribution and economic advantages.The main cause of their low efficiency is carrier loss resulting from recombination of photo-generated electron and hole.To overcome this,it is important to understand their electron-hole behavior characteristics.To determine the carrier separation characteristics,we measured the surface potential and the local current in terms of the absorber depth.The elemental variation in the intragrains(IGs)and at the grain boundaries(GBs)caused a band edge shift and bandgap(Eg)change.At the absorber surface and subsurface,an upward Ec and Ev band bending structure was observed at the GBs,and the carrier separation was improved.At the absorber center,both upward Ec and Ev and downward Ec-upward Ev band bending structures were observed at the GBs,and the carrier separation was degraded.To improve the carrier separation and suppress carrier recombination,an upward Ec and Ev band bending structure at the GBs is desirable.

关键词： carrier separation CZTSSe flexible solar cell local current surface potential

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