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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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Impact of next-generation sequencing on antimicrobial treatment in immunocompromised adults with suspected infections

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World Journal of Emergency Medicine 2024年第2期15卷 105-110页

作者： Jia Li Jiazhen Luo Tao Hu Ling Cheng Weiwei Shang Li Yan department of Intensive Care Unit Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China department of Emergency Medicine Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Tongji medical College Huazhong University of Science and TechnologyWuhan 430030China department of Geriatrics Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China

BACKGROUND:Prompt pathogen identification can have a substantial impact on the optimization of antimicrobial *** objective of the study was to assess the diagnostic value of next-generation sequencing(NGS)for identifying pathogen and its clinical impact on antimicrobial intervention in immunocompromised patients with suspected ***:This was a retrospective *** January and August 2020,47 adult immunocompromised patients underwent NGS testing under the following clinical conditions:1)prolonged fever and negative conventional cultures;2)new-onset fever despite empiric antimicrobial treatment;and 3)afebrile with suspected infections on *** data,including conventional microbial test results and antimicrobial treatment before and after NGS,were *** were analyzed according to documented changes in antimicrobial treatment(escalated,no change,or deescalated)after the NGS ***:The median time from hospitalization to NGS sampling was 19 *** relevant pathogens were detected via NGS in 61.7% of patients(29/47),more than half of whom suffered from fungemia(n=17),resulting in an antimicrobial escalation in 53.2% of patients(25/47)and antimicrobial de-escalation in 0.2% of patients(1/47).Antimicrobial changes were mostly due to the identification of fastidious organisms such as Legionella,Pneumocystis jirovecii,and *** the remaining three cases,NGS detected clinically relevant pathogens also detected by conventional cultures a few days *** antimicrobial treatment was subsequently adjusted according to the susceptibility test ***,NGS changed antimicrobial management in 55.3%(26/47)of patients,and conventional culture detected clinically relevant pathogens in 14.9% of the patients(7/47).CONCLUSION:With its rapid identification and high sensitivity,NGS could be a promising tool for identifying relevant pathogens and enabling rapid appropriate treatment in immunocompromised patients w

关键词： Immunocompromised patients Next-generation sequencing Antimicrobial management

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Survival Analysis of Patients Undergoing Intraoperative Contrast-enhanced Ultrasound in the Surgical Treatment of Malignant Glioma

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Current medical science 2024年第2期44卷 399-405页

作者： Xu CHEN Ya-ni PENG Fang-ling CHENG Dan CAO An-yu TAO Jian CHEN department of Neurosurgery Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China department of Urology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China department of medical Ultrasound Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China

Objective:Complete resection of malignant gliomas is often *** previous study indicated that intraoperative contrast-enhanced ultrasound(ICEUS)could aid in the detection of residual tumor remnants and the total removal of brain *** study aimed to investigate the survival rates of patients undergoing resection with or without the use of ICEUS and to assess the impact of ICEUS on the prognosis of patients with malignant ***:A total of 64 patients diagnosed with malignant glioma(WHO grade HI and IV)who underwent surgery between 2012 and 2018 were *** them,29 patients received *** effects of ICEUS on overall survival(OS)and progression-free survival(PFS)of patients were evaluated.A quantitative analysis was performed to compare ICEUS parameters between gliomas and the surrounding ***:The ICEUS group showed better survival rates both in OS and PFS than the control *** univariate analysis revealed that age,pathology and ICEUS were significant prognostic factors for PFS,with only age being a significant prognostic factor for *** multivariate analysis,age and ICEUS were significant prognostic factors for both OS and *** quantitative analysis showed that the intensity and transit time of microbubbles reaching the tumors were significantly different from those of microbubbles reaching the surrounding ***:ICEUS facilitates the identification of residual *** and ICEUS are prognostic factors for malignant glioma surgery,and use of ICEUS offers a better prognosis for patients with malignant glioma.

关键词： intraoperative contrast-enhanced ultrasound malignant glioma extent of resection survival prognosis

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Efficacy of tadalafil on improvement of men with erectile dysfunction caused by COVID-19:A randomized placebo-controlled trial

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Asian Journal of Urology 2024年第1期11卷 128-133页

作者： Iman Shamohammadi Seyedmohammad Kazemeyni Mohammadali Sadighi Tara Hasanzadeh Alireza Dizavi department of Urology Nemazee HospitalShiraz University of Medical ScienceShirazIran department of Urology Shariati HospitalTehran University of Medical ScienceTehranIran

Objective: According to the high prevalence of COVID-19 and the subsequent risk of men's sexual health, we decided to investigate the efficacy of tadalafil on improvement of men with erectile dysfunction caused by ***: In this study, 70 outpatients who were recovered from COVID-19 without acute respiratory distress syndrome with negative polymerase chain reaction test and a complaint of erectile dysfunction were divided into two groups: 35 patients who received tadalafil 5 mg daily and 35 who received placebo. For each patient, basic assessment of sexual function was performed using the 5-item version of the International Index of Erectile Function (IIEF-5) questionnaire. Then, treatment was started from 2 months after complete recovery of COVID-19 with negative polymerase chain reaction test for 3 months. At the end of the treatments, the patients were re-evaluated for sexual function using the complete version of IIEF questionnaire. Finally, the results before and after treatment in the intervention group were compared with those of the control ***: Treatment with both tadalafil and placebo improved the patients' sexual function criteria compared to the baseline. However, this improvement was significantly higher in the intervention group with tadalafil than the control group with placebo (p<0.05).Conclusion: Daily administration of tadalafil 5 mg seems to be effective and safe for improvement of erectile dysfunction caused by COVID-19.

关键词： Tadalafil Erectile dysfunction COVID-19 Sexual function

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Role of glutathione transferase in phase separation of FUS and TAF15 in neurons

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Neural Regeneration Research 2025年第7期20卷 1999-2000页

作者： Kiyoung Kim department of medical science Soonchunhyang UniversityAsanKorea

Amyotrophic lateral sclerosis(ALS)is a progressive neurodegenerative disorder characterized by the degeneration of motor neurons in the brain and spinal cord,leading to muscle weakness,paralysis,and ultimately death(Cleveland and Rothstein,2001).Frontotemporal lobar degeneration(FTLD)is a neurodegenerative disease affecting the frontal and temporal lobes of the brain,leading to changes in behavior,personality,and language(Van Langenhove et al.,2012).Both ALS and FTLD are classified as proteinopathies in which abnormal protein aggregation and accumulation in neurons contribute to the disease *** in sarcoma(FUS)is a DNA/RNA-binding protein involved in various cellular processes,including transcriptional regulation,RNA splicing,and DNA *** in the FUS gene have been linked to familial ALS,highlighting the importance of FUS in the disease pathogenesis(Vance et al.,2009).In ALS and FTLD,aberrant post-translational modifications(PTMs)of FUS,such as phosphorylation,acetylation,and methylation,have been implicated in the promotion of FUS aggregation and neurotoxicity(Choi et al.,2023).Therefore,understanding the regulatory mechanisms of FUS PTMs is crucial for developing targeted therapies against these diseases.

关键词： degeneration FUS aggregation

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Cellular senescence-driven transcriptional reprogramming of the MAFB/NOTCH3 axis activates the PI3K/AKT pathway and promotes osteosarcoma progression

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Genes & Diseases 2024年第2期11卷 952-963页

作者： Zhenhao Zhang Doudou Jing Baijun Xuan Zhicai Zhang Wei Wu Zengwu Shao department of Orthopedics Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei 430022China department of Orthopedics The Second Hospital of Shanxi Medical UniversityTaiyuanShanxi 030001China department of Cardiology Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei 430022China

Osteosarcoma is the most common primary malignancy of bones and primarily occurs in adolescents and young ***,a second smaller peak of osteosarcoma incidence was reported in the elderly aged more than *** patients with osteosarcoma exhibit different characteristics compared to young patients,which usually results in a poor *** mechanism underlying osteosarcoma development in elderly patients is intriguing and of significant value in clinical *** cells can accelerate tumor progression by metabolic *** research has shown that methylmalonic acid(MMA)was significantly up-regulated in the serum of older individuals and played a central role in the development of aggressive *** found that the significant accumulation of MMA in elderly patients imparted proliferative potential to osteosarcoma *** expression of MAFB was excessively up-regulated in osteosarcoma specimens and was further enhanced in response to MMA accumulation as the patient ***,we first confirmed a novel molecular mechanism between cellular senescence and cancer,in which the MMA-driven transcriptional reprogramming of the MAFB-NOTCH3 axis accelerated osteosarcoma progression via the activation of PI3K-AKT ***,the down-regulation of the MAFB-NOTCH3 axis increased the sensitivity and effect of AKT inhibitors in osteosarcoma through significant inhibition of AKT *** conclusion,we confirmed that MAFB is a novel age-dependent biomarker for osteosarcoma,and targeting the MAFB-NOTCH3 axis in combination with AKT inhibition can serve as a novel therapeutic strategy for elderly patients with osteosarcoma in experimental and clinical trials.

关键词： Cellular senescence Elderly patients MAFB-NOTCH3axis Methylmalonic acid Osteosarcoma PI3K-AKTpathway

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Independent and Combined Associations of Sleep Duration, Bedtime, and Polygenic Risk Score with the Risk of Hearing Loss among Middle-Aged and Old Chinese: The Dongfeng–Tongji Cohort Study

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Research 2024年第1期2023卷 721-733页

作者： Miao Liu Haiqing Zhang Zhichao Wang Tingting Mo Xuefeng Lai Yaling He Minghui Jiang Meian He Weijia Kong Tangchun Wu Xiaomin Zhang department of Occupational and Environmental Health Ministry of Education Key Laboratory of Environment and Healthand State Key Laboratory of Environmental Health(Incubating)School of Public HealthTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiChina department of Otorhinolaryngology Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiChina department of Epidemiology and Biostatistics School of Public HealthTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiChina

Evidence available on the independent and combined associations of sleep duration,bedtime,and genetic predisposition with hearing loss was *** present study included 15,827 participants from the Dongfeng–Tongji cohort *** risk was characterized by polygenic risk score(PRS)based on 37 genetic loci related to hearing *** conducted multivariate logistic regression models to assess the odds ratio(OR)for hearing loss with sleep duration and bedtime,as well as the joint association and interaction with *** showed that hearing loss was independently associated with sleeping≥9 h/night compared to the recommended 7 to9:00 *** 10:00 *** to those with bedtime>10:00 *** 11:00 p.m.,with estimated ORs of 1.25,1.27,and 1.16,respectively.

关键词： Middle hearing fen

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STAT3 ameliorates truncated tau-induced cognitive deficits

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Neural Regeneration Research 2024年第4期19卷 915-922页

作者： Bingge Zhang Huali Wan Maimaitijiang Maierwufu Qian Liu Ting Li Ye He Xin Wang Gongping Liu Xiaoyue Hong Qiong Feng department of Pathophysiology School of Basic Medicine and the Collaborative Innovation Center for Brain ScienceKey Laboratory of Ministry of Education of China and Hubei Province for Neurological DisordersTongji Medical CollegeHuazhong University of Science and Technology department of Laboratory Medicine Guangdong ProvincialPeople's Hospital(Guangdong Academy of Medical Sciences)Southern Medical University department of Laboratory Medicine Zhongnan Hospital of Wuhan University department of Pathology Wuhan Children's HospitalTongji Medical CollegeHuazhong University of Science and Technology

Proteolytic cleavage of tau by asparagine endopeptidase(AEP)creates tau-N368 fragments,which may drive the pathophysiology associated with synaptic dysfunction and memory deterioration in the brain of Alzheimer’s disease ***,the molecular mechanisms of truncated tau-induced cognitive deficits remain *** suggests that signal transduction and activator of transcription-3(STAT3)is associated with modulating synaptic plasticity,cell apoptosis,and cognitive *** luciferase reporter assays,electrophoretic mobility shift assays,western blotting,and immunofluorescence,we found that human tau-N368 accumulation inhibited STAT3 activity by suppressing STAT3 translocation into the *** of STAT3 improved tau-N368-induced synaptic deficits and reduced neuronal loss,thereby improving the cognitive deficits in tau-N368 ***,in tau-N368 mice,activation of STAT3 increased N-methyl-D-aspartic acid receptor levels,decreased Bcl-2 levels,reversed synaptic damage and neuronal loss,and thereby alleviated cognitive deficits caused by *** together,STAT3 plays a critical role in truncated tau-related neuropathological *** indicates a new mechanism behind the effect of tau-N368 on synapses and memory ***3 can be used as a new molecular target to treat tau-N368-induced protein pathology.

关键词： Alzheimer’s disease apoptosis cognitive deficit memory neurodegenerative disease neuron loss N-methyl-D-aspartic acid receptor STAT3 synapse tau-N368

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Comparison of cytokine levels in prostatic secretion between the Ⅲa and Ⅲb subtypes of prostatitis

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Asian Journal of Andrology 2024年第1期26卷 77-84页

作者： Cheng-Lin Han Yu-Xuan Deng Peng Hu Bin-Tao Hu Tao Wang Ji-Hong Liu Ming-Chao Li department of Urology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430000China

Chronic prostatitis/chronic pelvic pain syndrome(CP/CPPS),also known as National Institutes of Health(NIH)type Ⅲ prostatitis,is a common disorder with an unclear etiology and no known curative *** on the presence or absence of leukocytes in expressed prostatic secretion(EPS),CP/CPPS is classifiedfurther into Illa(inflammatory)and Illb(noninflammatory)***,the severity of symptoms is not entirely consistent with the white blood cell(WBC)*** the preliminary finding of a link between inflammatory cytokines and CP/CPPS,we performed this clinical study with the aim of identifying cytokines that are differentially expressed according to whether the prostatitis subtype is Ⅲa or Ⅲ*** found that granulocyte colony-stimulating factor(G-CSF),interleukin-18(IL-18),and monocyte chemoattractant protein-1(MCP-1)levels were significantly elevated and interferon-inducible protein-10(IP-10)and platelet-derived growth factor-BB(PDGF-BB)levels were downregulated in the EPS of patients with type Ⅲa *** a word,it is a meaningful study in which we investigate the levels of various cytokines in EPS according to whether prostatitis is the Ⅲa or Ⅲb *** combination of G-CSF,IL-18,MCP-1,IP-10,and PDGF-BB expression levels could form a basis for classification,diagnosis,and therapeutic targets in clinical P/CPPS.

关键词： chronic prostatitis/chronic pelvic pain syndrome(CP/CPPS) cytokines NIH-Ⅲa NIH-ⅢB

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The role of innate immunity in diabetic nephropathy and their therapeutic consequences

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Journal of Pharmaceutical Analysis 2024年第1期14卷 39-51页

作者： Min Yang Chun Zhang department of Nephrology Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430022China

Diabetic nephropathy (DN) is an enduring condition that leads to inflammation and affects a substantial number of individuals with diabetes worldwide. A gradual reduction in glomerular filtration and emergence of proteins in the urine are typical aspects of DN, ultimately resulting in renal failure. Mounting evidence suggests that immunological and inflammatory factors are crucial for the development of DN. Therefore, the activation of innate immunity by resident renal and immune cells is critical for initiating and perpetuating inflammation. Toll-like receptors (TLRs) are an important group of receptors that identify patterns and activate immune responses and inflammation. Meanwhile, inflammatory responses in the liver, pancreatic islets, and kidneys involve inflammasomes and chemokines that generate pro-inflammatory cytokines. Moreover, the activation of the complement cascade can be triggered by glycated proteins. This review highlights recent findings elucidating how the innate immune system contributes to tissue fibrosis and organ dysfunction, ultimately leading to renal failure. This review also discusses innovative approaches that can be utilized to modulate the innate immune responses in DN for therapeutic purposes.

关键词： Innate immunity Diabetic nephropathy Inflammation Toll-like receptor Inflammasomes

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