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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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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 COVID-19.Methods: 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 group.Results: 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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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 treatment.The 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 infections.METHODS:This was a retrospective study.Between 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 imaging.Clinical data,including conventional microbial test results and antimicrobial treatment before and after NGS,were collected.Data were analyzed according to documented changes in antimicrobial treatment(escalated,no change,or deescalated)after the NGS results.RESULTS:The median time from hospitalization to NGS sampling was 19 d.Clinically 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 Candida.In the remaining three cases,NGS detected clinically relevant pathogens also detected by conventional cultures a few days later.The antimicrobial treatment was subsequently adjusted according to the susceptibility test results.Overall,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 with suspected infections.

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 challenging.Our previous study indicated that intraoperative contrast-enhanced ultrasound(ICEUS)could aid in the detection of residual tumor remnants and the total removal of brain lesions.This 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 glioma.Methods:A total of 64 patients diagnosed with malignant glioma(WHO grade HI and IV)who underwent surgery between 2012 and 2018 were included.Among them,29 patients received ICEUS.The 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 tissues.Results:The ICEUS group showed better survival rates both in OS and PFS than the control group.The univariate analysis revealed that age,pathology and ICEUS were significant prognostic factors for PFS,with only age being a significant prognostic factor for OS.In multivariate analysis,age and ICEUS were significant prognostic factors for both OS and PFS.The quantitative analysis showed that the intensity and transit time of microbubbles reaching the tumors were significantly different from those of microbubbles reaching the surrounding tissue.Conclusion:ICEUS facilitates the identification of residual tumors.Age 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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Ultrasound-guided paravertebral nerve block anesthesia for percutaneous endoscopic laser unroofing treatment of symptomatic simple renal cysts—An innovative ambulatory surgery mode

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Asian Journal of Urology 2024年第1期11卷 65-71页

作者： Jia Hu Yuan Zhang Yong Liu Xiao Yu Shaogang Wang department of Urology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina department of Anesthesiology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina

Objective:This study was designed to evaluate the feasibility,efficacy,and safety of percutaneous ureteroscopy laser unroofing as an ambulatory surgery for symptomatic simple renal cysts under multilevel paravertebral nerve block anesthesia.Methods:From December 2015 to September 2017,33 simple renal cyst patients who had surgical indications were enrolled.Under ultrasound guidance,the T10/T11,T11/T12,and T12/L1 paravertebral spaces were identified,and 7-10 mL 0.5%ropivacaine was injected at each segment.Then a puncture needle was placed inside the cyst cavity under ultrasonic monitoring.A guidewire was introduced followed by sequential dilation up to 28/30 Fr.The extra parenchymal portion of the cyst wall was dissociated and incised using a thulium laser,and a pathological examination was performed.Results:Sensory loss to pinprick from T8 to L1 and sensory loss to ice from T6 to L2 were observed in all patients.None of the patients complained of pain during surgery.No serious complications occurred perioperatively.After the surgery,all patients recovered their lower limb muscle strength quickly,got out of bed,resumed oral feeding,and left the hospital within 24 h of admission.The pathologic diagnosis of all cyst walls was a simple renal cyst.The mean follow-up was 35.8 months.At the end of follow-up,the cyst units were reduced in size by more than 50%compared to the preoperative size,and no patient experienced a recurrence.Conclusion:Multi-level paravertebral nerve block for percutaneous ureteroscopy laser unroofing as an ambulatory surgery mode is feasible,safe,and effective for the treatment of simple renal cysts in selected patients.

关键词： Paravertebralnerve blockanesthesia Percutaneous puncture Simplerenalcyst Unroofing Ambulatorysurgery

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Assessment of cheese sign and its association with vascular risk factors: Data from PUMCH dementia cohort

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中华医学杂志(英文版) 2024年第7期137卷 830-836页

作者： Huang Xinying Hou Bo Wang Jie Li Jie Shang Li Mao Chenhui Dong Liling Liu Caiyan Feng Feng Gao Jing Peng Bin department of Neurology State Key Laboratory of Complex Severe and Rare Disease Peking Union medical College Hospital Chinese Academy of medical science and Peking Union medical College Beijing 100730 China department of Radiology Chinese Academy of medical sciences and Peking Union medical College

Background: In the clinic, practitioners encounter many patients with an abnormal pattern of dense punctate magnetic resonance imaging (MRI) signal in the basal ganglia, a phenomenon known as "cheese sign". This sign is reported as common in cerebrovascular diseases, dementia, and old age. Recently, cheese sign has been speculated to consist of dense perivascular space (PVS). This study aimed to assess the lesion types of cheese sign and analyze the correlation between this sign and vascular disease risk factors.Methods: A total of 812 patients from Peking Union medical College Hospital (PUMCH) dementia cohort were enrolled. We analyzed the relationship between cheese sign and vascular risk. For assessing cheese sign and defining its degree, the abnormal punctate signals were classified into basal ganglia hyperintensity (BGH), PVS, lacunae/infarctions and microbleeds, and counted separately. Each type of lesion was rated on a four-level scale, and then the sum was calculated; this total was defined as the cheese sign score. Fazekas and Age-Related White Matter Changes (ARWMC) scores were used to evaluate the paraventricular, deep, and subcortical gray/white matter hyperintensities.Results: A total of 118 patients (14.5%) in this dementia cohort were found to have cheese sign. Age (odds ratio [OR]: 1.090, 95% confidence interval [CI]: 1.064-1.120,P <0.001), hypertension (OR: 1.828, 95% CI: 1.123-2.983,P = 0.014), and stroke (OR: 1.901, 95% CI: 1.092-3.259,P = 0.025) were risk factors for cheese sign. There was no significant relationship between diabetes, hyperlipidemia, and cheese sign. The main components of cheese sign were BGH, PVS, and lacunae/infarction. The proportion of PVS increased with cheese sign severity.Conclusions: The risk factors for cheese sign were hypertension, age, and stroke. Cheese sign consists of BGH, PVS, and lacunae/infarction.

关键词： Dementia Cerebrovascular disease Cheese sign Dense punctate lesions Basal ganglia Risk factor White matter

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Ferroptosis: A therapeutic opportunity of inflammatory bowel disease

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中华医学杂志(英文版) 2024年第7期137卷 874-876页

作者： Ye Yulin Liu Limin Jing Yang Yao Shuangzhe Yang Mo Dai Xin Piao Meiyu Xu Xin Feng Zelin Wang Xiaoli Liu Yifei Miao Junming Gao Xingjie Yu Qingxiang Cao Xiaocang department of Gastroenterology and Hepatology Tianjin medical University General Hospital Tianjin medical University Tianjin 300070 China department of Biochemistry and Molecular Biology School of Basic medical science

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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 patients.Nonetheless,the molecular mechanisms of truncated tau-induced cognitive deficits remain unclear.Evidence suggests that signal transduction and activator of transcription-3(STAT3)is associated with modulating synaptic plasticity,cell apoptosis,and cognitive function.Using 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 nucleus.Overexpression of STAT3 improved tau-N368-induced synaptic deficits and reduced neuronal loss,thereby improving the cognitive deficits in tau-N368 mice.Moreover,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 tau-N368.Taken together,STAT3 plays a critical role in truncated tau-related neuropathological changes.This indicates a new mechanism behind the effect of tau-N368 on synapses and memory deficits.STAT3 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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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 lacking.The present study included 15,827 participants from the Dongfeng–Tongji cohort study.Genetic risk was characterized by polygenic risk score(PRS)based on 37 genetic loci related to hearing loss.We 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 PRS.Results showed that hearing loss was independently associated with sleeping≥9 h/night compared to the recommended 7 to9:00 p.***.to 10:00 p.***.compared to those with bedtime>10:00 p.***.to 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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Animal models of eosinophilic esophagitis,review and perspectives

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Animal Models and Experimental Medicine 2024年第2期7卷 127-135页

作者： Dong Li Yujia Wei Jing Wang Bo Wang department of Dermatology Huazhong University of Science and Technology Tongji Medical College Tongji HospitalWuhanChina Health Management Center Huazhong University of Science and Technology Tongji Medical College Tongji HospitalWuhanChina department of Gastroenterology Huazhong University of Science and Technology Tongji Medical College Tongji HospitalWuhanChina

Eosinophilic oesophagitis(EoE)is an allergen/immune-mediated chronic esophageal disease characterized by esophageal mucosal eosinophilic infiltration and esophageal dysfunction.Although the disease was originally attributed to a delayed allergic reaction to allergens and a Th2-type immune response,the exact pathogenesis is complex,and the efficacy of existing treatments is unsatisfactory.Therefore,the study of the pathophysiological process of EOE has received increasing attention.Animal models have been used extensively to study the molecular mechanism of EOE pathogenesis and also provide a preclinical platform for human clinical intervention studies of novel therapeutic agents.To maximize the use of existing animal models of EOE,it is important to understand the advantages or limitations of each modeling approach.This paper systematically describes the selection of experimental animals,types of allergens,and methods of sensitization and excitation during the preparation of animal models of EoE.It also discusses the utility and shortcomings of each model with the aim of providing the latest perspectives on EoE models and leading to better choices of animal models.

关键词： anaphylaxis disease models animal eosinophilic esophagitis methods

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