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SBL-JP-0004:A promising dual inhibitor of JAK2 and PI3KCD against gastric cancer

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Oncology Research 2025年第1期33卷 235-243页

作者： HASSAN M.OTIFI Department of pathology College of MedicineKing Khalid UniversityAbha62521Saudi Arabia

Background:Gastric cancer(GC)remains a global health burden and is often characterized by heterogeneous molecular profiles and resistance to conventional *** phosphoinositide 3-kinase and PI3K and Janus kinase(JAK)signal transducer and activator of transcription(JAK-STAT)pathways play pivotal roles in GC progression,making them attractive targets for therapeutic ***:This study applied a computational and molecular dynamics simulation approach to identify and characterize SBL-JP-0004 as a potential dual inhibitor of JAK2 and PI3KCD *** and SNU-5 GC cells were used for in vitro ***:SBL-JP-0004 exhibited a robust binding affinity for JAK2 and PI3KCD kinases,as evidenced by molecular docking scores and molecular dynamics *** interactions and Gibbs binding free energy estimates confirmed stable and favorable interactions with target ***-JP-0004 displayed an half-maximal inhibitory concentration(IC_(50))value of 118.9 nM against JAK2 kinase and 200.9 nM against PI3KCD ***-JP-0004 exhibited potent inhibition of cell proliferation in KATOIII and SNU-5 cells,with half-maximal growth inhibitory concentration(GI50)values of 250.8 and 516.3 nM,respectively.A significant elevation in the early phase apoptosis(28.53%in KATOIII cells and 26.85%in SNU-5 cells)and late phase apoptosis(17.37%in KATOIII cells and 10.05%in SNU-5 cells)were observed with SBL-JP-0004 treatment compared to 2.1%and 2.83%in their respective ***:The results highlight SBL-JP-0004 as a promising dual inhibitor targeting JAK2 and PI3KCD kinases for treating GC and warrant further preclinical and clinical investigations to validate its utility in clinical settings.

关键词： Gastric cancer(GC) Dual inhibition JAK2 PI3KCD SBL-JP-0004 Molecular docking Molecular dynamics simulation

Lenalidomide regulates the CCL21/CCR7/ERK1/2 axis to inhibit migration and proliferation in diffuse large B-cell lymphoma

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Oncology Research 2025年第1期33卷 199-212页

作者： WEN YANG BIN TANG DAN XU WENXIU YANG Department of pathology Guizhou Medical UniversityThe Affiliated Hospital of Guizhou Medical UniversityGuiyang550004China

Background:The prognostic significance of the chemokine receptor CCR7 in diffuse large B-cell lymphoma(DLBCL)has been reported ***,the detailed mechanisms of CCR7 in DLBCL,particularly regarding its interaction with lenalidomide treatment,are not fully ***:Our study utilized bioinformatics approaches to identify hub genes in SU-DHL-2 cell lines treated with lenalidomide compared to control *** data and clinical information from 122 patients with DLBCL were analyzed to assess the correlation of CCR7 and p-ERK1/2 expression with the prognosis of ***,in vitro and in vivo experiments were conducted to clarify the role of CCR7 in the response of DLBCL to lenalidomide ***:Our bioinformatics analysis pinpointed CCR7 as a hub gene in the context of lenalidomide treatment in ***,31.14%and 36.0%(44/122)of DLBCL cases showed positive expression for CCR7 and ERK1/2 respectively,establishing them as independent prognostic factors for adverse outcomes in DLBCL via multivariate Cox regression ***,our studies demonstrated that the external application of the protein CCL21 promoted proliferation,migration,invasion,and activation of the ERK1/2 pathway in SU-DHL-2 and OCI-LY3 cell lines with high levels of CCR7 *** effect was mitigated by CCR7 silencing through siRNA,application of ERK inhibitors,or lenalidomide *** vivo experiments reinforced the efficacy of lenalidomide,significantly reducing tumor growth rate,tumor mass,serum total LDH levels,and expression of CCR7 and p-ERK1/2 in a SUDHL-2 xenograft model in nude mice(p<0.05).Conclusion:Our study clarifies the potential role of the CCL21/CCR7/ERK1/2 axis in the therapeutic effects of lenalidomide in DLBCL treatment.

关键词： CCR7 CCL21 ERK1/2 Lenalidomide Diffuse large B-cell lymphoma(DLBCL)

Sudden cardiac death and valvular pathology

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Forensic Sciences Research 2019年第3期4卷 280-286页

作者： Rosa H.A.M.Henriques de Gouveia Francisco M.A.Corte Real Goncalves Forensic Clinical and pathology Service Central Branch of the National Institute of Legal Medicine and Forensic SciencesCoimbraPortugal

Sudden death due to valvular heart disease is reported to range from 1% to 5% in native valves and around 0.2%-0.9%/year in *** nature of the diseases is varied,from heritable,congenital to *** may affect both genders in multiple age *** authors show and comment examples of the major nosologic aetiologies underlying unexpected exitus letalis of valvular nature.

关键词： Forensic sciences forensic pathology sudden death cardiac valvular pathology

Genetic signatures of ERCC1 and ERCC2 expression,along with SNPs variants,unveil favorable prognosis in SCLC patients undergoing platinum-based chemotherapy

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Oncology Research 2025年第1期33卷 45-55页

作者： ENRICO CALIMAN SARA FANCELLI FEDERICO SCOLARI ADRIANO PASQUI CLARA MANNESCHI DANIELE LAVACCHI FRANCESCA MAZZONI FRANCESCA GENSINI VALERIA PASINI CAMILLA EVA COMIN LUCA VOLTOLINI SERENA PILLOZZI LORENZO ANTONUZZO Clinical Oncology Unit Careggi University HospitalFlorence50134Italy Department of Experimental and Clinical Medicine University of FlorenceFlorence50134Italy Department of Health Sciences University of FlorenceFlorence50134Italy Medical Oncology Unit Careggi University HospitalFlorence50134Italy Department of Experimental and Clinical Biomedical Sciences“Mario Serio” University of FlorenceFlorence50134Italy Section of Anatomic pathology Department of Health SciencesUniversity of FlorenceFlorence50139Italy Section of Surgery Histopathology and Molecular PathologyUniversity of FlorenceFlorence50139Italy Thoracic Surgery Unit Careggi University HospitalFlorence50134Italy

Background:Platinum chemotherapy(CT)remains the backbone of systemic therapy for patients with smallcell lung cancer(SCLC).The nucleotide excision repair(NER)pathway plays a central role in the repair of the DNA damage exerted by platinum *** in this repair mechanism may affect patients’*** and Methods:We conducted a retrospective analysis of data from 38 patients with extensive disease(ED)-SCLC who underwent platinum-CT at the Clinical Oncology Unit,Careggi University Hospital,Florence(Italy),from 2015 to *** expression analysis and single nucleotide polymorphism(SNP)characterization of three NER pathway genes—namely ERCC1,ERCC2,and ERCC5—were performed on patient tumor ***:Overall,elevated expression of ERCC genes was observed in SCLC patients compared to healthy *** with low ERCC1 and ERCC5 expression levels exhibited a better median progression-free survival(mPFS=7.1 vs.4.9 months,p=0.39 for ERCC1 and mPFS=6.9 vs.4.8 months,p=0.093 for ERCC5)and overall survival(mOS=8.7 vs.6.0 months,p=0.4 for ERCC1 and mOS=7.2 vs.6.2 months,p=0.13 for ERCC5).Genotyping analysis of five SNPs of ERCC genes showed a longer survival in patients harboring the wild-type genotype or the heterozygous variant of the ERCC1 rs11615 SNP(p=0.24 for PFS and p=0.14 for OS)and of the rs13181 and rs1799793 ERCC2 SNPs(p=0.43 and p=0.26 for PFS and p=0.21 and p=0.16 for OS,respectively)compared to patients with homozygous mutant ***:The comprehensive analysis of ERCC gene expression and SNP variants appears to identify patients who derive greater survival benefits from platinum-CT.

关键词： Small cell lung cancer(SCLC) Nucleotide excision repair(NER)pathway ERCC genes Single nucleotide polymorphisms(SNPs) Platinumchemotherapy(CT)

Small extracellular vesicles derived from cerebral endothelial cells with elevated microRNA 27a promote ischemic stroke recovery

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Neural Regeneration Research 2025年第1期20卷 224-233页

作者： Yi Zhang Zhongwu Liu Michael Chopp Michael Millman Yanfeng Li Pasquale Cepparulo Amy Kemper Chao Li Li Zhang Zheng Gang Zhang Department of Neurology Henry Ford HospitalDetroitMIUSA Department of Physics Oakland UniversityRochesterMIUSA Department of pathology Henry Ford HospitalDetroitMIUSA Division of Pharmacology Department of NeuroscienceReproductive and Dentistry SciencesSchool of MedicineUniversity of Naples“Federico Ⅱ”NaplesItaly

Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional *** previous in vitro study demonstrated that exosomes/small extracellular vesicles(sEVs)isolated from cerebral endothelial cells(CEC-sEVs)of ischemic brain promote axonal growth of embryonic cortical neurons and that microRNA 27a(miR-27a)is an elevated miRNA in ischemic *** the present study,we investigated whether normal CEC-sEVs engineered to enrich their levels of miR-27a(27a-sEVs)further enhance axonal growth and improve neurological outcomes after ischemic stroke when compared with treatment with non-engineered CEC-sEVs.27a-sEVs were isolated from the conditioned medium of healthy mouse CECs transfected with a lentiviral miR-27a expression *** EVs isolated from CECs transfected with a scramble vector(Scra-sEVs)were used as a *** male mice were subjected to permanent middle cerebral artery occlusion and then were randomly treated with 27a-sEVs or *** array of behavior assays was used to measure neurological *** with treatment of ischemic stroke with Scra-sEVs,treatment with 27a-sEVs significantly augmented axons and spines in the peri-infarct zone and in the corticospinal tract of the spinal grey matter of the denervated side,and significantly improved neurological *** vitro studies demonstrated that CEC-sEVs carrying reduced miR-27a abolished 27a-sEV-augmented axonal *** analysis revealed that 27a-sEVs systemically administered preferentially localized to the pre-synaptic active zone,while quantitative reverse transcription-polymerase chain reaction and Western Blot analysis showed elevated miR-27a,and reduced axonal inhibitory proteins Semaphorin 6A and Ras Homolog Family Member A in the peri-infarct *** of the Clathrin-dependent endocytosis pathway substantially reduced neuronal internalization of *** data provide evidence that 27a-sEVs have

关键词： axonal remodeling cerebral endothelial cells exosomes miR-27a mitochondria Semaphorin 6A small extracellular vesicles stroke

CORRELATION BETWEEN LAMININ AND CATHEPSIN D EXPRESSIONS IN BREAST CARCINOMA

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Chinese Journal of Cancer Research 2006年第4期18卷 261-264页

作者：陈峰陈伟红郑建明黄玲 Department of pathology Renji Hospital Chongming Branch Shanghai Jiaotong University Department of pathology Changhai Hospital

Objective： Laminin is a major glycoprotein component of basement membrance which is an important barrier to tumor cells which must be breeched before metastatic spread can occur. Proteolytic enzymes play an important role in mediating the passage of cancer cells through the basement membrane （BM） and extracellular matrix. We compared the patterns of laminin and cathepsin D （CD） expressions in a range of benign and malignant breast lesions to better understand the process of tumor progression. Methods： One hundred and sixty-two cases of breast samples comprising 18 fibroadeomas, 22 cases of fibrocystic disease, 96 cases of invasive ductal carcinoma and 26 carcinomas with intraductal components were evaluated for laminin and cathepsin D expressions by immunohistocbemical staining. Results： The prevalence of CD positivity in both neoplastic and stromal cell components were significantly higher in higher histological grade tumors compared to lower grades （P〈0.001）. Various severity of BM disruption correlated with histological grade of the carcinomas （P〈0.001）. There was a negative correlation between the laminin expression and CD presence. Conclusion： In the process of cancer cell invasion and metastasis, the basement membrane is disrupted by proteinase secreted by cancer cells, especially by stroma cells of cancer.

关键词： Breast carcinoma Laminin Cathepsin D Immunohsitochemistry

Calcium channels caught in peripheral glia’s tug-of-war on axon regeneration in Drosophila

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Neural Regeneration Research 2025年第2期20卷 475-476页

作者： Jackson Powell Tobias Steinschaden Rose Horowitz Yuanquan Song Raymond G.Perelman Center for Cellular and Molecular Therapeutics The Children’s Hospital of PhiladelphiaPhiladelphiaPAUSA The Neuroscience Graduate Group University of PennsylvaniaPhiladelphiaPAUSA Department of pathology and Laboratory Medicine University of PennsylvaniaPhiladelphiaPAUSA Medical University of Vienna Center for Brain ResearchDepartment of NeuroimmunologyViennaAustria

Neural damage or degeneration is at the crux of many diseases,and treatment of these diseases will require the development of therapeutics to enhance and guide neural *** intrinsic and extrinsic factors dictate a neuron’s ability to regenerate,and the combination of these factors results in the great regenerative capacity of the peripheral nervous system(PNS)and the poor regenerative capacity of the central nervous system(CNS)following *** the core of a neuron’s function is its ability to relay electrochemical signals,and a neuron’s excitability is a key factor in its ability to *** works have focused on the changes in neuronal electrophysiological properties,firing patterns,and ion flux after injury,which differentially activate signaling pathways at the core of *** role of glia in neuron regeneration has long been studied.

关键词： degeneration firing system

pathology of alcoholic liver disease, can it be differentiated from nonalcoholic steatohepatitis?

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World Journal of Gastroenterology 2014年第44期20卷 16474-16479页

作者： Puja Sakhuja Department of pathology GB Pant Hospital

The liver involvement in alcoholic liver disease(ALD) classically ranges from alcoholic steatosis, alcoholic hepatitis or steatohepatitis, alcoholic cirrhosis and even hepatocellular carcinoma. The more commonly seen histologic features include macrovesicular steatosis, neutrophilic lobular inflammation, ballooning degeneration, Mallory-Denk bodies, portal and pericellular fibrosis. Nonalcoholic steatohepatitis(NASH) is a condition with similar histology in the absence of a history of alcohol intake. Although the distinction is essentially based on presence or absence of a history of significant alcohol intake, certain histologic features favour one or the other diagnosis. This review aims at describing the histologic spectrum of alcoholic liver disease and at highlighting the histologic differences between ALD and NASH.

关键词： Alcoholic liver disease Steatosis Steatohepatitis Fibrosis Cirrhosis Hepatocellular carcinoma Non-alcoholic steatohepatitis

Gut microbiota-derived metabolites in the regulation of host immune responses and immune-related inflammatory diseases

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Cellular & Molecular Immunology 2021年第4期18卷 866-877页

作者： Wenjing Yang Yingzi Cong Department of Microbiology and Immunology University of Texas and 2Department of pathology University of Texas Medical BranchGalvestonTXUSA

The gut microbiota has a critical role in the maintenance of immune *** in the intestinal microbiota and gut microbiota-derived metabolites have been recognized in many immune-related inflammatory *** metabolites can be produced by gut microbiota from dietaiy components or by the host and can be modified by gut bacteria or synthesized de novo by gut *** microbiota-derived metabolites influence a plethora of immune cell responses,including T cells,B cells,dendritic cells,and *** e of these metabolites are involved in the pathogenesis of immune-related inflammatory diseases,such as inflammatory bowel diseases,diabetes,rheumatoid arthritis,and systemic lupus ***,we review the role of microbiota-derived metabolites in regulating the functions of different immune cells and the pathogenesis of chronic immune-related inflammatory diseases.

关键词： gut microbiota metabolites T cells B cells autoimmune diseases