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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 Medicine King Khalid University Abha 62521 Saudi Arabia.

Background:Gastric cancer (GC) remains a global health burden and is often characterized by heterogeneous molecular profiles and resistance to conventional therapies. The 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 interventions.Methods: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 kinases. KATOIII and SNU-5 GC cells were used for evaluation.Results:SBL-JP-0004 exhibited a robust binding affinity for JAK2 and PI3KCD kinases, as evidenced by molecular docking scores and molecular dynamics simulations. Binding interactions and Gibbs binding free energy estimates confirmed stable and favorable interactions with target proteins. SBL-JP-0004 displayed an half-maximal inhibitory concentration (IC) value of 118.9 nM against JAK2 kinase and 200.9 nM against PI3KCD enzymes. SBL-JP-0004 exhibited potent inhibition of cell proliferation in KATOIII and SNU-5 cells, with half-maximal growth inhibitory concentration (GI) 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 controls.Conclusion: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： Dual inhibition Gastric cancer (GC) JAK2 Molecular docking Molecular dynamics simulation PI3KCD SBL-JP-0004

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

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

Exploring the potential of extrachromosomal DNA as a novel oncogenic driver

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Science China Life Sciences 2025年第1期 144-157页

作者： Huanbo Zhu Longtao Huangfu Junbing Chen Jiafu Ji Xiaofang Xing Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing) Division of Gastrointestinal Cancer Translational Research LaboratoryPeking University Cancer Hospital & Institute department of Gastrointestinal Cancer Center Peking University Cancer Hospital & Institute department of liver Surgery & Transplantation Liver Cancer InstituteZhongshan HospitalFudan University Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers Beijing Key Laboratory of Carcinogenesis and Translational ResearchDivision of Gastrointestinal Cancer Translational Research LaboratoryPeking University Cancer Hospital & Institute

Extrachromosomal DNA(ecDNA) is a form of circular DNA mostly found in tumor cells. Unlike the typical chromosomal DNA, ecDNA is circular, self-replicating, and carries complete or partial gene fragments. Although ecDNA occurrence remains a rare event in cancer, recent studies have shown that oncogene amplification on ecDNA is widespread throughout many types of cancer, implying that ecDNA plays a central role in accelerating tumor evolution. ecDNA has also been associated with increased tumor mutation burden, chromosomal instability, and even tumor microenvironment remodeling. ecDNA may be crucial in influencing tumor heterogeneity, drug sensitivity,oncogenic senescence, and tumor immunogenicity, leading to a worsening prognosis for tumor patients. In this way, several clinical trials have been conducted to investigate the importance of ecDNA in clinical treatment. In this review, we summarize the biogenesis, characteristics, and current research methods of ecDNA, discuss the vital role of ecDNA-caused tumor heterogeneity in cancers, and highlight the potential role of ecDNA in cancer therapy.

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The emerging role of nitric oxide in the synaptic dysfunction of vascular dementia

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Neural Regeneration Research 2025年第2期20卷 402-415页

作者： Xiaorong Zhang Zhiying Chen Yinyi Xiong Qin Zhou Ling-Qiang Zhu Dan Liu department of pathology Affiliated Hospital of Jiujiang UniversityJiujiangJiangxi ProvinceChina Jiujiang Clinical Precision Medicine Research Center JiujiangJiangxi ProvinceChina Center for Cognitive Science and Transdisciplinary Studies Jiujiang UniversityJiangxi ProvinceChina department of Neurology Affiliated Hospital of Jiujiang UniversityJiujiangJiangxi ProvinceChina department of Rehabilitation Affiliated Hospital of Jiujiang UniversityJiujiangJiangxi ProvinceChina department of Pathophysiology School of Basic MedicineTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei ProvinceChina

With an increase in global aging,the number of people affected by cerebrovascular diseases is also increasing,and the incidence of vascular dementia-closely related to cerebrovascular risk-is increasing at an epidemic ***,few therapeutic options exist that can markedly improve the cognitive impairment and prognosis of vascular dementia *** in Alzheimer’s disease and other neurological disorders,synaptic dysfunction is recognized as the main reason for cognitive *** oxide is one of the ubiquitous gaseous cellular messengers involved in multiple physiological and pathological processes of the central nervous ***,nitric oxide has been implicated in regulating synaptic plasticity and plays an important role in the pathogenesis of vascular *** review introduces in detail the emerging role of nitric oxide in physiological and pathological states of vascular dementia and summarizes the diverse effects of nitric oxide on different aspects of synaptic dysfunction,neuroinflammation,oxidative stress,and blood-brain barrier dysfunction that underlie the progress of vascular ***,we propose that targeting the nitric oxide-sGC-cGMP pathway using certain specific approaches may provide a novel therapeutic strategy for vascular dementia.

关键词： endoplasmic reticulum stress endothelial nitric oxide synthase gene therapy nitric oxide NO-sGC-cGMP pathway synaptic dysfunction vascular dementia

Serum ferritin in neonatal cholestasis: A specific and active molecule or a non-specific bystander marker?

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Hepatobiliary & Pancreatic Diseases International 2019年第2期18卷 173-180页

作者： Behairy El-Sayed Behairy Hatem Abd-Alsattar Konswa Hanaa Talaat Ahmed Dina Shehata El-Azab Nermin Mohamed Adawy Ahmad Mohamed Sira department of Pediatric Hepatology Gastroenterology and Nutrition National Liver Institute Menofiya University department of pathology National Liver Institute Menofiya University

Background: Serum ferritin(SF) and consequently hepatic iron have long been considered important in liver fibrosis progression. They have been studied in different liver diseases with no previous reports in neonatal cholestasis(NC). This study aimed to measure SF in different etiologies of NC and investigate its relation to hepatic iron and fibrosis. Methods: SF was measured in 75 infants, including 50 with NC and 25 with sepsis. SF was compared between these two groups. Biochemical parameters, hepatic iron grades, and liver fibrosis and other histopathological characteristics and correlated with SF were assessed in NC group. Finally, a comparison between intrahepatic cholestasis and obstructive etiology was performed. Results: SF was elevated in NC(1598 ± 2405 ng/mL) with no significant difference from those with sepsis( P = 0.445). NC and sepsis constituted augmenting factors leading to more elevation of SF(2589 ± 3511 ng/mL). SF was significantly correlated with hepatic iron grades( r = 0.536, P liver fibrosis( P = 0.058). Conclusions: SF is non-specifically elevated in NC, with positive correlation to hepatic iron grades. SF ≥ 803.5 ng/mL can predict higher grades( ≥ grade 3) of hepatic iron. However, an active role of increased SF and hepatic iron in disease progression remains questionable.

关键词： Biliary atresia liver fibrosis Hepatic iron grade Intrahepatic cholestasis Iron

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 Hospital Florence 50134 Italy. department of Experimental and Clinical Medicine University of Florence Florence 50134 Italy. department of Health Sciences University of Florence Florence 50134 Italy. Medical Oncology Unit Careggi University Hospital Florence 50134 Italy. department of Experimental and Clinical Biomedical Sciences "Mario Serio" University of Florence Florence 50134 Italy. Section of Anatomic pathology Department of Health Sciences University of Florence Florence 50139 Italy. Section of Surgery Histopathology and Molecular Pathology University of Florence Florence 50139 Italy. Thoracic Surgery Unit Careggi University Hospital Florence 50134 Italy.

Background:Platinum chemotherapy (CT) remains the backbone of systemic therapy for patients with small-cell lung cancer (SCLC). The nucleotide excision repair (NER) pathway plays a central role in the repair of the DNA damage exerted by platinum agents. Alteration in this repair mechanism may affect patients' survival.Materials 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 2020. mRNA expression analysis and single nucleotide polymorphism (SNP) characterization of three NER pathway genes-namely , , and -were performed on patient tumor samples.Results:Overall, elevated expression of genes was observed in SCLC patients compared to healthy controls. Patients with low and expression levels exhibited a better median progression-free survival (mPFS = 7.1 . 4.9 months, = 0.39 for and mPFS = 6.9 . 4.8 months, = 0.093 for ) and overall survival (mOS = 8.7 . 6.0 months, = 0.4 for and mOS = 7.2 . 6.2 months, = 0.13 for ). Genotyping analysis of five SNPs of genes showed a longer survival in patients harboring the wild-type genotype or the heterozygous variant of the rs11615 SNP ( = 0.24 for PFS and = 0.14 for OS) and of the rs13181 and rs1799793 SNPs ( = 0.43 and = 0.26 for PFS and = 0.21 and = 0.16 for OS, respectively) compared to patients with homozygous mutant genotypes.Conclusions:The comprehensive analysis of gene expression and SNP variants appears to identify patients who derive greater survival benefits from platinum-CT.

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

Hepatocellular Tumors:Immunohistochemical Analyses for Classification and Prognostication

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Chinese Journal of Cancer Research 2011年第4期23卷 245-253页

作者： Regina Cheuk-Lam Lo Irene Oi-Lin Ng department of pathology and State Key Laboratory for liver Research The University of Hong Kong

Following the classification of hepatocellular nodules by the International Working Party in 1995 and further elaboration by the International Consensus Group for Hepatocellular Neoplasia in 2009, entities under the spectrum of hepatocellular nodules have been better characterized. Research work hence has been done to answer questions such as distinguishing high-grade dysplastic nodules from early hepatocellular carcinoma (HCC), delineating the tumor cell origin of HCC, identifying its prognostic markers, and subtyping hepatocellular adenomas. As a result, a copious amount of data at immunohistochemical and molecular levels has emerged. A panel of immunohistochemical markers including glypican-3, heat shock protein 70 and glutamine synthetase has been found to be of use in the diagnosis of small, well differentiated hepatocellular tumors and particularly of HCC. The use of liver fatty acid binding protein (L-FABP), β-catenin, glutamine synthetase, serum amyloid protein and C-reactive protein is found to be helpful in the subtyping of hepatocellular adenomas. The role of tissue biomarkers for prognostication in HCC and the use of biomarkers in subclassifying HCC based on tumor cell origin are also discussed.

关键词： Hepatocellular tumors Immunohistochemical Classification

Ubiquitin-specific protease 1 facilitates tumor immune escape from natural killer cells and predicts the prognosis in small cell lung cancer

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Oncology research 2025年第1期33卷 213-224页

作者： Shiqin Jiang Yichun Tang Feng Ma Yuchun Niu Lei Sun department of Clinical Pharmacy Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine Shenzhen 518104 China. department of pathology Zhujiang Hospital Southern Medical University Guangzhou 510280 China. department of Radiation Oncology The First People's Hospital of Foshan Foshan 528000 China. department of Oncology The First Affiliated Hospital of Jinan University Jinan University Guangzhou 510630 China. department of Oncology The First Dongguan Affiliated Hospital Guangdong Medical University Dongguan 523721 China.

Objective:Small cell lung cancer (SCLC) is commonly recognized as the most fatal lung cancer type. Despite substantial advances in immune checkpoint blockade therapies for treating solid cancers, their benefits are limited to a minority of patients with SCLC. In the present study, novel indicators for predicting the outcomes and molecular targets for SCLC treatment were elucidated.Methods:We conducted bioinformatics analysis to identify the key genes associated with tumor-infiltrating lymphocytes in SCLC. The functional role of the key gene identified in SCLC was determined both and .Results:A significant correlation was observed between patient survival and CD56dim natural killer (NK) cell proportion. Furthermore, we noted that the hub gene ubiquitin-specific protease 1 (USP1) is closely correlated with both CD56dim NK cells and overall survival in SCLC. Bioinformatics analysis revealed that USP1 is upregulated in SCLC. In addition, gene set enrichment analysis revealed that USP1 overexpression hinders NK cell-mediated immune responses. By co-cultivating NK-92 cells with SCLC cells, we demonstrated that NK cell cytotoxicity against SCLC could be improved either via USP1 knock-down or pharmacological inhibition. Furthermore, using a nude-mice xenograft tumor model, we noted that USP1 inhibition effectively suppressed tumor proliferation and increased the expression of NK cell-associated markers.Conclusions:Our study findings highlight the importance of NK cells in regulating SCLC. USP1 overexpression can inhibit NK cell-mediated immunity; therefore, USP1 may serve not only as a prognostic biomarker but also as a potential molecular target of SCLC therapy.

关键词： Immune escape Natural killer (NK) cell Prognosis Small cell lung cancer (SCLC) Ubiquitin-specific protease 1 (USP1)