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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

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

Esophageal carcinoma originating in the surface epithelium with immunohistochemically proven esophageal gland duct differentiation: A case report

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World Journal of gastroenterology 2017年第21期23卷 3928-3933页

作者： Hiromi Tamura Hirotsugu Saiki Takahiro Amano Masashi Yamamoto Shiro Hayashi Hiroka Ando Reiko Doi Tsutomu Nishida Katsumi Yamamoto Shiro Adachi department of pathology City Hospital of Toyonaka department of gastroenterology JCHO Osaka Hospital department of gastroenterology City Hospital of Toyonaka

A case of esophageal carcinoma exclusively composed of adenocarcinoma simulating an esophageal gland duct in a 61-year-old man is presented. The tumor arose as a slightly elevated lesion in the middle intrathoracic esophagus. It was almost completely overlaid with nonneoplastic stratified squamous epithelial cells. Beneath the overlying surface epithelium, an adenocarcinoma that was bilayered in structure diffusely invaded both the mucosal and submucosal layers. Although the tumor consisted exclusively of adenocarcinomatous cells, a keratinizing squamous cell carcinoma component was focally observed. The invasive carcinoma was focally continuous with the small area of the surface squamous epithelial layer, which was confirmed to be neoplastic by immunohistochemistry. Morphological and immunohistochemical examinations suggested that the adenocarcinomatous component arose from the esophageal surface epithelium and clearly differentiated into an esophageal gland duct. It is important to consider the possibility of this type of adenocarcinoma when diagnosing a ductal or glandular lesion of the esophagus in small biopsy specimens.

关键词： Esophageal adenocarcinoma Bilayered structure Esophageal gland duct

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)

Dramatic response of hepatitis C patients chronically infected with hepatitis C virus genotype 3 to sofosbuvirbased therapies in Punjab, Pakistan: A prospective study

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World Journal of gastroenterology 2017年第44期23卷 7899-7905页

作者： Sajjad Iqbal Muhammad Haroon Yousuf Muhammad Iftikhar Yousaf department of pathology Shalamar Hospital department of gastroenterology and Hepatology Shalamar Hospital

AIM To prospectively evaluate the efficacy of sofobuvir(SOF) in hepatitis C patients infected with hepatitis C virus(HCV) genotype 3 in *** The present study was performed with the coordination of gastroenterology and pathology departments of Shalamar Hospital Lahore from August 2014 to May 2016. The total number of patients included in this study was 1375 and all of them were infected with HCV genotype 3. On the basis of drug combinations, all the patients were separated into two groups. The first group of patients was treated for 24 wk with SOF(Sovaldi? by Gilead Sciences) plus ribavirin(RBV) [Ribazol? by Getz Pharma Pakistan(PVT) Ltd], while the patients of the second group were treated with SOF + RBV + pegylatedinterferon(peg IFN) alfa-2 a(Ropegra by Roach) for 12 wk. HCV genotyping and viral load measurement were performed on fully automated Abbott Real-Time PCR system(Abbott m24 sp automated nucleic acid extraction system and Abbott m2000 rt amplification system; abbott Molecular, Des Plaines, IL, United States). For the assessment of sustained virological response(SVR), all HCV RNA negative patients were followed for 12weeks after the treatment completion. Any patient with less than 12 IU/m L viral load after 12 wk of treatment completion was considered as a sustained virological responder(SVR-12).RESULTS A total of 1375 patients chronically infected with HCV genotype 3 were treated with two drug combinations SOF + RBV and SOF + RBV + peg IFN alfa-2 a. On the basis of these drug combinations, patients were divided into two groups(first and second). Overall SVR-12 was excellent in both groups(99.17% and 97.91%). Older patients(> 40 years) of second group showed lower SVR-12(93.46%) compared to first group older patients(98.79%), while in the younger patients of both groups, the SVR-12 rate was almost the same(99.54% in first group and 99.05% in second group). No such difference regarding SVR-12 rate was seen in males and females of first group pat

关键词： Sofosbuvir Sustained virological response Pakistan

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)

Gastric adenocarcinoma of fundic gland type with signet-ring cell carcinoma component: A case report and review of the literature

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World Journal of gastroenterology 2018年第26期24卷 2915-2920页

作者： Keita Kai Masaaki Satake Osamu Tokunaga department of pathology Saga University Hospital department of gastroenterology Koga Hospital 21 department of pathology Shin Koga Hospital

A depressed lesion was found at a gastric angle of 76-yearold Japanese woman by esophagogastroduodenoscopy. Four years prior, she was diagnosed with a Helicobacter pylori infection but no eradication was performed. The pathological diagnosis of biopsy specimens was signet-ring cell carcinoma. Endoscopic submucosal dissection(ESD) was performed. Histopathological examination of the ESD specimen revealed proliferation of well-differentiated tubular adenocarcinoma mimicking fundic gland cells at the deep layer of the lamina propria mucosae. These tumor cells expressed focally pepsinogen-Ⅰ, diffusely MUC6, and scattered H^+/K^+ ATPase according to immunohistochemistry. Therefore, we diagnosed this tumor as gastric adenocarcinoma of fundic gland type(GA-FG). Adjacent to the GA-FG, proliferation of signet-ring cell carcinoma which diffusely expressed MUC 2 and MUC 5AC was observed. Intestinal metaplasia was focally observed in the surrounding mucosa of the signet-ring cell carcinoma. To the best of our knowledge, this is the first case report of GA-FG with a signet-ring cell carcinoma component. The origin of signet-ring cell carcinoma, i.e., whether it accidentally arose from a non-neoplastic mucosa and coexisted with the GA-FG or dedifferentiated from the GA-FG is unclear at present. We expect the accumulation of similar cases and further analysis to clarify this issue.

关键词： Gastric adenocarcinoma of fundic gland type Endoscopic submucosal dissection Helicobacter pylori Intestinal metaplasia Signet-ring cell carcinoma