Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality with limited therapeutic options and poor prognosis, particularly in advanced stages. This study integrates computational and experimental approaches to evaluate metformin as a candidate for repurposing in HCC. Key oncogenic targets EGFR, MAPK3, MMP9, and PRKACA were prioritized via protein-protein interaction network analysis. Molecular docking predicted favorable metformin binding poses for EGFR (ΔG = -7.42 kcal/mol), MAPK3 (ΔG = -7.45 kcal/mol), MMP9 (ΔG = -7.84 kcal/mol), and PRKACA (ΔG = -8.33 kcal/mol). Using AmberTools/Antechamber-derived GAFF2 parameterization and AM1-BCC partial charges for ligand topology, repeated 100 ns molecular dynamics simulations showed ligand retention with target-specific receptor and pocket RMSD adaptation and stable radius-of-gyration profiles. Network toxicology predicted low hepatotoxicity risk using ProTox-II and ADMETlab 2.0 endpoints. ITC measurements produced detectable metformin-protein binding responses and apparent dissociation constants under the reverse-orientation assay conditions (20 µM protein in the cell and 200 µM metformin in the syringe). Western blot analysis showed reduced total EGFR, MAPK3, and MMP9 expression after metformin treatment, while PRKACA changed only slightly. Triplicate MTT assays showed concentration-dependent inhibition of HepG2 cell viability, with an IC50 of 16.02 µM.

Metformin and HCC-associated targets were collected from SwissTargetPrediction, DrugBank, GeneCards, DisGeNET, BindingDB, and OMIM. PPI networks were constructed using STRING (confidence >  = 0.7, Homo sapiens) and visualized with Cytoscape v3.10.1; core targets were identified via CytoHubba. Hepatotoxicity and ADMET risk were evaluated using ProTox-II and ADMETlab 2.0. Molecular docking was performed using MOE 2022 with Amber99 force field and MOPAC7.0, generating 30 poses per target. MD simulations (100 ns) were conducted in GROMACS using AMBER99SB-ILDN protein topologies and metformin parameters generated with AmberTools/Antechamber, GAFF2, AM1-BCC partial charges, parmchk2, and ACPYPE, followed by NVT/NPT equilibration and production runs at 298 K/1 bar with particle mesh Ewald electrostatics. ITC analysis was performed using MicroCal VP-ITC at 25 °C in PBS (pH 7.4), using 20 µM protein in the cell and 200 µM metformin in the syringe. Western blot (HepG2, 50 µM metformin, 24 h) and MTT assay (0.01-500 µM, 48 h) were performed in triplicate as in vitro validation.

IntroductionHepatocellular carcinoma (HCC) is characterized by a complex tumor microenvironment and limited therapeutic options. Synaptogyrin-2 (SYNGR2), a transmembrane protein, has been implicated in cancer but its comprehensive role in HCC prognosis, immune regulation, and treatment response remains unclear.MethodsMultiomics bioinformatics analysis was performed via RNA-seq data from the TCGA-LIHC cohort. Prognostic value was assessed via Cox regression and Kaplan‒Meier analysis. Immune cell infiltration was estimated via CIBERSORT, and drug sensitivity was predicted via the oncoPredict R package. In vitro validation was conducted using Hep3B and Huh7 cell lines. To establish causality, isogenic gain- and loss-of-function experiments were performed, followed by RT-qPCR, and CCK-8 assays.ResultsSYNGR2 expression was significantly elevated in HCC tissues and correlated with advanced tumor stage, poor differentiation, and poor overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) (all P<0.05). It served as an independent prognostic biomarker (AUC=0.923). High SYNGR2 expression was associated with an immunosuppressive microenvironment characterized by increased numbers of M0 macrophages and Tregs and strongly positively correlated with immune checkpoint genes (PD-1, CTLA-4, and PD-L1). Bioinformatic predictions revealed that SYNGR2-high tumors were more sensitive to MK-1775 (DNA damage inhibitor) and paclitaxel, whereas SYNGR2-low tumors were sensitive to JAK1/IAP inhibitors. In vitro, Hep3B cells (high endogenous SYNGR2) displayed a markedly lower IC50 for MK-1775 than Huh7 cells (low endogenous SYNGR2). Critically, plasmid-mediated overexpression of SYNGR2 in Huh7 cells significantly sensitized them to MK-1775, while siRNA-mediated knockdown of SYNGR2 in Hep3B cells conferred significant resistance, establishing a causal role for SYNGR2 in modulating sensitivity to this WEE1 inhibitor.ConclusionSYNGR2 has emerged as a multifaceted biomarker candidate in HCC, associated with prognosis, an immunosuppressive microenvironment, and differential therapeutic responses. Its integration into clinical models could enhance prognostic stratification and guide personalized treatment strategies, particularly in selecting patients for DNA damage-targeting agents.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that lacks the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2). There is a lack of predictive biomarkers for the response of patients with TNBC to targeted therapies.

Bioinformatics analysis was conducted to generate differentially expressed genes (DEGs) of the mammalian target of rapamycin complex 1 (MTORC1) gene set between normal tissues and primary tumors derived from TNBC patients using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Cox regression analysis was performed to identify independent prognostic factors. Endogenous expression levels of the identified prognostic genes were detected in a panel of TNBC cell lines and breast cancer tissues using western blotting and immunohistochemistry (IHC).

Our findings revealed two prognostic genes: FADS2 and TOMM40. TOMM40 (HR = 2.243) was a risk factor and FADS2 was a protective factor (HR = 0.652). A higher TOMM40/FADS2 ratio is associated with poor outcomes in patients with TNBC. The TOMM40/FADS2 ratio was significantly (p < 0.05) associated with age, tumor size, lymph node metastasis, pathologic stage, and overall survival of patients with TNBC. Remarkably, the MTT cytotoxicity assay revealed that TNBC cells, which possess a higher TOMM40/FADS2 ratio than TNBC cells with a lower TOMM40/FADS2 ratio, are more sensitive to mammalian target of rapamycin (mTOR) inhibitor treatment.

Our results provide a new therapeutic strategy using the TOMM40/FADS2 expression ratio to predict the cellular sensitivity to mTOR inhibitor treatment in TNBC.

Cervical cancer (CC) is a major cause of death among women of the reproductive age group worldwide. Approximately 95% of the cases occur due to HPV infection. CC is staged into various International Federation of Gynaecology and Obstetrics (FIGO) stages, based on tumor size, invasion, spread, cytology, and histopathology. Early-stage CC is mostly curable, while, at late-stages it is often fatal and therapy-resistant. Biomarkers are emerging as lucrative prognostic and therapeutic targets in cancers. Among the different categories of biomarkers available, the epigenetic biomarkers are emerging as important therapeutic targets. Long non-coding RNAs (lncRNAs) are excellent targets because of their stagewise differential expression levels, and functional roles in cancer development, and progression. They act by targeting various microRNAs (miRNAs), other RNAs or DNA, histone protein complexes, regulatory loops, controlling epigenetic modifications and gene or protein expressions. Moreover, they are easily accessible and can serve as accurate biomarkers for easy and fast detection of cancers, probably even to the level of specific cancer stages. However, much has not yet been elucidated about the regulatory roles of lncRNAs, especially in the context of CC. In this article, we have thoroughly discussed the known roles of lncRNAs, which have been explored as prognostic biomarkers in CC. We have also identified some uniquely upregulated lncRNAs at various stages of CC from our analysis from Gene Expression Omnibus (GEO). If explored properly, lncRNAs might serve as targets for the cure of CC, in future.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide. Understanding the complex molecular networks that underlie this aggressive behavior is critical for developing novel diagnostic and therapeutic strategies. This study aimed to identify key molecular regulators of CRC progression by integrating Weighted Gene Co-expression Network Analysis (WGCNA) with machine learning algorithms. Hub genes were initially identified by intersecting genes from the most significant module with CRC-related and glycolysis-related targets from the GeneCards database, as well as upregulated differentially expressed genes (DEGs) from the GSE113513 dataset. Lasso regression and random forest (RF) algorithms were employed to screen for key genes from this intersection. The expression of the identified key gene was validated using quantitative real-time PCR (qRT-PCR) and Western blotting. Functional assays, including Cell Counting Kit-8 (CCK-8), colony formation, Transwell invasion, flow cytometry, and metabolic analyses, were conducted to analyze the malignant behaviors of CRC cells. The regulatory relationship between cyclin dependent kinase 1 (CDK1) and transcription factor AP-4 (TFAP4) was validated through chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. A xenograft mouse model was used to evaluate the effect of TFAP4 knockdown on the malignant progression of CRC cells in vivo. WGCNA and machine learning analyses identified three key genes: MET, MYC, and CDK1. CDK1 was selected for further investigation and found to be significantly upregulated in CRC tissues and cell lines. Functionally, CDK1 knockdown markedly inhibited CRC cell proliferation, invasion, and glycolysis while promoting apoptosis. Mechanistically, the transcription factor TFAP4 was identified as an upstream regulator that directly activated CDK1 transcription. Moreover, CDK1 and TFAP4 expression were associated with metastatic stage. TFAP4 exerted its oncogenic effects by positively regulating CDK1. Furthermore, silencing TFAP4 significantly suppressed tumor growth in vivo. This study establishes the TFAP4-CDK1 axis as a critical driver of malignant progression in CRC. Targeting this pathway could lead to the development of novel interventions for CRC.

MYB is a key transcriptional regulator of hematopoietic cell proliferation, survival, and lineage commitment. Aberrant MYB activity has been linked to hematologic malignancies and clinically relevant features, including poor prognosis and drug resistance. However, the mechanisms by which MYB contributes to drug resistance in leukemia remain unclear.

Here, we show that altered MYB alternative promoter usage may contribute to DNR resistance in leukemia cells, at least in part through ABCA2 upregulation. CCK8 assays showed that ΔN MYB promoted leukemia cell proliferation and enhanced DNR resistance more potently than full-length MYB. RT-qPCR showed that both full-length MYB and ΔN MYB up-regulated ABC transporter genes, with ΔN MYB exerting a stronger effect than full-length MYB and ABCA2 showing the most pronounced increase. RT-qPCR analysis of DNR-resistant leukemia cells showed no obvious change in total MYB expression and MYB exon 2 level, whereas MYB exon 1 level was decreased, the MYB exon 2/exon 1 ratio and ABCA2 expression were markedly increased. Rescue experiments showed that ABCA2 knockdown partially reversed the proliferation-promoting and DNR-resistant effects of ΔN MYB in leukemia cells.

These findings suggest that increased MYB TSS2-associated transcription contributes to DNR resistance in human leukemia cells, potentially through ΔN MYB-associated ABCA2 upregulation. This pathway may represent a potential therapeutic target for overcoming DNR resistance in leukemia.

Sepsis-associated acute lung injury represents a severe complication. It is characterized by an overwhelming inflammatory response and the disruption of pulmonary barrier function, leading to high morbidity and mortality. Despite advances in supportive care, effective therapeutic strategies remain limited. Mesenchymal stem cells derived from the human chorionic membrane, commonly referred to as HCMSCs, represent a highly promising option in the field of regenerative medicine. This is largely owing to their remarkable abilities to modulate the immune system and repair damaged tissues. Nevertheless, the specific biological processes through which these cells exert their influence on lung injury caused by sepsis, especially regarding the modulation of critical molecular signaling pathways, remain to be fully elucidated. A mouse model of sepsis-induced lung injury was established via intraperitoneal lipopolysaccharide (LPS) injection, while human pulmonary microvascular endothelial cells (HPMECs) were stimulated with LPS to mimic an in vitro model. Following the characterization of HCMSCs, the study evaluated their impact on endothelial cell apoptosis, proliferation, and barrier integrity. Inflammatory responses were quantified by measuring key cytokines. To elucidate the molecular mechanism, the study focused on the interaction between the transcription factor SOX18 and MECP2, which was confirmed using chromatin immunoprecipitation and luciferase reporter assays. Finally, the therapeutic efficacy was validated in mice by assessing lung histopathology, edema, and gene/protein expression. Results showed that HCMSCs successfully differentiated into adipocytes and osteoblasts, as confirmed by positive Oil Red O staining and ALP activity. Treatment with HCMSC-conditioned medium (HCMSC^CM) significantly attenuated LPS-induced inhibition of SOX18 expression in HPMECs. LPS-induced HPMEC apoptosis, inflammation, barrier dysfunction and proliferation inhibition were markedly alleviated by HCMSC^CM, as evidenced by reduced apoptosis, decreased IL-6, IL-1β, and TNF-α levels, increased number of EdU-positive cells, and restored expression of tight junction proteins (Occludin and ZO-1) along with TER. However, SOX18 knockdown reversed these protective effects. Mechanistically, SOX18 was found to transcriptionally activate MECP2 in HPMECs. HCMSC^CM effectively mitigated LPS-induced dysfunction in HPMECs through modulation of the SOX18/MECP2 signaling axis. In vivo, HCMSC^CM administration protected against LPS-induced lung injury in mice via regulation of the SOX18/MECP2 axis. In all, HCMSCs exerted protective effects against sepsis-induced lung injury by modulating the SOX18/MECP2 signaling pathway. These findings highlight the therapeutic potential of HCMSCs in treating sepsis-induced lung injury.

Obstructive sleep apnea (OSA) leads to organ ischemia, including that of the heart. The aim of this study was to assess the frequency of OSA by polygraphic examination in patients admitted with acute coronary syndrome, to evaluate the influence of OSA on echocardiographic findings and myocardial infarction markers and to describe the influence of CPAP treatment on OSA parameters and echocardiographic indices after myocardial infarction. We included 25 patients treated with primary coronary angioplasty, aged 60.3 ± 19.4 years, with a BMI of 32.2 ± 3.8.

Polygraphy showed OSA in 18 (72%) patients, and in 12 (48%) severe OSA (AHI > 30) was diagnosed. OSA predominantly affected obese patients (BMI < 30, n = 13: AHI 23.2 ± 17.4, BMI ≥ 30, n = 12: AHI 55.5 ± 23.6, p < 0.000001). In patients with normal RV structure and function AHI was significantly lower compared to those with RV dysfunction. In patients without OSA, CKMB and troponin levels were significantly lower as compared to those with OSA: AHI < 15: CKMB 41.7 ± 40.7, Tn 0.84 ± 1.0; AHI≥15: CKMB 169.2 ± 112.4, Tn 4.77 ± 4.43; p = 0.04. CPAP therapy was started only in 9 (50%) patients with OSA due to low patient compliance. In patients treated with CPAP, the therapy resulted in a significant decrease in OSA indices (AHI dropped from 52.0 ± 18.6 to 5.0 ± 1.0; p = 0.001). The function of the RV, as measured by TAPSE, improved only in patients treated with CPAP (CPAP: from 20.5 ± 3.3 to 22.3 ± 2.3, p = 0.04; no CPAP: 22.3 ± 4.7 to 23.6 ± 1.8; p-ns).

We demonstrate a high prevalence of OSA in patients presenting with acute coronary syndrome. OSA influences RV enlargement and dysfunction, as well as CKMB and troponin levels during myocardial infarction. After myocardial infarction, RV function improves only in patients treated with CPAP.

Blastomycosis is an invasive dimorphic fungal infection capable of causing severe disseminated disease in immunocompromised hosts. Although traditionally endemic to North America, increasing molecular evidence suggests a broader geographic distribution. Iran is not considered endemic, and no prior species-level confirmed cases of Blastomyces percursus have been reported. We report a 31-year-old liver transplant recipient who developed progressive diffuse papulopustular and verrucous necrotic cutaneous lesions 17 months after transplantation. Initial diagnostic evaluation was inconclusive. Detection of fungal DNA consistent with Aspergillus species in skin biopsy specimens prompted initiation of voriconazole therapy; however, the clinical course progressed despite treatment. The patient subsequently developed severe weight loss, high-level cytomegalovirus (CMV) viremia, pulmonary nodules, and mucosal involvement. Initial fungal culture suggested Pseudallescheria boydii, but re-evaluation at a reference mycology laboratory raised suspicion for blastomycosis. Definitive species identification was achieved by amplification and Sanger sequencing of the internal transcribed spacer (ITS1-5.8S-ITS2) region. The 520-bp sequence demonstrated 99.6-100% identity with reference Blastomyces percursus strains, and phylogenetic analysis confirmed clustering within the B. percursus clade. Despite targeted antifungal therapy with liposomal amphotericin B and antiviral treatment for CMV disease, the infection progressed to disseminated involvement with central nervous system manifestations, resulting in a fatal outcome. This case highlights the diagnostic complexity of invasive fungal infections in non-endemic regions and emphasizes the importance of early molecular identification in immunocompromised patients presenting with atypical cutaneous and systemic fungal disease.

ObjectivesThe relationship between physical or cognitive frailty and chronic obstructive pulmonary disease (COPD) has been established. This study aimed to evaluate the association between social frailty and disease severity as well as prognosis in people with COPD.MethodsEligible people with stable COPD were prospectively enrolled. Baseline data were collected via medical records and face-to-face interviews, and social frailty was assessed using the Makizako Index (grouping criteria). During a 1-year follow-up, changes in participants' disease status and prognostic outcomes were recorded. Multivariate logistic regression was applied to analyze the associations.ResultsOf 725 participants, 281 had social frailty and 444 were non-frail. Baseline social frailty was associated with a greater number of previous acute exacerbations (p<0.001); with a higher risk of frequent acute exacerbations during follow-up (p<0.001); and with higher risks of hospitalization >7 days and ICU stay >3 days at the first acute exacerbation during follow-up (p<0.001, p=0.006). It also predicted greater dyspnea, abnormal blood gas, worse pulmonary function, elevated inflammatory markers, triple therapy escalation, and escalated steroids during this acute exacerbation (all p<0.01).ConclusionSocial frailty may, to a certain extent, serve as a potential predictor for assessing the prognosis of people with COPD.