Bosnian Journal of Basic Medical Sciences (BJBMS)
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Endometrial mesonephric-like adenocarcinoma: Clinicopathologic features, treatment, and outcomes
Full text linkEndometrial mesonephric-like adenocarcinoma (MLA) is a rare subtype of uterine corpus endometrial carcinoma (UCEC) first described in 2016. The clinicopathological features, treatment options, and prognosis of endometrial MLA remain poorly understood. In this study, we retrospectively analyzed the clinicopathological characteristics, molecular features, treatment regimens, and outcomes of 11 patients diagnosed with endometrial MLA. The most prevalent symptom observed was postmenopausal bleeding. Notably, 78% (7 out of 9) of patients were diagnosed at advanced FIGO stages (II-IV), with four cases presenting with distant metastasis upon initial examination. Multivisceral metastases were identified in three cases, with lung metastases being the most common, occurring in 45% of patients. The median progression-free survival (PFS) was 16 months (95% confidence intervals: 6-26). All tumors tested negative for progesterone receptors (PR), while 91% of patients (10 out of 11) were negative for estrogen receptors (ER). Most patients exhibited positive immunohistochemical staining for "mesonephric-like" markers, including GATA-binding protein 3 (GATA-3), thyroid transcription factor-1 (TTF-1), and CD10. Furthermore, 91% of patients showed a wild-type p53 immunostaining pattern. Among the 11 patients, five underwent KRAS mutation testing, revealing KRAS mutations in all tested individuals (p.G12D in 2/5, p.G12A in 1/5, p.G12V in 1/5, and p.G13D in 1/5). These findings indicate that 78% of endometrial MLA patients were diagnosed at an advanced stage and suggest that this subtype may exhibit more aggressive behavior compared to endometrial endometrioid carcinoma. The consistent presence of KRAS mutations in patients who underwent testing highlights the potential role of KRAS in the initiation and progression of endometrial MLA, positioning it as a promising therapeutic target
Multidrug resistance, diagnostic challenges, and treatment gaps in Pandoraea infections: A review
Full text linkPandoraea species are emerging multidrug-resistant pathogens increasingly associated with respiratory tract infections, particularly in cystic fibrosis patients. Despite their growing clinical relevance, these bacteria are underrepresented in the scientific literature. This review aims to consolidate existing evidence regarding Pandoraea species as emerging multidrug-resistant pathogens, with a focus on their taxonomy, diagnostic methodologies, antimicrobial resistance mechanisms, and treatment challenges. By identifying gaps in current therapeutic strategies and the limited clinical outcome data, this review underscores the necessity of advancing research into innovative interventions, such as bacteriophages, antimicrobial peptides, and combination therapies, to enhance patient management and infection control. A comprehensive literature search was conducted using PubMed and Google Scholar, employing relevant keywords to identify case reports, clinical studies, and in vitro research related to Pandoraea infections, resistance mechanisms, and therapeutic strategies. Our findings reveal a significant lack of comprehensive data on therapeutic approaches, particularly concerning bacteriophages, antimicrobial peptides, and combination antibiotic therapies. Furthermore, clinical data on treatment efficacy remain sparse, with the majority of evidence stemming from in vitro studies rather than real-world clinical settings. This review emphasizes the urgent need for further research to address these knowledge deficits and to develop effective therapeutic interventions against Pandoraea infections
EPAS1 amplifies asthma pathogenesis through JAK2/STAT3-mediated ferroptosis and inflammation
Full text linkAsthma is a chronic respiratory disorder marked by airway hyperresponsiveness and inflammation, yet the specific molecular mechanisms driving these processes remain only partially understood. This study aims to better understand how the JAK2/STAT3/EPAS1 axis regulates inflammation and ferroptosis in asthma. Asthma-related datasets were retrieved from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) were identified. Weighted Gene Co-expression Network Analysis (WGCNA) was used to detect gene modules associated with asthma. A protein-protein interaction (PPI) network was then constructed by intersecting WGCNA-derived genes with ferroptosis-related genes to identify key hub genes. The diagnostic value of these ferroptosis-associated genes was evaluated using Receiver Operating Characteristic (ROC) curve analysis. Additionally, immune cell infiltration in asthma patients was analyzed using the Immune Cell AI database in relation to ferroptosis-related genes. Functional experiments at the cellular level were conducted to assess the effects of key genes on cell viability, inflammation, and ferroptosis. Bioinformatics analysis identified 1,698 DEGs linked to asthma. Five hub genes with clinical diagnostic value— Endothelial PAS Domain Protein 1 (EPAS1), STAT3, G6PD, CYBB, and CBS—were identified. Immune analysis revealed that EPAS1 is closely associated with immune cell infiltration in asthma. Functional experiments further demonstrated that the JAK2/STAT3 axis promotes ferroptosis and inflammatory responses by upregulating EPAS1 expression. Notably, these findings highlight the JAK2/STAT3/EPAS1 axis as a potential therapeutic target for asthma, offering new insights into its molecular mechanisms and identifying novel biomarkers for diagnosis and treatment
Alleviating the IL-1β-stimulated extracellular matrix degradation in osteoarthritis, and chondrocyte inflammation by Morinda officinalis polysaccharide via the SIRT6/NF-κB pathway
Full text linkMorinda officinalis polysaccharide (MOP) is a major active component of Morinda officinalis, known for its roles in supporting bone health and reducing oxidation and inflammation. However, no studies to date have specifically examined the effects of MOP on interleukin-1β (IL-1β)-stimulated chondrocyte inflammation or the progression of osteoarthritis (OA). To investigate, cell counting kit-8 assays were performed to evaluate MOP’s impact on the viability of human chondrocytes (C28/I2 cells). Cell damage was assessed using flow cytometry and Hoechst 33258 fluorescent staining. Inflammatory factor levels were measured via western blot and ELISA, while extracellular matrix (ECM) degradation was analyzed through immunofluorescence. The involvement of the NF-κB pathway and its regulation by Sirtuin 6 (SIRT6) were also explored using western blot. Following IL-1β treatment, C28/I2 cell viability decreased, inflammatory factor secretion increased, and ECM degradation was observed. MOP counteracted these effects by mitigating IL-1β-induced cell damage, preventing ECM degradation, and reducing inflammatory factor secretion, in a dose-dependent manner. Furthermore, IL-1β treatment suppressed SIRT6 expression, whereas MOP upregulated it. Notably, silencing SIRT6 diminished MOP’s protective effects on C28/I2 cells and reversed MOP’s suppression of the NF-κB pathway. In conclusion, MOP alleviates IL-1β-induced C28/I2 cell injury by inhibiting the NF-κB pathway through activation of SIRT6. This, in turn, reduces the inflammatory response, prevents ECM degradation, and ultimately slows OA progression
Predictive value of TGF-β1 and SMAD-7 expression at diagnosis for treatment response in low-risk myelodysplastic syndrome
Full text linkMyelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disease. Supportive treatments, such as erythropoiesis-stimulating agents (ESAs), are commonly used in patients with low-risk MDS. This study aimed to retrospectively assess the impact of bone marrow Mothers against decapentaplegic homolog 7 (SMAD-7) and transforming growth factor beta 1 (TGF-β1) protein expression on prognosis and response to ESA treatment in patients with low-risk MDS. We retrospectively analyzed patients diagnosed with low-risk MDS at the adult hematology department of Bursa Uludağ University Hospital. A total of 56 patients classified as low or very low risk were included in the study. Immunohistochemical analysis of bone marrow specimens at diagnosis showed that only five patients (9.8%) exhibited low SMAD-7 staining, while 51 patients (90.2%) showed no staining. Regarding TGF-β1 staining, 18 patients (32.1%) demonstrated moderate to high staining, whereas 38 patients (67.9%) exhibited low (36/38) or no staining (2/38). A statistically significant correlation was found between TGF-β1 staining levels and ESA treatment administration (P = 0.011). Additionally, a significant relationship was observed between lower erythropoietin (EPO) levels and moderate to high TGF-β1 staining (P = 0.04). However, when TGF-β1 staining status was compared with first- and third-month treatment responses in patients receiving ESA therapy, no significant difference was detected between groups. These findings suggest that while TGF-β1 alone may not be sufficient to predict ESA treatment response, additional parameters related to the TGF-β/SMAD pathway should be considered. Strong TGF-β1 staining, alongside EPO levels, may influence the decision to initiate ESA therapy
Trends in noninvasive ocular nanoparticle drug delivery: A bibliometric analysis (2004–2023)
Full text linkThis study presents a bibliometric analysis of research on noninvasive nanoparticle drug delivery systems for the transocular surface from 2004 to 2023. Relevant publications were retrieved from the Web of Science Core Collection. VOSviewer and CiteSpace were used to map contributions by countries/regions, authors, institutions, journals, keywords, keyword clusters, and timeline trends. A total of 695 articles were analyzed, showing a steady year-by-year increase in publications. China, the United States, and Spain were the leading contributors. Among authors, Alvarez-Lorenzo, Carmen was the most prolific, while Chanhan, Anuj’s work received the most citations among the top 10 prolific researchers. The International Journal of Pharmaceutics published the highest number of articles in this field, whereas the Journal of Controlled Release was the most frequently cited among the top 10 most productive journals. The University of Santiago de Compostela and the University of Florida were among the most active institutions in this research area. Keyword analysis identified recent key themes, such as controlled release, cell interaction, dry eye, mechanisms, gene expression, and ocular drug delivery. The growing interest in transocular surface nanoparticle drugs is driven by their advantages, including increased solubility, improved stability, reduced administration frequency, sustained therapeutic concentrations, enhanced corneal penetration, and prolonged ocular surface residence time
TNFSF14 and CD44 are overexpressed in glioblastoma and associated with immunosuppressive microenvironment
Full text linkGlioblastoma (GBM) is one of the deadliest cancers, and the survival rate has remained low for decades. The aim of the study was the construction of the programmed death-ligand 1 (PD-L1) network, identification of its interactors and over-represented pathways, and analysis of the association between the identified genes and the immunosuppressive microenvironment of GBM. The PD-L1 network was constructed using Cytoscape and Search Tool for the Retrieval of Interacting Genes/Proteins (STRING). Over-representation analysis was performed on WebGestalt using Kyoto Encyclopedia of Genes and Genomes (KEGG), Protein ANalysis THrough Evolutionary Relationships (Panther), and Reactome Pathway Database (Reactome). Gene expression levels were examined in silico using three large datasets (The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Rembrandt), as well as with qPCR. The association between PD-L1 gene expression and immune cell infiltration was analyzed using the Tumor Immune Estimation Resource (TIMER 2.0) online tool. Cluster of differentiation 44 (CD44) and tumor necrosis factor superfamily member 14 (TNFSF14) were found to be significantly overexpressed in GBM compared to lower-grade glioma (LGG) and normal brain tissue. Their overexpression was associated with worse overall survival and demonstrated a strong ability to differentiate between GBM and reference brain tissue. Notably, CD44 and TNFSF14 were linked to the mesenchymal subtype of GBM and positively correlated with the presence of regulatory T cells, resting natural killer (NK) cells, and PD-L1 expression. Our findings highlight the overexpression of CD44 and TNFSF14 in GBM and their potential involvement in creating an immunosuppressive microenvironment. Unraveling the PD-L1 interaction network and its associated pathways offers the potential not only to identify novel biomarkers for GBM prognosis but also to pinpoint alternative therapeutic targets that could be more effective in overcoming the immunosuppressive hurdles inherent in GBM treatment
Influence of maternal diabetes during pregnancy on ultrasound-measured fetal epicardial fat thickness: A meta-analysis
Full text linkMaternal diabetes during pregnancy, including gestational diabetes mellitus (GDM) and pregestational diabetes mellitus (PDM), has been linked to alterations in fetal development. This meta-analysis aimed to investigate the impact of maternal diabetes on fetal epicardial fat thickness (fEFT), measured via ultrasound—a potential marker of cardiometabolic risk. A systematic search of PubMed, Embase, and Web of Science was conducted to identify observational studies assessing fEFT in pregnant women with and without diabetes. A random-effects model was used to calculate the mean difference (MD) in fEFT between groups. Heterogeneity was evaluated using the I² statistic, and sensitivity, subgroup, and meta-regression analyses were performed to explore sources of variability. Data from 10 studies, comprising 12 datasets and 1303 participants, were pooled. Women with diabetes during pregnancy had significantly higher fEFT compared to those without diabetes (MD: 0.37 mm, 95% confidence interval [CI]: 0.26 to 0.49, P < 0.001), with moderate heterogeneity (I² = 69%). Sensitivity analyses, conducted by excluding one dataset at a time, confirmed the robustness of the findings (all P values < 0.05). Meta-regression revealed a positive correlation between gestational age (GA) at fEFT measurement and fEFT differences (coefficient = 0.040, P = 0.005), accounting for 83.2% of the heterogeneity. Subgroup analyses demonstrated consistent results across study designs, maternal diabetes types, and demographic factors but highlighted greater fEFT differences in studies where GA at fEFT measurement was >26 weeks. In conclusion, maternal diabetes during pregnancy is associated with increased fEFT, particularly in later gestation
Machine learning integration of single-cell and bulk transcriptomics identifies fibroblast-driven prognostic markers in colorectal cancer
Full text linkSingle-cell RNA sequencing (scRNA-seq) has significantly advanced our understanding of cellular heterogeneity and the complex interplay within the tumor microenvironment (TME) of colorectal cancer (CRC). However, translating these molecular insights into clinically actionable prognostic biomarkers and therapeutic strategies remains a considerable challenge. In this study, we conducted a comprehensive scRNA-seq analysis of 306 CRC samples comprising 448,255 cells to characterize the TME in depth. By constructing intercellular communication networks based on connection counts and communication probabilities, we identified fibroblasts as central regulatory hubs within the TME. Using Wilcoxon rank-sum tests and univariate survival analyses, we initially identified 23 prognostic fibroblast markers. These were refined to a seven-gene fibroblast-related prognostic signature via an integrated machine learning approach. The signature exhibited robust predictive performance in the The Cancer Genome Atlas - Colon Adenocarcinoma (TCGA-COAD) training cohort (n=351; C-index=0.65) and was successfully validated in the GSE17536 dataset (n=177; C-index=0.63). Functional enrichment analyses revealed that this signature is involved in immune regulation and multiple tumor-associated cellular pathways. Notably, high-risk patients displayed increased macrophage and NK cell infiltration, impaired immune function, and elevated immune rejection scores, while low-risk patients demonstrated heightened sensitivity to camptothecin and irinotecan. Together, our findings underscore the prognostic value of fibroblast-derived signatures in CRC and support their potential utility in risk stratification and the development of personalized therapeutic strategies, contributing to the advancement of precision oncology
Predictive value of inflammatory markers in inguinal hernia surgery: General vs. spinal anesthesia
Full text linkInguinal hernia is a prevalent condition requiring surgical intervention, and accumulating evidence suggests that the type of anesthesia administered may influence systemic inflammatory responses. This study investigates the concentrations of inflammatory parameters in patients with inguinal hernia who underwent surgery utilizing either general or spinal anesthesia. The cohort comprised 87 male patients with inguinal hernia, classified as American Society of Anesthesiologists (ASA) physical status 1-2, who underwent elective surgical procedures. Participants were divided into two groups based on the anesthesia type: 44 received general anesthesia while 43 received spinal anesthesia. Plasma concentrations of leukocytes, C-reactive protein (CRP), interleukin-6 (IL-6), and lipopolysaccharide-binding protein (LBP) were quantified using automated immunoassays and a hematological analyzer. Standard parametric and non-parametric statistical tests were employed for data analysis, and the predictive capacity of select parameters, along with body mass index (BMI) and age, was assessed through Receiver Operating Characteristic (ROC) analysis with Area Under the Curve (AUC). Statistical analysis via the t-test identified significant differences in LBP concentrations (LBP 1, LBP 2, and LBP 3) between patients receiving general and spinal anesthesia. Correlation analysis of BMI and the measured parameters revealed statistically significant positive correlations for LBP 1 and LBP 2 in patients who underwent spinal anesthesia. Notably, the preoperative concentration of LBP, with a cutoff value exceeding 9.7 µg/mL, suggests a potentially superior approach with spinal anesthesia compared to general anesthesia, demonstrating 50% sensitivity and 81.4% specificity. Other parameters did not exhibit statistical significance in differentiating the type of anesthesia used for inguinal hernia surgery