Search Results (17,843)

Background: Aberrant glycosylation is closely associated with tumor progression, changes in the tumor microenvironment, and chemoresistance. This study aimed to identify prognostic sialylation-related genes in bladder cancer and define the role of ST3GAL6 in gemcitabine–cisplatin resistance. Methods: Molecular subtype analysis, prognostic analysis, and risk model construction were performed for sialylation-related genes using transcriptomic data and clinical information from the TCGA database. GC-resistant bladder cancer cell models were established for transcriptomic sequencing and untargeted metabolomic analysis. Cell proliferation and drug sensitivity assays were performed to evaluate the function of ST3GAL6. The regulatory relationship between IGF2BP3, ST3GAL6, and the PI3K pathway was further assessed by combining database analysis with molecular experiments. Results: Sialylation-related molecular patterns were associated with patient prognosis and tumor microenvironment features, particularly fibroblast-related characteristics, in bladder cancer. The key model gene ST3GAL6 was upregulated in bladder cancer tissues and was closely associated with prognosis. In GC-resistant bladder cancer cells, ST3GAL6 expression was significantly increased and accompanied by enhanced sialylation activity. ST3GAL6 promoted bladder cancer cell proliferation and reduced sensitivity to cisplatin and gemcitabine, at least in part through the PI3K-AKT-mTOR pathway. IGF2BP3 was also upregulated in resistant cells, is positively correlated with ST3GAL6, and may help maintain ST3GAL6’s expression by stabilizing its mRNA. Conclusions: Our findings suggest that aberrant sialylation is involved in bladder cancer progression and GC resistance. The IGF2BP3-ST3GAL6-PI3K/AKT/mTOR signaling axis may contribute to this process and may serve as a potential biomarker and therapeutic target in bladder cancer. Full article

(1) Background: Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide. Aberrant remodeling of the extracellular matrix (ECM) is a hallmark of GC progression; however, the mechanisms by which GC cells sense and exploit ECM cues remain unclear. (2) Methods: ITGA11 was identified through integrative bioinformatic analyses. Its expression, clinical significance, and association with ECM-related signatures were evaluated in GC tissues and public datasets. The function of ITGA11 and its role in regulating the FAK/PI3K/AKT/mTOR pathway were investigated using in vitro and in vivo assays, and the inhibitory effect of Naringenin on ITGA11-associated oncogenic activity was assessed. (3) Results: ITGA11 was upregulated in GC tissues and correlated with an ECM-related gene signature, aggressive clinicopathological features and poor patient survival. ITGA11 promoted malignant phenotypes of GC cells in vitro and in vivo. Importantly, molecular docking and target engagement assays suggested a potential interaction between Naringenin and ITGA11. Functional experiments showed that Naringenin attenuated ITGA11-associated oncogenic activity by reducing ITGA11 levels, suppressing pathway activation, and inhibiting malignant phenotypes. (4) Conclusions: Our findings identify ITGA11 as a potential prognostic biomarker and functional driver of GC progression and suggest that Naringenin may represent a promising bioactive compound for modulating the ITGA11/FAK/PI3K/AKT/mTOR axis in GC. Full article

Background/Objectives: Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries, with increasing incidence and limited options in advanced disease. Molecular classification has redefined risk stratification and therapeutic decision-making, particularly with the incorporation of immunotherapy. This review provides a clinically oriented overview of immunotherapy in EC across molecular subgroups and treatment settings. Methods: A narrative review was conducted using PubMed/MEDLINE, Embase, and Web of Science, focusing on clinical trials and studies with direct clinical relevance. Results: Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have demonstrated significant benefit in EC, particularly in mismatch repair-deficient (dMMR)/microsatellite instability–high (MSI-H) tumors, where durable responses are observed. In contrast, mismatch repair-proficient (pMMR) tumors show limited sensitivity to monotherapy and require combination approaches. Recent phase III trials have established chemoimmunotherapy as a first-line standard, with greater benefit in dMMR tumors and clinically meaningful improvements in pMMR disease. In the second-line setting, PD-1 inhibitor monotherapy is standard for dMMR tumors, while lenvatinib plus pembrolizumab is a key option for pMMR disease. However, responses remain heterogeneous and are not fully explained by MMR status alone. Conclusions: Immunotherapy is a cornerstone in advanced EC management, guided by molecular classification. Key challenges include limited efficacy in pMMR tumors, lack of robust predictive biomarkers, and uncertainty in treatment sequencing. Future strategies should focus on biomarker-driven approaches and rational combinations. Full article

The Oncotype DX^® 21-gene recurrence score (RS) guides adjuvant chemotherapy decisions in estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2−) breast cancer, yet requires invasive tissue sampling and involves substantial costs. This study evaluated intratumoral tumor ecological diversity (iTED), a habitat imaging approach, as a non-invasive complement for predicting Oncotype DX^® high-risk classification (RS > 25). This retrospective multi-center study included 312 patients with ER+/HER2− invasive breast cancer who underwent Oncotype DX^® testing (development: n = 168; external validation: n = 144). The iTED framework employed superpixel-based habitat determination using Gaussian mixture models on pretreatment dynamic contrast-enhanced MRI. Four predictive models were compared: clinical, conventional whole-tumor radiomics (C-radiomics), iTED, and combined (Clinical + iTED). The iTED model achieved higher discriminative performance compared with C-radiomics in both development (area under the curve [AUC]: 0.868 ± 0.068 vs. 0.730 ± 0.112) and external validation (AUC: 0.811 vs. 0.587) sets. The combined model further improved performance (development AUC: 0.908 ± 0.043; external AUC: 0.889). Habitat imaging-based iTED features achieved numerically higher performance than conventional radiomics in predicting Oncotype DX^® high-risk classification. These findings suggest the potential of iTED as a non-invasive imaging biomarker to support molecular testing in clinical decision-making. Full article

Background: Head trauma is a major public health concern. Computed tomography (CT) is frequently used to evaluate these patients but may expose them to unnecessary radiation exposure. Various biomarkers have been investigated to predict prognosis and reduce the need for unnecessary imaging. Red cell distribution width (RDW), neutrophil/lymphocyte ratio (NLR), and platelet/lymphocyte ratio (PLR) have been proposed as inflammatory markers; however, their diagnostic value in head trauma remains controversial. This study aimed to determine the value of complete blood count parameters in identifying intracranial injury in patients with mild head trauma. Methods: This prospective, single-center study enrolled 100 adults with mild head trauma. Demographic data, vital signs, neurological assessments, complete blood counts, CT results, and clinical outcomes were also recorded. Patients were categorized as intracranial injury positive (Group 1) or intracranial injury negative (Group 2). We statistically compared the laboratory and demographic data of the groups. Statistical significance was set at p < 0.05. Results: The study included 100 patients with mild head trauma who presented to the emergency department, of whom 11 were in Group 1. The median PLR and lymphocyte levels differed significantly between the groups (p < 0.05). Conclusions: The PLR may serve as a preliminary supportive marker to aid clinical assessment; however, its modest discriminatory performance suggests that it should not be used as a standalone diagnostic tool. Full article

Background: SGLT2 inhibitors improve outcomes in heart failure with reduced ejection fraction (HFrEF), but whether early recovery patterns after initiation differ according to HF etiology in real-world practice remains uncertain. Objective: To evaluate whether ischemic versus non-ischemic etiology is associated with different 6-month cardiac, renal, biomarker, and exploratory metabolic trajectories after early in-hospital SGLT2 inhibitor initiation in HFrEF. Materials and Methods: In this prospective single-center observational cohort (2022–2025), consecutive adults hospitalized with first-presentation acute HFrEF who initiated empagliflozin or dapagliflozin within 48 h of admission were enrolled. Patients were classified as having ischemic cardiomyopathy (ICM) or non-ischemic cardiomyopathy (NICM). The primary analytic cohort included patients with paired baseline and 6-month echocardiography. The primary outcome was change in left ventricular ejection fraction (LVEF); eGFR and NT-proBNP were secondary outcomes. Exploratory metabolic/laboratory variables were summarized descriptively using paired available-case follow-up. The study was approved by the institutional ethics committee and registered in ClinicalTrials.gov under the CaRD registry framework (NCT06090591). Results: The paired 6-month echocardiographic analytic cohort comprised 241 patients who survived to reassessment (ICM n = 90; NICM n = 151). NICM showed greater improvement in LVEF than ICM (ΔLVEF +10% [IQR 0–18] vs. +5% [IQR 0–12]; p = 0.049) and a more favorable eGFR trajectory (ΔeGFR 0.30 [IQR −5.90 to 6.60] vs. −2.70 [IQR −12.60 to 3.40] mL/min/1.73 m²; p = 0.038). NT-proBNP declined substantially in both groups, with no between-group difference in change magnitude (p = 0.845), although 6-month values remained higher in ICM (p = 0.034). However, after multivariable adjustment, ischemic etiology was no longer independently associated with 6-month LVEF or eGFR outcomes. Exploratory metabolic findings varied descriptively by etiology but should be interpreted cautiously because follow-up completeness and background treatment intensity varied across variables. Conclusions: In this real-world cohort of patients with HFrEF who initiated SGLT2 inhibitors during hospitalization, HF etiology was associated with different short-term cardiorenal recovery patterns, whereas NT-proBNP reduction was similar across groups. These findings characterize etiology-related recovery within a treated cohort rather than differential SGLT2 inhibitor efficacy and should therefore be considered as hypothesis-generating. Full article

Background: Elevated gamma-glutamyl transferase (GGT) is a biomarker associated with alcohol-related hepatic stress and oxidative imbalance. Although alcohol abstinence is the primary determinant of GGT normalization, adjunctive strategies may support biochemical improvement in real-world settings. Methods: This non-randomized cohort study included 197 of 1957 screened participants (10.1%), stratified according to baseline GGT into 55–99 U/L (n = 95) and ≥100 U/L (n = 102). Participants in the higher baseline subgroup underwent a multimodal intervention consisting of nutraceutical supplementation (silymarin, essential phospholipids, and a polyherbal antioxidant formulation) combined with structured psychological support aimed at promoting alcohol abstinence. The primary outcome was the change in GGT between baseline (T1) and follow-up (T2). Secondary outcomes included the proportion of participants achieving GGT reduction and the magnitude of change according to baseline severity. Clinical trial registration: ClinicalTrials.gov Identifier: NCT07603726. Results: Among participants with baseline GGT ≥ 100 U/L, GGT levels decreased from a median of 133.73 to 97.41 U/L (p < 0.001), whereas in the 55–99 U/L subgroup, median GGT changed from 67.49 to 66.51 U/L without reaching statistical significance (p = 0.072). Participants in the higher baseline subgroup demonstrated greater GGT reductions (median ΔGGT: −35.25 vs. −2.58 U/L), a higher proportion achieving GGT reduction (91.2% vs. 70.5%), and higher odds of GGT reduction at follow-up in exploratory analysis (OR = 4.32, 95% CI: 1.91–9.75). Conclusions: In this real-world cohort, reductions in GGT levels were observed, particularly among individuals with elevated baseline values (≥100 U/L) who underwent the multimodal intervention. These findings support monitoring GGT dynamics in routine clinical practice, where GGT remains a practical and accessible biomarker due to its widespread availability, low cost, and sensitivity to oxidative and alcohol-related hepatic stress. Full article

Background: Vestibular migraine (VM) is a common cause of episodic vertigo, yet its diagnosis remains primarily clinical and is often complicated by the absence of reliable objective biomarkers. Pupillary nystagmus, reflecting spontaneous oscillations of pupil diameter, has been proposed as a potential clinical sign of VM, but its quantitative characterization remains limited. Objective: The objective of this study is to evaluate the diagnostic value of pupillary nystagmus in VM and to provide a quantitative assessment using infrared pupillometry. Methods: In this case–control study, 137 patients with vestibular migraine and 102 healthy controls underwent comprehensive neuro-otological evaluation, including vestibular testing and pupillometric assessment. Pupillary activity was recorded using a dedicated infrared pupillometer, and oscillatory dynamics were quantified using the Pupillary Unrest Activity Level (PUAL), which was derived through spectral analysis (Larson–Neice algorithm). Statistical comparisons were performed using non-parametric methods. Results: PUAL values differed significantly between VM patients and controls (Mann–Whitney test p < 0.001), demonstrating a clear separation between groups. A cut-off value of 0.325 was identified as the upper limit of normality, suggesting that elevated PUAL values may indicate vestibular migraine. Conclusions: Pupillary nystagmus represents a clinically accessible sign that can be objectively quantified through infrared pupillometry. The PUAL index provides a measurable parameter reflecting altered vestibulo–autonomic dynamics in VM and may serve as a promising neuro-otological biomarker. The integration of pupillometric analysis with clinical evaluation may improve diagnostic accuracy and support the development of objective diagnostic tools in vestibular migraine. Full article

Responsive microgels have emerged as a versatile class of soft materials for biomedical applications owing to their tunable physicochemical properties, high water content, and ability to respond dynamically to external and biological stimuli. This review summarizes recent advances in the design, synthesis, and biomedical utilization of responsive microgels, with a focus on their functional roles across key application domains. First, the fundamental principles governing microgel responsiveness and structure–property relationships are briefly introduced. The application of responsive microgels in controlled drug delivery is then discussed, highlighting stimulus-triggered release mechanisms, payload protection, and spatiotemporal control of therapeutic delivery. Advances in tissue engineering are reviewed with emphasis on microgel-based scaffolds, injectable constructs, and cell–matrix interactions that promote tissue regeneration. The use of microgels in biomedical imaging is examined, including their roles as contrast agents, signal amplifiers, and carriers for imaging probes. Finally, recent developments in microgel-enabled diagnostics are presented, showcasing their utility in biosensing, biomarker detection, and point-of-care platforms. The literature was selected based on the authors’ expertise, focusing on representative and recent studies, and identified through general academic databases and key references. Collectively, this review provides a comprehensive overview of the multifunctional capabilities of responsive microgels and discusses current challenges and future opportunities toward their clinical translation. Full article

Oxidative stress is a fundamental mechanism that impacts reproductive function by altering gamete quality, fertilisation, and the initial development of embryos. Excessive reactive oxygen species lead to the oxidation of polyunsaturated fatty acids in the cell membranes of sperm, oocytes, and adjacent somatic cells. F2-isoprostanes and isofurans are two of the most dependable indicators of oxidative lipid damage among the byproducts generated during free radical-mediated lipid oxidation. Both arise from the non-enzymatic peroxidation of arachidonic acid and provide a chemically stable depiction of in vivo oxidative processes. Reproductive studies indicate that elevated levels of F2-isoprostanes are associated with diminished sperm motility, compromised membrane stability, and an increased risk of DNA fragmentation in various forms of male infertility. Lipid peroxidation products have been detected in follicular fluid inside the female reproductive system, suggesting a relationship between oxidative imbalance, granulosa cell metabolism, and oocyte competency. Isofurans, which are more prevalent in the presence of elevated oxygen levels, may indicate oxidative stress in mitochondria and complications with cellular respiration. The current comprehension of lipid peroxidation indicators in infertility and assisted reproduction remains insufficient. This review aims to synthesise current information on isoprostanes and isofurans as reliable indicators of oxidative lipid damage in reproductive biology, highlighting their effects on gamete quality, mitochondrial dysfunction, and results in assisted reproduction. Our research seeks to clarify the biological importance of current experimental and clinical findings, highlighting their potential as clinically relevant biomarkers in reproductive medicine. Full article

Acerola (Malpighia emarginata DC.) is one of the richest natural sources of vitamin C and an important source of phenolic compounds, carotenoids, and bioactive polysaccharides. Although the fruit can be consumed fresh, it is more commonly processed into juices and frozen pulp, generating substantial amounts of by-products (pomace, peels, and seeds), corresponding to approximately 20–60% of the fruit biomass, with high phytochemical content. These fractions represent underutilized sources of bioactive compounds. This narrative review, supported by a structured literature search, integrates evidence on the phytochemical composition of acerola pulp and its by-products and relates these profiles to biological effects in experimental and human studies, focusing on compound characterization, composition–function relationships, and underlying mechanisms. Key compounds, including ascorbic acid, hydroxycinnamic acids, flavonoids, and polysaccharides, are associated with the modulation of redox homeostasis, inflammatory signaling, and lipid metabolism, particularly under high-fat dietary conditions. Human evidence remains limited but suggests matrix-dependent effects on vitamin C bioavailability and selected cardiometabolic markers. Overall, the evidence is constrained by methodological heterogeneity, limited clinical data, and insufficient characterization of bioactive fractions. Future research should prioritize detailed phytochemical profiling, dose–response relationships, bioavailability assessment, and well-controlled clinical trials incorporating molecular biomarkers, supporting the development of acerola-derived matrices as functional and bioactive-rich ingredients. Full article

Background/Objectives: Bipolar disorder affects about 40 million people worldwide, and the greatest burden of the disease is associated with depressive episodes. About 25% of patients experience drug-resistant depression, in which standard treatment turns out to be insufficient, and monotherapy often does not bring full remission. Despite the use of second-generation antipsychotics, the effectiveness of therapy in TRBD remains limited, which necessitates rational polypharmacotherapy and augmentation strategies. The paper discusses the receptor mechanisms of drug combination, current therapeutic regimens and new interventions such as ketamine acting on the glutamate anergic system. The aim was to synthetically compare the efficacy and safety of available augmentation strategies and polypharmacotherapy. Methods: The material consists of published clinical, observational and randomized trials on pharmacotherapy of drug-resistant bipolar depression, including atypical neuroleptics, ketamine, pramipexole, modafinil, lamotrigine, celecoxib and memantine. The authors analyze receptor mechanisms, neurobiological data and clinical trial results, comparing them with current definitions of TRBD according to ISBD and CINP. Biomarker data, such as the Systemic Immune-Inflammation Index, and the results of neuroimaging and metabolomic studies were also used in the work. Results: The analysis showed that atypical neuroleptics showed limited efficacy and high rates of side effects, while ketamine has the fastest and most pronounced antidepressant effect with a low risk of phase change. Pramipexole has shown promise in terms of long-term efficacy, but its use reduces the high risk of induction of mania and impulse control disorders. Celecoxib as an anti-inflammatory therapy significantly increased response and remission rates compared to escitalopram alone, and memantine showed only an early, short-term antidepressant effect. The results highlight that TRBD requires targeted polypharmacotherapy, with the most promising directions being glutamatergic modulation and anti-inflammatory therapies. Conclusions: Drug-resistant bipolar depression requires a departure from classical monotherapy in favor of rational, mechanistically justified polypharmacotherapy, targeting complex monoaminergic, glutamatergic and neuroinflammatory disorders. Available data indicate that ketamine has the greatest clinical potential among the current strategies, characterized by a rapid onset of action and a favorable safety profile compared to atypical neuroleptics or dopamine agonists. Modulation of inflammatory processes with the use of celecoxib also has promising results, which highlights the importance of biomarkers and personalization of therapy. However, further, large, and well-designed studies are needed to unambiguously determine optimal treatment strategies for TRBD and to verify the effectiveness of new pharmacological interventions. Full article

The diagnostic field of prostate cancer (PCa) has undergone a significant evolution with the widespread integration of multiparametric magnetic resonance imaging (mpMRI) and mpMRI-targeted biopsies (TBx). This approach has been shown to improve the detection of clinically significant prostate cancer (csPCa) while reducing the overdiagnosis of low-risk disease. However, a conceptual and clinical challenge, which can be referred to as the “Precision Paradox,” has emerged. By directing biopsy cores almost exclusively into the most suspicious MRI lesions, clinicians may inadvertently overrepresent the biological significance of a limited high-grade component. This can lead to grade migration and pathological downgrading at the time of radical prostatectomy (RP). Although downgrading does not automatically equate to clinical overtreatment, it introduces prognostic uncertainty that complicates risk stratification for active surveillance (AS) and focal therapy. This conceptual commentary provides a critical perspective on this diagnostic issue. We synthesize recent meta-analyses to evaluate the true rates of grade mismatch associated with TBx and combined biopsy approaches. Furthermore, we discuss the spatial limitations of biopsy sampling, the pathological mechanisms driving grade discordance, and the clinical relevance of minor high-grade components such as cribriform architecture. Finally, we highlight the role of multi-omics and validated genomic biomarkers in risk models, ultimately fostering improved shared decision-making in the modern mpMRI era. Full article

Pediatric septic shock remains a major cause of morbidity and mortality in critically ill children and is increasingly recognized as a syndrome of profound immunometabolic dysregulation. This narrative review synthesizes current clinical, translational, and mechanistic evidence on the glutamate–glutamine axis in pediatric septic shock. The review focuses on how glutamine and glutamate metabolism may interact with immune-cell function, mitochondrial substrate handling, redox defense, and intestinal barrier integrity, while distinguishing biological plausibility from validated clinical utility. Current evidence supports the glutamate–glutamine axis as a mechanistically relevant pathway and a source of candidate biomarkers, but pediatric-specific data remain limited and do not yet justify routine biomarker use or glutamine-based intervention in unselected children with septic shock. Future studies should use standardized sampling, reproducible analytical methods, pediatric validation cohorts, and phenotype-guided trial designs before this axis can be translated into clinical decision making. Full article

Major depressive disorder (MDD) and anxiety disorders are increasingly understood as conditions involving complex metabolic dysregulation across multiple biological domains. This review aimed to synthesize current clinical and translational evidence on amino acid metabolism, lipid metabolism and short-chain fatty acids (SCFAs) as potential biomarkers, and components of integrative metabolic profiling in these disorders. A structured narrative approach was applied, focusing on studies assessing metabolomic alterations, their clinical correlates and their potential role in patient stratification, and treatment response. The available evidence indicates that amino acid disturbances, particularly within the tryptophan–kynurenine pathway, represent the most consistent and clinically interpretable findings. Lipid-related alterations, especially involving long-chain polyunsaturated fatty acids, provide complementary insights into membrane function, inflammation and neuroplasticity. In contrast, SCFAs appear to function as context-dependent markers rather than robust standalone biomarkers, with their clinical relevance depending on biological matrix, metabolic context and host–microbiota interactions. Importantly, most studies assess individual metabolites rather than integrated metabolic profiles, limiting their interpretability within a metabolomic framework. Overall, current evidence supports a shift toward integrative biomarker models that combine metabolic data with selected molecular and clinical parameters. Future research should focus on standardized, reproducible profiling approaches to enable biologically informed stratification and personalized treatment strategies. Full article