Search Results (1,029)

Alternative pre-mRNA splicing is a central layer of gene regulation that enables a limited number of genes to generate a far larger and more context-dependent transcriptome and proteome. In cancer, splicing is disrupted by mutations in cis-regulatory sequences, recurrent lesions in spliceosome components, altered abundance or activity of RNA-binding proteins, and changes in transcription, chromatin, RNA modification, metabolism and stress signalling. These alterations are not merely by-products of malignant transformation. They can create oncogenic protein isoforms, eliminate tumour-suppressive products, remodel cellular identity, promote metastasis and drug resistance, and generate tumour-restricted peptides that are visible to the immune system. Large pan-cancer datasets, long-read sequencing, single-cell isoform profiling, proteogenomics and functional perturbation screens are now resolving this complexity at unprecedented scale. In parallel, multiple therapeutic strategies are advancing, including modulators of the SF3B complex, molecular glues that degrade RBM39, inhibitors of protein arginine methyltransferases and splicing kinases, splice-switching oligonucleotides, programmable RNA-targeting systems, and vaccines or T-cell receptors directed against splicing-derived neoantigens. This review integrates the molecular logic of splice-site selection with the cancer-specific mechanisms that perturb it, summarizes representative isoform switches across the hallmarks of cancer, evaluates emerging technologies and clinical biomarkers, and discusses the opportunities and constraints of translating splicing biology into precision oncology. Particular emphasis is placed on tumour specificity, intratumoural heterogeneity, proteomic validation, therapeutic windows and rational combination strategies. Full article

Over the past decades, green alder (Alnus alnobetula) has spread rapidly across the Alps, expanding from moist, north-facing slopes into areas with limited water availability. Despite its growing ecological relevance in alpine environments, the species’ physiological limits under drought are largely unknown. To evaluate the species’ drought tolerance, we conducted a greenhouse experiment in which juvenile plants were subjected to drought periods of different durations, while monitoring stomatal conductance (gs) and quantum yields of photosystem II. Once the soil water potential fell below the wilting point (Θ_WP), gs declined to less than 25% of the control level. After re-irrigation, gs remained reduced for several weeks, indicating a post-drought legacy effect. Under prolonged drought, the maximum quantum yield of photosystem II (Fv/Fm) declined to 20% of control values. The correlation between effective quantum yield and radiation proved a useful indicator for moderate drought stress. During recurrent drought, plants showed an acclimation to dry conditions, and both gs and Fv/Fm declined significantly (p < 0.01) at moderate drought, indicating a short-term, drought-induced adjustment in stomatal regulation. Although green alder showed signs of acclimation under repeated drought, recurrent severe drought led to high mortality in juvenile plants, indicating vulnerability at drought-prone sites. Full article

Background and Objectives: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterised by recurrent nodules, abscesses, sinus tract formation, and tissue remodelling. Increasing evidence suggests that oxidative stress contributes to HS pathogenesis; however, the role of the Nrf2–Keap1–Sestrin-2 axis and its interaction with matrix remodelling pathways remains poorly understood. This study aimed to evaluate serum levels of Nrf2, Keap1, Sestrin-2, asprosin, MMP-1, and TIMP-1 in patients with HS and to investigate their potential roles in disease pathophysiology. Materials and Methods: A total of 26 patients with hidradenitis suppurativa and 20 healthy volunteers were enrolled in the study. Serum biomarkers were measured in patients with HS and healthy controls. In addition to conventional statistical analyses, multivariate analyses, including PCA, PLS-DA, VIP scoring, correlation mapping, ROC analysis, heatmap visualisation, and biplot assessment, were performed to characterise biomarker interactions and discriminatory performance. Results: HS patients exhibited significantly increased serum asprosin, Keap1, and MMP-1 levels, whereas Nrf2, Sestrin-2, and TIMP-1 levels were significantly reduced compared with controls. Multivariate analyses demonstrated clear separation between patient and control groups within the cohort, indicating a distinct biochemical signature associated with HS. VIP analysis identified Nrf2, Sestrin-2, and TIMP-1 as the most influential variables contributing to group discrimination. Within the HS group, none of the pairwise biomarker correlations remained statistically significant after Benjamini–Hochberg false discovery rate (FDR) correction. ROC analysis showed diagnostic performance for Nrf2 and Sestrin-2. Conclusions: These findings suggest that alterations in serum markers related to the Nrf2–Keap1–Sestrin-2 axis and the MMP-1/TIMP-1 balance are associated with oxidative stress, inflammation, and tissue remodelling in HS. Nrf2 and Sestrin-2 may represent candidate biomarkers; however, given the modest sample size and single-centre design, their discriminatory performance should be considered exploratory and requires confirmation in larger independent cohorts. Full article

A standardized extract of cultured Lentinula edodes mycelia (ECLM), commercially known as AHCC^®, shows anti-inflammatory, immunomodulatory, and organ-protective properties. Experimental studies have indicated that ECLM modulates innate and adaptive immunity, including natural killer (NK) cell activity, antigen-presenting cell function, T-cell responses, and cytokine balance. These effects are particularly relevant in oncology because surgical stress and ischemia–reperfusion injury (IRI) generate a transient perioperative environment characterized by immune suppression, inflammation, and conditions favorable for metastatic progression. Recent animal studies have demonstrated the protective effects of ECLM in intestinal and hepatic IRI models, providing a potential mechanistic rationale for improving the perioperative host microenvironment. Clinical studies on hepatocellular carcinoma, pancreatic cancer, and gynecological malignancies suggest that ECLM may offer potential benefits in immune preservation, nutritional support, symptom management, and recurrence prevention, although most studies are small and hypothesis-generating. Emerging evidence from patient-derived xenograft and spontaneous carcinogenesis models further suggests that ECLM may influence tumor biology beyond host immune activation, although the underlying mechanisms require elucidation. This review summarizes the mechanistic, preclinical, translational, and clinical evidence supporting the use of ECLM as a candidate for perioperative immunonutritional strategies. We propose the hypothesis that ECLM may function as a perioperative microenvironmental stabilizer that integrates immune preservation and intestinal barrier protection. Full article

Background/Objectives: Recurrent pregnancy loss (RPL) has traditionally been investigated predominantly through maternal factors, while the clinical role of paternal assessment remains inconsistently defined. Current guidelines differ substantially regarding semen analysis, sperm DNA fragmentation (SDF), genetic testing, and referral for andrological evaluation. This review aimed to compare contemporary guideline recommendations, critically appraise the directness, prognostic value, and clinical utility of the supporting evidence, and classify paternal assessment strategies as routine, selective, or investigational. Methods: A structured narrative review was conducted using PubMed and Scopus searches through June 2026. International RPL, obstetric, reproductive medicine, and andrology guidelines were compared. Evidence from systematic reviews, meta-analyses, clinical studies, and clinically relevant molecular investigations was evaluated according to its directness to RPL populations, diagnostic and prognostic value, and evidence that test-guided interventions improve miscarriage or live-birth outcomes. Results: Routine paternal assessment should include age, reproductive and medical history, body weight, lifestyle, medication exposure, and relevant environmental or occupational risks. Conventional semen analysis is appropriate primarily when RPL coexists with infertility or suspected male reproductive disease. SDF is the most extensively studied advanced paternal biomarker and is frequently elevated in RPL cohorts, but findings vary by assay and comparator population, while prospective prediction of subsequent live birth and benefit from SDF-directed treatment remain unproven. Parental karyotyping has established counselling value but should be risk-stratified. Sperm aneuploidy testing, oxidative stress assays, seminal microbiome profiling, epigenetic biomarkers, and biomarker-directed interventions remain investigational. Conclusions: Paternal assessment in RPL should be couple-based, clinically targeted, and evidence-informed. Current evidence supports routine clinical evaluation, selective use of semen analysis, SDF testing, genetic assessment, and reproductive urology referral, and restriction of unvalidated biomarkers and treatments to research settings. Full article

Epilptogenesis is a long-term process that involves the transformation of a healthy brain into a seizure-producing brain. Since approximately 30% of epilepsy patients suffer from drug-resistant seizures, the concept of inhibiting the epileptogenesis process and thus preventing seizures has emerged. The search for effective methods of inhibiting epileptogenesis is possible thanks to animal models, which include kindled seizures; models based on the induction of status epilepticus resulting in subsequent spontaneous recurrent seizures, or brain trauma; and genetic models. Blood–brain barrier dysfunction, inflammatory processes in the brain, and oxidative stress appear to play a major role in epileptogenesis. This prompted testing of a number of anti-inflammatory agents and antioxidants in the epileptogenic process. One noteworthy finding was that losartan (an antihypertensive drug), as a TGF-β antagonist, proved effective in inhibiting epileptogenesis due to blood–brain barrier damage. Due to the many mechanisms involved in the process of epileptogenesis, it seems that the use of a combination of drugs will be an effective method of inhibiting it. The most promising combination includes levetiracetam (a second-generation antiseizure drug), atorvastatin, and ceftriaxone (a beta-lactam antibiotic), which effectively inhibits spontaneous seizures in animals experiencing status epilepticus. Any clinical trials on the inhibition of epileptogenesis must take into account the fact that a small percentage of patients develop epileptic seizures after stroke or brain injury. Recently suggested markers predicting a high probability of epileptic seizures after brain damage may facilitate appropriate patient selection for studies on inhibition of epileptogenesis. Full article

Background/Objectives: Oxidative stress is a major cause of RBC membrane damage, especially in individuals with G6PD deficiency who have impaired antioxidant defenses. Triphala, a phenolic-rich herbal formulation with known antioxidant activity, was evaluated for its phytochemical profile, antioxidant and anti-hemolytic effects, and molecular mechanisms in H₂O₂-induced oxidative stress models using normal and G6PD-deficient human RBCs. Methods: Triphala aqueous extract was characterized using LC-MS and GC-MS. Antioxidant activity was evaluated by DPPH and ABTS assays. Cytotoxicity, membrane stability, and protection against H₂O₂-induced hemolysis were assessed in normal and G6PD-deficient RBCs. Network pharmacology, molecular docking and MD simulation analyses were performed to predict antioxidant-related mechanisms. Statistical analysis was conducted using one-way ANOVA (p < 0.05). Results: LC-MS identified gallic acid as the predominant phenolic compound, while GC-MS revealed pyrogallol as the major constituent. The extract showed strong radical scavenging activity and significantly reduced H₂O₂-induced hemolysis in both normal and G6PD-deficient RBCs without cytotoxicity (p < 0.05). Network pharmacology revealed that G6PD-related antioxidant regulation, oxidative stress response, and inflammatory signaling pathways are the key enriched biological processes. Network pharmacology analysis ranked PPARG, PTGS2, EGFR, MMP9, TLR4, ACE, REN, PPARA, SERPINE1, and MMP2 as the top hub proteins, highlighting their central roles in oxidative stress, inflammation, and metabolic signaling pathways. Kynurenic acid binds strongly to PTGS2 (COX-2) and ACE with binding affinities below −7.0 kcal/mol, forming multiple hydrogen bonds that stabilize its interactions within the active sites. MD simulations confirmed that kynurenic acid binds stably to ACE and PTGS2, with RMSD values plateauing near 2.4 Å and 3.0 Å, RMSF values mostly below 2 Å, and recurrent hydrogen bonding and electrostatic contacts with key residues, collectively underscoring its conformational stability, adaptive flexibility, and modulatory potential. Conclusions: Triphala aqueous extract exhibits potent antioxidant and anti-hemolytic activities and may serve as a natural adjunct strategy for reducing oxidative damage in G6PD deficiency and related RBC disorders. Full article

Replication and transcription share the DNA template and must be coordinated to preserve genome integrity. Although temporally organized across the cell cycle, essential transcriptional programs—encoding replication machinery, canonical histones, and DNA repair factors—operate concurrently with DNA synthesis during S phase. Transcription–replication conflicts (TRCs) therefore constitute a recurrent endogenous source of replication stress (RS), particularly under hypertranscriptional or chromatin-constrained conditions. A frequent outcome of TRCs is the formation of R-loops–RNA:DNA hybrids that can stall or collapse replication forks, leading to DNA damage. This review summarizes current evidence supporting a broader involvement of ERCC6/CSB at the transcription–replication interface beyond its established role in transcription-coupled repair. We discuss how ERCC6 participates in RNA polymerase II processing, chromatin remodeling, R-loop metabolism, replication fork protection, and repair pathway engagement following RS, operating through both its ATPase domain and intrinsically disordered regions. Conversely, in homologous recombination-deficient contexts, ERCC6 may favor mutagenic restart mechanisms, including break-induced replication; and recent evidence indicates that ERCC6 status influences cellular fate and the genomic distribution of stress-induced mutations, linking transcription-coupled repair with transcription-dependent mutagenesis. These observations support a model in which ERCC6 coordinates transcription-associated repair with RS responses, shaping genome maintenance and mutational outcomes, with implications for cancer and therapeutic strategies. Full article

Long non-coding RNAs (lncRNAs) are emerging as important regulators of cellular adaptation to environmental and molecular stress, but the extent to which their responses remain reproducible and stress-type-dependent across human stress conditions remains unclear. Here, we performed an integrative transcriptomic meta-analysis of human stress-response datasets from ASTRA and GEO, focusing on normal, non-cancerous, wild-type human cell lines exposed to oxidative stress (H₂O₂), hypoxia, heat stress, or UV-induced DNA damage. Gene Ontology (GO) enrichment analysis of differentially expressed (DE) protein-coding mRNAs confirmed that the resulting stress-stratified comparison captured biologically coherent transcriptional programmes to oxidative stress signaling, hypoxic and metabolic adaptation, heat-induced proteostasis, UV-induced DNA damage signaling, apoptosis, and cell-cycle regulation. Differential expression analysis was subsequently integrated with Weighted Gene Co-expression Network Analysis (WGCNA) -based module–treatment associations to rank network-supported lncRNA candidates. By prioritizing candidates for recurrence across at least two different stress studies, we identified lncRNAs with increased recurrence and consistent stress-type-dependent expression regulation, embedded within coordinated stress-associated mRNA programs. Full article

Background: Tibial bone stress injury (TBSI) with associated bone marrow edema (BME) is a common and clinically challenging condition in athletes, often requiring prolonged load restriction and delayed return to sport. Evidence for adjunctive interventions that improve both symptoms and MRI-derived recovery remains limited. The aim of this study was to investigate whether adding Functional Magnetic Stimulation (FMS) to standardized rehabilitation improves pain, function, and MRI-derived outcomes over 16 weeks in athletes with MRI-confirmed TBSI. Materials and Methods: Forty athletes with Fredericson grade 2–3 TBSI were randomized to FMS plus rehabilitation (n = 20) or rehabilitation alone (n = 20). Both groups completed a 4-week load-based rehabilitation program, while the FMS group additionally received eight 30 min FMS sessions at 40 Hz. Outcomes were assessed at baseline, 4 weeks, and 16 weeks. The primary outcome was activity-related pain (NPRS), while secondary outcomes included lower-limb function (LEFS-GR), BME extent, and Fredericson grade. Continuous outcomes were analyzed using two-way mixed ANOVA, whereas Fredericson grade was analyzed using an ordinal generalized estimating equation model. The level of statistical significance was set at p < 0.05. Results: Groups were comparable at baseline. Significant group × time interactions favored FMS for NPRS, F(2, 76) = 12.46, p < 0.001, η²p = 0.247; LEFS-GR, F(1.08, 41.09) = 81.56, p < 0.001, η²p = 0.682; and BME extent, F(1.44, 54.85) = 49.33, p < 0.001, η²p = 0.565. At 16 weeks, the FMS group showed lower NPRS scores, higher LEFS-GR scores, and lower BME extent than controls. Fredericson grade also showed a significant group × time effect, Wald χ²(2) = 20.38, p < 0.001. The FMS group had significantly lower cumulative odds of classification in a higher Fredericson grade at 4 weeks (OR = 0.045, 95% CI: 0.012–0.163, p < 0.001), whereas the corresponding difference at 16 weeks remained directionally favorable but did not reach statistical significance (OR = 0.033, 95% CI: 0.001–1.029, p = 0.052). Conclusions: The addition of FMS to load-based rehabilitation was associated with greater clinical and functional improvements, greater reductions in BME extent, and a more favorable longitudinal trajectory in MRI severity classification than rehabilitation alone in athletes with TBSI. However, because the study did not include a sham-FMS condition and participants could not be blinded, the self-reported pain and functional outcomes should be interpreted cautiously. FMS may represent a useful adjunct to structured rehabilitation, although sham-controlled and longer-term studies should determine its effects on return-to-sport progression and recurrence risk. Full article

Background/Objectives: Bovine heat-stress RNA-seq studies differ in tissue, age, physiological state, and exposure design. We asked which responses recur across these contexts and which depend on the evidence base. Methods: We reprocessed 107 libraries from five in vivo Bos taurus studies and synthesized within-study heat-minus-control log₂ fold changes using restricted maximum-likelihood random-effects models with modified Knapp–Hartung inference. Eight tissue- and age-aware scenarios tested the cross-context estimate. A six-component heat-stress transcriptomic stability index (HSTSI) was benchmarked against five simpler rankings, and an independent mammary single-nucleus dataset provided cell-resolved comparison. Results: Of 266 FDR-significant pathways, 259 retained direction across all five study deletions and 21 remained significant in every deletion. Translation, ribosome, protein folding, endoplasmic-reticulum processing, proteasome, and heat-response programs formed the most recurrent axis. Four principal sensitivity scenarios retained 0.920–0.932 gene-direction agreement and 0.957–0.981 effect-rank correlation with the five-study analysis. In the single-nucleus dataset, leading-edge genes from the principal proteostasis programs showed 89.4–100% pooled-nucleus direction agreement and 94.7–100% agreement among published cluster-level differentially expressed genes. HSTSI had the highest mean top-200 held-out direction agreement (0.583 versus 0.516–0.562), with variation among folds. None of 16,756 genes met a modified Knapp–Hartung FDR below 0.10. IL1R2 and SDCBP2 were externally concordant, whereas GZMK and CD8A were context-dependent. Conclusions: A coordinated proteostasis program was the most transferable heat-stress signal. Energy remodeling, immune-associated bulk signals, and individual genes showed greater context dependence and define priorities for tissue-matched follow-up. Full article

Background: Endometriosis is a chronic estrogen-dependent disease characterized by the presence of endometrial-like tissue outside the uterine cavity. Its pathogenesis involves interactions between inflammatory, angiogenic, hormonal, oxidative stress-related, and cell survival-associated pathways, contributing to lesion development and persistence. Current treatment options are often limited by adverse effects, incomplete symptom control, and high recurrence rates. Methods: This integrative review summarizes the molecular mechanisms involved in endometriosis and the potential role of natural bioactive compounds in their modulation. A literature search was conducted using PubMed, Scopus, and Web of Science, and evidence from experimental, animal, and clinical studies was reviewed. Results: Natural compounds such as curcumin, resveratrol, quercetin, EGCG (epigallocatechin-3 gallate) and genistein have been reported to modulate multiple pathways involved in endometriosis. Their biological activity includes modulation of inflammatory signaling, angiogenesis, estrogen-dependent processes, epithelial–mesenchymal transition, oxidative stress, and apoptosis. While some compounds influence several interconnected pathways, others appear to exert more selective effects. Conclusions: The findings summarized in this review suggest that natural bioactive compounds may influence several interconnected mechanisms involved in endometriosis. Although clinical evidence remains limited, these compounds warrant further investigation as potential adjuncts to current therapeutic approaches. Full article

Background: Stress is regarded as one of the natural and unavoidable elements of human life and, at the same time, one of the key determinants of physical and mental health. Stress is not a new phenomenon; it has accompanied human beings since the beginning of life as a reaction to everyday challenges. This study aimed to assess the prevalence and severity of stress, as well as stress-coping strategies, in a group of patients treated for oncological reasons. Methods: The study included 108 patients hospitalized at the Independent Public Clinical Hospital No. 1 in Lublin, Poland, in the following departments: the 2nd Department of General, Gastroenterological and Gastrointestinal Oncological Surgery; the Department of Oncological Surgery; and the Department of Hemato-Oncology and Bone Marrow Transplantation. Three standardized questionnaires were used: the Perceived Stress Scale (PSS-10), the Type D Personality Scale (DS-14), and the “How Do I Cope” Inventory (JSR). Statistical analysis was performed with IBM SPSS Statistics, version 25; statistical significance was set at α < 0.05. Results: Patients treated for oncological reasons constitute a group exceptionally exposed to stress, which accompanies them at every stage of the disease, from diagnosis, through treatment, to the terminal phase. In patients whose treatment resulted in remission, stress related to the possibility of recurrence accompanies every follow-up examination and every worrying symptom. Given the range of situations that provoke stress, the overall level of stress in this group can be regarded as high. Stress-coping strategies among oncological patients are shaped by multiple factors, including selected sociodemographic characteristics; taking into account the diversity of these factors, coping strategies varied considerably across the sample. The level of coping strategies was not associated with age or sex but was significantly associated with educational attainment. Conclusions: Oncological patients experience a high and pervasive level of stress that persists throughout diagnosis, treatment, and follow-up. Stress-coping strategies are heterogeneous, are not determined by age or sex, but are shaped by education, indicating a need for individualized psychosocial and educational support integrated into routine oncological care. Full article

Background/Objectives: Outborn neonates—those born outside tertiary perinatal centres and transferred postnatally—may experience higher mortality and morbidity than inborn infants. This systematic review without meta-analysis synthesised contemporary evidence on neonatal interfacility transfer to tertiary and quaternary neonatal centres, focusing on mortality, major morbidity, physiological instability, prognostic tools, and organisational determinants. Methods: Four electronic databases (PubMed/MEDLINE, Scopus, Web of Science, and the Cochrane Library) were searched for English-language publications from January 2010 to December 2025. Study selection and data extraction were performed independently by two reviewers, with disagreements resolved by consensus. Narrative synthesis followed PRISMA 2020 and SWiM principles. Of the 2456 records identified, 44 publications were retained: 31 primary studies and 13 contextual or methodological sources. Results: Across the primary evidence, outborn status was generally associated with higher mortality and major morbidity, particularly among very preterm infants, although effect magnitude varied across healthcare systems. Hypothermia, respiratory deterioration, and haemodynamic instability were recurrent transport-related complications. Specialised teams, standardised stabilisation, and thermal-management bundles were associated with better physiological stability. TRIPS and TRIPS-II showed prognostic utility. Conclusions: Predominantly observational evidence suggests that neonatal transport outcomes reflect interactions between biological vulnerability, transport-related stress, and system organisation. Strengthening regionalised transport pathways and standardising stabilisation practices may improve outcomes, but causal inference remains limited. Full article

High-sensitivity cardiac troponin has made the diagnosis of myocardial infarction (MI) faster and more precise, but it does not measure the broader biological vulnerability that often determines the outcome after an acute coronary syndrome (ACS). Growth differentiation factor-15 (GDF-15) is induced by ischemic stress, inflammation, oxidative injury, renal dysfunction, metabolic disease, and ageing. This biology explains its appeal in ACS, but also its diagnostic limitation: GDF-15 is not cardiac-specific and should not be used as an alternative to electrocardiography and high-sensitivity troponin algorithms for early MI diagnosis. Its better supported role is prognostic. Across emergency department chest pain cohorts, non-ST elevation MI, ST elevation MI, post-ACS trial populations, and serial biomarker studies, higher GDF-15 concentrations are most consistently associated with all-cause mortality, cardiovascular mortality, heart failure, and major bleeding, while associations with recurrent ischemic events alone are less specific. The key unresolved issue is incremental clinical value. GDF-15 may improve discrimination and reclassification beyond clinical predictors, troponin, natriuretic peptides, renal function and GRACE or GRACE 2.0 in selected settings, but statistical association is not equivalent to clinical utility. Its possible role in bleeding risk estimation and antithrombotic benefit–risk assessment is clinically important, especially after the PLATO biomarker analyses, yet routine GDF-15-guided dual antiplatelet therapy decisions remain unsupported. Future implementation requires validated thresholds, calibration, decision curve evidence, health economic evaluation, and trials in which GDF-15-guided management changes care and improves outcomes. Full article