Search Results (30,694)

Background/Objectives: Advanced-stage hepatocellular carcinoma is characterized by a very poor prognosis; thus, highly effective medication is still needed. Often overexpressed heat shock protein 90 is a promising target due to its pivotal role in carcinogenesis. Methods: Antiproliferative effects of 246TMP-3SF5 on HepG2 and HuH-7 cells were assessed by crystal violet staining. Apoptosis was evaluated via subG1 peak, caspase-3 activity and PARP cleavage, and ferroptosis via ROS, glutathione and malondialdehyde levels. Migration was assessed by scratch assay, and in ovo models were used to study angiogenesis and drug effects on microtumors. CAM vascular networks were quantified by semi-automatic segmentation, morphometric and box-counting fractal analysis. Molecular docking and molecular dynamics simulation of heat shock protein 90 were carried out using Autodock Vina and Gromacs respectively. Results: Profound dose- and time-dependent antiproliferative effects of 246TMP-3SF5 against HCC cell lines were observed, revealing low micromolecular IC₅₀ values and selectivity for carcinoma cells with selectivity indices > 1. A significant increase in the sub-G1 peak, key effector caspase-3 activity, as well as cleavage of PARP strongly suggested apoptosis playing a crucial role in the antiproliferative effects. Additionally, HuH-7 cells revealed an elevation of reactive oxygen species and both cell lines showed significant glutathione depletion concomitant with an increase in malondialdehyde concentration upon treatment. The observed effect could be partially reversed by applying ferrostatin-1, suggesting ferroptosis as an additional relevant mode of action. Changes in the cell cycle as well as impaired tumor cell migration were observed. Upon treatment, angiogenesis was impaired and mass of microtumors was significantly reduced. Quantitative CAM analysis showed that vascularized area fraction increased in controls but decreased under both 17-AAG and 246TMP-3SF5. Likewise global mean vessel width decreased relative to controls, while box-counting dimension was reduced under 246TMP-3SF5. Molecular docking and molecular dynamics simulation analysis predicts 246TMP-3SF5 to be binding in catalytic site of heat shock protein 90. Conclusions: 246TMP-3SF5 is a promising novel inhibitor meriting further research as a potential treatment against hepatocellular carcinoma. Full article

Pain arising from the ischial region is commonly attributed to proximal hamstring injury or ischial bursitis, whereas injury to the ischiocondylar portion of the adductor magnus remains less commonly considered because of its deep location and complex anatomy. We report a 63-year-old woman who developed persistent proximal posterior thigh pain after sprinting, followed by progressive sitting pain despite conservative treatment. High-resolution musculoskeletal ultrasonography revealed focal structural abnormalities of the ischiocondylar portion of the adductor magnus at the tendon insertion and musculotendinous junction that were consistent with a partial tear, accompanied by surrounding inflammatory changes and ischial bursal fluid. The lesion was identified beginning with the short-axis view of the ischial tuberosity, followed by an oblique long-axis view of the ischiocondylar tendon. Conservative rehabilitation, activity modification, and low-level laser therapy resulted in complete symptom resolution without recurrence. This report emphasizes that injury of the ischiocondylar portion of the adductor magnus represents an uncommon differential consideration in patients presenting with proximal posterior thigh or ischial pain. A systematic ultrasound examination with appropriate transducer orientation facilitates accurate diagnosis and appropriate management. Full article

Superoxide dismutase 2 (SOD2), a key mitochondrial antioxidant enzyme, is essential for maintaining cellular redox homeostasis by scavenging superoxide radicals. While viruses often induce oxidative stress, the specific role of SOD2 in antiviral defense remains unclear. Here, we report that vaccinia virus (VACV) infection triggers mitochondrial and cellular reactive oxygen species (ROS) and selectively upregulates SOD2, but not SOD1. Genetic knockout of SOD2 exacerbated mitochondrial ROS (mtROS) accumulation and significantly enhanced VACV replication and spread, resulting in larger viral plaques. Conversely, SOD2 overexpression constrained plaque formation and suppressed viral dissemination. Mechanistically, the antiviral function of SOD2 does not strictly rely on its enzymatic activity or mitochondrial targeting, as neither the deacetylation-mimicking mutant nor the mutant lacking the mitochondrial localization signal peptide appreciably impaired its antiviral potency. Furthermore, in a rabbit model, local overexpression of human SOD2 attenuated the poxvirus lesion formation. Our findings unveil an important yet easily overlooked role of SOD2 in antiviral defense and posit it as a promising candidate for the development of host-directed therapeutics against poxviruses. Full article

Background: Falls among older adults are linked to central nervous system deterioration and executive function deficits. Objectives: This study evaluates the feasibility of a gamified EEG-based neurofeedback intervention combined with adaptive working-memory training, targeting neural processes associated with attentional inhibition and working memory in older adults, and characterises, as exploratory secondary outcomes, the oscillatory and functional measures that change over the training period. Methods: Twenty healthy older adults ($65.0\pm 3.3$ years) completed a 24-session longitudinal training programme. The intervention combined real-time alpha-band neurofeedback (NF), targeting left-frontal alpha activity associated with inhibitory control, with an adaptive N-back task engaging theta-band working memory processes. Behavioural outcomes included the Colour Trail Making Test A and B (CTMT-A/B), the Berg Balance Scale short form (BBS-3P), and the four-item Dynamic Gait Index (DGI-4). EEG was recorded at the Early, Middle, and Later stages to characterise training-related neural and behavioural changes. Results: The programme proved highly deliverable: adherence was 100% across all 24 sessions, no session was terminated early, and no severe adverse events occurred. Participants acquired control of the trained signal, with left-frontal alpha power rising across training at the neurofeedback target site, and frontal theta increased bilaterally under adaptive working memory load, consistent with the reduced hemispheric asymmetry characteristic of this age group. Scores changed in the direction of improvement on all four behavioural measures; however, functional changes were small, and cognitive changes cannot be separated from repeated-testing effects. Of sixteen candidate EEG–behaviour associations, four showed moderate-to-large participant-level coefficients and were retained as candidate associations: right-frontal alpha with balance ($r=-0.64$) and with gait adaptability ($r=-0.48$), and bilateral frontal theta with processing speed ($r=-0.53$ and $-0.51$). Several associations that appeared strong when observations were pooled across stages did not survive participant-level modelling, indicating that repeated-measures methods are needed in this literature. All associations are exploratory, uncorrected for multiplicity, and reported with effect sizes and confidence intervals. Conclusions: The gamified neurofeedback and working-memory training programme was feasible, well tolerated, and fully adhered to in a supervised experimental setting by community-dwelling older adults and was accompanied by measurable modulation of the targeted frontal rhythms. This study delivers a shortlist of candidate EEG features, with the effect-size estimates needed to power a confirmatory trial. Because the design is single-arm, both functional scales approached ceiling, and the same test forms were repeated at each stage, practice effects cannot be separated from intervention effects, and these associations are hypothesis-generating; a sham-controlled trial in a fall-prone population is the appropriate next step. Full article

Clinical trials and naturalistic studies describe psychedelics under markedly different exposure conditions. This narrative review searched PubMed/MEDLINE, the Cochrane Library, ClinicalTrials.gov, and regulatory sources through 15 July 2026, and examined safety and outcomes across four dimensions of exposure: dose, frequency, person, and context. In screened adults receiving one to three supervised doses, transient headache, nausea, anxiety, and cardiovascular activation are common; serious reactions are uncommon but include persistent anxiety, suicidality signals, and a recent case of hallucinogen persisting perception disorder. Evidence supports MDMA (3,4-Methylenedioxymethamphetamine) -assisted therapy for post-traumatic stress disorder and psilocybin-based interventions for depression, although functional unblinding, selected samples, inconsistent comparators, and a recent negative primary trial constrain certainty. Naturalistic studies suggest that vulnerability and context modify outcomes, but frequency is inconsistently measured and rarely linked to cumulative exposure or long-term health. Short-term microdosing trials show limited benefit, whereas long-term cardiac and psychiatric safety remains unresolved. Exposure-defined cohorts, prospective registries, echocardiographic surveillance, and blinding-aware comparative trials are priorities. Full article

The impact of epigenetic mechanisms on molecular and cellular processes of regeneration remains a less-investigated field, especially concerning earthworm segment restoration. To evaluate distinct methylated cytosines under different conditions, earthworm segments were collected: decitabine-treated and controls; anterior and posterior amputation; intact and regenerated (2- and 4-week). 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) distribution in tissues was assessed by immunohistochemistry (IHC), and in genomic DNA by dot blot. DNA-methyltransferase (DNMT) and ten-eleven translocation (TET) dioxygenase activity was determined by immuno-based colorimetry. DNMT1 and TET gene expressions were verified with real-time PCR. Decitabine treatment reduced 5mC levels in most tissues, persisting in the anterior coelomic cavity (intact and blastemas). 5hmC remained elevated in most tissues, remarkably in 2-week blastemas. In the same period, DNMT and TET presented the highest activity in anterior treated samples compared to other treated periods. Concurrently, DNMT1 gene expression increased prominently in anterior segments, while TET showed the highest expression in both anterior and posterior 2-week treated groups. Thus far, our observations indicate that, despite decitabine’s effect on the DNA methylation machinery of the earthworm model, the region of amputation and the regeneration period also interfere with activity and expression of epigenetic enzymes, affecting 5mC and 5hmC distribution. Full article

Background: IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide and is associated with increased cardiovascular (CV) morbidity and mortality. Galectin-3 is a marker of fibrosis and adverse CV outcomes in chronic kidney disease (CKD), while mid-regional pro-atrial natriuretic peptide (MR-proANP) and heart-type fatty acid-binding protein (H-FABP) reflect myocardial wall stress and subclinical myocardial injury. Data on the combined behavior of these biomarkers in IgAN are limited. We investigated their association with renal function and cardiovascular parameters in IgAN. Methods: In this cross-sectional study, 90 patients with biopsy-proven IgAN were examined, but 76 patients’ data were evaluated. Serum galectin-3, MR-proANP, and H-FABP concentrations were measured by ELISA. Renal function was assessed using estimated glomerular filtration rate (eGFR, CKD-EPI). All patients underwent transthoracic echocardiography and arterial stiffness assessment, including pulse wave velocity of the aorta (PWVao) and central systolic blood pressure (SBPao). Results: Patients with reduced renal function (eGFR <60 mL/min/1.73 m²) had significantly higher galectin-3 (p = 0.011), MR-proANP (p < 0.001), and H-FABP (p < 0.001) concentrations. Biomarker levels increased progressively with declining eGFR. Galectin-3 concentrations were higher in patients with increased left ventricular mass index (p = 0.015). All three biomarkers were elevated in patients with higher central aortic systolic pressure. MR-proANP and H-FABP increased with worsening albuminuria, whereas galectin-3 did not. In multivariate analyses, eGFR was the only independent predictor of all three biomarkers. Conclusions: In IgAN, galectin-3, MR-proANP, and H-FABP concentrations are closely linked to renal function and markers of cardiovascular remodeling. These findings suggest that galectin-3, MR-proANP, and H-FABP provide complementary information regarding the complex interaction between renal dysfunction and cardiovascular remodeling in IgA nephropathy. Prospective multicenter studies are warranted to determine their incremental prognostic value and potential clinical utility for cardiovascular risk stratification. Full article

Previous analyses of substance-involved craniofacial trauma have often combined alcohol and drug/medication involvement. We conducted a cross-sectional analysis comparing alcohol-only and drug/medication-only facial injury encounters in the public Consumer Product Safety Commission National Electronic Injury Surveillance System (NEISS), 2019–2023. Primary facial injuries (Body_Part = 76) were classified using the released Alcohol_Involved and Drug_Involved fields. Survey-weighted estimates and Taylor-linearized 95% confidence intervals incorporated the released PSU, stratum, and weight variables; design-based logistic regression evaluated code-4 hospitalization. Among 146,857 observed facial injury encounters, 4117 were alcohol-only and 2302 were drug/medication-only. Weighted annual alcohol-only proportions were stable (trend odds ratio [OR] per year, 0.99; 95% CI, 0.96–1.03; p = 0.716), whereas drug/medication-only proportions increased (OR, 1.15; 95% CI, 1.04–1.27; p = 0.009). Compared with alcohol-only encounters, drug/medication-only encounters involved older patients (weighted mean age, 63.1 vs. 47.6 years) and a lower weighted male proportion (55.6% vs. 67.5%). Weighted code-4 hospitalization was 23.1% versus 11.8%; the adjusted OR was 1.91 (95% CI, 1.45–2.53; p < 0.001). Adult-only and alternative-period sensitivity analyses supported the main conclusions. Separate classification of alcohol and drug/medication involvement revealed distinct demographic, temporal, and disposition patterns among NEISS-captured product-associated ED encounters. Full article

MicroRNAs (miRNAs) have been associated with the initiation, development, and progression of various cancers, including cervical cancer. Their involvement in cervical cancer is extensively documented, as they influence critical biological pathways, including apoptosis, cell cycle progression, immune evasion, and metastasis. In cervical cancer, deregulated miRNA expression contributes to tumor aggressiveness by interfering with key molecular pathways, many of which are also influenced by high-risk human papillomavirus (HPV) oncoproteins. In this review, we highlight key signaling pathways regulated by miRNAs linked to cancer hallmarks, particularly sustained proliferative signaling, which was the most frequently affected pathway across the studies reviewed. Furthermore, the interplay among HPV oncoproteins, dysregulated miRNA expression, and altered signaling pathways drives key oncogenic processes, including uncontrolled proliferation, evasion of apoptosis, and metastasis. Full article

Fusobacterium nucleatum has been implicated in colorectal cancer, but its role in adenomas remains unclear. We applied an RNA-based detection of F. nucleatum in formalin-fixed paraffin-embedded adenoma tissue and explored the mutational landscape and transcriptomic profile of F. nucleatum+ patients in comparison to F. nucleatum- patients. Bespoke F. nucleatum probes successfully detected F. nucleatum in 11% of adenomas. F. nucleatum+ patients exhibited a positively enriched anti-bacterial defence response and immune-related transcriptomic signatures, as well as a proliferative profile. These findings suggest that F. nucleatum positivity is associated with immune and proliferative transcriptomic signatures in colorectal adenomas, but this requires validation in larger, longitudinal cohorts. Full article

HS-1-associated protein X-1 (HAX-1) is a ubiquitously expressed, multifunctional protein that regulates Ca²⁺ homeostasis and cell survival in cardiac muscle. In addition to its well-established anti-apoptotic function, HAX-1 has recently been implicated in autophagy regulation. In the present study, we explored the molecular mechanisms underlying HAX-1-mediated autophagy modulation in cellular models, including cardiac-derived H9c2 myotubes. HAX-1 overexpression enhanced autophagic activity, as evidenced by decreased sequestosome-1 (p62), increased microtubule-associated protein light chain 3-II (LC3-II), enhanced LC3 puncta formation, and elevated autophagic flux. Conversely, HAX-1 knockdown attenuated autophagic activity. Mechanistically, co-immunoprecipitation assays showed that HAX-1 associates with both p62 and LC3. Bioinformatic analysis of the HAX-1 protein sequence identified two conserved LC3-interacting region (LIR) motifs within its N-terminal domain. Deletion of this LIR-containing region (HAX-1ΔLIR) reduced LC3 association, decreased autophagic activity, and impaired autophagy-dependent clearance of HAX-1 itself following autophagy induction, suggesting the importance of these motifs. At a cardiac-relevant level, HAX-1 promoted a chloroquine-sensitive reduction in protein levels of its known binding partner, phospholamban (PLN), a key regulator of sarcoplasmic reticulum (SR) Ca²⁺ cycling. These findings indicate a previously unrecognized LC3/LIR-dependent mechanism underlying HAX-1-mediated autophagy modulation and suggest a potential role for HAX-1 in SR protein proteostasis. Full article

Background and Clinical Significance: This report investigates the complex intersection of macrostructural neuroprotection and cortical hyperexcitability during long-acting atypical antipsychotic maintenance. We present a novel clinical case demonstrating an apparent absence of detectable cerebellar vermis atrophy progression during long-acting injectable (LAI) aripiprazole maintenance, which temporally coincided with the emergence of a potential epileptogenic risk in an adolescent with bipolar disorder (BD) and cannabis use disorder. Beyond motor precision, the vermis modulates emotional-cognitive networks; deficits in these circuits impair impulse control, frequently driving comorbid substance use in youth. Case Presentation: A 16-year-old female with BD and cannabis use disorder presented with pronounced cerebellar and vermis atrophy on brain CT during an acute behavioral crisis. Following diagnostic reformulation, maintenance therapy was initiated via off-label monthly LAI aripiprazole (400 mg) alongside lithium. At 9-month follow-up, psychiatric relapses and cannabis use remitted completely. Repeat CT suggested macrostructural stability with zero apparent atrophy progression. However, during the 9th month, she abruptly developed daily generalized myoclonus. An awake electroencephalogram (EEG) revealed intense cortical hyperexcitability, documenting frequent interictal and ictal epileptiform discharges with generalized 3–4 Hz spike-wave complexes synchronized with the clinical myoclonus. Introduction of levetiracetam (500 mg BID) and cessation of adjunct methylphenidate led to complete clinical and neurophysiological remission. Conclusions: LAI aripiprazole may favorably influence the macrostructural trajectory of the cerebellum/vermis in adolescent BD, suggesting volume stabilization. However, clinicians must monitor for a drug-induced lowering of the seizure threshold, where macrostructural volume preservation coexists with microstructural electrical destabilization. Full article

Introduction: Pediatric clavicle fractures are among the most common fractures in this age group. Current research supports the efficacy of nonoperative treatment for these injuries in pediatric patients. Our study seeks to examine the current trends in the management of these fractures and determine whether they align with the existing evidence-based guidelines. Methods: A retrospective analysis of pediatric patients with clavicle fractures between 1 January 2014 and 31 December 2024 was analyzed. A retrospective query was performed using the TriNetX Research Network. Patients were dichotomized into two groups based on open reduction internal fixation and nonoperative or closed treatment codes over this period, performing subgroup analyses by sex, race, and age. Results: We evaluated 78,251 patients between 10 and 18 years with clavicle fractures from 2014 to 2024, of whom 3546 underwent open reduction and internal fixation (ORIF). ORIF utilization increased from 1.62% in 2014 to 5.89% in 2024, representing a 263.6% increase from the 2014 baseline. Males consistently underwent ORIF more often than females. Adolescents (15–18 years) had substantially higher and faster-rising ORIF rates than younger patients (10–14 years), increasing from 3.4% to 12.4% versus 0.8% to 2.5% between 2014 and 2024 (APC 7.5% vs. 0%, p = 0.001). White patients had higher ORIF rates than African American patients, although some disparities narrowed over time. Conclusions: Despite limited supporting evidence, current trends demonstrate a substantial increase in the surgical management of pediatric clavicle fractures, with operative treatment rising by 263.6% by 2024. This increase in ORIF procedures may expose patients to potentially avoidable risks, including infection, anesthesia-related complications, implant-related issues, and prolonged recovery, without clearly established benefits in many cases. Full article

Background/Objectives: Spinal cord epidural stimulation (scES) holds significant potential for restoring autonomic function after chronic spinal cord injury (SCI). A significant and often debilitating sequela of SCI is neurogenic lower urinary tract dysfunction, characterized by loss of voluntary bladder control, which adversely impacts patients’ dignity, urological health, and overall quality of life. In a pilot study of three individuals with SCI, an epidural electrode array was implanted between L2 and sacral segments to modulate lower urinary tract function for efficient emptying. Methods: Three participants with chronic thoracic clinically complete SCI were implanted with an epidural stimulator over the lumbosacral spinal cord. Array placement was confirmed using intraoperative and postoperative spatiotemporal mapping of known motor neuron pools following published protocols. In a controlled laboratory mapping, bladder storage and voiding neural networks were targeted during filling cystometry by interactively optimizing lower urinary tract stimulation parameters (electrode configuration, frequency, intensity, and pulse width). Efficacy was assessed during six-hour laboratory sessions of natural bladder filling, followed by approximately four months of daily at-home use. Results: Pre-implant cystometry revealed poor voiding efficiency and absent bladder sensation. Following bladder scES mapping and home training, one of the three participants regained direct bladder sensation, exceeded the 90% clinical threshold for efficient voiding, and continues to use scES for bladder management instead of intermittent catheterization, with no urinary tract infections reported since completion of training (February 2022). The inability of two participants to attain high voiding efficiency may be due to suboptimal adherence to prescribed bladder training protocols in one case and the presence of an elevated bladder neck in the other. All three participants reported off-target improvements in bowel and sexual functions. Conclusions: The present novel pilot study provides the first evidence supporting the potential use of epidural stimulation for bladder management and the importance of activity-based recovery training for durable performance. Full article

Cardiovascular disease remains the leading cause of death among women, yet female cardiovascular risk continues to be underrecognized, and women remain underrepresented in many cardiovascular trials. Sex-related differences in hormonal exposure, immune regulation, vascular function, pregnancy-related conditions, and clinical presentation contribute to heterogeneity in cardiovascular disease across the life course. Statins reduce atherosclerotic cardiovascular events in women and men, with no consistent evidence of treatment-effect heterogeneity by sex. In addition to lowering low-density lipoprotein cholesterol, statins influence inflammatory signaling, endothelial nitric oxide bioavailability, oxidative stress, thrombosis, and plaque biology. These effects are biologically relevant to atherosclerosis; however, current clinical evidence does not establish that LDL-independent statin effects confer a uniquely greater benefit in women. Historical pathological studies suggested that plaque erosion may contribute relatively more often to acute coronary thrombosis in selected younger women, whereas contemporary optical coherence tomography studies show similar overall frequencies of plaque rupture and erosion between sexes and important age-related variation. Evidence for a female-specific effect of statins on post-myocardial infarction remodeling, cognition, or pharmacogenomic susceptibility is also insufficient. This narrative review distinguishes established clinical evidence from mechanistic plausibility and unresolved sex-specific hypotheses. It emphasizes equitable implementation of guideline-directed lipid-lowering therapy, careful evaluation of statin-associated symptoms, and the need for adequately powered studies reporting sex-stratified estimates and formal treatment-by-sex interactions. Full article