Search Results (12,974)

Background/Objectives: Back table fluorescence imaging performed on freshly excised tissue specimens represents a critical step in fluorescence-guided surgery, enabling rapid assessment of tumor margins before final pathology. While most preclinical NIR-II imaging platforms, such as the IR VIVO (Photon, etc.), offer high-resolution and depth-sensitive imaging under controlled, enclosed conditions, they are not designed for intraoperative or point-of-care use. This study compares the IR VIVO with the LightIR system, a more compact and clinically adaptable imaging platform using the same Alizé 1.7 InGaAs detector, to evaluate whether the LightIR can offer comparable performance for back table NIR-II imaging under ambient light. Methods: Standardized QUEL phantoms containing indocyanine green (ICG) and custom agar-based tissue-mimicking phantoms loaded with IR-1048 were imaged on both systems. Imaging sensitivity, spatial resolution, and depth penetration were quantitatively assessed. LightIR was operated in pulse-mode under ambient lighting, mimicking back table or intraoperative use, while IR VIVO was operated in a fully enclosed configuration. Results: The IR VIVO system achieved high spatial resolution (~125 µm) and detected ICG concentrations as low as 30 nM in NIR-I and 300 nM in NIR-II. The LightIR system, though requiring longer exposure times, successfully resolved features down to ~250 µm and detected ICG to depths ≥4 mm. Importantly, the LightIR maintained robust NIR-II contrast under ambient lighting, aided by real-time background subtraction, and enabled clear visualization of subsurface IR-1048 targets in unshielded phantom setups, conditions relevant to back table workflows. Conclusions: LightIR offers performance comparable to the IR VIVO in terms of depth penetration and spatial resolution, while also enabling open-field NIR-II imaging without the need for a blackout enclosure. These features position the LightIR as a practical alternative for rapid, high-contrast fluorescence assessment during back table imaging. The availability of such clinical-grade systems may catalyze the development of new NIR-II fluorophores tailored for real-time surgical applications. Full article

VEXAS syndrome (Vacuoles, E1-enzyme, X-linked, Autoinflammation, and Somatic) is a recently identified late-onset autoinflammatory disorder characterized by a unique interplay between hematological and inflammatory manifestations. It results from somatic mutations in the UBA1 gene, located on the short arm of the X chromosome. Initially, females were considered mere carriers, with the syndrome primarily affecting males over 50. However, recent evidence indicates that heterozygous females can exhibit symptoms as severe as those seen in hemizygous males. The disease manifests as systemic inflammation, macrocytic anemia, thrombocytopenia, chondritis, neutrophilic dermatoses, and steroid-dependent inflammatory symptoms. Due to its overlap with autoimmune and hematologic disorders such as relapsing polychondritis, Still’s disease, and myelodysplastic syndromes, misdiagnosis is common. At the molecular level, VEXAS syndrome is driven by impaired ubiquitination pathways, resulting in dysregulated immune responses and clonal hematopoiesis. A key diagnostic marker is the presence of cytoplasmic vacuoles in myeloid and erythroid precursors, though definitive diagnosis requires genetic testing for UBA1 mutations. Traditional immunosuppressants and TNF inhibitors are generally ineffective, while JAK inhibitors and IL-6 blockade provide partial symptom control. Azacitidine and decitabine have shown promise in reducing disease burden, but hematopoietic stem cell transplantation (HSCT) remains the only curative treatment, albeit with significant risks. This review provides a comprehensive analysis of VEXAS syndrome, examining its clinical features, differential diagnoses, diagnostic challenges, and treatment approaches, including both pharmacological and non-pharmacological strategies. By enhancing clinical awareness and optimizing therapeutic interventions, this article aims to bridge emerging genetic insights with practical patient management, ultimately improving outcomes for those affected by this complex and often life-threatening disease. Full article

Background: Perioperative factors significantly impact oncologic outcomes after radical cystectomy (RC) for bladder cancer. This study aimed to identify key perioperative predictors for overall (OS) and progression-free survival (PFS) and to develop a prognostic nomogram for the identification of high-risk patients adapted to the clinical routines and standard of care of our country. Methods: We retrospectively analyzed 121 patients undergoing RC (2014–2024). Data on patient demographics, comorbidities, tumor pathology, neoadjuvant treatments, extensive intraoperative factors, and postoperative events were assessed using COX models. A prognostic nomogram for 3-year OS was constructed. Results: Median follow-up was 44.33 months. Significant predictors for worse OS included lymphovascular invasion (LVI) (HR 2.22), higher T stage (HR 8.75), N+ status (HR 1.10), and intraoperative complications (HR 3.04). Similar predictors were noted for PFS. The developed nomogram incorporated T-, N-stages, sex, grade, intraoperative complications and early (12 months) recurrence, and was able to significantly identify patients with a higher mortality risk (p < 0.001) with a C-index of 0.74. Conclusions: Our nomogram for mortality prediction of BC patients offers a promising tool for individualized risk stratification. Further studies are required for its external validation. Full article

Lactylation, a recently identified post-translational modification (PTM) triggered by excessive lactate accumulation, has emerged as a crucial regulator linking metabolic reprogramming to pathological processes in liver diseases. In hepatic contexts, aberrant lactylation contributes to a range of pathological processes, including inflammation, dysregulation of lipid metabolism, angiogenesis, and fibrosis. Importantly, lactylation has been shown to impact tumor growth, metastasis, and therapy resistance by modulating oncogene expression, metabolic adaptation, stemness, angiogenesis, and altering the tumor microenvironment (TME). This review synthesizes current knowledge on the biochemical mechanisms of lactylation, encompassing both enzymatic and non-enzymatic pathways, and its roles in specific liver diseases. From a therapeutic perspective, targeting lactate availability and transport, as well as the enzymes regulating lactylation, has demonstrated promise in preclinical models. Additionally, combinatorial approaches and natural compounds have shown efficacy in disrupting lactylation-driven pathways, providing insights into future research directions for hepatic diseases. Although the emerging role of lactylation is gaining attention, its spatiotemporal dynamics and potential for clinical translation are not yet well comprehended. This review aims to synthesize the multifaceted roles of lactylation, thereby bridging mechanistic insights with actionable therapeutic strategies for liver diseases. Full article

Background/Objectives: SMARCA4-deficient or SMARCA4-mutated cancers are rare but highly aggressive tumors with poor differentiation, resistance to conventional treatments, and limited clinical guidance. While thoracic SMARCA4-deficient undifferentiated tumors are relatively well described, the full spectrum of SMARCA4-altered cancers across different organs and their therapeutic responses remains poorly understood. This study aimed to systematically review published case reports and case series to clarify the clinical characteristics, molecular features, treatment patterns, and survival outcomes of SMARCA4-altered malignancies. Methods: We conducted a systematic review of case reports and case series published between 2015 and 2025 using PubMed, Embase, and Web of Science. Eligible studies included adult patients with immunohistochemically or genetically confirmed SMARCA4-deficient or SMARCA4-mutated tumors. Key clinical, pathological, molecular, therapeutic, and outcome-related data were extracted. Descriptive statistics were used, and exploratory subgroup analyses were performed based on tumor type and treatment modality. The review protocol was registered in PROSPERO (CRD420251088805). Results: A total of 109 studies reporting 160 individual patients were included. Most tumors arose in the thorax (40.0%), followed by gastrointestinal (17.5%) and gynecologic sites (15.6%). The median age was 58 years, with a male predominance (70.0%) and frequent smoking history (44.4%). Platinum-based chemotherapy was administered in 62.5% of cases, and immune checkpoint inhibitors (ICIs) were used in 25.6%. Among ICI-treated patients, partial responses or stable disease were observed in 80.5%. The median progression-free survival (PFS) was 4.0 months, and the median overall survival (OS) was 5.0 months. Conclusions: SMARCA4-altered cancers are clinically and molecularly diverse but uniformly aggressive, with limited therapeutic benefit from conventional chemotherapy. Immune checkpoint inhibitors may offer improved outcomes in select patients, particularly those with thoracic tumors. Early molecular profiling, rare tumor registries, and biomarker-driven trials are crucial for guiding future treatment strategies. Full article

Reproductive failure in cattle production is a global concern and is influenced by various factors, including genetic alterations. This study explored the relationship between an X-linked single-nucleotide variant (NC_037357.1: g.87298881A>G, rs135720414) in the upstream of the bovine forkhead box P3 (FOXP3) gene and infertility. To this end, we examined the genotypes of the variant in old Asian cattle breeds, including 48 Bali and 5 Jaliteng cattle, and 20 water buffaloes, which have recently shown subclinical signs of infertility and repeated breeding problems among populations in Indonesia. We also examined the genotypes in 69 parous and 39 non-parous Holstein Friesian (HF) cows and investigated the relationship between the genotypes and serum concentration of anti-Müllerian hormone (AMH). The G allele frequency was markedly high in Bali (0.944) and Jaliteng cattle (0.714), and water buffaloes (1), suggesting that the G allele may be originally a wild-type variant in old Asian cattle and buffaloes. In HF cows, the G allele frequency was moderately high, and the AMH concentration was significantly lower (p < 0.05) in parous cows carrying the G allele (A/G and G/G genotypes) than in parous cows with the A/A genotype. In contrast, there were no significant differences in AMH concentrations among the three genotypes of non-parous HF cows. This suggests that both G allele and aging are associated with infertility in HF cows. In conclusion, the G allele of the FOXP3 gene variant may potentially be associated with infertility in different bovine breeds and species. Therefore, special attention should be paid to this variant, and infertility in bovine herds may be improved by selection and/or introduction of the A allele. Full article

Background/Objectives: Intraoperative frozen biopsies are essential during surgery for Hirschsprung’s disease (HD). However, this method has several limitations with the need for a faster and real-time diagnostic alternative. For this, consistent histoanatomical and morphometric differences between aganglionic and ganglionic bowel must be established. The primary objective was to compare dimensions of bowel wall layers between aganglionic and ganglionic segments histopathologically in resected rectosigmoid specimens from children with HD. Secondary objectives were to design a diagnostic algorithm to distinguish aganglionosis from ganglionosis and assess whether full bowel wall thickness correlates with patient weight and age. Methods: Each histoanatomic bowel wall layer—mucosa, submucosa, and muscularis propria’s layers—was delineated manually on histopathological images. Mean thicknesses were calculated automatically using an in-house image analysis software. Paired parametric tests compared measurements in aganglionic and ganglionic segments. Results: Resected specimens from 30 children with HD were included. Compared to aganglionic bowel, ganglionic bowel showed a thicker muscularis interna (mean 0.666 mm versus 0.461 mm, CI −0.257–(−0.153), p < 0.001), and a higher muscularis interna/muscularis externa ratio (2.047 mm versus 1.287 mm, CI −0.954–(−0.565), p < 0.001). An algorithm based on these features achieved 100% accuracy in distinguishing aganglionosis from ganglionosis. No significant difference in full bowel wall thickness was found between aganglionic and ganglionic segments, nor any correlation with patient weight or age. Conclusions: Histoanatomic layer thickness differs between aganglionic and ganglionic bowel, forming the basis of a diagnostic algorithm. Full bowel wall thickness was independent of patient weight and age. Full article

Background/Objectives: Dyslipidemia is a prevalent metabolic disorder closely linked to cardiovascular complications and muscular pathologies, often managed using statins such as simvastatin. However, statin-induced myopathy remains a significant treatment-limiting side effect, necessitating the exploration of safe, natural alternatives. Spirulina platensis, a phytochemical-rich marine-derived cyanobacterium, has emerged as a promising bioactive nutraceutical with potent antioxidant and anti-inflammatory properties. This study evaluated the comparative effects of Spirulina platensis and simvastatin in attenuating dyslipidemia-induced skeletal muscle injury in adult male albino rats. Methods: Forty animals were allocated to the control and high-fat diet (HFD) groups. After 4 weeks, the dyslipidemic rats were subdivided into untreated, simvastatin-treated, and Spirulina platensis-treated subgroups. Serum lipid profile, creatine kinase (CK), and malondialdehyde (MDA) levels were assessed. Histological, ultrastructural, and immunohistochemical analyses were conducted to assess muscle fiber integrity and expression of TGF-β1 and Bcl2. Results: Spirulina platensis significantly improved lipid parameters, reduced CK and MDA levels, preserved muscle histoarchitecture, and downregulated fibrotic (↓TGF-β1) and apoptotic (↑Bcl2) responses compared to the dyslipidemic and simvastatin-treated groups. Our results proved that Spirulina platensis ameliorates the effects of statin-associated myopathy while exerting lipid-lowering, cytoprotective, and antifibrotic effects. Conclusion: These molecular and ultrastructural benefits position Spirulina platensis as a promising, natural alternative to statins for managing dyslipidemia and preventing statin-induced myopathy. Future translational and clinical studies are warranted to further validate its efficacy and safety, supporting its broader application in metabolic and muscle-related disorders. Full article

Background: Post-hamstring-injury residual pain may persist despite muscle-tissue healing and impairs athletes seeking early full recovery. Given their unclear cause, recent attention has focused on the role of fascial dysfunction and a method to restore fascial mobility, namely, hydrorelease (HR), involving the ultrasound (US)-guided injection of saline. We evaluated the clinical efficacy of HR for treating residual pain and ascertained the underlying pathological mechanisms. Methods: Seven patients (aged 17–49 years) with residual pain ≥8 weeks after hamstring injury were included. All exhibited localized tenderness and US findings of fascial thickening around the aponeurotic fascia (APF). HR with 6.0 mL saline–lidocaine solution (0.17% lidocaine) was performed and targeted the peri-APF loose connective tissues. Pain was evaluated using a numerical rating scale (NRS) before and after HR. Passive straight leg raise (SLR) was used to assess tightness. Results: Post-HR, the mean NRS score significantly decreased from 10 to 0.86 (p = 0.017). Four patients required a single HR session; three required two–four sessions. Post-HR, the tightness of all patients improved. Short-axis US of the posterior thigh revealed APF fascial thickening in the area of tenderness, including the posterior femoral cutaneous nerve (PFCN). No adverse events or recurrence occurred during the follow-up (mean: 6.6 months). Conclusions: HR targeting the peri-PFCN-APF effectively reduced residual pain following hamstring injury. These findings support the concept of “Perineural fascial pain”—a pathology wherein persistent pain originates not from direct nerve damage or classical myofascial pain syndrome but rather from the dysfunction of the surrounding fascia. Full article

Cyclophilins (Cyps), a family of peptidyl-prolyl isomerases, play essential roles in the life cycle of coronaviruses by interacting with viral proteins and modulating host immune responses. In this systematic review, we examined cell culture, animal model, and clinical studies assessing the anti-viral efficacy of cyclosporine A (CsA, PubChem CID: 5284373) and its non-immunosuppressive derivatives against coronaviruses. CsA demonstrated robust anti-viral activity in vitro across a broad range of coronaviruses, including but not limited to HCoV-229E, SARS-CoV, MERS-CoV, and SARS-CoV-2, with potent EC₅₀ values in the low micromolar range. Non-immunosuppressive analogs such as Alisporivir and NIM811 exhibited similar inhibitory effects. In vivo, CsA treatment significantly reduced viral load, ameliorated lung pathology, and improved survival in coronavirus-infected animals. Clinical studies further indicated that CsA administration was associated with improved outcomes in COVID-19 patients, including reduced mortality and shorter hospital stays. Mechanistic studies revealed that CsA disrupts the formation of viral replication complexes, interferes with critical Cyp–viral protein interactions, and modulates innate immune signaling. These findings collectively demonstrate the therapeutic potential of cyclophilin inhibitors as broad-spectrum anti-virals against current and emerging coronaviruses. Full article

Heart failure (HF) is characterized by adverse myocardial remodeling involving both the contractile cardiomyocytes and the conduction tissue. HF is often associated with atrioventricular (AV) node dysfunction, which frequently leads to conduction delays and subsequent dyssynchrony ultimately related to adverse clinical outcomes. Despite its clinical relevance, AV node pathology in HF remains poorly explored. This review aims to investigate the pathophysiology underlying AV node dysfunction and the clinical implications for patients with HF, and to provide an overview of current therapeutic approaches, including an analysis of potential future treatments. Full article

Cardiovascular Disease (CVD) remains the number one cause of morbidity and mortality, accounting for 17.9 million deaths every year. Precise and early diagnosis is therefore critical to the betterment of the patient’s outcomes and the many burdens that weigh on the healthcare systems. This work presents for the first time an innovative approach using the DenseNet architecture that allows for the automatic recognition of CVD from clinical data. The data is preprocessed and augmented, with a heterogeneous dataset of cardiovascular-related images like angiograms, echocardiograms, and magnetic resonance images used. Optimizing the deep features for robust model performance is conducted through fine-tuning a custom DenseNet architecture along with rigorous hyper parameter tuning and sophisticated strategies to handle class imbalance. The DenseNet model, after training, shows high accuracy, sensitivity, and specificity in the identification of CVD compared to baseline approaches. Apart from the quantitative measures, detailed visualizations are conducted to show that the model is able to localize and classify pathological areas within an image. The accuracy of the model was found to be 0.92, precision 0.91, and recall 0.95 for class 1, and an overall weighted average F1-score of 0.93, which establishes the efficacy of the model. There is great clinical applicability in this research in terms of accurate detection of CVD to provide time-interventional personalized treatments. This DenseNet-based approach advances the improvement on the diagnosis of CVD through state-of-the-art technology to be used by radiologists and clinicians. Future work, therefore, would probably focus on improving the model’s interpretability towards a broader population of patients and its generalization towards it, revolutionizing the diagnosis and management of CVD. Full article

The integration of artificial intelligence (AI) in medical imaging has revolutionized diagnostic capabilities, yet the black-box nature of deep learning models poses significant challenges for clinical adoption. Current explainable AI (XAI) approaches, including SHAP, LIME, and Grad-CAM, predominantly focus on post hoc explanations that may inadvertently undermine clinical decision-making by providing misleading confidence in AI outputs. This paper presents a systematic review and meta-analysis of 67 studies (covering 23 radiology, 19 pathology, and 25 ophthalmology applications) evaluating XAI fidelity, stability, and performance trade-offs across medical imaging modalities. Our meta-analysis of 847 initially identified studies reveals that LIME achieves superior fidelity (0.81, 95% CI: 0.78–0.84) compared to SHAP (0.38, 95% CI: 0.35–0.41) and Grad-CAM (0.54, 95% CI: 0.51–0.57) across all modalities. Post hoc explanations demonstrated poor stability under noise perturbation, with SHAP showing 53% degradation in ophthalmology applications (ρ = 0.42 at 10% noise) compared to 11% in radiology (ρ = 0.89). We demonstrate a consistent 5–7% AUC performance penalty for interpretable models but identify modality-specific stability patterns suggesting that tailored XAI approaches are necessary. Based on these empirical findings, we propose a comprehensive three-pillar accountability framework that prioritizes transparency in model development, interpretability in architecture design, and a cautious deployment of post hoc explanations with explicit uncertainty quantification. This approach offers a pathway toward genuinely accountable AI systems that enhance rather than compromise clinical decision-making quality and patient safety. Full article

Osteoarthritis (OA) is a multifactorial joint disease traditionally characterized by cartilage degradation, while growing evidence underscores the critical role of synovial fibrosis in driving disease progression. The synovium exhibits pathological remodeling in OA, primarily due to the phenotypic transition of fibroblast-like synoviocytes (FLSs) into myofibroblasts. This fibroblast–myofibroblast transition (FMT) results in excessive deposition of extracellular matrix (ECM) and increased tissue stiffness and contractility, collectively contributing to chronic inflammation and fibrotic stiffening of the joint capsule. These fibrotic changes not only impair synovial function but also exacerbate cartilage degeneration, nociceptive sensitization, and joint dysfunction, thereby amplifying OA severity. Focusing on the frequently overlooked role of the FMT of synovial fibroblasts in OA, this review introduces the biological characteristics of FLSs and myofibroblasts and systematically examines the key molecular pathways implicated in OA-related FMT, including TGF-β, Wnt/β-catenin, YAP/TAZ, and inflammatory signaling cascades. It also discusses emerging therapeutic strategies targeting synovial fibrosis and FMT and considers their implications for the clinical management of OA. By highlighting recent advances and unresolved challenges, this review provides critical insights into the fibroblast–myofibroblast axis as a central contributor to OA progression and a promising therapeutic target for modifying disease trajectory. Full article

Poorly differentiated thyroid malignancy, a rare histological type of aggressive thyroid malignancy with associated difficulties and gaps in its histological and molecular characterization, might lead to challenging clinical presentations that require a prompt multimodal approach. This case study involved a 56-year-old, non-smoking male with a rapidly developing goiter (within 2–3 months) in association with mild, non-specific neck compressive symptoms. His medical history was irrelevant. A voluminous goiter with substernal and posterior extension up to the vertebral bodies was detected using an ultrasound and computed tomography (CT) scan and required emergency thyroidectomy. He had normal thyroid function, as well as negative thyroid autoimmunity and serum calcitonin. The surgery was successful upon “Y” incision, which was used to give better access to the retrosternal component in order to avoid a sternotomy. Post-operatively, the subject developed hypoparathyroidism-related hypocalcemia and showed a very high serum thyroglobulin level (>550 ng/mL). The pathological report confirmed poorly differentiated, multifocal thyroid carcinoma (with an insular, solid, and trabecular pattern) against a background of papillary carcinoma (pT3b, pN0, and pM1; L1; V2; Pn0; R1; and stage IVB). The subject received 200 mCi of radioiodine therapy for 6 weeks following the thoracic surgery. Whole-body scintigraphy was performed before radioiodine therapy and showed increased radiotracer uptake at the thyroid remnants and pre-tracheal levels. Additionally, single-photon emission computed tomography combined with CT (SPECT/CT) was performed, and confirmed the areas of intense uptake, in addition to a moderate uptake in the right and left pulmonary parenchyma, suggesting lung metastasis. To conclude, an overall low level of statistical evidence exists regarding poorly differentiated malignancy in substernal goiters, and the data also remains scarce regarding the impact of genetic and molecular configurations, such as the BRAF-positive profile, in this specific instance. Furthermore, multimodal management includes additional diagnosis methods such as SPECT/CT, while long-term multilayered therapy includes tyrosine kinase inhibitors if the outcome shows an iodine-resistant profile with a poor prognosis. Awareness remains a key factor in cases of a poorly differentiated carcinoma presenting as a rapidly growing goiter with substernal extension in an apparently healthy adult. A surgical approach, while varying with the surgeon’s skills, represents a mandatory step to ensure a better prognosis. In addition to a meticulous histological characterization, genetic/molecular features provide valuable information regarding the outcome and can further help with the decision to use new anti-cancer drugs if tumor response upon radioiodine therapy is no longer achieved; such a development is expected in this disease stage in association with a BRAF-positive configuration. Full article