Search Results (12,496)

Background/Objectives: Tumor thrombus is an uncommon but serious finding in sarcoma, with limited pediatric data. While adult cases indicate a median survival of ~14 months, outcomes in children remain poorly understood. Methods: A retrospective review (1990–2025) was conducted at a single pediatric tertiary center. Patients <18 years with pathologically confirmed bone or soft tissue sarcoma and radiographic or histologic evidence of tumor thrombus were included. Minimum follow-up was 3 years or until end of life. The primary outcome was survival after tumor thrombus diagnosis. Results: Thirteen patients (nine males, four females) met the inclusion criteria. The median age at sarcoma diagnosis was 10.5 years. Osteosarcoma was the most common subtype (69.2%), with 76.9% of tumors arising in bone. Disease was localized in 53.8% and metastatic in 46.2% at presentation. Tumor thrombus was contiguous in 61.5% and noncontiguous in 38.5%. The median time from sarcoma diagnosis to death was 44.2 months; from tumor thrombus diagnosis to death, this was 15.2 months. The overall survival after tumor thrombus diagnosis was 30.8%. Conclusions: Pediatric sarcoma with tumor thrombus is associated with poor prognosis, and surgical intervention did not appear to result in long-term survival in this small series. Tumor thrombus may be noncontiguous from the primary tumor, emphasizing the importance of advanced imaging and its implications for treatment planning and counseling. Full article

Background/Objectives: Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms may influence folate metabolism and DNA synthesis, potentially affecting disease characteristics and clinical outcomes in hematologic malignancies. This study investigated the associations of MTHFR C677T and A1298C polymorphisms with clinical features and survival outcomes in adult patients with acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL). Methods: A total of 92 adult patients with ALL or NHL treated with standard chemotherapy were retrospectively analyzed. MTHFR C677T and A1298C genotypes were determined using real-time polymerase chain reaction. Associations between genotypes and baseline clinical features, treatment response, toxicity, overall survival (OS), and progression-free survival (PFS) were examined. Results: The C677T heterozygous genotype was significantly associated with the presence of B symptoms (p = 0.027). No significant differences were observed across genotypes with respect to other baseline clinical features, treatment response, or treatment-related toxicity. In the overall cohort (ALL + NHL), OS and PFS did not differ significantly by C677T or A1298C genotypes. However, in the NHL cohort, carriers of the C677T variant demonstrated significantly shorter PFS (p = 0.048) and a non-significant trend toward lower OS. This association was also observed in the DLBCL subgroup for PFS (p = 0.043), with a similar non-significant trend observed for OS. Conclusions: Although MTHFR genotyping appears to have limited value for broad clinical stratification, the observed association between the C677T polymorphism and PFS in NHL—particularly in the DLBCL subgroup—suggests a potential subtype-specific relevance that warrants further validation in larger, disease-specific cohorts. Full article

Inflammation is a key feature in breast cancer progression, with neutrophil extracellular traps (NETs) playing an important role. NETs are DNA-based structures released by neutrophils that can promote tumor adhesion, invasion, and immune evasion. Another crucial mechanism is the inflammasome, a multiprotein complex that drives inflammation through cytokine release. Both mechanisms are present in tumors and may act synergistically. In this study, we evaluated how isolated NETs modulate the NLRP3 inflammasome in a human breast cancer model. Exposure of MDA-MB-231 cells to NETs increased the expression of NLRP3, CASP1, and IL1B. Blocking IL-1R with Anakinra reduced IL1B expression, while inhibition of the P2X7 receptor with A740003 decreased NLRP3 and IL1B. ELISA confirmed that NETs stimulate IL-1β release, which was reduced by MCC950, Anakinra, and A740003. Functionally, NETs accelerated tumor cell migration, and this effect was inhibited by MCC950 and Anakinra. Bioinformatics analysis of TCGA breast cancer samples showed differential inflammasome gene expression among subtypes and a positive correlation between inflammasome components and NET-related genes. These findings highlight the interplay between inflammatory and immune mechanisms in breast cancer progression and may support the development of new therapeutic strategies. Full article

Galanin is a highly conserved neuropeptide widely expressed in the central nervous system (CNS), where it regulates neurotransmission, neuroplasticity, and neuroendocrine functions. Its effects are mediated through three G protein-coupled galanin receptor subtypes, GalR1, GalR2, and GalR3, each exhibiting distinct tissue distributions, ligand affinities, and intracellular signaling mechanisms. Endogenous ligands, including galanin, galanin-like peptide (GALP), and spexin, interact with these receptors to trigger receptor-specific pathways, such as adenylyl cyclase (AC) inhibition (GalR1/GalR3) and phospholipase C-mediated calcium signaling (GalR2), enabling modulation of neuronal excitability, neurotransmitter release, and cell survival. Exogenous ligands, including peptide analogs and non-peptide agonists, have further elucidated receptor function and highlighted opportunities for pharmacological intervention. Preclinical evidence demonstrates that targeting galanin receptors (GalRs) can influence mood, cognition, pain perception, epilepsy, metabolic regulation, and neuroprotection, suggesting therapeutic potential across diverse CNS disorders. By integrating knowledge of ligand–receptor interactions and downstream signaling, this review highlights the central role of GalRs in CNS physiology and their emerging relevance as targets for clinical applications. Full article

Background/Objectives: Streptococcus pneumoniae remains a major cause of invasive disease, and antimicrobial resistance is shaped by antibiotic selection and pneumococcal conjugate vaccination. A unified framework is needed to compare proposed mechanisms that maintain coexistence of antibiotic-sensitive and -resistant strains and to interpret post-vaccine resistance trajectories. Methods: We formulated a susceptible–exposed–vaccinated–infectious–recovered (SEVIR) transmission model that tracks antibiotic-sensitive and -resistant pneumococcal infections under vaccination and treatment. The basic reproduction number ($R_0$) was derived using the next-generation matrix method and used to assess local stability of the disease-free equilibrium. Using the same core structure, we evaluated three mechanism-specific extensions: treatment diversity (heterogeneous antibiotic use across host groups), pathogen diversity (serotype/subtype heterogeneity under vaccine targeting), and treatment competition (within-host competition with treatment-induced selection). Results: Treatment diversity generated stable coexistence by creating low-treatment refugia that counterbalanced strong selection in highly treated groups, supporting resistance persistence at moderate population-average treatment. Pathogen diversity reproduced serotype-specific replacement and concentration of resistance within particular subtypes after vaccination. Treatment competition produced nonlinear responses to antibiotic intensity and transient resistance surges. Overall, each mechanism explained a distinct subset of benchmark resistance patterns, suggesting that dominant drivers depend on epidemiological context. Conclusions: Interactions between vaccination, antibiotic pressure, population heterogeneity, pathogen diversity and within-host competition can yield qualitatively different resistance dynamics. Strategies combining high vaccine uptake with targeted antibiotic stewardship are likely required to curb resistance while limiting unintended serotype replacement. Full article

Distant metastasis is the main cause of breast cancer (BC) mortality, yet current prognostic models remain largely tumor-centric and underutilize stromal biology. In this study, we quantified reactive stroma, a collagen-rich and fibrotic fraction of the stromal compartment, as a subtype-independent biomarker of metastatic risk. A retrospective cohort of 182 FFPE primary BC biopsies (2006–2020) was analyzed. Total stroma was quantified on H&E-stained sections and reactive stroma on Masson’s trichrome using QuPath with pathologist validation. Cutoffs were defined using maximally selected rank statistics, and overall survival (OS) and metastasis-free survival (MFS) were evaluated by Kaplan–Meier analysis and multivariable Cox regression. RNA sequencing was performed in a subset of cases to characterize associated transcriptomic programs. While total stromal content showed univariate associations with OS and MFS, it was not independently prognostic after adjustment. In contrast, high reactive stroma (cutoff 53.2%) independently predicted shorter MFS (HR = 3.76; p < 0.001), irrespective of molecular subtype and clinicopathological variables. Tumors with high reactive stroma exhibited upregulation of extracellular matrix and profibrotic genes (including FN1, OLR1, and EDN2), enrichment of collagen remodeling and TGF-β signaling pathways, and reduced T-cell activation signatures. These findings demonstrate that quantitative assessment of reactive stroma from standard histological stains is a reproducible, subtype-independent biomarker of metastatic risk in BC and can be readily integrated into routine pathology workflows to improve risk stratification. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder in which metabolic, inflammatory and proteostatic disturbances converge to drive dopaminergic neuron loss and widespread network failure. In this narrative review, we synthesize clinical, epidemiological and experimental evidence to organize PD pathophysiology around three interconnected metabolic axes: mitochondrial dysfunction and impaired glucose and lipid metabolism; chronic oxidative stress; and glial reprogramming and neuroinflammation, with α-synuclein acting as a central integrator at their interface. We then map how currently available dopaminergic, neuromodulatory and rehabilitative therapies interact with these axes, largely providing downstream symptomatic compensation while leaving core metabolic and inflammatory drivers only partially addressed. Next, we review RNA sequencing (RNA-Seq) and related transcriptomic studies in human brain and peripheral tissues, highlighting convergent differentially expressed genes in mitochondrial, synaptic, immune and proteostasis pathways, as well as major methodological challenges and opportunities for molecular subtyping and biomarker discovery. Together, these lines of evidence support a systems-level view of PD in which α-synuclein–centered metabolic failure and glial dysregulation are key therapeutic targets and in which high-quality RNA-Seq, integrated with advanced bioinformatics, may help define biologically grounded PD endotypes and accelerate the development of truly disease-modifying interventions. Full article

Objective: This study aimed to investigate erythrocyte morphological alterations in hematological malignancies, with particular emphasis on structural differences among leukemia subtypes and anemia. Materials and Methods: Peripheral blood samples were obtained from 60 patients, including individuals with anemia (n = 10), acute lymphoblastic leukemia (ALL, n = 15), acute myeloid leukemia (AML, n = 15), chronic lymphocytic leukemia (CLL, n = 15), and chronic myeloid leukemia (CML, n = 5), as well as 10 healthy controls. Erythrocyte morphology was evaluated using light microscopy and scanning electron microscopy. Morphological abnormalities, including loss of biconcavity, poikilocytosis, echinocyte transformation, burr cells, and stomatocytes, were assessed in accordance with International Council for Standardization in Haematology (ICSH)-based morphological definitions. Results: Distinct erythrocyte morphological alterations were observed across disease groups. AML cases demonstrated pronounced central depression-like or perforation-like structures and hypochromasia. Lymphoid malignancies, particularly ALL and CLL, exhibited increased echinocyte formation, whereas chronic leukemias showed a higher prevalence of stomatocytes and cup-shaped cells. Quantitative scoring indicated that loss of biconcavity was most prominent in anemia, followed by AML, CML, ALL, and CLL. Poikilocytosis was most frequent in anemia, followed by ALL, CLL, AML, and CML. Conclusions: The findings indicate that erythrocyte shape alterations are more heterogeneous and prominent in lymphoid leukemias, whereas myeloid leukemias exhibit distinct ultrastructural membrane abnormalities. Although studies focusing on erythrocyte morphology in leukemia remain limited, the present results provide a foundational morphological reference dataset that may support the development and validation of artificial intelligence-based diagnostic approaches. Further studies involving larger cohorts and expanded imaging analyses are warranted to improve diagnostic accuracy and translational applicability. Full article

Background and Objectives: This study aimed to assess the prognostic value of several inflammation-based hematological indices in patients with ischemic and hemorrhagic stroke and to evaluate whether their prognostic significance differs between stroke types. The analyzed indices included the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic inflammatory response index (SIRI), systemic immune-inflammation index (SII), and aggregate index of systemic inflammation (AISI). Materials and Methods: This retrospective cohort study analyzed the medical records of stroke patients admitted to two hospitals in Shymkent, Kazakhstan. Hematological parameters were calculated from routine complete blood counts obtained on the third day of hospitalization. Nonparametric tests, univariable and multivariable logistic regression, and receiver operating characteristic (ROC) analysis were used to evaluate associations between inflammatory indices and in-hospital mortality. Results: A total of 199 patients who met the inclusion criteria were classified into three groups according to in-hospital outcome at discharge: (1) patients discharged alive (favorable outcome), (2) patients who died during hospitalization due to ischemic stroke (unfavorable ischemic stroke), and (3) patients who died during hospitalization due to hemorrhagic stroke (unfavorable hemorrhagic stroke). NLR, SIRI, AISI, and SII values were significantly higher in both unfavorable outcome groups compared with the favorable outcome group (p < 0.001, effect size r > 0.6). No statistically significant differences were observed between unfavorable ischemic and hemorrhagic stroke outcomes. In logistic regression analysis, NLR (OR = 1.65) and SIRI (OR = 2.36) showed the strongest associations with in-hospital mortality. ROC analysis demonstrated good predictive performance, with AUC values of 0.885 for NLR and 0.867 for SIRI. Conclusions: The inflammatory indices evaluated in this study were associated with stroke outcomes regardless of stroke subtype. Among them, SIRI and NLR showed the highest prognostic value. These indices may serve as accessible markers of disease severity but should not be considered independent clinical decision-making tools. Full article

Background: Cardiovascular disease (CVD) remains the leading cause of death and disability worldwide. Among its subtypes, coronary artery disease (CAD) is the most common and often develops silently, without noticeable symptoms. CAD-related murmurs typically fall below the human hearing threshold, limiting the effectiveness of traditional stethoscope-based auscultation. Currently, the gold standard for CAD diagnosis is coronary angiography, an invasive and expensive procedure usually reserved for symptomatic patients. This highlights the global need for a non-invasive, cost-effective pre-screening tool for asymptomatic CAD detection. Objectives: This study investigates the effectiveness of a wearable vest equipped with multiple digital stethoscopes to detect CAD. By applying signal processing and machine learning to multichannel phonocardiogram (PCG) data, we aim to evaluate the accuracy of CAD detection. We further assess the impact of incorporating patient metadata to enhance model performance. Methods: Data were collected from 40 CAD patients and 40 non-CAD individuals using a wearable vest with seven embedded PCG sensors. Subjects performed 10 s breath-hold recordings in a clinical setting. Linear-frequency cepstral coefficients were extracted from the PCG signals and classified using a support vector machine. Metadata, including body mass index, blood pressure, type 2 diabetes, and hypertension, were integrated to assess performance gains. Results: A combination of four channels achieved an accuracy of 80.44%, a 7% improvement over the best single-channel result. Incorporating metadata increased accuracy to 82.08%. Conclusions: The wearable vest demonstrated promising clinical potential, exceeding a 75% sensitivity-specificity average, and may support accessible, automated CAD screening in future validated settings. Full article

Background/Objectives: The retina is enriched in polyunsaturated fatty acids (PUFAs) which are indispensable for normal vision, and recent clinical studies have shown that dietary supplementation of ω-6-and ω-3-polyunsaturated fatty acids (PUFAs) can provide a protective role against retinopathy of prematurity (ROP). Our study aims to understand the mechanisms by which altering ω-6-and ω-3-polyunsaturated fatty acids (PUFAs) in the eye can protect against pathologic retinal neovascularization (NV). Methods: We interrogated the effects of endogenous ω-3-PUFA enrichment using transgenic fat-1 mice which convert ω-6-PUFAs to ω-3-PUFAs in the oxygen-induced retinopathy (OIR) murine model. In the OIR model, mice are exposed to 75% oxygen from postnatal day 7 (P7) to P12, then returned to room air (RA). We used a combination of immunofluorescence, bulk retinal RNA sequencing, and lipid mediator profiling by UHPLC-MS/MS in P17 mouse retinas to identify mechanisms underlying the protective effect against NV seen in fat-1 mice exposed to OIR. Results:Fat-1 OIR mice were protected against the development of retinopathy, demonstrating 15.1% less vaso-obliteration (75.5% relative reduction) after OIR and a 6.1% reduction in neovascularization (71.8% relative reduction) at P17 (p < 0.0001 for both). We found a dampened transcriptional response to OIR in the retina of fat-1 mice as compared to WT mouse retinas (198 vs. 782 genes, adjusted p-value < 0.01). Pathway analyses confirmed these findings, with significant OIR-induced transcriptional shifts in angiogenesis (adjusted p-value < 10⁻²⁷), inflammation (adjusted p-value < 10⁻²⁵), and microglial activation pathways (adjusted p-value < 10⁻⁹) in WT mouse retina that were not observed in fat-1 mice. Enrichment scores obtained through the integration of our bulk transcriptomics data with cell-resolved retina data indicate that the protective phenotype observed in fat-1 mice could be associated with intrinsic differences in microglia cell subtypes between WT and fat-1 mice. In situ, WT OIR mice demonstrated an increase in Iba1+ microglia compared to WT RA mice, whereas fat-1 OIR mice showed no difference when compared to fat-1 RA mice. Three ARA-derived oxylipins, 12-hydroxyeicosatetraenoic acid (12-HETE), prostaglandin D2 (PGD2), and thromboxane B2 (TXB2) demonstrated a pattern of upregulation in WT OIR compared to WT RA, but no upregulation in fat-1 OIR mice compared to fat-1 RA. Two EPA-derived specialized pro-resolving mediators and two LA-derived oxylipins were also differentially expressed. Conclusions: These findings show that a lower ω-6:ω-3 protects against neovascularization and is associated with attenuation of hyperoxia-induced microglial recruitment and activation, as well as inflammation and angiogenic signaling. Full article

Renal cell carcinoma (RCC), particularly the clear cell subtype, is a solid tumor characterized by a high degree of immune cell infiltration, progressive immune dysfunction, and favorable response to immune checkpoint inhibitors (ICIs). Dual checkpoint inhibition or single-agent ICIs with anti-angiogenic therapies have become the standard of care in the treatment of advanced and metastatic RCCs. Locally advanced and oligometastatic RCCs are distinct clinical categories that are characterized by local invasion and initially limited metastatic spread, respectively, with different therapeutic responses and prognoses compared to either localized or advanced diseases. Herein, we summarize the biology, treatment, and molecular profiling of RCCs, providing an update on the clinical trials pertaining to cancer patients with locally advanced and oligometastatic RCC. We also discuss molecular features that could contribute to a better understanding of the tumor biology driving locally advanced and oligometastatic RCC. Full article

Background/Objectives: Transcatheter edge-to-edge repair (TEER) has become an established therapeutic option for selected patients with mitral regurgitation (MR). However, primary (degenerative) and secondary (functional) MR represent distinct disease entities, characterized by different pathophysiological mechanisms, clinical trajectories, and determinants of benefit. This review aims to provide an interventional cardiology-oriented synthesis of TEER, emphasizing the fundamental differences between primary and secondary MR and their implications for patient selection, procedural strategy, and outcome interpretation. Methods: A targeted literature search was performed in PubMed and Embase to identify pivotal randomized trials, registries, guideline documents, and high-quality reviews addressing TEER in MR. The available evidence was synthesized narratively, with a focus on mechanistic insights, TEER-specific imaging and procedural endpoints, and clinically relevant outcomes. Results: In primary MR, TEER functions as a valve-centered therapy, with procedural success primarily determined by anatomical suitability and the balance between durable MR reduction and avoidance of elevated transmitral gradients. In secondary MR, TEER should be considered an adjunctive intervention within a comprehensive heart failure strategy, with benefit dependent on patient phenotype, myocardial substrate, optimization of background therapy, and appropriate timing. Emerging phenotypes, such as atrial functional MR, further challenge traditional classification and highlight the need for mechanism-based selection. Across MR subtypes, residual MR and transmitral gradients emerge as key post-procedural endpoints with differential prognostic implications. Conclusions: TEER represents a phenotype-specific intervention rather than a uniform solution for MR. Recognizing the distinct interventional paradigms of primary and secondary MR is essential to optimizing patient selection, procedural decision-making, and clinical outcomes. Full article

Background: Esophageal squamous cell carcinoma (ESCC) is the predominant subtype of esophageal cancer, with poor outcomes following neoadjuvant chemoradiotherapy (NCRT). Neoadjuvant chemoimmunotherapy (NCIT) has emerged as a promising strategy, but reliable predictive biomarkers remain lacking. This study aimed to develop an AI-driven pathomic model for NCIT response prediction and explore its biological mechanisms. Methods: We analyzed 269 H&E-stained whole-slide images (WSIs) from 198 ESCC patients (104 from Tongji Hospital, 94 from TCGA). Using ResNet152, we segmented WSIs into four tissue categories (tumor cells, stroma, lymphocytes, and necrosis), extracted spatially weighted pathomic features, and constructed the ECiT score via logistic regression. An integrated model combining the ECiT score with clinical variables (T stage, P53 status) was developed. Mechanistic analyses were performed using TCGA-ESCA and GSE160269 datasets. Results: The integrated model achieved AUCs of 0.897 (training) and 0.809 (temporal validation), outperforming clinical (AUC = 0.624) and pathomic-only (AUC = 0.751) models. Mechanistically, a high ECiT score correlated with enhanced immune activation (elevated CD4⁺ memory T cell infiltration), while low scores were linked to endoplasmic reticulum (ER) stress-unfolded protein response (UPR) activation. EIF2S3 was identified as a key molecular mediator, correlating with three pathomic features, UPR activation, and poor prognosis. Conclusions: This study may offer a preliminary indicator that could assist in personalized clinical decision-making. Correlative evidence suggests that the EIF2S3-mediated ER stress–UPR axis represents a potential candidate therapeutic target to overcome NCIT resistance, generating testable hypotheses to advance precision oncology for resectable locally advanced ESCC. Full article

Undifferentiated melanoma (UM) is a rare and diagnostically challenging subtype of malignant melanoma that often lacks traditional histological features and immunophenotypic expression. We report the case of a 58-year-old man with a history of a previously excised melanoma in-situ (lentigo maligna type) of the scalp who later developed a painful chest wall mass. Subsequent workup revealed a high-grade malignant neoplasm with only focal weak S100P positivity while molecular analysis with next-generation sequencing (NGS) revealed an ultra-high TMB tumor mutational burden (>150 mut/Mb), NF1 mutation, TERT promoter mutation, TP53 mutations, PTPRD mutations, and a UV mutational signature (100% SBS7a), supportive of a diagnosis of UM. This case highlights the diagnostic value of comprehensive molecular testing in UM and its role in informing immunotherapy decisions. Full article