Search Results (45,001)

As cancer mortality rates rise globally, malignancies have become the second leading cause of death. Recently, efforts have been made to understand the impact of the tumor microenvironment that involves fluid shear forces. Biomechanical stimulation, which uses shear stress to activate mechanosensitive ion channels, e.g., Piezo1, increases calcium influx into the intracellular space and activates T cells. Novel 3D cancer cultures with T cells have been proposed. Such models use cell/scaffold constructs to recapitulate interactions between cells and the extracellular matrix. In addition, flow perfusion bioreactors investigate the impact of fluid shear forces on immune and/or cancer cells. These bioreactors have biosensors that allow monitoring of immune cell activation. Furthermore, they provide a biomimetic environment for the study of the interaction of T cells and cancer cells. Hence, immune checkpoint inhibitors have demonstrated immunotherapeutic efficacy, but a single-target blockade has often proved insufficient. Co-delivery of CCL19 pDNA and the PD-1/PD-L1 interaction inhibitor BMS-1 using RGD-modified nanocarriers targeting tumor integrins enhanced local antitumor immunity. This review highlights recent insights into how fluid shear stress (FSS) regulates cancer progression and immune responses in three-dimensional in vitro models, with a focus on bioreactors and the surface modification of scaffold materials. Full article

Advanced melanoma remains difficult to treat due to its intrinsic resistance to conventional therapies and the frequent development of acquired resistance to targeted agents, such as BRAF inhibitors. Onconase (ONC), an amphibian ribonuclease with established antitumor activity, had been previously shown to have selective cytotoxicity toward melanoma cells. In this study, we investigated the molecular mechanisms underlying ONC-induced cytotoxicity in BRAF-mutated melanoma cell lines that are either sensitive or resistant to the BRAF inhibitor dabrafenib. We focused on oxidative stress regulation, mitochondrial dynamics, and cell death-related signaling pathways. ONC treatment resulted in a marked increase in reactive oxygen species (ROS) levels, concomitant with a pronounced downregulation of NRF2 and multiple NRF2-dependent antioxidant proteins. These effects were particularly evident in dabrafenib-resistant melanoma cells. In parallel, ONC impaired mitochondrial plasticity by inhibiting mitochondrial biogenesis and fission, as evidenced by reduced PGC1α, DRP1, and FIS1 expression. Confocal analysis confirmed the presence of more enlarged mitochondria in ONC-treated cells. Mitophagy and autophagy are hindered by ONC due to the downregulation of PINK1, beclin1, ATG3 expression, as well as the lack of LC3B activation. These mitochondrial defects were associated with mitochondrial-dependent apoptosis, characterized by caspase-9 activation and strong downregulation of the antiapoptotic protein survivin. Lipid peroxidation was also induced by ONC, especially in the A375 cell line. Additionally, ONC inhibited key proliferation-related signaling pathways, including STAT3 and NF-κB, and reduced cyclin-dependent kinase 1, 2, and 4 activities. Collectively, these findings demonstrate that ONC disrupts redox homeostasis, mitochondrial function, and survival signaling in melanoma cells, exerting particularly potent effects in BRAF inhibitor-resistant populations. This study provides mechanistic insight into the anti-melanoma activity of ONC and supports its potential therapeutic application in drug-resistant melanoma. Full article

Abdominal Aortic Aneurysm (AAA) remains a significant public health challenge, with an 82.1% increase in related fatalities from 1990 to 2019. In the United States alone, AAA complications resulted in an estimated 13,640 deaths between 2018 and 2021. In clinical practice, computed tomography angiography (CTA) is the primary imaging modality for monitoring and pre-surgical planning of AAA patients. CTA provides high-resolution vascular imaging, enabling detailed assessments of aneurysm morphology and informing critical clinical decisions. However, manual segmentation of CTA images is labor-intensive and time consuming, underscoring the need for automated segmentation algorithms, particularly when feature extraction from clinical images can inform treatment decisions. We propose a framework to automatically segment the outer wall of the abdominal aorta from CTA images and estimate AAA wall stress. Our approach employs a patch-based dilated modified U-Net model to accurately delineate the outer wall boundary of AAAs and Nonlinear Elastic Membrane Analysis (NEMA) to estimate their wall stress. We further integrate Non-Uniform Rational B-Splines (NURBS) to refine the segmentation. During prediction, our deep learning architecture requires $17\pm 0.02$ milliseconds per frame to generate the final segmented output. The latter is used to provide critical insight into the biomechanical state of stress of an AAA. This modeling strategy merges advanced deep learning architecture, the precision of NURBS, and the advantages of NEMA to deliver a robust and efficient method for computational analysis of AAAs. Full article

Esca disease, the most widespread grapevine trunk disease in Europe, is characterized by both chronic and acute forms. In both cases, alterations in the plant’s physiological processes are significant and lead to yield losses and/or plant death. Studies have highlighted the effects of a mixture of foliar fertilizers and seaweeds in reducing foliar symptoms and improving both the quantity and quality of yield. These effects have now been evaluated on additional cultivars and in other vineyard areas. Furthermore, for the first time, the activity of the fertilizer mixture in reducing apoplexy and the resulting vine mortality has been assessed. During the 2022–2023 biennium, in four vineyards of the Lambrusco cultivar in the Province of Reggio Emilia, Northern Italy, affected by both chronic and acute forms of the disease, foliar applications of the mixture were carried out at 10-day intervals starting from the “nine leaves unfolded” BBCH (Biologische Bundesanstalt, Bundessortenamt and Chemical industry) stage 19 up to the “berries developing color” BBCH stage 83. The results confirmed the activity of the fertilizer mixture in reducing chronic symptoms, which appeared particularly pronounced in 2022, when rainfall quantity and distribution allowed regular development of phenological stages. In that year, in all vineyards, a reduction of approximately 50% and 60% in the incidence and severity of chronic leaf symptoms was recorded. Under these optimal growth conditions, treated vines generally showed superior yield and quality. Conversely, in 2023, characterized by heavy rains, smaller effects on foliar symptoms and no improvements in yield were observed. Applications of the mixture resulted in a significant reduction in apoplexy and, consequently, vine mortality, as verified in 2024. This effect did not appear to be influenced by climatic conditions. This study confirms that applications of the mixture aimed at reducing symptom expression and yield damage are a valid addition to the few available control practices. The positive effects observed on the acute form for the first time require further investigation. Full article

Ambient air pollution is a major environmental health risk, with impacts that may be unevenly distributed across vulnerable populations, particularly in urban areas under changing climate conditions. This study assessed whether social conditions modify the association between exposure to fine particulate matter (PM_2.5) and deaths from circulatory and respiratory diseases in Campinas, Brazil. An ecological time-series study was conducted from 2010 to 2023 using monthly death data aggregated at the catchment-area level of 63 Primary Health Care Centers, stratified into four vulnerability groups. Associations between monthly PM_2.5 concentrations and mortality rates were estimated using distributed lag non-linear models within a generalized additive modeling framework, adjusting for meteorological variables, ozone, seasonality, and long-term trends. A total of 38,311 cardiorespiratory deaths were recorded. Mortality rates varied non-linearly across strata, and a statistically significant positive association between PM_2.5 exposure and mortality was observed only in the intermediate–high vulnerability group at higher pollution levels. No significant associations were identified in the lowest or highest vulnerability strata. These findings indicate that social context modifies air pollution–related mortality risks, highlighting the importance of incorporating vulnerability dimensions into air quality assessments and climate-related public health strategies. Full article

Background/Objectives: The study evaluated whether the cumulative burden of multiple, modifiable risk factors worsened cardiovascular disease (CVD) mortality in West Virginia. Methods: This retrospective observational study looked at all CVD mortality rates per county of West Virginia between 2011 and 2020 and each county’s modifiable risks. Income, ratio of people per PCP (PCP Ratio), and Food Desert Status (FDS), and the death rate from the Census Bureau, AMA, US Department of Agriculture, and the West Virginia Department of Health and Human Services (WV HHS) were collected, respectively. Multiple linear regression and ANOVA analyses were performed for each combination of factors towards the death rate. Results: Multiple linear regression demonstrated that combined risk factors were more strongly associated with CVD mortality than any single factor alone. Over the 10-year period, West Virginia’s population aged overall. Each individual risk factor was significantly associated with CVD mortality (Income: F(1,537) = 53.39, p < 0.0001; PCP Ratio: F(1,537) = 21.49, p < 0.0001; FDS: F(1,537) = 5.13, p = 0.024). Two two-way interactions were significant (PCP Ratio:Income: F(1,537) = 22.03, p < 0.001; FDS:Income: F(1,537) = 5.23, p = 0.022), while the PCP Ratio:FDS interaction and the three-way interaction were not. Conclusions: Counties burdened by several modifiable risk factors experienced disproportionately elevated CVD mortality, exceeding what would be predicted by the additive effects of each risk factor individually. These findings highlighted the importance of addressing cumulative socioeconomic and healthcare access factors at the county level. Full article

Many ant species play a relevant role in the successional patterns of insects colonizing human and animal corpses. Although feeding behavior in ants depends on the trophic preferences of each taxon, these insects are often reported in several studies as predators of eggs, larvae, and adults of necrophagous insects. Among ants, some species are known to cause damage on human and animal dermis, known as post-mortem skin artifacts. The extensive activity of worker ants on corpses may hinder forensic pathological investigations aimed at determining the cause and location of death, as well as the assessment of entomologists in estimating the minimum post-mortem interval. We report for the first time a case of skin lesions on a human corpse found in a suburban area of the city of Cosenza (Calabria, Southern Italy), caused by the ant Pheidole pallidula (Hymenoptera: Formicidae). During the autopsy, numerous individuals (major and minor workers) were observed feeding on the corpse, but no other insects were found on it. We discuss the appearance of skin artifacts caused by P. pallidula and provide an overview of the genus Pheidole in forensic entomology. Full article

A 78-year-old woman with a history of rheumatoid arthritis (treated with methotrexate) developed disturbed consciousness, emesis, and intestinal perforation. Initial labs revealed hyperammonemia (189 μg/dL) and hypertonic dehydration. Despite ammonia normalization, her neurological status improved only slightly, necessitating additional tests. Cerebrospinal fluid analysis showed no pleocytosis but positive oligoclonal bands and markedly elevated myelin basic protein (>500 pg/mL). Serum autoimmune markers were negative, including anti-aquaporin-4 (AQP4), anti-myelin oligodendrocyte glycoprotein (MOG), and anti-glial fibrillary acidic protein (GFAP) antibodies. MRI revealed T2/DWI-hyperintense lesions in the left parietal lobe and cerebellum. Crucially, extensive T2/DWI-hyperintense lesions with diffusion restriction spanned the white matter from the medulla oblongata to the lumbar spinal cord. Axial spinal DWI demonstrated diffuse hyperintensity throughout the entire white matter, accompanied by gray matter atrophy. Subsequent metabolic screening revealed low folate and hypocupremia (34 μg/dL) as well as urinary orotic acid and low serum citrulline, suggesting late-onset ornithine transcarbamylase (OTC) deficiency. Given the clinical context, this was interpreted as a metabolic breakdown rather than an established genetic diagnosis. This case is characterized by a long, diffusion-restricted lesion from the brainstem to the spinal cord that does not correspond to vascular territories. She experienced sudden death. We hypothesize that an underlying metabolic disorder, nutritional deficiencies and drug-induced neurotoxicity contributed to lesion formation. Full article

Background/Objectives: Although curcumin (CUR) and resveratrol (RSV) are natural polyphenolic compounds with reported anticancer and anti-inflammatory properties, their combined anticancer effects in melanoma cells remain incompletely characterized. This study aimed to evaluate the anticancer efficacy of CUR and RSV, individually, and in combination, in melanoma cells compared to normal melanocytes. Methods: Cell viability and intracellular ATP levels were quantified, and dose–response analyses performed. Cellular morphology and nuclear alterations were examined by phase-contrast microscopy and DAPI staining. Cell cycle distribution and apoptosis were analyzed by Muse™ Cell Analyzer with dedicated assay kits. Survival- and death-related signaling proteins were evaluated by Western blotting. Results: Combined treatment with CUR (60 μM) and RSV (40 μM) for 48 h synergistically reduced melanoma cell viability and markedly depleted intracellular ATP levels, while exerting minimal cytotoxic effects on normal melanocytes. CUR/RSV co-treatment induced pronounced morphological and nuclear alterations, significantly increased apoptotic cell populations, and modulated key signaling pathways regulating cell survival and programmed cell death in melanoma cells. Conclusions: These findings demonstrate that combined CUR and RSV treatment exerts enhanced, melanoma-selective anticancer activity while sparing normal melanocytes. The results provide a strong experimental rationale for further in vivo validation of CUR/RSV-based combination strategies as a potential therapeutic approach for melanoma. Full article

Background: Treatment for advanced non-small-cell lung cancer (NSCLC) has evolved substantially over the past decade, necessitating evaluation of real-world treatment patterns and effectiveness before and after the introduction of newer therapies. Methods: This retrospective cohort study included adult patients initiating a non-curative first-line therapy for advanced NSCLC between 2014 and 2021 at the IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST), with follow-up through 2022. Overall survival (OS) and real-world progression-free survival from the start date of the first line of therapy for advanced NSCLC were estimated using Kaplan–Meier methods. Results: Overall, 910 patients were included; at diagnosis, 83% had a de novo diagnosis and 17% had recurrent disease. During the study, 41% of patients received platinum-based chemotherapy alone; 22% received non-platinum-based chemotherapy alone; 21% received anti-programmed death (PD)-(ligand [L])1 immune checkpoint inhibitors (ICIs), alone or with chemotherapy; and 16% received targeted therapy (single-agent tyrosine kinase inhibitors) as first-line therapy for advanced disease. From 2014 to 2021, the proportion of patients receiving first-line anti-PD-(L)1 ICIs increased from 0% to 58% and the proportion of those receiving first-line platinum-based chemotherapy decreased from 65% to 6%. Median (95% CI) OS was 8.2 (7.5–9.2) months; the minimum-to-maximum range of median OS was 6.0–7.4 months from 2014 to 2017 and 8.4–15.9 months from 2018 to 2021. Median OS was numerically longer in patients with recurrent disease versus a de novo diagnosis, first-line targeted versus other therapy, high versus low PD-L1 expression, and non-squamous/other versus squamous histology. Conclusions: This study provides real-world data further supporting (i) the benefits of precision targeted therapy for patients with advanced NSCLC and actionable genomic alterations and (ii) the positive impact of immunotherapy approvals on the treatment paradigm for advanced NSCLC. Full article

Background/Objectives: Lung cancer remains the leading cause of cancer-related deaths worldwide, with Non-Small Cell Lung Cancer (NSCLC) accounting for the majority of cases, primarily Squamous Cell Carcinoma (SCC) and Adenocarcinoma (ADC). The aim of this systematic review is to summarise and critically appraise the performance of machine learning (ML)-based radiomics models in the differential diagnosis and overall survival analysis for lung SCC and ADC. Methods: PRISMA standards were followed in conducting the review. The quality of the studies was assessed using the Radiomics quality score (RQS) tool. Results: A total of 11 studies were included, demonstrating that deep learning and radiomics-based machine learning models significantly improve the non-invasive classification of lung squamous cell carcinoma and adenocarcinoma. Deep learning systems achieved an accuracy of 67–97%, and machine learning models showed an accuracy of 75–87%. The integration of radiomic features further enhanced diagnostic precision, showing strong potential for reliable histologic subtype differentiation. Conclusions: Machine learning-based radiomics models and deep learning significantly enhance the non-invasive, accurate differentiation of lung squamous and adenocarcinoma cell carcinoma when combined with clinical and pathological data. Full article

Oxidative and nitrosative stress are central mechanisms in the pathogenesis of neurodegenerative diseases, where excessive production of reactive oxygen and nitrogen species (ROS/RNS) leads to mitochondrial dysfunction, membrane damage, and neuronal death. In this study, we established and compared short-term (2 h) and long-term (20 h) exposure paradigms to sodium nitroprusside (SNP), used as a xenobiotic nitric oxide donor, in two neuronal cell lines (mHippoE-18 and PC12) and zebrafish larvae, aiming to provide a preclinical framework for neurodegenerative drug discovery. In vitro, SNP exposure caused concentration-dependent reductions in viability and alterations in oxidative balance, with mHippoE-18 cells exhibiting higher susceptibility than PC12 cells. In the short-term exposure paradigm, cytotoxicity was primarily associated with membrane disruption at higher concentrations, whereas oxidative stress contributed more strongly at intermediate doses. In the long-term exposure, mHippoE-18 cells showed strong integrated correlations between ROS, LDH release, and viability loss, highlighting their increased vulnerability to nitrosative stress. In zebrafish, SNP exposure impaired metabolic activity and swimming behavior in both paradigms. Long-term exposure led to consistent dose-dependent increases in ROS, accompanied by locomotor deficits tightly linked to energy metabolism. Overall, the higher sensitivity of mHippoE-18 cells compared with PC12 cells, together with the dose-dependent metabolic and behavioral impairments observed in zebrafish, indicates that cellular responses partially mirror in vivo outcomes. This integrative approach underscores the value of combining neuronal cell lines with zebrafish larvae to capture complementary aspects of SNP-induced neurotoxicity and to strengthen preclinical evaluation of candidate compounds with protective or therapeutic potential. These findings support the use of SNP as a xenobiotic model to probe nitrosative stress-driven neurotoxicity across cellular and organismal systems. Full article

Malaria remains a global health threat, with Plasmodium falciparum causing most deaths, especially in sub-Saharan Africa. Although artemisinin-based therapies reduce the burden, drug-resistant parasites threaten control efforts. Mapping the distribution and evolution of molecular resistance markers is vital for evidence-based strategies. This systematic review mapped the global distribution, pooled prevalence, and temporal trends of key P. falciparum antimalarial resistance markers. Following the PRISMA methodology (PROSPERO: CRD4202511098991), databases (PubMed, Web of Science, Scopus, and Google Scholar) and gray sources were searched (July 2005–July 2025). Data were extracted in Rayyan, assessed via the JBI prevalence tool, and analyzed using Python v3.13 for WHO regional distribution, temporal trends, and treatment outcome trends. Of the 1972 records, 261 studies from 64 countries qualified for inclusion in this review. The pooled prevalence was highest for pfdhfr (85.7%), followed by pfcrt (78.0%), pfdhps (73.7%), pfmdr1 (60.5%), and pfk13 (45.0%). High heterogeneity (I² > 95%) and rising pfk13 since 2012 highlight emerging artemisinin resistance, while persistent pfdhfr/pfdhps mutations show that ongoing sulfadoxine–pyrimethamine (SP) pressure on P. falciparum drug resistance, decreased parasite clearance, and treatment failure remain widespread and evolving in Africa. Integrating molecular surveillance into national malaria programs is essential to guide treatment modalities and support progress toward malaria elimination. Full article

Background: AMR is a public health concern which leads to high global morbidity and mortality. Immunocompromised patients, who are more susceptible to contracting potentially life-threatening infections, are faced with reduced treatment options due to emerging AMR. Ceftolozane/tazobactam is a novel β-lactam/β-lactamase inhibitor which displays effectiveness against resistant Gram-negative infections. Methods: SPECTRA was a multinational, observational study conducted in seven countries including 617 patients who received ≥48 h of ceftolozane/tazobactam. Medical-record data were collected up to 6 months before treatment and 30 days after the final dose or until death. This analysis describes clinical outcomes and healthcare resource use in patients with sepsis or who were immunocompromised, specifically in patients with hematologic malignancy with and without solid tumor, febrile neutropenia, and solid organ transplant patients. Results: Clinical success ranged from 50.0% in patients with hematologic malignancy and solid tumor to 69.4% in 38 patients with febrile neutropenia. All-cause in-hospital mortality was 23.1–42.9%, with the lowest rates in patients with solid organ transplant. ICU admission was 46.4–68.2% across subpopulations (excluding febrile neutropenia) with the lowest rates in patients with hematologic malignancy. ICU length of stay was lowest within transplant patients (9 days) and highest within the hematologic malignancy and solid tumor population (32 days). Conclusions: The results from this sub analysis of SPECTRA showed that ceftolozane/tazobactam was associated with clinical success in the selected immunocompromised and sepsis patient populations and may lead to reduced morbidity, mortality, and healthcare-resource use. Further research is required to standardize treatment protocols and improve patient outcomes. Full article

Background/Objectives: Proton pump inhibitors (PPIs) are widely used, yet questions persist about kidney-related adverse events. We evaluated disproportional reporting of acute kidney injury (AKI) and tubulointerstitial nephritis (TIN) with PPIs in the FDA Adverse Event Reporting System (FAERS) from 2020 to 2025. Methods: FAERS reports were screened using MedDRA Preferred Terms. Report characteristics and annual counts of AKI and TIN reports were summarized. Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Empirical Bayes Geometric Mean (EBGM), and Information Content (IC) were used to assess disproportionality. Results: We identified 13,654 PPI-associated AKI reports and 2409 TIN reports in FAERS (2020–2025). Reports were predominantly from the United States, and missing age/sex information was common. Hospitalization was reported in 12.3% of AKI and 22.7% of TIN reports, and death in 9.1% and 5.0%, respectively. Across all years, disproportionality analyses using ROR, PRR, EBGM, and IC consistently met signal thresholds for both outcomes, with stronger signals in 2020–2022 and attenuation thereafter alongside declining report counts. Conclusions: FAERS data show persistent disproportional reporting of AKI and TIN with PPI use. Causality cannot be inferred, but the findings support cautious, indication-based PPI prescribing and highlight the need for robust studies to clarify renal safety. Full article