Search Results (45,516)

Background: Melanoma is one of the most dangerous types of skin cancer, with its global incidence having surged in recent years. There exists an urgent clinical need for novel therapeutic strategies that combine high efficacy, low toxicity, and multiple mechanisms of action. Methods: This study applies a “Property Optimization and Therapeutic Synergy” strategy, selecting the natural active polysaccharide component, Cordyceps polysaccharides (WCP), as a functional carrier to encapsulate the broad-spectrum chemotherapeutic agent, 10-Hydroxycamptothecin (10HCPT, HCPT). Leveraging non-covalent interactions between the two components, a self-assembly nanoscale drug delivery system (H-W NPs) with high stability and dual antitumor activity was constructed to achieve more efficient and precise antitumor effects. Results: The H-W NPs demonstrated outstanding antitumor efficacy both in vitro and in vivo. The H-W NPs achieved a threefold increase in the inhibition rate against B16-F10 cells compared to free HCPT in vitro and demonstrated a remarkable tumor inhibition rate of 95.08% in vivo. The therapeutic effect may be attributed to the dual antitumor mechanisms of the H-W NPs. Mechanistic studies revealed a synergistic dual-mode of action driving this potent efficacy. Firstly, H-W NPs efficiently induced caspase-3-mediated apoptosis in tumor cells. RNA sequencing analysis suggested the involvement of pathways related to cell cycle arrest and apoptosis. Additionally, H-W NPs promoted the expansion and activation of CD8⁺ T cells in the spleen. These activated cytotoxic T cells reinforced the apoptotic cascade, effectively amplifying the caspase-3-mediated death signal. Conclusions: In summary, the self-assembly nanoscale drug system achieved potent antitumor efficacy through the synergistic action of direct tumor cell killing and immune modulation, offering a highly promising strategy for the development of novel formulations against melanoma. Full article

Colorectal cancer (CRC) is still a leading cause of cancer-related death worldwide, and often, conventional chemotherapeutics exhibit limited efficacy. The hydroalcoholic leaf extract of Cynara cardunculus subsp. cardunculus (wild artichoke) was investigated for its anticancer potential in CRC and effects on enteric pathogens. Nine phenolic compounds were identified by high-performance liquid chromatography with diode-array detection (HPLC-DAD), and spectrophotometric analyses were applied for total phenolic (TPC: 178.33 mg GAE/g) and total flavonoid (TFC: 52.21 mg CE/g) content quantification. The extract exhibited good antioxidant activity on DPPH (IC₅₀: 21.35 μg/mL), ^−•O₂ (IC₅₀: 1.56 μg/mL), and H₂O₂ (IC₅₀: 314.73 μg/mL) and was found to inhibit the growth of pathogenic enteric bacteria, with Enterococcus faecalis and Staphylococcus aureus being the most sensitive. In CaCo-2 CRC cells, the extract induced a concentration-dependent cytotoxicity (IC₅₀: 13.07 μg/mL at 24 h) through increased production of reactive oxygen species (ROS), upregulation of Nrf2, and induction of apoptosis, as evidenced by elevated p53, Bax, cytochrome c, and caspase-3 levels. No necrosis, measured by lactate dehydrogenase (LDH) release, or toxicity to HFF-1 normal fibroblasts was observed at concentrations up to 50 μg/mL. Additionally, CCE demonstrated synergistic effects with 5-FU (combination index < 0.8). This evidence suggests that CCE exhibits selective antitumor activity and chemosensitizing properties, supporting its possible development as an adjunctive agent in CRC therapy. Full article

Background: Multiple sclerosis (MS) is a long-term and unpredictable condition that can cause considerable psychological distress, including perceived stress and death anxiety. Identifying psychological factors that may mitigate these effects is important for improving the psychosocial well-being of patients with MS. This study aimed to examine the mediating role of self-compassion in the relationship between perceived stress and death anxiety in patients with MS. Methods: This cross-sectional, descriptive, and correlational study included 169 Turkish patients diagnosed with MS between October 2024 and April 2025. A regression-based mediation analysis using the Hayes PROCESS macro with bootstrapping was conducted to assess the mediating role of self-compassion. Results: Death anxiety scores were positively but weakly correlated with perceived stress scores (r = 0.172, p = 0.026). Perceived stress scores were strongly and negatively correlated with self-compassion scores (r = −0.704, p < 0.001), whereas self-compassion scores showed a weak-to-moderate negative correlation with death anxiety scores (r = −0.287, p < 0.01). In the mediation model, perceived stress significantly predicted self-compassion (B = −0.087, p < 0.001), and self-compassion significantly predicted death anxiety (B = −1.758, p < 0.001). The direct effect of perceived stress on death anxiety was not statistically significant (B = −0.058; p = 0.344), whereas the indirect effect was significant (B = 0.153; 95% CI [0.079, 0.232]). The total effect was also significant (B = 0.095; p = 0.036). Conclusions: The findings indicate that self-compassion mediates the relationship between perceived stress and death anxiety in patients with MS. Higher levels of self-compassion were associated with lower levels of perceived stress and death anxiety, suggesting that self-compassion may function as an important psychological resource in coping with disease-related stress and death-related concerns. From a clinical and nursing perspective, integrating strategies that support self-compassion within holistic care may contribute to improving the psychosocial well-being of patients with MS. Full article

Background/Objectives: Butyricimonas species constitute a genus of Gram-negative, anaerobic bacteria that are part of the human gut microbiota. Infections caused by these organisms are extremely rare in clinical practice. While uncommon in the general population, their occurrence is higher among immunocompromised individuals or patients with significant underlying health conditions. This review aims to compile and analyze all reported cases of human Butyricimonas infections, focusing on epidemiology, microbiological characteristics, antimicrobial resistance patterns, treatment strategies, and associated mortality. Methods: This review was conducted using data retrieved from the PubMed/MEDLINE and Scopus databases. Results: A total of 14 publications described Butyricimonas infections affecting 14 patients. The mean age of those affected was 66.46 years, and 10 (71.4%) were male. The most frequently reported predisposing factor was a history of malignancy, observed in almost one-third of cases (30.8%). Clinically, fever, organ dysfunction, and shock were the most common presentations (fivecases), followed by sepsis and the need for ICU in fourpatients. In vitro studies indicated that the isolates were generally susceptible to carbapenems and metronidazole, with only high resistance levels observed to penicillin. Among the antimicrobial therapies used, carbapenems were the most commonly administered (50%), followed by piperacillin/tazobactam (41.7%) and metronidazole (33.3%). The overall mortality rate across the cohort was 16.7%, with infection-attributable deaths representing 8.3% of cases. Conclusions: Given the potential of Butyricimonas species to cause severe infections, clinicians should consider this organism in patients presenting with unexplained bacteremia or intra-abdominal infections, particularly in the setting of mucosal disruption or immune dysfunction. Full article

Given the challenges in treating metastatic melanomas, there is a growing need for novel and effective therapeutic strategies. This study aimed to understand molecular mechanisms underlying synergistic effects of a Tempol and ML210 combination in B16F10 murine melanoma cells and to evaluate its therapeutic potential. We hypothesized that this combination would synergistically induce cell death by increasing oxidative stress and triggering ER stress. B16F10 melanoma cells were treated with Tempol and ML210 alone or in combination for 48 h. Cell viability was determined using MTT assay. Oxidative stress was evaluated by measuring Total Antioxidant Status (TAS), Total Oxidant Status (TOS), and intracellular H₂O₂ levels. Apoptotic markers (caspase-3, Bax, Bcl-2) and ER stress proteins (GRP78, GADD153, IRE1α, ATF6) were quantified by ELISA. Combination treatment significantly inhibited cell proliferation compared to monotherapies. Molecular analyses revealed that combination caused depletion of TAS and increase in TOS and intracellular H₂O₂ levels. Furthermore, combination treatment synergistically upregulated ER stress markers and pro-apoptotic proteins while significantly suppressing anti-apoptotic Bcl-2 expression. In conclusion, the combination of Tempol and ML210 synergistically induces cell death in B16F10 melanoma cells by disrupting redox balance and activating ER stress-mediated apoptosis. These findings suggest a potential strategy for melanoma treatment that warrants further in vivo investigation. Full article

Plants utilize cell surface pattern recognition receptors to recognize pathogen-associated molecular patterns (PAMPs) and activate pattern-triggered immunity (PTI) responses. Late blight, caused by the oomycete plant pathogen Phytophthora infestans, poses a major threat to global potato production. The oomycete PAMP, P. infestans cell wall ceramide D, triggers reactive oxygen species (ROS) production in potato and Arabidopsis. It is specifically recognized by the lectin receptor-like kinase RESISTANT TO DFPM-INHIBITION OF ABSCISIC ACID SIGNALING 2 (RDA2) in Arabidopsis. Treatment with P. infestans ceramide D enhances potato resistance against P. infestans. However, the function of RDA2 homologs in potato remains uncharacterized. Herein, potato RDA2 genes were identified through sequence alignment analysis. Their expression levels were subsequently measured in a potato inbred line infected with P. infestans. Notably, transient expression of StRDA2A, but not its kinase-dead mutant StRDA2A^K543M, caused cell death and enhanced disease resistance in Nicotiana benthamiana. Additionally, two RXLR-type effector proteins significantly inhibited StRDA2A-induced cell death. The findings of this study suggest that potato receptor kinase RDA2 proteins confer disease resistance, which is attenuated by RXLR effectors secreted by P. infestans. Full article

Ferroptosis is a recently discovered form of cell death, driven by membrane lipid peroxidation with the contribution of intracellular iron. In recent years, many researchers have discovered the involvement of ferroptotic mechanisms in the etiology of various diseases, including several forms of cancer. Different points in the ferroptotic pathway can be crucial for arising or sustained pathologies, given the contribution of numerous molecular mechanisms concerning membrane channels, several proteins, enzymes, and also kinases. The latter, in particular, seems to be very important in the control of ferroptosis in different manners depending on the pathology. Therefore, many articles in recent years have described how the pathways that involve kinases can determine, control, or alter the physiological ferroptotic contribution. Interestingly, in a tumoral context, oncogenes and tumor suppressor activity affect the correct ferroptotic process directly or indirectly promoted by abnormal kinase activity. Expanding the understanding of how kinases contribute to tumorigenesis by altering ferroptosis mechanisms may provide important insights to improve current anticancer therapies. Furthermore, new data have indicated how kinase-dependent ferroptotic activity may influence the efficacy of immunotherapy. Since one of the major obstacles to this promising anticancer therapy concerns the resistance induced by cancer cells, finding new targets, such as kinases, to improve ferroptosis in tumor cells could open an intriguing door to enhancing immunotherapy and overcoming the current obstacle. Full article

Background: Accurate perioperative cardiovascular risk stratification remains challenging in patients undergoing noncardiac surgery. Although treadmill testing (TMT) is widely used for functional assessment, its ability to identify truly high-risk patients is limited. Natriuretic peptides reflect integrated myocardial stress and may provide complementary prognostic information, particularly in patients with abnormal functional test results. Methods: In this prospective multicenter observational study, 178 patients with at least one Revised Cardiac Risk Index risk factor undergoing noncardiac surgery were included. All patients underwent preoperative TMT and had available N-terminal pro–B-type natriuretic peptide (NT-proBNP) measurements. The primary endpoint was 30-day major adverse cardiac events (MACE), defined as a composite of cardiac death, nonfatal myocardial infarction, myocardial injury after noncardiac surgery, pulmonary edema with heart failure, and clinically significant arrhythmias. Incremental prognostic value was assessed using the area under the receiver operating characteristic curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI), with internal validation using bootstrap resampling. Results: At 30 days, 26 patients (14.6%) experienced MACE, of whom seven experienced more than one event. Log-transformed NT-proBNP was independently associated with perioperative events in parsimonious multivariable models. Elevated NT-proBNP, particularly NT-proBNP ≥ 1000 pg/mL, was independently associated with perioperative events after multivariable adjustment. Importantly, the incremental prognostic value of NT-proBNP was most pronounced in patients with a positive TMT, in whom NT-proBNP improved risk discrimination (ΔAUC = +0.09) and reclassification (NRI = 1.00). In contrast, among patients with a negative TMT, the additional prognostic contribution of NT-proBNP was modest and not statistically significant. Subgroup findings should be interpreted cautiously, given the limited number of events. Conclusions: Preoperative NT-proBNP provides modest but independent incremental prognostic value beyond treadmill testing, with the greatest impact observed in patients with positive TMT results. Although improvements in discrimination were moderate, NT-proBNP may help refine perioperative risk assessment in selected intermediate- to high-risk patients. These findings support a complementary biomarker-based approach to MACE. Full article

Background/Objectives: Penile squamous cell carcinoma (PSCC) is a rare malignancy with a potential major impact on survival. Prognostic assessment remains challenging, particularly in underrepresented eastern European populations, where region-specific evidence is lacking. This paper aimed to identify independent predictors of overall survival in surgically treated patients with PSCC from a Romanian high-volume tertiary center. Methods: This retrospective cohort study analyzed 60 patients who were surgically treated for PSCC between October 2020 and December 2024. Univariate and multivariate Cox proportional hazards regression analyses were performed to identify independent prognostic factors. Results: The mean patient age was 62 ± 12 years. T-stage distribution showed 30% pT1, 35% pT2, 31.67% pT3, and 3.33% pT4, with 55% of patients presenting with nodal metastases. Univariate analyses demonstrated significant associations between lymphovascular invasion (p < 0.001), perineural invasion (p = 0.022), and positive surgical margins (p = 0.030) and risk of death. Multivariate analysis identified three independent prognostic factors: absence of histologically documented urethral invasion (HR 0.32; p = 0.027), T3–T4 disease (HR 8.26; p = 0.005 vs. T1), and N3 stage (HR 3.53; p = 0.030 vs. N0–N1). Patients without urethral invasion demonstrated significantly longer median overall survival (63 months vs. 11 months). The final three-variable prognostic model demonstrated good discrimination (C-index 0.78), providing a potential practical risk stratification tool. Conclusions: Urethral invasion, advanced T-stage, and N3 disease independently predict poor survival in surgically treated PSCC. The identification of urethral invasion as an independent prognostic factor warrants consideration in clinical practice. This is the first study of a Romanian cohort to provide critical data for risk-adapted treatment strategies in underrepresented eastern European populations. Full article

Freshwater ecosystems play an important role in human survival, ecosystem functioning, and biodiversity conservation, yet industrialisation and urbanisation dump over 80% of untreated sewage into them. This inadequate wastewater management leads to enteric pathogens like Escherichia coli, Salmonella, Shigella, Campylobacter, Vibrio cholerae, Pseudomonas aeruginosa, and Legionella pneumophila that are responsible for a wide range of waterborne human diseases globally with extensive morbidity and mortality. The World Health Organization (WHO) estimates that at least 2 billion individuals drink water contaminated with pathogens, resulting in illnesses like cholera, dysentery, and diarrhoea, and approximately 50,000 diarrheal deaths annually. Classical epidemiology approaches are the basis for determining disease burden in public health, but they are limited in their capacity to predict future health risks. Quantitative microbial risk assessment (QMRA) addresses this by estimating the potential health risks of any exposure to microbial pathogens in any environment using four key elements, which include the identification of the microbial hazards, human exposure to the hazard through diverse activities, dose–response relationships, and the estimated risk of the infection. This review summarises information on freshwater pathogens, their occurrence, sources and health implications. The methodological approaches of QMRA in freshwater systems are reviewed with examples drawn from recreational activities, drinking water, and wastewater-impacted environments. Global QMRA studies indicate a wide range of infection risk estimates, reflecting differences in water sources, pathogens, and exposure conditions. Thus, QMRA is known to be a valuable public health tool for freshwater ecosystems, linking microbial contamination dynamics to health risk estimates that support proactive management and policy-relevant decision-making. Full article

Death from acute radiation syndrome (ARS) has been a long-standing threat. Given the current heightened risk of a nuclear event, e.g., a conflict bomb, terror bomb, reactor core dispersion, or recurrent exposure to medical radiation, a systemic treatment to reduce or eliminate ARS death would be beneficial. This study utilizes step-wise progression to (i) identify why lethally irradiated mice die from ARS and (ii) identify a multidrug regimen, administered before or after irradiation, that prevents or treats ARS pathologies to significantly suppress or eliminate ARS death. Lethal blood-borne E. coli septic infection was found in 97% of near-death, irradiated mice; this observation was consistent with the numerous breaches observed in GI histology showing a broken and breached GI epithelium and GI muscularis externa. Our study found (i) a new and clear explanation of why irradiated mice die from ARS; (ii) identified two drugs (PrC-210, ciprofloxacin), which, when administered minutes pre-radiation, conferred 100% survival benefit or 56% when administered a day after irradiation; and (iii) a three-drug regimen (PrC-210, ciprofloxacin, GCSF) that conferred 92% survival benefit when administered 1–2 days after radiation. These drug regimens can be “field-deployed” to field staging areas and home medicine chests to enable the simple, widespread use of the regimens in the face of radiation threat. Full article

As a novel form of cell death, the discovery of cuproptosis presents significant opportunities and challenges for the field of cancer therapy. Notably, polyphenolic compounds have attracted considerable research attention for their ability to induce cuproptosis. These natural compounds not only exhibit marked anti-inflammatory and antioxidant properties, but their polyhydroxy structures also enable effective chelation and transport of copper ions. This provides novel insights into cuproptosis-mediated cancer therapy. Therefore, in this review, we systematically outline copper metabolism, the mechanisms of cuproptosis, and its association with cancer, while providing an in-depth discussion of the effects and mechanisms by which polyphenolic compounds act as copper ionophores to inhibit tumor growth and progression through the induction of cuproptosis. This review indicates the promising potential of polyphenolic compounds in the field of cancer therapy and provides a theoretical basis for therapeutic strategies based on cuproptosis. Full article

Candida species are frequently detected in bile cultures during endoscopic retrograde cholangiopancreatography (ERCP), but their clinical significance and the value of antifungal treatment remain unclear. We performed a retrospective single-center cohort study of adults with growth of Candida species from bile cultures collected by ERCP performed between 2010 and 2023. We compared inpatients who received vs. those who did not receive antifungals within one week of ERCP and a subgroup with acute cholangitis. The primary outcome was a composite of death and invasive candidiasis within one year. Secondary outcomes included death, invasive candidiasis, and rehospitalization. Inverse probability of treatment weighting (IPTW) was performed using baseline characteristics. Adjusted hazard ratios and odds ratios were calculated. Among 197 inpatients, 51 (25.9%) received antifungals. At one year, the primary outcome occurred in 23 of 51 patients (45.1%) receiving antifungal therapy and in 67 of 146 patients (45.9%) who did not; the IPTW-adjusted hazard ratio was 0.93 (95% confidence interval 0.69–1.27; p = 0.66). No significant differences were seen in the acute cholangitis subgroup (n = 117). In this study, antifungal therapy was not associated with improved survival, lower rates of invasive candidiasis, or fewer readmissions. Findings support a conservative, stewardship-oriented approach to managing Candida-positive bile cultures in the absence of invasive disease. Full article

Zoonotic diseases account for approximately one billion cases of illness and millions of deaths globally each year. Increasing contact between humans and competent wildlife hosts elevates the risk of zoonotic spillover. Synanthropic bird species are key players in the transmission of zoonotic pathogens, including flaviviruses such as West Nile virus (WNV) and influenza A viruses like Avian Influenza Virus (AIV). Active surveillance of sentinel birds inhabiting urban areas allows for early detection of emerging pathogens before they cause zoonotic outbreaks. Despite nesting in close proximity to humans, the role of the house martin (Delichon urbicum) in the circulation of flaviviruses and AIV remains poorly understood. Here, we analyzed the presence of antibodies against flaviviruses and AIV in a colony of house martins from southwestern Spain. In addition, we aimed to detect amplicons of the matrix and nucleoprotein genes of AIV using RT-qPCR. While none of the samples tested positive for AIV by RT-qPCR, we observed an AIV seroprevalence of 2.13% based on non-subtyped ELISA. Notably, this is the first report of AIV-seropositive D. urbicum individuals captured in Spain. Moreover, we detected a flavivirus-group seroprevalence of 24.34%, similar to rates reported in the same house martin population between 2018 and 2020, suggesting widespread circulation of flaviviruses within this synanthropic species. These results support the hypothesis that house martins may participate in the transmission of these viruses between wild bird populations and humans in urban environments. Full article

Hepatocellular carcinoma (HCC) is a leading cause of cancer death, characterized by poor prognosis in advanced stages despite available therapies. Dysfunctional mitochondrial can initiate both tumor progression and antitumor immunity. Altered mitochondrial quality control mechanisms, including dynamics, biogenesis, and degradation, contribute to mitochondrial decline supporting hepatocarcinogenesis and tumor survival. Within the immunosuppressive tumor microenvironment, HCC cells shift their metabolism toward glycolysis, which reduces nutrient availability and triggers mitochondrial dysfunction in infiltrating immune cells, leading to T-cell exhaustion and weakened cytotoxic activity. Herein, we discuss how immune checkpoint inhibitors may respond to this exhaustion. While most findings showing that these therapies partially restore mitochondrial bioenergetics in T cells have been conducted in preclinical studies, direct clinical evidence in HCC patients remains limited. By combining current knowledge on mitochondrial metabolism, immune escape, and treatment resistance, we discuss how targeting mitochondrial pathways may help improve immunotherapy responses and support new combination treatment approaches against HCC. Full article