Search Results (1,384)

Objectives. Pancreatic cancer remains one of the most lethal malignancies, and the lack of effective therapies highlights the need for novel treatment strategies. In this study, we evaluated the antitumor potential of the attenuated Streptococcus pyogenes strain GURSA1—engineered to knockout the M protein completely—in a murine model of orthotopically transplanted pancreatic ductal adenocarcinoma. Methods. Female C57Bl/6 mice received intratumoral injections of GURSA1 at doses of 5 × 10⁵ or 1 × 10⁶ CFU per animal. Animal survival, body weight, tumor engraftment, metastasis intensity, tumor mass and volume, and hematological, biochemical, histological, and microbiological parameters were assessed. Results. Intratumoral administration of GURSA1 produced dose-dependent antitumor effects on tumor growth and metastatic burden, but did not result in a statistically significant survival benefit. The strain reduced tumor engraftment, the overall metastasis score, and the incidence of hemorrhagic ascites, while also decreasing tumor mass and volume, with the strongest effects observed at a dose of 1 × 10⁶ CFU. Treatment increased platelet counts and reduced urea and ALT levels toward values observed in intact mice, without affecting anemia, neutrophilia, or changes in AST, alkaline phosphatase, glucose, and total protein levels. Conclusions. These findings demonstrate that GURSA1 attenuates partial reduction in primary tumor burden in vivo and support further investigation of this strain as a potential oncolytic agent. Full article

Background/Objectives:This study evaluated how variations in emulsion composition influence the viability of a probiotic strain Lactobacillus rhamnosus GG within biphasic systems, as well as the overall stability of the resulting formulations. Methods:Eight biphasic emulsions were prepared, each in two versions—with and without a preservative—and subsequently analysed for pH, FTIR spectroscopy, and emulsion type. The viability of L. rhamnosus GG in each formulation was determined using the plate count method. This method is regarded as the reference technique for the quantitative determination of viable bacteria, expressed as colony-forming units (CFUs). Results: The pH indicated that an emulsion with a pH of 4.65 provides the most favorable conditions for L. rhamnosus GG survival, as values below pH 6 promote its proliferation. This acidity aligns with the natural pH of human skin, although it falls slightly below the recommended 4–5 range for topical formulations. FTIR analysis confirmed the structural stability of the emulsions and revealed spectral shifts attributable to the presence of the bacteria. The spectra remained largely consistent throughout the study period, demonstrating good temporal stability. Conclusions: Microbiological evaluation showed that all produced formulations supported bacterial growth, the presence of the preservative did not inhibit viability of L. rhamnosus GG, corroborating findings from an independent assessment. All emulsions were classified as O/W systems, due to the high water content which is advantageous for microbial viability. Furthermore, O/W emulsions are user-friendly, easy to remove, limit the penetration of the active component into deeper skin layers, supporting their suitability for probiotic-based topical applications. Full article

Objectives: The study explores the comparative effects of atorvastatin (ATV), policosanol (PCO), and their combination (ATV+PCO) on metabolic stress and associated organ damage in hyperlipidemic–hyperglycemic zebrafish. Methodology: Hyperlipidemic–hyperglycemic zebrafish (n = 112) were segregated into four groups (n = 28/group) and fed either with a high-cholesterol (HC, 4% w/w) and a high-galactose (HG, 30% w/w) diet, HCHG diet with policosanol (PCO, 0.1% w/w), atorvastatin (ATV, 0.1% w/w), or ATV+PCO (0.1% w/w each). After 12 weeks of supplementation, survivability and embryo production were assessed, along with biochemical and histological examinations of various organs across the groups. Results: Following a 12-week dietary regime, compromised zebrafish survival probability (0.75) was observed in the ATV group, compared to the PCO group (0.89), which increased to 0.82 with combined intake of ATV+PCO. A significantly greater effect of ATV than PCO was observed in reducing the HCHG elevated TC, TG, and LDL-C levels. However, compared to the ATV, a significantly higher HDL-C/TC (%) ratio was spotted in the PCO. Unlike individual supplementation (ATV or PCO), a combined intake (ATV+PCO) proved highly effective in counteracting dyslipidemia, especially by augmenting the HDL-C/TC (%) ratio. Interestingly, no protective effect of ATV was observed against elevated blood glucose levels, oxidative stress, or diminished antioxidant markers. Whereas ATV, in combination with PCO, significantly reduced blood glucose and MDA levels and elevated sulfhydryl content and antioxidant variables (ferric iron reduction ability and paraoxonase activity). ATV+PCO supplementation effectively mitigated HCHG-induced fatty liver, inflammation, ROS generation in the kidney, and brain senescence. Likewise, ATV+PCO improved reproductive health, elevating spermatozoa counts and embryo production ability of zebrafish. Notably, ATV+PCO supplementation significantly inhibited the HCHG-induced eye damage and demyelination in the retina, while ATV alone failed to establish any such changes. Conclusions: The study indicates the combinational therapy of ATV+PCO may offer a possible treatment to counter the metabolic stress and associated events in hyperlipidemic–hyperglycemic zebrafish. Full article

Colostrum is crucial for the survival, development, and the future productivity of newborns. In this study, we evaluated the immunological and microbiological quality of colostrum in 28 Rasa Aragonesa ewes and its relationship with offspring growth during the first 48 h postpartum. Colostrum samples were collected by hand milking immediately after parturition. Immunoglobulin concentration was assessed using Brix refractometry and the samples were categorised according to their immunoglobulin content: high (>24 Brix value), medium (19–23 Brix value), and low (< 19 Brix value). Bacterial counts of aerobes and coliforms were determined with the 3M Petrifilm™ system and the weight of the lambs was recorded using a digital suspension scale. The mean aerobic count (AC) was 3.63 ± 0.69 log₁₀ CFU/mL after 24 h of incubation and the mean coliform count (CC) was 1.59 ± 0.82 log₁₀ CFU/mL after 24 h of incubation. Colostrum with a high immunoglobulin concentration had lower aerobic count after 48 h of incubation than that with poor immunological quality. In relation to coliform counts, similar values were found in all groups. No significant differences were observed in terms of lamb weight gain according to colostrum quality. In conclusion, the immunological quality of colostrum affected the AC determined, but it did not affect CC or early postnatal lamb weight. These findings offer preliminary insights into the usefulness of the Petrifilm™ system in microbiological quality determination of colostrum and its relationship with immunological quality determined in vitro. Full article

Background and Objectives: Interest in biomarkers reflecting the inflammatory nature of Hodgkin lymphoma (HL) is increasing. This study aimed to evaluate the prognostic significance of the Systemic Inflammation Response Index (SIRI) in patients with HL. Materials and Methods: In this study, 105 patients diagnosed with classical HL at the Hematology Clinic of Recep Tayyip Erdoğan University Faculty of Medicine between January 2015 and April 2025 were retrospectively evaluated. Patients were divided into 2 groups according to the SIRI cut-off value. Results: A high SIRI (≥3.78) was significantly associated with advanced disease stage, poor performance status, higher IPS-7 and IPS-3 scores, non-response or partial response to treatment, relapse, and increased mortality. A positive correlation was found between SIRI and IPS 7 scores (p < 0.001, rho = 0.355). In the univariate analysis for progression-free survival (PFS), hemoglobin, IPS 7 score, and SIRI were identified as prognostic factors; in the multivariate analysis, high SIRI was identified as an independent prognostic factor (p = 0.033). In the univariate analysis for overall survival (OS), age, hemoglobin, albumin, lymphocyte count, IPS 7 score, and SIRI were identified as prognostic factors; and, in the multivariate analysis, age over 45 and high SIRI were identified as independent prognostic factors (p = 0.016, p = 0.012). In the survival analysis, high SIRI levels were associated with shorter PFS and OS (p = 0.001, p < 0.001). Additionally, PFS and OS durations were shorter in patients with high IPS 7 scores (p < 0.001, p < 0.001). Conclusions: A high SIRI prior to treatment was identified as an independent prognostic factor in HL patients and was associated with shorter PFS and OS. This index may help identify high-risk patients and assist clinicians in their decision-making processes by enabling individualized risk assessment. Full article

Background: Sepsis is a life-threatening condition characterized by a dysregulated host response to infection. Hemadsorption therapies remove inflammatory mediators and are used as adjunctive treatment in selected patients. Although increased immature granulocyte (IG) levels correlate with inflammatory severity, changes in IG levels after hemadsorption therapy have not been previously evaluated. Methods: This retrospective observational study included patients with sepsis who received hemadsorption therapy in intensive care units between January 2021 and July 2025. Sepsis was diagnosed according to the Surviving Sepsis Campaign 2021 guidelines, and hemadsorption was initiated for persistent hemodynamic instability despite standard therapy. Treatment was performed using a Jafron HA330 cartridge for at least three 6 h sessions. IG count and percentage, inflammatory parameters, lactate levels, and organ dysfunction scores were recorded before and after therapy. ICU mortality was the primary outcome. Statistical analyses included paired comparisons, multivariable logistic regression, and ROC curve analysis. Results: Among 887 patients with sepsis, 196 met the inclusion criteria. The ICU mortality rate was 43.9%, and the median time between pre- and post-treatment measurements was 4 days (IQR: 3–5). After hemadsorption therapy, IG count, IG%, inflammatory parameters, lactate levels, SOFA scores, and vasopressor requirements decreased (all p-values < 0.001). IG parameters were higher in non-survivors. Post-treatment IG# (AUC 0.880) and IG% (AUC 0.812) showed good discriminative performance. Conclusions: Hemadsorption therapy was associated with reductions in IG parameters and inflammatory indicators in sepsis. These findings support IG parameters as complementary measures of immune and inflammatory dynamics during hemadsorption therapy. Accordingly, this study should be regarded as a hypothesis-generating investigation describing associations of IG dynamics in septic patients undergoing hemadsorption, rather than demonstrating treatment efficacy or causal effects. Full article

Background: The characteristics and prognosis of HIV-associated Kaposi sarcoma (KS) among people living with HIV (PLWH), and their association with HHV-8 viral load are not well understood in Japan. Methods: We conducted a retrospective study of PLWH diagnosed with KS at Tokyo Medical University from 2000 to 2023. Results: Seventy cases of KS were identified; HHV-8 viral load data were available for twenty-three of these cases. The median age was 43 years (interquartile range [IQR], 11 years). The median HIV viral load at diagnosis was 150,000 copies/mL (IQR, 560,000 copies/mL). The median CD4 count was 76.0/μL (IQR, 157/μL). Lesions other than those of the skin were observed in the gastrointestinal tract (nine cases, 39.1%), oropharynx (three cases, 13.0%), and bronchial/lung (two cases, 8.7%). The median HHV-8 viral load was 0.0 copies/10⁶ WBC (IQR, 1500 copies/10⁶ WBC). Among the nine deceased PLWH, KS inflammatory cytokine syndrome (KICS) was diagnosed in five PLWH. Older age (≥50 years) and a high HHV-8 viral load (>615 copies/10⁶ WBCs) were significantly associated with worse survival. Conclusion: A high HHV-8 viral load may be a risk factor for mortality in PLWH with KS. Notably, all PLWH diagnosed with KICS in this study died, underscoring the poor prognosis associated with this condition. Full article

Recent developments in discrete probability models play a crucial role in reliability and survival analysis when lifetimes are recorded as counts. Motivated by this need, we introduce the discrete ZLindley (DZL) distribution, a novel discretization of the continuous ZL law. Constructed using a survival-function approach, the DZL retains the analytical tractability of its continuous parent while simultaneously exhibiting a monotonically decreasing probability mass function and a strictly increasing hazard rate—properties that are rarely achieved together in existing discrete models. We derive key statistical properties of the proposed distribution, including moments, quantiles, order statistics, and reliability indices such as stress–strength reliability and the mean residual life. These results demonstrate the DZL’s flexibility in modeling skewness, over-dispersion, and heavy-tailed behavior. For statistical inference, we develop maximum likelihood and symmetric Bayesian estimation procedures under censored sampling schemes, supported by asymptotic approximations, bootstrap methods, and Markov chain Monte Carlo techniques. Monte Carlo simulation studies confirm the robustness and efficiency of the Bayesian estimators, particularly under informative prior specifications. The practical applicability of the DZL is illustrated using two real datasets: failure times (in hours) of 18 electronic systems and remission durations (in weeks) of 20 leukemia patients. In both cases, the DZL provides substantially better fits than nine established discrete distributions. By combining structural simplicity, inferential flexibility, and strong empirical performance, the DZL distribution advances discrete reliability theory and offers a versatile tool for contemporary statistical modeling. Full article

Background: Mucosal malignant melanoma (MMM) is a rare and aggressive malignancy with a dismal prognosis. While the Systemic Immune-Inflammation Index (SII) has emerged as a prognostic marker in various solid tumors, its specific value in MMM remains undefined. This study investigated the association between pretreatment SII and overall survival (OS) in patients with MMM. Methods: We retrospectively analyzed 106 adults with histologically confirmed MMM treated at six oncology centers in Turkey between 2005 and 2025. The baseline SII was calculated as platelet × neutrophil/lymphocyte counts obtained before definitive treatment. A receiver operating characteristic (ROC) analysis identified an optimal SII cutoff of 776 for overall survival (OS), defining low (<776) and high (≥776) SII groups. Results: Gastrointestinal and head and neck mucosa were the most frequent primary sites, and one-third of patients presented with metastatic disease. The median OS for the entire cohort was 23.3 months. Patients with a high versus low SII had a shorter OS (16.2 vs. 35.2 months; HR 2.71, 95% CI 1.67–4.40; p < 0.001). In multivariable analysis, a high SII (HR 1.88, 95% CI 1.12–3.14; p = 0.016), gastrointestinal primary site (HR 1.99, 95% CI 1.23–3.23; p = 0.005), and metastatic disease at diagnosis (HR 4.01, 95% CI 2.32–6.94; p < 0.001) independently predicted a worse OS. Conclusions: The SII is a novel, independent prognostic biomarker in MMM. Elevated pretreatment SII correlates with aggressive clinicopathologic features and inferior survival. As a readily accessible and cost-effective marker, SII may facilitate improved risk stratification in routine clinical practice for MMM patients. Full article

Background: Thrombocytopenia (platelet count < 100 × 10⁹/L) occurs in 20–40% of critically ill patients with sepsis and is associated with adverse outcomes. Most prior studies have treated thrombocytopenia as a static risk indicator rather than a dynamic process. We investigated whether platelet recovery within 7 days provides independent prognostic information in patients with sepsis. Methods: We performed a retrospective cohort study using the MIMIC-IV database. Among 22,513 adults with sepsis admitted to intensive care units, 5401 developed thrombocytopenia within 24 h of admission and had sufficient follow-up data. The primary exposure was sustained platelet recovery to ≥100 × 10⁹/L within 7 days. The primary outcomes were 28-day and in-hospital mortality. Propensity-score matching and overlap weighting were used to adjust for demographic characteristics, comorbid conditions, illness severity, and organ-support therapies. Results: Among 5401 septic ICU patients with thrombocytopenia, 3193 (59%) achieved platelet recovery within 7 days. A total of 2056 patients (38%) recovered by day 3, and 1137 (21%) recovered between days 4 and 7. After multivariable adjustment, platelet recovery was independently associated with markedly lower mortality (adjusted risk ratio, 0.56; 95% CI, 0.53–0.67 for in-hospital death; and 0.60; 95% CI, 0.53–0.67 for 28-day death) and more than a doubling of survival time (adjusted ratio, 2.08; 95% CI, 1.65–2.63). Early and intermediate recovery conferred similar benefits. Higher baseline platelet counts, antiplatelet therapy, and heparin use were associated with recovery, whereas cirrhosis, greater illness severity, and continuous renal replacement therapy were associated with non-recovery. Conclusions: In patients with sepsis and thrombocytopenia, platelet recovery within 7 days was a strong and independent predictor of survival. Exploratory timing-stratified analyses yielded similar associations across subgroups. These findings support platelet recovery as a useful prognostic marker reflecting broader physiologic stabilization in sepsis. Full article

Lymph node evaluation is a central determinant of oncologic quality in the surgical management of non-small-cell lung cancer (NSCLC). Accurate assessment of hilar and mediastinal lymph nodes underpins pathologic staging, informs postoperative treatment decisions, and remains essential for prognostic stratification and assessment of resection completeness. Although international guidelines provide clear recommendations, real-world data consistently demonstrate substantial variability in lymph node staging practices, with inadequate evaluation frequently observed across institutions and surgical settings. Insufficient nodal assessment, manifested as the omission of mediastinal staging, limited station sampling, or low lymph node yield, is associated with reduced nodal upstaging, inappropriate omission of adjuvant therapy, higher recurrence rates, and inferior long-term survival. Contemporary guidance from major societies, including the National Comprehensive Cancer Network, European Society of Thoracic Surgeons, International Association for the Study of Lung Cancer, and the Commission on Cancer, has increasingly converged on a station-based definition of adequacy, emphasizing systematic evaluation of both N1 and N2 nodal stations rather than reliance on absolute node counts alone. In parallel, preoperative mediastinal staging algorithms have evolved toward routine use of endobronchial and esophageal ultrasound as first-line invasive modalities, reserving surgical mediastinoscopy for selected high-risk or inconclusive cases. Evidence from randomized trials, population-level databases, and meta-analyses indicates that thorough nodal assessment improves staging accuracy and survival, while recent data support the selective use of lobe-specific or tailored lymphadenectomy in carefully staged, low-risk early disease. Finally, emerging quality improvement interventions, including standardized specimen handling, operative checklists, and multidisciplinary feedback mechanisms, have demonstrated measurable improvements in guideline adherence and patient outcomes. This narrative review integrates contemporary evidence and guideline recommendations to outline a practical framework for implementing reliable, high-quality lymph node staging in modern lung cancer surgery. Full article

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL); however, a significant proportion of patients fail to achieve a durable response, underscoring the need for reliable predictive biomarkers. We characterize T-lymphocyte subpopulations in apheresis samples from 23 r/r large B-cell lymphoma (LBCL) patients who received axicabtagene ciloleucel (axi-cel) to identify pre-treatment cell biomarkers associated with CAR T-cell kinetics and clinical outcomes. Immunophenotyping of T-cells within fresh apheresis samples and monitoring of circulating CAR T-cells were performed by multiparametric flow cytometry. The median peak CAR T-cell count was 45.2 CAR T-cells/mL. Strong CAR-T expanders (≥45.2 CAR T-cells/mL) exhibited higher values of both CD4⁺ (p = 0.011) and CD8⁺ (p = 0.023) central memory T-cells (T_CM; CCR7⁺CD45RA⁻), as well as lower proportions of CD8⁺CD38⁺ T-cells in apheresis samples. In apheresis, a cut-off value of >4.3% of CD8⁺ T_CM predicted strong CAR-T expansion (AUC: 0.80; p = 0.023) and superior progression-free survival (p = 0.04) compared with patients who had CD8⁺ T_CM below the cut-off. Our data suggest that high frequencies of CD8⁺ T_CM cells in apheresis samples may represent a promising pre-treatment biomarker associated with strong CAR-T expansion and superior clinical outcome in r/r LBCL patients following axi-cel. Full article

Adherent-invasive E. coli (AIEC) is closely related to inflammatory bowel disease (IBD). However, its pathogenic mechanism has not yet been fully elucidated. Using a BLASTP search, we discovered that the amino acid sequence of a putative protein (UFP37798.1) in the AIEC LF82 strain is highly homologous to some regulators in the SlyA family. We named it EruA. We displayed the secondary structures of EruA using bioinformatics, overexpressed the His₆-tagged EruA protein using SDS-PAGE, and dissected the genetic organization of the eruA chromosomal region using 5′RACE. We constructed an eruA deletion mutant (ΔeruA) and a complementary strain (CΔeruA) of the LF82 strain. The transcriptomes of wild-type (WT) and ΔeruA bacteria were compared using RNA sequencing and qRT-PCR, thereby identifying 32 differentially expressed genes (DEGs). Based on YASARA software and EMSA analysis, EruA directly binds to the consensus sequences (P_fimA and P_tnaB) in the promoter region of the fimA and tnaB genes from these DEGs. By using a super-resolution confocal microscope (SCM), counting CFUs of colonies on plates, indole quantification, and crystal violet staining of biofilms adhered to tubes or 96-well plates, we found that EruA activates the fimA to promote bacterial adhesion to intestinal epithelial cells and activates the tnaB to enhance bacterial indole production and biofilm formation. Moreover, EruA helps AIEC resist environmental stress and enhances bacterial survival within macrophages as well as loading in mouse tissues. Notably, EruA promotes AIEC colonization in the colons of mice and exacerbates intestinal inflammation caused by bacterial infection in mice with DSS-induced inflammatory colitis, manifested by weight loss, colon length shortening, and pathological changes in colon tissues. Therefore, EruA plays a key role in the pathogenicity of AIEC. Full article

Background/Objectives: Some patients initially diagnosed with non-high-risk neuroblastoma follow a high-risk clinical course and have poor survival compared to those initially diagnosed with high-risk neuroblastoma. We aimed to identify molecular aberrations present at diagnosis that may explain the high-risk clinical course in this patient group. Methods: Data were collected from non-high-risk neuroblastoma patients diagnosed at our center between 2014 and 2021. Segmental chromosomal aberrations (SCAs), gene amplifications and mutations at diagnosis were detected by a single-nucleotide polymorphism array and next-generation sequencing. Telomere maintenance mechanisms (TMMs) were investigated using fluorescent in situ hybridization, whole genome sequencing (WGS) and RNA sequencing. SCA counts were imputed by using multiple imputation. Results: The total cohort included 89 patients. Thirteen patients developed a high-risk clinical course (group A) due to progression (n = 4), local relapse (n = 4), refractory disease (n = 3) or metastases (n = 2). Seventy-six patients followed a non-high-risk clinical course (group B). An SCA profile (≥1 SCA) was present in 76% of patients in group A and only 15% in group B (p = 0.004). 1p deletion was associated with a high-risk clinical course (p = 0.034). Gains of 1q, 2p and 17q, and deletions of 4p and 11q were more common in group A. After imputation, SCA count was associated with a high-risk clinical course (pooled OR 1.256 with 95% CI 1.006–1.568, p = 0.044). Two patients, both group A, exhibited MDM2/CDK4 amplification. Alternative lengthening of telomeres (ALT) was activated in 57% of group A. Conclusions: SCA profile and 1p deletion are associated with a high-risk clinical course. ALT activation, MDM2/CDK4 co-amplification, SCA count, gains of 1q, 2p, and 17q, and deletions of 4p and 11q may also be relevant molecular markers. Larger studies are needed for confirmation of these findings. Full article

Traditional villages are vital carriers of cultural heritage and key foundations for rural revitalization and sustainable development, yet rapid urbanization increasingly threatens their survival, making it necessary to clarify their spatial distribution and driving mechanisms to support effective conservation and rational utilization. Yunnan Province, home to 777 nationally recognized traditional villages and the highest number in China, offers a representative context for such analysis. Methodologically, this study uses a 12 km × 12 km geographic grid (3005 cells) rather than administrative units. The count of catalogued traditional villages in each cell is taken as the dependent variable, and nine indicators selected from five dimensions (traffic accessibility, natural topography, climatic conditions, socioeconomic factors, and historical and cultural factors) serve as explanatory variables. Assuming that relationships between villages and their environment are spatially nonstationary and operate at multiple spatial scales, we combine spatial autocorrelation analysis with a multiscale geographically weighted regression (MGWR) model to detect clustering patterns and estimate location-specific coefficients and bandwidths. The results indicate that: (1) traditional villages in Yunnan exhibit significant clustering, with over 60% concentrated in Dali, Baoshan, Honghe, and Lijiang; (2) the spatial pattern follows a “more in the northwest, fewer in the southeast, dense in mountainous areas” distribution, shaped by both natural and socioeconomic factors; (3) natural geographic factors show the strongest associations, with sunshine duration and water availability strongly promoting village presence, while slope exhibits regionally differentiated effects; (4) socioeconomic development and transportation accessibility are generally negatively associated with village distribution, but in tourism-driven areas such as Dali and Lijiang, road improvements have facilitated protection and revitalization; and (5) historical and cultural factors, particularly proximity to nationally protected cultural heritage sites, contribute to spatial clustering and long-term preservation. The MGWR model achieves strong explanatory power (R² = 0.555, adjusted R² = 0.495) and outperforms OLS and standard GWR, confirming its suitability for analyzing the spatial mechanisms of traditional villages. Finally, the study offers targeted recommendations for the conservation and sustainable development of traditional villages in Yunnan. Full article