Search Results (62,339)

We introduce the one-parameter bounded p-exponential distribution on $(0,p+1)$, which includes the uniform model as a special case and converges pointwise to the exponential law as $p\to \infty$. Closed-form expressions are derived for the CDF and PDF, the survival function, an explicit increasing-failure-rate hazard function, the quantile function (enabling inversion-based simulation), moments, and entropy, along with a constructive scaled beta or Kumaraswamy representation. We also establish stochastic ordering with respect to p in stop-loss and increasing convex order, formalizing how dispersion varies with the parameter while preserving the mean scale. Inference is discussed under parameter-dependent support, a non-regular setting, and we develop and compare several estimation procedures, including a likelihood-based boundary MLE, a variance-matching method-of-moments estimator, and Bayesian estimation under a gamma prior implemented via numerical quadrature or MCMC. Monte Carlo simulation studies evaluate finite-sample performance and interval behavior, and two real-world applications in survival and reliability analysis illustrate competitive goodness-of-fit relative to standard benchmark models. Full article

Background: Urothelial bladder cancer (UBC) is a molecularly heterogeneous disease, and most sequencing studies have relied on bladder-specific or solid tumor-restricted panels. Whether broader pan-cancer assays provide additional clinically relevant information remains unclear. Methods: We performed targeted next-generation sequencing using an extended gene panel on tumor samples from 100 patients with UBC treated at a tertiary center. Somatic single-nucleotide variants, small insertions/deletions, copy-number alterations, and gene co-occurrence patterns were analyzed and correlated with clinicopathological features, disease-free survival (DFS), and overall survival (OS). Results: Recurrent alterations were identified in FGFR3 (≈50%), TP53 (≈35%), STAG2 (≈25%), and PIK3CA (≈20%), consistent with established molecular pathways in UBC. Less frequent but potentially actionable alterations, including mutations in BRCA1 and ALK, were also detected, reflecting the extended coverage of the panel. TP53 mutations were independently associated with worse OS, whereas STAG2 alterations were associated with improved OS, particularly in tumors without concurrent TP53 mutations. FGFR3 mutations showed a favorable but non-independent trend. No gene retained independent prognostic significance for DFS. Co-occurrence analysis revealed an FGFR3/PIK3CA-associated pathway and relative mutual exclusivity between FGFR3 and TP53. Copy-number alterations were modest overall. Comparison with TCGA data demonstrated a higher frequency of FGFR3 alterations in our cohort, likely reflecting the larger proportion of non–muscle-invasive tumors. Conclusions: Pan-cancer targeted sequencing provided a comprehensive genomic landscape of UBC, capturing canonical drivers and additional alterations that may be overlooked by bladder-restricted assays. The identification of TP53 and STAG2 as prognostic markers highlights the potential value of broader genomic profiling for biologically informed risk stratification in urothelial bladder cancer. Full article

The SERPINE1 gene encodes the serine protease inhibitor plasminogen activator inhibitor type-1 (PAI-1), a major negative regulator of the plasmin-dependent pericellular proteolytic cascade and a crucial determinant in the program of stromal remodeling. Recent omics approaches confirmed that high tumor SERPINE1 levels are prognostic for poor disease outcomes and shorter disease-free survival in various malignancies. Kinetic analysis of biomarkers of cell cycle transit in growth-synchronized p53 dual mutant human keratinocytes confirmed that PAI-1 transcription occurred early after growth activation of quiescent (G₀) cells and prior to G1 entry. Previous evidence has confirmed that differential residence of USF family members (USF1→USF2 switch) at the PE2 region hexanucleotide E box motif (CACGTG) in the SERPINE1 proximal promoter characterizes the G₀→G₁ transition period and the transcriptional status of the SERPINE1 gene. A consensus PE2 E box motif (5′-CACGTG-3′) at nucleotides −566 to −561 is required for USF occupancy of the PE2 E box and serum-stimulated SERPINE1 transcription. Interference with USF2 occupancy of the PE2 E Box site by a double-stranded PE2 “decoy”, or induced expression of a dominant-negative USF (A-USF) construct, attenuate serum- and TGF-β1-stimulated SERPINE1 synthesis. Tet-Off activation of an A-USF insert reduced both PAI-1 and PAI-2 transcripts while increasing the fraction of proliferating (Ki-67⁺ cells). Conversely, overexpression of USF2 or adenoviral delivery of a PAI-1 vector inhibited HaCaT colony expansion. These findings are discussed in this review and collectively suggest that the USF1→USF2 transition at the PE2 E box site and subsequent SERPINE1 transcription impact serum-stimulated keratinocyte growth and, likely, cell cycle progression. Full article

Background: This study aims to evaluate the real-world efficacy and safety of dalpiciclib in patients with hormone receptor-positive (HR+) advanced breast cancer and explore the impact of different clinical characteristics on treatment outcomes. Methods: This was a two-center, retrospective cohort study involving 76 patients treated with dalpiciclib between January 2022 and June 2024 at two affiliated hospitals of Anhui Medical University in China. Data on progression-free survival (PFS), adverse events, and key clinical factors were collected and analyzed. Kaplan–Meier estimates were used for statistical analysis. Results: The median PFS (mPFS) for the entire cohort was 12.00 months (95% CI: 10.09–13.91 months). Patients receiving dalpiciclib as first-line therapy had significantly better outcomes (mPFS: 17.00 months, 95% CI: 9.19–24.81 months) than those receiving later-line therapy (p < 0.001). Patients with prior exposure to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and those with endocrine resistance had poorer outcomes. Multivariate Cox proportional hazards regression analysis confirmed that earlier treatment line (HR for second-line vs. first-line: 3.89, p = 0.015; HR for third-line or later vs. first-line: 5.56, p = 0.006) and prior CDK4/6i treatment (HR = 3.42, p = 0.040) were independent predictors of PFS. The most common adverse events were hematologic toxicities, including leukopenia (76.6%) and neutropenia (72.4%), mostly grade 1–2. No febrile neutropenia cases were reported, indicating a manageable safety profile. Conclusions: Dalpiciclib combined with endocrine therapy is associated with favorable efficacy and safety in real-world settings, with early-line treatment and lower tumor proliferative activity associated with better outcomes. While findings suggest potential for clinical application, further large-scale prospective studies are needed to validate its effectiveness in different patient subgroups and optimize treatment strategies. Full article

Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense desmoplastic stroma that actively drives malignant progression. However, the specific contributions of E3 ubiquitin ligases within the cancer-associated fibroblast (CAFs) compartment to the PDAC landscape remain largely elusive. Methods: Pancreatic tissue samples were collected from the First Affiliated Hospital of Harbin Medical University. Gene expression was analyzed by RT-PCR, and single-cell RNA sequencing (scRNA-seq) data were integrated for cell subtype identification. Kaplan-Meier survival analysis assessed gene expression and survival. Pseudotime analysis and CellChat evaluated fibroblast transitions and intercellular communication. Cell lines were transfected with RBX1 siRNAs, and protein levels were measured by Western blotting. Proliferation was assessed using colony formation and EdU staining. Statistical analyses were performed using R (v4.4) and GraphPad Prism 8.0. Results: Thirteen E3 ubiquitin ligases were significantly upregulated in PDAC and correlated with unfavorable clinical outcomes. Among these, RBX1 was identified as a candidate preferentially expressed in CAF populations and strongly associated with poor prognosis. Single-cell transcriptomic profiling and pseudotime analysis further revealed that RBX1-positive CAFs were predominantly involved in extracellular matrix remodeling and pro-tumorigenic pathways. Functional assays demonstrated that silencing RBX1 markedly inhibited PAAD cell proliferation and tumor growth both in vitro and in xenograft models. Mechanistically, RBX1 was found to upregulate Tenascin C (TNC) expression, while ectopic overexpression of TNC partially rescued the growth suppression induced by RBX1 knockdown. Conclusions: Our findings suggest that RBX1 facilitates PDAC progression through a CAF-related mechanism and TNC regulation, positioning RBX1 as a potential therapeutic target for PDAC intervention. Full article

Background: Oral gene delivery vectors, such as those derived from attenuated Salmonella strains, have shown great promise in oral vaccine development against various human diseases. Human cytomegalovirus (CMV) is a herpesvirus capable of affecting the global population and establishing lifelong infection. Generation of an anti-CMV vaccine is a major public health priority. Methods: This study reports the development of a novel weakened Salmonella strain, S713, and the effects of this strain as an oral vaccine candidate against murine cytomegalovirus (MCMV) infection in mice. Results: The weakened Salmonella strain S713 was attenuated in killing mice in vivo by >500,000 fold compared to a clinical strain, following intragastric instillation in animals. Mice intragastrically immunized with S713 that produced MCMV M24 protein exhibited elevated anti-MCMV mucosal IgA and serum IgG titers and enhanced anti-MCMV T cell responses. Moreover, immunization with the generated vaccine in MCMV-challenged mice not only suppressed viral replication in lungs, spleens, livers, and salivary glands but also increased animal survival. Conclusions: These findings demonstrate strong and effective anti-MCMV immune responses induced by the generated M24-expressing vaccine. Furthermore, our results reveal the promising capability of weakened strain S713 expressing different CMV proteins to act as oral vaccines against CMV infections and diseases. Full article

Lymphoma is the most common neoplastic disease in cats; however, lomustine has been insufficiently evaluated as a first-line chemotherapeutic agent. This study assessed treatment response, survival, and progression-free interval (PFI) in cats with intermediate-to-large cell lymphoma treated with lomustine and prednisolone as first-line therapy. Twenty-eight cats with cytologically or histopathologically confirmed lymphoma received lomustine (10 mg/cat every 3 weeks) and prednisolone until disease progression or unacceptable toxicity. All cats were feline leukemia virus- and feline immunodeficiency virus-negative, with a mean age of 9.93 years; alimentary lymphoma was most common (75%). Treatment responses included complete response (CR, 5/28), partial response (5/28), stable disease (11/28), and progressive disease (7/28). The median PFI for all cats was 51 days, and the median survival time was not reached during the study period. No significant associations were identified between PFI or survival and age, sex, packed cell volume, drug dosage, tumor size, or tumor location. Cats achieving CR showed significantly prolonged PFI compared with cats with other responses (median, 561 vs. 42 days; p = 0.0004), and overall survival was also significantly longer (p = 0.0009). These findings may serve as a clinically meaningful guide for the use of lomustine and prednisolone in the treatment of feline lymphoma. Full article

Background and Objectives: High-grade serous ovarian carcinoma (HGSOC) remains the most lethal gynecologic malignancy, with outcomes heavily dependent on early diagnosis and timely multimodal treatment. The COVID-19 pandemic profoundly disrupted oncologic care, leading to diagnostic delays, modified treatment algorithms, and deferred surgeries. This study aimed to assess how these disruptions influenced disease presentation, surgical complexity, and postoperative outcomes during the pandemic and post-pandemic periods in a Romanian tertiary oncology center. Materials and Methods: A retrospective, single-center cohort analysis was conducted on 112 patients with histologically confirmed HGSOC who underwent surgical treatment between 26 February 2020 and 25 February 2024. The cohort was divided into two equal groups: a pandemic cohort (2020–2022) and a post-pandemic cohort (2022–2024). Clinical, pathological, and therapeutic parameters were compared, including FIGO and T staging, surgical duration, ICU admissions, and treatment intervals. Results: The post-pandemic period was marked by a significant rise in advanced-stage presentations (FIGO IV: 17.8% vs. 33.9%, p = 0.003), peritoneal carcinomatosis (58.9% vs. 82.1%, p = 0.004), and multiorgan invasion (7.1% vs. 16.0%, p = 0.039). Mean operative time increased significantly post-pandemic (94.0 ± 36.3 vs. 123.5 ± 52.5 min, p = 0.003), as did ICU admissions (35.7% vs. 60.7%, p = 0.002). While the number of neoadjuvant and adjuvant chemotherapy cycles remained consistent between cohorts, a greater surgical complexity and longer postoperative recovery characterized the post-pandemic cases, suggesting cumulative disease progression and increased treatment demands. Conclusions: The findings indicate an association between the post-pandemic period and more advanced disease profiles at presentation, as well as increased surgical complexity, highlighting potential long-term effects of healthcare disruption. These results highlight the necessity for resilient cancer care systems emphasizing early detection, multidisciplinary coordination, and adaptive treatment models to mitigate future systemic disruptions and preserve survival outcomes in women with HGSOC. Full article

Background/Objectives: Atezolizumab plus bevacizumab (Atez/Bev) is a standard treatment for unresectable hepatocellular carcinoma (HCC), but its anti-tumor efficacy remains limited. Combining intrahepatic locoregional treatment (IHLRT) with Atez/Bev has been explored as a strategy to overcome this limitation. This study aimed to clarify the significance of IHLRT in Atez/Bev treatment for unresectable HCC. Methods: Eighty consecutive patients with unresectable HCC treated with Atez/Bev were retrospectively analyzed. IHLRT was performed in patients with residual viable hepatic lesions amenable to locoregional treatment during Atez/Bev therapy. Anti-tumor response was evaluated by RECIST; and progression-free survival (PFS), overall survival (OS), potential biomarkers, and contributing factors to OS were also assessed. Results: IHLRT was selectively performed in 20 patients based on individual clinical conditions. Pretreatment characteristics were comparable between patients who did and did not receive IHLRT. Both best and initial tumor responses were superior in the IHLRT group, and PFS was significantly longer (16.2 vs. 8.4 months, p = 0.019), with comparable rates of severe treatment-related adverse events. On multivariate analysis, hepatic reserve function, objective response, neutrophil-to-lymphocyte ratio (NLR) and IHLRT were independent predictors of OS (HR: 2.17, 3.13, 0.58, and 1.62; p = 0.02, <0.01, 0.03 and 0.03, respectively). Although high NLR was a negative predictive factor, IHLRT appeared to mitigate the negative prognostic impact of an elevated NLR. Conclusions: On-demand, selective IHLRT during Atez/Bev treatment is well tolerated and provides superior and more durable tumor control, particularly in patients achieving an initial objective response. Full article

Background: Hepatitis B virus infection has been linked to liver cancer and may influence metastasis in other malignancies, but its role in gastric cancer liver metastasis (GCLM) is unclear. Methods: We retrospectively analyzed 776 gastric cancer patients with HBV testing. HBV infection was defined as HBsAg+ (chronic HBV, CHB) or HBsAg− with HBcAb/HBeAb+ (occult HBV, OHB). Among the 776 patients, 300 (38.6%) were classified as HBV+. The association between HBV infection and GCLM was evaluated, and propensity score matching (PSM) was performed to adjust for age and gender. Furthermore, the impact of HBV infection on overall survival (OS) was analyzed. Results: GCLM occurred in 19.5% of patients. HBV+ patients had a higher GCLM prevalence than HBV− patients (25.3% vs. 15.8%; p = 0.001), persisting after PSM (25.3% vs. 15.3%; p = 0.002). HBV infection was an independent risk factor for GCLM (OR = 2.563, p < 0.001). Both OHB and CHB groups showed significantly higher GCLM rates than HBV− patients in univariate and multivariate analyses. However, OS did not differ between groups (p = 0.737). Conclusion: HBV infection significantly increases the risk of liver metastasis in gastric cancer. Enhanced surveillance for liver metastasis is warranted in these patients. Full article

The compatibility of insecticides with biological control agents is a critical component of integrated pest management (IPM). In this study, the lethal and sublethal effects of acrinactrin, chlorantraniliprole, flupyradifurone, pyriproxyfen, spinosad, and spiromesifen on the egg stage of Orius niger (Wollf) (Hemiptera: Anthocoridae) were evaluated under laboratory conditions. Egg hatchability, immature survival, reproductive performance, and population parameters were analyzed using the age-stage, two-sex life table. Egg hatchability was lowest in the acrinactrin treatment (51%) and highest in the pyriproxyfen treatment (93%). Nymphal survival varied from 0% to 80%, with acrinactrin causing complete mortality and a significant reduction in spinosad, while the highest nymphal survival and population growth was recorded in spiromesifen treatment. The intrinsic rate of increase (r, day⁻¹) was 0.00, 0.05, 0.05, 0.08, 0.004, and 0.06 for acrinactrin, chlorantraniliprole, flupyradifurone, pyriproxyfen, spinosad, and spiromesifen, respectively, while fecundity (F, eggs female⁻¹) values were 0, 15.20, 15.83, 42.32, 10.37, and 21.85, respectively. According to the International Organization for Biological Control (IOBC) classification, acrinactrin was harmful, spinosad moderately harmful, and the remaining insecticides slightly harmful to O. niger eggs. Pyriproxyfen and spiromesifen were the most compatible with IPM programs. Caution is warranted for chlorantraniliprole due to its effects on reproductive parameters, whereas spinosad and acrinactrin should be avoided on O. niger eggs. Full article

The interplay between TP53 alterations and Wnt/β-catenin signaling in colorectal cancer (CRC) remains unclear regarding mismatch repair (MMR) status, tumor budding (TB), poorly differentiated cluster (PDC), and prognosis. We analyzed 146 resected CRC cases, quantifying p53, Wnt3, and β-CTN indices and assessing MMR by PMS2 and MSH6 immunohistochemistry. p53 overexpression was associated with younger patients, left-sided tumors, nodal metastasis, and advanced stage, whereas wild-type tumors showed more mucinous differentiation. Deficient MMR was enriched among wild-type p53 cases. Principal component analysis identified distinct axes defined by p53, Wnt3, and β-CTN. Despite comparable Wnt3 levels, nuclear β-CTN accumulation was enhanced in tumors with aberrant (overexpression or null) p53 tumors, with increased TB and PDC indices. Low nuclear β-CTN independently predicted recurrence in stage I–III disease and worse overall survival in proficient MMR tumors (HR 3.07 and 2.52; p = 0.03 for both). A composite score integrating p53 binary status (aberrant vs. wild) with Wnt3 and whole β-CTN indices predicted survival beyond stage; each 1-point increase conferred a 2.56- and 1.77-fold higher risk of cancer-specific and overall mortality (p = 0.004 and 0.04). These findings suggest that p53 dysfunction is associated with alterations in Wnt/β-CTN signaling and that integrating signaling markers with staging may improve prognostic assessment in colorectal cancer. Full article

For deep-draft cylindrical platforms with a large annular column boot, the influence of the column boot diameter-to-height ratio (d/h) on motion performance remains unclear. This study investigates the effect of d/h on platform hydrodynamics while keeping the main body geometry, displacement, and draft unchanged. A hybrid numerical model validated against tests is adopted: STAR-CCM+ free-decay simulations identify equivalent linear damping, and ANSYS AQWA predicts hydrodynamic coefficients, response amplitude operators, and coupled time-domain responses under a 100-year survival sea state in the western South China Sea. Increasing d/h substantially increases heave added mass and added pitch moment of inertia, leading to longer natural periods and higher damping in heave and pitch. However, its effect on motion responses is non-monotonic and strongly response-dependent. As d/h increases, the responses are initially reduced markedly. The minimum surge and heave responses occur at d/h = 2.39 and 4.67, with reductions of about 34.0% and 87.2%, respectively, while the pitch response is already reduced by about 67.3% at d/h = 7.22. Further increases in d/h may weaken surge and heave mitigation while providing limited additional benefit for pitch. These findings provide qualitative understanding and quantitative guidance for response-oriented column boot design and optimization of similar platforms. Full article

Background/Objectives: Adequate cardiopulmonary resuscitation (CPR), defibrillation, and treatment of reversible causes are essential for improving the survival of patients suffering from out-of-hospital cardiac arrests (OHCAs). The Advanced Life Support (ALS) algorithm includes reversible causes for cardiac arrest. This study aimed to develop an interactive mobile checklist to identify reversible causes of OHCA (REBECCA) and evaluate their usability and usefulness among emergency physicians. Methods: This mixed-methods study was conducted at the Emergency Medical Service Vienna, Austria. All participants were emergency physicians from the Medical University of Vienna. An interactive mobile checklist was developed using a participatory design approach involving a focus group of 10 emergency physicians. Usability and applicability were assessed using structured questionnaires. Descriptive statistics were used to summarize participant characteristics and evaluation outcomes. Results: Among the included participants, 70% were specialists with a median prehospital experience of 2.0 (1.0–4.3) years. Although most participants were confident about their level of professional experience with OHCA, 85% still found the checklist to be helpful. The majority of the participants preferred the digital checklist over the paper-based checklist and appreciated its integration with the point-of-care ultrasound (POCUS) application. Although the participants did not communicate a significant need for further details on most causes, a small majority favored more information on intoxication and electrolyte disorders. Conclusions: The majority of the included emergency physicians found the REBECCA checklist helpful regardless of training level, whereas almost no physician needed further detailed information on the reversible causes. Our findings underscore the potential importance of future investigations aiming to reduce the cognitive load of emergency physicians during OHCA scenarios. Full article

To improve the vitrification efficiency of bovine germinal vesicle (GV) oocytes, the use of hydroxyapatite (HA) nanoparticles as a novel cryopreservation additive represents a promising approach. This study aimed to investigate the effects of HA nanoparticles and permeable cryoprotective agents (CPAs) on the ultrastructure, developmental competence, and gene expression of bovine GV oocytes following vitrification. Oocytes were vitrified in vitrification solutions containing HA nanoparticles of different sizes (20, 40, or 60 nm) and concentrations (0.01%, 0.05%, or 0.1%) to determine the optimal conditions based on survival rate, mitochondrial membrane potential (MMP) level, and developmental competence. Subsequently, the synergistic effects of HA nanoparticles and permeable CPAs (VS: 20% EG + 20% DMSO; VS1: 17.5% EG + 17.5% DMSO) were further evaluated. The optimal treatment (40 nm 0.05% HA nanoparticles) significantly increased MMP level, and improved developmental competence compared with the vitrified control group (p < 0.05). Among the vitrified groups, vitrified oocytes in the VS1-HA group (combining HA nanoparticles with reduced concentrations of permeable CPAs) exhibited the highest MMP level (1.89), maturation rate (50.39%), cleavage rate (27.07%), and blastocyst rate (10.53%) (p < 0.05). Ultrastructural analysis further revealed that the VS1-HA group maintained more intact zona pellucida structures and showed reduced mitochondrial swelling compared with the vitrified control group. Moreover, the expression levels of genes associated with zona pellucida formation (ZP3), mitochondrial fusion (MFN1), and chromatin remodeling (NPM2) were significantly upregulated in the VS1-HA group relative to the vitrified control group. Overall, these findings indicate that the combination of HA nanoparticles with lower concentrations of permeable CPAs enhances MMP level, alleviates vitrification-induced ultrastructural damage, and upregulates the expression of key developmental genes, thereby improving the developmental competence of vitrified bovine GV oocytes. Full article