Search Results (307)

Background and Objectives: The prognostic significance of body mass index (BMI) in metastatic HER2-positive breast cancer (BC) remains unclear, with previous studies yielding conflicting results. This multicenter real-world study aimed to investigate the prognostic role of BMI in this patient population. Materials and Methods: A total of 169 female patients with metastatic HER2-positive BC who received trastuzumab-based treatment between 2010 and 2024 were included. Patients were categorized by BMI (<30 kg/m² vs. ≥30 kg/m²). The primary endpoints were overall survival (OS) and progression-free survival (PFS). Kaplan–Meier and Cox regression analyses were performed overall and in subgroups stratified by hormone receptor (HR) status. Results: In the overall cohort, a BMI ≥ 30 was not significantly associated with OS or PFS. However, in the HR-positive/HER2-positive subgroup, BMI ≥ 30 kg/m² was linked to significantly shorter OS (p = 0.024) and PFS (p = 0.047) by Kaplan–Meier analysis. However, these associations did not remain statistically significant in multivariate analyses. No significant BMI-related differences were observed in the HR-negative subgroup. Other independent negative prognostic factors included recurrent disease, the presence of brain metastases, and a high Ki-67 index. Conclusions: BMI was not identified as an independent prognostic factor in the overall population. However, among HR-positive/HER2-positive patients, obesity was associated with poorer survival in univariate analysis, but this was not confirmed in multivariate analysis. These findings underscore the need for prospective studies to clarify the prognostic role of adiposity, considering biological subtypes. Full article

Trypanosoma cruzi is a hemoflagellate protozoan and the causative agent of Chagas disease, also known as American trypanosomiasis. Transmission occurs through the feces of triatomine insects, its biological vector. It is estimated that around 7 million people are infected across Mexico, Central America, and South America. This study aimed to identify and characterize T. cruzi isolates obtained from wild triatomine vectors collected in Aguascalientes, Mexico. Molecular identification was performed at different developmental stages—epimastigotes in culture media, metacyclic trypomastigotes in triatomine feces, and amastigotes in mouse cardiac tissue—using endpoint PCR targeting satDNA and mtCytB regions. In addition, next-generation sequencing was employed to analyze variable regions of kinetoplast DNA minicircles. The pathogenicity of the isolated and identified T. cruzi strain was assessed in a murine model, where trypomastigote stages were detected in peripheral blood and amastigote stages in muscle tissue. Molecular analyses confirmed the presence of T. cruzi across different developmental stages from wild vectors, demonstrating that the isolated wild strain possesses pathogenic potential when completing its life cycle in an experimental mammalian host, specifically BALB/c mice. Full article

Dysregulation contributes to Alzheimer’s disease (AD) pathophysiology. Zinc therapy promotes enterocyte copper sequestration, potentially reducing systemic copper. Individual biological responses may vary. Methods: ZINCAiD was a 24-week, randomized, double-blind, placebo-controlled phase II trial assessing zinc therapy in individuals with mild cognitive impairment (MCI) due to AD (EudraCT No.: 2019-000604-15; registered on 26 March 2020). Participants were randomized 2:1 to receive elemental zinc (135 mg/day for 12 weeks, then 65 mg/day) or placebo. Ceruloplasmin was measured at predefined intervals for safety monitoring, blinded to the investigators. Post hoc, “Zinc Responders” were defined by ≥20% reduction in ceruloplasmin at week 12. The primary cognitive endpoint was the Cognitive Composite 2 scale (CC2); secondary endpoints included MMSE and CDR-Sob. Findings: Of the 48 participants randomized, 9 discontinued, primarily due to unrelated clinical deterioration; 39 had complete ceruloplasmin data. Two serious adverse events occurred in the Placebo group. Mild gastrointestinal symptoms occurred in eight participants, with only four leading to dropout. In the primary zinc vs. placebo analysis, no significant differences emerged in cognitive outcomes. A post hoc exploratory analysis stratified participants by pharmacodynamic response: 12 individuals with MCI due to AD (31%) met the criteria for “Zinc Responder,” defined by ≥20% reduction in serum ceruloplasmin at week 12. Only Zinc Responders maintained cognitive stability over 24 weeks, whereas the combined group of Zinc Non-Responders and placebo-treated participants showed a significant decline. For the composite cognitive score (CC2), the interaction between visit and response group was significant (p = 0.030), with deterioration observed only in the Non-Responder + Placebo group (Δ = –2.72, p < 0.0001 vs. –0.71, p = 0.35 in Responders). Similar patterns were observed for CDR-Sob (interaction p = 0.017) and MMSE (trend p = 0.09). Interpretation: Zinc therapy stabilized cognition in a pharmacodynamically defined MCI subgroup. These exploratory findings suggest serum ceruloplasmin as a feasible biomarker of target engagement. Larger trials are needed for confirmation. Full article

Background: Structurally active phospholipoproteomic formulations that lack pharmacodynamic targets or systemic absorption present unique challenges for validation. Designed for immune compatibility or structural modulation—rather than therapeutic effect—these platforms cannot be evaluated through conventional clinical or molecular frameworks. Methods: This study introduces a standardized, non-invasive ex vivo protocol using real-time kinetic imaging to document biological behavior under neutral conditions. Eight human tumor-derived adherent cell lines were selected for phenotypic stability and imaging compatibility. Phospholipoproteomic preparations were applied under harmonized conditions, and cellular responses were recorded continuously over 48 h. Results: Key parameters included signal continuity, morphological integrity, and inter-batch reproducibility. The system achieved high technical consistency without labeling, endpoint disruption, or destructive assays. Outputs included full kinetic curves and viability signals across multiple cell–fraction pairings. Conclusions: This method provides a regulatorily compatible foundation for functional documentation in non-pharmacodynamic programs where clinical trials are infeasible. It supports early-stage screening, batch comparability, and audit-ready records within SAP, CTD, or real-world evidence (RWE) ecosystems. By decoupling validation from systemic exposure, the protocol enables scalable, technically grounded decision-making for structurally defined immunobiological platforms. Full article

Background/Objectives: This multicenter retrospective study aims to evaluate the role of Ablative Radiotherapy (RT) in patients with unresectable pleural mesothelioma (PM) who experienced radiological progression after at least one line of chemotherapy, with a maximum involvement of three pleural or extrapleural sites. Methods: Adult patients (≥18 years) with PM treated with stereotactic radiotherapy between 2011 and 2022, limited to a maximum of three pleural or extrapleural sites, were included in the analysis. Ablative RT was required to be administered with radical intent. Endpoints were time to further systemic therapy (TFST), local control (LC), progression-free survival (PFS), overall survival (OS), and acute and late radiotherapy-related toxicity. Results: A total of 56 patients were identified from six Italian and one Swiss radiotherapy center. Treatment was generally well tolerated. Ten patients experienced grade 1 or 2 acute toxicity, while four patients reported persistent chest pain, with one case reaching grade 3 as late toxicity. The median TFST was 18.6 months, with TFST rates of 61.7% and 46.4% at 12 and 24 months, respectively. The median OS was 37.63 months, with 1- and 2-year OS rates of 85.2% and 65.6%. Local control was favorable (79% at 1 year), but most patients experienced disease recurrence outside the SABR treatment volume. The median disease progression-free survival (DPFS) was 8.17 months, with 1- and 2-year DPFS rates of 36% and 19%, respectively. Smoking history correlated with OS and DPFS in univariate analysis, while statistical significance for OS was maintained in multivariate analysis. Additionally, nodal status and PTV volume were associated with OS. Conclusion: SABR is a safe and effective approach for the treatment of oligorecurrent/oligoprogressive PM. The time to further systemic therapy was extended up to 18 months. At two years, 10% of patients remained disease-free, and more than half were alive at three years, suggesting a potentially indolent biological behavior in oligometastatic PM. Full article

Background: In healthy adults, probiotic supplementation alone does not increase Urolithin A (UroA) and rarely increases butyrate, both microbiome-derived metabolites that influence key biological functions involved in regulating gastrointestinal symptoms. Accordingly, this clinical trial evaluated key biological functions of a multi-species synbiotic with 24 probiotic strains and a polyphenol-based prebiotic using capsule-in-capsule delivery technology. Methods: We conducted a randomized, placebo-controlled trial among healthy participants (n = 32). Participants were administered a daily synbiotic (53.6 billion AFU multi-species probiotic and 400 mg Indian pomegranate extract; DS-01) or matching placebo for 91 days. Samples were obtained at baseline Day 0, and Days 7, 14, 49, and 91. Endpoints included changes in fecal microbiome composition, urinary UroA, fecal butyrate, serum CRP, and safety. Results: The synbiotic significantly increased alpha-diversity of Bifidobacterium and Lactobacillus spp. at all timepoints, including at end-of-study (Day 91, p < 0.0001) and increased native beneficial microbes. UroA production was significantly increased in the synbiotic arm at short-term (Day 7, 12-fold, p < 0.02) and long-term (Day 91, 49-fold, p < 0.001) timepoints. A higher proportion of synbiotic participants were capable of converting polyphenols into UroA (Day 91, 100% vs. 44.4%; p < 0.01). Mechanistically, synbiotic participants showed an increased abundance of Lactobacillus species involved in UroA precursor metabolism and UroA-producing Gordonibacter species. The synbiotic also significantly increased fecal butyrate levels (p < 0.03), and butyrate-producing species, in low-baseline butyrate producers, through Day 91, and was associated with reduced systemic inflammation. Conclusions: This multi-species synbiotic significantly increases diversity and abundance of key beneficial bacteria, enhances UroA production and butyrate levels, and is associated with lowered systemic inflammation. This is the first synbiotic to increase both UroA and butyrate. Full article

Background: Diagnosing and predicting outcomes in elderly patients with heart failure (HF) is challenging due to atypical symptoms and the limited value of natriuretic peptides, highlighting the need to search for new risk stratification biomarkers in this population. Aim: We aimed to analyze factors associated with the composite endpoint (all-cause mortality or decompensated HF-related hospitalization) within six months of follow-up in elderly patients with left ventricular systolic dysfunction and decompensated HF, with particular emphasis on copeptin concentration. Methods: This is a retrospective observational study based on prospectively collected data of 279 consecutive elderly patients hospitalized between 2018 and 2023 due to decompensated HF. Inclusion criteria were age > 65 years, history of HF diagnosed at least two years before the index hospitalization, and left ventricular ejection fraction < 40% on admission echocardiography. Serum copeptin levels were measured using an Enzyme-Linked Immunosorbent Assay (ELISA) (Human Copeptin ELISA kit, Sunred Biological Technology Co, Shanghai, China). The primary endpoint was all-cause mortality or decompensated HF-related hospitalization during the six-month follow-up. Results: The median age of the study population was 77 years (IQR: 69–79), and 221 (79.2%) were male. The composite endpoint occurred in 110 patients (38.1%). Multivariable analysis showed that serum concentrations of copeptin [hazard ratio (HR) 1.053 (1.042–1.064), p < 0.0001], bilirubin [HR 1.085 (1.057–1.114), p < 0.0001], uric acid [HR 1.005 (1.003–1.006), p < 0.0001], high-sensitivity C-reactive protein (hs-CRP) [HR 1.208 (1.088–1.342), p < 0.0001], and sodium [HR 1.111 (1.025–1.203), p = 0.01], as well as ischemic etiology of HF [HR 3.969 (2.396–6.575), p < 0.0001], were independently associated with worse outcomes. Conclusions: Our study demonstrated that higher concentrations of copeptin, bilirubin, hs-CRP, and uric acid, as well as lower sodium levels and ischemic etiology of HF, were independently associated with all-cause mortality or HF-related hospitalization during a six-month follow-up in elderly patients with decompensated HF. Full article

Background and Aim: The therapeutic landscape for ulcerative colitis (UC) is rapidly evolving, with an increasing number of biologic agents available. This systematic review and meta-analysis synthesized randomized controlled trials (RCTs) data on biologic therapies for achieving key endoscopic and histologic endpoints in moderate to severe UC. Methods: A systematic search of MEDLINE, EMBASE, Cochrane Library, Web of Science and grey literature was conducted through November 2024. Separate meta-analyses were performed for induction and maintenance. A random-effects model was used to estimate relative risks (RR), with 95% confidence intervals (CI), and confidence in estimates was evaluated with the GRADE approach (Grading of Recommendation Assessment, Development and Evaluation). Results: We included 40 RCTs (13 therapies, 14,369 patients). Thirty-two trials provided data in induction and twenty-eight in maintenance. During induction, all biologic therapies, except mirikizumab and filgotinib 100 mg, demonstrated superiority over placebo (RR 2.02, 95% CI: 1.76–2.31, I² = 72%) for endoscopic improvement. Upadacitinib showed the highest efficacy (RR 5.53, 95% CI: 3.78–8.09). For mucosal healing, all interventions were superior to placebo (RR 2.95, 95% CI: 2.11–4.13, I² = 61%), except filgotinib 100 mg. Risankizumab showed the highest efficacy (RR 10.25, 95% CI: 2.49–42.11). In maintenance, all therapies showed superiority over placebo for endoscopic improvement. For mucosal healing all therapies were superior to placebo, except risankizumab. Upadacitinib 30 mg showed the highest efficacy (RR 4.01, 95% CI: 1.81–8.87). Conclusions: Biologic and small-molecule therapies demonstrated substantial efficacy in achieving key endpoints. Standardized outcome definitions and further head-to-head RCTs are essential to strengthen confidence in our findings. Full article

Chronic airway inflammation with variable airflow obstruction is clinical asthma, and it arises from distinct molecular and pathological mechanisms called endotypes. Biomarkers allow for precise endotype characterization and have been used in clinical trials to design, monitor, and evaluate outcomes for asthma biologic therapies. This review will highlight the central and evolving role of biomarkers for past, present, and future asthma, with a focus on regulatory-approved biologic therapies and emerging biomarkers. Established biomarkers, including serum immunoglobulin E (IgE), blood eosinophils, the fraction of exhaled nitric oxide (FeNO), and serum periostin, helped elucidate the complex pathophysiology of the eosinophilic type 2 (T2) asthma endotype. Emerging biomarkers, or older biomarkers with emerging utility, include sputum inflammatory cells (eosinophils, neutrophils, interleukins), thymus and activation-regulated chemokine (TARC), plasma eotaxin-3, eosinophil peroxidase (EPX), Clara/club cell secretory protein (CC16), and quantitative computerized tomography (QCT) imaging biomarkers (evaluating mucus plugging, air trapping, airway wall thickness, small airway remolding) and are increasingly used in clinical trials as secondary endpoints in evaluating efficacy, as well as in the clinical setting at specialized centers. The rapid advances in asthma research, due in part to biomarkers and biologic therapies, may soon standardize an end goal: symptom-free asthma remission without exacerbations. Full article

Vascularization remains a critical challenge in tissue engineering, limiting graft survival, integration, and clinical translation. Although bioprinting enables spatial control over vascular architectures, many existing approaches prioritize geometric precision over biological performance. Bioprinted vasculature can be understood as a dynamic and time-dependent system that requires tissue-specific maturation. Within this framework, hydrogel systems act as active microenvironments rather than passive scaffolds. Hydrogel platforms vary from natural matrices and synthetic polymers to bioinspired or stimuli-responsive systems, each offering tunable control over stiffness, degradation, and biochemical signaling needed for vascular maturation. The design requirements of large and small vessels differ in terms of mechanical demands, remodeling capacity, and host integration. A key limitation in current models is the absence of time-resolved evaluation, as critical processes such as lumen formation, pericyte recruitment, and flow-induced remodeling occur progressively and are not captured by static endpoints. Advancements in bioprinting technologies are evaluated based on their capacity to support hydrogel-mediated vascularization across varying length scales and structural complexities. A framework for functional assessment is proposed, and translational challenges related to immunogenicity, scalability, and regulatory requirements are discussed. Such integration of hydrogel-driven biological cues and bioprinting fidelity is critical to advancing vascularized constructs toward clinical translation. Full article

As the body of knowledge on feline mammary tumors (FMTs) continues to grow, their histological classification and grading systems have undergone revisions and updates to better reflect the biological behavior of these tumors. In this review, the historical evolution of these frameworks is traced and later revisited in the context of their prognostic relevance. Numerous studies have investigated clinicopathological prognostic factors in feline mammary carcinomas (FMCs); however, the heterogeneity in assessment methods, inclusion criteria for survival analysis, and the clinical endpoints considered can often complicate direct comparisons across different studies and may contribute to seemingly conflicting results. Furthermore, the small cohort size of many studies limits the robustness and transferability of their findings. This paper provides an updated overview of the epidemiological, clinical, and pathological prognostic factors of these tumors, while also highlighting current challenges, methodological limitations, and areas for future improvement. Full article

Background/Objectives: In the era of treat-to-target strategies in inflammatory bowel disease (IBD), transmural healing (TH) is gaining recognition as a promising therapeutic goal. TH has been associated with significantly better long-term outcomes, including reduced rates of hospitalization, surgery, and the need for therapy escalation. Cross-sectional imaging techniques, such as intestinal ultrasound (IUS), magnetic resonance imaging (MRI), and computed tomography enterography (CTE), offer a comprehensive, non-invasive means to assess this deeper level of healing. This review explores how TH is currently defined across various imaging modalities and evaluates the feasibility and cost-effectiveness of achieving TH with available therapies. Methods: A literature search was conducted across PubMed, Scopus, and Embase using keywords, including “transmural healing”, “intestinal ultrasonography”, “magnetic resonance imaging”, “computed tomography enterography”, “Crohn’s disease”, “ulcerative colitis”, and “inflammatory bowel disease”. Only English-language studies were considered. Results: Despite growing interest, there is no standardized definition of TH across imaging platforms. Among the modalities, IUS emerges as the most feasible and cost-effective tool, owing to its accessibility, accuracy (sensitivity 62–95.2%, specificity 61.5–100%), and real-time capabilities, though it does have limitations. Current advanced therapies induce TH in roughly 20–40% of patients, with no consistent differences observed between biologics and small molecules. However, TH has only been evaluated as a formal endpoint in a single randomized controlled trial to date. Conclusions: A unified and validated definition of transmural healing is critically needed to harmonize research and guide clinical decision-making. While TH holds promise as a meaningful treatment target linked to improved outcomes, existing therapies often fall short of achieving complete transmural resolution. Further studies are essential to clarify its role and optimize strategies for deep healing in IBD. Full article

A vast proportion of scientific data remains locked behind dynamic web interfaces, often called the deep web—inaccessible to conventional search engines and standard crawlers. This gap between data availability and machine usability hampers the goals of open science and automation. While registries like FAIRsharing offer structured metadata describing data standards, repositories, and policies aligned with the FAIR (Findable, Accessible, Interoperable, and Reusable) principles, they do not enable seamless, programmatic access to the underlying datasets. We present FAIRFind, a system designed to bridge this accessibility gap. FAIRFind autonomously discovers, interprets, and operationalizes access paths to biological databases on the deep web, regardless of their FAIR compliance. Central to our approach is the Deep Web Communication Protocol (DWCP), a resource description language that represents web forms, HyperText Markup Language (HTML) tables, and file-based data interfaces in a machine-actionable format. Leveraging large language models (LLMs), FAIRFind combines a specialized deep web crawler and web-form comprehension engine to transform passive web metadata into executable workflows. By indexing and embedding these workflows, FAIRFind enables natural language querying over diverse biological data sources and returns structured, source-resolved results. Evaluation across multiple open-source LLMs and database types demonstrates over 90% success in structured data extraction and high semantic retrieval accuracy. FAIRFind advances existing registries by turning linked resources from static references into actionable endpoints, laying a foundation for intelligent, autonomous data discovery across scientific domains. Full article

Impedance-based cellular assays allow determination of biological functions of cell populations in real-time by measuring electrical impedance. As compared to end-point assays, such as trans-epithelial electrical resistance assays, for example, they enable fast, non-invasive, and easy detection of cell kinetics—their growth, attachment, and interaction can be monitored over time. In our experiment, Caco-2 cells were cultured on E-plates 16. Next, fully differentiated cells were treated with either TNF-α or 3,4-dihydroxy-L-phenylalanine (L-DOPA). We aimed to verify the possibility of real-time testing of the viability, monolayer formation, and integrity (i.e., the presence of a functional and polarized monolayer) of Caco-2 cells by the xCELLigence real-time cell analyzer (RTCA) S16 system (Agilent Technologies). Full article

Background: Sex differences in type 2 diabetes (T2D) are a growing area of diabetes research. No data have been reported on sex differences with oral semaglutide (oSEMA) in a real-world setting. Methods: We included people with T2D who started treatment with oSEMA in routine clinical practice between November 2021 and November 2022, with at least one report of clinical follow-up (FU) data at 3 months. We evaluated in women with T2D (WWT2D) the clinical effectiveness of oSEMA and factors associated with clinical response and persistence. We also analyzed differences in baseline characteristics, clinical effectiveness, persistence rates and safety according to biological sex. Results: Of the 1018 subjects [median age: 63 years, body mass index (BMI): 33.8 kg/m², HbA1c: 7.8%], 469 were WWT2D. In WWT2D, oSEMA reduced HbA1c by 0.7% [−0.1 to −1.3] and 0.9% [−0.2 to −1.5] at the 6- and 12-month FU visits, while weight decreased by 4.6% [2.0 to 7.9] and 7.2% [2.5 to 10.9], respectively. Weight loss was >10% in 29.8% of WWT2D (95% CI 25.8 to 34.1); meanwhile, the combined endpoint (HbA1c decrease ≥ 1% + weight reduction ≥ 5%) was achieved in 23.5% (95% CI 19.8 to 27.5%) of WWT2D at the 12-month FU visit. Achievement of glycaemic targets was similar in women and men (59.3% vs. 61.1%). We found no sex differences in weight loss (6.9% vs. 6.8%), oSEMA maintenance dose, persistence rate (76.3% vs. 77.3%), or adverse events. Conclusions: oSEMA was effective and safe in WWT2D in a real-world setting, with nearly one-third of patients reporting weight loss >10% and more than two-thirds achieving HbA1c < 7%. oSEMA showed no sex bias in terms of effectiveness and safety. Full article