Search Results (464)

The diterpene sessein, isolated from Salvia sessei, is a metabolite of interest due to its conjugated p-quinone system, δ-lactone ring, and phenolic hydroxyl in C-12. These functionalities make it an ideal starting point for reactivity studies and semi-synthetic derivatization. In this work, we report the obtainment of two derivatives by selective esterification of phenolic hydroxyl in C-12, through acetylation and benzoylation reactions under mild conditions and with high yields. The structures were characterized by UPLC-MS, FTIR, and NMR spectroscopy ¹H, ¹³C, and 2D, which allowed to precisely confirm the modifications made in the derivatives. These results confirm that hydroxyl in C-12 constitutes a privileged site of reactivity within the royleanone family, consolidating sessein as a versatile nucleus for the generation of derivatives. Finally, the preliminary evaluation of the antimicrobial activity showed that sessein shows a broad spectrum of action against Gram-positive, Gram-negative, and Candida albicans strains. The acetylated derivative showed an increase in activity against gram-negative bacteria, while the benzoyl derivative had a loss of effect at the concentrations evaluated. These findings demonstrate that structural modifications influence the properties of the derivatives with respect to the compound sessein. Full article

Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. They can cause immune-mediated colitis (IMC), a potentially severe adverse event. Current data on severe IMC (grade 3–4) are limited, particularly regarding clinical, endoscopic, and histological features. Methods: We conducted a multicenter, retrospective observational study promoted by GETECCU, including adults with solid tumors who developed grade 3–4 IMC requiring hospitalization and systemic therapy. Clinical symptoms, endoscopic findings (Mayo and UCEIS indices), and histological features were systematically collected and analyzed. Results: A total of 196 patients were included. Diarrhea was universal (median 8 bowel movements/day), with 76% reporting abdominal pain and 39% rectal bleeding. Endoscopy (n = 139) revealed vascular pattern loss (80%), mucosal lesions (69%), and Mayo scores ≥2 in 69%. Histopathology (n = 141) showed abnormalities in 85%, including cryptitis (50%), lymphocytic infiltration (48%), and crypt abscesses (37%). Notably, 72% of patients with normal endoscopy had histological inflammation. Endoscopic severity correlated with bleeding and impaired general condition but not with stool frequency or pain intensity. Histological and endoscopic severity were modestly associated. Conclusions: Severe IMC presents with heterogeneous clinical, endoscopic, and histological features, with limited correlation between these domains. Endoscopic findings were often ulcerative and inflammatory, yet histological abnormalities were frequently present even in endoscopically inactive disease. These findings highlight the importance of biopsy in all suspected IMC cases and underscore the need for validated multidimensional assessment tools for accurate diagnosis and management of severe IMC. Full article

Background/Objectives: Interactions between colorectal tumours and their immune microenvironment critically influence disease progression and response to immunotherapy. However, most organoid systems fail to preserve the complex architecture and immune composition of the original tissue. Here, we applied the air–liquid interface (ALI) organoid model to paired tumour and perilesional colon tissues from colorectal cancer patients to evaluate its ability to retain immune and genetic features and to reproduce responses to chemotherapy and immune checkpoint blockade. Methods: Fresh human tumour and matched healthy colon tissues were processed to generate ALI organoids. Their histological organization, immune cell composition (including CD45⁺ subsets), and genomic profiles were compared with those of the parental tissues and with conventional Matrigel organoids, either alone or co-cultured with peripheral blood mononuclear cells (PBMCs). Organoids were exposed to 5-FU and nivolumab (anti–PD-1) to assess local immune modulation. Results: ALI organoids faithfully preserved the three-dimensional architecture, native immune infiltrates, and somatic mutational landscape of the source tissues. Importantly, upon PD-1 blockade with nivolumab, ALI organoids consistently exhibited a local expansion of regulatory T cells (Tregs), a phenomenon that could contribute to adaptive immune resistance. This response was not reproduced in PBMC–Matrigel co-culture systems, highlighting the importance of preserving endogenous tumour–immune interactions. Conclusions: Patient-derived ALI organoids represent a physiologically relevant platform that conserves key structural, immunological, and genomic hallmarks of colorectal cancer. By capturing clinically relevant immune remodeling events, such as Treg expansion following PD-1 blockade, this model provides a powerful tool for dissecting tumour–immune interactions. Full article

Background: Janus kinase inhibitors (JAKi) are approved for the treatment of rheumatoid arthritis (RA), aiming to achieve clinical remission. Composite scores such as Disease Activity Score in 28 joints with C-reactive protein (DAS28-CRP) are influenced by subjective factors, and JAKi may impact these dimensions beyond inflammation. Ultrasound provides a sensitive and objective assessment of synovial activity. Objective: To evaluate clinical and ultrasound-defined remission in RA patients treated with JAKi under routine care. Methods: This cross-sectional study included all consecutive patients treated with baricitinib, filgotinib, tofacitinib, or upadacitinib between 1 November 2022 and 30 April 2023. Clinical remission was defined as DAS28-CRP and ultrasound remission as absence of power Doppler (PD) signal across a standardized 32-joint evaluation. Results: We include 78 patients with established RA; 87.2% were female, with mean age of 59.5 ± 10.8 years and disease duration of 10.6 ± 8.0 years. Most were seropositive for RF and/or ACPA (74.4%), and comorbidities were highly prevalent (93.6%). Clinical remission was observed in 42.3% and ultrasound remission in 56.4%, with no statistically significant differences between JAKi groups. Among 50 patients meeting remission by either definition, 30 (60%) fulfilled both criteria, 11 (22%) had ultrasound remission only, and 9 (18%) met clinical remission without sonographic confirmation. Discordant cases were often associated with osteoarthritis, fibromyalgia, mood disorders, and elevated inflammatory markers. Conclusions: JAKi were effective in achieving remission in many RA patients. Ultrasound revealed residual synovitis despite clinial remission and, conversely, silent remission in cases not meeting DAS28-CRP criterion, reinforcing its value for accurate monitoring and personalized therapeutic decisions. No meaningful clinical or ultrasonographic differences were observed between the various JAK inhibitors, indicating comparable perfomance across agents in routine practice. Full article

Coffee silverskin is generated in large quantities as a co-product during the roasting process of coffee beans. This co-product is rich in bioactive compounds that offer potential health benefits, justifying its consideration as a functional ingredient in food. In this study, silverskin from the species Coffea arabica and Coffea canephora from six different countries was characterized to highlight its potential and applicability as a safe ingredient in new food formulations. The results revealed a dietary fiber content ranging from 71.81 to 76.86 g/100 g, with a high portion of insoluble fiber ranging from 54.02 to 60.58 g/100 g. The mineral content showed that, in all samples, potassium and calcium were the main elements with values ranging from 6.66 to 17.57 mg/g and from 9.25 to 16.44 mg/g, respectively. The caffeine content was quantified with levels ranging from 0.81 to 7.32 mg/g. In addition, high levels of phenolic compounds were identified in free and bound forms, with 5-caffeoylquinic, 3-caffeoylquinic, 4,5-dicaffeoylquinic, and ferulic acids being the main components in both fractions. All samples analyzed showed a good antioxidant capacity in the four different methods used, with values ranging from 8.12 to 10.85 mg Trolox Equivalents (mgTE/g) in the DPPH assay; from 9.69 to 19.68 mgTE/g in the FRAP assay; from 5.96 to 11.05 mgTE/g in the FRAP assay; and from 0.21 to 1.11 and 4.69 mg EDTA/g sample in the FIC assay. In conclusion, coffee silverskin has the potential to play a beneficial role as an ingredient in new food formulations, thus contributing to the development of a circular economy in the food industry. Full article

Background and Objectives: Crohn’s Disease (CD) is a chronic inflammatory condition often treated with anti-TNF agents such as infliximab (IFX) and adalimumab (ADA). This study compares the efficacy, immunogenicity, and pharmacokinetics of IFX and ADA over a 54-week period. Materials and Methods: A prospective, multicentre cohort study was conducted involving 72 patients with active CD (Crohn’s disease activity index, CDAI > 150), who received treatment with either IFX (n = 42) or ADA (n = 30). Results: By week 54, treatment discontinuation occurred in 31% of IFX-treated patients (13/42) and 37% of ADA-treated patients (11/30), with no significant difference between groups (p = 0.612). Among those who completed the study, clinical remission (CDAI ≤ 150) was achieved in 65% of the IFX group and 95% of the ADA group (OR = 8.10; 95% CI = 1.10–20.11; p = 0.049). Loss of clinical response was more frequent in the IFX group (31%) than in the ADA group (10%), with an OR of 0.25 (95% CI: 0.06–0.97; p = 0.045). Fibrinogen levels declined in both groups, with a greater reduction observed in ADA-treated patients. The area under the ROC curve (AUC) for fibrinogen in distinguishing remission from active disease was 0.608 for IFX and 0.711 for ADA. Anti-drug antibodies were detected more frequently in IFX-treated patients (16.7%, 7/42) compared to those receiving ADA (6.7%, 2/30). Conclusions: Treatment with ADA demonstrated superior efficacy compared to IFX in maintaining clinical remission in CD, which was paralleled by a more effective normalization of fibrinogen levels (Clinical trial: GET-CRO-2010-01). Full article

Objective: We aimed to provide real-world insights into the management of non-small cell lung cancer stage III (NSCLC-SIII) in Spain. Methods: The GOECP-SEOR group conducted an observational, retrospective, multicenter study in which data from patients diagnosed with NSCLC-SIII treated in Spanish radiotherapy departments (RTDs) were collected. Results: A total of 1505 NSCLC-SIII patients from 35 RTDs from 2018 to 2021 were recruited. A total of 871 patients (57.9%) received concurrent chemoradiotherapy (cCRT), and 390 patients (25.91%) received maintenance durvalumab. The immunotherapy (IT) was well tolerated, with Common Terminology Criteria for Adverse Events (CTCAE) Grade 0–2 toxicity observed in 85% of the patients (295 patients). The median overall survival (OS) was 26 months (95% CI 9.4-Not Reached NR). There was a statistically significant difference when patients were stratified by IT, with a median OS of 40 months (95% CI 22.1-NR) in the IT maintenance cohort compared with 19.4 months (95% CI 7.1–58.1) in the non-IT cohort. Differences were also noted in progression-free survival (PFS), with a median PFS of 20.8 months (95% CI 9.6-NR) in the IT cohort versus 8.4 months (95% CI 3.1–25.1) in the non-IT cohort. These differences remained significant according to the multivariate model (OS: HR 0.45 [95% CI 0.36–0.56], p < 0.001; PFS: HR 0.5 [95% CI 0.42–0.59], p < 0.001). Conclusions: The management of NSCLC-SIII patients can vary, leading to differences in treatment outcomes. The treatment of lung cancer in NSCLC-SIII patients in RTDs across Spain aligns with international guidelines and expert recommendations. Full article

Background: How the tumor microenvironment (TME) influences treatment response in HER2+ breast cancer following HER2-directed therapy is crucial for individualizing therapies and is currently understudied. The purpose of this exploratory analysis was to elucidate changes in the TME following treatment with trastuzumab. Methods: Fourteen HER2+ early-stage breast cancer patients underwent tissue biopsies before and after a dose of trastuzumab. Samples were evaluated for stromal tumor-infiltrating lymphocytes (TILs) and RNA-based cell and gene expression signatures. Tumor inflammation signature scores were generated to measure whether an adaptive immune response developed to trastuzumab within the tumor. Patients were also stratified as immune responders or non-responders based on changes in TILs. Results: Of the 14 enrolled patients, 13 had samples available for analysis, and 7 had an immune response as assessed by changes in TILs compared to 6 non-responders. Trastuzumab treatment decreased PD-L1 and TGF-Beta signatures and increased CTLA4 gene signatures, although results were not statistically significant, and increased DUSP1 expression. In the TIL responder group, there was increased expression of dendritic cells as well as MARCO expression. Conclusions: These findings, although exploratory in nature, highlight trastuzumab’s ability to induce an immune response and suggest that some patients may be more primed to mount an immune response following treatment than others. Patients without a robust response in TILs may benefit from additional agents to favorably modulate the TME for optimized responses to HER2-directed therapy, an area of research which warrants further study. Full article

Background/Objectives: Anti–PD-1/PD-L1 blockers have revolutionized the treatment landscape of non–small cell lung cancer (NSCLC) lacking oncogene-addicted alterations, particularly in tumors with high PD-L1 expression (tumor proportion score [TPS] ≥ 50%). Cemiplimab is approved as first-line monotherapy in this setting. However, real-world data remain scarce. This study aimed to evaluate the efficacy and safety of single-agent cemiplimab in a multicenter Spanish cohort and compare outcomes with a historical pembrolizumab cohort. Methods: Cemi-SPA is a retrospective multicenter study including 150 patients with advanced NSCLC and PD-L1 ≥ 50% treated with cemiplimab as first-line monotherapy across 21 Spanish centers. Clinical outcomes were analyzed and compared with a historical cohort of 144 patients treated with pembrolizumab. Propensity score matching (PSM) was performed to adjust for baseline differences. Results: Median progression-free survival (PFS) and overall survival (OS) were 8.1 and 12.6 months, respectively. ECOG performance status ≥ 2 was independently associated with worse outcomes, whereas the development of immune-related adverse events correlated with improved PFS and OS. After PSM, no significant differences were observed between cemiplimab and pembrolizumab in terms of efficacy. Conclusions: Cemiplimab demonstrated comparable real-world efficacy and safety to pembrolizumab in patients with advanced NSCLC and PD-L1 ≥ 50%. ECOG performance status emerged as the strongest prognostic factor, highlighting the importance of patient selection in routine clinical practice. Full article

Wastewater treatment plants (WWTPs) are recognized hotspots for the convergence and dissemination of antimicrobial-resistant bacteria (ARB) and antimicrobial resistance genes (ARGs) into the environment. Among ARB, carbapenem-resistant Enterobacterales (CR-E) and extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae (ESBL-Ec/Kp) are of particular concern due to their clinical relevance. We characterized 30 CR-E and 176 ESBL-Ec/Kp isolates (two of them were both ESBL-producing and carbapenem-resistant) recovered from influent, intermediate, effluent, sludge, and downstream river samples collected from two WWTPs in northern Spain. Isolates were evaluated for resistance phenotypes against 12 antimicrobials, and β-lactamase-encoding genes were assessed by PCR and sequencing. Notably, among CR-E isolates, bla_KPC-2 was the most prevalent (93%), followed by bla_OXA-48-like, detected in two isolates from non-treated and pasteurized sludge; both isolates also carried bla_CTX-M-15, a finding not previously reported specifically in sludge samples. Among ESBL-Ec/Kp, a broad diversity of ESBL genes was identified, including bla_{CTX-M group 1} (variants 1, 3, 15, 32, 55), bla_{CTX-M group 9} (variants 14, 27, 65, 97), bla_SHV-12 and bla_TEM-169. The most prevalent ESBL gene was bla_CTX-M-15 (48.3%), followed by bla_CTX-M-14, bla_CTX-M-32, and bla_SHV-12, detected in 10.8%, 8.5%, and 6.8% of isolates, respectively. CR-E and ESBL-Ec/Kp were found in all sample types and were still detectable at terminal stages, indicating persistence throughout treatment. These findings support the need to improve and optimize current wastewater treatment methods and underscore the importance of integrating culture-based and molecular methods into routine WWTP monitoring for early detection of microbiological hazards, although further research is still needed. Full article

Procyanidins are oligomeric flavonoids with several bioactive properties. Their antidiabetic potential is related to their capacity to inhibit enzymes responsible for the absorption of dietary carbohydrates, such as pancreatic α-amylase. Procyanidins possess great structural diversity, including types of monomers and interflavanic bonds (A- or B-), and the degree of polymerization. However, there is a lack of evidence that systematically analyzes the effect of these structural features on their α-amylase inhibitory activity. In this paper, the activity of a mammalian pancreatic α-amylase was assessed using two different substrates, and the inhibitory activity of five commercially available procyanidins and three monomeric flavonoids was compared. The enzyme-binding sites of the eight compounds were predicted by in silico analysis to help explain the different enzyme-inhibitory activities. The inhibitory activity of procyanidins and monomeric flavonoids depended on the substrate used. A-type dimers presented the best activity against a polymeric substrate, while a B-type dimer was the best inhibitor for an oligomeric substrate. The predicted binding site for dimers and monomers was close to the active site. For the B-type trimer, the binding site was on the back side (approximately 180°) of the catalytic triad. In silico predictions suggested that dimeric procyanidins, especially A-type, could better enter the active site cavity, which could explain their superior inhibitory activity. We may conclude that inhibition of pancreatic α-amylase by procyanidins is mainly related to the type of interflavanic bond and the degree of polymerization. Dimers could be the most effective procyanidins to mildly inhibit this enzyme and present antidiabetic potential. Full article

Background: Understanding the immune mechanisms that differentiate protective from pathogenic responses during dengue virus (DENV) infection is critical for effective vaccine development. Objective: To investigate how CD4⁺ T cell depletion alters viral control and the humoral immune response during primary DENV2 infection in a non-human primate (NHP) model. Methods: Rhesus macaques were depleted of CD4⁺ T cells prior to DENV2 infection. Viral kinetics, B cell activation, antibody specificity, and functional outcomes were evaluated longitudinally, including cross-reactivity and antibody-dependent enhancement (ADE) potential. Results: CD4⁺ T cells were essential for early viral clearance and the generation of robust, type-specific neutralizing antibodies. In their absence, animals exhibited early non-specific polyclonal B cell activation, delayed isotype switching, and an expanded repertoire of cross-reactive antibodies to DENV and Zika virus (ZIKV), with diminished neutralizing capacity. CD4-depleted macaques also showed increased ADE potential, particularly against ZIKV, and elevated anti-NS1 IgG titers that persisted one-year post-infection. Conclusion: CD4⁺ T cells play a critical role in orchestrating effective, durable, and type-specific antibody responses during primary DENV infection. Their absence leads to delayed antibody maturation, greater cross-reactivity, and higher ADE potential. These findings emphasize the need for DENV and ZIKV vaccines to include CD4⁺ T cell epitopes that promote high-quality, type-specific antibody responses and minimize ADE risk. Full article

The substantial energy consumption and associated CO₂ emissions from industrial operations pose significant environmental and economic challenges for factories and surrounding communities. Within the context of industrial energy management, the steel industry represents a major energy consumer. The imperative to optimize energy use in this sector is driven by a combination of environmental concerns, economic incentives, and technological advancements. This study presents a machine learning model that integrates the whale optimization algorithm (WOA) with multivariate adaptive regression splines (MARS) to forecast electric energy consumption. Utilizing a dataset comprising 35,040 real-world energy consumption records from Gwangyang Steelworks in South Korea, the model was benchmarked against other regression techniques (ridge, lasso, and elastic-net), demonstrating that the proposed WOA-MARS approach achieves a significant improvement in the RMSE (vs. elastic-net or lasso regression techniques) while maintaining interpretability through hinge function analysis. The WOA-tuned MARS model achieves a coefficient of determination (R²) of 0.9972, underscoring its effectiveness for energy optimization in steel manufacturing. The key findings reveal that CO₂ emissions and reactive power variables are the strongest predictors. Full article

Background/Objectives: The semi-school-based model (SSBM) has gained momentum in Mexico post-COVID-19, providing flexibility for students managing work, family, and academics. However, little is known about how high-stakes academic evaluations affect the emotional well-being and lifestyle habits of students in this alternative setting. This study aims to assess two key research questions: (1) Does exposure to a high-stakes academic exam increase anxiety and depression levels in SSBM students? (2) Does exam-related stress affect dietary habits and physiological stress markers in these students? Methods: A prospective, longitudinal, quantitative study was conducted in September 2023 with 94 fourth-term high school students in an SSBM program in Mexico Assessments. Evaluations were conducted at two specific time points; Pre-exam Assessment Day (RCD): ~30–50 min before normal Saturday classes, and Exam-day Assessment (ED): ~30–50 min before the mathematics exam. Data included sociodemographic, HADS scores, dietary habits, and physiological measures (blood pressure, heart rate, oxygen saturation). Analyses were conducted in SPSS v28. Normality was tested using Kolmogorov–Smirnov. Paired continuous and categorical variables were compared with Wilcoxon signed-rank and McNemar’s or Fisher’s exact tests, respectively. Relative risks (RR) and multivariate logistic regression identified factors associated with anxiety and depression. Significance was set at p < 0.05. Results: Anxiety prevalence increased significantly on the exam day (from 22.3% to 59.6%, p < 0.001; RR = 14.281, 95% CI: 2.620–161.296), with no significant change in depression. Wilcoxon tests confirmed higher anxiety scores across both sexes. Systolic and diastolic blood pressure and heart rate increased significantly, particularly among females (p < 0.001), whereas oxygen saturation remained stable. Eating patterns shifted on ED, with higher consumption of fried foods, sweet bread, and sugar-sweetened beverages (p < 0.001), especially among males, and decreased intake of meat protein and vegetables, particularly among females. Meat consumption was significantly associated with increased anxiety (adjusted RR = 3.405; 95% CI: 1.035–11.194; p = 0.044). Conclusions: High-stakes academic exams in SSBM settings are associated with acute increases in anxiety and unhealthy dietary changes, even without significant depressive symptoms. These findings highlight the need for interventions supporting emotional regulation and healthy lifestyle behaviors among students facing academic stress in non-traditional educational environments. Full article

Background and Objectives: Ixekizumab is a human monoclonal antibody targeting interleukin-17A, approved for the treatment of moderate-to-severe plaque psoriasis. Given its demonstrated efficacy and safety in clinical trials, this study aimed to evaluate the real-world drug survival of Ixekizumab and identify clinical predictors of treatment discontinuation. Materials and Methods: A retrospective, observational, hospital-based study was conducted in the Department of Dermatology at the Central University Hospital of Asturias (HUCA). Patients with moderate-to-severe plaque psoriasis who initiated treatment with Ixekizumab (Taltz^®) between 8 June 2017 and 10 October 2024, were included. Demographic data, comorbidities, age at disease onset, family history, PASI score, and previous treatments were recorded. Drug survival was assessed using Kaplan–Meier survival curves and the log-rank test. Predictors of discontinuation were analyzed using univariate and multivariate Cox proportional hazards models. Results: A total of 103 patients (55.3% women) were included. Drug survival rates were 85% at one year, 73% at two years, and 61% at four years, with a mean treatment duration of 52.5 months (95% CI: 46.01–58.99). Multivariate analysis showed that patients under the age of 65 had a significantly higher risk of treatment discontinuation (hazard ratio: 1.813; p < 0.05). The most common reason for discontinuation was secondary treatment failure (45.16%). Ixekizumab demonstrated sustained drug survival in a real-world setting, with rates falling within the mid-to-upper range reported in the literature. Older age (>65 years) was associated with greater treatment persistence, highlighting a potential influence of age on long-term therapeutic adherence. Full article