Three-dimensional (3D) co-culture is a rapidly evolving technique for researchers looking to accurately study cell-cell interactions using in vitro experiments. The limitations of monolayer cell culture, including limited interactions between the cellular and extracellular environment and disturbed cell morphology, are addressed by simulating the in vivo cellular environment. Using a scaffold to provide structural support and including biologically active extracellular matrix components, 3D cultures display behaviours and morphologies more congruent with tissue. Incorporating multiple cell types into this kind of 3D environment allows for the study of cell-cell interactions inside a biomimetic model system. A wide range of 3D co-culture technologies has emerged, each with its own advantages and challenges. Often these technologies require specialized equipment, a complex setup, or specific technical knowledge. As well, there exist a few standardized methods for studying indirect cell-cell interactions between two cell types separated by a reconstituted basement membrane. Here, we describe a 3D co-culture method that requires only fundamental technical skills and uses more widely applicable materials to successfully recapitulate indirect cell-cell interactions across a basement membrane. A monolayer of cells is covered in a layer of extracellular matrix, in the form of Matrigel, and a second cell type is seeded on top. The resultant co-culture is maintained for five days, at which point cells are analyzed for morphological changes by immunofluorescence or extracted from the co-culture for more detailed genomic, transcriptomic, or proteomic analyses. This protocol is ideal for studying the impact of cell-cell communication on cell behaviour when physical contact is prohibited by a basement membrane. As researchers continue to opt for more in vivo-relevant cell culture methods, a streamlined approach is necessary to avoid high barriers to entry.
Lack of adherence to international recommendations leads to worse outcomes. During the COVID-19 pandemic, the total number and proportion of hospitalized patients increased, consequently straining hospital care and hindering adherence. To evaluate adherence to clinical guidelines at our center, before, during, and shortly after the COVID-19 pandemic-induced hospital strain, and its association with clinical outcomes, using a random, balanced retrospective cohort. A balanced and randomized sample of 50 patients per year between 2019 and 2022 was drawn from electronic medical records and analyzed with multivariable and logistic regression models. The primary outcome was a composite of in-hospital death, hemodynamic decompensation within the first 7 days, and in-hospital bleeding. The global non-adherence in our study was 45.4%. The main risk factors for non-adherence were any mortality risk classification above low-risk PE and a PESI class different from class I, with ORs of 3.47 (95% CI 2.07-5.82) and 1.57 (95% CI 1.04-2.37), respectively. In both periods (COVID-19 season and non-COVID-19 season), non-adherent management strongly correlated with the composite outcome, OR = 2.36 (95% CI, 1.23-4.54). Non-adherence was also associated with worse in-hospital outcomes, with an incidence rate of the composite outcome of 21.08 per 1000 days/person (95% CI 10.97-40.51) and 47.7 per 1000 days/person (95% CI 33.39-67.50), and an attributable risk of 1.09% (95% CI -8.47%-10.64%). Overall, our findings highlight the need to prioritize human and material resources to ensure adherence to the standards of care for PE patients.
Sex differences in mental health are often overlooked, yet gut microbiota-host metabolite interactions may contribute to sexual dimorphism in depression. In a population-based cohort, we investigated sex-specific links among plasma tryptophan metabolites, depressive symptoms (PHQ-9), and the gut microbiome, controlling for smoking, diet, alcohol, and physical activity. Women (N = 419) exhibited higher plasma indole-3-acetic acid (IAA) and picolinic acid (PA) concentrations, but lower trigonelline (TRIG) than men (N = 383). Machine learning models with SHAP explanations revealed that IAA and TRIG were positively associated, whereas PA was negatively associated with depression severity in women, whereas only kynurenic acid (KA) was inversely associated in men. In women, depression severity strongly correlated with methanogenic archaea, including Methanobrevibacter smithii, and microbial methane-production pathways. Methanobrevibacter and specifically M. smithii were negatively linked to genes for tryptophan, PA, and KA biosynthesis, but positively to genes for IAA and nicotinate/nicotinamide metabolism. Most microbial species associated with depression severity in women were predicted to produce IAA. These findings reveal pronounced sex-specific microbiome-metabolite interactions, highlighting potentially distinct microbial mechanisms shaping depression in men and women.
ObjectivesTo compare the treatments used for the first episode of lupus nephritis (LN) in two Latin American cohorts (historical and contemporary) over a 25-year period, and their associations with clinical outcomes.MethodsPatients with biopsy-confirmed first LN episode were classified as non-proliferative (class V) or proliferative (classes III/IV). Sociodemographic, clinical, and treatment variables were described. Propensity score matching was used to examine the associations with four outcomes: mortality, damage accrual (SDI), hospitalization, and end-stage renal disease (ESRD).ResultsA total of 532 SLE patients were included: 362 from GLADEL 1.0 (historical cohort) and 170 from GLADEL 2.0. (contemporary). Compared to GLADEL 1.0, patients in GLADEL 2.0 received lower doses of oral glucocorticoids (GC), more frequently GC pulses and antimalarials but less frequently cyclophosphamide. An increase in the use of mycophenolate mofetil and other immunosuppressants was also observed. In the logistic regression models, SDI was associated with baseline SDI and GC pulses, whereas belonging to the GLADEL 2.0 was a protective factor. Mortality was associated with Mestizo ethnicity and partial health coverage; antimalarial was identified as a protective factor. Hospitalizations were associated with baseline SLEDAI and SDI, follow-up time, and lower educational level. Belonging to the GLADEL 2.0 cohort was protective against the occurrence of ESRD.ConclusionsPatients in the contemporary cohort benefited from advances in treatment strategies, with less cumulative damage and progression to ESRD, although mortality remained unchanged. These improvements likely reflect the increased use of newer therapies, more targeted approaches, in line with current treatment guidelines, and better access to specialized care.
Deep marine sediments generate large amounts of methane, but most of this gas is consumed by the anaerobic oxidation of methane (AOM) mediated by microscopic consortia of anaerobic methane-oxidizing archaea (ANME) and sulfate-reducing bacteria (SRB). In this study, we investigated the AOM within a sulfate-methane transition zone (SMTZ) at a depth of ~9.6 m at the rim of the Ginsburg mud volcano in the Gulf of Cádiz. The SMTZ is supplied with sulfate from both overlying seawater and an underlying evaporitic deposit, and it coincides with a fracture zone that hosts a visible biofilm. Here, carbon dioxide shows the strongest 13C-depletion, indicating intense methane consumption. Metagenomic and lipid biomarker analysis of the biofilm revealed an exceptionally simple microbial community dominated by ANME-1b archaea (63%), which predominantly produce strongly 13C-depleted glycerol dialkyl glycerol tetraethers and, to a lesser extent, the less common macrocyclic archaeols. The putative partner bacterium Seep-SRB1c (Desulfobacterota) is less abundant (9%). Additionally, the biofilm contained five low-abundance heterotrophs that likely rely on biomass or metabolites released from the ANME-SRB consortium. Our study highlights the presence of active methanotrophic biofilms in subsurface sediments and suggests that these communities may play an overlooked role in mitigating seafloor methane emissions.
Calcium tartrate (CaT) instability in bottled wines has become a recurrent issue. Conventional stabilization strategies, such as cold stabilization or the use of protective colloids, can be ineffective or yield inconsistent results. Cation-exchange resins and electrodialysis can reduce the risk of CaT precipitation, but their use is limited by cost and availability. Therefore, the aim of this study was to assess sodium alginate, a natural divalent metal chelator, as a processing aid to remove calcium and improve CaT stability. The study began with the characterization of the alginate composites formed in wines, followed by an evaluation of different doses and contact times. Subsequently, a series of conventional and dealcoholized wines was evaluated, showing significant reductions in calcium concentration (i.e., 27-32% in conventional wines and 10-21% in dealcoholized or reduced-alcohol wines) and improved CaT stability. Besides a significant increase in sodium content, conductivity, and turbidity (p < 0.05), most other compositional parameters remained stable, with variations observed only in some wines for certain parameters (e.g., CIELab parameters). These findings demonstrate the potential of sodium alginate as a practical calcium-binding agent and suggest the need for further studies to continue evaluating its applicability in winemaking.
Obesity is increasingly recognized as a multifactorial disease influenced by environmental exposures, including endocrine-disrupting chemicals (EDCs). These substances interfere with hormonal signaling and may contribute to adipogenesis and metabolic dysfunction. This narrative mini-review drew on epidemiological, experimental, and clinical research and examined the most recent literature on the role of EDCs in adipogenesis. It focuses on the mechanisms of action. Studies report that a wide variety of EDCs affect adipogenic differentiation through pathways mediated by nuclear receptors (PPARγ/RXR) and through broader endocrine disruptions involving estrogen-, glucocorticoid-, and thyroid-related pathways. Adiposity, including body weight, BMI, and abdominal obesity, is associated with chemical exposure, according to clinical data from human studies. Since they may differ based on the EDCs, the timing of exposure, and sex, the strength and consistency of the effects are still not entirely understood. One important environmental factor in the development of obesity is EDCs. Public health interventions should prioritize identifying and regulating them.
Gestational weight gain (GWG) and birth weight (BW) have a multifactorial etiology, which makes identifying the most influential determinants difficult. The association between variants of the FTO and LEPR genes has been explored as contributing factors to obesity in various age groups; however, their role in GWG and BW in adolescent mothers and their offspring is uncertain. To determine whether the presence of polymorphisms rs9939609 (FTO) and rs1137101 (LEPR) is associated with gestational weight gain and newborn weight in a cohort of adolescent mothers. Methods: A prospective cohort study of 305 mother-child dyads was conducted between 2020 and 2024. Genotyping of the single nucleotide variants (SNVs) rs9939609 of the FTO gene and rs1137101 of the LEPR gene was performed using real-time PCR and high-resolution melting analysis (qPCR-HRM), using maternal peripheral blood and umbilical cord blood samples. GWG, BW, energy intake, and other perinatal data were recorded and classified. Genetic data from 305 mother-offspring dyads were analyzed. The median maternal age was 16 years, and 71.4% had a normal pre-pregnancy body mass index (BMI). The most frequent genotypes were TT for FTO rs9939609 and AG for LEPR rs1137101. In both groups, the genotypic distribution significantly deviated from Hardy-Weinberg equilibrium (p < 0.0001). The AA genotype of FTO was associated with a higher probability of excessive gestational weight gain (GWG) after adjustment for pre-pregnancy BMI and dietary and sociodemographic factors. High protein and lipid intake increased the risk of excessive GWG, whereas adequate intake of carbohydrates and legumes showed a protective effect. An initial significant association was identified between the LEPR rs1137101 variant (AA allele) and low birth weight (LBW); however, this association was lost after adjustment for confounding factors. The FTO rs9939609 variant was significantly associated with GWG. On the other hand, the LEPR rs1137101 variant in the offspring showed an association with BW categorized by percentiles (in crude analysis), while the FTO variant showed no relationship with birth weight.
Polygenic risk scores (PRSs) improve prediction of the development of type 2 diabetes over the use of clinical risk factors alone; however, they perform poorly in populations of non-European ancestry, limiting their global clinical utility. We aimed to deliver comprehensive and rigorously tested multi-ancestry PRSs for prediction in type 2 diabetes. We conducted meta-analyses using data from type 2 diabetes genome-wide association studies (GWAS) across cohorts from five major global ancestries: European, African or African American, Admixed American, South Asian, and East Asian. We used summary statistics from the GWAS to construct single-ancestry PRSs (using the continuous-shrinkage PRS-CS method) and multi-ancestry PRSs (using the PRS-CSx method), and constructed ancestry-specific linkage disequilibrium panels to model pairwise correlations between single-nucleotide polymorphisms in GWAS during PRS construction. Models were validated for association with type 2 diabetes in at least four independent cohorts per ancestry. The effect sizes of PRSs were estimated as the odds ratio (OR) per SD of the PRS, and ORs for individuals at the 90th, 95th, and 97·5th PRS percentiles were compared with the IQR as a reference. We also tested our PRS models for prediction of diabetes incidence with or without additional clinical factors, as well as microvascular complications and comorbidities. Our analysis used data from 409 959 individuals with type 2 diabetes and 1 983 345 controls: respectively, 359 819 and 1 825 729 indivduals were included in the GWAS dataset, with 10 992 and 31 792 individuals in the training dataset and 39 148 and 125 824 individuals in the validation dataset. The best predictive performance for the single-ancestry PRSs was in European (incremental AUC 0·07-0·14) and East Asian (0·02-0·16) ancestries, whereas prediction was poorer for African or African American (0·02-0·03), Admixed American (0·02-0·04), and South Asian (0·02-0·04) ancestries, correlating with sample sizes in the GWAS. Compared with single-ancestry PRSs, our multi-ancestry PRSs showed higher effect sizes and smaller 95% CIs across all ancestries: OR per SD 1·73 (95% CI 1·67-1·80) in African or African American, 2·82 (2·67-2·97) in Admixed American, 2·45 (2·36-2·54) in East Asian, 2·36 (2·32-2·41) in European, and 2·23 (2·05-2·42) in South Asian ancestries. Individuals in the 97·5th PRS percentile had a 3-7 times increased risk of type 2 diabetes compared with those in the IQR (OR 3·43 [95% CI 2·80-4·21] in African or African American, 7·47 [5·64-9·89] in Admixed American, 6·62 [5·58-7·85] in East Asian, 6·25 [5·72-6·82] in European, and 4·50 [2·70-7·53] in South Asian ancestries). These PRSs were also associated with earlier onset of type 2 diabetes, higher risk of developing microvascular complications, and provide additional predictive value beyond clinical factors. In individuals with type 2 diabetes, the association between multi-ancestry PRSs and risk of microvascular complications and comorbidity was studied in populations of African, Admixed American, and European ancestries and was significant in all three ancestry groups for diabetic retinopathy (ORs per SD 1·28-1·57), diabetic nephropathy (1·25-1·58), proliferative diabetic retinopathy (1·39-2·08), and end-stage diabetic nephropathy (1·44-1·87); PRS was associated with coronary artery disease in the Admixed American ancestry group only (1·16 [95% CI 1·08-1·25]). These validated, publicly available PRSs can improve risk stratification for type 2 diabetes onset and complications across diverse ancestries, supporting their further evaluation in clinical settings. The National Human Genome Research Institute of the US National Institutes of Health.
X-linked myotubular myopathy (XLMTM) is a severe, rare, familial neuromuscular disease caused by mutations in the MTM1 gene. XLMTM presents a wide spectrum of clinical manifestations, including neuromuscular symptoms such as hypotonia and severe generalised muscle weakness, which lead to respiratory and orthopaedic complications; and extramuscular manifestations such as hepatobiliary and gastrointestinal involvement. As there is no curative treatment for XLMTM, and given the complications associated with the disease and its high morbidity and mortality, survival and quality of life in these patients rely on a comprehensive, multidisciplinary approach. A group of paediatric neurologists, one pulmonologist, one hepatologist, one intensivist, and rehabilitation specialists from Spain and Portugal with in-depth understanding and experience in XLMTM management present a multicentre series of 24 patients with XLMTM and problems and experience on its clinical management. Severe phenotypes showed significant neuromuscular and non-neuromuscular involvement. Multidisciplinary management, including respiratory support, nutritional interventions, and rehabilitation, is essential. Unmet needs include better neurocognitive assessment tools, improved access to multidisciplinary care, and resources for physical therapy. Communication aids are crucial for patient development. Multidisciplinary management of XLMTM is essential for improving outcomes, with significant unmet needs in several areas of clinical care.
Nepetalactone (NL) is a volatile iridoid monoterpene widely used in biopesticidal and repellent applications, yet its toxicokinetic behavior and metabolic fate as a pure compound remain poorly characterized. This study aimed to provide an integrated toxicokinetic evaluation of NL by combining in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) modeling with in vitro metabolism assays using rat and human liver microsomes, supported by UHPLC-MS/MS analysis for metabolite identification. The in silico biotransformation predicted extensive phase I oxidation followed by phase II conjugation, while ADMET predictions indicated low systemic persistence and limited toxicological concern for most metabolites. The performed in vitro microsomal assays confirmed the in silico prediction by a rapid and time-dependent NL metabolism via both oxidative (86% reduction in NL concentration after 120 min) and conjugative (89% reduction in NL concentration after 120 min) pathways in rat and human systems, with comparable depletion kinetics between species. UHPLC-MS/MS enabled the identification of multiple phase I and phase II metabolites, pointing to pronounced interspecies differences in conjugative metabolism. In this sense, while oxidoreduction and hydrolysis reactions were consistent with previously reported iridoid metabolism. This study suggests the possible formation of previously unreported amino acid-related derivatives, although these require further confirmation. Overall, these findings advance the understanding of NL biotransformation, propose a new, previously unknown, metabolic pathway for iridoids, and provide relevant data to support human health and environmental risk assessment frameworks.
This study aims to explore the application of machine learning techniques in assessing macrophage activation syndrome (MAS) in Still's disease. A multicenter, observational, prospective study was conducted, including patients with Still's disease enrolled in the Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) AOSD Study Group and the AutoInflammatory Disease Alliance (AIDA) Network Still's Disease Registry. A total of 737 patients (age: 35.5 ± 17.8, male sex: 44.7%) with Still's disease were assessed; 11.4% were affected by MAS, and 3% had a poor prognosis. First, random forest imputation was applied to the original dataset. Subsequently, a machine-learning-driven assessment was developed to explore MAS occurrence. Collectively, regression models, an exploration decision tree, and a random forest were applied, suggesting the importance of ferritin, age, C-reactive protein (CRP), and systemic score. A logistic regression model accounting for data leakage concerns was then generated using these variables, and missing values were imputed using random forest imputation. This analysis supported the role of the selected variables, which were further combined across different clinical scenarios to estimate the probability of MAS. The highest risk of MAS was estimated for patients simultaneously characterized by age ≥ 45 years, ferritin ≥ 4,178.10 ng/mL, CRP ≥ 27.15 mg/L, and a systemic score ≥ 7, corresponding to a 34.7% probability of MAS, as well as for those characterized by ferritin ≥ 4,178.10 ng/mL, CRP ≥ 27.15 mg/L, and systemic score ≥ 7, corresponding to a 33.5% probability of MAS. A machine-learning-driven prediction of MAS was explored in Still's disease, highlighting the importance of age of onset, hyperferritinaemia, increased CRP, and multiorgan involvement. A combination of these features may suggest a clinician-friendly algorithm for stratifying the probability of MAS during Still's disease.
Endogenous heat shock cognate 73 kDa protein (HSC70) plays a role in early embryonic development and cellular stress regulation. This study evaluated the effects of exogenous recombinant HSC70 supplementation on bovine embryo development and the expression of apoptosis-related genes under in vitro conditions. Expression analyses of HSPA1A, HSPA8, BCL-2, and BAX were performed on Day 7 bovine embryos produced in vivo and in vitro. In vitro embryos exhibited higher basal expressions of HSPA8, BAX and BCL-2 compared with in vivo embryos (p ≤ 0.001). Supplementation with 500 or 1000 ng/mL HSC70 was associated with increased expression of HSPA1A, HSPA8, BCL-2, and BAX relative to control embryos (p ≤ 0.01). The 1000 ng/mL group showed significantly higher HSPA8 expression compared with both the control and 500 ng/mL groups. Morphological evaluation indicated that embryos supplemented with 500 ng/mL were associated with improved blastocyst yield and quality compared with control and 1000 ng/mL groups.In conclusion, supplementation with 500 ng/mL recombinant HSC70 was associated with modulation of apoptosis-related gene expression and improved morphological developmental parameters under in vitro conditions. These findings indicate dose-dependent regulatory effects of HSC70 on apoptosis-related signaling pathways; however, as apoptosis was assessed at the transcriptional level, the results should be interpreted as molecular associations rather than direct confirmation of altered apoptotic activity.
This study reviews the main candidate genes involved in the pathophysiology of Polycystic Ovary Syndrome (PCOS). PCOS is a common endocrine-metabolic disorder in women of reproductive age, characterized by menstrual irregularity, hyperandrogenism, and polycystic ovarian morphology. It is associated with increased metabolic and cardiovascular risk and is a leading cause of infertility. Although its pathophysiology is not fully understood, alterations in the hypothalamic-pituitary-ovarian axis, insulin metabolism, and steroidogenesis have been described. Polymorphisms in genes encoding hormones, enzymes, and receptors in these pathways contribute to clinical variability and ethnic differences, offering potential for early diagnosis and personalized medicine. This review summarizes key candidate genes related to insulin metabolism (INS, INSR, IRS-1), the hypothalamic-pituitary-ovarian axis (LHβ, LHCGR, FSHR, GnRHR, AMH, AMHR2, KISS1, CAPN10), steroidogenesis (CYP11A, CYP17A1, CYP19A1, CYP21, 17β-HSD, SHBG, AR, STAR), and other clinically relevant mechanisms such as obesity, lipid metabolism (PPARG, VDR, FTO), and follicular development (ACE).
Background/Objectives: Dysphagia is associated with an increased risk of in-hospital complications and adverse outcomes. Prognosis in frail hospitalized populations is influenced by systemic inflammation and reduced muscle mass. Calf circumference (CC) and an estimated appendicular skeletal muscle index (ASMI) can serve as indirect measures of muscle mass, while inflammatory status may be captured by C-reactive protein (CRP), albumin, and the CRP/albumin ratio. This study aimed to evaluate the prognostic value of indirect biomarkers of inflammation and muscle mass to predict prognosis in hospitalized patients with suspected dysphagia. Methods: A retrospective observational study was conducted at a tertiary hospital and included patients admitted with suspected dysphagia between April 2015 and October 2024. On admission, demographic variables (sex and age), anthropometry (weight, height, and CC), EAT-10 (Eating Assessment Tool) score, and serum laboratory parameters (CRP, albumin) were collected. ASMI was estimated using the formula -10.427 + (CC × 0.768) - (age × 0.029) + (sex × 7.523)/(height2). Outcomes were in-hospital mortality and length of hospital stay. Comparisons were performed between survivors and non-survivors, and multivariable models adjusted for age and sex were used to identify independent associations with mortality. Results: A total of 4241 patients were included (51.2% women), with a median age of 85 (Interquartile range [IQR] 14) years and a mean EAT-10 score of 15.98 (SD 7.79). In-hospital mortality was 18.13% (n = 769). Non-survivors were older (86 [IQR 11] vs. 84 [IQR 14] years; p < 0.001) and displayed a more inflammatory profile, with higher CRP (78.1 [IQR 114.28] vs. 44 [IQR 96] mg/L) and CRP/albumin ratio (27.27 [IQR 43.04] vs. 13.64 [IQR 31.77]; p < 0.001), and lower albumin (3 [IQR 0.8] vs. 3.3 [IQR 0.8] g/dL; p < 0.001). They also had lower muscle mass, with reduced CC and lower ASMI in both sexes. In multivariable analysis, a higher CRP/albumin ratio was independently associated with increased odds of death (OR 1.011; 95% CI 1.008-1.014; p < 0.001), whereas a higher ASMI was protective (OR 0.885; 95% CI 0.801-0.978; p = 0.017). Higher CRP/albumin ratios were also associated with longer hospital stays and lower albumin, CC, and ASMI values. Conclusions: In hospitalized patients with suspected dysphagia, systemic inflammation and lower muscle mass were associated with worse clinical outcomes. The CRP/albumin ratio independently predicted higher in-hospital mortality and prolonged hospitalization, whereas higher estimated ASMI was associated with lower mortality risk, supporting the combined prognostic value of inflammatory and muscle-mass indicators in this population.
Smoothies represent a promising vehicle for increasing fruit and vegetable consumption and bioactive diversity. However, their formulation often lacks a rigorous analytical validation of phytochemical complementarity. This study establishes a methodological framework for the design of potential functional plant-based beverages, centered on a high-resolution LC-MS/MS-driven strategy. Through a targeted screening of 57 (poly)phenolic compounds, a precise phytochemical mapping of diverse botanical matrices was performed to optimize ingredient selection based on chemical diversity rather than empirical blending. A novel formulation combining Granny Smith apple, green celery, dried green chicory, and peppermint leaves was developed to maximize both bioactive density and structural variety. The resulting matrix achieved a total (poly)phenol concentration of 2947.68 ± 5.17 µg/g dm, encompasses six major subclasses: flavan-3-ols, hydroxycinnamic acids, flavanones, flavonols, flavones, and dihydrochalcones. The results demonstrate that analytical fingerprinting allows for the strategic enrichment of food systems, ensuring a highly characterized and diversified phenolic spectrum. This research shifts the focus toward the evidence-based molecular design of health-promoting foods with verified nutritional properties.
Immune checkpoint inhibitors (ICIs) have transformed modern cancer therapy by restoring antitumor T-cell responses through blockade of immune tolerance pathways such as CTLA-4 and PD-1/PD-L1. However, the same immune activation that underlies their clinical efficacy can also lead to immune-related adverse events (irAEs), a broad spectrum of inflammatory and autoimmune toxicities that may affect virtually any organ system. The incidence and severity of these events vary according to the specific agent, tumor type, and treatment strategy. While irAEs have traditionally been attributed to dysregulated adaptive immunity, emerging evidence highlights a central and previously underappreciated role for innate immune mechanisms. In this review, we integrate the concepts of immunosurveillance and tumor immunoediting to illustrate how innate immunity contributes to both effective antitumor responses and immune-mediated toxicity. We describe how damage-associated signals and tumor microenvironment cues reprogram innate immune populations-including neutrophils, macrophages, dendritic cells, myeloid-derived suppressor cells, and innate lymphoid cells-toward pro-inflammatory or immunosuppressive states that influence therapeutic outcomes and toxicity risk. Finally, emerging biomarkers are highlighted and key knowledge gaps that currently limit the prediction and prevention of irAEs, positioning innate immunity as a critical regulatory axis and a promising target for developing strategies to mitigate toxicity without compromising anticancer efficacy.
The prevalence of thyroid nodular disease (TND) varies depending on study type. Nevertheless, a study including autopsies of patients from all over the country, covering almost three decades, is required to deepen our understanding of benign, borderline, and malignant lesions after the World Health Organization 2022 update. This study aimed to identify the prevalence of follicular TND (FTND), borderline, and malignant nodules in autopsies from a third-level hospital in Mexico City, as well as to determine the association between salt iodination and thyroid nodule genesis. Autopsies performed between 1992 and 2019 were considered if archived thyroid remnants and clinical data were available. Cases with known premortem thyroid pathology were excluded. Nodules were considered diagnosed if gland morphology was grossly distorted. The study included 487 autopsies, of which 276/59.2% were women. The mean age was 46.6 years. Of 487 glands, 266 (55%) had TND. Nodular glands had a higher weight than normal glands (17.8 vs. 16.1 g), with a 1.9:1 female-to-male ratio. No increase in the prevalence of nodules was observed after 2004 when salt iodination was regulated (0.40 vs. 0.39; p = 0.969). The median age of patients with FTND was 49 years for men and 51 years for women. Papillary thyroid carcinoma was observed in 44/9.4% glands, and the recently characterized non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)/an indeterminate lesion was only identified in seven (1.5%) cases. TND was not associated with salt iodine regulation in Mexico, and prospective studies are needed to explain this finding in this country. Understanding the prevalence of subclinical FTND, NIFTP, and carcinomas is relevant and can contribute to reducing the rate of overdiagnosis in thyroid pathology.
The transition from high school to college involves lifestyle changes that can lead to increased body weight, a phenomenon commonly referred to as the Freshman 15. Although educational settings may differ across countries, this period could also present a risk of weight gain. To determine the weight gain in Mexican students during the transition from high school to a public university and identify the primary associated modifiable factors. Two hundred twenty-six students of both sexes, aged 17-21 years, were evaluated at the beginning and end of the first semester. Anthropometric characteristics, lifestyle habits, and self-perceived stress were analyzed. Intra-subject differences were assessed using the general linear model with repeated measures, and categorical variables were evaluated using non-parametric tests. A significant weight increase of 0.8 kg was observed regardless of sex. Adolescents who ate under 20 min or lived in a rooming house without appliances exhibited the highest weight gain. Regression analyses revealed that female sex (β = -0.929, p = 0.008) and eating time of 21 min or more (β = 0.756, p = 0.050) were significantly associated with body weight change. In the multiple regression model, only sex remained a significant factor (p = 0.018). Weight gain in university students, especially in men, highlights this stage as a vulnerable period. It is essential to study habits and behaviors according to gender to design interventions that promote healthy eating. Further research is needed to identify modifiable factors associated with weight gain.
Assessing insulin sensitivity is a central component of clinical research in metabolism. Although considered the gold standard, the euglycemic-hyperinsulinemic clamp evaluates insulin sensitivity under non-physiological conditions and is highly burdensome and costly, thereby prompting the development of alternative methods. The 24-h urinary C-peptide excretion rate adjusted for energy intake is a surrogate marker of insulin sensitivity in non-diabetic adults. We hypothesized that the combination of 24-h continuous glucose monitoring (CGM) and 24-h urinary C-peptide excretion (24 h-glycemia/C-peptide ratio) would be a better predictor of insulin sensitivity than the C-peptide excretion rate adjusted for energy intake or other widely accepted indexes. Thirteen non-diabetic individuals (7 women, 6 men; 52.2 ± 13.8 years; BMI: 26.1 ± 3.7 kg/m2) participated in this cross-sectional study. They completed a 24-h stay in a whole-room indirect calorimeter wearing a CGM sensor (Dexcom G6 Pro) while all produced urine was collected. Insulin sensitivity was assessed by a 2-step hyperinsulinemic-euglycemic clamp [180 min at 10 mU/min/m2 (low-dose) and 120 min at 80 mU/min/m2 (high-dose)]. The 24 h-glycemia/C-peptide ratio was positively associated with the clamp's low-dose glucose infusion rate (GIR: R2 = 0.401, p = 0.020) and tended to be associated with the high-dose GIR (R2 = 0.266, p = 0.086). The associations between GIR and previously accepted markers of insulin sensitivity resulted in R2 ranging from 0.248 to 0.456 for the clamp low dose and R2 ranging from 0.108 to 0.174 for the clamp high dose. These results suggest that the 24 h-glycemia/C-peptide ratio is a promising simple, inexpensive, non-invasive, and physiological marker of insulin sensitivity that deserves further investigation.