Colorectal cancer (CRC) is a major global cause of death, with metastases and chemotherapy resistance contributing to poor outcomes. To identify natural compounds with anticancer potential against CRC and elucidate their action mechanisms, the cytotoxicity of 37 natural compounds was evaluated against the HCT116, leading to the identification of conferone as the lead candidate. Its anti-migratory and anti-invasive effects were evaluated in HCT116, Colo205, and SW480 cells. The interactions between conferone and focal adhesion kinase (FAK) were assessed through protein expression analysis and molecular docking. Glutaminolysis regulation was determined by LC-MS/MS, and related enzyme levels were detected by western blotting. Conferone inhibited migration and invasion in all three CRC cell lines, though it showed limited anti-proliferative activity. At 10 μM, conferone reduced FAK and p-FAK (Tyr397) protein levels, reversing the epithelial-mesenchymal transition. Docking analysis confirmed direct FAK binding and predicted inhibition of its phosphorylation, with greater affinity than the FAK inhibitor 1,2,4,5-benzene tetramine tetrahydrochloride. Conferone also downregulated glutaminase and glutamate-ammonia ligase, increasing glutamine and decreasing glutamic acid. Additionally, it suppressed c-raf phosphorylation and reduced c-Myc expression, blocking glutaminolysis-driven metabolism. These findings highlight conferone as a potential therapeutic agent that targets FAK, alters metabolic reprogramming, and impedes CRC progression.

Estrogen receptor alpha (ERα)-positive luminal breast cancer is commonly treated with aromatase inhibitors (AI) to block estrogen signaling; however, resistance frequently develops, limiting therapy success.

We observed that GLYATL1 (Glycine-N-Acyltransferase Like 1) expression is upregulated in AI-resistant breast cancer cell models and in patients undergoing AI therapy, correlating with poorer survival. Here we demonstrate that GLYATL1 promotes resistance to estrogen deprivation by elevating succinate levels and altering epigenetic histone marks associated with active transcription. Knockdown or knockout of GLYATL1 reverses these effects and reduces proliferation under estrogen-deprived conditions. Notably, GLYATL1 expression is positively regulated by estrogen receptor alpha signaling, however, independently of estrogen.

These findings reveal GLYATL1 as a metabolic and epigenetic mediator of endocrine therapy resistance, suggesting it as a potential target to overcome AI resistance in luminal breast cancer.

Environmental exposure to toxic and trace metals has been implicated in colorectal carcinogenesis through oxidative DNA damage and epigenetic dysregulation. However, human evidence linking tissue-level metal accumulation with epigenetic and genotoxic biomarkers remains limited, particularly in studies using paired tumor and adjacent non-cancerous colon tissues.

This study aimed to (i) characterize concentrations of selected toxic and trace metals in paired cancerous and non-cancerous colon tissues, (ii) examine associations between tissue metal concentrations and global DNA methylation in colon tissue, and (iii) evaluate relationships between tissue metal burden and circulating biomarkers of oxidative DNA damage and global DNA methylation in peripheral blood.

Fifty adult patients with newly diagnosed primary colon cancer undergoing surgical resection were included. Concentrations of lead (Pb), cadmium (Cd), mercury (Hg), arsenic (As), chromium (Cr), and titanium (Ti) were measured in paired colon tissue samples using ICP-MS. Global DNA methylation was assessed in colon tissue and peripheral blood using ELISA-based quantification of 5-methylcytosine, while oxidative DNA damage in peripheral blood lymphocytes was measured using the comet assay (tail moment). Paired comparisons were conducted using the Wilcoxon signed-rank test. Multivariable linear regression models adjusted for age, sex, body mass index, education, and tumor location were used to evaluate associations between metals, a composite Metal Burden Index, DNA methylation, and oxidative DNA damage.

Cadmium concentrations were significantly lower in cancerous compared with non-cancerous colon tissue (median 0.011 vs. 0.019 μg/g wet weight; p = 0.005), while no significant differences were observed for Pb, Hg, As, Cr, or Ti. No statistically significant associations were found between individual tissue metals or the Metal Burden Index and global DNA methylation in either colon tissue type. Tissue metal concentrations were generally not associated with blood global DNA methylation. An inverse association was observed between Hg concentration in cancerous tissue and blood comet assay tail moment (β = -0.582; 95% CI: -1.004 to -0.160; p = 0.008), which should be interpreted cautiously. Correlations between tissue and blood-based epigenetic and genotoxic biomarkers were weak.

In this cross-sectional study, metal accumulation in colon tissue was not consistently associated with global DNA methylation in tissue or blood. The limited concordance between tissue-based metal concentrations and circulating epigenetic or genotoxic biomarkers highlights the complexity of exposure-biomarker relationships in established colon cancer and suggests that blood-based markers may inadequately reflect localized tissue-level processes, with implications for environmental exposure assessment and public health biomonitoring.

A subset of individuals experience prolonged neurological and psychiatric symptoms following SARS-CoV-2 infection, a condition referred to as long COVID (LC). Limited evidence implicates ongoing neuroinflammatory processes as a driver of LC. This study investigates neuroinflammation in LC using translocator protein positron emission tomography (TSPO PET).

14 LC, 11 healthy control (HC) and 13 multiple sclerosis (MS) participants were included in the study. They underwent [¹¹C]PK11195 TSPO PET and 3T magnetic resonance imaging (MRI) to evaluate glial activation, white matter (WM) pathology and brain volumetrics. Serum neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) were measured as markers of neuronal and glial damage. LC participants completed neurological examinations and mental health assessments.

TSPO availability, measured as distribution volume ratio (DVR), was not elevated in LC compared to HCs but was significantly lower in LC compared to MS (WM DVR 1.03 vs. 1.06; p = 0.007). Individuals imaged within 16 months of SARS-CoV-2 infection showed higher WM DVR compared to those with a longer disease duration (1.05 vs. 1.02; p = 0.04). Moreover, lower quality of life was associated with higher DVRs in the hippocampus, amygdala and thalamus (ρ = - 0.83- - 0.70), and depression and anxiety correlated positively with DVRs in the hippocampus and amygdala (ρ = 0.75-0.97).

LC TSPO availability did not differ from HCs in any studied brain area. However, lower WM TSPO availability in individuals with longer LC duration suggests COVID-19-associated neuroinflammation may subside with time, while the association between limbic TSPO availability and LC severity may imply a role for limbic activity in LC symptomology.

To understand adolescents' responses to the Covid-19 pandemic, considering their beliefs and attitudes towards the threat of contagion and transmissibility.

Qualitative study, based on the theoretical framework of the Health Belief Model, conducted in a municipality in northeastern Brazil. Six focus groups were held, with the participation of 45 adolescents. The statements were transcribed, organized into a textual corpus, and submitted to content analysis using IRAMUTEQ software.

Three thematic categories emerged: 1. Perception of risk and susceptibility to Covid-19 - threat, death; 2. Severity and gravity of COVID-19 - isolation, fear; 3. Prevention and protective measures against coronavirus contamination - social distancing, hygiene.

The study showed that the perception of risk and severity of the health crisis contributed to adolescents adopting self-protective behaviors for themselves and their families. Their mental health was affected by feelings of fear and anxiety, reflected in their social interactions during the isolation and post-pandemic periods. It is suggested that there be a greater focus on health actions for this population, as well as studies that identify other outcomes of the period experienced.

ObjectiveThe ROX index, combining oxygenation and respiratory rate, is widely used to assess respiratory failure. However, its prognostic value in critically ill patients with chronic obstructive pulmonary disease (COPD) remains unclear. This study aimed to explore the association between the ROX index and mortality in ICU patients with COPD.MethodsThis retrospective cohort study included patients with COPD from two large databases: MIMIC-IV (v3.1) and eICU-CRD (v2.0). The ROX index was calculated within the first 24 hours of ICU admission. The primary outcome was in-hospital mortality, with ICU mortality and 28-day mortality as secondary outcomes. Cox regression models, Kaplan-Meier survival curves, restricted cubic spline (RCS) analysis, and subgroup analyses were used to evaluate the association between ROX and mortality.ResultsA total of 1,639 patients from the MIMIC-IV cohort and 2,170 from the eICU-CRD cohort were included. In multivariable Cox regression, a higher ROX index was independently associated with a lower risk of in-hospital mortality (MIMIC-IV: HR = 0.96, 95% CI: 0.93-0.98; eICU-CRD: HR = 0.95, 95% CI: 0.92-0.98). Similar associations were observed for ICU and 28-day mortality. RCS analysis demonstrated a linear negative correlation between ROX and the risk of death. Subgroup analyses showed consistent results across various clinical strata. The E-value analysis suggested that a considerable amount of unaccounted confounding would be necessary to invalidate the observed associations.ConclusionsThe ROX index is inversely associated with mortality in critically ill patients with COPD, with higher values indicating better prognosis. It may serve as a simple, non-invasive, and valuable tool for early risk stratification in the ICU setting.

Bordetella bronchiseptica (Bb) is a common respiratory infection in dogs with potentially serious clinical consequences. A subset of Bb cases require referral to tertiary care institutions, yet these dogs lack characterization.

Describe the clinical features, diagnostic findings, management, and outcomes of dogs diagnosed with Bb infections at a tertiary care institution, and evaluate risk factors associated with severe, refractory, or recurrent Bb infections.

Fifty-nine client-owned dogs diagnosed with Bb infections at a tertiary care hospital.

Retrospective, observational study (1995-2024). Univariable and multivariable logistic regression models were used to identify risk factors associated with negative disease outcomes.

Cavalier King Charles Spaniels (CKCS) and Yorkshire Terriers were overrepresented (17.0% and 10.2%, respectively) when compared with hospital admissions from the same period (P <.0001 for both). Nearly 80% of infections were classified as chronic in this population, with a median duration of clinical signs of 30 days. Approximately 40% of cases were classified as severe infections (ie, pneumonia), whereas 54% were classified as refractory. Recurrent Bb infections were uncommon (7%). Mycoplasma spp. coinfections were reported in 37% of cases but were not associated with outcomes. Although no variables were identified as predictors of severe disease, respiratory tract comorbidities (eg, brachycephaly) were associated with refractory infections (P = .04).

Yorkshire Terriers and CKCS were overrepresented for Bb infections in a referral population, which could indicate underlying risk factors within these breeds. Structural respiratory tract abnormalities may predispose dogs to refractory Bb infections.

Test-negative designs, a form of case-cohort studies, have been commonly used to assess infectious disease interventions. Early examples of the design included the evaluation of seasonal influenza vaccines in the field. Recently, they have also been widely used to evaluate the efficacy of COVID-19 vaccines in preventing symptomatic disease for different variants [32]. The design hinges on individuals being tested for the disease of interest; upon recruitment, such individuals are subjected to a definitive test for the presence of the disease of interest (test-positives) or not (test-negatives), along with the determination of whether the individual has been exposed to the intervention under study (e.g., vaccination). In most early TND studies, individuals were tested because they were suffering from symptoms consistent with the disease in question, and the TND was a tool to reduce confounding due to healthcare-seeking behavior. However, in many cases, such as COVID-19 and Ebola, testing results were available at healthcare facilities for individuals who presented for a variety of reasons in addition to symptoms (e.g., case contact tracing, etc.). Aggregating samples from symptomatic and asymptomatic test results leads to bias in the assessment of the efficacy of the intervention. Here we consider these issues in the context of a specific version of the 'multiple reasons for testing problem,' motivated by a vaccine trial designed to assess a new Ebola viral disease vaccine (EVD) [22]. Some participants are recruited in the usual TND fashion as they present for care suffering from symptoms consistent with an Ebola diagnosis (and are thus tested); in addition, however, any test-positive identified in this fashion leads to immediate testing for Ebola for all close contacts of the test-positive who are likely asymptomatic at that point. We examine a simple approach to estimate the common efficacy of the vaccine intervention based on these two sources of test positives and test negatives, complemented by an assessment of whether efficacy is the same for both sources. The EVD trial was not completed for the fortunate reason that the prevailing disease outbreak ended; nevertheless, the approach here will be important if this trial is ever recommenced or similar trials are conducted in the future.

The 2024/2025 influenza season in Italy was characterised by cocirculation of influenza A and B viruses. Monitoring influenza vaccine effectiveness (IVE) remains essential to guide public health policy due to antigenic shifts and varying strain circulation. In this study, we aimed to estimate IVE in primary care and hospital settings during the 2024/2025 season in Italy. A nationwide test-negative control design was used. Data were collected from the RespiVirNet surveillance system, encompassing both primary care and hospital settings. A total of 8842 participants were included in the primary care analysis and 2492 in the hospital analysis. Adjusted vaccine effectiveness (aVE) against any influenza virus was 69.0% (95% CI: 60.4%-75.9%) in primary care and 62.3% (95% CI: 45.9%-74.2%) in hospital settings. Effectiveness was highest among individuals under 18 years and decreased with age. Influenza B showed the highest aVE (83.6% in primary care; 95.0% in hospital settings), particularly among younger individuals. aVE for influenza A subtypes was lower, with A H1N1pdm09 (54.0% in primary care; 63.8% in hospital) and A H3N2 (60.1% in primary care; 45.5% in hospital) showing moderate effectiveness. The results suggest that influenza vaccines were effective in preventing medically attended influenza disease, both in primary care and hospital settings. These findings provide valuable insights for public health planning and vaccine policy in Italy.

Cats are among the most common household pets in Malaysia, and cat dander is a significant aeroallergen. This study aimed to estimate the prevalence of cat dander sensitisation, characterise allergic disease patterns across age groups, and explore the relationship between cat dander sensitisation and allergic multimorbidity.

A retrospective cross-sectional study was conducted on laboratory records of patients tested for specific immunoglobulin E to cat dander between January 2023 and December 2024. Specific immunoglobulin E levels were measured using fluoroenzyme immunoassay on the Phadia ImmunoCAP 250 system. Demographic information, allergic diseases history, and co-sensitisation patterns were analysed.

Of 2840 patients tested, 30% (n=851) were sensitised to cat dander, with 817 included in the final analysis. Most sensitised patients had single allergic disease (asthma, allergic rhinitis, or eczema) (51.2%), followed by those with allergic multimorbidity (35.6%). Asthma was the most common allergic disease (25%), followed by the combination of asthma and allergic rhinitis (18.4%). There was a significant association between age group and allergic disease patterns (p<0.001), where eczema was more prevalent in children and allergic airway diseases increased with age. Allergic multimorbidity peaked among school-aged children. Polysensitisation (≥4 allergens) was observed in 65.9% of patients. House dust mite was the most common co-sensitised allergen (96.3%), followed by cockroach (84.8%), grass pollen (62.6%) and fungal (45.7%).

Cat dander sensitisation affects nearly one-third of tested patients in Malaysia, and is frequently associated with polysensitisation. Age-specific disease patterns align with the atopic march paradigm, highlighting the need for targeted, age-appropriate intervention and prevention strategies.