Glutamine is the most abundant free amino acid in the body. It plays a central role in cellular metabolism, connecting synthetic and catabolic pathways, and maintaining life activities under physiological and pathological conditions. This review systematically explores the dual role of glutamine metabolism in health and disease. Glutamine is not only the main energy and nitrogen source for rapidly proliferating cells, such as immune cells, intestinal epithelial cells, and cancer cells but also participates in several key biological processes, such as nucleotide synthesis, REDOX balance, and immune regulation. Glutamine metabolism is often abnormally activated or disrupted in disease states, such as "glutamine addiction" in cancer and excitotoxicity and mitochondrial dysfunction in neurodegenerative diseases. Disorders of glutamine metabolism are also present in metabolic diseases (such as diabetes and MAFLD) and cardiovascular diseases. In addition, gut microbes regulate host glutamine metabolism through metabolites and signaling pathways, further affecting the disease process. Therapeutic strategies to target glutamine metabolism include inhibition of key enzymes or transporters, as well as exogenous glutamine supplementation. However, the effects of these strategies are context-dependent and need to be applied individually according to the specific pathological status of patients. Future research should focus on tissue-specific metabolic profiling, integrated multiomics analysis, and the development of combined treatment strategies to fully realize the potential of glutamine metabolism in disease treatment.

Human papillomavirus (HPV)-positive oropharyngeal cancer (OPC) is characterized by a distinct immune microenvironment; however, the biological significance of immune-related transcriptional programs may vary according to their spatial localization. We investigated the spatial organization of HPV-associated transcriptional programs across anatomically distinct tissue compartments in OPC.

An oropharynx-restricted The Cancer Genome Atlas (TCGA)-oropharyngeal squamous cell carcinoma (OPSCC) cohort comprising 77 tumors (51 HPV-positive and 26 HPV-negative) was analyzed using single-sample gene set enrichment analysis (ssGSEA). Spatial transcriptomic profiling using GeoMx Digital Spatial Profiling was evaluated in lymphoid follicular regions (LFRs) and tumor tissue regions (TTRs) from six OPC patients (four HPV-positive and two HPV-negative), with the patient treated as the primary experimental unit. Tumor-free surrounding palatine tonsillar tissue (PTT) was analyzed in an independent microarray cohort comprising 23 HPV-positive and four HPV-negative cases. Eight prespecified immune- and metabolism-related transcriptional programs were evaluated, with additional exploratory cell-type deconvolution and overall survival analyses.

In TCGA-OPSCC, all five immune-related programs were higher in HPV-positive tumors, and Stem-like, Tpex, B-cell activity, and T-cell activity remained significantly associated with HPV-positive status after adjustment for clinicopathological covariates and FDR correction. In paired GeoMx analyses, all five immune-related programs were higher in LFRs than in TTRs in all six patients, whereas Estrogen Response Early and Estrogen Response Late were higher in TTRs in all six patients (BH-FDR = 0.0357 for each program). Bile Acid Metabolism showed no consistent compartment-specific difference. HPV-associated differences within individual GeoMx compartments and HPV-by-compartment interactions were not statistically significant after FDR correction. In PTT, immune-related and metabolic programs showed directional HPV-associated differences, but none remained significant after FDR correction. Higher scores for several immune-related programs were associated with improved overall survival in univariable TCGA-OPSCC analyses, but these associations were attenuated after accounting for HPV status.

HPV-associated immune transcriptional programs identified in bulk OPC show consistent spatial organization across lymphoid follicular and tumor tissue compartments. The most robust spatial feature was within-patient compartmentalization between LFRs and TTRs, whereas evidence for HPV-associated differences within individual spatial compartments was limited. These findings emphasize the importance of anatomical context when interpreting transcriptional programs in OPC.

B cells can suppress anti-tumor T cell responses, representing a potential mechanism of resistance to immunotherapy. Multiple Breg subsets have been described in humans and mice. Bregs inhibit anti-tumor immunity through cytokine secretion, immune checkpoint expression, and potentially adenosine generation, which collectively suppress effector T cells, and strengthen immunosuppressive signaling. Hypoxia is a hallmark of pancreatic ductal adenocarcinoma (PDAC) and contributes to immune dysregulation within the tumor microenvironment (TME); however, the effects of hypoxia on B cell subsets remain poorly defined. In this study, we investigated how hypoxic stress shapes regulatory B cell phenotype using murine PDAC models. We show that nearly half of intratumoral B cells are hypoxic, which also increased across systemic B cell compartments with tumor burden. Hypoxic B cells were enriched for CD39 and CD73 ectonucleotidases and suppressed T cell activation via adenosine receptor-dependent mechanisms. Hypoxia preferentially induced CD39⁺CD73⁺ expression in peritoneal-derived B cells, indicating tissue-specific regulation, while splenic B cells showed limited responsiveness ex vivo. Conversely, hypoxia reduced IL-35 production by splenic Bregs through decreased Ebi3 expression and reduced activation marker levels. Within tumors, hypoxia correlated with CD11b⁺ and CD39⁺CD73⁺ B cells but not IL-35-producing subsets. Mechanistically, Ebi3 loss enhanced CD39 expression under hypoxia, whereas recombinant IL-35 suppressed CD39⁺CD73⁺ induction, suggesting reciprocal regulation between IL-35 and adenosine pathways. These findings reveal hypoxia-driven plasticity in immunosuppressive B cell programs in PDAC, characterized by suppression of IL-35-producing Bregs and promotion of adenosine-generating CD39⁺CD73⁺ B cells, highlighting potential therapeutic targets to modulate tumor-associated immunosuppression.

The mechanisms enabling disseminating tumor cells to survive and colonize peritoneal niches during ovarian cancer metastasis remain incompletely understood. Here, we present MetTag, a single-cell barcoding and transcriptome profiling approach with time-stamped batch identifiers to resolve temporal dynamics of dissemination. Sequencing of MetTag barcodes reveals enrichment of early-disseminated clones across metastatic sites, and targeted depletion of pioneers diminishes the outgrowth of later arriving cells. MetTag-coupled single-cell RNA sequencing uncovers a distinct interferon-gamma-centric transcriptional trajectory enriched among pioneer clones. CRISPR/Cas9 screening and subsequent interferon-gamma receptor 1 knockout in pioneer cells significantly reduces metastatic burden, highlighting a critical window where active interferon-gamma signaling shapes the post-seeding metastatic niche and outgrowth. Mechanistically, the tumor-intrinsic interferon-gamma response and peritoneal macrophages cooperatively shield disseminating tumor cells from anoikis. Our study defines the temporal clonal architecture of peritoneal metastasis, revealing a first come, first served dissemination principle, where pioneer fitness determines the success of subsequent colonizers.

Cancer mortality levels have declined across high-income countries, but progress has been uneven by cancer type. Examining birth-cohort patterns of lifestyle-related cancer mortality in an international context can shed light on how shared and differential global lifestyle transitions manifest differently across national contexts.

We used harmonized cause-of-death data from the Human Cause of Death series of the Human Mortality Database for Canada, Czechia, England & Wales, France, Germany, Japan, Spain, and the USA from 2000 to 2020. We examined mortality from lung and larynx, colorectal, stomach, and liver cancer for ages 30-84 years by using rates of mortality improvement displayed on Lexis surfaces. Single-age death rates were estimated from grouped data by using penalized composite link models. Two-factor Poisson models and sex-stratified surfaces served as sensitivity analyses.

All eight countries showed declining age-standardized cancer mortality, but with diverging trends by cause and birth cohorts. Lung and larynx cancer declined broadly, with mortality patterns reflecting cohort cigarette-smoking histories. Colorectal cancer mortality increased among cohorts born after 1960 in the USA, Canada, and England & Wales, with a similar but delayed pattern in France and Germany. Liver cancer mortality was higher for cohorts born in 1945-55 than for earlier and later cohorts in several countries, with a re-emerging adverse pattern among cohorts born in around 1970-80.

Birth-cohort patterns in lifestyle-associated cancer mortality differ across national contexts. Worsening colorectal and liver cancer trends among younger cohorts call for increased prevention and screening strategies.

Mask ventilation is a cornerstone of airway management during general anesthesia, yet the need for airway adjuncts during mask ventilation remains poorly predicted by current preoperative assessments. We aimed to identify independent clinical predictors of this outcome in Thai adults undergoing elective surgery.

This single-center prospective observational study included 266 adults undergoing elective general anesthesia at a university hospital in Thailand between September 2018 and October 2019. Preoperative airway assessment included Mallampati classification, dentition status, neck circumference, history of snoring or obstructive sleep apnea (OSA), and other standard variables. The primary outcome was the need for airway adjuncts or optimization during mask ventilation, defined as Han grade ≥2. Han grade ≥2 was selected because only 10 grade-3 events occurred, yielding an events-per-variable ratio of 2.5 under the grade ≥3 definition - insufficient for reliable multivariable regression. Independent predictors were identified using multivariable logistic regression with backward stepwise elimination. Discriminative ability was evaluated using receiver operating characteristic (ROC) analysis and area under the curve (AUC) for both neck circumference alone and the complete four-variable model. Bootstrap internal validation (1,000 resamples) was performed by repeating the model-building procedure, including univariable screening and backward stepwise elimination, within each resample.

The need for airway adjuncts (Han grade ≥2) occurred in 48 patients (18.0%); 38 (14.3%) had Han grade 2 and 10 (3.8%) had Han grade 3. Four variables were independently associated with the need for airway adjuncts in the multivariable logistic regression analysis: snoring or OSA (aOR 5.27, 95% CI 1.94-14.35), absence of ≥2 upper incisors (aOR 2.30, 95% CI 1.08-4.89), neck circumference ≥35 cm (aOR 3.02, 95% CI 1.42-6.44), and Mallampati class III-IV (aOR 2.47, 95% CI 1.22-4.97). The final four-variable model had an apparent AUC of 0.804 (95% CI 0.745-0.862). Bootstrap internal validation with 1,000 resamples, repeating the model-building procedure within each resample, yielded a mean optimism of 0.040 and an optimism-corrected AUC of 0.764 (95% bootstrap interval 0.708-0.820). The Hosmer-Lemeshow goodness-of-fit test showed no evidence of poor model fit (P = 0.077). A simple bedside integer risk score (0-5 points) had an AUC of 0.801. At an exploratory cutoff of ≥3, the sensitivity was 0.85, specificity 0.63, PPV 0.34, and NPV 0.95.

Snoring or OSA, neck circumference ≥35 cm, Mallampati class III-IV, and absence of ≥2 upper incisors were independently associated with the need for airway adjuncts during mask ventilation in Thai adult patients. All four predictors can be assessed at the bedside without additional equipment, suggesting their integration into routine preoperative airway evaluation. As a single-center derivation study, these findings are hypothesis-generating and require external validation in independent Southeast Asian cohorts before clinical adoption.

Residential greenness is considered protective for mental health, but its impact on clinically diagnosed psychiatric disorders following COVID-19 remains unclear. This study investigated the association between residential greenness and risk of common mental disorders after COVID-19, and whether this relationship differed by population subgroup.

We conducted a nationwide cohort study of 3,097,179 adults aged ≥19 years with confirmed COVID-19 in South Korea between 2018 and 2023 using the K-COV-N cohort, which integrates administrative and clinical data from the National Health Insurance Service and COVID-19 data from the Korea Disease Control and Prevention Agency. Residential greenness was assessed using the normalized difference vegetation index (NDVI) and categorized as low (0.2- < 0.4), moderate (0.4- < 0.6), or high (≥0.6). The primary outcome was first diagnosis of anxiety disorder, depression, insomnia, or bipolar disorder ≥30 days post-infection. Weighted Cox proportional hazards models with inverse probability of treatment weighting were used to estimate adjusted hazard ratios (aHRs).

Compared to low NDVI, moderate NDVI was associated with reduced risk of any common mental disorder (aHR, 0.97; 95% CI, 0.96-0.98), with the strongest effect for bipolar disorder (0.84; 0.79-0.88). High NDVI showed no overall benefit (1.00; 0.99-1.01) and was associated with increased anxiety risk (1.04; 1.03-1.06), especially in older adults and those with comorbidities. Younger individuals experienced the greatest benefit from moderate greenness.

Moderate residential greenness was linked to lower risk of mental disorders following COVID-19, while high greenness conferred limited benefit and potential risk. Greening strategies should be paired with strengthened health and social infrastructure to reduce disparities.

Pneumonia is a leading cause of morbidity and mortality in children and older adults. COVID-19 related disruptions in healthcare and surveillance may have altered incidence, hospitalizations, and deaths. We assessed pneumonia incidence, hospitalizations, and mortality rates in children under five and adults older than 60 years in Peru during the COVID-19 pandemic (2020-22) versus the pre-pandemic period (2015-19).

We conducted a retrospective population-based time series study using nationwide surveillance system data on reported pneumonia cases, hospitalizations, and deaths in Peru from 2015 to 2022. Age- and region-specific incidence rates (IRs) and incidence rate ratios (IRRs) with 95% confidence intervals were estimated for pneumonia cases, hospitalizations, and deaths by comparing the pandemic period (2020-22) with the pooled pre-pandemic period (2015-19).

Between January 1, 2015, and December 31, 2022, 170,558 pneumonia cases were reported among children younger than 5 years and 163,938 among adults aged >60 years in Peru. During the same period, 56,680 and 68,476 hospitalizations and 1,563 and 16,485 deaths occurred in these age groups, respectively. Compared with the pre-pandemic period (2015-2019), pneumonia incidence among children younger than 5 years declined markedly during the pandemic, decreasing by 71% in 2020 (IRR, 0.29; 95% CI, 0.28-0.30), 63% in 2021 (IRR, 0.37; 95% CI, 0.36-0.38), and 12% in 2022 (IRR, 0.88; 95% CI, 0.87-0.90). Hospitalizations and mortality in this group also decreased. In contrast, adults aged >60 years experienced increased hospitalization and mortality rates, particularly in 2021 (hospitalizations: IRR, 2.04; 95% CI, 1.97-2.09; mortality: IRR, 4.28; 95% CI, 4.01-4.57). Substantial regional heterogeneity was observed across Peru.

During the COVID-19 pandemic, pneumonia epidemiology in Peru showed contrasting patterns by age, with sustained declines in incidence, hospitalizations, and mortality among children younger than 5 years, but increased hospitalizations and mortality among adults aged >60 years, underscoring the need to strengthen surveillance, access to timely care, and vaccination programs.

Weight reduction is recommended in all overweight and obese patients with obstructive sleep apnea (OSA). Glucagon-like peptide-1 (GLP-1) receptor agonists-based therapies have demonstrated clinical benefits in reducing weight and could potentially improve OSA outcomes. We aim to analyze the efficacy and safety of GLP-1 receptor agonists-based therapies in patients with moderate-to-severe OSA.

We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) that compared GLP-1 receptor agonists-based therapies versus control in adults with moderate-to-severe OSA. We systematically searched electronic databases and registries up to February 10, 2025. Outcomes assessed included apnea-hypopnea index (AHI), body weight, oxygen desaturation index (ODI), minimum oxygen saturation, systolic blood pressure (SBP), diastolic blood pressure (DBP), and adverse events.

A total of 6 RCTs involving 1,069 participants were included, four evaluating liraglutide and two tirzepatide. Compared with control, GLP-1 receptor agonist-based therapies reduced AHI by - 9.99 events/hour (95% CI, - 16.47 to - 3.50; p < 0.01; I² = 87%) and body weight by - 9.68 kg (95% CI, - 15.84 to - 3.51; p < 0.01; I² = 98%). These therapies also reduced SBP by -4.77 mmHg (95% CI, -7.04 to -2.51; p < 0.01), and DBP by -1.41 mmHg (95% CI, -2.71 to -0.11; p = 0.03). No significant differences were observed in ODI or minimum oxygen saturation. GLP-1 receptor agonists-based therapies did not increase the risk of adverse events.

GLP-1 receptor agonist-based therapies reduced AHI and body weight in the populations studied. Substantial heterogeneity limits interpretation of the pooled effect magnitude. These findings support their potential role within comprehensive OSA management but do not establish them as substitutes for CPAP.

International Prospective Register of Systematic Reviews; No.: CRD42024564018; URL: https://www.crd.york.ac.uk/prospero/ .

To describe the variant class associations with phenotype, natural history, treatment response, and outcomes in children with TBX4-associated pulmonary hypertension (TBX4-PH).

Retrospective cohort analysis of children < 18 years referred to the National Paediatric Pulmonary Hypertension Service between 2001 and 2025.

Twenty-one children were identified carrying either a copy number variant (CNV group = 10) encompassing TBX4 or a single nucleotide variant (SNV group = 11). Distinct phenotypic differences were observed between variant classes. Children in the CNV group were referred at a younger age (p = 0.03), more frequently had prolonged oxygen dependence from birth (p < 0.01), more severe lung disease (p < 0.01) and cyanosis (p = 0.04), congenital heart disease (p = 0.03), neurodevelopmental disorders (p < 0.01), and deafness (p = 0.01). Children in the SNV group were less likely to have any lung disease (p = 0.03). Histopathology from five children (CNV = 3, SNV = 2) demonstrated predominantly lung growth abnormalities with variable pulmonary vascular remodeling. Twenty of 21 (95%) children received long-term pulmonary vasodilator therapy, and 9 (43%) received concurrent calcium-channel blockers. Treatment-naïve children (n = 12) demonstrated stable/improved functional class with therapy initiation. Median follow-up was 7.1 years (range 0.7-17.2). Transplant- or Potts shunt-free survival at 1 and 5 years was 100% and 94.4% respectively and was worse in the CNV group (Log-rank p < 0.05).

In this large pediatric TBX4-PH cohort, children carrying CNVs had greater multisystem involvement and poorer outcomes than those carrying SNVs, highlighting the importance of the underlying genetic finding for risk stratification and tailored management strategies.