Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome driven by comorbidities, chronic low-grade inflammation, and cardiac remodeling. Cardiac resident macrophages (CRMs) and monocyte-derived macrophages (MDMs) play central roles in linking immunometabolism to HFpEF pathogenesis. Resident CCR2- macrophages maintain homeostasis and tissue repair, whereas monocyte-derived CCR2+ macrophages drive inflammation, fibrosis, and diastolic dysfunction. In HFpEF, comorbidity-induced metabolic shifts promote pro-inflammatory macrophage polarization, while metabolites like fatty acids, lactate, and succinate modulate these responses through metabolic and epigenetic pathways. Targeting specific macrophage subsets offers promising therapeutic avenues, though challenges like off-target effects and clinical translation remain. This review summarizes cardiac macrophage heterogeneity, immunometabolic crosstalk, and regulatory mechanisms in HFpEF, highlighting emerging subset-specific therapeutic strategies.
Atopic dermatitis is a chronic inflammatory skin disease characterized by type 2 immune responses and severe itching; however, the molecular mechanisms linking lipid metabolism to epithelial–immune signaling remain incompletely understood. Herein, we show that group IIF secreted phospholipase A2 (PLA2G2F), which is induced by type 2 cytokines and selectively generates plasmalogen-derived lysophosphatidylethanolamine (lysoplasmalogen; P-LPE) in keratinocytes, contributes to the aggravation of atopic dermatitis and itching. Genetic deletion of Pla2g2f attenuated IL-33 expression in keratinocytes and reduced epidermal hyperplasia, serum IgE levels, type 2 inflammation and scratching behavior, without directly affecting neuronal structure and function, in a mouse model of atopic dermatitis. Topical application of a secreted PLA2 inhibitor or forcible enzymatic degradation of P-LPE suppressed the itch response in wild-type mice, whereas exogenous P-LPE partially restored scratching behavior in Pla2g2f-deficient mice. Importantly, P-LPE levels were significantly elevated in the stratum corneum of patients with atopic dermatitis and positively correlated with disease severity. Collectively, the present study highlights that the PLA2G2F/P-LPE axis, originally identified in psoriasis, is a key regulator that connects epidermal lipid metabolism to IL-33–mediated type 2 inflammation and itching, suggesting that this pathway could be a novel therapeutic target and biomarker of this disease.
RationaleChronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. As lung transplantation is the only curative option and current therapies are largely based on managing clinical symptoms, novel treatments are urgently needed.ObjectivePreviously, we showed that the first-generation incretin Exedine-4 could attenuate airway mucus dysregulation induced by the Pseudomonas aeruginosa redox-active toxin pyocyanin by modulating GLP1R-PPARγ signaling. In this study, we compared the efficacy of currently approved next-generation GLP1R agonists and PPARγ agonists in improving airway mucus homeostasis, mucociliary escalator function, and P. aeruginosa clearance after chronic exposure to pyocyanin, as well as the underlying mechanisms.MethodsSix GLP-1R agonists and two PPARγ agonists were compared based on their ability to attenuate pyocyanin-induced oxidative stress and mucin overexpression in 16HBE14o− cells by the cellular reactive oxygen species (ROS) assays, immunoblotting, and confocal immunofluorescence microscopy. The ability of these agonists to restore the mucociliary escalator function in air-liquid interface (ALI) cultures of primary human small airway epithelial cells (SAECs) was captured by confocal immunofluorescence microscopy. Then, we examined whether these agonists could restore mucus homeostasis, neutralize lung proinflammatory responses, and reduce bacterial burden in C57BL/6 mice. Finally, the expression of relevant pro- and anti-mucin biosynthesis signaling pathways was investigated.Measurements and main resultsSemaglutide and Pioglitazone are the most effective in decreasing the expression of mucus biomarker MUC5AC mucin and ROS production in response to pyocyanin, both in vitro and in vivo. Additionally, these agonists restore mucociliary beat frequency and mucociliary transport impaired by pyocyanin. The protective effects of these drugs were partially abolished by respective antagonists, Exendin(9-39) and GW9662, against GLP1R and PPARγ, confirming the GLP1R signaling pathway-dependent mechanisms. Moreover, Semaglutide and Pioglitazone also attenuated type 2 immune responses and neutrophil influx, both of which are known drivers of mucus hypersecretion, and reduced the P. aeruginosa burden in a chronic bronchitis model of infection in mouse lungs.ConclusionsOur findings identify a promising adjunctive therapeutic avenue for COPD by repurposing FDA-approved Semaglutide and Pioglitazone, which are readily available for clinical use.
IntroductionELF4 is an ETS family transcription factor involved in immune regulation, including antiviral responses and inflammatory signaling. Germline loss-of-function variants in ELF4 cause deficiency in ELF4, X-linked (DEX), a disorder characterized by recurrent mucocutaneous inflammation and variable immune abnormalities. To date, ELF4-related disease has been reported only in association with germline mutations. Here, we report a pediatric patient with autoinflammatory disease harboring a truncating ELF4 variant (c.239T>A, p.L80*).MethodsClinical and genetic evaluations were performed in the patient and his family. The ELF4 c.239T>A variant was assessed by Sanger sequencing in peripheral blood and buccal mucosa samples. ELF4 protein expression was examined in patient-derived cells and ectopic expression of wild-type and mutant ELF4 constructs in HEK293T cells by immunoblotting. Full-length single-cell RNA sequencing was performed on whole-blood leukocytes to compare mutant-assigned and wild-type-assigned immune cells within the same individual.ResultsAn ELF4 truncating variant (c.239T>A, p.L80*) was detected in peripheral blood but was not detected in parental blood samples or the patient’s buccal mucosa by Sanger sequencing. Given the limited sensitivity of Sanger sequencing, the developmental origin and tissue distribution of the variant could not be definitively determined. A reduced full-length ELF4 signal was observed in patient-derived PBMCs and in the p.L80* HEK293T overexpression system, together with impaired transcriptional activity in an IFN-β promoter reporter assay. Single-cell transcriptomic analysis identified cells with p.L80*-supporting transcripts across multiple immune lineages and suggested cell type-specific transcriptional alterations. Pathway analyses indicated reduced antiviral and interferon-related programs in mutant-assigned NK cells. Exploratory analysis of mutant-assigned CD16+ monocytes also suggested inflammation-related pathway alterations, although the limited number of allele-informative cells warrants cautious interpretation.ConclusionsELF4 is an ETS family transcription factor that plays an important role in immune regulation. Our study identifies a functionally impaired ELF4 p.L80* variant in a pediatric patient with autoinflammatory disease and provides preliminary evidence of cell type-specific transcriptional alterations associated with this variant.
Anti-p200 pemphigoid is a rare autoimmune subepidermal blistering disease with limited evidence guiding its management. We report a 49-year-old woman with refractory anti-p200 pemphigoid who failed treatment with high-dose prednisone and dapsone and developed significant corticosteroid-related toxicity, including hypertension, hypertrichosis, steroid-induced myopathy, and psychological distress. Given her history of complicated diverticulitis requiring bowel resection, dupilumab was initiated as a steroid-sparing therapeutic option. Pruritus improved within two weeks, near-complete remission was achieved after two months, and sustained disease control was maintained for six months, allowing substantial corticosteroid tapering without treatment-related adverse events.
Chronic lymphocytic leukemia (CLL) predominantly affects older adults; however, approximately 10% of patients are diagnosed at a younger age. Although overall survival appears comparable across age groups, emerging evidence suggests that early-onset CLL may represent a biologically distinct disease subset. Given the profound effects of aging on immune competence and tumor-host interactions, we investigated whether age at diagnosis influences leukemic cell behavior, microenvironmental responsiveness, and immune dysfunction in CLL. We first analyzed the clinical impact of age at diagnosis in a Uruguayan cohort of 462 CLL patients and subsequently explored the biological basis underlying age-associated differences. Patients were stratified according to age at diagnosis, and disease progression was assessed by time-to-first treatment (TTFT). Metabolic analysis evaluated leukemic cell responses to prototypical tumor microenvironment (TME) stimuli, including CD40L plus IL-4 and CpG-ODN plus IL-15. In parallel, we characterized proliferative and quiescent leukemic fractions in peripheral blood, assessed T-cell exhaustion profiles, and analyzed metabolic reprogramming following microenvironmental stimulation. Patients diagnosed at ≤55 years of age exhibited the shortest TTFT (median 39 months), whereas those aged ≥65 years showed a significantly longer TTFT (median 97,6) confirming the more aggressive clinical course of early-onset CLL, despite the longer overall survival as previously described. Metabolic studies revealed that leukemic cells from younger patients displayed enhanced responsiveness to TME-derived signals, characterized by increased metabolic fitness and greater metabolic reprogramming following stimulation. Moreover, early-onset CLL was enriched in proliferative leukemic fractions, whereas the frequency and distribution of exhausted T-cell subsets were comparable between age groups. Collectively, our findings indicate that age-dependent differences in CLL behavior are primarily associated with intrinsic leukemic cell properties rather than major alterations in T-cell dysfunction. Early-onset CLL is characterized by enhanced metabolic adaptability and enrichment of proliferative leukemic cells, supporting the concept that it constitutes a biologically distinct subset of the disease. Despite the absence of differences in survival between age groups, our results provide new insights into CLL heterogeneity and suggest that age-related differences in leukemic cell–microenvironment interactions may contribute to the more aggressive clinical behavior observed in younger patients.
BackgroundPathological response after neoadjuvant chemotherapy is a key treatment milestone in osteosarcoma. We evaluated whether a rule-derived preoperative peripheral inflammatory-lymphocyte recovery phenotype constructed from routinely collected laboratory measurements was associated with poor pathological response.MethodsThis single-center retrospective cohort included patients with osteosarcoma who completed neoadjuvant chemotherapy, underwent definitive surgery, had pathological response assessed, and had valid baseline (T0) and preoperative (T3) laboratory measurements. A failure score combined standardized myeloid-inflammatory burden and lymphocyte-nutritional reserve. Patients were classified as favorable recovery, intermediate recovery phenotype, or persistent recovery failure using the primary T0-T3 rule. The primary outcome was tumor necrosis <90%. The primary association was estimated using parsimonious Firth logistic regression, with modified-Poisson risk ratios and standardized absolute risks. Model comparisons used nested full-pipeline repeated cross-validation. Event-related analyses were exploratory.ResultsAmong 162 patients, 88 (54.3%) had poor pathological response; 65 were classified as favorable recovery, 45 as intermediate, and 52 as persistent recovery failure. Persistent failure was associated with poor pathological response versus favorable recovery (Firth OR, 5.72; 95% CI, 2.42-13.53; P<0.001; adjusted RR, 2.10; 95% CI, 1.46-3.01). Standardized risks were 37.2% for favorable recovery and 75.7% for persistent failure, corresponding to a risk difference of 38.6 percentage points (95% CI, 19.7-52.7). In nested full-pipeline cross-validation, the phenotype model had an AUC of 0.641 and did not outperform the continuous T3 score (AUC, 0.665); its out-of-fold calibration slope was 0.587 (95% CI, 0.220-0.953). Exploratory associations were observed for event-free survival (EFS) and pulmonary metastasis, whereas overall survival (OS) was immature with 24 deaths.ConclusionA rule-derived preoperative peripheral inflammatory-lymphocyte recovery phenotype was associated with pathological response among patients who completed neoadjuvant chemotherapy and underwent definitive surgery for osteosarcoma. The association was robust across alternative definitions and sensitivity analyses; however, the categorical phenotype did not outperform the continuous preoperative T3 score, and out-of-fold calibration indicated residual overfitting. Event-related findings and biological interpretation require external validation.
BackgroundThis study evaluated the feasibility of dual-energy CT (DECT) for assessing the correlation between hydroxyproline (HYP) levels in lung tissue of patients with nonspecific interstitial pneumonia (NSIP) and lung volume and pulmonary function.MethodsWe retrospectively analyzed 99 NSIP patients (51 cellular, 48 fibrotic) and 40 controls. All underwent DECT imaging. Lung HYP‑equivalent density (HYP‑ED) and volume were quantified using spectral post-processing. Pulmonary function parameters, including FVC% Pred and DLCO% Pred, were collected. Intergroup differences, correlations, and diagnostic performance were assessed.ResultsLung volume was higher in controls (3797.40 ± 1155.68 cc) than in cellular (2796.88 ± 334.03 cc) and fibrotic NSIP (2156.76 ± 423.40 cc; P < 0.001). HYP‑ED was lower in controls (206.29 ± 22.40 mg/cm3) than in cellular (264.31 ± 24.99 mg/cm3) and fibrotic NSIP (327.12 ± 36.26 mg/cm3; P < 0.001), and lower in cellular than fibrotic NSIP (P < 0.001). FVC% Pred and DLCO% Pred were higher in cellular NSIP (75.98 ± 4.07% and 69.96 ± 4.41%) than in fibrotic NSIP (71.44 ± 5.49% and 64.58 ± 3.38%; P < 0.05). HYP‑ED content showed significant negative correlations with lung volume and pulmonary function (all P < 0.01). HYP‑ED demonstrated excellent diagnostic performance for distinguishing NSIP subtypes (AUC 0.977), with 91.8% sensitivity and 92.9% specificity.ConclusionsDECT enables noninvasive quantification of lung HYP-ED in NSIP. HYP‑ED correlates with disease severity and may serve as a promising imaging biomarker for fibrosis assessment and monitoring.
IntroductionOnly a subset of epithelial cells can initiate progressive lung adenocarcinoma (LUAD), yet the founder cell states that confer this competence remain poorly defined.MethodsWe established a barcoded KrasG12D, Trp53 loss mouse LUAD organoid model that couples 15-nucleotide lineage tracing with single-cell RNA sequencing (scRNA-seq) before and after syngeneic transplantation. Candidate markers for expansion states were further evaluated using wild-type lung organoid, spatial transcriptomics, and independent human scRNA-seq datasets.ResultsBarcoded organoids generated LUAD-like tumors. Paired barcode recovery identified expanded, diminished and failed lineages and showed that expanded lineages were enriched for surfaceome genes associated with stemness. Among candidate surface markers, Plxna2 showed the strongest enrichment in baseline organoid cells that expanded after transplantation and marked cells with stronger stemness features. These cells underwent stage-specific reprogramming, with early EMT and inflammatory adaptation followed by late metabolic and MYC programs rebound within an immunosuppressive microenvironment. Wild-type lung organoid analysis showed that Plxna2 marks an alveolar remodeling state sharing expansion signature. Spatial transcriptomics placed Plxna2high tumor epithelial cells in EMT-rich and stromal-interface niches. Human LUAD scRNA-seq cohorts further showed enrichment of PLXNA2high malignant cells within expansion and stemness states.DiscussionThese findings identify PLXNA2 as a candidate marker of expansion state and provide a lineage-based framework for discovering tumor-initiating programs in LUAD.
BackgroundAcute myeloid leukemia (AML) shows substantial biological and clinical heterogeneity that extends beyond leukemia-intrinsic genetic alterations. MRC1, which encodes the myeloid receptor CD206, has been linked to monocytic differentiation and immunoregulatory states in AML. We investigated whether the MRC1 variants rs691005 and rs2253120 are associated with AML occurrence, development and prognosis.MethodsWe genotyped rs691005 and rs2253120 in 335 patients with AML and 326 healthy controls. Their associations with AML susceptibility, cytogenetic abnormalities, risk stratification, complete remission after two treatment cycles, and overall survival (OS) were examined under co-dominant, dominant, and recessive models. Independent prognostic effects were assessed using multivariable Cox regression. The relationship between SNP and MRC1 expression was evaluated using GTEx eQTL data and genotype-stratified expression measurements in primary AML bone marrow CD34+ cells. TCGA datasets were used to assess MRC1 expression and survival in AML. Virtual MRC1 knockdown and pathway analysis was performed using a single-cell RNA-sequencing dataset generated at our center.ResultsNeither variant was associated with AML susceptibility, cytogenetic abnormalities, or early remission. rs691005 was associated with adverse risk stratification and showed a nominal association with shorter OS in Kaplan-Meier analysis. rs2253120 AA homozygosity was associated with improved OS after multivariable adjustment and was linked to lower MRC1 expression in GTEx and primary AML samples. Higher MRC1 expression was associated with poorer OS in TCGA-LAML. Virtual MRC1 knockdown revealed exploratory enrichment patterns related to myeloid differentiation, adhesion, cytokine production, and immune regulation.ConclusionsMRC1 rs691005 was linked to adverse risk stratification and shorter OS, whereas rs2253120 AA homozygosity was independently associated with better OS and lower MRC1 expression. These findings support a potential role for inherited variation at the MRC1 locus in the clinical and immune heterogeneity of AML.
BackgroundThis study evaluates the quality of study design, potential biases, and evidence strength for childhood risk factors associated with allergic rhinitis (AR), while summarizing the key identified factors.MethodsThe protocol for this review was registered in PROSPERO (CRD420251248436). Relevant literature was systematically retrieved from PubMed, Web of Science, Embase, and the Cochrane Database of Systematic Reviews, covering the period from inception to May 2025. Methodological quality and evidence certainty were independently evaluated using AMSTAR and GRADE.ResultsThis review identified 75 risk factors: 22 were linked to a higher risk of AR in children, 7 were protective, and 46 showed insufficient evidence to determine an association. Overall, evidence quality was low or very low, with only one factor supported by moderate-quality evidence. Key findings indicate that early-life antibiotic use, cesarean section, smoking during pregnancy, air pollution, ADHD diagnosis, ASD diagnosis, Kawasaki disease and maternal OCP exposure were associated with higher risk, while pet exposure, raw milk and fish consumption, birth order ≥ 2, and number of siblings ≥ 2 are associated with reduced risk.ConclusionThis first umbrella review systematically compiles all available meta-analytic data on pediatric AR risk factors, offering a provisional evidence map that prioritizes candidate modifiable targets for future research. Earlylife food sensitization is the only factor with moderate certainty. However, the generally low certainty of evidence underscores an urgent need for more rigorous and standardized primary studies and meta-analyses to strengthen the foundation for clinical and public health interventions.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251248436.
BackgroundPatients with unresectable stage IIIB/C-IV non-squamous non-small cell lung cancer (NSCLC) lacking driver mutations (EGFR/ALK/ROS1/RET/BRAF/MET) face limited treatment options. This single-center prospective exploratory pilot case series, limited to a small pre-selected cohort, aims to descriptively characterize real-world efficacy, survival signals and safety profiles of sequential platinum-doublet chemotherapy followed by individualized stereotactic body radiotherapy (SBRT) combined with tislelizumab; this work cannot draw definitive therapeutic conclusions and only generates preliminary hypothesis-building observations.MethodsThis exploratory pilot case series enrolled only patients who maintained disease control after 4-cycle platinum-based chemotherapy (introducing notable selection bias favoring chemo-sensitive tumors). Individualized SBRT with heterogeneous dose/fractionation schemes (3–10 Gy/fx) was delivered to metastatic lesions, with tislelizumab 200 mg q3w initiated within five SBRT fractions and maintained until progression or intolerable toxicity. We added standardized multi-modal toxicity surveillance and grading-based intervention protocols for differentiating radiation versus immune pneumonitis. Endpoints were analyzed purely for descriptive purposes, including 1-year PFS rate, median PFS, OS, ORR, DCR, and treatment-related adverse events (TRAEs).ResultsThe 1-year PFS rate was 25%. The median PFS was 10.14 months (95%CI: 3.65–17.38). Median OS was 26.89 months (95%CI: 17.68–30.19), with 1-year and 2-year OS rates of 100% and 62.5%, respectively. The best overall response rate (BOR), defined as the best response recorded from the start of treatment until disease progression or initiation of new anticancer therapy, was 87.5%, with 7 patients achieving partial response (PR) and 1 patient achieving stable disease (SD) as best response. At the fixed 1-year time point, the ORR was 12.5% (1/8 patients in PR) and the DCR was 100% (1 patient in PR and 7 patients in SD). Treatment-related adverse events (TRAEs) were observed in all patients (100%). The incidence of grade ≥3 TRAEs was 62.5%.ConclusionThis small exploratory case series provides only preliminary, hypothesis-generating signals regarding the feasibility of sequential SBRT and tislelizumab after chemotherapy in selected patients with advanced nsNSCLC. The observed efficacy and safety data are insufficient to establish definitive conclusions or clinical recommendations. These findings require rigorous validation in larger, controlled trials before any therapeutic inference can be drawn.
BackgroundChronic inflammatory rheumatic diseases, such as ankylosing spondylitis, psoriatic arthritis, reactive arthritis, and enteropathic arthritis, are collectively referred to as spondyloarthropathies (SpA). However, Real-world evidence on the effectiveness and safety of ixekizumab in spondyloarthropathies remains limited, particularly in diverse populations outside clinical trial settings.AimThis study aimed to evaluate patient demographics, treatment outcomes, drug survival, and safety profile of ixekizumab in patients with SpA in a real-world clinical setting.MethodsWe conducted a retrospective cohort study at a tertiary care hospital in Riyadh, Saudi Arabia, from January 2018 to December 2024. Patients aged ≥14 years with SpA who received ixekizumab were included. The primary outcomes included drug survival, treatment discontinuation rates, and reasons for discontinuation. Kaplan-Meier survival analysis and Cox proportional hazards regression were performed to identify the predictors of treatment discontinuation.ResultsAmong 93 patients (mean age 44.2 ± 13.2 years, 60.2% female), psoriatic arthritis spectrum disorders predominated (71.0%), followed by ankylosing spondylitis (23.7%). Most patients (87.1%) had prior biologic exposure, with ixekizumab used predominantly as a second-line therapy (59.1%). Drug survival rates were 69.9% at 12 months and 43.0% at 24 months, with a median survival of 23.0 months (95% CI: 19.5-26.5). The overall discontinuation rate was 34.4%, primarily due to lack of efficacy (59.4%) and adverse events (18.8%). Treatment-emergent adverse events occurred in 7.5% of patients, with no serious adverse events reported. Disease type significantly influenced drug survival (p = 0.018), with psoriatic arthritis showing superior retention compared with ankylosing spondylitis (77.8% vs. 60.0% at 12 months). Multivariate analysis identified third-line or later therapy (HR 2.58, 95% CI 1.04-6.40, p = 0.041) and the presence of treatment-emergent adverse events (HR 9.86, 95% CI 3.42-28.41, p < 0.001) as independent predictors of discontinuation.ConclusionIxekizumab demonstrated acceptable drug survival and safety profiles in real-world patients with spondyloarthritis, with differential effectiveness across disease subtypes. Earlier treatment initiation and proactive management of adverse events may optimize treatment outcomes, supporting personalized therapeutic approaches for spondyloarthropathy management.
MethodepiTOol is a web-based application for transplantation immunogenetics and immunology, providing easy and reliable translation of high-resolution HLA typing into either predicted or confirmed epitopes. Unacceptable or acceptable HLA incompatibilities or mismatches are then easily definable, and the data is exported for further analyses. Unlike other similar tools, epiTOol allows for upload and analysis of large datasets of patient-donor combinations without the need for manual data entry. The results can be directly exported in table and text format for subsequent utilization in medical reports or data sheets.ConclusionepiTOol is designed for utilization in research activities dedicated to transplantation immunology in respective centers dealing with solid organ transplantation but will also be applicable to stem cell transplantation since the role of HLA-specific antibodies also increases dramatically here.
Kawasaki disease (KD) is an acute systemic vasculitis that can affect multiple organs. Kawasaki disease shock syndrome (KDSS) is a severe complication of KD. Pulmonary involvement is uncommon in KD, and there are very few reports of patients with KD who develop KDSS and pulmonary lesions. This report presents the case of a 9-year-old boy who was hospitalized for fever, neck mass and rash, and was subsequently diagnosed with KDSS. During the administration of intravenous immunoglobulin (IVIG), he experienced acute dyspnea, which required urgent invasive mechanical ventilation and bronchoscopy. He was successfully weaned off ventilation shortly and recovered completely. No coronary dilatation or pulmonary fibrosis was detected at the 1-month post-discharge follow-up. This case suggests that KD can trigger rare but severe complications including KDSS and pulmonary involvement. The relationship between pulmonary complications, transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO) remains to be further elucidated. Early aggressive management and comprehensive treatment may improve prognosis.
BackgroundExercise can modulate immune function and inflammatory signaling in cancer populations; however, its effects on the immune system in men with localized prostate cancer undergoing active surveillance are unknown. This study examined the effects of high-intensity interval training (HIIT) on circulating immune cell phenotypes, function, and systemic cytokine levels in this clinical setting.MethodsThis was a secondary analysis of the Exercise During Active Surveillance for Prostate Cancer (ERASE) trial, a single-center randomized controlled trial. Fifty-two men with localized prostate cancer on active surveillance were randomized to a 12-week supervised aerobic HIIT program (n=26) or usual care (n=26). HIIT consisted of three sessions per week at 85% to 95% of peak oxygen consumption. Fasting blood samples were collected at baseline and post-intervention. Changes in immune cell subsets (T cells, B cells, and NK cells; flow cytometry), NK cell cytotoxicity, and plasma cytokine concentrations were assessed. Analyses of covariance were used to compare between-group differences.ResultsThe HIIT group attended 96% of prescribed sessions. Compared with usual care, the HIIT group showed a significant increase in the proportion of the circulating major NK-cell subset (CD3−CD56+CD16+) (adjusted between-group difference, 2.0%; 95% CI, 0.3 to 3.7; p=0.024) and PBMC-mediated cytotoxicity against K562 (2.9%; 95% CI, 0.3 to 5.4; p=0.031). A significant between-group decrease was also observed in basophil counts (-0.04 ×109/L; 95% CI, -0.07 to -0.01; p = 0.011), with no differences in other leukocyte populations. HIIT significantly reduced plasma levels of IL-4 (-0.02 pg/mL; 95% CI, -0.03 to -0.01; p = 0.011) and IL-12p70 (-0.14 pg/mL; 95% CI, -0.23 to -0.06; p = 0.002) compared with usual care. No significant between-group differences were observed in T cell or B cell subsets, or other inflammatory cytokines including IL-6 and TNF-α.ConclusionsA 12-week supervised HIIT program significantly increased the proportion of the circulating major NK-cell subset and PBMC-mediated cytotoxicity while reducing IL-4 and IL-12p70 concentrations in men with prostate cancer undergoing active surveillance. Because these were peripheral-blood measures rather than tumor-level readouts, and given the exploratory design and number of comparisons, these findings should be interpreted as hypothesis-generating and require confirmation in larger, adequately powered studies.
BackgroundThe tumor microenvironment (TME) of gastric adenocarcinoma is exceptionally heterogeneous, and epithelial-mesenchymal transition (EMT) is a central mechanism promoting local invasion and metastatic spread. Even so, how EMT-programmed cells are spatially arranged within tumor tissue, how they interact with neighboring immune populations, and which molecular nodes might be exploited therapeutically remain incompletely defined.MethodsWe built a large-scale, multi-layered analytical pipeline that combined single-cell transcriptomics (approximately 250,000 cells drawn from two independent patient cohorts), Visium-based spatial transcriptomics processed through Bayesian cell2location deconvolution, niche-level SpaTopic modeling, deep-learning histology analysis (ResNet50 feature extraction paired with CellProfiler-derived morphometrics), and ensemble survival modeling spanning over one hundred algorithmic combinations. Gaussian mixture modeling was used to define EMT-high cell states, the Scissor framework was applied to link fibroblast subsets to patient mortality, and a multi-tier filtering scheme was used to nominate druggable candidate genes. The top candidate, PVR/CD155, was interrogated experimentally by RT-qPCR, Western blotting, immunohistochemistry, and siRNA knockdown in AGS cells. We further evaluated PVR druggability by molecular docking, a 100-nanosecond molecular dynamics trajectory, and MM/GBSA binding-energy estimation using PP-121 as a candidate ligand.ResultsSub-clustering identified seven fibroblast subclusters: Fib_APOD, Fib_COL4A1, Fib_SLPI, Fib_COL1A1, Fib_CCL4, Fib_STMN1, and Fib_S100B. The SLPI-high subset preferentially localized to peritoneal metastases. Phenotype-guided Scissor mapping nominated a survival-associated fibroblast program enriched within COL4A1-expressing fibroblast states. PVR/CD155 was prioritized as an EMT-linked candidate gene; single-cell expression profiling showed that PVR was most frequently detected in endothelial, epithelial and fibroblast compartments, with low detection in lymphoid and plasma cells. PVR/CD155 was significantly upregulated in gastric cancer cell lines and tumor tissues. PVR/CD155 knockdown in AGS cells decreased proliferation, migration and invasion, supporting a tumor cell-intrinsic functional role rather than establishing PVR as a stromal immune biomarker. Molecular docking and dynamics simulations identified PP-121 as a candidate PVR-binding ligand for future biochemical validation.ConclusionThe proposed framework connects single-cell resolution with spatial and histological data, produces validated prognostic tools and nominates PVR/CD155 as a tumor cell-intrinsic EMT-associated target candidate for gastric cancer. Stromal or immune regulatory roles of PVR remain plausible but require direct compartment-specific and functional validation.
ObjectiveSepsis is a life-threatening condition with high mortality and complex pathology. Early diagnosis is critical but remains challenging due to a lack of effective biomarkers. This study aims to identify specific diagnostic markers to distinguish sepsis from non-sepsis, and to develop a robust diagnostic model.MethodsPBMC transcriptome data from our cohort (24 healthy controls, 29 common infections, 51 sepsis patients) were analyzed to identify genes with expression levels increasing or decreasing with infection severity. Low-expression genes were excluded, and candidate markers were evaluated using multiple GEO datasets. Top-performing genes were selected to build a LASSO regression-based diagnostic model. Model performance was assessed by AUC, BSS, ROC and calibration curves, nomogram, DCA, and CIC curves. Functional analyses (GO, KEGG, immune infiltration, GSEA, PPI network) were performed to explore underlying immune mechanisms.ResultsA total of 114 genes showing expression changes with infection severity were identified. Four genes—MMP8, DDX24, RNASE2, and EMB—were selected based on diagnostic performance. The resulting model performed well in both our cohort and public datasets (AUC: 0.811–1; BSS: -0.464 – 0.964). In the GSE69686 dataset, the model also showed predictive value for neonatal and pediatric sepsis (AUC: 0.666–0.852; BSS: -1.34 – -0.293). Immune infiltration and GSEA revealed enrichment of these genes in neutrophils, monocytes, and T cells, reflecting key immune features of sepsis.ConclusionThe four identified genes—MMP8, DDX24, RNASE2, and EMB—collectively form a diagnostic model that effectively distinguishes sepsis patients from those with non-sepsis individuals.
