Metastasis is the primary cause of mortality in colorectal cancer (CRC), a leading global malignancy. Although metabolic reprogramming is a hallmark of cancer, the stage-associated transcriptional features of metabolic pathways during CRC progression remain incompletely understood. This study aimed to characterize transcriptionally inferred metabolic heterogeneity during CRC progression and identify candidate molecular factors associated with metastasis.

We performed an integrated transcriptomic analysis using TCGA and GEO datasets and compared metabolic pathway signatures across normal tissues, primary tumors, and metastatic lesions. An exploratory tumor lactate metabolism score (TLMS) was developed using Cox regression and LASSO analysis. Consensus clustering identified metabolic subtypes, and their associations with computationally estimated immune-cell signatures were assessed. The functional consequences of ENO3 loss were preliminarily evaluated using CRISPR/Cas9 knockout, cell proliferation assays, and an NSG tail-vein experimental lung colonization model.

We observed a stage-associated reversal-like transcriptional pattern: primary tumors showed broad suppression of metabolic pathway signatures relative to normal tissues, whereas metastatic lesions showed reactivation of several signatures, including the pentose phosphate pathway. A six-gene lactate metabolism-related signature stratified patients into prognostic groups within the TCGA cohort. The high-risk group showed higher ssGSEA-inferred neutrophil abundance and enrichment of a neutrophil extracellular trap (NET)-associated transcriptional signature. ENO3 expression was associated with poor outcome, while ENO3 knockout reduced MC38 cell proliferation and experimental lung colonization in NSG mice.

CRC progression is accompanied by stage-associated changes in transcriptomically inferred metabolic programs. TLMS and ENO3 represent exploratory candidate biomarkers that require independent clinical validation and further mechanistic investigation, particularly with respect to lactate metabolism and the tumor immune microenvironment.

Stereotactic body radiotherapy (SBRT) and conventional external beam radiotherapy (cEBRT) are widely used treatment options for the management of painful bone metastases. Randomized phase III trials have provided direct comparative evidence for SBRT and cEBRT; however, their results vary according to treatment regimen and clinical endpoint, supporting a broader quantitative synthesis of pain response, local control, retreatment, and safety outcomes. A systematic search was conducted in PubMed, Scopus, the Cochrane Library, and Google Scholar from database inception through January 2026. Comparative clinical studies evaluating SBRT versus cEBRT for bone metastases were included. Outcomes assessed encompassed pain-related measures (change in Visual Analog Scale scores at 3 and 6 months; complete, partial, stable, and progressive pain response), opioid consumption at 3 and 6 months, radiologic local progression or treatment failure at 8 months, re-irradiation at 12 months, skeletal-related events (vertebral and non-vertebral compression fractures), spinal cord compression, treatment-related toxicity, and overall survival at 1 year. Pooled analyses were performed using random-effects models. Early pain reduction at 3 months, partial and stable pain response, and opioid consumption at 3 and 6 months were comparable between SBRT and cEBRT (all p > 0.05). However, SBRT demonstrated superior mid-term outcomes, with a significantly higher complete pain response at 6 months (RR = 1.43; p = 0.001) and a significantly lower rate of progressive pain response at 6 months (RR = 0.61; p = 0.03). SBRT was also associated with markedly improved local disease control, reflected by lower rates of radiologic local progression or treatment failure at 8 months (RR = 0.36; p < 0.001) and a substantially reduced need for re-irradiation at 12 months (RR = 0.13; p < 0.001). Rates of vertebral and non-vertebral compression fractures, spinal cord compression, treatment-related toxicity, and overall survival at 1 year did not differ significantly between treatment modalities. This meta-analysis demonstrates that both SBRT and cEBRT are safe and effective treatment options for patients with painful bone metastases. While early pain palliation and safety outcomes are comparable, SBRT provides superior durability of pain control, reduced pain progression, improved local tumor control, and a markedly lower need for re-irradiation. SBRT may be particularly advantageous for patients with longer expected survival, oligometastatic disease, or lesions at higher risk of progression, whereas cEBRT remains an effective and accessible option for rapid symptom palliation in patients with limited prognosis.

Pulmonary nodules are highly prevalent in adult human populations, with a substantial proportion representing dormant cancerous lesions. We hypothesized that these pulmonary dormant cancers debilitate in growth owing to the lack of an angiogenic switch in tumors. In this study, we comprehensively investigated the hypothesis that specific pathological triggers can activate this angiogenic switch utilizing severe acute respiratory coronavirus 2 (SARS-CoV-2) infection-induced hypoxia as a primary physiological stimulus. Our findings provide compelling experimental evidence demonstrating that SARS-CoV-2 infection induces profound pulmonary hypoxia and severe tissue inflammation in animal models. This microenvironmental disruption markedly upregulates the expression of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR2) within lung tissues. The resulting hyperactivation of the downstream VEGF-VEGFR2 signaling pathway effectively drives robust pulmonary neovascularization, a phenomenon frequently documented in clinical observations of COVID-19 patients. Furthermore, employing an established experimental tumor model, we demonstrated that SARS-CoV-2 infection directly accelerates tumor outgrowth via this specific VEGF angiogenesis-dependent cascade. Crucially, the targeted administration of a neutralizing antibody to block VEGF significantly suppressed tumor progression and outgrowth in SARS-CoV-2-infected, tumor-bearing animals. Our data show that the COVID-19-induced hypoxia-VEGF-angiogenesis axis serves as one of the mechanisms for initiating tumor outgrowth in pulmonary tissues.

Oral vaccines hold great promise for colorectal cancer (CRC) immunotherapy but are limited by inefficient mucosal delivery and a lack of spatiotemporal control over immune activation. Here we report a spatiotemporally programmed oral nanovaccine that implements a dual-site vaccination strategy through a sequential and causally linked immune cascade, initiating immune priming in Peyer's patches of the small intestine and subsequently amplifying immunity at colorectal tumor sites. The nanovaccine (DPML@OVA-CpG), composed of antigen- and CpG-loaded mesoporous polydopamine nanoparticles stabilized by β-glucan and plant-derived lipids, resists gastrointestinal degradation and targets gut-associated lymphoid tissues. Following oral administration, it induces robust systemic effector and memory T cell responses via small intestinal priming, while a fraction traffics to colorectal tumors. There, near-infrared irradiation triggers immunogenic cell death of tumor cells and, together with locally released CpG, converts tumors into autologous in situ vaccine factories. This spatiotemporally orchestrated strategy achieves potent therapeutic efficacy against liver metastatic CRC, extending survival compared to PD-L1 antibody therapy and traditional single-site oral vaccination.

Receptor tyrosine kinases (RTKs), constituting a major family of cell-surface transmembrane receptors, are essential for intracellular tyrosine phosphorylation and signal transduction. RTK signaling is crucial for cellular fate regulation and tissue homeostasis, and its disruption is linked to numerous diseases. Herein, we present a comprehensive review of signaling pathways involving RTKs, with a focus on their signal transduction mechanisms and key components, along with their interactions with major signaling cascades such as G protein-coupled receptors, Wnt, and transforming growth factor β pathways. We also elucidate the multidimensional roles of RTKs in cancer development and progression, highlighting their key effects on cancer stem cell maintenance, tumor microenvironment modulation, and other factors. Furthermore, we systematically summarize the roles of RTKs in noncancerous diseases, including cardiovascular disorders, neurodegenerative diseases, metabolic syndrome, autoimmune conditions, and fibrotic disorders. We then examine current RTK-targeted therapeutics, including small-molecule inhibitors and monoclonal antibodies, for the treatment of various cancers. Finally, novel therapeutic strategies, along with the challenges associated with their development and application, are discussed. In summary, this review will enhance the understanding of the mechanistic aspects of RTK signaling in major disease pathways and provide a detailed overview of recent advancements in targeted therapeutic interventions.

This study aimed to quantify how rapidly robot-assisted colon resection billing diffused after reimbursement in Japan and whether geographic variation narrowed as uptake expanded. We analyzed National Database (NDB) Open Data for fiscal years (FYs) 2022-2024. The primary outcome was the robot-assisted share of two laparoscopic billing categories for malignant colon tumor resection (robot-assisted and conventional). Variation across treating-institution prefectures was summarized using the interquartile range (IQR) for absolute spread and the coefficient of variation (CV) and Gini coefficient for relative dispersion. Longitudinal analyses included prefectures with unmasked values in all relevant years; FY2024 permitted a complete 47-prefecture cross-section. The national robot-assisted share rose from 3.38% in FY2022 to 11.40% in FY2023 and 19.55% in FY2024. In the common 33-prefecture panel, the IQR widened from 5.73 to 6.61 and 11.79 percentage points, whereas the CV fell from 1.086 to 0.630 and 0.482 and the Gini coefficient from 0.565 to 0.347 and 0.269. Across all 47 prefectures in FY2024, shares ranged from 0.00% to 41.47%; the complete cross-section was more heterogeneous than the restricted longitudinal panel, and the 14 prefectures excluded because of earlier masking had a lower median share (6.83% versus 18.05%). Rapid national growth did not translate into geographically uniform billing-based uptake. Relative dispersion decreased while absolute percentage-point spread widened, so apparent geographic convergence depended on the scale used. Post-reimbursement surveillance should report both dimensions and account for selection introduced by disclosure-related masking.

Pancreatic ductal adenocarcinoma (PAAD) is characterized by extreme malignancy and profound resistance to therapy, largely driven by a fibrotic and immunosuppressive tumour microenvironment (TME). The deubiquitinase OTU domain-containing protein 7B (OTUD7B) has been implicated in inflammatory and oncogenic signalling, but its role in PAAD and its TME remains unclear. This study integrated single-cell RNA-seq datasets from the GEO and bulk RNA-seq data from the TCGA to delineate the cellular ecosystem of PAAD, and employed cell-cell communication analysis, high-dimensional weighted gene coexpression network analysis (hdWGCNA), and nonnegative matrix factorization (NMF) to identify OTUD7B-associated modules and epithelial subpopulations, while assessing the survival and clinicopathologic correlations of OTUD7B in the TCGA-PAAD cohort. Quantitative proteomics of OTUD7B-knockout PAAD cells was performed and combined with GO/KEGG and GSEA to explore downstream pathways, and immune infiltration was inferred by deconvolution algorithms and validated by multiplex immunofluorescence staining of OTUD7B, CD4, and FOXP3. Single-cell RNA-seq revealed the expansion of epithelial cells, fibroblasts, and macrophages with dense ligand-receptor networks, alongside the depletion of effector T and NK cells, indicating a shift toward an immunosuppressive TME. hdWGCNA identified epithelial-ECM modules in which OTUD7B served as a hub gene, and NMF revealed an OTUD7B-high epithelial subset enriched in glycosylation-related metabolic programs and positioned at an early stage of the malignant trajectory. OTUD7B was significantly upregulated in PAAD and was associated with higher grade, lymph node metastasis, and advanced stage, and predicted poorer overall survival. Proteomic profiling of OTUD7B-deficient cells revealed broad remodelling of mitochondrial oxidative phosphorylation, ROS metabolism, and redox homeostasis. OTUD7B expression was positively correlated with M2 macrophage infiltration, immunomodulatory gene expression, and CD4⁺FOXP3⁺ regulatory T-cell accumulation, and tissue staining further confirmed the positive association between OTUD7B expression and Treg-rich regions. Collectively, OTUD7B acts as a key integrative node that links epithelial remodelling, mitochondrial metabolic reprogramming, and TME immunosuppression in PAAD, serving as an adverse prognostic biomarker and a potential therapeutic target to remodel tumour metabolism and enhance antitumor immunity.

The current study investigated host genetic associations with disease severity in COVID-19 patients of South Asian origin and explored its molecular basis.

Covid-19 patients were stratified into disease severity groups based on the clinical and radiographic findings. Genomic DNA was extracted from peripheral blood samples. A two-step discovery and validation approach was utilized for genetic analysis. Whole-exome sequencing (WES) based variant prioritization was performed in a discovery cohort of severe disease patients followed by validation in an independent cohort. Bioinformatics analysis including data alignment, and annotation to the GRCh38 human reference genome was done by Ensembl VEP software. WES filtration pipeline utilizing predicted pathogenicity and population allele frequencies focused on the low-frequency and rare variants to filter out the variants of concern. Computational predictive tools and simulations were utilized for the structural and functional analysis of the identified high-risk SNP. Statistical analyses were done by SPSS version 24 and GraphPad Prism version 10.

The missense variant rs199726033 of SVIL gene demonstrated the highest recurrence in the WES discovery cohort. The minor allele frequency (29.2%) was substantially higher than that reported for South Asians in the gnomAD v4 database (1.051%). A significant association of the mutant AC genotype of rs199726033 and disease severity was found in the validation cohort. Protein modeling and structural analysis localized the variant within a functionally conserved Gelsolin domain. Moreover, functional and pathway analysis of the SVIL variant indicates its potential role in actin filament remodeling relevant to COVID-19 related vasculopathy and cytoskeleton dynamics thus influencing host-viral interactions.

A SVIL missense variant is associated with disease severity and may influence host cytoskeletal processes relevant to COVID-19 severity.

Low peak expiratory flow (PEF) may precede the first self-report of recognized lung disease, but cross-cohort consistency and incremental value are uncertain.

We analysed Health and Retirement Study (HRS) discovery and prespecified person-disjoint replication samples and the English Longitudinal Study of Ageing (ELSA). The estimand linked baseline PEF to the first subsequently observed self-report of recognized lung disease, not biological onset. HRS used a prespecified nominal lower-decile z score and ELSA an empirical lower decile. Participant-clustered models adjusted for demographic, clinical and functional factors. Weighting and a stroke comparator were sensitivity analyses. Post-hoc ELSA benchmarking compared PEF with FEV1 and FVC using person-disjoint cross-validation and full-pipeline bootstrap sensitivity.

Models included 18,510 HRS discovery windows (320 reports), 11,424 replication windows (188), and 8,634 ELSA person-waves (95). Low PEF was associated with first report in discovery (odds ratio [OR] 3.36, 95% confidence interval [CI] 2.54-4.45), replication (3.14, 2.19-4.49), and ELSA (3.77, 2.36-6.01). Weighted estimates were similar; stroke associations were weaker or null. After adjustment for separate FEV1 and FVC indices, the continuous-PEF OR was 1.04 (0.90-1.20). In 1,584 fixed-horizon participants (95 events), AUCs were 0.650 for covariates, 0.684 with PEF, 0.745 with FEV1 and FVC, and 0.739 with all three. Full-pipeline bootstrap sensitivity found no clear incremental evidence beyond FEV1 and FVC. Across differing horizons, low-PEF rules identified fewer than one-third of reports in HRS replication and ELSA.

Lower PEF was associated with a subsequent first observed lung-disease report; cohort-specific low-PEF rules identified fewer than one-third. In exploratory fixed out-of-fold predictions, PEF improved average precision and prediction error over covariates; no clear incremental evidence remained after FEV1 and FVC. Same-protocol collection does not establish a peak-flow-only pathway.

Alcohol use often fluctuates following disasters, but individual trajectories and their links to mental health remain poorly understood. This study examined long-term patterns of alcohol use among disaster-exposed adults and their associations with depression and illness anxiety (a preoccupation with having or acquiring a serious illness).

Data (N = 941) came from five waves (2016-2024) of the Survey of Trauma, Resilience, and Opportunity among Neighborhoods in the Gulf (STRONG), a longitudinal cohort of adults in the U.S. Gulf Coast region. Growth mixture modeling identified latent trajectories of alcohol use across nine years encompassing multiple disasters (Deepwater Horizon oil spill, hurricanes, COVID-19 pandemic). Multinomial regression examined demographic and disaster exposure correlates of trajectory membership. Linear mixed-effects models assessed associations between drinking trajectories and longitudinal changes in depression and illness anxiety.

A four-class model best fit the data: Low Stable (36%), Elevated Stable (47%), Decreasing (11%), and Increasing (7%) drinking trajectories. Elevated Stable drinkers were younger, more educated, and less likely to be female or Black. Disaster exposure differed modestly by class, with only oil spill exposure and COVID-19 disruptions associated with drinking patterns. Over time, depression increased among Elevated Stable and Increasing drinkers, while illness anxiety rose among Elevated Stable and Decreasing drinkers.

Alcohol use and mental health trajectories following disasters are heterogeneous and interrelated. Persistent or increasing drinking was linked to worsening depression, while illness anxiety followed distinct patterns. Tailored prevention and intervention strategies should consider individual drinking trajectories and disaster context.