ESM1 facilitates the EGFR/HER3-triggered epithelial-to-mesenchymal transition and progression of gastric cancer via modulating interplay between Akt and angiopoietin-2 signaling.

Gastric cancer (GC) poses global challenges due to its difficult early diagnosis and drug resistance, necessitating the identification of early detection markers and understanding of oncogenic pathways for effective GC therapy. Endothelial cell-specific molecule 1 (ESM1), a secreted glycoprotein, is elevated in various cancers, but its role in GC remains controversial. In our study, ESM1 was elevated in GC tissues, and its concentration was correlated with progression and poorer patient prognosis in independent cohorts. Functionally, ESM1 expression promoted proliferation, anoikis resistance, and motility of GC cells, as well as tumor growth in PDOs and in GC xenograft models. Mechanistically, ESM1 expression triggered the epithelial-to-mesenchymal transition (EMT) of GC cells by enhancing epidermal growth factor receptor (EGFR)/human EGFR 3 (HER3) association and activating the EGFR/HER3-Akt pathway. Additionally, angiopoietin-2 (ANGPT2) was found to be highly correlated with ESM1 and interplayed with Akt to induce the EMT and cancer progression. Use of a signal peptide deletion mutant (ESM1-19del) showed that the secreted form of ESM1 is crucial for its protumorigenic effects by activating the EGFR/HER3-Akt/ANGPT2 pathway to promote the EMT. Patients with high levels of both ESM1 and ANGPT2 had the poorest prognoses. Furthermore, therapeutic peptides successfully inhibited ESM1's induction of the aforementioned signals and motility of GC cells. ESM1's oncogenic role in GC involves activating the EGFR/HER3-Akt/ANGPT2 pathway, presenting a potential therapeutic target for GC.

The oncogenic ADAMTS1-VCAN-EGFR cyclic axis drives anoikis resistance and invasion in renal cell carcinoma.

BACKGROUND: Metastasis, the leading cause of renal cell carcinoma (RCC) mortality, involves cancer cells resisting anoikis and invading. Until now, the role of the matrix metalloproteinase (MMP)-related enzyme, A disintegrin and metalloprotease with thrombospondin motifs 1 (ADAMTS1), in RCC anoikis regulation remains unclear. METHODS: The clinical significance of ADAMTS1 and its associated molecules in patients with RCC was investigated using data from the Gene Expression Omnibus (GEO) and TCGA datasets. Human phosphoreceptor tyrosine kinase (RTK) array, luciferase reporter assays, immunoprecipitation (IP) assays, western blotting, and real-time reverse-transcription quantitative polymerase chain reaction (RT-qPCR) were used to elucidate the underlying mechanisms of ADAMTS1. Functional assays, including anoikis resistance assays, invasion assays, and a Zebrafish xenotransplantation model, were conducted to assess the roles of ADAMTS1 in conferring resistance to anoikis in RCC. RESULTS: This study found elevated ADAMTS1 transcripts in RCC tissues that were correlated with a poor prognosis. ADAMTS1 manipulation significantly affected cell anoikis through the mitochondrial pathway in RCC cells. Human receptor tyrosine kinase (RTK) array screening identified that epidermal growth factor receptor (EGFR) activation was responsible for ADAMTS1-induced anoikis resistance and invasion. Further investigations revealed that enzymatically active ADAMTS1-induced versican V1 (VCAN V1) proteolysis led to EGFR transactivation, which in turn, through positive feedback, regulated ADAMTS1. Additionally, ADAMTS1 can form a complex with p53 to influence EGFR signaling. In vivo, VCAN or EGFR knockdown reversed ADAMTS1-induced prometastatic characteristics of RCC. A clinical analysis revealed a positive correlation between ADAMTS1 and VCAN or the EGFR and patients with RCC with high ADAMTS1 and VCAN expression had the worst prognoses. CONCLUSIONS: Our results collectively uncover a novel cyclic axis involving ADAMTS1-VCAN-EGFR, which significantly contributes to RCC invasion and resistance to anoikis, thus presenting a promising therapeutic target for RCC metastasis.

Opioid use in cancer patients compared with noncancer pain patients in a veteran population.

BACKGROUND: Opioid safety initiatives may secondarily impact opioid prescribing and pain outcomes for cancer care. METHODS: We reviewed electronic health record data at a tertiary Veterans Affairs system (VA Palo Alto) for all patients from 2015 to 2021. We collected outpatient Schedule II opioid prescriptions data and calculated morphine milligram equivalents (MMEs) using Centers for Disease Control and Prevention conversion formulas. To determine the clinical impact of changes in opioid prescription, we used the highest level of pain reported by each patient on the 0-to-10 Numeric Rating Scale in each year, categorized into mild (0-3), moderate (4-6), and severe (7 and above). RESULTS: Among 89 569 patients, 9073 had a cancer diagnosis. Cancer patients were almost twice as likely to have an opioid prescription compared with noncancer patients (69.0% vs 36.7%, respectively). The proportion of patients who received an opioid prescription decreased from 27.1% to 18.1% (trend P < .01) in cancer patients and from 17.0% to 10.2% in noncancer patients (trend P < .01). Cancer and noncancer patients had similar declines of MMEs per year between 2015 and 2019, but the decline was more rapid for cancer patients (1462.5 to 946.4, 35.3%) compared with noncancer patients (1315.6 to 927.7, 29.5%) from 2019 to 2021. During the study period, the proportion of noncancer patients who experienced severe pain was almost unchanged, whereas it increased among cancer patients, reaching a significantly higher rate than among noncancer patients in 2021 (31.9% vs 27.4%, P < .01). CONCLUSIONS: Our findings suggest potential unintended consequences for cancer care because of efforts to manage opioid-related risks.

Cyclic increase in the ADAMTS1-L1CAM-EGFR axis promotes the EMT and cervical lymph node metastasis of oral squamous cell carcinoma.

The matrix metalloprotease A disintegrin and metalloprotease with thrombospondin motifs 1 (ADAMTS1) was reported to be involved in tumor progression in several cancer types, but its contributions appear discrepant. At present, the role of ADAMTS1 in oral squamous cell carcinoma (SCC; OSCC) remains unclear. Herein, The Cancer Genome Atlas (TCGA) database showed that ADAMTS1 transcripts were downregulated in head and neck SCC (HNSCC) tissues compared to normal tissues, but ADAMTS1 levels were correlated with poorer prognoses of HNSCC patients. In vitro, we observed that ADAMTS1 expression levels were correlated with the invasive abilities of four OSCC cell lines, HSC-3, SCC9, HSC-3M, and SAS. Knockdown of ADAMTS1 in OSCC cells led to a decrease and its overexpression led to an increase in cell-invasive abilities in vitro as well as tumor growth and lymph node (LN) metastasis in OSCC xenografts. Mechanistic investigations showed that the cyclic increase in ADAMTS1-L1 cell adhesion molecule (L1CAM) axis-mediated epidermal growth factor receptor (EGFR) activation led to exacerbation of the invasive abilities of OSCC cells via inducing epithelial-mesenchymal transition (EMT) progression. Clinical analyses revealed that ADAMTS1, L1CAM, and EGFR levels were all correlated with worse prognoses of HNSCC patients, and patients with ADAMTS1high/L1CAMhigh or EGFRhigh tumors had the shortest overall and disease-specific survival times. As to therapeutic aspects, we discovered that an edible plant-derived flavonoid, apigenin (API), drastically inhibited expression of the ADAMTS1-L1CAM-EGFR axis and reduced the ADAMTS1-triggered invasion and LN metastasis of OSCC cells in vitro and in vivo. Most importantly, API treatment significantly prolonged survival rates of xenograft mice with OSCC. In summary, ADAMTS1 may be a useful biomarker for predicting OSCC progression, and API potentially retarded OSCC progression by targeting the ADAMTS1-L1CAM-EGFR signaling pathway.

Matched analysis of detailed peripheral blood and tumor immune microenvironment profiles in bladder cancer.

Background: Bladder cancer and therapy responses hinge on immune profiles in the tumor microenvironment (TME) and blood, yet studies linking tumor-infiltrating immune cells to peripheral immune profiles are limited. Methods: DNA methylation cytometry quantified TME and matched peripheral blood immune cell proportions. With tumor immune profile data as the input, subjects were grouped by immune infiltration status and consensus clustering. Results: Immune hot and cold groups had different immune compositions in the TME but not in circulating blood. Two clusters of patients identified with consensus clustering had different immune compositions not only in the TME but also in blood. Conclusion: Detailed immune profiling via methylation cytometry reveals the significance of understanding tumor and systemic immune relationships in cancer patients.

Bladder cancer and treatment outcomes depend on the immune profiles in the tumor and blood. Our study, using DNA methylation cytometry, measured immune cell proportions in both areas. Patients were grouped based on immune status and consensus clustering. Results showed distinct immune compositions in the tumor, but not in blood, for hot and cold groups. Consensus clustering revealed two patient clusters with differing immune compositions in both tumor and blood. This detailed immune profiling highlights the importance of understanding the complex interplay between tumor and systemic immunity in bladder cancer patients.

Loss of LECT2 promotes ovarian cancer progression by inducing cancer invasiveness and facilitating an immunosuppressive environment.

Leukocyte cell-derived chemotaxin 2 (LECT2) is a multifunctional cytokine that can bind to several receptors and mediate distinct molecular pathways in various cell settings. Changing levels of LECT2 have been implicated in multiple human disease states, including cancers. Here, we have demonstrated reduced serum levels of LECT2 in patients with epithelial ovarian cancer (EOC) and down-regulated circulating Lect2 as the disease progresses in a syngeneic mouse ID8 EOC model. Using the murine EOC model, we discovered that loss of Lect2 promotes EOC progression by modulating both tumor cells and the tumor microenvironment. Lect2 inhibited EOC cells' invasive phenotype and suppressed EOC's transcoelomic metastasis by targeting c-Met signaling. In addition, Lect2 downregulation induced the accumulation and activation of myeloid-derived suppressor cells (MDSCs). This fostered an immunosuppressive microenvironment in EOC by inhibiting T-cell activation and skewing macrophages toward an M2 phenotype. The therapeutic efficacy of programmed cell death-1 (PD-1)/PD-L1 pathway blockade for the ID8 model was significantly hindered. Overall, our data highlight multiple functions of Lect2 during EOC progression and reveal a rationale for synergistic immunotherapeutic strategies by targeting Lect2.

Deciphering the role of immune cell composition in epigenetic age acceleration: Insights from cell-type deconvolution applied to human blood epigenetic clocks.

Aging is a significant risk factor for various human disorders, and DNA methylation clocks have emerged as powerful tools for estimating biological age and predicting health-related outcomes. Methylation data from blood DNA has been a focus of more recently developed DNA methylation clocks. However, the impact of immune cell composition on epigenetic age acceleration (EAA) remains unclear as only some clocks incorporate partial cell type composition information when analyzing EAA. We investigated associations of 12 immune cell types measured by cell-type deconvolution with EAA predicted by six widely-used DNA methylation clocks in data from >10,000 blood samples. We observed significant associations of immune cell composition with EAA for all six clocks tested. Across the clocks, nine or more of the 12 cell types tested exhibited significant associations with EAA. Higher memory lymphocyte subtype proportions were associated with increased EAA, and naïve lymphocyte subtypes were associated with decreased EAA. To demonstrate the potential confounding of EAA by immune cell composition, we applied EAA in rheumatoid arthritis. Our research maps immune cell type contributions to EAA in human blood and offers opportunities to adjust for immune cell composition in EAA studies to a significantly more granular level. Understanding associations of EAA with immune profiles has implications for the interpretation of epigenetic age and its relevance in aging and disease research. Our detailed map of immune cell type contributions serves as a resource for studies utilizing epigenetic clocks across diverse research fields, including aging-related diseases, precision medicine, and therapeutic interventions.

Detailed immune profiling in pediatric Crohn's disease using methylation cytometry.

DNA methylation has been extensively utilized to study epigenetic patterns across many diseases as well as to deconvolve blood cell type proportions. This study builds upon previous studies examining methylation patterns in paediatric patients with varying stages of Crohn's disease to extend the immune profiling of these patients using a novel deconvolution approach. Compared with control subjects, we observed significantly decreased levels of CD4 memory and naive, CD8 naive, and natural killer cells and elevated neutrophil levels in Crohn's disease. In addition, Crohn's patients had a significantly elevated neutrophil-to-lymphocyte ratio. Using an epigenome-wide association approach and adjusting for potential confounders, including cell type, we observed 397 differentially methylated CpG (DMC) sites associated with Crohn's disease. The top genetic pathway associated with the DMCs was the regulation of arginine metabolic processes which are involved in the regulation of T cells.

Development and Mechanical Analysis of Human Liver Model During Impact.

Liver injury is one of the most severe traffic trauma. The development of accurate liver finite element model is beneficial for improving the biofidelity and validity in crash simulations, aiming to analyze the injury in accidents. 12 human liver finite element models in the current research were constructed from high resolution CT data of a Chinese male 50th percentile human subject, including the main structures like left lobe, right lobe, capsule, parenchyma and falciform ligament. The simulations based on Nava et al. experiment were conducted to validate the models and make comparisons of modeling method accuracy. The results demonstrated that the larger deviation happened to the tetra models due to the stiffer algorithm compared to the hex models, which were more sensitive to element size. The existence of capsule had significant effects on the liver mechanical responses, reducing the liver tissue pressure. Shell elements were more suitable for modeling the capsule.

Adaptive fuzzy prescribed time tracking control for nonlinear systems with input saturation.

This article investigates the adaptive fuzzy prescribed time tracking control problem for a class of strict-feedback systems simultaneously considering the user-defined asymmetric tracking performance, input saturation, and external disturbances. From the perspective of ensuring the reliability for control implementation, a saturation-based fixed-time funnel boundary is constructed by embedding the modification signals related to input saturation errors into a funnel function, which is capable of automatically enlarging or recovering itself when input saturation occurs or disappears, thereby reducing the risk of system singularity. Subsequently, by constructing a fixed-time tracking performance function, any known bounded tracking error is recast into a new variable with a zero initial value. With such a treatment, funnel boundaries are no longer redeveloped for different initial tracking errors, and meanwhile the behavior of the tracking error is pre-specified as needed over a finite time interval. Also, auxiliary systems are devised to generate the aforesaid modification signals, while compensating for the adverse impact resulting from input saturation. Remarkably, by feat of the backstepping design based on the fuzzy approximation, it is proven that the tracking error converges to a user-defined region within a prescribed time (known as the practically prescribed time tracking), which is achieved without the fractional power feedback of system states. Finally, two simulation examples are presented to confirm the feasibility and effectiveness of the developed approach.