Cells sense their microenvironment and neighboring cells by exerting finely tuned mechanical forces through receptor-ligand interactions, which shape mechanophenotypes critical to biological development, immunity, and disease. Profiling these mechanophenotypes requires ligands with variable avidities. However, conventional strategies based on discrete valency changes lack the precision for continuous modulation, limiting the resolution of subtle mechanotypic differences. Here, we introduce a bivariate strategy to construct heteromultivalent ligands that independently modulate both unit affinity and valency within a single DNA nanoscaffold. By co-assembling two aptamers with distinct binding affinities, each targeting different epitopes of the same receptor, we generate ligand architectures with tunable avidities through precise stoichiometric modulation. This strategy produces a continuous avidity spectrum, overcoming the limitations of traditional homovalent systems, which are constrained by the discrete nature of valency adjustments. These heteromultivalent ligands enhance the sensitivity of force measurements, revealing subtle mechanical differences in cells with varying epithelial cell adhesion molecule (EpCAM) expressions, and enabling efficient, sequential sorting of phenotypically similar subpopulations via simple flow rate adjustments. These findings underscore the critical importance of avidity modulation in multivalent interaction engineering and mechanical cell profiling, showcasing the advantages of molecularly assembled heteromultivalent interactions over conventional homovalent strategies.

Adhesion G protein-coupled receptors (aGPCRs) are key cell-adhesion molecules involved in many cellular functions and contribute to human diseases, including cancer. aGPCRs are characterized by large extracellular regions that could serve as readily accessible antigens. However, the potential of aGPCRs as targets for biologic therapeutics has not been extensively explored. CD97, also known as ADGRE5, is an aGPCR that is upregulated in various cancer types, including acute myeloid leukemia (AML) and glioblastoma (GBM), and their respective cancer stem cells. Here, we developed antibody-drug conjugates (ADCs) targeting CD97 and assessed their efficacy against AML and GBM cells. We generated a panel of synthetic human antibodies targeting distinct epitopes of CD97, from which we identified an antibody that was efficiently internalized. This antibody binds to all isoforms of human CD97 but not to its close homolog, EMR2. Structure determination by single-particle cryo-electron microscopy revealed that this antibody targets the CD97 GPCR autoproteolysis-inducing (GAIN) domain, whose presence is conserved in aGPCRs, through an unconventional binding mode where it extensively utilizes the light chain framework for antigen recognition. Screening of conjugation methods and payloads resulted in a stable ADC that effectively killed AML and GBM cell lines, as well as patient-derived GBM stem cells, with minimal cytotoxicity against peripheral blood mononuclear cells from healthy donors. Our study demonstrates the therapeutic potential of targeting CD97, as well as the aGPCR GAIN domain in general, and uncovers a previously unrecognized surface that an antibody can utilize for antigen recognition.

Platelet indices are non-invasive biomarkers used to assess disease status. Observational studies have shown that platelet indices are related to liver cancer. However, the specific relationship between the two is still inconclusive. We conducted a Mendelian randomization (MR) study to investigate the causal relationship between platelet indices and liver cancer. We identified 2 cancer outcomes (liver cell carcinoma, malignant neoplasm of liver and intrahepatic bile ducts) from genome-wide association studies (GWAS). We used inverse variance weighted (IVW) method as the main method. In order to evaluate the potential horizontal pleiotropy or heterogeneity, sensitivity analyses were examined via MR-Egger regression, heterogeneity test, pleiotropy test. Two-Sample MR analysis showed there were causal relationships between platelet indices and liver cancer. The mean platelet volume was positively associated with hepatocellular carcinoma (HCC) risk, while platelet count was inversely correlated with HCC risk, platelet endothelial cell adhesion molecule levels were significantly related to an increased malignant neoplasm of liver and intrahepatic bile ducts risk. In addition, we conducted reverse MR analyses and found that malignant neoplasm of liver and intrahepatic bile ducts was positively associated with platelet count and platelet crit, but negatively correlated with platelet distribution width. Following multivariable mendelian randomization adjustments for potential confounding variables, the independent effects of platelet indices on HCC were not statistically significant. The bidirectional causal relationship between platelet indices and liver cancer may be mediated by confounding factors such as liver cirrhosis. Further validation through mediation MR analyses or larger-scale replication studies is required to elucidate these causal pathways.

Blood vessel embolization is a well-established treatment modality for liver cancer. Novel shear-thinning hydrogels (STH) have been developed to address the need for safer and more effective local delivery of embolic agents and therapeutics. However, embolization therapies are currently optimized in animal models, which often differ from humans at the cellular, tissue, and organ levels. We aim to evaluate the efficacy of novel embolic agents such as STH using a human-relevantin vitromodel that recapitulates human hepatocellular carcinoma capillary networks. A vascularized human liver-tumor-on-a-chip model was developed to assess embolic agent performance. The effects of drug-eluting STH (DESTH) on tumor cell viability, surface marker expression, vasculature morphology, and cytokine responses were evaluated. To study the effects of embolization on microvasculature morphology independent of the chemotherapy compound, we evaluated the effect of different drug-free embolic agents on the vascular tumor microenvironment under flow conditions. DESTH treatment induced tumor cell death, downregulated the expression of epithelial cell adhesion molecules in HepG2, increased levels of cytokines such as interleukin-4 (IL-4), granulocyte-macrophage colony-stimulating factor, and vascular endothelial growth factor, and decreased albumin secretion. Furthermore, different embolic agents exert distinct effects on microvascular morphology, with STH causing complete regression of the microvascular networks. This vascularized liver tumor-on-a-chip model enables human-relevant, real-time assessment of embolic agent efficacy and vascular response and can be applied for the development of innovative and effective embolization therapies for liver cancer.

SummaryControlled signaling activity is vital for normal tissue homeostasis and oncogenic signaling activation facilitates tumorigenesis. Here we use single-cell transcriptomics to investigate the effects of pro-proliferative signaling on epithelial homeostasis using the Drosophila follicle cell lineage. Notably, EGFR-Ras overactivation induces cell cycle defects by activating the transcription factors Pointed and E2f1 and impedes differentiation. Hh signaling simultaneously promotes an undifferentiated state and induces differentiation via activation of EMT-associated transcription factors zfh1 and Mef2. As a result, overactivation of Hh signaling generates a transcriptional hybrid state comparable to epithelial-mesenchymal-transition. Co-overactivation of Hh signaling with EGFR-Ras signaling blocks differentiation and induces key characteristics of tumor cells including a loss of tissue architecture caused by reduced expression of cell adhesion molecules, sustained proliferation and an evasion of cell cycle checkpoints. These findings provide new insight into how non-interacting signaling pathways converge at the transcriptional level to prevent malignant cell behavior.

DNA tetrahedra (DTN)could enhance the circulation and targetingcapabilities of aptamers. This study constructs a gallium-68 (68Ga) radiolabeled DTN-SYL3C aptamer conjugate to evaluatetheir imaging potential for detecting epithelial cell adhesion molecule(EpCAM)-positive colorectal cancer (CRC). [68Ga]­Ga-DTN-SYL3Cwas prepared by hybridizing T20-DTN-SYL3C with [68Ga]­Ga-NOTA-ssDNA(A20) through base complementary pairing. Dynamic PET imaging wasconducted in EpCAM-positive HT-29 tumor-bearing BALB/c nude mice using[68Ga]­Ga-DTN and [68Ga]­Ga-SYL3C as controls.T20-DTN-SYL3C was synthesized and characterized by agarose gel electrophoresis,while [68Ga]­Ga-DTN-SYL3C was verified by high-performanceliquid chromatography (HPLC). The radiolabeling yield of [68Ga]­Ga-DTN-SYL3C was approximately 90%. Biodistribution studies indicatedmetabolism by the kidneys and liver. The blood half-life of [68Ga]­Ga-DTN-SYL3C was 11.39 ± 2.66 min, longer than thatof [68Ga]­Ga-SYL3C (7.26 ± 0.17 min) in pharmacokineticstudies. Dynamic PET results showed tumor uptake of 0.89 ± 0.30%ID/gfor [68Ga]­Ga-DTN-SYL3C, 0.27 ± 0.22%ID/g for [68Ga]­Ga-DTN, and 0.32 ± 0.16%ID/g for [68Ga]­Ga-SYL3Cat 1 h (n = 3). In conclusion, the [68Ga]­Ga-labeled DTN-SYL3C aptamer conjugate effectively targets EpCAM-positiveCRC and may serve as a promising imaging tool for detection and monitoring.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths, with a five-year survival rate around 12%. In PDAC, cancer-associated fibroblasts (CAFs) play a vital role in promoting the desmoplastic and immunosuppressive tumor microenvironment (TME), and have emerged as relevant cancer targets. CAFs produce intratumoral hyaluronic acid (HA) whose accumulation induces high interstitial fluid-pressure (IFP) which can interfere with drug delivery. Moreover, HA has been linked with tumor escape from immune surveillance. Systemic administration of Hyaluronidase, via the PEGPH20 formulation, has reduced stromal HA, normalized IFP, and consequently improved the efficiency of the cytotoxic compound, gemcitabine, leading to increased survival in mice. In this study we have decided to eliminate HA by a different approach involving its synthesis rather than inducing its degradation. To this end, we have genetically targeted the three genes encoding HA synthases (Has1, 2, 3). Has1 and Has3 null alleles were generated by CRISPR technology in mouse embryos since they are nor essential for embryonic development. To eliminate Has2, we used existing conditional Has2lox alleles (Matsumoto et al. 2019, PMID XXXX) along an inducible allele, Rosa26-CreERT2, encoding an inducible Cre-ERT2 recombinase to allow the systemic ablation of the conditional Has2lox alleles in adult mice upon exposure to a Tamoxifen-containing (TAM) diet. These alleles were added to the standard KPF strain (KRas +/FSFG12V;P53F/F;Pdx1-FlpO) to determine the effect of HA elimination in tumor-bearing mice. Exposure of these adult animals to the TMA diet induced significant levels of HA depletion leading to reprogramming of tumoral, stromal and immune cells leading to significantly reduced tumor progression. Tumor cells were more differentiated as illustrated by higher expression of cytokeratin19 and additional epithelial cell adhesion molecules. Furthermore, these tumor cells displayed reduced proliferative capacity, mor limited EMT, migration and invasive capacity. Interestingly, they also exhibited upregulated Kras expression. At the stroma level, we observed less fibrotic tissue, decreased collagen deposition, reduced CAFs activation,and changes in the CAF populations, with high content of iCAFs (Inflammatory CAFs) and very low content in myCAFs (Myofibroblast CAFs). More importantly, we also observed infiltration of CD8+ T cells. Notably, HA depletion enhanced the efficacy of gemcitabine, the anti-CTLA-4 and the panras inhibitor darasonrasib, either alone or in combination of anti-CTLA-4. In summary, HA depletion in PDAC produced multiple changes at different levels that opens up new opportunities for therapeutic interventions. Citation Format: Pian Sun, Ángeles Durán, Federico Virga, María Diaz-Meco, Jorge Moscat, Carmen Guerra, Mariano Barbacid. Targeting hyaluronic acid in pancreatic ductal adenocarcinoma uncovers novel therapeutic opportunities [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B031.

Objective: This study utilizes bioinformatics technology to screen and predict potential diagnostic autophagy related biomarkers in CIS. Methods: By analyzing genes in the GEO dataset GSE16561 and the autophagy database HADb, differentially expressed genes (DEGs) related to autophagy in CIS were identified. GO and KEGG enriched and analyzed these autophagy related DEGs. Subsequently, module analysis was conducted using LASSO and SVM-REF algorithms, and finally, the diagnostic value of autophagy related biomarkers in CIS was evaluated through subject operating characteristic curve (ROC) univariate analysis. Results: After intersection of differential genes and autophagy gene data, a total of 31 DEGs related to autophagy were identified. GO and KEGG analysis showed that these autophagy related DEGs are mainly enriched in the reactions of autophagy, apoptosis, inflammation, and aging. They have molecular functions such as binding to cadherin and cell adhesion molecules, and are involved in utilizing autophagy mechanisms, biological processes of apoptosis, and cellular components of lysosomes, whole membranes, cytoplasmic colloids, and cytoplasmic vesicles. And it is related to the FoxO signaling pathway, NOD like receptor signaling pathway, chemokine signaling pathway, PI3K Akt signaling pathway, IL-17 signaling pathway, etc. In addition, LASSO and SVM-REF identified 10 autophagy related biomarkers, namely CASP4, FOXO3, HSPA8, EIF2AK2, PRKCQ, GAA, NLRC4, TNFSF10, CXCR4, RAB1A. ROC univariate analysis showed that CASP4, FOXO3, EIF2AK2, NLRC4, and CXCR4 have good expression and diagnostic value in CIS. Conclusion: CASP4, FOXO3, EIF2AK2, NLRC4, and CXCR4 genes may be potential autophagy related biomarkers for the diagnosis and treatment of CIS, and provide some evidence for the important role of autophagy in CIS.

Vascular barrier disruption is a hallmark of diseases such as cardiovascular disease, stroke, hypertension, pulmonary disorders, infections, and cancer. Endothelium permeability is tightly regulated by shear stress, allowing tissue perfusion, while disturbed flow leads to increased permeability. Cell-cell junctional proteins, including platelet/endothelial cell adhesion molecule-1 (PECAM-1)/CD31 and VE-cadherin, play significant roles in mechanotransduction and barrier integrity. The 70 kDa heat shock protein HSP70 has a well-established cytoprotective function in cardiovascular physiology. Here, we hypothesized that HSP70 interacts with and regulates these junctional proteins. We found that PECAM-1 and VE-cadherin co-immunoprecipitate with endogenous HSP70, and both proteins exhibited positive proximity ligation assay signals in the endothelial monolayers. HSP70 loss of function leads to disassembly of VE-cadherin and PECAM-1 at the cell surface and selectively decreases PECAM-1 steady-state expression. Consistent with its vascular protective role, HSP70 inhibition also reduced endothelial nitric oxide synthase (eNOS) levels. Furthermore, HSP70 was essential for maintaining normal paracellular flux in primary vein (HUVEC) and coronary artery endothelial cells (HCAEC) monolayers, as well as for promoting natural cell alignment under physiological laminar shear stress in HUVEC. These results demonstrate that HSP70 regulates the quality control of interendothelial adherens junctions, mediates responses to hemodynamic forces, and maintains monolayer barrier function across vascular beds. Our findings advance the mechanistic understanding of how human HSP70 mediates vascular homeostasis through endothelium responses to blood flow and permeability in addition to HSP70 role in migration, proliferation, and angiogenesis.

Glycosylphosphatidylinositol (GPI) anchoring is a widely conserved post-translational modification in eukaryotes, in which various proteins-such as receptors, cell adhesion molecules, and complement regulatory proteins-are modified with a GPI moiety and tethered to the cell membrane. GPI anchors are synthesized in the endoplasmic reticulum (ER), where they are attached to newly translated proteins. These GPI-anchored proteins (GPI-APs) then undergo structural remodeling and are transported to the cell surface. To date, approximately 30 gene products have been identified as essential for the GPI biosynthetic and remodeling pathways. In addition to paroxysmal nocturnal hemoglobinuria (PNH), a well-characterized acquired hematologic disorder caused by somatic mutations in GPI biosynthesis genes, an increasing number of inherited GPI deficiencies (IGDs) have recently been reported. These congenital disorders are typically caused by hypomorphic mutations in GPI biosynthetic genes and present with neurological abnormalities. In this review, we provide an overview of the biosynthetic pathway of GPI anchors in mammalian cells and the genetic disorders resulting from its dysfunction. We also discuss emerging therapeutic approaches currently under investigation, including gene therapy, which hold promise for improving clinical outcomes in patients with IGD.

BackgroundSickle cell disease (SCD) is characterized by a point mutation in the β globin molecule, causing the sickling of red blood cells, and leading to hemolytic anemia, pain, and end-organ damage. Hydroxyurea (HU) is a cornerstone of SCD patient treatment, while chronic transfusions (CT) are used as part of treatment for more severe SCD. Increases in aged neutrophils and inflammation have been linked to more severe SCD and contribute to vaso-occlusive crises. The current study was designed to test the hypothesis that HU reduces inflammation and aged neutrophils.Study designWe compared clinical characteristics, aged neutrophils, levels of select cytokines, chemokines, and cell adhesion molecules in the blood and the Shannon diversity index (SDI) and ratio of Firmicutes/Bacteroides (F:B) in stool samples from pediatric SCD patients treated with HU (n=40) versus CT (n=14).ResultsPatients in the HU group had significantly lower total and aged neutrophils (p<0.0001) compared to the CT group and also had lower levels of several chemokines including CXCL10 (IP-10), CCL2 (MCP-1) and CCL4 (MIP-1β) as well as IFN-γ and IL10. Conversely, HU was associated with higher levels of IL-1α, IL-6 and IL-8. There were no significant differences in cell adhesion markers or in markers of gut microbial dysbiosis between treatment groups. In a multivariable linear regression model, only being on CT was associated with increased number of aged neutrophils (p<0.001) whereas being on CT and having a lower SDI were associated with higher total neutrophil count.DiscussionLower numbers of total and aged neutrophils and lower levels of several cytokines and chemokines in the HU group highlight the drug’s potential to modulate leukocyte activation and recruitment. These findings suggest that adding or maintaining HU therapy in SCD patients undergoing CT could potentially enhance immunologic regulation and warrants further study.

Clinicopathological implications of EpCAM immunoexpression in canine gastric carcinoma and its association with other immunomarkers.

Inflammation drives damage in acute ischemic stroke (AIS). Here, we map temporal and molecular mechanisms of immune-vascular response in patients with AIS treated with endovascular thrombectomy (EVT) for anterior circulation large-vessel occlusion. In this prospective cohort, 52 patients underwent serial peripheral blood sampling at groin puncture (Pre), catheter withdrawal (T0), and 6, 24, and 48 hours post-reperfusion. Thirteen immune and vascular players were quantified by mesoscale multiplex assays. Clinical outcomes were the modified Rankin Scale (mRS) score at 3 months and the National Institutes of Health Stroke Scale (NIHSS) at 24 hours. Adjusted by age, baseline Alberta Stroke Program Early CT Score (ASPECTS) and NIHSS scores, higher pre-EVT peripheral blood levels of interleukin (IL)-1β, IL-4, IL-10, and IL-13 were associated with poorer 24-hours NIHSS. Post-EVT reperfusion, IL-6 and its downstream effectors vascular cell adhesion molecule- (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) levels rose in peripheral blood over time, suggesting cerebrovascular inflammation, accompanied by the increased levels of acute-phase reactants C-reactive protein (CRP) and serum amyloid A (SAA), indicative of a systemic inflammatory engagement. In the same timeframe, interferon-gamma (IFN-γ) blood levels decreased. Adjusted by age, baseline ASPECT and NIHSS scores, and pre-thrombectomy biomarker levels, higher post-EVT levels of IL-6, VCAM-1, ICAM-1, and SAA were associated with poorer 24-hours NIHSS and unfavorable mRS 3 month outcomes, supporting an evolving immune dysregulation following AIS. This exploratory study points to immune and vascular activation mechanisms from pre- to post-EVT, representing possible disease indicators and targets.

Hepatic ischemia-reperfusion injury (IRI) disrupts cellular signaling pathways and contributes to early allograft dysfunction (EAD) in orthotopic liver transplantation (OLT). In this study, we found that the hepatic RNA binding protein Human Antigen R (HuR) regulated the 3' untranslated region (UTR) of Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 (Ceacam1) following ischemic stress. Hepatocyte-specific preinjury HuR-null mice exhibited elevated LDH-5 isoenzyme activity and reduced Ceacam1-S expression, reflecting tissue-specific injury. In situ hybridization demonstrated that the stability of Ceacam1 mRNA depended on HuR. Luciferase assays identified Ceacam1 3'UTR cis-elements responsive to high oxygen tension. HuR-targeting short-activating RNAs (saRNAs) preferentially induced the alternative splicing of Ceacam1-S. Antisense oligos directed to the Ceacam1 3'UTR protected WT mice against acute liver injury. In the clinical arm, increased HuR and CEACAM1 expression were associated with reduced proinflammatory phenotype and a lower incidence of EAD in patients with OLT (n = 164). Human discarded livers with elevated ELAVL1/CEACAM1 levels correlated with improved tissue homeostasis. These findings suggest that HuR regulation of Ceacam1 represents a key determinant of donor tissue quality and offers a potential target for future therapeutic strategies in OLT recipients.

CHD7 and CHD8 are chromatin remodeling proteins that regulate several neurodevelopmental events. Mutations in these chromatin remodeling genes occur in neurodevelopmental disorders including CHARGE Syndrome and Autism Spectrum Disorders. Kismet (Kis) is the sole Drosophila homolog of CHD7 and CHD8. We investigated the possibility that Kis influences retrograde synaptic signaling given that Kis restricts the synaptic levels of several cell adhesion molecules and facilitates endocytosis. Our data indicate that Kis restricts synaptic pMad while facilitating the localization of pMad to presynaptic motor neuron nuclei. While the increase in pMad at kis mutant synapses may contribute to the loss of Endophilin B, it may not influence the mislocalization of glutamate receptors relative to active zones or the locomotor phenotypes observed in kis mutants. Kis may antagonize Polycomb Repressive Complex 2 (PRC2) signaling to restrict synaptic pMad. Kis, including its chromatin remodeling/ATPase activity, is required in presynaptic motor neurons for proper synaptic pMad levels. In contrast, an ATPase-deficient Kis can rescue synaptic pMad when expressed in all tissues. Similarly, expression of human CHD7 in all tissues of kis mutants rescues synaptic pMad. Our data suggest a model where Kis restricts synaptic pMad both by transcription-dependent and transcription-independent mechanisms. These data may aid in a better understanding of the importance of chromatin remodeling for synaptic structure and function and the molecular changes correlated with neurodevelopmental disorders.

Presbycusis, or age-related hearing loss (ARHL), is a progressive condition that involves a steady decline in auditory function, primarily caused by the physiological alterations that occur with aging. This disorder arises from the combined effect of multiple interconnected factors that progressively affect the auditory system over time. Genome-wide association studies (GWAS) and transcriptomic analyses in human populations are valuable approaches for identifying potential genes associated with ARHL. This research seeks to assess the potential of protective drugs or strategies for treating ARHL by analyzing target gene-miRNA interactions identified in human blood and associated with presbycusis. We performed RNA sequencing to analyze the transcriptomes of peripheral blood leukocytes from ARHL patients. To identify genes associated with ARHL, the RNA-sequencing data from the peripheral blood leukocytes were compared and further validated by real-time polymerase chain reaction (RT-qPCR) using whole blood samples from the same ARHL patients. To explore the involvement of target genes and microRNAs (miRNAs) in ARHL, we examined miRNA expression patterns using RT-qPCR and reporter gene assays. We found that four genes were up-expressed in ARHL serum: Fas Ligand (FASLG), Neural Cell Adhesion Molecule 1 (NCAM1), Nectin Cell Adhesion Molecule 1 (NECTIN1), Macrophage Receptor with Collagenous Structure (MARCO). The up-expressed FASLG is associated with cell apoptosis and aging. Additionally, we showed that miR‑5195 and miR-3941 regulated FASLG expression in House Ear Institute-Organ of Corti 1 (HEI-OC-1) and HeLa cells via targeting of FASLG using luciferase reporter assays. Finally, the over-expression of the FASLG gene may be associated with the development of ARHL, and the inhibitory role of miR-5195 and miR-3941 could be a key factor in the prevention or protection against ARHL.

This study evaluates and compares the effects of continuous and interval training on inflammatory and adhesion molecules in subjects with Type 1 diabetes mellitus (T1D) and healthy controls. Using Luminex X-MAP, serum inflammatory and adhesion molecules were measured in 50 non-obese, sedentary adults (78% women; mean age 34years), including 27 with T1D and 23 healthy controls. Subjects with T1D exhibited a tendency towards decreased interleukin 10 (IL-10) levels and increased intercellular adhesion molecule (ICAM1) levels compared to controls. Exercise training, specifically high-intensity interval training (HIIT), increased IL-10 levels in the T1D group. Among controls, we observed a decrease in vascular cell adhesion molecule 1 (VCAM1) after continuous training, and in platelet selectin (P-selectin) after HIIT. The correlation studies revealed that subjects with higher baseline maximal oxygen uptake (VO2max) achieved greater reductions in P-selectin levels with training and that levels of VCAM1 were further reduced by training in subjects with higher baseline metabolic equivalents (METS). Our findings show that the effects of exercise on inflammatory cytokines and adhesion molecules vary depending on the training modality and the population studied. Additionally, our data suggest that physical activity and fitness levels influence individual responses to exercise in relation to adhesion molecules in healthy and subjects with T1D.

Intervertebral disc degeneration (IDD) can contribute to lower back and neck pain. In IDD, the most affected component of the intervertebral disc is the nucleus pulposus (NP). Derived from the notochord, where cells are organized into a tandem configuration, young NP cells cluster in three-dimensional (3D) networks embedded in a gelatinous matrix. Here, we review the current understanding of NP development, homeostasis, physiology, and degeneration with a focus on the roles of the cell adhesion molecule N-cadherin in these processes. Based on the literature, we hypothesize that N-cadherin contributes to the architectural transition from the notochord to the NP by mediating a switch in cellular organization from tandem to random orientational cell adhesions (OCAs). We further hypothesize that the 3D clustering of NP cells may facilitate N-cadherin to act as a mechanosensor to modulate NP gene expression under mechanical stresses. We hope these hypotheses promote future research on the etiology of human IDD and the development of measures to prevent and treat IDD. Some open questions on N-cadherin functions in the NP are also discussed.

The micropapillary histological subtype is a high-grade element and a poor prognostic marker in lung adenocarcinoma (LUAD). This subtype develops through the lepidic-filigree micropapillary (filigree)-conventional/overt micropapillary (mPAP) pathway. The present study aimed to identify key molecules that promote this progression. To this end, gene expression profiles specific to lepidic, filigree and mPAP elements were investigated in histological sections obtained from 4 different LUAD cases. The 10× Genomics Visium Spatial Gene Expression Solution was used due to its superior resolution compared with conventional microdissection techniques. Cellular retinoic acid binding protein 2 (CRABP2), carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) and mucin 21 (MUC21) were identified as common molecules with significantly elevated levels along the lepidic-filigree-mPAP pathway. Furthermore, the present findings indicated that CRABP2 may serve an important role in the early stage of this process, as its level significantly increases during the transition from the lepidic to the filigree substage. Immunohistochemical analysis of the expression of CRABP2, CEACAM5 and MUC21 proteins in 207 surgically resected LUAD samples (expanded sample size) was performed. The present study revealed an increase in the expression levels of CRABP2 between the lepidic and filigree elements, and between filigree and mPAP for CEACAM5 and MUC21. Thus, these three proteins were demonstrated to serve roles in the lepidic-filigree-mPAP pathway at different stages. Notably, these molecules were associated with poor prognosis, characterized by an elevated recurrence rate and poor survival rate. In conclusion, crucial molecules that promote the lepidic-filigree-mPAP pathway, and exhibit potential clinical utility as prognostic markers and molecular therapeutic targets, were identified.

Advances in bioinformatics have greatly contributed to the discovery of epithelial–mesenchymal transition (EMT) markers, such as epithelial cell adhesion molecule (EPCAM). This study aimed to conduct an EPCAM-centered meta-analyses of previously RNA-sequencing data for identifying pan-cancer EMT markers in circulating tumor cells (CTCs) utilizing bioinformatics- and machine learning (ML)-based approaches. In this study, the RNA sequencing data of seven different cancer types from two datasets, namely GSE273023 and GSE274442, were analyzed. Gene–gene correlation among included cancer samples and EPCAM-centered gene–gene correlation analysis were performed. The data were subjected to ML-based pathway and gene clustering analysis. Notably, the results showed that most of the cancers presented similar gene expression profile, albeit with some differences, which were primarily attributed to differences in mitochondrial gene expression. Furthermore, gene–gene correlation analysis revealed multiple genes with significantly altered expression, including CBWD2, MED23, QRSL1, ZNF568, and INTU. Similarly, TRPS1 was found to be significantly correlated with EPCAM. Overall, the findings of this study reveal the association between EPCAM–TRPS1 and CBWD2-associated MED23–QRSL1–ZNF568–INTU axes, thereby showing their potential as co-markers and for the development of multiplexed immunoassay for a robust pan-cancer CTC detection approach.