Interaction Of Adhesion Molecules Research Articles

ADAM10 modulates the efficacy of T-cell-mediated therapy in solid tumors.

T-cell-mediated therapeutic strategies are the most potent effectors of cancer immunotherapy. However, an essential barrier to this therapy in solid tumors is disrupting the anti-cancer immune response, cancer-immunity cycle, T-cell priming, trafficking and T-cell cytotoxic capacity. Thus, reinforcingtheanti-cancer immune response is needed to improve the effectiveness of T-cell-mediated therapy. Tumor-associated protease ADAM10, endothelial cells (ECs) and cytotoxic CD8+ Tcells engage in complex communication via adhesion, transmigration and chemotactic mechanisms to facilitate an anti-cancer immune response. The precise impact of ADAM10 on the intricate mechanisms underlying these interactions remains unclear. This paper broadly explores how ADAM10, through different routes, influences the efficacy of T-cell-mediated therapy. ADAM10 cleaves CD8+ T-cell-targeting genes and impacts their expression and specificity. In addition, ADAM10 mediates the interactions of adhesion molecules with Tcells and influences CD8+ T-cell activity and trafficking. Thus, understanding the role of ADAM10 in these events may lead to innovative strategies for advancing T-cell-mediated therapies.

Modular Satellite Nanoparticles for Remedying Primary and Secondary Injury in Cerebral Ischemia‐Reperfusion

AbstractReperfusion therapy, employed in the treatment of acute stroke, frequently proves to be inadequate in addressing the primary brain tissue injury and may even give rise to secondary damage. The study introduces a satellite nanoparticle platform named MEps, which combine the neural repair properties of bone marrow mesenchymal stem cell exosomes (Exos) with the inflammatory site‐targeting abilities of macrophage membranes (MMs). MMs and Exos in MEps act like satellites, ensuring precise positioning and information transmission. MEps rapidly form a protective barrier on the damaged cerebral vascular endothelial cells through the interaction of adhesion molecules with their receptors, blocking the infiltration of neutrophils. Subsequently, repair factors in Exos repair the damaged cells and initiate neurogenesis. The results indicate that this innovative approach effectively mitigates ischemic‐reperfusion injury at multiple levels and demonstrates strong biocompatibility. This strategy holds promise for clinical applications in alleviating ischemic‐reperfusion injury.

Two-phase kinetics and cell cortex elastic behavior in Xenopus gastrula cell-cell adhesion

Morphogenetic movements during animal development involve repeated making and breaking of cell-cell contacts. Recent biophysical models of cell-cell adhesion integrate adhesion molecule interactions and cortical cytoskeletal tension modulation, describing equilibrium states for established contacts. We extend this emerging unified concept of adhesion to contact formation kinetics, showing that aggregating Xenopus embryonic cells rapidly achieve Ca2+-independent low-contact states. Subsequent transitions to cadherin-dependent high-contact states show rapid decreases in contact cortical F-actin levels but slow contact area growth. We developed a biophysical model that predicted contact growth quantitatively from known cellular and cytoskeletal parameters, revealing that elastic resistance to deformation and cytoskeletal network turnover are essential determinants of adhesion kinetics. Characteristic time scales of contact growth to low and high states differ by an order of magnitude, being at a few minutes and tens of minutes, respectively, thus providing insight into the timescales of cell-rearrangement-dependent tissue movements.

Identification of potential classes of glycoligands mediating dynamic endothelial adhesion of human tumor cells.

One critical step of metastasis formation is the extravasation of circulating tumor cells from the bloodstream. This process requires the dynamic interaction of cell adhesion molecules like E-selectin on endothelial cells with carbohydrate ligands on tumor cells. To characterize these glycans in a comprehensible approach, the rolling, tethering, and firm adhesion of nine human tumor cell lines on human umbilical vein endothelial cells was analyzed using laminar flow adhesion assays. The tumor cell lines were grouped into three subsets by their canonical E-selectin ligand status (sialyl-Lewis A and X +/+, -/+, -/-) and their adhesiveness was compared after enzymatic, pharmacologic, chemical treatment or antibody blockade of the tumor cells or endothelial cells, respectively. Tumor cells were also screened regarding their glycosyltransferase expression profile. We found that although E-selectin and terminal α2,3-sialic acid largely determined firm adhesion, adhesive events did not exclusively depend on the presence of sialyl-Lewis A and/or sialyl-Lewis X. Nevertheless, two of the three sialyl-Lewis A/X-/- tumor cells additionally or fully depended on vascular cell adhesion molecule-1 for firm adhesion. The significance of O-GalNAc- and N-glycans for adhesion varied remarkably among the tumor cells. The sialyl-Lewis A/X+/+ subset showed glycoprotein-independent adhesion, suggesting a role of glycolipids as well. All sialyl-Lewis A/X-/- tumor cells lacked FUT3 and FUT7 expression as opposed to sialyl-Lewis A/X+/+ or -/+ cell lines. In summary, the glycans on tumor cells mediating endothelial adhesion are not as much restricted to sialyl-Lewis A /X as previously assumed. The present study specifically suggests α2,3-linked sialic acid, O-GalNAc glycans, glycosphingolipids, and FUT3/FUT7 products as promising targets for future studies.

COVID-19 induced remission of biliary and renal cell carcinomas.

e14598 Background: Clear cell renal carcinoma and cholangiocarcinoma are resistant to standard therapy. Complete remissions are rare. SARS-CoV-2 (COVID-19) boosts anti-viral immune responses but effects on cancers are unknown. Case reports of hematologic cancer remissions after COVID infection are emerging. Anti PD1/PD-L1 antibody therapy have prolonged remission in 20% of solid tumor patients. mRNA COVID-19 vaccines and COVID-19 active infections create anti-viral immune responses - increased IgG titers, SARS-CoV-2-specific antibodies, and boost T-cell response. Anti PD-1/PD-L1 antibodies immune responses, are presumed independent of the immune response to COVID vaccination/infection. Two previous case reports of hematologic remission were seen after COVID infection. (Hodgkins, multiple myeloma). There are no cases of solid cancer remission after COVID-19 exposure. Methods: Three patients with solid cancers and complete/near complete radiographic remissions after COVID-19 exposure. Two on low carbohydrate diets. History, dietary course and clinical outcomes are presented. Results: Case 1: 58 year old male diagnosed with stage IV clear cell renal carcinoma (lung nodules, mediastinal nodes). After 5 years he progressed on Sunitinib and began Nivolumab. His cancer stabilized but hypophysitis, diarrhea, severe jaw pain ended his treatment. After COVID-19 booster vaccine, he became anorexic, lost 50 lbs over 8 weeks (267 to 211 lb). Relapse was suspected but PET CT showed complete resolution of his lung nodules and adenopathy. Asymptomatic and in remission over 9 months post vaccine. Case 2: 51 year old male heavily pretreated stage 4 renal cell cancer, bone, liver, nodal metastases. On Nivolumab with stable disease but after COVID booster vaccine had high fever, fatigue, myalgia. PET CT scans later showed near complete resolution of his bony, hepatic and nodal metastatic sites. Case 3: 75 year old male with unresectable cholangiocarcinoma on second line Atezolizumab. COVID-19 infection was followed by complete radiographic remission. Conclusions: Effects of SARS-CoV-2 (COVID-19) on cancers remain unknown. Few case reports of cancer remissions after infections are emerging. These are two cases of renal cell cancers in complete remission after COVID-19 vaccination while on immunotherapy. Both followed low glycemic diets. Third case was a complete remission of biliary cancer after an acute COVID-19 infection. Proposed anti-cancer mechanisms - pathogen specific T cell action, anti-inflammatory effects against COVID-19 infection, cross-reactivity against tumor antigens, natural killer cell activation. COVID-19 proteins have oncolytic properties - HIV related B cell apoptosis and Coxsackievirus A21 oncolytic effects on myeloma and CD138+ plasma cells via intercellular adhesion molecule interaction. COVID-19’s effects plus the anti PD-1/PD-L1 antibodies immune response may be synergistic and merits further research.

Neutrophil membrane biomimetic delivery system (Ptdser-NM-Lipo/Fer-1) designed for targeting atherosclerosis therapy.

Atherosclerosis is a progressive inflammatory disease characterised by excessive lipid accumulation and inflammatory cell infiltration and is the basis of most cardiovascular diseases and peripheral arterial diseases. Therefore, an effectively targeted delivery system is urgently needed to deliver ferroptosis-specific inhibitors to the site of arterial plaque and the inflammatory microenvironment. Inspired by the fact that neutrophils can be recruited to arterial plaques under the action of adhesion molecules and chemokines, the authors developed a neutrophil membrane hybrid liposome nano-mimetic system (Ptdser-NM-Lipo/Fer-1) that delivers Ferrostatin-1 (Fer-1) to the atherosclerotic plaque effectively, which is composed of Fer-1-loaded Ptdser-modified liposomes core and neutrophils shell. Fer-1 was released at the AS plaque site to remove reactive oxygen species (ROS) and improve the inflammatory microenvironment. In vitro ROS clearance experiments have shown that 50μmol/ml Fer-1 can significantly remove ROS produced by H2 O2 -induced MOVAS cells and Ptdser-NM-Lipo/Fer-1 revealed a 3-fold increase in the inhibition rate of ROS than free Fer-1 in induced-RAW264.7, demonstrating its superior ROS-cleaning effect. Based on the interaction of adhesion molecules, such as vascular cell adhesion molecule 1, ICAM-1, P-selectin, E-selectin, and chemokines released in the inflamed site, the aorta in NM-Lipo-treated mice displayed 1.3-fold greater radiant efficiency than platelet membrane-Lipo-treated mice. Meanwhile, due to the modification of the Ptdser, the aorta in Ptdser-NM-Lipo/Fer-1-treated mice exhibited the highest fluorescence intensity, demonstrating its excellent targeting ability for atherosclerosis. Therefore, we present a specific formulation for the treatment of atherosclerosis with the potential for novel therapeutic uses.

Modeling Brain Vasculature Immune Interactions In Vitro.

The endothelial blood-brain barrier (BBB) protects central nervous system (CNS) neurons from the changeable milieu of the bloodstream by strictly controlling the movement of molecules and immune cells between the blood and the CNS. Immune cell migration across the vascular wall is a multistep process regulated by the sequential interaction of different signaling and adhesion molecules on the endothelium and the immune cells. Accounting for its unique barrier properties and trafficking molecule expression profile, particular adaptions in immune cell migration across the BBB have been observed. Thus, in vitro models of the BBB are desirable to explore the precise cellular and molecular mechanisms involved in immune cell trafficking across the BBB. The challenge to overcome is that barrier properties of brain microvascular endothelial cells are not intrinsic and readily lost in culture. With a focus on human in vitro BBB models, we here discuss the suitability of available in vitro models for the BBB for exploring the specific mechanisms involved in immune cell trafficking across the BBB.

Amyloid precursor protein (APP) and amyloid β (Aβ) interact with cell adhesion molecules: Implications in Alzheimer's disease and normal physiology.

Alzheimer’s disease (AD) is an incurable neurodegenerative disorder in which dysfunction and loss of synapses and neurons lead to cognitive impairment and death. Accumulation and aggregation of neurotoxic amyloid-β (Aβ) peptides generated via amyloidogenic processing of amyloid precursor protein (APP) is considered to play a central role in the disease etiology. APP interacts with cell adhesion molecules, which influence the normal physiological functions of APP, its amyloidogenic and non-amyloidogenic processing, and formation of Aβ aggregates. These cell surface glycoproteins also mediate attachment of Aβ to the neuronal cell surface and induce intracellular signaling contributing to Aβ toxicity. In this review, we discuss the current knowledge surrounding the interactions of cell adhesion molecules with APP and Aβ and analyze the evidence of the critical role these proteins play in regulating the processing and physiological function of APP as well as Aβ toxicity. This is a necessary piece of the complex AD puzzle, which we should understand in order to develop safe and effective therapeutic interventions for AD.

Live imaging-based assay for visualising species-specific interactions in gamete adhesion molecules

Successful gamete fusion requires species-specific membrane adhesion. However, the interaction of adhesion molecules in gametes is difficult to study in real time through low-throughput microscopic observation. Therefore, we developed a live imaging-based adhesion molecule (LIAM) assay to study gamete adhesion molecule interactions in cultured cells. First, we modified a fusion assay previously established for fusogens introduced into cultured cells, and confirmed that our live imaging technique could visualise cell–cell fusion in the modified fusion assay. Next, instead of fusogen, we introduced adhesion molecules including a mammalian gamete adhesion molecule pair, IZUMO1 and JUNO, and detected their temporal accumulation at the contact interfaces of adjacent cells. Accumulated IZUMO1 or JUNO was partly translocated to the opposite cells as discrete spots; the mutation in amino acids required for their interaction impaired accumulation and translocation. By using the LIAM assay, we investigated the species specificity of IZUMO1 and JUNO of mouse, human, hamster, and pig in all combinations. IZUMO1 and JUNO accumulation and translocation were observed in conspecific, and some interspecific, combinations, suggesting potentially interchangeable combinations of IZUMO1 and JUNO from different species.

Adhesion Molecule Profile and the Effect of Anti-VLA-4 mAb Treatment in Experimental Autoimmune Encephalomyelitis, a Mouse Model of Multiple Sclerosis.

In the course of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), the infiltration of lymphocytes and other inflammatory cells across the blood–brain barrier is associated with interactions between adhesion molecules expressed by infiltrating cells and vascular endothelium. Monoclonal antibodies (mAb) against the α4 subunit of α4-β1 integrin (VLA-4) show beneficial effects in both MS and EAE. (1) Background: The aim of this study was to examine the expression of selected adhesion molecules: VLA-4, VCAM-1, LFA-1, ICAM-1 and PECAM-1 in the successive phases of EAE and the effect of anti-VLA-4 mAb treatment on that expression. (2) Methods: EAE was induced in C57BL/6 mice by immunization with MOG35–55 peptide. The animals were killed in three successive phases of the disease: onset (day 13), peak (day 18) and chronic (day 28). Frozen sections of the lumbar spinal cord were examined by quantitative immunofluorescence microscopy. The expression of the studied molecules was quantified as the percentage of the cross-sectioned spinal cord lesion area occupied by immunopositive structures. (3) Results: The expression of the studied molecules showed two temporal patterns: (1) an increase in the onset phase, a maximum in the peak phase and a decrease in the chronic phase, which corresponded to the temporal pattern of the clinical score, the number of lesions and the inflammation level (ICAM-1, LFA-1 and PECAM-1), and (2) an increase in the peak phase and no significant change or further increase in the chronic phase (VCAM-1, VLA-4). Among the molecules studied, ICAM-1 and LFA-1 exhibited the highest expression levels in the peak phase of EAE. Anti-VLA-4 mAb inhibited the expression of not only VLA-4 but also other adhesion molecules. (4) Conclusions: The interactions of adhesion molecules governing the migration of leukocytes across the blood–brain barrier change in the successive phases of EAE. The therapeutic mechanism of anti-VLA-4 mAb treatment seems to include a complex influence on a variety of adhesion molecules expressed by infiltrating cells and vascular endothelium.

Differential Expression of the TLR4 Gene in Pan-Cancer and Its Related Mechanism.

Previous studies have revealed the relationship between toll-like receptor 4 (TLR4) polymorphisms and cancer susceptibility. However, the relationship between TLR4 and prognosis and immune cell infiltration in pan-cancer patients is still unclear. Through the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases, the distinct expression of the TLR4 gene in 24 tumors and normal tissues was analyzed. Univariate Cox proportional hazards regression analysis was used to identify the cancer types whose TLR4 gene expression was related to prognosis. The relationship between TLR4 and tumor cell immune invasion was studied. Spearman’s rank correlation coefficient was used to analyze the relationship among TLR4 and immune neoantigens, tumor mutation burden (TMB), microsatellite instability (MSI), DNA repair genes, and DNA methylation. Gene Set Enrichment Analysis (GSEA) was used to identify the tumor-related pathways that the TLR4 gene was highly expressed in; the expression of the TLR4 gene was verified with the Human Protein Atlas (HPA) database. Low expression of TLR4 was associated with an inferior prognosis in kidney renal clear cell carcinoma (KIRC), skin cutaneous melanoma (SKCM), and uterine corpus endometrial carcinoma (UCEC), while high expression was related to a poor prognosis in head and neck squamous cell carcinoma (HNSC), prostate adenocarcinoma (PRAD), stomach adenocarcinoma (STAD), and testicular germ cell tumor (TGCT). The expression of TLR4 was negatively correlated with the expression of B cells in STAD. The expression of TLR4 was positively correlated with the infiltration of B cells, CD4 and CD8 T cells, neutrophils, macrophages, and dendritic cells in STAD, KIRC, UCEC, TGCT, and SKCM. The expression of the TLR4 gene in KIRC, SKCM, STAD, TGCT, and UCEC was highly correlated with inducible T-cell costimulator (ICOS), cytotoxic T lymphocyte-associated molecule 4 (CTLA4), and CD28 immune checkpoints. Spearman’s rank correlation coefficient showed that the expression of TLR4 gene was significantly correlated with TMB in STAD and UCEC and was prominently correlated with MSI in TGCT, STAD, and SKCM. The expression of the TLR4 gene was highly correlated with MLH1, MSH2, and MSH6 in KIRC, SKCM, and STAD. The expression of the TLR4 gene was remarkably correlated with the methyltransferases DNA methyltransferase 2 (DNMT2) and DNA methyltransferase 3-beta (DNMT3B) in SKCM and STAD. Enrichment analysis showed that TLR4 was highly expressed in the chemokine signaling pathway and the cell adhesion molecule and cytokine receptor interaction pathway. In summary, the expression of TLR4 is linked to the prognosis of KIRC, SKCM, STAD, TGCT, and UCEC patients and the level of immune infiltration of CD4, CD8 T cells, macrophages, neutrophils, and dendritic cells.

Association between Inflammation and Function of Cell Adhesion Molecules Influence on Gastrointestinal Cancer Development

Gastrointestinal cancer is highly associated with inflammatory processes inducing the release of cytokines from cancer or immune cells, including interferons, interleukins, chemokines, colony-stimulating factors, and growth factors, which promote or suppress tumor progression. Inflammatory cytokines within the tumor microenvironment promote immune cell infiltration. Infiltrating immune, and tumor-surrounding stromal cells support tumor growth, angiogenesis, metastasis, and immunosuppression through communication with inflammatory cytokines and cell adhesion molecules. Notably, infiltrating immune and tumor cells present immunosuppressive molecules, such as programmed death-ligand 1 (PD-L1) and CD80/CD86. Suppression of cytotoxic T cells promotes tumor avoidance of immune surveillance and greater malignancy. Moreover, glycosylation and sialylation of proteins hyperexpressed on the cancer cell surface have been shown to enhance immune escape and metastasis. Cytokine treatments and immune checkpoint inhibitors are widely used in clinical practice. However, the tumor microenvironment is a rapidly changing milieu involving several factors. In this review, we have provided a summary of the interactions of inflammation and cell adhesion molecules between cancer and other cell types, to improve understanding of the tumor microenvironment.

Roles of type IIa receptor protein tyrosine phosphatases as synaptic organizers.

Neurons establish circuits for brain functions such as cognition, emotion, learning, and memory. Their connections are mediated by synapses, which are specialized cell-cell adhesions responsible for neuronal signal transmission. During neurodevelopment, synapse formation is triggered by interactions of cell adhesion molecules termed synaptic organizers or synapse organizers. Type IIa receptor protein tyrosine phosphatases (IIa RPTPs; also known as leukocyte common antigen-related receptor tyrosine phosphatases or LAR-RPTPs) play important roles in axon guidance and neurite extension, and also serve as presynaptic organizers. IIa RPTPs transsynaptically interact with multiple sets of postsynaptic organizers, mostly in a splicing-dependent fashion. Here, we review and update research progress on IIa RPTPs, particularly regarding their functional roles in vivo demonstrated using conditional knockout approach and structural insights into their extracellular and intracellular molecular interactions revealed by crystallography and other biophysical techniques. Future directions in the research field of IIa RPTPs are also discussed, including recent findings of the molecular assembly mechanism underlying the formation of synapse-specific nanostructures essential for synaptic functions.

Immune cell trafficking across the blood-brain barrier in the absence and presence of neuroinflammation.

To maintain the homeostatic environment required for proper function of CNS neurons the endothelial cells of CNS microvessels tightly regulate the movement of ions and molecules between the blood and the CNS. The unique properties of these blood vascular endothelial cells are termed blood-brain barrier (BBB) and extend to regulating immune cell trafficking into the immune privileged CNS during health and disease. In general, extravasation of circulating immune cells is a multi-step process regulated by the sequential interaction of adhesion and signalling molecules between the endothelial cells and the immune cells. Accounting for the unique barrier properties of CNS microvessels, immune cell migration across the BBB is distinct and characterized by several adaptations. Here we describe the mechanisms that regulate immune cell trafficking across the BBB during immune surveillance and neuroinflammation, with a focus on the current state-of-the-art in vitro and in vivo imaging observations.

Casein Kinase 1δ Stabilizes Mature Axons by Inhibiting Transcription Termination of Ankyrin.

After axon outgrowth and synapse formation, the nervous system transitions to a stable architecture. In C.elegans, this transition is marked by the appearance of casein kinase 1δ (CK1δ) in the nucleus. In CK1δ mutants, neurons continue to sprout growth cones into adulthood, leading to a highly ramified nervous system. Nervous system architecture in these mutants is completely restored by suppressor mutations in ten genes involved in transcription termination. CK1δ prevents termination by phosphorylating and inhibiting SSUP-72. SSUP-72 would normally remodel the C-terminal domain of RNA polymerase in anticipation of termination. The antitermination activity of CK1δ establishes the mature state of a neuron by promoting the expression of the long isoform of a single gene, the cytoskeleton protein Ankyrin.

β7 Integrin Inhibition Can Increase Intestinal Inflammation by Impairing Homing of CD25hiFoxP3+ Regulatory T Cells.

Background & AimsIntegrin α4β7 mediates lymphocyte trafficking to the gut and gut-associated lymphoid tissues, a process critical for recruitment of effector lymphocytes from the circulation to the gut mucosa in inflammatory bowel disease (IBD) and murine models of intestinal inflammation. Antibody blockade of β7 integrins generally is efficacious in IBD; however, some patients fail to respond, and a few patients can experience exacerbations. This study examined the effects of loss of β7 integrin function in murine models of IBD.MethodsIn a mouse IBD model caused by lack of interleukin 10, a cytokine important in CD25hiFoxP3+ regulatory T cell (Treg) function, genetic deletion of β7 integrin or antibody blockade of α4β7–mucosal addressin cell adhesion molecule-1 interaction paradoxically exacerbated colitis.ResultsLoss of β7 impaired the capacity of Tregs homing to the gut and therefore suppress intestinal inflammation in an adoptive T-cell transfer model; however, the intrinsic suppressive function of β7-deficient Tregs remained intact, indicating that the β7 deficiency selectively impacts gut homing. Deletion of β7 integrin did not worsen colitis in an acute dextran sodium sulfate model in which Treg number and function were normal.ConclusionsIn Integrin subunit beta (Itgb)7-/-Il10-/- mice, loss of β7-dependent Treg homing to gut-associated lymphoid tissues combined with loss of intrinsic Treg function exacerbated intestinal inflammation. These results suggest that IBD patients with reduced CD25hiFoxP3+ Treg numbers or function or lack of interleukin 10 could be at risk for failure of α4β7 blocking therapy.

Hyperglycemia-induced ubiquitination and degradation of β-catenin with the loss of platelet endothelial cell adhesion molecule-1 in retinal endothelial cells.

Increased retinal vascular permeability is one of the earliest manifestations of diabetic retinopathy. The aim of this study was to investigate the role of hyperglycemia-induced platelet endothelial cell adhesion molecule-1 loss on retinal vascular permeability via the β-catenin pathway. Type I diabetes was induced in male Wistar rats using streptozotocin injections, with age-matched non-diabetic rats as controls. Rat retinal microvascular endothelial cells were grown under normal or high glucose conditions for 6days. Small interfering Ribonucleic Acid was used to knock down platelet endothelial cell adhesion molecule-1 in rat retinal microvascular endothelial cells for loss-of-function studies. Retinas and rat retinal microvascular endothelial cells were subjected to Western blot, immunofluorescence labeling, and co-immunoprecipitation analyses to assess protein levels and interactions. A biotinylated gelatin and fluorescein isothiocyanate-avidin assay was used for retinal endothelial cell permeability studies. β-catenin, β-catenin/platelet endothelial cell adhesion molecule-1 interaction, active Src homology 2 domain-containing protein tyrosine phosphatasewere significantly decreased, while β-catenin ubiquitination levels and endothelial permeability were significantly increased, in hyperglycemic retinal endothelial cells. Similar results were observed with platelet endothelial cell adhesion molecule-1 partial knockdown, where β-catenin and active Src homology 2 domain-containing protein tyrosine phosphatase levels were decreased, while phospho-β-catenin and retinal endothelial cell permeability were increased. Platelet endothelial cell adhesion molecule-1 loss may contribute to increased retinal endothelial cell permeability by attenuating β-catenin levels under hyperglycemic conditions.

Radiogenomics of breast cancer using dynamic contrast enhanced MRI and gene expression profiling

BackgroundImaging techniques can provide information about the tumor non-invasively and have been shown to provide information about the underlying genetic makeup. Correlating image-based phenotypes (radiomics) with genomic analyses is an emerging area of research commonly referred to as “radiogenomics” or “imaging-genomics”. The purpose of this study was to assess the potential for using an automated, quantitative radiomics platform on magnetic resonance (MR) breast imaging for inferring underlying activity of clinically relevant gene pathways derived from RNA sequencing of invasive breast cancers prior to therapy.MethodsWe performed quantitative radiomic analysis on 47 invasive breast cancers based on dynamic contrast enhanced 3 Tesla MR images acquired before surgery and obtained gene expression data by performing total RNA sequencing on corresponding fresh frozen tissue samples. We used gene set enrichment analysis to identify significant associations between the 186 gene pathways and the 38 image-based features that have previously been validated.ResultsAll radiomic size features were positively associated with multiple replication and proliferation pathways and were negatively associated with the apoptosis pathway. Gene pathways related to immune system regulation and extracellular signaling had the highest number of significant radiomic feature associations, with an average of 18.9 and 16 features per pathway, respectively. Tumors with upregulation of immune signaling pathways such as T-cell receptor signaling and chemokine signaling as well as extracellular signaling pathways such as cell adhesion molecule and cytokine-cytokine interactions were smaller, more spherical, and had a more heterogeneous texture upon contrast enhancement. Tumors with higher expression levels of JAK/STAT and VEGF pathways had more intratumor heterogeneity in image enhancement texture. Other pathways with robust associations to image-based features include metabolic and catabolic pathways.ConclusionsWe provide further evidence that MR imaging of breast tumors can infer underlying gene expression by using RNA sequencing. Size and shape features were appropriately correlated with proliferative and apoptotic pathways. Given the high number of radiomic feature associations with immune pathways, our results raise the possibility of using MR imaging to distinguish tumors that are more immunologically active, although further studies are necessary to confirm this observation.

Evolutionarily conserved and divergent functions for cell adhesion molecules in neural circuit assembly.

The developing nervous system generates remarkably precise synaptic connections between neurons and their postsynaptic target cells. Numerous neural cell adhesion proteins have been identified to mediate cell recognition between synaptic partners in several model organisms. Here, I review the role of protein interactions of cell adhesion molecules in neural circuit assembly and address how these interactions are utilized to form different neural circuitries in different species. The emerging evidence suggests that the extracellular trans-interactions of cell adhesion proteins for neural wiring are evolutionarily conserved across taxa, but they are often used in different steps of circuit assembly. I also highlight how these conserved protein interactions work together as a group to specify neural connectivity.

Abstract A195: Mechanosensory mechanisms and in vivo tissue topology contribute to rheology of circulating leukocytes resulting in efficient post-capillary vessel wall adhesion and recruitment

Abstract Efficient recruitment of circulating immune cells to various tissues plays a critical role in homeostasis and immune surveillance, a process that serves as the basis of any successful cell-based immunotherapeutic strategies in cancer, particularly for solid tumors and cancers residing in body sites outside of blood vessels and sinusoid network. Clinical and experimental observations suggest that in vivo leukocyte adhesion and extravasation are maximal near the transition from capillary to post-capillary venule, through a multistep process that includes the intravascular capture, rolling, arrest, crawling of cells through interactions of adhesion molecules (selectins, integrins, chemokines/receptors, for example), eventually leading to transcellular or paracellular transmigration through intact endothelium. These cellular and molecular processes are strongly influenced by a confluence of scale-dependent physical effects. Mimicking the scale of physiologic vessels using in vitro microfluidic systems allows the capture and investigation of these effects on leukocyte adhesion assays, but imposes practical limits on reproducibility and reliable quantification. We have developed a microfluidic platform that provides multiple (54-512) technical replicates within a 15-minute sample collection time, coupled with an automated computer vision analysis pipeline that captures leukocyte adhesion probabilities as a function of not only shear stress imposed on leukocytes within the vessels as conventional wisdom dictates, but also of the extensional stresses imposed by the topology of post-capillary venules and the rheology of circulating leukocytes in these vessels. We identified that in post-capillary channels of physiologic scale, efficient leukocyte adhesion requires erythrocytes forcing leukocytes against the wall, a phenomenon that is promoted by the transitional flow in post-capillary venule expansions and highly dependent on the adhesion molecule ICAM-1. These studies help identified a mechanosensory mechanism that determines the increased likelihood of leukocyte adhesion in post-capillary venules, and further suggests a significant role of mechanosensory channel(s) in influencing leukocyte integrin affinity for cellular capture to the vessel wall. Through a series of truncation mutants, we have narrowed down a small region of putative interacting domain between integrin and a candidate mechanosensory channel—PIEZO1—on leukocytes. These ongoing investigations offer new insights into immune cellular recruitment and new molecular targets to enhance leukocyte recruitment to peripheral tumor sites. Citation Format: Alex Y. Huang, Bryan L. Benson, Luis Correa, Lucy Li, Jay T. Myers, Umut A. Gurkan, Richard Ransohoff. Mechanosensory mechanisms and in vivo tissue topology contribute to rheology of circulating leukocytes resulting in efficient post-capillary vessel wall adhesion and recruitment [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A195.