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Background: Inflammation markers in the blood may indicate a higher risk of unstable atherosclerosis. Selectins, a group of transmembrane glycoproteins, contribute to inflammation by helping certain blood cells bind to the endothelium. Methods: The study included 100 patients with stable early-onset coronary artery disease (CAD), 75 men (aged 50–54) and 25 women (aged 55–64). Tests performed included biochemical analysis, ultrasound, and Doppler imaging of arteries and peripheral vessels. A biochemical control group of 50 cases without CAD (74% men, average age 48 ± 3.20 years) was also studied. Results: Higher triglyceride levels were strongly linked to elevated plasma E-selectin levels. However, no significant relationship was found between plasma E-selectin levels and biochemical, clinical, radiographic, or echographic measures. Conclusion: Plasma E-selectin levels are not a reliable marker for detecting atherosclerotic plaques or related problems in individuals with stable, well-managed CAD. While E-selectin levels can be measured in clinical labs using immunoassays, they cannot replace standard cardiological and vascular imaging tests for diagnosing cardiac or vascular conditions. [ABSTRACT FROM AUTHOR]

Cancers utilize a simple glycan, Sialic Acid, to engage in metastatic processes via the Sialic acid (Sia) -Selectin pathway. Selectins recognize and bind to sialylated substrates, resulting in adhesion, migration, and extravasation, however, how deviations from the canonical form of Sia regulate binding to Selectin receptors (E, L, and P) on hemopoietic cells resulting in these metastatic processes, remained a gap in knowledge. De-O-acetylated Sias has been recently shown to be an integral substrate to the binding of sialic acid binding proteins. The two proteins responsible for regulating the acetyl functional group on Sia's C6 tail, are Sialic acid acetylesterase (SIAE) and Sialic acid O acetyltransferase (CASD1). To elucidate the contribution of functional group alterations on Sia, 9-O and 7,9-O-acetylation of Sia was modulated via the use of CRISRP-Cas9 gene editing and with Sialyl Glycan Recognition Probes, to produce either O-acetylated-Sia or de-O-acetylated- Sia, respectively. In vitro experiments revealed that increased cell surface expression of de-O-acetylated- Sia resulted in an increase in Selectin binding, enhanced cell proliferation, and increased migration capabilities both in lung and colon cancer. These results delineate for the first time the mechanistic contribution of de-O-acetylated-Sia to Selectin binding, reinforcing the importance of elucidating functional group alterations on Sia and their contribution. Without accurate identification of which functionalized form of Sia is being utilized to bind to sialic acid binding proteins, we cannot accurately produce glycan therapeutics with the correct specificity and reactivity, thus this work contributes an integral component in the development of promising therapeutic avenues, for example in the realm of enzyme antibody drug conjugates. [ABSTRACT FROM AUTHOR]

Quantitative transcriptomics offers a new way to obtain a detailed picture of freshly isolated cells. By direct isolation, the cells are unaffected by in vitro culture, and the isolation at cold temperatures maintains the cells relatively unaltered in phenotype by avoiding activation through receptor cross-linking or plastic adherence. Simultaneous analysis of several cell types provides the opportunity to obtain detailed pictures of transcriptomic differences between them. Here, we present such an analysis focusing on four human blood cell populations and compare those to isolated human skin mast cells. Pure CD19+ peripheral blood B cells, CD14+ monocytes, and CD4+ and CD8+ T cells were obtained by fluorescence-activated cell sorting, and KIT+ human connective tissue mast cells (MCs) were purified by MACS sorting from healthy skin. Detailed information concerning expression levels of the different granule proteases, protease inhibitors, Fc receptors, other receptors, transcription factors, cell signaling components, cytoskeletal proteins, and many other protein families relevant to the functions of these cells were obtained and comprehensively discussed. The MC granule proteases were found exclusively in the MC samples, and the T-cell granzymes in the T cells, of which several were present in both CD4+ and CD8+ T cells. High levels of CD4 were also observed in MCs and monocytes. We found a large variation between the different cell populations in the expression of Fc receptors, as well as for lipid mediators, proteoglycan synthesis enzymes, cytokines, cytokine receptors, and transcription factors. This detailed quantitative comparative analysis of more than 780 proteins of importance for the function of these populations can now serve as a good reference material for research into how these entities shape the role of these cells in immunity and tissue homeostasis. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to ascertain the serum levels of selectins (E, L, P) and platelet‐endothelial adhesion molecule‐1 (PECAM‐1) in preschool children with autism spectrum disorder (ASD) and to establish a comparison with the levels observed in healthy controls. Methods: The study included 34 children aged 2–7 years diagnosed with ASD (ASD group) and 34 randomly selected healthy children matched for age and sex to the ASD group. The children were free of any genetic or physical disease, clinically active infection, or medication use. The sociodemographic data form was completed by all parents. The Childhood Autism Rating Scale (CARS) and the Autism Behavior Checklist (ABC) were administered to the patient group, and the Aberrant Behavior Checklist (AbBC) was completed by the families of all children. Serum selectin (E, L, P) and PECAM‐1 levels were measured using enzyme‐linked immunosorbent assay (ELISA) kits. Results: The results showed that the levels of both L‐selectin (p = 0.007) and PECAM‐1 (p = 0.019) were significantly lower in the ASD group than in the control group. No significant difference was observed between the groups concerning E‐selectin and P‐selectin levels (p > 0.05). It was observed that P‐selectin variables were statistically significant in predicting the presence of ASD (p = 0.019). A remarkable inverse correlation was found between the AbBC irritability subscale score and L‐selectin (r = −0.296, p = 0.014) and PECAM‐1 (r = −0.276, p = 0. 023); the AbBC Lethargy‐Social Withdrawal subscale score and E‐Selectin (r = −0.239, p = 0.049), L‐Selectin (r = −0.297, p = 0.014) and PECAM‐1 (r = −0.264, p = 0.029); L‐Selectin levels and the AbBC stereotypic behavior subscale (r = −0.248, p = 0.042). No statistically significant relationship was observed between selectins (E, L, P) and PECAM‐1 levels and CARS scale, ABC subscale or total scores and age variables (p > 0.05). Conclusions: These study results suggest that L‐selectin, P‐selectin and PECAM‐1 may play a role in the pathophysiology of ASD. [ABSTRACT FROM AUTHOR]

Introduction: Patients with systemic sclerosis (SSc) have an increased risk of endothelial dysfunction, atherosclerosis, and cardiovascular events compared to the general population. Therefore, the availability of robust circulating biomarkers of endothelial dysfunction and atherogenesis may facilitate early recognition and management of cardiovascular risk in SSc. We sought to address this issue by conducting a systematic review and meta-analysis of studies investigating various types of circulating cell adhesion molecules involved in endothelial dysfunction and atherogenesis (i.e., immunoglobulin-like vascular cell, VCAM-1, intercellular, ICAM-1, platelet endothelial cell, PECAM-1, neural cell, NCAM, Down syndrome cell, DSCAM, and endothelial cell-selective, ESAM, adhesion molecules, E-, L-, and P-selectin, integrins, and cadherins) in SSc patients and healthy controls. Methods: We searched PubMed, Scopus, and Web of Science from inception to 1 May 2024. Risk of bias and certainty of evidence were assessed using validated tools. Results: In 43 eligible studies, compared to controls, patients with SSc had significantly higher plasma or serum concentrations of ICAM-1 (standard mean difference, SMD=1.16, 95% CI 0.88 to 1.44, p<0.001; moderate certainty), VCAM-1 (SMD=1.09, 95% CI 0.72 to 1.46, p<0.001; moderate certainty), PECAM-1 (SMD=1.65, 95% CI 0.33 to 2.98, p=0.014; very low certainty), E-selectin (SMD=1.17, 95% CI 0.72 to 1.62, p<0.001; moderate certainty), and P-selectin (SMD=1.10, 95% CI 0.31 to 1.90, p=0.007; low certainty). There were no significant between-group differences in L-selectin concentrations (SMD=-0.35, 95% CI -1.03 to 0.32, p=0.31; very low certainty), whereas minimal/no evidence was available for cadherins, NCAM, DSCAM, ESAM, or integrins. Overall, no significant associations were observed between the effect size and various patient and study characteristics in meta-regression and subgroup analyses. Discussion: The results of this systematic review and meta-analysis suggest that specific circulating cell adhesion molecules, i.e., ICAM-1, VCAM-1, PECAM-1, E-selectin, and P-selectin, can be helpful as biomarkers of endothelial dysfunction and atherogenesis in the assessment of cardiovascular risk in SSc patients. [ABSTRACT FROM AUTHOR]

Background: Early diagnosis and treatment of Systemic lupus erythematosus (SLE) and Systemic sclerosis (SSc) present significant challenges for clinicians. Although various studies have observed changes in serum levels of selectins between healthy donors and patients with autoimmune diseases, including SLE and SSc, their potential as biomarkers has not been thoroughly explored. We aimed to investigate serum profiles of PSGL-1 (sPSGL-1), ADAM8 (sADAM8) and P-, E- and L-selectins (sP-, sE- and sL-selectins) in defined SLE and SSc patient cohorts to identify disease-associated molecular patterns. Methods: We collected blood samples from 64 SLE patients, 58 SSc patients, and 81 healthy donors (HD). Levels of sPSGL-1, sADAM8 and selectins were analyzed by ELISA and leukocyte membrane expression of L-selectin and ADAM8 by flow cytometry. Results: Compared to HD, SLE and SSc patients exhibited elevated sE-selectin and reduced sL-selectin levels. Additionally, SLE patients exhibited elevated sPSGL-1 and sADAM8 levels. Compared to SSc, SLE patients had decreased sLselectin and increased sADAM8 levels. Furthermore, L-selectin membrane expression was lower in SLE and SSc leukocytes than in HD leukocytes, and ADAM8 membrane expression was lower in SLE neutrophils compared to SSc neutrophils. These alterations associated with some clinical characteristics of each disease. Using logistic regression analysis, the sL-selectin/sADAM8 ratio in SLE, and a combination of sL-selectin/sE-selectin and sE-selectin/sPSGL-1 ratios in SSc were identified and cross-validated as potential serum markers to discriminate these patients from HD. Compared to available diagnostic biomarkers for each disease, both sL-selectin/sADAM8 ratio for SLE and combined ratios for SSc provided higher sensitivity (98% SLE and and 67% SSc correctly classified patients). Importantly, the sADAM8/% ADAM8(+) neutrophils ratio discriminated between SSc and SLE patients with the same sensitivity and specificity than current disease-specific biomarkers. Conclusion: SLE and SSc present specific profiles of sPSGL-1, sE-, sL-selectins, sADAM8 and neutrophil membrane expression which are potentially relevant to their pathogenesis and might aid in their early diagnosis. [ABSTRACT FROM AUTHOR]

Cancers utilize a simple glycan, Sialic Acid, to engage in metastatic processes via the Sialic acid (Sia) -Selectin pathway. Selectins recognize and bind to sialylated substrates, resulting in adhesion, migration, and extravasation, however, how deviations from the canonical form of Sia regulate binding to Selectin receptors (E, L, and P) on hemopoietic cells resulting in these metastatic processes, remained a gap in knowledge. De-O-acetylated Sias has been recently shown to be an integral substrate to the binding of sialic acid binding proteins. The two proteins responsible for regulating the acetyl functional group on Sia’s C6 tail, are Sialic acid acetylesterase (SIAE) and Sialic acid O acetyltransferase (CASD1). To elucidate the contribution of functional group alterations on Sia, 9-O and 7,9-O-acetylation of Sia was modulated via the use of CRISRP-Cas9 gene editing and with Sialyl Glycan Recognition Probes, to produce either O-acetylated-Sia or de-O-acetylated- Sia, respectively. In vitro experiments revealed that increased cell surface expression of de-O-acetylated- Sia resulted in an increase in Selectin binding, enhanced cell proliferation, and increased migration capabilities both in lung and colon cancer. These results delineate for the first time the mechanistic contribution of de-O-acetylated-Sia to Selectin binding, reinforcing the importance of elucidating functional group alterations on Sia and their contribution. Without accurate identification of which functionalized form of Sia is being utilized to bind to sialic acid binding proteins, we cannot accurately produce glycan therapeutics with the correct specificity and reactivity, thus this work contributes an integral component in the development of promising therapeutic avenues, for example in the realm of enzyme antibody drug conjugates.

Objectives Detecting occult cancer in patients with unprovoked venous thromboembolism (VTE) remains a significant challenge. Our objective was to investigate the potential predictive role of coagulation-related biomarkers in the diagnosis of occult malignancies. Methods We conducted a nested case-control study with a 1-year prospective cohort of 214 patients with unprovoked VTE, with a focus on identifying occult cancer. At the time of VTE diagnosis, we measured various biomarkers, including soluble P-selectin (sP-selectin), dimerized plasmin fragment D (D-dimer), platelets, leukocytes, hemoglobin, total extracellular vesicles (EVs), EVs expressing tissue factor on their surface (TF+EVs), and EVs expressing P-selectin on their surface (Psel+EVs) in all participants. Results We observed statistically significant increased levels of sP-selectin (P =.015) in patients with occult cancer. Despite an increase in Psel+EVs, TF+EVs, D-dimer, and platelets within this group, however, no significant differences were found. When sP-selectin exceeded 62 ng/mL and D-dimer surpassed 10,000 µg/L, the diagnosis of occult cancer demonstrated a specificity of up to 91% (95% CI, 79.9%-96.7%). Conclusions The combination of sP-selectin and D-dimer can be a valuable biomarker in detecting occult cancer in patients with unprovoked VTE. Further research is necessary to ascertain whether easily measurable biomarkers such as sP-selectin and D-dimer can effectively distinguish between patients who have VTE with and without hidden malignancies. [ABSTRACT FROM AUTHOR]

IntroductionPatients with systemic sclerosis (SSc) have an increased risk of endothelial dysfunction, atherosclerosis, and cardiovascular events compared to the general population. Therefore, the availability of robust circulating biomarkers of endothelial dysfunction and atherogenesis may facilitate early recognition and management of cardiovascular risk in SSc. We sought to address this issue by conducting a systematic review and meta-analysis of studies investigating various types of circulating cell adhesion molecules involved in endothelial dysfunction and atherogenesis (i.e., immunoglobulin-like vascular cell, VCAM-1, intercellular, ICAM-1, platelet endothelial cell, PECAM-1, neural cell, NCAM, Down syndrome cell, DSCAM, and endothelial cell-selective, ESAM, adhesion molecules, E-, L-, and P-selectin, integrins, and cadherins) in SSc patients and healthy controls.MethodsWe searched PubMed, Scopus, and Web of Science from inception to 1 May 2024. Risk of bias and certainty of evidence were assessed using validated tools.ResultsIn 43 eligible studies, compared to controls, patients with SSc had significantly higher plasma or serum concentrations of ICAM-1 (standard mean difference, SMD=1.16, 95% CI 0.88 to 1.44, p

BackgroundEarly diagnosis and treatment of Systemic lupus erythematosus (SLE) and Systemic sclerosis (SSc) present significant challenges for clinicians. Although various studies have observed changes in serum levels of selectins between healthy donors and patients with autoimmune diseases, including SLE and SSc, their potential as biomarkers has not been thoroughly explored. We aimed to investigate serum profiles of PSGL-1 (sPSGL-1), ADAM8 (sADAM8) and P-, E- and L-selectins (sP-, sE- and sL-selectins) in defined SLE and SSc patient cohorts to identify disease-associated molecular patterns.MethodsWe collected blood samples from 64 SLE patients, 58 SSc patients, and 81 healthy donors (HD). Levels of sPSGL-1, sADAM8 and selectins were analyzed by ELISA and leukocyte membrane expression of L-selectin and ADAM8 by flow cytometry.ResultsCompared to HD, SLE and SSc patients exhibited elevated sE-selectin and reduced sL-selectin levels. Additionally, SLE patients exhibited elevated sPSGL-1 and sADAM8 levels. Compared to SSc, SLE patients had decreased sL-selectin and increased sADAM8 levels. Furthermore, L-selectin membrane expression was lower in SLE and SSc leukocytes than in HD leukocytes, and ADAM8 membrane expression was lower in SLE neutrophils compared to SSc neutrophils. These alterations associated with some clinical characteristics of each disease. Using logistic regression analysis, the sL-selectin/sADAM8 ratio in SLE, and a combination of sL-selectin/sE-selectin and sE-selectin/sPSGL-1 ratios in SSc were identified and cross-validated as potential serum markers to discriminate these patients from HD. Compared to available diagnostic biomarkers for each disease, both sL-selectin/sADAM8 ratio for SLE and combined ratios for SSc provided higher sensitivity (98% SLE and and 67% SSc correctly classified patients). Importantly, the sADAM8/% ADAM8(+) neutrophils ratio discriminated between SSc and SLE patients with the same sensitivity and specificity than current disease-specific biomarkers.ConclusionSLE and SSc present specific profiles of sPSGL-1, sE-, sL-selectins, sADAM8 and neutrophil membrane expression which are potentially relevant to their pathogenesis and might aid in their early diagnosis.

Abstract Background Nitrous oxide (N2O) is a gas used in medicine for its analgesic, anxiolytic and amnesic properties. It is a drug considered safe if adequately administered. In the literature, accidental N2O-related deaths are rare. They are mostly related to inhalation of this substance for recreational and autoerotic purposes; rarely are reported deaths due to incorrect administration of medical gas in anesthesia. The diagnosis of death from acute N2O intoxication is complex and is generally an exclusion diagnosis: the macroscopic and microscopic post-mortem signs are entirely nonspecific. Furthermore, the circumstantial data are not always supportive and can even be confusing, mainly if the death occurred inside a hospital. Case presentation We describe a particular case of death from acute nitrous oxide poisoning in a hospital environment, of a Caucasian male of 72-years-old. The intoxication occurred during a minimally invasive vascular surgery due to an incorrect assembly of the supply lines of medical gases (O2 and N2O). The identification of the cause of death resulted from the analysis of circumstantial data, macroscopic and microscopic autoptic findings, and immunohistochemical investigations based on the search for antibodies anti E-selectin, P-selectin, and HIF 1-α. Conclusion Although not pathognomonic of asphyxiation by N2O, the latter molecules are a valid and early marker of hypoxic insult. Therefore, in concert with all other findings, it may constitute valid support for the forensic pathologist to ascertain the cause of death in case of suspected intoxication by N2O.

Background: The availability of robust biomarkers of endothelial activation might enhance the identification of subclinical atherosclerosis in rheumatoid arthritis (RA). We investigated this issue by conducting a systematic review and meta-analysis of cell adhesion molecules in RA patients. Methods: We searched electronic databases from inception to 31 July 2023 for case–control studies assessing the circulating concentrations of immunoglobulin-like adhesion molecules (vascular cell, VCAM-1, intercellular, ICAM-1, and platelet endothelial cell, PECAM-1, adhesion molecule-1) and selectins (E, L, and P selectin) in RA patients and healthy controls. Risk of bias and certainty of evidence were assessed using the JBI checklist and GRADE, respectively. Results: In 39 studies, compared to controls, RA patients had significantly higher concentrations of ICAM-1 (standard mean difference, SMD = 0.81, 95% CI 0.62–1.00, p < 0.001; I2 = 83.0%, p < 0.001), VCAM-1 (SMD = 1.17, 95% CI 0.73–1.61, p < 0.001; I2 = 95.8%, p < 0.001), PECAM-1 (SMD = 0.82, 95% CI 0.57–1.08, p < 0.001; I2 = 0.0%, p = 0.90), E-selectin (SMD = 0.64, 95% CI 0.42–0.86, p < 0.001; I2 = 75.0%, p < 0.001), and P-selectin (SMD = 1.06, 95% CI 0.50–1.60, p < 0.001; I2 = 84.8%, p < 0.001), but not L-selectin. In meta-regression and subgroup analysis, significant associations were observed between the effect size and use of glucocorticoids (ICAM-1), erythrocyte sedimentation rate (VCAM-1), study continent (VCAM-1, E-selectin, and P-selectin), and matrix assessed (P-selectin). Conclusions: The results of our study support a significant role of cell adhesion molecules in mediating the interplay between RA and atherosclerosis. Further studies are warranted to determine whether the routine use of these biomarkers can facilitate the detection and management of early atherosclerosis in this patient group. PROSPERO Registration Number: CRD42023466662. [ABSTRACT FROM AUTHOR]

Among the long-standing efforts to elucidate the physical mechanisms of protein- ligand catch bonding, particular attention has been directed at the family of selectin proteins. Selectins exhibit slip, catch-slip, and slip-catch-slip bonding, with minor structural modifications causing major changes in selectins' response to force. How can a single structural mechanism allow interconversion between these various behaviors? We present a unifying theory of selectin-ligand catch bonding, using a structurally motivated free energy landscape to show how the topology of force-induced deformations of the molecular system produces the full range of observed behaviors. We find that the pathway of bond rupture deforms in non-trivial ways, such that unbinding dynamics depend sensitively on force. This implies a severe breakdown of Bell's theory-a paradigmatic theory used widely in catch bond modeling-raising questions about the suitability of Bell's theory in modeling other catch bonds. Our approach can be applied broadly to other protein-ligand systems. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests an association between schizophrenia and atherosclerosis. We conducted a systematic review and meta-analysis of cell adhesion molecules, critically involved in early atherosclerosis, in schizophrenia. We searched electronic databases from inception to 11 November 2023 for case-control studies assessing vascular cell, VCAM-1, intercellular, ICAM-1, platelet endothelial cell, PECAM-1, neural cell, NCAM, and Down syndrome cell, DSCAM, adhesion molecules, selectins (E-, L-, and P-selectin), integrins, and cadherins in patients with schizophrenia and healthy controls. Risk of bias and certainty of evidence were assessed using the JBI checklist and GRADE, respectively. In 19 eligible studies, there were non-significant between-group differences in the concentrations of cell adhesion molecules, barring higher P-selectin in patients with schizophrenia (standard mean difference, SMD = 2.05, 95 % CI 0.72 to 3.38, p = 0.003; I2 = 97.2 %, p<0.001; very low certainty of evidence). Limited or no information was available regarding PECAM-1, DSCAM, ESAM, integrins, and cadherins. In meta-regression and subgroup analysis, there were significant associations between the SMD of ICAM-1 and matrix used (plasma or serum) and pharmacological treatment of schizophrenia, and between the SMD of VCAM-1 and pharmacological treatment, but not with other study and patient characteristics. The results of our systematic review and meta-analysis do not support a significant role of immunoglobulin-like adhesion molecules, selectins, integrins, or cadherins in mediating the associations between schizophrenia, atherosclerosis, and cardiovascular disease. Further studies are warranted to investigate these associations in patients with different cardiovascular risk and the effects of antipsychotic treatments on cell adhesion molecules and surrogate markers of atherosclerosis (PROSPERO registration number: CRD42023463916). [ABSTRACT FROM AUTHOR]

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Simple Summary: Progression of chronic lymphocytic leukemia (CLL) and its response to therapies are largely dependent on the microenvironment of the bone marrow and lymph nodes, which nurtures leukemic cells and protects them from therapeutic agents. Hence, cell trafficking between the blood vessels and lymphatic tissues is critical for CLL pathophysiology. Cell adhesion molecules mediate the re-localization of CLL cells in different anatomical compartments and are involved in their survival and proliferation. Evaluation of the molecular mechanisms underlying their activation and functions has uncovered clinically relevant signaling pathways targeted by well-established and new therapeutic strategies. The aim of this review is to summarize the current knowledge regarding the microenvironment and the cell adhesion molecules that have been shown to be important in CLL and their role in transendothelial migration and cell adhesion-mediated drug resistance. We also discuss how novel therapeutic compounds modulate the functions of this important class of molecules. Chronic lymphocytic leukemia (CLL) is a B-cell malignancy whose progression largely depends on the lymph node and bone marrow microenvironment. Indeed, CLL cells actively proliferate in specific regions of these anatomical compartments, known as proliferation centers, while being quiescent in the blood stream. Hence, CLL cell adhesion and migration into these protective niches are critical for CLL pathophysiology. CLL cells are lodged in their microenvironment through a series of molecular interactions that are mediated by cellular adhesion molecules and their counter receptors. The importance of these adhesion molecules in the clinic is demonstrated by the correlation between the expression levels of some of them, in particular CD49d, and the prognostic likelihood. Furthermore, novel therapeutic agents, such as ibrutinib, impair the functions of these adhesion molecules, leading to an egress of CLL cells from the lymph nodes and bone marrow into the circulation together with an inhibition of homing into these survival niches, thereby preventing disease progression. Several adhesion molecules have been shown to participate in CLL adhesion and migration. Their importance also stems from the observation that they are involved in promoting, directly or indirectly, survival signals that sustain CLL proliferation and limit the efficacy of standard and novel chemotherapeutic drugs, a process known as cell adhesion-mediated drug resistance. In this respect, many studies have elucidated the molecular mechanisms underlying cell adhesion-mediated drug resistance, which have highlighted different signaling pathways that may represent potential therapeutic targets. Here, we review the role of the microenvironment and the adhesion molecules that have been shown to be important in CLL and their impact on transendothelial migration and cell-mediated drug resistance. We also discuss how novel therapeutic compounds modulate the function of this important class of molecules. [ABSTRACT FROM AUTHOR]

Background: Nitrous oxide (N2O) is a gas used in medicine for its analgesic, anxiolytic and amnesic properties. It is a drug considered safe if adequately administered. In the literature, accidental N2O-related deaths are rare. They are mostly related to inhalation of this substance for recreational and autoerotic purposes; rarely are reported deaths due to incorrect administration of medical gas in anesthesia. The diagnosis of death from acute N2O intoxication is complex and is generally an exclusion diagnosis: the macroscopic and microscopic post-mortem signs are entirely nonspecific. Furthermore, the circumstantial data are not always supportive and can even be confusing, mainly if the death occurred inside a hospital. Case presentation: We describe a particular case of death from acute nitrous oxide poisoning in a hospital environment, of a Caucasian male of 72-years-old. The intoxication occurred during a minimally invasive vascular surgery due to an incorrect assembly of the supply lines of medical gases (O2 and N2O). The identification of the cause of death resulted from the analysis of circumstantial data, macroscopic and microscopic autoptic findings, and immunohistochemical investigations based on the search for antibodies anti E-selectin, P-selectin, and HIF 1-α. Conclusion: Although not pathognomonic of asphyxiation by N2O, the latter molecules are a valid and early marker of hypoxic insult. Therefore, in concert with all other findings, it may constitute valid support for the forensic pathologist to ascertain the cause of death in case of suspected intoxication by N2O. [ABSTRACT FROM AUTHOR]

Background: Cell adhesion molecules (CAMs) are found on the surface of all cells, where they allow dynamic processes to take place. These include cadherins, integrins, selectins and Immunoglobulin superfamily. Directly associated with β-integrin tails is a multidomain protein known as paxillin. However, CAMs participate in cell-cell and extracellular matrix-cell interactions during histomorphogenesis in the various phases of odontogenesis. Some tumours or cysts like ameloblastoma (AB) or odontogenic keratocyst (OKC) having odontogenic origin show disturbance in the interaction of these CAMs. Hence, the assessment of paxillin expression in AB and OKC was carried out. Materials and Methods: The present observational study comprised 30 clinically and histologically confirmed cases of AB and OKC. All the slides were stained immunohistochemically using a paxillin antibody. Results: Upon comparison of staining intensity of paxillin among AB and OKC showed statistically significant result, whereas quantitative staining and final summation showed non-significant result. Gender-wise comparison of paxillin staining intensity, quantitative staining and final summation among OKC showed significant result; however, in AB, staining intensity showed non-significant result, whereas quantitative staining and final summation showed significant result. Conclusion: Paxillin has the greatest influence on tissue morphogenesis and development. The regulation of cell mobility is aided by the multiple roles that paxillin plays in a range of cells and tissues. However, further studies using a large sample size, along with other molecular analytical methods, may be essential to draw a definite conclusion about the association of paxillin and its exact function in OKC and AB. [ABSTRACT FROM AUTHOR]

Mechanisms underlying the pathogenesis of tissue fibrosis remain incompletely understood. Emerging evidence suggests that cell adhesion molecules (CAMs) are critical in fibrotic progression in many organs, including lung, kidney, skin, and liver. CAMs promote cell–cell and cell–extracellular matrix (ECM) interactions to maintain tissue architecture and normal function in homeostasis. However, dysregulated expression and function of CAMs can lead to chronic inflammation and tissue fibrosis. The major families of CAMs include integrins, cadherins, selectins, and immunoglobulins. Here, we review the role of the CAMs in fibrosis development across various organs with a focus on integrins and cadherins, and discuss their respective roles in the development of pulmonary fibrosis. [ABSTRACT FROM AUTHOR]

Over their lifetime, regulatory T cells (Treg) recalibrate their expression of trafficking receptors multiple times as they progress through development, respond to immune challenges, or adapt to the requirements of functioning in various non-lymphoid tissue environments. These trafficking receptors, which include chemokine receptors and other G-protein coupled receptors, integrins, as well as selectins and their ligands, enable Treg not only to enter appropriate tissues from the bloodstream via post-capillary venules, but also to navigate these tissues to locally execute their immune-regulatory functions, and finally to seek out the right antigen-presenting cells and interact with these, in part in order to receive the signals that sustain their survival, proliferation, and functional activity, in part in order to execute their immuno-regulatory function by altering antigen presenting cell function. Here, we will review our current knowledge of when and in what ways Treg alter their trafficking properties. We will focus on the chemokine system and try to identify specialized, non-redundant roles of individual receptors as well as similarities and differences to the conventional T cell compartment.

Unlike cytotoxic chemotherapy, cancer immunotherapy offers targeted therapies that exploit the effector mechanisms of the immune system to combat cancer. However, most therapeutic strategies have so far focused predominantly on the orchestration of the adaptive immune responses to anti-cancer immunotherapies. Unfortunately, the emergence of resistance and associated severe toxicities rendered this modality of treatment imperfect. Because of their complex nature and the late ability to selectively separate distinct innate immune responses, the enormous potential of innate immunity as an immunotherapy was largely neglected. Recently, the growing demand to find alternatives to adaptive immunity-based immunotherapy concurred with growing appreciation of the innate immune effectors contributions to anti-tumor immunity. In particular, the innate immunity anti-infective responses overlap with those that target cancer indicating that these responses can readily be manipulated to design new therapeutic approaches. The paradigm of lectin pathway in recognition of distinct ‘non-self’ (antigenic) glycans on the surface of pathogenic microbes in concert with cancer’s indigenous aberrant (antigenic) glycans render lectin pathway a canonical component of innate immune system that can be extrapolated to cancer immunotherapy. By virtue of recent advances in lectin engineering, the encouraging results of using engineered lectins as anti-viral agents can be replicated in cancer immunotherapy.

The interaction between monocytes and endothelial cells in inflammation is central to chemoattraction, adhesion, and transendothelial migration. Key players, such as selectins and their ligands, integrins, and other adhesion molecules, and their functions in these processes are well studied. Toll-like receptor 2 (TLR2), expressed in monocytes, is critical for sensing invading pathogens and initiating a rapid and effective immune response. However, the extended role of TLR2 in monocyte adhesion and migration has only been partially elucidated. To address this question, we performed several functional cell-based assays using monocyte-like wild type (WT), TLR2 knock-out (KO), and TLR2 knock-in (KI) THP-1 cells. We found that TLR2 promotes the faster and stronger adhesion of monocytes to the endothelium and a more intense endothelial barrier disruption after endothelial activation. In addition, we performed quantitative mass spectrometry, STRING protein analysis, and RT-qPCR, which not only revealed the association of TLR2 with specific integrins but also uncovered novel proteins affected by TLR2. In conclusion, we show that unstimulated TLR2 influences cell adhesion, endothelial barrier disruption, migration, and actin polymerization. [ABSTRACT FROM AUTHOR]

The brain functions through neuronal circuits and networks that are synaptically connected. This type of connection can exist due to physical forces that interact to stabilize local contacts in the brain. Adhesion is a fundamental physical phenomenon that allows different layers, phases, and tissues to connect. Similarly, synaptic connections are stabilized by specialized adhesion proteins. This review discusses the basic physical and chemical properties of adhesion. Cell adhesion molecules (CAMs) such as cadherins, integrins, selectins, and immunoglobulin family of cell adhesion molecules (IgSF) will be discussed, and their role in physiological and pathological brain function. Finally, the role of CAMs at the synapse will be described. In addition, methods for studying adhesion in the brain will be presented. [ABSTRACT FROM AUTHOR]

C-type lectins (CTLs) represent a large family of soluble and membrane-bound proteins which bind calcium dependently via carbohydrate recognition domains (CRDs) to glycan residues presented on the surface of a variety of pathogens. The deconvolution of a cell's glycan code by CTLs underpins several important physiological processes in mammals such as pathogen neutralization and opsonization, leukocyte trafficking, and the inflammatory response. However, as our knowledge of CTLs has developed it has become apparent that the role of this innate immune family of proteins can be double-edged, where some pathogens have developed approaches to subvert and exploit CTL interactions to promote infection and sustain the pathological state. Equally, CTL interactions with host glycoproteins can contribute to inflammatory diseases such as arthritis and cancer whereby, in certain contexts, they exacerbate inflammation and drive malignant progression. This review discusses the 'dual agent' roles of some of the major mammalian CTLs in both resolving and promoting infection, inflammation and inflammatory disease and highlights opportunities and emerging approaches for their therapeutic modulation. [ABSTRACT FROM AUTHOR]

Various factors are effective in reducing the fertility rate. This experiment aimed to investigate chlorpyrifos (CPF), an organophosphate, that could alter the structure of the uterus and the molecules involved in parental and fetal. CPF was injected intraperitoneally in thirty mice for five days in a week (six weeks). The animals were euthanized on the 5th day of gestation, then their blood and uterus were collected for biochemical and histopathological assays. Exposure to CPF resulted in a significant reduction in maternal weight gain and the number of litters. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were significantly increased in blood serum of the CPF group compared with the control. The number of uterus glands, endometrium thickness, and the uterine cavity were changed following CPF injection. Additional investigation indicated that the expressions of L-selectin, L-selectin ligand, and heparin-binding epidermal growth factor (HBEGF) as initial adhesion of mice blastocysts and maternal endometrium biomarkers were downregulated in the CPF group. Nevertheless, any mortality and abnormal clinical symptoms were not observed in the treated mice. This study revealed a potential molecular mechanism of continuous CPF-induced toxicity in fetal-maternal attachment without clinical symptoms. [ABSTRACT FROM AUTHOR]

Molecular recognition involving glycoprotein-mediated interactions is ubiquitous in both normal and pathological natural processes. Therefore, visualization of these interactions and the extent of expression of the sugars is a challenge in medical diagnosis, monitoring of therapy, and drug design. Here, we review the literature on the development and validation of probes for magnetic resonance imaging using carbohydrates either as targeting vectors or as a target. Lectins are important targeting vectors for carbohydrate end groups, whereas selectins, the asialoglycoprotein receptor, sialic acid end groups, hyaluronic acid, and glycated serum and hemoglobin are interesting carbohydrate targets. [ABSTRACT FROM AUTHOR]

To date, the only curative treatment for high-risk or refractory hematologic malignancies non-responsive to standard chemotherapy is allogeneic hematopoietic transplantation (allo-HCT). Acute graft-versus-host disease (GVHD) is a donor T cell-mediated immunological disorder that is frequently fatal and the leading cause of non-relapse mortality (NRM) in patients post allo-HCT. The pathogenesis of acute GVHD involves recognition of minor and/or major HLA mismatched host antigens by donor T cells followed by expansion, migration and finally end-organ damage due to combination of inflammatory cytokine secretion and direct cytotoxic effects. The endothelium is a thin layer of endothelial cells (EC) that line the innermost portion of the blood vessels and a key regulator in vascular homeostasis and inflammatory responses. Endothelial cells are activated by a wide range of inflammatory mediators including bacterial products, contents released from dying/apoptotic cells and cytokines and respond by secreting cytokines/chemokines that facilitate the recruitment of innate and adaptive immune cells to the site of inflammation. Endothelial cells can also be damaged prior to transplant as well as by alloreactive donor T cells. Prolonged EC activation results in dysfunction that plays a role in multiple post-transplant complications including but not limited to veno-occlusive disease (VOD), transplant associated thrombotic microangiopathy (TA-TMA), and idiopathic pneumonia syndrome. In this mini review, we summarize the biology of endothelial cells, factors regulating EC activation and the role of ECs in inflammation and GVHD pathogenesis. [ABSTRACT FROM AUTHOR]

Thromboembolic complications are the most reported cause of death in coronavirus disease-2019 (COVID-19). Hypercoagulability, platelets activation and endotheliopathy are well-recognized features in COVID-19 patients. The aim of this work was to evaluate circulating soluble selectins P, E and L at the time of hospital admission as predictors for upcoming thrombosis. This retrospective study included 103 hospitalized COVID-19 patients and 50 healthy volunteer controls. COVID-19 patients were categorized into two groups; group 1 who developed thrombosis during hospitalization and group 2 who did not. Soluble selectins were quantitated using ELISA technique. Higher levels of sP-selectin, sE-selectin and sL-selectin were detected in COVID-19 patients compared to controls. Furthermore, significantly higher levels were found in group 1 compared to group 2. Their means were [5.86 ± 1.72 ng/mL vs. 2.51 ± 0.81 ng/mL]; [50 ± 8.57 ng/mL vs. 23.96 ± 6.31 ng/mL] and [4.66 ± 0.83 ng/mL vs. 2.95 ± 0.66 ng/mL] for sP-selectin, sE-selectin and sL-selectin respectively. The elevated selectins correlated with the currently used laboratory biomarkers of disease severity. After adjustment of other factors, sP-selectin, sE-selectin and sL-selectin were independent predictors for thrombosis. At sP-selectin ≥ 3.2 ng/mL, sE-selectin ≥ 32.5 ng/mL and sL-selectin ≥ 3.6 ng/mL thrombosis could be predicted with 97.1%, 97.6% and 96.5% sensitivity. A panel of the three selectins provided 100% clinical sensitivity. Admission levels of circulating soluble selectins P, E and L can predict thrombosis in COVID-19 patients and could be used to identify patients who need prophylactic anticoagulants. E-selectin showed a superior clinical performance, as thrombo-inflammation biomarker, to the most commonly studied P-selectin. [ABSTRACT FROM AUTHOR]

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by thrombosis and/or obstetric complications in the presence of antiphospholipid antibodies (aPL). Catastrophic APS (CAPS) is the most severe form of the disease, in which microvascular thromboses develop rapidly, leading to multiorgan failure. Monocytes, along with endothelial cells, are critical players in the pathogenesis of APS. Recruitment of these cells to the site of injury/inflammation involves a series of events, including capture, rolling, adhesion enhancement, and transmigration, which are controlled by surface adhesion molecules. The aim of our study was to investigate the surface adhesion profile of monocytes from APS patients and monocytes stimulated in vitro with aPL from a CAPS patient. The surface expression of the adhesion molecules LFA1, L-selectin, MAC1, PSGL1, and VLA4 was analyzed by flow cytometry. To our knowledge, this preliminary study was the first to show that VLA4 was significantly increased on the surface of monocytes from APS patients. Moreover, in vitro stimulations mimicking CAPS showed an even greater increase in VLA4. Our data suggest that the surface adhesion profile on monocytes is altered in APS and CAPS and may be involved in the thrombotic pathophysiology of the disease by enhancing monocyte adhesion. [ABSTRACT FROM AUTHOR]

To date, the only curative treatment for high-risk or refractory hematologic malignancies non-responsive to standard chemotherapy is allogeneic hematopoietic transplantation (allo-HCT). Acute graft-versus-host disease (GVHD) is a donor T cell-mediated immunological disorder that is frequently fatal and the leading cause of non-relapse mortality (NRM) in patients post allo-HCT. The pathogenesis of acute GVHD involves recognition of minor and/or major HLA mismatched host antigens by donor T cells followed by expansion, migration and finally end-organ damage due to combination of inflammatory cytokine secretion and direct cytotoxic effects. The endothelium is a thin layer of endothelial cells (EC) that line the innermost portion of the blood vessels and a key regulator in vascular homeostasis and inflammatory responses. Endothelial cells are activated by a wide range of inflammatory mediators including bacterial products, contents released from dying/apoptotic cells and cytokines and respond by secreting cytokines/chemokines that facilitate the recruitment of innate and adaptive immune cells to the site of inflammation. Endothelial cells can also be damaged prior to transplant as well as by alloreactive donor T cells. Prolonged EC activation results in dysfunction that plays a role in multiple post-transplant complications including but not limited to veno-occlusive disease (VOD), transplant associated thrombotic microangiopathy (TA-TMA), and idiopathic pneumonia syndrome. In this mini review, we summarize the biology of endothelial cells, factors regulating EC activation and the role of ECs in inflammation and GVHD pathogenesis.

Expression of the extensively glycosylated Ebolavirus glycoprotein (EBOV-GP) induces physical alterations of surface molecules and plays a crucial role in viral pathogenicity. Here we investigate the interactions of EBOV-GP with host surface molecules using purified EBOV-GP, EBOV-GP-transfected cell lines, and EBOV-GP-pseudotyped lentiviral particles. Subsequently, we wanted to examine which receptors are involved in this recognition by binding studies to cells transfected with the EBOV-GP as well as to recombinant soluble EBOV-GP. As the viral components can also bind to inhibitory receptors of immune cells (e.g., Siglecs, TIM-1), they can even suppress the activity of immune effector cells. Our data show that natural killer (NK) cell receptors NKp44 and NKp46, selectins (CD62E/P/L), the host factors DC-SIGNR/DC-SIGN, and inhibitory Siglecs function as receptors for EBOV-GP. Our results show also moderate to strong avidity of homing receptors (P-, L-, and E-selectin) and DC-SIGNR/DC-SIGN to purified EBOV-GP, to cells transfected with EBOV-GP, as well as to the envelope of a pseudotyped lentiviral vector carrying the EBOV-GP. The concomitant activation and inhibition of the immune system exemplifies the evolutionary antagonism between the immune system and pathogens. Altogether these interactions with activating and inhibitory receptors result in a reduced NK cell-mediated lysis of EBOV-GP-expressing cells. Modulation of these interactions may provide new strategies for treating infections caused by this virus.