scholarly journals SELP Asp603Asn and severe thrombosis in COVID-19 males: implication for anti P-selectin monoclonal antibodies treatment

2021 ◽  
Author(s):  
Chiara Fallerini ◽  
Sergio Daga ◽  
Elisa Benetti ◽  
Nicola Picchiotti ◽  
Kristina Zguro ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Monoclonal Antibodies ◽  
Cell Adhesion ◽  
Androgen Receptor ◽  
Adjuvant Therapy ◽  
Odds Ratio ◽  
Cell Adhesion Molecule ◽  
Common Coding ◽  
Whole Exome ◽  
Coding Variants

Thromboembolism is a frequent cause of severity and mortality in COVID-19. However, the etiology of this phenomenon is not well understood. A cohort of 1,186 subjects, from the GEN-COVID consortium, infected by SARS-CoV-2 with different severity were stratified by sex and adjusted by age. Then, common coding variants from whole exome sequencing were mined by LASSO logistic regression. The homozygosity of the cell adhesion molecule P-selectin gene (SELP) rs6127 (c.1807G>A; p.Asp603Asn) which increases platelet activation is found to be associated with severity in the male subcohort of 513 subjects (Odds Ratio= 2.27, 95% Confidence Interval 1.54-3.36). As the SELP gene is downregulated by testosterone, the odd ratio is increased in males older than 50 (OR 2.42, 95% CI 1.53-3.82). Asn/Asn homozygotes have increased D-dimers values especially when associated with poly Q≥23 in the androgen receptor (AR) gene (OR 3.26, 95% CI 1.41-7.52). These results provide a rationale for the repurposing of antibodies against P-selectin as adjuvant therapy in rs6127 male homozygotes especially if older than 50 or with impaired AR gene.

scholarly journals SELP Asp603Asn and severe thrombosis in COVID-19 males

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Chiara Fallerini ◽  
Sergio Daga ◽  
Elisa Benetti ◽  
Nicola Picchiotti ◽  
Kristina Zguro ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Cell Adhesion ◽  
Androgen Receptor ◽  
Adjuvant Therapy ◽  
Odds Ratio ◽  
Cell Adhesion Molecule ◽  
Thrombotic Risk ◽  
Common Coding ◽  
Whole Exome ◽  
Coding Variants

AbstractThromboembolism is a frequent cause of severity and mortality in COVID-19. However, the etiology of this phenomenon is not well understood. A cohort of 1186 subjects, from the GEN-COVID consortium, infected by SARS-CoV-2 with different severity was stratified by sex and adjusted by age. Then, common coding variants from whole exome sequencing were mined by LASSO logistic regression. The homozygosity of the cell adhesion molecule P-selectin gene (SELP) rs6127 (c.1807G > A; p.Asp603Asn) which has been already associated with thrombotic risk is found to be associated with severity in the male subcohort of 513 subjects (odds ratio = 2.27, 95% Confidence Interval 1.54–3.36). As the SELP gene is downregulated by testosterone, the odd ratio is increased in males older than 50 (OR 2.42, 95% CI 1.53–3.82). Asn/Asn homozygotes have increased D-dimers values especially when associated with poly Q ≥ 23 in the androgen receptor (OR 3.26, 95% CI 1.41–7.52). These results provide a rationale for the repurposing of antibodies against P-selectin as adjuvant therapy in rs6127 male homozygotes especially if older than 50 or with an impaired androgen receptor.

scholarly journals Mapping of three carbohydrate attachment sites in embryonic and adult forms of the neural cell adhesion molecule.

1984 ◽  
Vol 99 (5) ◽  
pp. 1848-1855 ◽  
Author(s):  
K L Crossin ◽  
G M Edelman ◽  
B A Cunningham
Keyword(s):  
Monoclonal Antibody ◽  
Monoclonal Antibodies ◽  
Cell Adhesion ◽  
Sialic Acid ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Neural Cell Adhesion Molecule ◽  
Neural Cell ◽  
Attachment Sites ◽  
Neural Cell Adhesion

The sialic-rich carbohydrate moiety of the neural cell adhesion molecule (N-CAM) undergoes major structural changes during development and plays a significant role in altering the homophilic binding of the molecule. In order to understand the mechanism of these changes, a cyanogen bromide (CNBr) fragment that contained 90% of the sialic acid of N-CAM was isolated and characterized according to the number of carbohydrate attachment sites and reactivity with specific monoclonal antibodies. The CNBr sialopeptide migrated on SDS PAGE as a broad zone of Mr 42,000-60,000. Upon treatment with neuraminidase, it was converted to a single component of Mr 42,000, and subsequent, limited treatment with endoglycosidase F gave four evenly spaced components of Mr 35,000-42,000, suggesting that it contained three attachment sites for N-linked oligosaccharides. The fragment reacted with monoclonal antibody 15G8, which detects the sialic acid in embryonic N-CAM, and with a monoclonal antibody, anti-(N-CAM) No. 2. Treatment with neuraminidase or with endoglycosidase F destroyed reactivity with 15G8 but not with anti-(N-CAM) No. 2. A similar CNBr sialopeptide was obtained from adult N-CAM; it contained sialic acid, had three N-linked oligosaccharides and reacted with anti-(N-CAM) No. 2 but not with 15G8 monoclonal antibodies. A peptide fragment, Fr2, comprising the NH2 terminal and middle regions of the molecule yielded a CNBr fragment closely similar to the fragment obtained from the whole molecule. The CNBr fragment from Fr2 reacted with monoclonal antibody anti-(N-CAM) No. 2. Fr1, comprising the NH2 terminal region alone, failed to react. These data confirm that the majority of the sialic acid is localized in the middle region of the N-CAM molecule and support the hypothesis that embryonic to adult conversion of N-CAM is the result of differences in sialidase or sialytransferase activity.

scholarly journals Biodistribution Studies of Epithelial Cell Adhesion Molecule (EpCAM)-Directed Monoclonal Antibodies in the EpCAM-Transgenic Mouse Tumor Model

2007 ◽  
Vol 179 (2) ◽  
pp. 1362-1368 ◽  
Author(s):  
Jos G. W. Kosterink ◽  
Pamela M. J. McLaughlin ◽  
Marjolijn N. Lub-de Hooge ◽  
Harry H. Hendrikse ◽  
Jacoba van Zanten ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Cell Adhesion ◽  
Epithelial Cell ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Tumor Model ◽  
Mouse Tumor ◽  
Epithelial Cell Adhesion Molecule ◽  
Mouse Tumor Model ◽  
Biodistribution Studies

scholarly journals Effect of Cetuximab-Conjugated Gold Nanoparticles on the Cytotoxicity and Phenotypic Evolution of Colorectal Cancer Cells

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 567
Author(s):  
Ralph El Hallal ◽  
Nana Lyu ◽  
Yuling Wang
Keyword(s):  
Colorectal Cancer ◽  
Gold Nanoparticles ◽  
Epidermal Growth Factor Receptor ◽  
Monoclonal Antibodies ◽  
Cell Adhesion ◽  
Growth Factor ◽  
Cell Surface ◽  
Cell Adhesion Molecule ◽  
Growth Factor Receptor ◽  
Epidermal Growth

Epidermal growth factor receptor (EGFR) is estimated to be overexpressed in 60~80% of colorectal cancer (CRC), which is associated with a poor prognosis. Anti-EGFR targeted monoclonal antibodies (cetuximab and panitumumab) have played an important role in the treatment of metastatic CRC. However, the therapeutic response of anti-EGFR monoclonal antibodies is limited due to multiple resistance mechanisms. With the discovery of new functions for gold nanoparticles (AuNPs), we hypothesize that cetuximab-conjugated AuNPs (cetuximab-AuNPs) will not only improve the cytotoxicity for cancer cells, but also introduce expression change of the related biomarkers on cancer cell surface. In this contribution, we investigated the size-dependent cytotoxicity of cetuximab-AuNPs to CRC cell line (HT-29), while also monitored the expression of cell surface biomarkers in response to treatment with cetuximab and cetuximab-AuNPs. AuNPs with the size of 60 nm showed the highest impact for cell cytotoxicity, which was tested by cell counting kit-8 (CCK-8) assay. Three cell surface biomarkers including epithelial cell adhesion molecule (EpCAM), melanoma cell adhesion molecule (MCAM), and human epidermal growth factor receptor-3 (HER-3) were found to be expressed at higher heterogeneity when cetuximab was conjugated to AuNPs. Both surface-enhanced Raman scattering/spectroscopy (SERS) and flow cytometry demonstrated the correlation of cell surface biomarkers in response to the drug treatment. We thus believe this study provides powerful potential for drug-conjugated AuNPs to enhance cancer prognosis and therapy.

scholarly journals Identification of a peptide sequence involved in homophilic binding in the neural cell adhesion molecule NCAM.

1992 ◽  
Vol 118 (4) ◽  
pp. 937-949 ◽  
Author(s):  
Y Rao ◽  
X F Wu ◽  
J Gariepy ◽  
U Rutishauser ◽  
C H Siu
Keyword(s):  
Monoclonal Antibodies ◽  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Neural Cell Adhesion Molecule ◽  
Neural Cell ◽  
Peptide Sequence ◽  
Homophilic Binding ◽  
Neural Cell Adhesion ◽  
Cell Cell

The neural cell adhesion molecule NCAM is capable of mediating cell-cell adhesion via homophilic interactions. In this study, three strategies have been combined to identify regions of NCAM that participate directly in NCAM-NCAM binding: analysis of domain deletion mutations, mapping of epitopes of monoclonal antibodies, and use of synthetic peptides to inhibit NCAM activity. Studies on L cells transfected with NCAM mutant cDNAs using cell aggregation and NCAM-covasphere binding assays indicate that the third immunoglobulin-like domain is involved in homophilic binding. The epitopes of four monoclonal antibodies that have been previously shown to affect cell-cell adhesion mediated by NCAM were also mapped to domain 3. Overlapping hexapeptides were synthesized on plastic pins and assayed for binding with these monoclonal antibodies. One of them (PP) reacted specifically with the sequence KYSFNY. Synthetic oligopeptides containing the PP epitope were potent and specific inhibitors of NCAM binding activity. A substratum containing immobilized peptide conjugates also exhibited adhesiveness for neural retinal cells. Cell attachment was specifically inhibited by peptides that contained the PP-epitope and by anti-NCAM univalent antibodies. The shortest active peptide has the sequence KYSFNYDGSE, suggesting that this site is directly involved in NCAM homophilic interaction.

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