Frequent co-expression of EGFR and NeuGcGM3 ganglioside in cancer: it’s potential therapeutic implications

Interaction between epidermal growth factor receptor (EGFR) signaling with GM3 ganglioside expression has been previously described. However, little is known about EGFR and NeuGcGM3 co-expression in cancer patients and their therapeutic implications. In this paper, we evaluate the co-expression of EGFR and NeuGcGM3 ganglioside in tumors from 92 patients and in two spontaneous lung metastasis models of mice (Lewis lung carcinoma (3LL-D122) in C57BL/6 and mammary carcinoma (4T1) in BALB/c). As results, co-expression of EGFR and NeuGcGM3 ganglioside was frequently observed in 63 of 92 patients (68 %), independently of histological subtype. Moreover, EGFR is co-expressed with NeuGcGM3 ganglioside in the metastasis of 3LL-D122 and 4T1 murine models. Such dual expression appears to be therapeutically relevant, since combined therapy with mAbs against these two molecules synergistically increase the survival of mice treated. Overall, our results suggest that NeuGcGM3 and EGFR may coordinately contribute to the tumor cell biology and that therapeutic combinations against these two targets might be a valid strategy to explore.Fil: Palomo, Addys González. Centro de Inmunología Molecular; CubaFil: Santana, Rancés Blanco. Centro de Inmunología Molecular; CubaFil: Pérez, Xiomara Escobar. Instituto Nacional de Oncología y Radiobiología; CubaFil: Santana, Damián Blanco. Instituto Nacional de Oncología y Radiobiología; CubaFil: Gabri, Mariano Rolando. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; ArgentinaFil: Monzon, Kalet León. Centro de Inmunología Molecular; CubaFil: Pérez, Adriana Carr. Centro de Inmunología Molecular; Cub

Marine seagrass extract of Thalassia testudinum suppresses colorectal tumor growth, motility and angiogenesis by autophagic stress and immunogenic cell death pathways

Marine plants have become an inexhaustible reservoir of new phytopharmaceuticals for cancer treatment. We demonstrate in vitro/in vivo antitumor efficacy of a standardized polyphenol extract from the marine angiosperm Thalassia testudinum (TTE) in colon tumor cell lines (RKO, SW480, and CT26) and a syngeneic allograft murine colorectal cancer model. MTT assays revealed a dose-dependent decrease of cell viability of RKO, CT26, and SW480 cells upon TTE treatment with IC50 values of, respectively, 175, 115, and 60 mu g/mL. Furthermore, TTE significantly prevented basal and bFGF-induced angiogenesis in the chicken chorioallantoic membrane angiogenesis assay. In addition, TTE suppressed bFGF-induced migration of endothelial cells in a wound closure assay. Finally, TTE treatment abrogated CT26 colorectal cancer growth and increased overall organism survival in a syngeneic murine allograft model. Corresponding transcriptome profiling and pathway analysis allowed for the identification of the mechanism of action for the antitumor effects of TTE. In line with our in vitro/in vivo results, TTE treatment triggers ATF4-P53-NF kappa B specific gene expression and autophagy stress pathways. This results in suppression of colon cancer cell growth, cell motility, and angiogenesis pathways in vitro and in addition promotes antitumor immunogenic cell death in vivo

Synergistic potentiation of the anti-metastatic effect of anti EGFR mAb by its combination with immunotherapies targeting the ganglioside NGcGM3

Several Anti-EGFR mAbs are register for the treatment of human cancer. However, their impact on patients overall survival has been limited by tumor resistance. N-Glycolyl variant of GM3 ganglioside (NGcGM3) is specifically expressed in some human tumors, and it has been associated with a poor prognosis. Several reports have documented that GM3 physically associates to EGFR inhibiting its ligand depend phosphorylation, but it also facilitates an alternative/compensatory signaling cascade mediated by Uroquinase Plasminogen Activator Receptor (uPAR) and integrin α5β1 interaction. However, the difference between NGc and N-Acetylated (NAc) variants of GM3 regarding such interactions is unknown. We hypothesized that enrichment of NGcGM3 expression in tumors relates to advantages of this ganglioside, on ensuring both EGFR and uPAR pathways optimal function. We explored the impact of combining an anti-EGFR (7A7 mAb) with anti-NGcGM3 therapies: NGcGM3/VSSP vaccine or 14F7 mAb. Both combinations synergistically increase overall survival in two models of lung metastasis: 3LL-D122 and 4T1; but combination with NGcGM3/VSSP vaccine is significantly more effective. In 3LL-D122-metastasis, of mice treated with the best combination, both EGFR and uPAR/α5β1 integrin pathways are turn off (I.e expression of uPAR/α5β1; and phosphorylation of EGFR, Stat3, Src and FAK are reduced); and tumor angiogenesis is decreased. Interestingly, combination treatment increases tumor infiltrating CD4+T, CD8+T and NK+-cells. Furthermore, a positive clinical outcome is reported for a cancer patient treated with an anti-EGFR mAb and anti-NGcGM3 therapy. Overall, our results support the combination of anti EGFR antibodies with therapies targeting NGcGM3 to increase their efficacy in future clinical trials.Fil: González Palomo, Addys. No especifíca;Fil: López Medinilla, Armando. No especifíca;Fil: Segatori, Valeria Inés. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Barroso, María del Carmen. No especifíca;Fil: Blanco, Rances. No especifíca;Fil: Gabri, Mariano Rolando. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Pérez, Adriana Carr. No especifíca;Fil: Monzón, Kalet León. No especifíca

Reduced alcohol consumption during the COVID-19 pandemic:Analyses of 17 000 patients seeking primary health care in Colombia and Mexico

BACKGROUND: During the COVID-19 pandemic, an increase of heavy alcohol use has been reported in several high-income countries. We examined changes in alcohol use during the pandemic among primary health care (PHC) patients in two middle income countries, Colombia and Mexico. METHODS: Data were collected during routine consultations in 34 PHC centres as part of a large-scale implementation study. Providers measured patients’ alcohol consumption with the three item ‘Alcohol Use Disorders Identification Test’ (AUDIT-C). Generalized linear mixed models were performed to examine changes in two dependent variables over time (pre-pandemic and during pandemic): 1) the AUDIT-C score and 2) the proportion of heavy drinking patients (8+ on AUDIT-C). RESULTS: Over a period of more than 600 days, data from N = 17 273 patients were collected. During the pandemic, the number of patients with their alcohol consumption measured decreased in Colombia and Mexico. Each month into the pandemic was associated with a 1.5% and 1.9% reduction in the mean AUDIT-C score in Colombia and Mexico, respectively. The proportion of heavy drinking patients declined during the pandemic in Colombia (pre-pandemic: 5.4%, 95% confidence interval (CI) = 4.8% to 6.0%; during the pandemic: 0.8%, 95% CI = 0.6% to 1.1%) but did not change in Mexico. CONCLUSIONS: Average consumption levels declined and the prevalence of heavy drinking patterns did not increase. In addition to reduced opportunities for social drinking during the pandemic, changes in the population seeking PHC and restrictions in alcohol availability and affordability are likely drivers for lower levels of alcohol use by patients in this study

Impact of COVID-19 infection on lung function and nutritional status amongst individuals with cystic fibrosis: A global cohort study

International audienceBackground: Factors associated with severe COVID-19 infection have been identified; however, the impact of infection on longer-term outcomes is unclear. The objective of this study was to examine the impact of COVID-19 infection on the trajectory of lung function and nutritional status in people with cystic fibrosis (pwCF).Methods: This is a retrospective global cohort study of pwCF who had confirmed COVID-19 infection diagnosed between January 1, 2020 and December 31, 2021. Forced expiratory volume in one second percent predicted (ppFEV 1 ) and body mass index (BMI) twelve months prior to and following a diagnosis of COVID-19 were recorded. Change in mean ppFEV 1 and BMI were compared using a t-test. A linear mixed-effects model was used to estimate change over time and to compare the rate of change before and after infection.Results: A total of 6,500 cases of COVID-19 in pwCF from 33 countries were included for analysis. The mean difference in ppFEV 1 pre-and post-infection was 1.4 %, (95 % CI 1.1, 1.7). In those not on modulators, the difference in rate of change pre-and post-infection was 1.34 %, (95 % CI -0.88, 3.56) per year (p = 0.24) and -0.74 % (-1.89, 0.41) per year (p = 0.21) for those on elexacaftor/tezacaftor/ivacaftor. No clinically significant change was noted in BMI or BMI percentile before and after COVID-19 infection.Conclusions: No clinically meaningful impact on lung function and BMI trajectory in the year following infection with COVID-19 was identified. This work highlights the ability of the global CF community to unify and address critical issues facing pwCF