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.
Las razones por las que la medicina y la biotecnología son de importancia fundamental en Cuba constituyen objeto de debate. Las causas sociales, económicas e históricas se presentan divididas en los ...períodos colonial, neocolonial y revolucionario (después de 1959). En estos contextos, se discute la contribución del profesional y la influencia de las instituciones más importantes en la creación de tradiciones biocientíficas. Asimismo, se hace referencia a la contribución de la comunidad de físicos al desarrollo de la investigación biotecnológica y farmacéutica. Se mencionan dos de los más grandes proyectos en los que la física realiza una contribución fundamental, se propone revisar los enfoques investigativos en el campo de las ciencias biológicas en Cuba, de acuerdo con las tendencias internacionales de la convergencia tecnológica. Se debaten nuevos enfoques sobre la tercera revolución en la biología, así como las ventajas de su puesta en práctica. Se reexaminan aspectos fundamentales del sistema de educación superior cubano en relación con carreras científicas y con el funcionamiento del sistema científico nacional. Se exponen algunos de los riesgos principales para el futuro del desarrollo científico nacional.
Advanced non-small cell lung cancer (NSCLC) has faced a therapeutic revolution with the advent of tyrosine kinase inhibitors (TKIs) and immune checkpoints inhibitors (ICIs) approved for first and ...subsequent therapies. CIMAvax-EGF is a chemical conjugate between human-recombinant EGF and P64, a recombinant protein from
, which induces neutralizing antibodies against EGF. In the last 15 years, it has been extensively evaluated in advanced NSCLC patients. CIMAvax-EGF is safe, even after extended use, and able to keep EGF serum concentration below detectable levels. In a randomized phase III study, CIMAvax-EGF increased median overall survival of advanced NSCLC patients with at least stable disease after front-line chemotherapy. Patients bearing squamous-cell or adenocarcinomas and serum EGF concentration above 870 pg/ml had better survival compared to control patients treated with best supportive care as maintenance, confirming tumors' sensitivity to the EGF depletion. This manuscript reviews the state-of-the-art NSCLC therapy and proposes the most promising scenarios for evaluating CIMAvax-EGF, particularly in combination with TKIs or ICIs. We hypothesize that the optimal combination of CIMAvax-EGF with established therapies can further contribute to transform advanced cancer into a manageable chronic disease, compatible with years of good quality of life.
RESUMEN Introducción: La vacuna cubana CIMAvax-EGF®, es útil en pacientes con cáncer de pulmón de células no pequeñas con altas concentraciones séricas de factor de crecimiento epidérmico, su actual ...predictor de respuesta. Sin embargo, la discriminación por factor de crecimiento epidérmico entre individuos sanos y pacientes con cáncer de pulmón de células no pequeñas, que determina la exactitud diagnóstica y eficacia del biomarcador, es cuestionable debido principalmente a deficiencias metodológicas en su medición. Métodos: En este trabajo se desarrolló una metodología para la cuantificación de factor de crecimiento epidérmico sérico humano, dirigida a controlar los factores causa de sesgo y variabilidad en las estimaciones. La misma incluyó el desarrollo del estuche de cuantificación UMELISA EGF®, la estandarización de la separación de los sueros y la normalización de las concentraciones con referencia al conteo plaquetario, así como su interpretación. Resultados: El estudio evidenció que pacientes y controles sanos se diferencian por el factor de crecimiento epidérmico en circulación, medido en sueros separados 1 h después de la flebotomía (EGF1h), y no por su provisión total en plaquetas, estimada en sueros colectados 4 h después de la extracción de la sangre (EGF4h). Varias variables relacionadas con el factor de crecimiento epidérmico, con poder discriminatorio (valor diagnóstico) y potencialidad como biomarcador en cáncer de pulmón de células no pequeñas, fueron identificadas. En particular el factor de crecimiento epidérmico circulante (EGF1h) y el retenido en las plaquetas (EGF4h-EGF1h), ambos normalizados por conteo plaquetario, discriminan mejor los pacientes que el EGF circulante o total. Conclusiones, la mayor capacidad discriminatoria de las variables normalizadas indica su relación más directa con la biología del tumor, comparadas con el biomarcador de eficacia actual; así como su mejor desempeño en la predicción de respuesta a terapias anti EGF/EGFR y a la vacuna CIMAvax-EGF® en particular; lo que unido a la inocuidad y el bajo costo de la prueba UMELISA EGF®, sugiere su posible empleo en la pesquisa y el diagnóstico temprano de la enfermedad en poblaciones de riesgo.
Background
NeuroEPO (NeuralCIM®) is a variant of EPO, which contains low sialic acid. NeuralCIM® is devoid of hematopoietic effects and produces clinical benefits in subjects with mild‐to‐moderate ...Alzheimer’s clinical syndrome. NeuralCIM® has received accelerated approval as a treatment for mild‐moderate AD, from the Cuban Regulatory Authority (CECMED).
Method
NeuralCIM® 0.5 mg was evaluated in patients who, after completing the clinical trial, continued to be treated with the drug, whether they had been included in the NeuralCIM® or placebo arm during trial. They were compared with subjects who did not request to continue treatment or who never received it, because they were included in the placebo group during the clinical study.
Result
After the clinical trial, the patients who continue to be treated with NeuralCIM® for two years from their inclusion in the clinical study, stabilized the disease. On the other hand, the subjects who did not continue the treatment with the drug, present a cognitive impairment characteristic of the progression of the disease. No serious adverse events related with NeuralCIM® were reported.
Conclusion
NeuralCIM® treatment, stabilized the progression of AD clinical syndrome, during two years of treatment.
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.
-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
-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.
The modified Gompertz equation has been proposed to fit experimental data for direct current treated tumors when multiple-straight needle electrodes are individually inserted into the base ...perpendicular to the tumor long axis. The aim of this work is to evaluate the efficacy of direct current generated by multiple-electrode arrays on F3II mammary carcinoma that grow in the male and female BALB/c/Cenp mice, when multiple-straight needle electrodes and multiple-pairs of electrodes are inserted in the tumor.
A longitudinal and retrospective preclinical study was carried out. Male and female BALB/c/Cenp mice, the modified Gompertz equation, intensities (2, 6 and 10 mA) and exposure times (10 and 20 min) of direct current, and three geometries of multiple-electrodes (one formed by collinear electrodes and two by pair-electrodes) were used. Tumor volume and mice weight were measured. In addition, the mean tumor doubling time, tumor regression percentage, tumor growth delay, direct current overall effectiveness and mice survival were calculated.
The greatest growth retardation, mean doubling time, regression percentage and growth delay of the primary F3II mammary carcinoma in male and female mice were observed when the geometry of multiple-pairs of electrodes was arranged in the tumor at 45, 135, 225 and 325
and the longest exposure time. In addition, highest direct current overall effectiveness (above 66%) was observed for this EChT scheme.
It is concluded that electrochemical therapy may be potentially addressed to highly aggressive and metastic primary F3II murine mammary carcinoma and the modified Gompertz equation may be used to fit data of this direct current treated carcinoma. Additionally, electrochemical therapy effectiveness depends on the exposure time, geometry of multiple-electrodes and ratio between the direct current intensity applied and the polarization current induced in the tumor.
Introducción: La neumonía COVID-19 puede conducir a un estado hiperinflamatorio. El CD6 es una glicoproteína expresada en linfocitos T maduros que constituye un regulador crucial de la activación de ...las células T. El itolizumab es un anticuerpo monoclonal que reconoce el CD6. Los datos clínicos en enfermedades autoinmunes indican que reduce múltiples citocinas proinflamatorias. Objetivo: evaluar la seguridad y el impacto de itolizumab sobre la interleucina-6, la función pulmonar y la mortalidad de los pacientes con COVID-19. Métodos: Se incluyeron 68 pacientes moderados, severos y críticos en un ensayo de acceso expandido en Cuba. El itolizumab se administró junto con otras terapias incluidas en el protocolo nacional para el SARS-CoV-2. Resultados: Todos los pacientes completaron la primera infusión y 41, recibieron 2 dosis. La mediana de edad fue de 68 años y el 94 % era portador de comorbilidades. El itolizumab mejoró la función pulmonar y fue bien tolerado; 3 sujetos tuvieron eventos adversos graves relacionados. La interleucina-6 disminuyó en individuos con niveles altos y no se incrementó en aquellos pacientes con concentraciones más bajas. La tasa de letalidad a los 14 días fue del 4 % y del 18 % para los pacientes moderados y graves. Aunque este estudio no fue aleatorizado, los datos preliminares sugieren que itolizumab redujo la probabilidad de muerte en comparación con los controles. El tiempo de tratamiento, las manifestaciones neurológicas y los biomarcadores como la razón entre neutrófilos y linfocitos, recuento de neutrófilos y la interleucina-6 se asociaron significativamente con mayor letalidad. Conclusiones. El itolizumab puede interrumpir la cascada inflamatoria y prevenir la morbilidad y mortalidad asociada al COVID-19.
PDF
