RESUMEN
New pyridine-based chalcones 4a-h and pyrazolines 5a-h (N-acetyl), 6a-h (N-phenyl), and 7a-h (N-4-chlorophenyl) were synthesized and evaluated by the National Cancer Institute (NCI) against 60 different human cancer cell lines. Pyrazolines 6a, 6c-h, and 7a-h satisfied the pre-determined threshold inhibition criteria, obtaining that compounds 6c and 6f exhibited high antiproliferative activity, reaching submicromolar GI50 values from 0.38 to 0.45 µM, respectively. Moreover, compound 7g (4-CH3) exhibited the highest cytostatic activity of these series against different cancer cell lines from leukemia, nonsmall cell lung, colon, ovarian, renal, and prostate cancer, with LC50 values ranging from 5.41 to 8.35 µM, showing better cytotoxic activity than doxorubicin. Furthermore, the compounds were tested for antibacterial and antiplasmodial activities. Chalcone 4c was the most active with minimal inhibitory concentration (MIC) = 2 µg/mL against methicillin-resistant Staphylococcus aureus (MRSA), while the pyrazoline 6h showed a MIC = 8 µg/mL against Neisseria gonorrhoeae. For anti-Plasmodium falciparum activity, the chalcones display higher activity with EC50 values ranging from 10.26 to 10.94 µg/mL. Docking studies were conducted against relevant proteins from P. falciparum, exhibiting the minimum binding energy with plasmepsin II. In vivo toxicity assay in Galleria mellonella suggests that most compounds are low or nontoxic.
Asunto(s)
Antibacterianos , Antimaláricos , Antineoplásicos , Chalconas , Pruebas de Sensibilidad Microbiana , Plasmodium falciparum , Pirazoles , Piridinas , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Chalconas/farmacología , Chalconas/síntesis química , Chalconas/química , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Línea Celular Tumoral , Relación Estructura-Actividad , Plasmodium falciparum/efectos de los fármacos , Pirazoles/farmacología , Pirazoles/química , Pirazoles/síntesis química , Piridinas/farmacología , Piridinas/química , Piridinas/síntesis química , Antimaláricos/farmacología , Antimaláricos/síntesis química , Antimaláricos/química , Simulación del Acoplamiento Molecular , Ensayos de Selección de Medicamentos Antitumorales , Proliferación Celular/efectos de los fármacos , Estructura Molecular , Animales , Relación Dosis-Respuesta a Droga , Neisseria gonorrhoeae/efectos de los fármacosRESUMEN
BACKGROUND AND AIMS: Cancer predisposition goes beyond BRCA and DNA Mismatch Repair (MMR) genes since multi-gene panel testing has become the routine diagnostic tool for hereditary cancer suspicion (HCS) cases. CHEK2 and PALB2 are some of the foremost-mutated non-BRCA/MMR actionable genes in families with a significant familial aggregation. Therefore, the purpose of this work is to unravel which tumours other than breast, ovary or colorectal display the patients. MATERIALS AND METHODS: We have analysed 528 probands that meet the inclusion criteria for Hereditary Breast and Ovarian Cancer and Lynch Syndrome established by our Hereditary Cancer Regional Program with a customized 35 genes-panel by using Ion Torrent™ Technology. RESULTS: We have identified pathogenic variants (PVs) in 61 families (1.55%), of which more than half (31 probands) harboured PVs in CHEK2 and PALB2 genes. Ours results reveal that not only were PVs CHEK2 and PALB2 carriers more likely to have family history of cancer not limited to breast, ovarian or colorectal cancers, but also they are prone to other extracolonic cancers, noteworthy endometrial and gastric cancers. CONCLUSIONS: Multigene panel testing improves the chance of finding PVs in actionable genes in families with HCS. In addition, the coexistence of variants should be recorded to implement a polygenic risk algorithm that might explain the missing heritability in the aforementioned families.
Asunto(s)
Neoplasias de la Mama , Neoplasias Colorrectales , Neoplasias Ováricas , Femenino , Humanos , Mutación de Línea Germinal/genética , Predisposición Genética a la Enfermedad , Neoplasias Ováricas/genética , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Neoplasias de la Mama/genética , Pruebas Genéticas/métodos , Quinasa de Punto de Control 2/genética , Proteína del Grupo de Complementación N de la Anemia de Fanconi/genéticaRESUMEN
The probability of carrying two pathogenic variants (PVs) in dominant cancer-predisposing genes for hereditary breast and ovarian cancer and lynch syndromes in the same patient is uncommon, except in populations where founder effects exist. Two breast cancer women that are double heterozygotes (DH) for both BRCA1/BRCA2, one ovarian cancer case DH for BRCA1/RAD51C, and another breast and colorectal cancer who is DH for BRCA2/PMS2 were identified in our cohort. Ages at diagnosis and severity of disease in BRCA1/BRCA2 DH resembled BRCA1 single-carrier features. Similarly, the co-existence of the BRCA2 and PMS2 mutations prompted the development of breast and colorectal cancer in the same patient. The first BRCA1/BRCA2 DH was identified by HA-based and Sanger sequencing (1 of 623 families with BRCA PVs). However, this ratio has increased up to 2.9% (1 DH carrier vs. 103 single PV carriers) since using a custom 35-cancer gene on-demand panel. The type of cancer developed in each DH patient was consistent with the independently inherited condition, and the clinical outcome was no worse than in patients with single BRCA1 mutations. Therefore, the clinical impact, especially in patients with two hereditary syndromes, lies in genetic counseling tailor-made for each family based on the clinical guidelines for each syndrome. The number of DH is expected to be increased in the future as a result of next generation sequencing routines.
Asunto(s)
Neoplasias de la Mama , Neoplasias Colorrectales Hereditarias sin Poliposis , Neoplasias Ováricas , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Carcinoma Epitelial de Ovario/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Femenino , Genes BRCA2 , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Humanos , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/genética , Mutación , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/genéticaAsunto(s)
Humanos , Femenino , Anciano , Cadera/anomalías , Dolor , Fiebre , Prótesis e Implantes/efectos adversosRESUMEN
Se emplió la omegometría para evaluar el régimen de entrenamiento periódico del personal de vuelo en el Profilactorio del Centro de Descanso "Escambray" . Se realizaron una serie de estudios anatómicos y fisiológicos en un grupo de 32 pilotos, previos al registro de la omegometría, y posteriormente fueron sometidos a la prueba de Cooper (distancia máxima alcanzada). Se puso en evidencia que había afectaciones de los mecanismos de regulación neurofisioógicos; pero se observaron incrementos significativos en la capacidad física, lo que confirma la efectividad del régimen del Profilactario para mejorar los mecanismos regulatorios cardiovasculares. Se demostró que no se logra la eliminación de la sobrecarga de los procesos de regulación del sistema nervioso en cifras comparables con aquéllas.
Asunto(s)
Adulto , Potenciales Evocados , Cerebro/fisiopatología , Sistema Cardiovascular/fisiopatología , Adaptación Fisiológica , Peso Corporal/fisiología , Presión Sanguínea/fisiología , Frecuencia Cardíaca/fisiología , Educación y Entrenamiento Físico , Personal Militar , AviaciónRESUMEN
Se emplió la omegometría para evaluar el régimen de entrenamiento periódico del personal de vuelo en el Profilactorio del Centro de Descanso "Escambray" . Se realizaron una serie de estudios anatómicos y fisiológicos en un grupo de 32 pilotos, previos al registro de la omegometría, y posteriormente fueron sometidos a la prueba de Cooper (distancia máxima alcanzada). Se puso en evidencia que había afectaciones de los mecanismos de regulación neurofisioógicos; pero se observaron incrementos significativos en la capacidad física, lo que confirma la efectividad del régimen del Profilactario para mejorar los mecanismos regulatorios cardiovasculares. Se demostró que no se logra la eliminación de la sobrecarga de los procesos de regulación del sistema nervioso en cifras comparables con aquéllas