RESUMEN
BRAF and TERT oncogenes hotspot mutations are associated with a more aggressive outcome in thyroid carcinomas (TC). TERT promoter (pTERT) mutations (C228T and C250T) are related to cancer growth and reduced overall- and disease-free survivals in TC. We report a patient followed up for 8 years with a poorly differentiated thyroid carcinoma (PDTC) presenting an extremely aggressive course, who developed a large volume of metastases in a short period. Molecular analysis of the primary tumor revealed two pTERT mutations (C228T and C250T), and no BRAF V600E mutation. pTERT mutations C228T and C250T have been described as mutually exclusive, indicating that one mutation is enough for telomerase activation and exerts its action in thyroid tumorigenesis. This report describes both pTERT hotspot mutations in the same PDTC patient presenting a very aggressive course, even for PDTC, suggesting a relationship between the two events. However, more studies are needed to prove this causality.
Asunto(s)
Adenocarcinoma , Telomerasa , Neoplasias de la Tiroides , Humanos , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Mutación , Regiones Promotoras Genéticas/genética , Adenocarcinoma/genética , Proteínas Proto-Oncogénicas B-raf/genética , Telomerasa/genéticaRESUMEN
Cancer is a group of diseases involving disordered growth of abnormal cells with the potential to invade and spread to other parts of the body. Today, immunotherapy is the most efficient treatment, with fewer side effects. Notably, the employment of monoclonal antibodies to inhibit checkpoint proteins, such as CTLA-4, has caused much excitement among cancer immunotherapy researchers. Thus, in-depth analysis through quantum biochemistry and molecular dynamics simulations was performed to understand the complex formed by ipilimumab and its target CTLA-4. Our computational results provide a better understanding of the binding mechanisms and new insights about the CTLA-4: ipilimumab interaction, identifying essential amino acid residues to support the complex. Additionally, we report new interactions such as aromatic-aromatic, aromatic-sulfur, and cation-pi interactions to stabilize the CTLA-4:ipilimumab complex. Finally, quantum biochemistry analyses reveal the most important amino acid residues involved in the CTLA-4:ipilimumab interface, which were used to design synthetic peptides to inhibit CTLA-4. The computational results presented here provide a better understanding of the CTLA-4:ipilimumab binding mechanisms, and can support the development of alternative antibody-based drugs with high relevance in cancer immunotherapy.
Asunto(s)
Antineoplásicos/uso terapéutico , Antígeno CTLA-4/inmunología , Diseño de Fármacos , Inmunoterapia , Ipilimumab/uso terapéutico , Neoplasias/inmunología , Neoplasias/terapia , Péptidos/uso terapéutico , Antígeno CTLA-4/química , Electricidad , Humanos , Ipilimumab/química , Simulación de Dinámica Molecular , Péptidos/química , Unión Proteica , Proteolisis , TermodinámicaRESUMEN
UNLABELLED: Studying molecules that are differentially expressed in cancers as well as benign and normal tissues is crucial for identifying novel biomarkers for cancer immunotherapy. This study aimed to investigate the clinical utility of the immunochemical expression of the proliferative cell marker Ki-67 and the apoptotic blocker Mcl-1 in papillary thyroid carcinoma (PTC). METHODS: We built a tissue microarray with 282 thyroid specimens. There were 59 PTCs including 35 classic (CPTC), 3 tall cell (TCPTC) and 21 follicular variants (FVPTC); 79 benign thyroid diseases (22 follicular adenomas; 57 adenomatoid hyperplasia); 33 Hashimoto's thyroiditis (HT) specimens; and 111 normal thyroid tissues. Clinical history and ultrasound data were retrospectively obtained by chart review. RESULTS: Mcl-1 overexpression was evident in 66.7% of the PTC tissues compared to 32% of the benign thyroid diseases. Mcl-1 strong staining distinguished benign from malignant thyroid lesions (sensitivity=61.3%; specificity=72.8%; negative predictive value, NPV=68%; positive predictive value, PPV=66.7% and 67.5% accuracy). Positive nuclear Ki-67 staining was observed in 34% of PTCs vs. 19% of thyroid adenomas (P=0.031). Strong Mcl-1 and Ki-67 co-expression was identified in 57.5% of PTCs with a higher PPV (75.8%). Mcl-1 and Ki-67 expression was not associated with any clinicopathological feature of malignancy. No deaths occurred during the follow-up. CONCLUSIONS: Mcl-1 immunochemical overexpression allowed differentiating low-risk PTC from the benign thyroid lesions. We suggest that Mcl-1 expression may help differentiate follicular patterned thyroid lesions. The influence of the Mcl-1 expression on several features of tumor aggressiveness has to be studied in large series of high-risk thyroid carcinomas.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma/metabolismo , Antígeno Ki-67/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Neoplasias de la Tiroides/metabolismo , Adulto , Carcinoma Papilar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Cáncer Papilar TiroideoRESUMEN
We present the structural, electronic, and optical properties of anhydrous crystals of DNA nucleobases (guanine, adenine, cytosine, and thymine) found after DFT (Density Functional Theory) calculations within the local density approximation, as well as experimental measurements of optical absorption for powders of these crystals. Guanine and cytosine (adenine and thymine) anhydrous crystals are predicted from the DFT simulations to be direct (indirect) band gap semiconductors, with values 2.68 eV and 3.30 eV (2.83 eV and 3.22 eV), respectively, while the experimentally estimated band gaps we have measured are 3.83 eV and 3.84 eV (3.89 eV and 4.07 eV), in the same order. The electronic effective masses we have obtained at band extremes show that, at low temperatures, these crystals behave like wide gap semiconductors for electrons moving along the nucleobases stacking direction, while the hole transport are somewhat limited. Lastly, the calculated electronic dielectric functions of DNA nucleobases crystals in the parallel and perpendicular directions to the stacking planes exhibit a high degree of anisotropy (except cytosine), in agreement with published experimental results.
Asunto(s)
Adenina/química , Citosina/química , Guanina/química , Semiconductores , Timina/química , Cristalización , ADN/química , Modelos Moleculares , Agua/químicaRESUMEN
Adsorption of ascorbic acid (AsA) on C60 is investigated using classical molecular mechanics and density functional theory (DFT). Classical annealing was performed to explore the space of molecular configurations of ascorbic acid adsorbed on C60, searching for optimal geometries. From the structure with the smallest total energy, 10 initial configurations were prepared by applying rotations of 90 degrees about three orthogonal axes. Each one of these configurations was optimized using DFT (for both LDA and GGA exchange-correlation functionals), and an estimate of their total and adsorption energies was found. Different configurations have minimal adsorption energies (defined here as the total energy of the adsorbate minus the total energy of the separate molecules) from -0.54 to -0.10 eV, with distinct optimal distances between the AsA and C60 centers of mass. According to a Hirshfeld population analysis, AsA is, in general, an acceptor of electrons from C60. Our results demonstrate the feasibility of noncovalent functionalization of C60 with AsA and provide minimal energy values for the several different configurations investigated. These results should be considered in reactions as a possible way to prevent against the oxidative damage and toxicity of C60. The beneficial effects of using AsA-C60 includes its action when administered together with levodopa, against the neurotoxicity generated by levodopa isolated, which opens new strategies for the Parkinson's disease treatment.