RESUMEN
Microtubule doublets (MTDs), consisting of an incomplete B-microtubule at the surface of a complete A-microtubule, provide a structural scaffold mediating intraflagellar transport and ciliary beating. Despite the fundamental role of MTDs, the molecular mechanism governing their formation is unknown. We used a cell-free assay to demonstrate a crucial inhibitory role of the carboxyl-terminal (C-terminal) tail of tubulin in MTD assembly. Removal of the C-terminal tail of an assembled A-microtubule allowed for the nucleation of a B-microtubule on its surface. C-terminal tails of only one A-microtubule protofilament inhibited this side-to-surface tubulin interaction, which would be overcome in vivo with binding protein partners. The dynamics of B-microtubule nucleation and its distinctive isotropic elongation was elucidated by using live imaging. Thus, inherent interaction properties of tubulin provide a structural basis driving flagellar MTD assembly.
Asunto(s)
Cilios/ultraestructura , Microtúbulos/ultraestructura , Tubulina (Proteína)/química , Animales , Bovinos , Cilios/química , Simulación por Computador , Microscopía por Crioelectrón , Técnica del Anticuerpo Fluorescente , Microtúbulos/química , Modelos Moleculares , Unión Proteica , Subtilisina , Porcinos , Tetrahymena thermophilaRESUMEN
PURPOSE: The management of malignant brain metastases becomes a main issue for the treatment of patients, because of the survival extension related to the improvement in systemic treatments. Robotic stereotactic radiosurgery (RSR) is a new approach in this indication. The purpose of this analysis was to define the efficacy of RSR, in order to determine prognostic factors of survival and factors of response. PATIENTS AND METHODS: It was a retrospective, single center (polyclinique de Bordeaux Nord Aquitaine) analysis performed from 2012 to 2015, involving patients with malignant brain metastases treated by RSR using the Cyberknife® technique. We analyzed the following parameters: response to RSR, prognostic and predictive factors of response, and survival. RESULTS: A total of 72 RSRs were performed among 55 analyzed patients; 62 treatments were assessable with a median follow-up of 9.4 months. The main delivered dose on the 80%-isodose was 20Gy. A complete response was achieved in 40.3% of patients (stability or regression=83.9%). The overall survival was 13 months. The risk of failure was significantly correlated with the increase in metastasis size and non-adenocarcinoma histology. A performance status<2 was the main prognostic factor of survival. CONCLUSIONS: The RSR allowed treating 3 to 5 brain metastases, avoiding an entire brain irradiation, and maintaining survival and quality of life.
Asunto(s)
Neoplasias Encefálicas/cirugía , Radiocirugia , Procedimientos Quirúrgicos Robotizados , Robótica , Adulto , Anciano , Anciano de 80 o más Años , Encéfalo/cirugía , Neoplasias Encefálicas/patología , Femenino , Humanos , Imagenología Tridimensional/métodos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia/terapia , Calidad de Vida , Radiocirugia/métodos , Inducción de RemisiónRESUMEN
How cellular organelles assemble is a fundamental question in biology. The centriole organelle organizes around a nine-fold symmetrical cartwheel structure typically â¼100 nm high comprising a stack of rings that each accommodates nine homodimers of SAS-6 proteins. Whether nine-fold symmetrical ring-like assemblies of SAS-6 proteins harbour more peripheral cartwheel elements is unclear. Furthermore, the mechanisms governing ring stacking are not known. Here we develop a cell-free reconstitution system for core cartwheel assembly. Using cryo-electron tomography, we uncover that the Chlamydomonas reinhardtii proteins CrSAS-6 and Bld10p together drive assembly of the core cartwheel. Moreover, we discover that CrSAS-6 possesses autonomous properties that ensure self-organized ring stacking. Mathematical fitting of reconstituted cartwheel height distribution suggests a mechanism whereby preferential addition of pairs of SAS-6 rings governs cartwheel growth. In conclusion, we have developed a cell-free reconstitution system that reveals fundamental assembly principles at the root of centriole biogenesis.
Asunto(s)
Proteínas Algáceas/metabolismo , Proteínas de Ciclo Celular/metabolismo , Centriolos/metabolismo , Chlamydomonas reinhardtii/metabolismo , Orgánulos/metabolismo , Proteínas Algáceas/ultraestructura , Proteínas de Ciclo Celular/ultraestructura , Centriolos/ultraestructura , Chlamydomonas reinhardtii/ultraestructura , Microscopía por Crioelectrón/métodos , Tomografía con Microscopio Electrónico/métodos , Modelos Biológicos , Orgánulos/ultraestructuraRESUMEN
BACKGROUND: We investigated whether circulating endothelial cells (CECs) predict clinical outcome of first-line chemotherapy and bevacizumab in metastatic colorectal cancer (mCRC) patients. PATIENTS AND METHODS: In a substudy of the randomized phase II FNCLCC ACCORD 13/0503 trial, CECs (CD45- CD31+ CD146+ 7-amino-actinomycin- cells) were enumerated in 99 patients by four-color flow cytometry at baseline and after one cycle of treatment. We correlated CEC levels with objective response rate (ORR), 6-month progression-free survival (PFS) rate (primary end point of the trial), PFS, and overall survival (OS). Multivariate analyses of potential prognostic factors, including CEC counts and Köhne score, were carried out. RESULTS: By multivariate analysis, high baseline CEC levels were the only independent prognostic factor for 6-month PFS rate (P < 0.01) and were independently associated with worse PFS (P = 0.02). High CEC levels after one cycle were the only independent prognostic factor for ORR (P = 0.03). High CEC levels at both time points independently predicted worse ORR (P = 0.025), 6-month PFS rate (P = 0.007), and PFS (P = 0.02). Köhne score was the only variable associated with OS. CONCLUSION: CEC levels at baseline and after one treatment cycle may independently predict ORR and PFS in mCRC patients starting first-line bevacizumab and chemotherapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Células Endoteliales/patología , Endotelio Vascular/patología , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Bevacizumab , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Capecitabina , Recuento de Células , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/mortalidad , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Citometría de Flujo , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Humanos , Irinotecán , Estimación de Kaplan-Meier , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Análisis Multivariante , Metástasis de la Neoplasia , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
Two groups living in southeast France several centuries apart were compared to assess changes in occlusion from medieval times to the present day. The present-day sample included 82 people, and the medieval sample included the skulls of 58 people who lived between the 8th and the 17th centuries. Variations in tooth contacts were examined in accordance with Angle classification. A decrease in Class III occlusion (mesioclusion) was noted from medieval to present-day populations. The rate of Class II occlusion (distoclusion) has increased progressively and has became a general feature in the present-day population (34%). Although the rate of Class I occlusion has generally decreased from proto-historic and medieval times to the present day, it is still the highest percentage (45%) and thus the "normal" reference in European populations. This study highlights distoclusion in human teeth and allowed us to ask questions about functional, genetic, psychological, and environmental factors that cause this malocclusion as opposed to the global harmony that Angle described.
Asunto(s)
Maloclusión/historia , Adolescente , Adulto , Distribución de Chi-Cuadrado , Francia , Historia del Siglo XV , Historia del Siglo XVI , Historia del Siglo XVII , Historia del Siglo XX , Historia Medieval , Humanos , Persona de Mediana EdadRESUMEN
Diabetics exhibit a greater incidence of cardiovascular disease than non-diabetics. The vascular changes that occur are well documented and are thought to promote other clinical manifestations such as cardiomyopathy. Research has shown that the pathogenic events in the myocyte may occur independently of atherosclerotic processes. The atherosclerotic changes in diabetes involve non-enzymatic glycation of extracellular basement membrane proteins. We hypothesize that intracellular glycation events occur in cardiac tissue that alter intermediary metabolism, particularly Ca2+ homeostasis, which leads to cell dysfunction. Additionally, we hypothesize that the high steady state intracellular concentrations of unphosphorylated creatine may offer protection against the formation of advanced glycation endproducts by reacting directly with glucose metabolites that may have reached toxic levels in the myocyte of diabetics.
Asunto(s)
Cardiomiopatías/etiología , Creatina/fisiología , Diabetes Mellitus/fisiopatología , Modelos Cardiovasculares , Arteriosclerosis/fisiopatología , Calcio/metabolismo , Cardiomiopatías/fisiopatología , Complicaciones de la Diabetes , Diabetes Mellitus/metabolismo , Angiopatías Diabéticas/fisiopatología , Productos Finales de Glicación Avanzada/metabolismo , Glicosilación , HumanosRESUMEN
Fifteen patients with ruptured intracranial aneurysm have been operated before undergoing post surgery xenon inhalation for cerebral blood flow valuation: first measurement has been performed as CBF reference; 2nd measurement has been done after 0.1 mg.kg-1 I.V. bolus of nicardipine; sides effects are mainly due to BP fall 2/15 and some consequent neurological distress have been noticed (2/15); results should be carefully interpreted. Significant CBF increase have been measured after nicardipine injection, specially in brain area correlated to low CBF before injection (the lower the CBF, the higher the increase of local flow). The study prompt us to check the effect of nicardipine on patient (with CBF measurement after nicardipine test) before giving the treatment. Problems remain to be solved with further studies and not yet established: correlation between hemodynamics changes and clinical status and also which time of disease evolution is the best to be treated.