Mario Guzmán

RAD51 foci as a functional biomarker of homologous recombination repair and PARP inhibitor resistance in germline BRCA-mutated breast cancer

Abstract Background BRCA1 and BRCA2 (BRCA1/2)-deficient tumors display impaired homologous recombination repair (HRR) and enhanced sensitivity to DNA damaging agents or to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi). Their efficacy in germline BRCA1/2 (gBRCA1/2)-mutated metastatic breast cancers has been recently confirmed in clinical trials. Numerous mechanisms of PARPi resistance have been described, whose clinical relevance in gBRCA-mutated breast cancer is unknown. This highlights the need to identify functional biomarkers to better predict PARPi sensitivity. Patients and methods We investigated the in vivo mechanisms of PARPi resistance in gBRCA1 patient-derived tumor xenografts (PDXs) exhibiting differential response to PARPi. Analysis included exome sequencing and immunostaining of DNA damage response proteins to functionally evaluate HRR. Findings were validated in a retrospective sample set from gBRCA1/2-cancer patients treated with PARPi. Results RAD51 nuclear foci, a surrogate marker of HRR functionality, were the only common feature in PDX and patient samples with primary or acquired PARPi resistance. Consistently, low RAD51 was associated with objective response to PARPi. Evaluation of the RAD51 biomarker in untreated tumors was feasible due to endogenous DNA damage. In PARPi-resistant gBRCA1 PDXs, genetic analysis found no in-frame secondary mutations, but BRCA1 hypomorphic proteins in 60% of the models, TP53BP1-loss in 20% and RAD51-amplification in one sample, none mutually exclusive. Conversely, one of three PARPi-resistant gBRCA2 tumors displayed BRCA2 restoration by exome sequencing. In PDXs, PARPi resistance could be reverted upon combination of a PARPi with an ataxia-telangiectasia mutated (ATM) inhibitor. Conclusion Detection of RAD51 foci in gBRCA tumors correlates with PARPi resistance regardless of the underlying mechanism restoring HRR function. This is a promising biomarker to be used in the clinic to better select patients for PARPi therapy. Our study also supports the clinical development of PARPi combinations such as those with ATM inhibitors.

Wear of the Primary WaveOne single file when shaping vestibular root canals of first maxillary molar

Background It is very important for a clinician to know the increased wear of mechanized files when establishing endodontic therapy. The aim of this study was to check the wear of the Primary WaveOne file upon shaping two, four and six maxillary molar vestibular canals. Material and Methods The deterioration of 40 files, divided into four groups, was evaluated microscopically: group 1, control (unused); group 2, two canals; group 3, four canals; and group 4, six canals. After instrumentation, the files were embedded in resin and sectioned at their apical third into three equal parts. To analyze the wear of edges in the different sections, AutoCAD software was used and analysis of variance (ANOVA) was then performed to compare the mean rake angles. Results The files with two and four uses showed slight wear, whereas those with six applications showed significant wear (p<0.05). Conclusions Primary WaveOne files can be used in up to four root canals without their edges losing effectiveness. Key words:Files wear, reciprocating motion, shaping capacity, WaveOne.

WaveOne: A Simple and Safe Way to Perform an Endodontic Treatment

Las variaciones anatomicas de los canales radiculares juegan un papel importante en el exito del tratamiento endodontico, sobre todo en dientes con necrosis pulpar. Tradicionalmente, la preparacion de los canales radiculares se realizo con el uso de limas de acero inoxidable, pero en los ultimos anos, nuevos instrumentos flexibles se introdujeron para evitar o reducir al minimo errores o iatrogenias en la conformacion del sistema canalicular. Se ha propuesto el movimiento reciprocante como alternativa al movimiento de rotacion continua, con el fin de reducir el riesgo de fractura del instrumento y la deformacion del canal radicular. El objetivo de este articulo fue presentar un caso clinico que describe una forma sencilla de realizar el tratamiento endodontico de un premolar maxilar con tres canales radiculares utilizando el sistema reciprocante WaveOne.

Estudio de las Fuerzas de Avance en un Proceso de Taladrado utilizando Brocas con Geometría Mejorada

Two types of drills were submitted to a drilling process with the objective of determining which tool design offers a decrease in the thrust forces when holes of the same diameter are drilled, under the same mechanizing conditions. One of the drills was with conventional geometry and the other one was with improved geometry. The capture of the mechanized forces is done through a dynamometer platform with piezoelectric sensors. The data is put under a filtering process, to then determine and plot the experimental data and simulated behavior of the drilling processes. The results obtained show a decrease of the thrust forces when drilling with drills that have their active part improved.