Deoxycytidine kinase (dCK) inhibition is synthetic lethal with BRCA2 deficiency.

BRCA2 is a well-established cancer driver in several human malignancies. While the remarkable success of PARP inhibitors proved the clinical potential of targeting BRCA deficiencies, the emergence of resistance mechanisms underscores the importance of seeking novel Synthetic Lethal (SL) targets for future drug development efforts. In this work, we performed a BRCA2-centric SL screen with a collection of plant-derived compounds from South America. We identified the steroidal alkaloid Solanocapsine as a selective SL inducer, and we were able to substantially increase its potency by deriving multiple analogs. The use of two complementary chemoproteomic approaches led to the identification of the nucleotide salvage pathway enzyme deoxycytidine kinase (dCK) as Solanocapsine's target responsible for its BRCA2-linked SL induction. Additional confirmatory evidence was obtained by using the highly specific dCK inhibitor (DI-87), which induces SL in multiple BRCA2-deficient and KO contexts. Interestingly, dCK-induced SL is mechanistically different from the one induced by PARP inhibitors. dCK inhibition generates substantially lower levels of DNA damage, and cytotoxic phenotypes are associated exclusively with mitosis, thus suggesting that the fine-tuning of nucleotide supply in mitosis is critical for the survival of BRCA2-deficient cells. Moreover, by using a xenograft model of contralateral tumors, we show that dCK impairment suffices to trigger SL in-vivo. Taken together, our findings unveil dCK as a promising new target for BRCA2-deficient cancers, thus setting the ground for future therapeutic alternatives to PARP inhibitors.

Effects of exposure to oxamyl, carbofuran, dichlorvos, and lindane on acetylcholinesterase activity in the gills of the Pacific oyster Crassostrea gigas.

Acetylcholinesterase (AChE) activity has been used to test the exposure of mollusk bivalves to pesticides and other pollutants. The Pacific oyster Crassostrea gigas is a species with a worldwide distribution, and it has a high commercial value. The use of this species as a bioindicator in the marine environment, and the use of measurements of AChE activity in tissues of C. gigas require prior evaluation of organisms exposed to several toxic compounds in the laboratory. In our study, the effects of pesticides on AChE activity in the gills and mantle tissues of C. gigas were analyzed by exposing animals to organophosphate (dichlorvos), carbamate (carbofuran and oxamyl), and organochlorine (lindane) pesticides. Adult Pacific oysters were exposed to several concentrations (0.1-200 microM) of dichlorvos, carbofuran, and oxamyl for 96 h, and lindane (1.0 and 2.5 microM) was applied for 12 days. In gill tissues, all pesticides analyzed caused a decrease in AChE activity when compared to the control unexposed group. The mean inhibition concentration (IC(50)) values were determined for dichlorvos, carbofuran, and oxamyl pesticides. Dichlorvos had the highest toxic effect, with an IC(50) of 1.08 microM; lesser effects were caused by oxamyl and carbofuran, with IC(50)s of 1.67 and 3.03 microM, respectively. This study reports the effects of pesticides with several chemical structures and validates measurement of AChE activity in the gill tissues of C. gigas for use in environmental evaluations or food quality tests.

Recommended Guidelines for Developing, Qualifying, and Implementing Complex In Vitro Models (CIVMs) for Drug Discovery.

The pharmaceutical industry is continuing to face high research and development (R&D) costs and low overall success rates of clinical compounds during drug development. There is an increasing demand for development and validation of healthy or disease-relevant and physiological human cellular models that can be implemented in early-stage discovery, thereby shifting attrition of future therapeutics to a point in discovery at which the costs are significantly lower. There needs to be a paradigm shift in the early drug discovery phase (which is lengthy and costly), away from simplistic cellular models that show an inability to effectively and efficiently reproduce healthy or human disease-relevant states to steer target and compound selection for safety, pharmacology, and efficacy questions. This perspective article covers the various stages of early drug discovery from target identification (ID) and validation to the hit/lead discovery phase, lead optimization, and preclinical safety. We outline key aspects that should be considered when developing, qualifying, and implementing complex in vitro models (CIVMs) during these phases, because criteria such as cell types (e.g., cell lines, primary cells, stem cells, and tissue), platform (e.g., spheroids, scaffolds or hydrogels, organoids, microphysiological systems, and bioprinting), throughput, automation, and single and multiplexing endpoints will vary. The article emphasizes the need to adequately qualify these CIVMs such that they are suitable for various applications (e.g., context of use) of drug discovery and translational research. The article ends looking to the future, in which there is an increase in combining computational modeling, artificial intelligence and machine learning (AI/ML), and CIVMs.

Morphometric relationships between the mandibular canal and the molar teeth: a tomographic analysis report / Relaciones morfométricas entre el canal mandibular y los dientes molares: reporte de un análisis tomográfico

Some dental treatments that are performed in the mandibular teeth involve manipulation of anatomical structures near the dental periapex, so it is likely to cause nerve damage due to the proximity of the inferior alveolar nerve with the apices of the mandibular teeth, mainly in the molar area. The aim of this study was to determine through Computed Tomography (CT) scan the existing distance between the mandibular canal and the anatomical structures adjacent to its path which will help to reduce the risk of injury to the inferior alveolar nerve during the different dental treatments developed in this zone. A cross-sectional study was performed where the study population consisted of 50 patients of both sexes, between 20 and 30 years with a full dentition mandible. Patients underwent a CT study of the mandible with coronal planes at 1.5 mm, the right side and the left side of each jaw were considered for the analysis and millimetric measuring was held of the distances of the mandibular canal (MC) from different anatomical structures. Subsequently, a statistical analysis was performed to obtain the mean and standard deviation of the distances between the mandibular canal and some adjacent anatomical structures. The distance from the alveolar nerve canal to the apex of the lower third molar in average was 1.49 mm on the right side and 1.69 mm on the left side, the distance between the mandibular canal and lingual cortical at the lower first molar level on average was 3.54 mm on the right side and 4.02 mm on the left side and the distance between the lingual cortical at the second molar level was on average 2.86 mm on the right side and 3.6 mm on the left side.

Algunos tratamientos dentales que se realizan en los dientes mandibulares implican la manipulación de estructuras anatómicas cercanas al periapice dental, por lo que existe la probabilidad de causar lesiones nerviosas debido a la cercanía del canal mandibular con los ápices de los dientes mandibulares, principalmente los molares. El objetivo de este estudio fue determinar a través de tomografía computarizada la distancia existente entre el canal mandibular a las estructuras anatómicas adyacentes a su trayecto lo que ayudará a disminuir el riesgo de lesiones del nervio alveolar inferior durante los diferentes tratamientos dentales desarrollados en esta zona. Se realizó un estudio transversal en donde la población de estudio estuvo compuesta por 50 pacientes de ambos sexos, entre 20 a 30 años con dentición completa en mandíbula. A los pacientes se les realizó un estudio de Tomografía Computarizada (TC) en mandíbula con cortes coronales a 1.5mm, se consideraron para el análisis el lado derecho y el lado izquierdo de cada mandíbula, y se realizó la medición milimétrica de las distancias que existen desde el CNAI a diferentes estructuras anatómicas. Posteriormente, se realizó un análisis estadístico para obtener Medias y Desviación Estándar de las distancias que existen entre el canal mandibular y algunas estructuras anatómicas adyacentes. La distancia del canal mandibular al ápice del tercer molar inferior en promedio fue de 1,49 mm del lado derecho y de 1,69 mm del lado izquierdo,la distancia entre el canal mandibular y la cortical lingual a nivel del primer molar inferior en promedio fue de 3,54 mm del lado derecho y de 4,02 mm del lado izquierdo y la distancia entre la cortical lingual a nivel del segundo molar fue en promedio de 2,86 mm del lado derecho y de 3,6 mm del lado izquierdo.

Síndrome de Eagle. Manejo del paciente en el Hospital Regional «Licenciado Adolfo López Mateos¼ / Eagle's syndrome. Patient handling at the «Licenciado Adolfo López Mateos¼ Hospital Mexico City

El síndrome de Eagle es definido como la elongación del proceso estiloides y calcificación del ligamento estilohioideo, se caracteriza por sintomatología dolorosa faríngea, odinofagia, disfagia, cefalea, irradiación de dolor a oreja y dolor cervical. El promedio de longitud del proceso estiloides es de 2.5 cm. La etiología del síndrome es poco conocida. Se reporta el caso de un paciente masculino de 53 años de edad con cervicalgia, dolor en región lateral del cuello, limitación de movimientos de lateralidad del cuello. Inicia protocolo para exéresis de ligamento estilohioideo por abordaje extraoral de tipo submandibular extendido. El objetivo del artículo es dar a conocer las ventajas del abordaje extraoral para esta patología, así como la terapia complementaria postquirúrgica empleada en el Hospital Regional «Licenciado Adolfo López Mateos¼ del ISSSTE.

Eagle's syndrome can be defined as the elongation of the styloid process and the calcification of the stylohyoid ligament. It is characterized by painful pharyngeal symptoms, odynophagia, dysphagia, headaches, pain irradiation to the ear and cervical pain. The average length of the styloid process is 2.5 cm. Eagle's syndrome etiology is not well known. The present study reports the case of a 53 year old male patient who presented cervical pain, pain at the lateral region of the neck, as well as limitations in neck lateral movements. Protocol was initiated for stylohyoid ligament resection via extended sub-mandibular extra-oral approach. The aim of the present article was to raise awareness on the advantages of extraoral approach in these cases, as well as supplementary postsurgical therapy used at the Regional Hospital «Licenciado Adolfo López Mateos¼, ISSSTE (Mexico).

Síncope. Estrategia diagnóstica. Utilidad del Holter Implantable / Syncope. Diagnostic strategy. Utility of Holter implants

Se puede definir el síncope como una pérdida breve y súbita del nivel de conciencia que se asocia a una pérdida del tono postural, con recuperación espontánea. La fisiopatología de todas las formas de síncope consiste en un descenso brusco del flujo sanguíneo cerebral. El síncope es una patología común, invalidante y que se asocia posiblemente a un riesgo de muerte súbita, aunque sus causas son en ocasiones difíciles de determinar y precisa de numerosas pruebas diangósticas. Una historia clínica cuidadosa junto con una exploración física completa son esenciales en la evaluación del síncope y deben conducir o al menos sugerir el diagnóstico que debe ser confirmado mediante distintas pruebas. El electrocardiograma se recomienda en todos los pacientes, a pesar del bajo rendimiento pues los hallazgos pueden audar a tomar decisiones para el manejo inmediato de la causa subyacente (por ejemplo, la implantación de un marcapasos en un bloqueo auriculoventricular completo) o para el plantamiento de futuras pruebas diagnósticas. Tras el análisis inicial (historia clínica, exploración física y electrocardiograma) las pruebas diagnósticas a realizar se harán según la sospecha clínica. Sin embargo, existe poca información acerca de la utilidad del holter implantable en el manejo diagnóstico del síncope. Este artículo pretende hacer una revisión sobre la evaluación del síncope así como el papel que juega el holter implantable en el manejo diagnóstico del síncope. Palabras clave: Síncope, holter implantable, diagnóstico.

Prevención de la fibrilación auricular en los pacientes con insuficiencia cardiaca / Prevention of atrial fibrillation in patients with heart failure

La insuficiencia cardiaca promueve la aparición de fibrilación auricular y ésta agrava la insuficiencia cardiaca. La fibrilación auricular puede afectar en cualquier momento a un gran porcentaje de los pacientes con insuficiencia cardiaca. La manifestación y presentación clínica cambia con el paso del tiempo y depende de cada paciente. Empeora la sintomatología de los pacientes, como una complicación más de su enfermedad, y causa frustración tanto a los pacientes como a los médicos. Se estima que hasta un 50% de los pacientes con insuficiencia cardiaca presentan fibrilación auricular en algún momento de su evolución, por lo que son necesarias medidas tanto para la prevención de la embolia como para el alivio de los síntomas. La interferencia farmacológica con señales específicas de las vías de transducción es prometedora. Hasta ahora, los agentes más efectivos son los inhibidores de la enzima de conversión de la angiotensina y los antagonistas de los receptores de la angiotensina II, que reducen el estrés oxidativo, restauran las concentraciones de óxido nítrico, inhiben la formación de tejido fibroso y pueden reducir la ectopia de las venas pulmonares. El desenmascaramiento de factores genéticos implicados aún no conocidos puede tener gran repercusión. Es necesario un mejor conocimiento de la fisiología molecular. Esto puede ayudar a desarrollar nuevos regímenes de tratamiento o terapia híbrida con combinación de fármacos «antiarrítmicos» y «no antiarrítmicos» para aumentar la eficacia del tratamiento (AU)

The presence of heart failure increases the risk of atrial fibrillation, a condition which in turn aggravates heart failure. At any point in time, a large percentage of patients with heart failure are affected by atrial fibrillation. Its clinical characteristics change over time and vary according to the individual patient. It worsens patients’ symptoms, adds a further a complication to their illness, and is problematic for both patients and physicians. It is estimated that 50% of patients with heart failure will experience atrial fibrillation, and will require treatment to prevent embolism and relieve symptoms. The ability of drugs to interfere with specific signal transduction pathways is promising. To date, the most effective agents appear to be angiotensin-converting enzyme inhibitors and angiotensin-II receptor antagonists. These compounds reduce oxidative stress, restore the nitric oxide level, inhibit the formation of fibrous tissue, and can ameliorate pulmonary vein ectopy. Uncovering the, as yet unknown, genetic factors involved could have significant implications. Better understanding of the relevant molecular biology is essential. This could lead to new treatment regimes or to hybrid therapy with a combination of antiarrhythmic and non-antiarrhythmic drugs, which could improve treatment effectiveness (AU)