Small molecule inhibition of RAS/MAPK signaling ameliorates developmental pathologies of Kabuki Syndrome.

Kabuki Syndrome (KS) is a rare disorder characterized by distinctive facial features, short stature, skeletal abnormalities, and neurodevelopmental deficits. Previously, we showed that loss of function of RAP1A, a RAF1 regulator, can activate the RAS/MAPK pathway and cause KS, an observation recapitulated in other genetic models of the disorder. These data suggested that suppression of this signaling cascade might be of therapeutic benefit for some features of KS. To pursue this possibility, we performed a focused small molecule screen of a series of RAS/MAPK pathway inhibitors, where we tested their ability to rescue disease-relevant phenotypes in a zebrafish model of the most common KS locus, kmt2d. Consistent with a pathway-driven screening paradigm, two of 27 compounds showed reproducible rescue of early developmental pathologies. Further analyses showed that one compound, desmethyl-Dabrafenib (dmDf), induced no overt pathologies in zebrafish embryos but could rescue MEK hyperactivation in vivo and, concomitantly, structural KS-relevant phenotypes in all KS zebrafish models (kmt2d, kmd6a and rap1). Mass spectrometry quantitation suggested that a 100 nM dose resulted in sub-nanomolar exposure of this inhibitor and was sufficient to rescue both mandibular and neurodevelopmental defects. Crucially, germline kmt2d mutants recapitulated the gastrulation movement defects, micrognathia and neurogenesis phenotypes of transient models; treatment with dmDf ameliorated all of them significantly. Taken together, our data reinforce a causal link between MEK hyperactivation and KS and suggest that chemical suppression of BRAF might be of potential clinical utility for some features of this disorder.

PAN-AMPK activator O304 improves glucose homeostasis and microvascular perfusion in mice and type 2 diabetes patients.

AMPK activated protein kinase (AMPK), a master regulator of energy homeostasis, is activated in response to an energy shortage imposed by physical activity and caloric restriction. We here report on the identification of PAN-AMPK activator O304, which - in diet-induced obese mice - increased glucose uptake in skeletal muscle, reduced ß cell stress, and promoted ß cell rest. Accordingly, O304 reduced fasting plasma glucose levels and homeostasis model assessment of insulin resistance (HOMA-IR) in a proof-of-concept phase IIa clinical trial in type 2 diabetes (T2D) patients on Metformin. T2D is associated with devastating micro- and macrovascular complications, and O304 improved peripheral microvascular perfusion and reduced blood pressure both in animals and T2D patients. Moreover, like exercise, O304 activated AMPK in the heart, increased cardiac glucose uptake, reduced cardiac glycogen levels, and improved left ventricular stroke volume in mice, but it did not increase heart weight in mice or rats. Thus, O304 exhibits a great potential as a novel drug to treat T2D and associated cardiovascular complications.

Long-term effect of chemotherapy-intensity-modulated radiation therapy (chemo-IMRT) on dentofacial development in head and neck rhabdomyosarcoma patients.

Dentofacial developmental abnormalities have been reported in head and neck rhabdomyosarcoma (HNRMS) patients treated with conventional radiotherapy technique and chemotherapy. This current study investigates dentofacial long-term effects among HNRMS survivors managed with intensity-modulated radiotherapy (IMRT) and chemotherapy. In general, IMRT is a more effective 3D-conformal radiotherapy technique, which delivers high doses of radiation to the tumor target while minimizing doses received by the surrounding normal tissues. The medical records and radiographs of thirteen patients were reviewed to identify the following: 1. Facial asymmetry and jaw hypoplasia. 2. Effects on the dental tissue causing tooth agenesis/hypodontia, root agenesis/stunting/malformation, and/or enamel hypoplasia. 3. Trismus, hyposalivation/xerostomia. Seven patients presented with facial asymmetry and jaw hypoplasia, 9 patients presented with effects on the dental tissue [root agenesis/stunting/malformation (9), tooth agenesis/hypodontia (7) and enamel hypoplasia (3)] and 7 patients developed trismus and /or xerostomia. All patients with facial asymmetry and jaw hypoplasia also developed dental abnormalities. Patients with dentofacial developmental abnormalities were ≤7 years of age at treatment. Our study shows that dentofacial developmental abnormalities are still a burden in the era of IMRT and as prognosis of childhood malignancy improves and more patients survive, these late dentofacial sequelae among childhood cancer survivors will become more common. Dental oncologists should be integral members in the management of children with head and neck cancers.

Lo que el odontopediatra debe conocer sobre lactancia materna / What the pediatric dentist should know about breastfeeding

La lactancia materna exclusiva, a través de la provisión de leche materna del seno de la madre, proporciona múltiples beneficios para lograr un correcto desarrollo y crecimiento físico, intelectural y emocional. Además, favorece un adecuado desarrollo de las estructuras neuromusculares del sistema estomatognático del bebé. Por otro lado, disminuye el riesgo de adoptar hábitos bucales no nutritivos que con el tiempo podrían originar maloclusiones dentarias. Tanto el niño como la madre obtienen beneficios de la lactancia materna. Sin embargo, debido a diferentes factores, la práctica de este tipo de alimentación ha disminuido en el transcurso del tiempo, reemplazándola por sustitutos tomados en biberón, lo que se conoce como lactancia artificial. Es importante que el odontopediatra tenga conocimientos acerca de la importancia de la lactancia materna y de las consecuencias que puede acarrear la falta o disminuir el tiempo de ésta. Además, deberá fomentar la práctica de lactancia materna exclusiva durante losprimeros seis meses de vida evitando así problemas futuros en la salud de los niños.

Evaluación del impacto del taller sobre lactancia materna y su rol preventivo en las anomalías dentomaxilofaciales: 2003 / Assessment of the impact of the Braest Feeding and its preventive role in tooh and jaw abnormalities workshop: 2003

A fin de evaluar el impacto del taller de capacitación integral para gestantes sobre la lactancia materna en la prevención de las anomalías dentomaxilofaciales, se realizó un estudio prospectivo y descriptivo en 42 gestantes ingresadas en el bloque ginecoobstétrico del Hospital Provincial Abel Santamaría, en el período comprendido del 1ro. de enero al 31 de marzo de 2003. Los datos se recogieron en un formulario que incluía un examen diseñado al efecto, con el objetivo de evaluar el grado de conocimiento que poseían las gestantes en relación con la importancia de la lactancia materna en la prevención de anomalías dentomaxilofaciales. Las variables analizadas fueron: edad, ocupación, procedencia y resultados de la calificación del examen. Una vez aplicado el examen, se impartió un taller acerca de este tema y posteriormente se les reaplicó a las gestantes el mismo examen. Se obtuvo que el nivel de conocimiento de las gestantes sobre la importancia de la lactancia materna y la función masticatoria en el desarrollo del sistema estomatognático fue inadecuado en los distintos grupos de edad y variables bio-psico-sociales estudiadas, antes de la capacitación. Las temáticas que mayor dificultad tuvieron fueron las relacionadas con el desarrollo adecuado de la mandíbula, la respiración nasal y la deglución. Se concluye que el taller de capacitación impartido a las gestantes tuvo un gran impacto, pues se logró que adquirieran los conocimientos básicos en el amamantamiento natural e introducción de la alimentación sólida y sobre la lactancia materna en la prevención de las anomalías dentomaxilofaciales(AU)

With the objective of assessing the impact of comprehensive training workshop on the role of breast-feeding in the prevention of tooth and jaw abnormalities aimed at pregnant women, a prospective descriptive study of 42 pregnant women, who were admitted to the gynecological-obstetric area of "Abel Santamaría" provincial hospital from January 1st to March 31st, 2003 was conducted. Data were collected into a form that included a test to evaluate the level of knowledge of these women about the importance of breast-feeding in the prevention of tooth and jaw abnormalities. Analytical variables were age, job, origin and test marks. Once the test was applied, participating pregnant women were given a workshop on this topic and later, they made the test again. Before the training course, their level of knowledge on the significance of breast-feeding and the masticatory function on the development of the stomatognatic system was poor at the various age groups and biological and psycho-social variables studied. The most difficult topics were those related with jaw, nasal respiration and deglutition development. It was concluded that the training workshop for pregnant women had a great impact since it succeeded in conveying basic pieces of knowledge about natural feeding and the introduction of solid feeding in addition to the role of breast-feeding in the prevention of tooth and jaw abnormalities(AU)

Cheilognathopalatoschisis and its prophylaxis in animal experiments.

Cheilognathopalatoschisis (cleft lip, -maxilla, and -palate) is the second most frequent malformation in humans. The ontogenetic causes are mostly multifactorial. Some researchers have succeeded in lowering the frequency of occurrence of such clefts in children of predisposed women by giving the latter an applied symptomatic replacement therapy with multivitamin preparations or other substance classes during early pregnancy. However, the dosage of these substances was only anecdotal and their effect unspecific. Many research groups world-wide are conducting animal experiments in order to investigate the efficacy of vitamins and other substances as prophylactics. The experiments are usually conducted with laboratory rats and mice, and clefts are often induced by applying chemical noxa. The results of these trials, however, are controversial. Where some authors were able to prove protective effects of the vitamins or other substances they employed, others found evidence that such replacement therapy has no prophylactic effect. This paper provides insight into such studies with experimental animals, and compares their results.

[The problems in studying the prevalence and the organization of the prevention of maxillodental anomalies in children]. / Problemy izucheniia rasprostranennosti i organizatsii profilaktiki zubocheliustnykh anomalii u detei.

Methodological aspects of studies of the prevalence and organization of prevention of maxillodental abnormalities in children are discussed, effects of a number of factors on the incidence of such abnormalities shown. The author emphasizes that prevention of abnormalities should start in early age and be based on an individual approach to a child. A conclusion is made on the necessity of development of a unified program of epidemiological study of abnormalities in the country.