A multiplexed, confinable CRISPR/Cas9 gene drive can propagate in caged Aedes aegypti populations.

Aedes aegypti is the main vector of several major pathogens including dengue, Zika and chikungunya viruses. Classical mosquito control strategies utilizing insecticides are threatened by rising resistance. This has stimulated interest in new genetic systems such as gene drivesHere, we test the regulatory sequences from the Ae. aegypti benign gonial cell neoplasm (bgcn) homolog to express Cas9 and a separate multiplexing sgRNA-expressing cassette inserted into the Ae. aegypti kynurenine 3-monooxygenase (kmo) gene. When combined, these two elements provide highly effective germline cutting at the kmo locus and act as a gene drive. Our target genetic element drives through a cage trial population such that carrier frequency of the element increases from 50% to up to 89% of the population despite significant fitness costs to kmo insertions. Deep sequencing suggests that the multiplexing design could mitigate resistance allele formation in our gene drive system.

MITF Expression Predicts Therapeutic Vulnerability to p300 Inhibition in Human Melanoma.

Histone modifications, largely regulated by histone acetyltransferases (HAT) and histone deacetylases, have been recognized as major regulatory mechanisms governing human diseases, including cancer. Despite significant effort and recent advances, the mechanism by which the HAT and transcriptional coactivator p300 mediates tumorigenesis remains unclear. Here, we use a genetic and chemical approach to identify the microphthalmia-associated transcription factor (MITF) as a critical downstream target of p300 driving human melanoma growth. Direct transcriptional control of MITF by p300-dependent histone acetylation within proximal gene regulatory regions was coupled to cellular proliferation, suggesting a significant growth regulatory axis. Further analysis revealed forkhead box M1 (FOXM1) as a key effector of the p300-MITF axis driving cell growth that is selectively activated in human melanomas. Targeted chemical inhibition of p300 acetyltransferase activity using a potent and selective catalytic p300/CBP inhibitor demonstrated significant growth inhibitory effects in melanoma cells expressing high levels of MITF. Collectively, these data confirm the critical role of the p300-MITF-FOXM1 axis in melanoma and support p300 as a promising novel epigenetic therapeutic target in human melanoma. SIGNIFICANCE: These results show that MITF is a major downstream target of p300 in human melanoma whose expression is predictive of melanoma response to small-molecule inhibition of p300 HAT activity.

Emerging Biomarkers in Cutaneous Melanoma.

Earlier identification of aggressive melanoma remains a goal in the field of melanoma research. With new targeted and immune therapies that have revolutionized the care of patients with melanoma, the ability to predict progression and monitor or predict response to therapy has become the new focus of research into biomarkers in melanoma. In this review, promising biomarkers are highlighted. These biomarkers have been used to diagnose melanoma as well as predict progression to advanced disease and response to therapy. The biomarkers take various forms, including protein expression at the level of tissue, genetic mutations of cancer cells, and detection of circulating DNA. First, a brief description is provided about the conventional tissue markers used to stage melanoma, including tumor depth. Next, protein biomarkers, which provide both diagnostic and prognostic information, are described. This is followed by a discussion of important genetic mutations, microRNA, and epigenetic modifications that can provide therapeutic and prognostic material. Finally, emerging serologic biomarkers are reviewed, including circulating melanoma cells and exosomes. Overall the goal is to identify biomarkers that aid in the earlier identification and improved treatment of aggressive melanoma.

DNA damage in Mexican women with cervical dysplasia evaluated by comet assay.

OBJECTIVE: To investigate the association between the progressive stage of cervical dysplasia and DNA damage by comet assay. STUDY DESIGN: A hospital-based, unmatched, case-control study was performed. DNA damage levels (none, low, medium and high) in the cervical epithelial cells of 31 women (10 with low grade squamous intraepithelial lesions [LSIL], 10 with high grade [HSIL] and 11 with no cervical lesion) were evaluated using the comet assay. RESULTS: A significant increase in medium DNA damage was observed in women with HSIL (17 +/- 8.9) relative to that in the control women (9 +/- 6.1). A significant increase in high DNA damage was also observed in women with LSIL (23 +/- 15.4) or HSIL (32 +/- 13.1) relative to that in the control women (12 +/- 7.9). CONCLUSION: These findings confirm that the grade of a cervical lesion correlates with the degree of genomic instability.

Maltrato infantil: experiencia multidisciplinaria unidad de salud mental Hospital General Pediátrico Niños de Acosta Ñú / Child abuse: the experience of the multi-disciplinary mental health unit of the Niños de Acosta Ñú General Pediatric Hospital

El Maltrato Infantil ocupa el cuarto lugar en frecuencia de diagnósticos del total de consultas de la Unidad de Salud Mental según un estudio previo realizado en el Hospital General Pediátrico, y le siguen los trastornos del aprendizaje, del estado ánimo y conductuales. Este estudio tiene como objetivo describir las características epidemiológicas, los motivos de consultas más frecuentes y los diagnósticos asociados al maltrato infantil. Se revisaron 1356 fichas clínicas, período Julio 2001-Setiembre 2009. Correspondió al sexo Masculino (45%) Femenino (55%). El grupo de edades mas afectado estuvo entre los 4-14 años (56.5%), las víctimas procedían en su mayoría del Departamento Central (77%). La negligencia o abandono fue el tipo de maltrato más frecuente (51%), seguido del Abuso Sexual (18.3%). Las víctimas fueron maltratadas con mayor frecuencia por ambos padres (38%), padre (16%) y madre (14%); representando un total de (68%). Conocía al agresor en un (99%). Los casos fueron referidos en mayor porcentaje del Consultorio Externo (19%). Consultó por síntomas depresivos (26.8 %); mientras que (8%) por intentos de suicidio y (11, 3%) por violencia intrafamiliar. Los diagnósticos más frecuentes asociados al maltrato infantil fueron los trastornos depresivos (60.5%), seguido de trastornos del comportamiento y de la atención (7.7%). Se concluye que la presencia de trastornos depresivos o síntomas depresivos con o sin intento de suicidio deberían alertar al pediatra a la sospecha de maltrato infantil.

Child abuse is the fourth most commonly diagnosed condition for patients seen at the mental health unit according to a previous study done at the general pediatric hospital, following only learning, mood, and behavior disorders. The objective of our study was to describe the epidemiological characteristics, most frequent motives for consultation, and diagnoses associated with child abuse. We reviewed 1356 medical records covering the period of July 2001 to September 2009, of which 45% were for male and 55% for female patients. The most affected age group were those from ages 4-14 years (56.5%), with most victims (77%) being from the country's Central Department. Negligence or abandonment were the most common types of abuse (51%), followed by sexual abuse (18.3%). Victims were mistreated in a plurality of cases (38%) by both parents, by the father alone in 16% and by the mother alone in 14%, with these categories jointly making up 68% of the total cases. In 99% of cases the child knew the abuser. A plurality of cases (19%) were referred for treatment by the institution's own outpatient clinic. Of all cases examined, 26.8% consulted for symptoms of depression, while attempted suicide motivated 8% of consultations, and domestic violence 11.3%. Diagnoses most commonly associated with child abuse were depressive disorders (60.5%), followed by behavior or attention deficit disorders (7.7%). It is concluded that the presence of depressive disorders or symptoms with or without suicide attempts should alert the pediatrician to suspect child abuse.

Manejo odontopediatrico integral en distonia orofacial infantil: caso reporte / Integral odontopediatric management in patients with cerebral palsy

Se revisa el caso de un niño de 12 años de edad con paralisis cerebral discinética, quien es referido para el manejo de toxina botulínica en la musculatura masticatoria por presentar retracción y dificultad en la apertura mandibular bilateral. Se evaluó por procedimientos odontológicos presentando una apertura mandibular de 4 mm lo que imposibilitaba el uso de guarda oclusal ortodónsico. Se aplicó toxina botulínica tipo A mediante monitoreo electromiográfico, obteniendo mejoría en la apertura hasta 15 mm que permitió la colocación de la órtesis bucal. La toxina botulínica en los desórdenes orofaciales distónicos puede mejorar la alineación y apertura mandibular evitando así el desarollo de complicaciones relacionadas con la articulación témporomandibular.

Avaliaçao da amplitude de movimento e força da cintura escapular em pacientes de pós-operatório tardio de mastectomia radical modificada / Shoulder motion range and strength assessment in late post-operative patients having undergone modified radical mastectomy

O câncer de mama é a neoplasia que mais afeta as mulheres e a cirurgia tem sido o tratamento de escolha, que pode assumir vários graus, até mastectomia radical modificada e alargada.Após a cirurgia, podem surgir sequelas como alterações na amplitude articular do ombro homolateral...

Breast cancer is the most frequent neoplasm among women; it is traditionally treated by surgery ranging from quadrantectomy to widened modified radical mastectomy, of which common sequels are changes in articular range of motion, muscle strength decrease, lymphedema, and...