DNA repair, genome stability and cancer: a historical perspective

The multistep process of cancer progresses over many years. The prevention of mutations by DNA repair pathways led to an early appreciation of a role for repair in cancer avoidance. However, the broader role of the DNA damage response (DDR) emerged more slowly. In this Timeline article, we reflect on how our understanding of the steps leading to cancer developed, focusing on the role of the DDR. We also consider how our current knowledge can be exploited for cancer therapy

Clinical anticancer drug development: targeting the cyclin-dependent kinases

Cell division involves a cyclical biochemical process composed of several step-wise reactions that have to occur once per cell cycle. Dysregulation of cell division is a hallmark of all cancers. Genetic and epigenetic mechanisms frequently result in deranged expression and/or activity of cell-cycle proteins including the cyclins, cyclin-dependent kinases (Cdks), Cdk inhibitors and checkpoint control proteins. The critical nature of these proteins in cell cycling raises hope that targeting them may result in selective cytotoxicity and valuable anticancer activity

Transurethral high-intensity ultrasound for treatment of stress urinary incontinence (SUI): simulation studies with patient-specific models

BackgroundStress urinary incontinence (SUI) is prevalent in adult women, attributed to weakened endopelvic supporting tissues, and typically treated using drugs and invasive surgical procedures. The objective of this in silico study is to explore transurethral high-intensity ultrasound for delivery of precise thermal therapy to the endopelvic tissues adjacent to the mid-urethra, to induce thermal remodeling as a potential minimally invasive treatment alternative.Methods3D acoustic (Rayleigh-Sommerfeld) and biothermal (Pennes bioheat) models of the ultrasound applicator and surrounding tissues were devised. Parametric studies over transducer configuration [frequency, radius-of-curvature (ROC)] and treatment settings (power, duration) were performed, and select cases on patient-specific models were used for further evaluation. Transient temperature and thermal dose distributions were calculated, and temperature and dose metrics reported.ResultsConfigurations using a 5-MHz curvilinear transducer (3.5 × 10 mm, 28 mm ROC) with single 90 s sonication can create heated zones with 11 mm penetration (>50 °C) while sparing the inner 1.8 mm (<45 °C) radial depth of the urethral mucosa. Sequential and discrete applicator rotations can sweep out bilateral coagulation volumes (1.4 W power, 15° rotations, 600 s total time), produce large volumetric (1124 mm³ above 60 EM43 °C) and wide angular (∼50.5° per lateral sweep) coverage, with up to 15.6 mm thermal penetration and at least 1.6 mm radial urethral protection (<5 EM43 °C).ConclusionTransurethral applicators with curvilinear ultrasound transducers can deliver spatially selective temperature elevations to lateral mid-urethral targets as a possible means to tighten the endopelvic fascia and adjacent tissues

The CDK inhibitors in cancer research and therapy

Chemical compounds that interfere with an enzymatic function of kinases are useful for gaining insight into the complicated biochemical processes in mammalian cells. Cyclin-dependent kinases (CDK) play an essential role in the control of the cell cycle and/or proliferation. These kinases as well as their regulators are frequently deregulated in different human tumors. Aberrations in CDK activity have also been observed in viral infections, Alzheimer’s, Parkinson’s diseases, ischemia and some proliferative disorders. This led to an intensive search for small-molecule CDK inhibitors not only for research purposes, but also for therapeutic applications. Here, we discuss seventeen CDK inhibitors and their use in cancer research or therapy. This review should help researchers to decide which inhibitor is best suited for the specific purpose of their research. For this purpose, the targets, commercial availability and IC50 values are provided for each inhibitor. The review will also provide an overview of the clinical studies performed with some of these inhibitors

Aleitamento materno exclusivo e adiposidade Amamantamiento materno exclusivo y adiposidad Exclusive breastfeeding and adiposity

OBJETIVO: Associar o tempo de amamentação exclusiva da criança à adiposidade central e periférica, por meio do índice de massa corporal, dos perímetros da cintura e do braço, e das dobras cutâneas triciptal, subescapular e a somatória destas em pré-escolares. MÉTODOS: Pesquisa de delineamento transversal, em que 134 pré-escolares entre três e cinco anos de idade de uma escola par-ticular de Brasília, DF, foram avaliados quanto a: massa corporal, estatura, perímetros do braço e da cintura, dobras cutâneas triciptal e subescapular. Os pais das crianças responderam a um questionário sobre tempo de amamentação. O diagnóstico de sobrepeso e obe-sidade foi realizado de acordo com a classificação da Organização Mundial da Saúde para o índice de massa corporal por idade. RESULTADOS: As meninas tiveram maior concentração adiposa na dobra cutânea triciptal (p=0,001), subescapular (p=0,044) e na somatória destas (p=0,003) em relação aos meninos. A prevalência de sobrepeso e obesidade foi similar nos dois sexos (25,4% nos meninos e 22,6% nas meninas), assim como o tempo médio de amamentação exclusiva (4,3 meses para meninos e 4,6 meses para meninas). Notou-se correlação inversa significativa entre tempo de amamentação exclusiva e perímetro da cintura (r=-0,166; p=0,05). As demais variáveis também mostraram tendência de correlação inversa com o tempo de aleitamento materno exclusivo, porém sem valores significativos. CONCLUSÕES: A associação inversa entre o tempo de ama-mentação e o perímetro da cintura mostra um possível efeito do aleitamento materno sobre a distribuição de gordura corporal no pré-escolar.<br>OBJETIVO: Asociar el tiempo de amamantamiento exclusivo del niño con la adiposidad central y periférica mediante el índice de masa corporal, perímetros de la cintura y del brazo, y pliegues cutáneos ticipital, subescapular y la suma de estos en pre-escolares. MÉTODOS: Investigación de delineación transversal, en la que 134 pre-escolares entre 3 y 5 años de edad de una escuela privada de Brasilia, Brasil, fueron evaluados respecto a: masa corporal, estatura, perímetros del brazo y de la cintura, pliegues cutáneos tricipital y subescapular. Los padres de los niños contestaron a un cuestionario sobre el tiempo de amamantamiento. El diagnóstico de sobrepeso y obesidad fue realizado conforme a la clasificación de la Organización Mundial de la Salud para el índice de masa corporal por edad. RESULTADOS: Las niñas tuvieron mayor concentración adiposa en el pliegue cutáneo tricipital (p=0,001), subescapular (p=0,044) y en la suma de éstos (p=0,003) respecto a los niños. La prevalencia de sobrepeso y obesidad fue similar en los dos sexos (25,4% en los niños y 22,6% en las niñas), así como el tiempo mediano de amamantamiento exclusivo (4,3 meses para niños y 4,6 meses para niñas). Se notó correlación inversa significativa entre tiempo de amamantamiento exclusivo y perímetro de la cintura (r=-0,166; p=0,05). Las otras variables también mostraron tendencia de correlación inversa con el tiempo de amamantamiento materno exclusivo, pero sin valores significativos. CONCLUSIONES: La asociación inversa entre el tiempo de amamantamiento y el perímetro de la cintura muestra un posible efecto del amamantamiento materno sobre la distribución de grasa corporal en el pre-escolar.<br>OBJECTIVE: To associate exclusive breastfeeding with central and peripheral adiposity measured by body mass index, waist and arm circumferences, triceps and subscapular skinfolds and their sum in preschool children. METHODS: This cross-sectional study enrolled 134 preschool children aged 3-5 years from a private school in Brasília, Brazil. All children had their body weight, height, waist and arm circumferences, and triceps and subscapular skinfolds measured. Children's parents an-swered a questionnaire about breastfeeding duration. Overweight and obesity were diagnosed based on the World Health Organization's classification for the body mass index for age. RESULTS: Girls had higher adiposity in the triceps skinfold (p=0.001), subscapular skinfold (p=0.044) and in their sum (p=0.003), when compared to boys. Prevalence of overweight and obesity was similar between genders (25.4% for boys and 22.6% for girls), as it was exclusive breastfeeding (4.3 months for boys and 4.6 months for girls). A significant inverse correlation was found only between exclusive breastfeeding and waist circumference (r=-0.166; p=0.05). Other anthropometric variables showed a trend to present an inverse correlation with exclusive breastfeeding, but lacked statistical significance. CONCLUSIONS: The significant inverse association between exclusive breastfeeding and waist circumference indicates a possible effect of breastfeeding in body fat distribution in preschool children