Summary
Increased androgen receptor (AR) activity drives therapeutic resistance in advanced prostate cancer. The most common resistance mechanism is amplification of this locus presumably targeting the AR gene. Here, we identify and characterize a somatically acquired AR enhancer located 650 kilobases centromeric to the AR. Systematic perturbation of this enhancer using genome editing decreased proliferation by suppressing AR levels. Insertion of an additional copy of this region sufficed to increase proliferation under low androgen conditions and to decrease sensitivity to enzalutamide. Epigenetic data generated in localized prostate tumors and benign specimens support the notion that this region is a developmental enhancer. Collectively, these observations underscore the importance of epigenomic profiling in primary specimens and the value of deploying genome editing to functionally characterize noncoding elements. More broadly, this work identifies a therapeutic vulnerability for targeting the AR and emphasizes the importance of regulatory elements as highly recurrent oncogenic drivers.
Long-term survival with esophageal cancer is poor but survival of local esophageal cancer improved dramatically over the decades. Complete cure of nonmetastatic esophageal cancer seems possible in a growing number of patients. Early diagnosis and treatment are crucial.
A survey was conducted in order to gain current information on flea species (Siphonaptera: Pulicidae) infesting dogs and cats living in urban and rural areas of Hungary, along with data on the factors that affect the presence, distribution and seasonality of infestation. In addition, owner awareness of flea infestation was evaluated. Practitioners in 13 veterinary clinics were asked to examine all dogs and cats attending the clinic and to collect fleas, when present, on 2 days in each month from December 2005 to November 2006. They also completed a questionnaire for each animal examined. A total of 319 dogs (14.1%) were found to be infested; the highest prevalence (27.1%) of infestation on dogs occurred in August and the lowest (5.4%) in May. Prevalence of fleas on cats was higher (22.9%); the highest (35.0%) and lowest (8.1%) prevalences occurred in July and April, respectively. Fleas were more prevalent in rural (387/1924 animals, 20.2%) than in urban (161/1343 animals, 12.0%) areas. Three species, Ctenocephalides felis (Bouché), Ctenocephalides canis (Curtis) and Pulex irritans L., were found. On dogs, the prevalence of C. canis alone was 53.0%, whereas that of C. felis alone was 36.0%. Only 19 specimens of P. irritans were found on 14 dogs from rural habitats only. Prevalence of C. felis only on cats was 94.3%; the remaining cats were infested with either C. canis or with mixed infestations of C. felis and C. canis. More than half (51.4%) of the owners of infested dogs and cats had not used flea control products in the past year or more, and five times as many owners in rural than urban areas had not used flea control products in the same period. Very few owners reported having attempted to kill fleas in their animals' environment; instead, they believed that fleas were acquired from other cats or dogs.
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