Twist1 Suppresses Senescence Programs and Thereby Accelerates and Maintains Mutant Kras-Induced Lung Tumorigenesis

KRAS mutant lung cancers are generally refractory to chemotherapy as well targeted agents. To date, the identification of drugs to therapeutically inhibit K-RAS have been unsuccessful, suggesting that other approaches are required. We demonstrate in both a novel transgenic mutant Kras lung cancer mouse model and in human lung tumors that the inhibition of Twist1 restores a senescence program inducing the loss of a neoplastic phenotype. The Twist1 gene encodes for a transcription factor that is essential during embryogenesis. Twist1 has been suggested to play an important role during tumor progression. However, there is no in vivo evidence that Twist1 plays a role in autochthonous tumorigenesis. Through two novel transgenic mouse models, we show that Twist1 cooperates with KrasG12D to markedly accelerate lung tumorigenesis by abrogating cellular senescence programs and promoting the progression from benign adenomas to adenocarcinomas. Moreover, the suppression of Twist1 to physiological levels is sufficient to cause Kras mutant lung tumors to undergo senescence and lose their neoplastic features. Finally, we analyzed more than 500 human tumors to demonstrate that TWIST1 is frequently overexpressed in primary human lung tumors. The suppression of TWIST1 in human lung cancer cells also induced cellular senescence. Hence, TWIST1 is a critical regulator of cellular senescence programs, and the suppression of TWIST1 in human tumors may be an effective example of pro-senescence therapy

7th Drug hypersensitivity meeting: part two

No abstract availabl

Prevalence of Parkinson disease in an urban area of the Ciudad de La Habana province, Cuba. Door-to-door population study

To determine the prevalence of Parkinson's disease in an urban area of Havana City province, Cuba. Parkinson's disease is one of the most frequent chronic neurodegenerative diseases in the elderly. Prevalence varies widely between different geographic areas and type of studies. To the author's knowledge, there are not epidemiological data on Parkinson's disease in Cuban population that allows a real estimation of the true magnitude of the disease. A "door-to-door" population study was carried out between November and December 1997. The area total population aged 15 years and over (n = 17.784) was interviewed and examined during the first phase of the study. This phase was performed by the 33 family doctors practicing in that area. An experienced neurologist previously trained the family doctors on making Parkinson's disease diagnosis. Diagnosis was based on the Brain Bank Society criteria. In order to make a definitive diagnosis of Parkinson's disease every subject that received such a diagnosis during the first phase was re-evaluated by two experienced neurologists. Those subjects with final diagnosis of Parkinson's disease were asked about family history of the disease. Prevalence rates were calculated according to sex, age group, color of the skin and smoking status. A total of 24 subjects received the final diagnosis of Parkinson's disease, yielding a population prevalence rate of 135 x 100,000 inhabitants. Eight subjects (33.3%) received a diagnosis of Parkinson's disease for the first time (de novo cases). Subjects with white color of the skin and non-smoking subjects showed a statistically significant higher prevalence of Parkinson's disease than subjects with non-white color of the skin and non-smokers respectively. Only 3 (12.5%) subjects reported a family history of Parkinson's disease. The population of this area has a low prevalence rate of Parkinson's disease compared to that reported in other populations. The observed low frequency of family history of the disease suggests that the main determinants of Parkinson's disease are environmental factors yet to be identified

Application of a topical vapocoolant spray decreases pain at the site of initial intradermal anaesthetic injection during ultrasound-guided breast needle biopsy

To assess whether the application of a topical vapocoolant spray immediately prior to initial intradermal anaesthetic injection during ultrasound-guided breast biopsy decreases pain at the site of the initial injection. In this institutional review board-approved, Health Insurance Portability and Accountability Act (HIPAA)-compliant study, 50 women aged 49.1 ± 1.6 years (mean ± standard error) were recruited and provided written informed consent. Participants served as their own controls and were blinded as to whether a topical vapocoolant spray or a placebo was used immediately prior to the initial local anaesthetic injection at two separate biopsy sites. With the exception of the application of vapocoolant or placebo, the entire ultrasound-guided procedure was performed according to a routine protocol. Participants recorded pain at initial injection site on a visual analogue scale. General linear mixed models for repeated measures analysis of variance and a 0.05 significance level were used. Application of topical vapocoolant spray was shown to significantly decrease pain at the site of initial intradermal anaesthetic injection as compared to placebo (p<0.001). Treatment effect was independent of age of the subject, race/ethnicity, operator, type of biopsy device, and histopathology result. No complications from vapocoolant spray use were reported. Application of a topical vapocoolant spray immediately prior to initial intradermal anaesthetic injection during ultrasound-guided breast biopsy significantly decreases pain at the site of the initial injection and could contribute to improve the patient's overall procedural experience