ABSTRACT
Deregulated AKT kinase activity due to PTEN deficiency in cancer cells contributes to oncogenesis by incompletely understood mechanisms. Here, we show that PTEN deletion in HCT116 and DLD1 colon carcinoma cells leads to suppression of CHK1 and CHK2 activation in response to irradiation, impaired G2 checkpoint proficiency and radiosensitization. These defects are associated with reduced expression of MRE11, RAD50 and NBS1, components of the apical MRE11/RAD50/NBS1 (MRN) DNA damage response complex. Consistent with reduced MRN complex function, PTEN-deficient cells fail to resect DNA double-strand breaks efficiently after irradiation and show greatly diminished proficiency for DNA repair via the error-free homologous recombination (HR) repair pathway. MRE11 is highly unstable in PTEN-deficient cells but stability can be significantly restored by inhibiting mTORC1 or p70S6 kinase (p70S6K), downstream kinases whose activities are stimulated by AKT, or by mutating a residue in MRE11 that we show is phosphorylated by p70S6K in vitro. In primary human fibroblasts, activated AKT suppresses MRN complex expression to escalate RAS-induced DNA damage and thereby reinforce oncogene-induced senescence. Taken together, our data demonstrate that deregulation of the PI3K-AKT/ mTORC1/ p70S6K pathways, an event frequently observed in cancer, exert profound effects on genome stability via MRE11 with potential implications for tumour initiation and therapy.
Subject(s)
Genomic Instability/genetics , MRE11 Homologue Protein/genetics , Neoplasms/genetics , PTEN Phosphohydrolase/deficiency , Recombinational DNA Repair/genetics , DNA Damage/radiation effects , Down-Regulation , Fibroblasts , Gene Expression Regulation, Neoplastic/radiation effects , Genomic Instability/radiation effects , HCT116 Cells , Humans , MRE11 Homologue Protein/antagonists & inhibitors , MRE11 Homologue Protein/metabolism , Mechanistic Target of Rapamycin Complex 1/genetics , Mechanistic Target of Rapamycin Complex 1/metabolism , Neoplasms/radiotherapy , PTEN Phosphohydrolase/genetics , Phosphorylation , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Pyrimidinones/pharmacology , RNA, Small Interfering/metabolism , Radiation Tolerance/genetics , Recombinational DNA Repair/radiation effects , Ribosomal Protein S6 Kinases, 70-kDa/antagonists & inhibitors , Ribosomal Protein S6 Kinases, 70-kDa/genetics , Ribosomal Protein S6 Kinases, 70-kDa/metabolism , Signal Transduction/genetics , Thiones/pharmacology , X-Rays/adverse effectsABSTRACT
BACKGROUND: Urinary tract infection (UTI) is the most common infection experienced by humans after respiratory and gastro-intestinal infections, and also the most common cause of nosocomial infections for patients admitted to hospitals indeed UTIs are the most frequent bacterial infection in women. AIM: The aim was to determine the prevalence of UTI and to identify factors associated with an increased risk of UTI among nursing students. SUBJECTS AND METHODS: The cross-sectional study involved 177 unmarried nursing students aged 18-30 years studying in the SRMSIMS, Nursing College Bareilly. A structured questionnaire was used, and study subjects were asked regarding the symptoms of UTI in the previous 3 months. Chi-square test and Univariate Logistic Regression was used to analyze the data. RESULTS: The overall prevalence of UTI was found to be 19.8% (35/177). Rural background, inadequate water intake, and unsatisfactory toilet habits were found to be strong predictors of UTI. CONCLUSIONS: There is an urgent need to sensitize the nursing students regarding the growing need of the issue so that they themselves become aware in addition to raising the awareness of other high-risk groups.
ABSTRACT
Ethambutol (20 mg/kg) was administered orally to 10 patients of pulmonary tuberculosis for seven consecutive days at 8 a.m. after over night fast. On 7th day serum levels were measured at 2, 4, 6, 8 and 24 hr intervals and urinary excretion was estimated at 2, 4, 6 and 24 hr following ethambutol administration. Simultaneous administration of isoniazid (300 mg, orally) for next seven days to the same patients significantly raised the serum levels of ethambutol at 4, 6 and 8 hr and the cumulative per cent dose excreted was decreased significantly at 4, 6 and 24 hr. The serum levels and urinary elimination was not significantly different at 2 hr.
