Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:6.3.5.5 (CPS)
 1,262 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As a member of the Cancer Intervention and Surveillance Modeling Network (CISNET), the lung cancer (LC) group at Fred Hutchinson Cancer Research Center (FHCRC) developed a model for evaluating U.S. lung cancer mortality trends and the impact of changing tobacco consumption. Model components include a biologically based two-stage clonal expansion (TSCE) model; a smoking simulator to generate smoking histories and other cause mortality; and adjustments for period and birth cohort to improve calibration to U.S. LC mortality. The TSCE model was first calibrated to five substantial cohorts: British doctors, American Cancer Society CPS-I and CPS-II, Health Professionals' Follow-Up Study (HPFS), and Nurses' Health Study (NHS). The NHS and HPFS cohorts included the most detailed smoking histories and were chosen to represent the effects of smoking on U.S. LC mortality. The calibrated TSCE model and smoking simulator were used to simulate U.S. LC mortality. Further adjustments were necessary to account for unknown factors. This provided excellent fits between simulated and observed U.S. LC mortality for ages 30-84 and calendar years 1975-2000. The FHCRC LC model may be used to study the effects of public health information on U.S. LC trends and the impact of tobacco control policy. For example, we estimated that over 500,000 males and 200,000 females avoided LC death between 1975 and 2000 due to increasing awareness since the mid 1950s of the harmful effects of smoking. We estimated that 1.1 million male and 0.6 million female LC deaths were avoidable if smokers quit smoking in 1965.
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PMID:Chapter 8: The FHCRC lung cancer model. 2288 96

Radon is a known cause of human lung cancer. Previously, the authors observed a significant positive association between mean county-level residential radon concentrations and lung cancer mortality in the Cancer Prevention Study II (CPS-II), a large prospective study of nearly 1.2 million participants recruited in 1982 by the American Cancer Society. There was also a significant positive association with mortality from chronic obstructive pulmonary disease. Because it is unclear whether radon is associated with mortality from other malignant or nonmalignant disease, the authors examined the association between radon and nonrespiratory mortality in the CPS-II. Mean county-level residential radon concentrations (mean = 53.5 (standard deviation: 38.0) Bq/m(3)) were linked to participants by their zip code at enrollment. Cox proportional hazards regression models were used to estimate adjusted hazard ratios and 95% confidence intervals for all-cause (excluding lung cancer and respiratory mortality) and cause-specific mortality associated with radon concentrations. A total of 811,961 participants in 2,754 counties were analyzed, including 265,477 deaths through 2006. There were no clear associations between radon and nonrespiratory mortality in the CPS-II. These findings suggest that residential radon is not associated with any other mortality beyond lung cancer or chronic obstructive pulmonary disease.
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PMID:Radon and nonrespiratory mortality in the American Cancer Society cohort. 2304 72

Metabolic reprogramming by oncogenic signals promotes cancer initiation and progression. The oncogene KRAS and tumour suppressor STK11, which encodes the kinase LKB1, regulate metabolism and are frequently mutated in non-small-cell lung cancer (NSCLC). Concurrent occurrence of oncogenic KRAS and loss of LKB1 (KL) in cells specifies aggressive oncological behaviour. Here we show that human KL cells and tumours share metabolomic signatures of perturbed nitrogen handling. KL cells express the urea cycle enzyme carbamoyl phosphate synthetase-1 (CPS1), which produces carbamoyl phosphate in the mitochondria from ammonia and bicarbonate, initiating nitrogen disposal. Transcription of CPS1 is suppressed by LKB1 through AMPK, and CPS1 expression correlates inversely with LKB1 in human NSCLC. Silencing CPS1 in KL cells induces cell death and reduces tumour growth. Notably, cell death results from pyrimidine depletion rather than ammonia toxicity, as CPS1 enables an unconventional pathway of nitrogen flow from ammonia into pyrimidines. CPS1 loss reduces the pyrimidine to purine ratio, compromises S-phase progression and induces DNA-polymerase stalling and DNA damage. Exogenous pyrimidines reverse DNA damage and rescue growth. The data indicate that the KL oncological genotype imposes a metabolic vulnerability related to a dependence on a cross-compartmental pathway of pyrimidine metabolism in an aggressive subset of NSCLC.
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PMID:CPS1 maintains pyrimidine pools and DNA synthesis in KRAS/LKB1-mutant lung cancer cells. 3104 37


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