Cancer cells often require glutamine for growth, thereby distinguishing them from most normal cells. Here we show that PIK3CA mutations reprogram glutamine metabolism by upregulating glutamate pyruvate transaminase 2 (GPT2) in colorectal cancer (CRC) cells, making them more dependent on glutamine. Compared with isogenic wild-type (WT) cells, PIK3CA mutant CRCs convert substantially more glutamine to α-ketoglutarate to replenish the tricarboxylic acid cycle and generate ATP. Mutant p110α upregulates GPT2 gene expression through an AKT-independent, PDK1–RSK2–ATF4 signalling axis. Moreover, aminooxyacetate, which inhibits the enzymatic activity of aminotransferases including GPT2, suppresses xenograft tumour growth of CRCs with PIK3CA mutations, but not with WT PIK3CA. Together, these data establish oncogenic PIK3CA mutations as a cause of glutamine dependency in CRCs and suggest that targeting glutamine metabolism may be an effective approach to treat CRC patients harbouring PIK3CA mutations.

Background— The South Bay Heart Watch is a prospective cohort study designed to appraise the value of coronary calcium and risk factors for predicting outcomes in asymptomatic adults. Two factors that may be related to subsequent cardiovascular events are coronary calcium (CAC, a manifestation of subclinical atherosclerosis) and high-sensitivity C-reactive protein (CRP, a measure of chronic inflammation). Methods and Results— Between December 1990 and December 1992, 1461 participants without coronary heart disease underwent baseline risk factor screening, computed tomography for CAC, and measurement of CRP. Participants were followed up for 6.4±1.3 years. Cox regression analyses were conducted for the 967 nondiabetics with CRP levels ≤10 mg/L to estimate the risk-factor–adjusted relative risks of CAC and CRP for the occurrence of (1) nonfatal myocardial infarction (MI) or coronary death and (2) any cardiovascular event (MI, coronary death, coronary revascularization, or stroke). CAC was a predictor of both end points ( P <0.005), and CRP was a predictor of any cardiovascular event ( P =0.03). Risk group analysis defined by tertiles for CAC (<3.7, 3.7 to 142.1, >142.1) and the 75th percentile for CRP (>4.05 mg/L) indicated that there was increasing risk with increasing calcium and CRP. Relative risks for the medium-calcium/low-CRP risk group to high-calcium/high-CRP risk group ranged from 1.8 to 6.1 for MI/coronary death ( P =0.003) and 2.8 to 7.5 for any cardiovascular event ( P <0.001). Conclusions— Participants without diabetes and those at intermediate risk may benefit from risk stratification based on high-sensitivity CRP levels and CAC, because both factors contribute independently toward the incidence of cardiovascular events.

OBJECTIVE -The South Bay Heart Watch is a cohort study designed to determine the significance of coronary calcium in high-risk asymptomatic patients. This is a report of the relative risk (RR) for outcomes of coronary artery calcium in diabetic and nondiabetic subjects.RESEARCH DESIGN AND METHODS -A total of 1,312 diabetic and nondiabetic subjects underwent risk factor screening and computed tomography testing for coronary calcium at baseline and were followed clinically for 6.3 Ϯ 1.4 years. End points were either 1) hard events of nonfatal myocardial infarction (MI) or coronary death or 2) any cardiovascular event (nonfatal MI, coronary death, coronary revascularization, or stroke).RESULTS -The incidence rates of a hard event and any cardiovascular event for diabetic and nondiabetic subjects were 14.5 and 6.1% and 23.8 and 12.2%, respectively (P Ͻ 0.001). Cox regression analyses of the combined risk relationship of diabetes status and calcium score demonstrated that relative to nondiabetic subjects with low calcium scores (Ͻ2.8), diabetic subjects with calcium scores Ն2.8 exhibited at least a fourfold increase in the risk of either a hard or any cardiovascular event (P Ͻ 0.001). Cox regression analyses conducted separately for nondiabetic and diabetic subjects revealed that coronary calcium score risk groups were significantly associated with events in nondiabetic subjects (RR Ն 2.6, P Յ 0.01), but not in diabetic subjects (RR Յ 1.7, P Ͼ 0.05).CONCLUSIONS -The risk of coronary heart disease increases with increasing calcium scores and diabetes status. Calcium scores have less prognostic value in diabetic subjects. Diabetes Care 26:905-910, 2003

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Pooled analyses of these geographically diverse case-control data indicate a reduced thyroid cancer risk associated with current smoking. A reduced risk associated with alcohol was eliminated after adjustment for smoking, and caffeinated beverages did not alter thyroid cancer risk.