Systematic integration of molecular profiles identifies miR-22 as a regulator of lipid and folate metabolism in breast cancer cells.

Dysregulated microRNA (miRNA) mediate malignant phenotypes, including metabolic reprogramming. By performing an integrative analysis of miRNA and metabolome data for the NCI-60 cell line panel, we identified an miRNA cluster strongly associated with both c-Myc expression and global metabolic variation. Within this cluster the cancer-associated and cardioprotective miR-22 was shown to repress fatty acid synthesis and elongation in tumour cells by targeting ATP citrate lyase and fatty acid elongase 6, as well as impairing mitochondrial one-carbon metabolism by suppression of methylene tetrahydrofolate dehydrogenase/cyclohydrolase. Across several data sets, expression of these target genes were associated with poorer outcomes in breast cancer patients. Importantly, a beneficial effect of miR-22 on clinical outcomes in breast cancer was shown to depend on the expression levels of the identified target genes, demonstrating the relevance of miRNA/mRNA interactions to disease progression in vivo. Our systematic analysis establishes miR-22 as a novel regulator of tumour cell metabolism, a function that could contribute to the role of this miRNA in cellular differentiation and cancer development. Moreover, we provide a paradigmatic example of effect modification in outcome analysis as a consequence of miRNA-directed gene targeting, a phenomenon that could be exploited to improve patient prognosis and treatment.

Cavernous sinus syndrome due to metastatic renal cell carcinoma.

We describe a 49-year-old woman with a history of metastatic renal cell carcinoma and classic signs and symptoms of left-sided cavernous sinus syndrome. Magnetic resonance imaging showed a lesion in the left cavernous sinus consistent with metastatic renal cell carcinoma. The patient received radiation therapy totaling 4,600 cGy, with complete resolution of symptoms. This represents the first case report of renal cell carcinoma metastatic to the left cavernous sinus.

Transhiatal and transthoracic esophagectomy: a comparative study.

From January 1981 to December 1990, 55 consecutive patients underwent esophageal resection by either the transhiatal (THE, 26 patients) or transthoracic (TTE, 29 patients) approach. Patient age, tumor size, and tumor stage were similar in the two groups. THE patients had a significantly worse mean preoperative American Society of Anesthesiologists (ASA) risk class assigned by the anesthesiologist. Patients who underwent THE had a significantly lower operative mortality and rate of cardiopulmonary complications, significantly shorter intensive care unit and hospital length of stay, and a significantly better postoperative survival when operative deaths are included in the analysis. Operative deaths in the TTE group were concentrated among patients > 65 years of age (4 of 9 died), in an ASA risk class > or = III (3 of 7 died) or with moderate or severe cardiac or pulmonary impairment preoperatively (4 of 6 died).

Effects of a vitamin-A-free diet on tissue vitamin A concentration and dark adaptation of aging rats.

Changes in serum, hepatic, and ocular vitamin A levels were followed in 9-month-old Long Evans rats fed either a vitamin-A-free or vitamin-A-sufficient diet for up to 18 months. After 18 months, hepatic total vitamin A fell exponentially from 2542 +/- 433 to 48 +/- 12 micrograms/g wet weight, but these stores maintained normal serum retinol and ocular total vitamin A concentrations in vitamin-A-deprived rats. However, retinal dark-adaptation time, a functional indicator of photoreceptor integrity, was prolonged in elderly vitamin-A-deprived rats as compared to vitamin-A-sufficient controls (p less than 0.05). Aging appeared to be the most important factor that depressed the rate of dark adaptation, with vitamin A status having a secondary effect. The proportion of total ocular retinaldehyde decreased (p less than 0.05) and the concentration of retinyl ester increased (p less than 0.05) in the eyes of 27-month-old vitamin-A-deprived rats compared to age-matched vitamin-A-sufficient animals. Possible mechanisms of visual dysfunction include abnormal retinal rhodopsin recycling caused by a dependence on newly absorbed dietary vitamin A (e.g., chylomicron). Alternatively, in the vitamin-A-deprived rat, decreased hepatic oxidation of pentobarbital (used for electroretinographic anesthesia) could prolong retinal anesthetic exposure and either directly depress neural transmission or indirectly alter transmission by affecting rhodopsin recycling.

Increased risk for vitamin A toxicity in severe hypertriglyceridemia.

A 48-year-old woman with malabsorption and type V hyperlipoproteinemia developed hypervitaminosis A with a total plasma vitamin A level of 871 micrograms/dL during therapy with an oral dosage of 18,000 retinol equivalents (60,000 IU) daily. Twelve percent of the total plasma retinol was found to be transported in the chylomicron-very low density lipoprotein (VLDL) fraction, which does not contain retinol-binding protein. For comparison, concentrations of retinyl esters and retinol were determined in nine patients with type V hyperlipoproteinemia and nine control subjects, none of whom were using vitamin A supplements. Both retinyl esters and retinol were significantly elevated in the group with hyperlipoproteinemia (p less than 0.0005 in both cases). Eight of these nine patients had retinol present in the chylomicron-VLDL fraction, whereas retinol was not detectable in this fraction in any of the nine normal controls. The data suggest that patients with severe hypertriglyceridemia associated with type V hyperlipoproteinemia are at increased risk for hypervitaminosis A.

Correlation between skeletal calcium mass and muscle mass in man.

The measurements of total body potassium (TBK) and calcium (TBCa) were made on 317 subjects by the techniques of whole-body counting and total-body neutron activation analysis (TBNAA), respectively. The TBK/TBCa ratios are constant for normals over the age range studied. The males have more cellular mass (TBK) per unit skeletal mass (TBCa) than the females, as indicated by their respective TBK/TBCa ratios, 0.122 +/- 0.008 (1 SD), and 0.100 +/- 0.007 (1 SD). In general, patients with various metabolic disorders tend to follow the physiological trend found in the normals. In a number of metabolic disorders, the loss of TBK was usually approximately 60% of that of the TBCa when expressed in terms of the predicted normal values. This suggests that the mechanism causing the loss of calcium in physiological and altered metabolic states simultaneously involves both the skeleton and its associated musculature.