Bmi1 promotes prostate tumorigenesis via inhibiting p16(INK4A) and p14(ARF) expression.

We report here that the polycomb group protein Bmi1 promotes prostate tumorigenesis. Bmi1 is detected at higher levels in androgen-independent PC3 and DU145 than in androgen-dependent LNCaP prostate cancer (CaP) cells. Ectopic Bmi1 enhanced the expression of human telomerase reverse transcriptase (hTERT) and suppressed the exression of p16(INK4A) and p14(ARF) in CaP cells. Consistent with these observations, immunohistochemical staining of 51 cases of primary CaP specimens revealed 1.4 fold (p=0.014) and 1.3 fold (p=0.051) higher levels of Bmi1-positive cells in carcinoma compared to normal prostatic epithelial cells and PIN, respectively. In primary CaPs, Bmi1 expression was associated with a reduction in p16(INK4A) and p14(ARF). Furthermore, in comparison to empty vector-transfected cells, Bmi1-expressing DU145 cells formed significantly larger tumors in NOD/SCID mice. Taken together, we demonstrate that Bmi1 promotes prostate tumorigenesis.

Co-existence of high levels of the PTEN protein with enhanced Akt activation in renal cell carcinoma.

Recruiting Akt to the membrane-bound phosphatidylinositol (3,4,5) trisphosphate (PIP3) is required for Akt activation. While PI3 kinase (PI3K) produces PIP3, PTEN dephosphorylates the 3-position phosphate from PIP3, thereby directly inhibiting Akt activation. PTEN is the dominant PIP3 phosphatase, as knockdown of PTEN results in increases in Akt activation in mice. The PTEN tumor suppressor gene is frequently mutated in a variety of human cancers, consistent with an inverse correlation between levels of the PTEN protein and Akt activation. We have examined PTEN expression and Akt activation in 35 primary clear cell renal cell carcinomas RCCs (ccRCCs) and 9 papillary RCCs (pRCCs) and their respective non-tumor kidney tissues. The PTEN protein was reduced in 16 ccRCCs (16/35=45.7%) and 8 pRCCs (8/9=88.9%). In these RCCs, 25.0% (4/16) of ccRCCs and 25.0% (2/8) of pRCCs expressed elevated Akt activation. 19 ccRCCc (19/35=54.3%) expressed comparable or higher levels of PTEN. Of these ccRCCs, 31.6% (6/19) showed increases in Akt activation. As PTEN dominantly inhibits Akt activation, the coexistence of high levels of the PTEN protein with enhanced Akt activation suggests the existence of novel mechanisms which attenuate PTEN function in ccRCC. These mechanisms may reduce PTEN function or increase PIP3 production.

ATM activation is accompanied with earlier stages of prostate tumorigenesis.

The ATM (ataxia telangiectasia mutated) kinase plays an essential role in maintaining genome integrity by coordinating cell cycle arrest, apoptosis, and DNA damage repair. Phosphorylation of ATM at serine 1981 (ATMpSer1981) by DNA damage activates ATM, which subsequently phosphorylates H2AX Ser139 (gammaH2AX), Chk2 Thr68 (Chk2pThr68), and p53 Ser15 (p53pSer15). To determine the role of the ATM pathway in prostate cancer tumorigenesis, we have analyzed 35 primary prostate cancer specimens for ATMpSer1981 (ATM activation), Chk2pThr68, gammaH2AX, and p53pSer15 by immunohistochemistry (IHC) in normal glands, prostatic intraepithelial neoplasias (PINs), and carcinomas. Increases in the intensities of ATMpSer1981, Chk2pThr68, and gammaH2AX and in the percentage of cells that are positive for ATMpSer1981, Chk2pThr68, or gammaH2AX were observed in PINs (p<0.001) compared to normal prostatic glands and carcinoma. However, this pattern of immunostaining was not seen for p53pSer15. Thus, ATM and Chk2 are specifically activated in PINs. As PINs are generally regarded as precursors of prostatic carcinoma, our results suggest that ATM and Chk2 activation at earlier stages of prostate tumorigenesis suppresses tumor progression, with attenuation of ATM activation leading to cancer progression.

Nutrient inadequacy in obese and non-obese youth.

PURPOSE: In this study, the Dietary Reference Intake standards were used to evaluate the prevalence of inadequate intakes of micronutrients in obese and non-obese youth. METHODS: Dietary intake was analyzed with a dietary history taken by a registered dietitian. The obese group (n=156) had a body mass index (BMI) above the 95th percentile for age and sex. The non-obese group (n=90) was between the tenth and 85th BMI percentiles. RESULTS: In the obese subjects, the prevalence of inadequate intakes was 81% for vitamin E and 27% for magnesium; the proportions with intakes below the Adequate Intakes (AIs) for calcium and vitamin D were 55% and 46%, respectively. The obese children consumed 124% of estimated need for energy, 32% of which came from fat. The non-obese had a similar prevalence of inadequate intakes (vitamin E, 93%; magnesium, 29%; calcium, 51%; vitamin D, 44%). They consumed 107% of estimated need for energy, and 31% of energy came from fat. For both groups, all other nutrient intakes were adequate. CONCLUSIONS: Even though children may consume an excess of energy, they may not be meeting all of their micronutrient needs.

Comparison of laparoscopic radical renal surgery in morbidly obese and non-obese patients.

BACKGROUND AND PURPOSE: Laparoscopic radical nephrectomy is rapidly becoming accepted as the preferred management of low-stage renal masses not amenable to partial nephrectomy. Minimally invasive surgery is advantageous to decrease perioperative and postoperative morbidity and allows patients to return to normal activities faster. Obesity has been a relative contraindication to this technique, and these patients have traditionally undergone open surgery. We present a review of 23 morbidly obese patients in comparison with patients who were not morbidly obese who underwent radical laparoscopic nephrectomy and nephroureterectomy at our institution. PATIENTS AND METHODS: Hospital charts between April 2001 and October 2003 were reviewed for morbidly obese patients undergoing transperitoneal laparoscopic renal surgery who were compared with age- and sex-matched control patients who underwent laparoscopic renal surgery in the same institution for similar indications. The data were collected at the time of the surgery. RESULTS: Twenty-three patients with a mean BMI of 42.2 kg/m2 underwent successful transperitoneal laparoscopic surgery. The mean specimen mass was 865 g, which was significantly larger than in the control group. The mean operative time was 200 minutes, which was around half an hour longer than in the matched group. The mean estimated blood loss was 243 mL, which was comparable to that of the controls. There were two perioperative complications, and the mean hospital stay was 4.5 days, 1 day longer than in the control group. CONCLUSIONS: Laparoscopic transperitoneal renal surgery is technically more difficult in morbidly obese patients but is a feasible, effective, minimally invasive method of removing renal malignancies. It offers decreased respiratory and cardiac morbidity in this higher-risk population. This study showed a complication profile similar to that in non-obese patients.

Lower plasma adiponectin levels are associated with larger tumor size and metastasis in clear-cell carcinoma of the kidney.

OBJECTIVES: To examine a possible relationship between plasma adiponectin levels and renal cell carcinoma (RCC). Adiponectin, a cytokine secreted by adipocytes, is a potent antiangiogenic factor. Plasma levels of adiponectin in patients with RCC and tumor adiponectin receptors R1 and R2 (AdipoR1&2) expression levels were measured and correlated with disease characteristics. METHODS: Preoperative plasma samples from 42 patients were analyzed in triplicate for adiponectin levels with a specific ELISA assay. All patients had clear-cell RCC, including 15 with metastatic disease. Diabetic patients were excluded; all had normal renal function. The RCC and surrounding normal renal tissue were comparatively analyzed for AdipoR1&2 expressions (immunoblotting) in 15 patients. RESULTS: Mean, median, and range of plasma adiponectin levels were 6.33, 5.84, and 1-25.2 microg/ml, respectively. A strong inverse correlation was found between plasma adiponectin levels and tumor size with significantly lower levels of adiponectin in tumors > or =4 cm (p<0.01). The median adiponectin levels in metastatic and nonmetastatic patients were 4.08 and 7.4 microg/ml, respectively (p=0.029). A trend toward significant lower adiponectin levels in high versus low Fuhrman grade (3 and 4 vs. 1 and 2) was noted (p=0.057). Expression of AdipoR1&R2 was found to be lower in tumor tissue compared with the patient's normal surrounding kidney tissues in 40% of the cases. Metastatic tumors expressed lower levels of AdipoR2. Body mass index was not inversely correlated with adiponectin levels. CONCLUSIONS: Lower blood levels of adiponectin are positively associated with clear-cell RCC aggressiveness and could potentially be used as a biomarker.

Growth potential, but not body weight or moderate limitation of lysine intake, affects inevitable lysine catabolism in growing pigs.

Inevitable catabolism contributes to the inefficiency of using dietary lysine intake for body protein deposition (PD). This study was conducted to determine the effects of true ileal digestible (TID) lysine intake, body weight (BW), and growth potential on lysine catabolism in growing pigs. Starting at 15 kg BW, 16 female Yorkshire pigs were offered a purified diet providing all nutrients in excess of requirements for maximum protein deposition (PDmax). At approximately 25 kg BW, the pigs' PDmax was determined using the N-balance method. Thereafter, 4 pigs were allocated to each of 4 diets, first-limiting in lysine, providing lysine intakes corresponding to 60, 70, 80, and 90% of estimated requirements for PDmax. The pigs were surgically fitted with catheters in the jugular and femoral veins. Lysine catabolism was determined at 2 BW (40-45 kg, low; 70-75 kg, high) either directly (oxidation) using a primed, constant infusion of l-[1-(14)C]-lysine or indirectly (disappearance) using the N-balance method. There was no effect of BW on the rate (g/d) or fraction of TID lysine intake catabolized. Lysine catabolism decreased with increasing growth potential. Lysine disappearance and lysine oxidation (% of TID lysine intake) were independent of lysine intake, except for the lowest lysine intake level, where they were lower. When lysine catabolism was independent of intake, lysine oxidation based on plasma free lysine specific radioactivity (SRA) was lower (9.9% of TID intake) than lysine disappearance (17.4% of TID intake) or lysine oxidation based on liver free lysine SRA (13.4% of TID intake).