Mutations of the von Hippel-Lindau gene confer increased susceptibility to natural killer cells of clear-cell renal cell carcinoma.

The tumor suppressor gene von Hippel-Lindau (VHL) is involved in the development of sporadic clear-cell renal cell carcinoma (RCC). VHL interferes with angiogenesis and also controls cell adhesion and invasion. Therapies that target VHL-controlled genes are currently being evaluated in RCC patients. RCC is a immunogenic tumor and treatment with interleukin-2 (IL2) or interferon (IFN)-α results in regression in some patients. We used two renal tumor cell lines (RCC6 and RCC4) carrying VHL loss-of-function mutations to investigate the role of mutant VHL in susceptibility to natural killer (NK) cell-mediated lysis. The RCC6 and RCC4 cell lines were transfected with the wild-type gene to restore the function of VHL. The presence of the gene in RCC cells downregulated hypoxia-inducible factor (HIF)-1α and subsequently decreased vascular endothelial growth factor (VEGF) production. Relative to control transfectants and parental cells, pVHL-transfected cell lines activated resting and IL2-activated NK cells less strongly, as assessed by IFNγ secretion, NK degranulation and cell lysis. NKG2A, a human leukocyte antigen (HLA)-I-specific inhibitory NK receptor, controls the lysis of tumor targets. We show that HLA-I expression in RCC-pVHL cells is stronger than that in parental and controls cells, although the expression of activating receptor NK ligands remains unchanged. Blocking NKG2A/HLA-I interactions substantially increased lysis of RCC-pVHL, but had little effect on the lysis of VHL-mutated RCC cell lines. In addition, in response to IFNα, the exponential growth of RCC-pVHL was inhibited more than that of RCC-pE cells, indicating that VHL mutations may be involved in IFNα resistance. These results indicate that a decreased expression of HLA-I molecules in mutated VHL renal tumor cells sensitizes them to NK-mediated lysis. These results suggest that combined immunotherapy with anti-angiogenic drugs may be beneficial for patients with mutated VHL.

Comparison of phytotherapy (Permixon) with finasteride in the treatment of benign prostate hyperplasia: a randomized international study of 1,098 patients.

BACKGROUND: Controversy regarding the relative efficacy of treatments for the relief of the symptoms of benign prostatic hyperplasia (BPH). METHODS: This was a 6-month double-blind randomized equivalence study that compared the effects of a plant extract (320 mg Permixon) with those of a 5 alpha-reductase inhibitor (5 mg finasteride) in 1,098 men with moderate BPH using the International Prostate Symptom Score (IPSS) as the primary end-point. RESULTS: Both Permixon and finasteride decreased the IPSS (-37% and -39%, respectively), improved quality of life (by 38 and 41%), and increased peak urinary flow rate (+25% and +30%, P = 0.035), with no statistical difference in the percent of responders with a 3 ml/sec improvement. Finasteride markedly decreased prostate volume (-18%) and serum PSA levels (-41%); Permixon improved symptoms with little effect on volume (-6%) and no change in PSA levels. Permixon fared better than finasteride in a sexual function questionnaire and gave rise to less complaints of decreased libido and impotence. CONCLUSIONS: Both treatments relieve the symptoms of BPH in about two-thirds of patients but, unlike finasteride, Permixon has little effect on so-called androgen-dependent parameters. This suggests that other pathways might also be involved in the symptomatology of BPH.

Absorption balances and kinetics of nutrients and bacterial metabolites in conscious pigs after intake of maltose- or maltitol-rich diets.

Because sorbitol is poorly absorbed in the small intestine, it may be the origin of large amounts of residues reaching the large intestine and may be substrate for microbial activity. An experiment was conducted to study the quantitative appearance in the portal blood of nutrients and metabolites derived from enzymatic hydrolysis and microbial fermentation in the fore- and hindgut. Five Large White, castrated male pigs (mean BW of 61.2 +/- 1.7 kg) were fitted under anesthesia with an electromagnetic flow probe around the portal vein and with permanent cannulas in the portal vein and the carotid artery. From 10 d before surgery, they were accustomed to one of the two semisynthetic, well-balanced diets, containing a high level (53% of DM) of either a maltose-rich glucose syrup (SNat) or of a maltitol-rich hydrogenated glucose syrup (SHyd). Eight days after surgery and after an 18-h fast, each animal was given a last meal (800 g) of the diet to which it was formerly accustomed. For 12 h after this meal, blood samples were taken at 30- to 60-min intervals for glucose, sorbitol, amino N, VFA, D- and L-lactic acids, insulin, and glucagon determinations, and portal blood flow was continuously recorded. The absorption coefficients (amounts appearing for 12 h in the portal blood: amounts ingested, percentage) of glucose and of amino N were not significantly different between the two diets. The amount of sorbitol that appeared within 12 h in the portal blood after SHyd intake was 44 g (25% intake). The amount of VFA that appeared in the portal blood within 12 h was 2.7 times larger (P < .05) after intake of the maltitol-rich diet (SHyd:808 mmol) than after intake of the maltose-rich diet (300 mmol). This difference was due to an increase in absorbed amounts of propionate (SHyd 402 vs SNat 56 mmol, P < .05), butyrate (SHyd 63 vs SNat 17 mmol, P < .01), isovalerate (SHyd 17 vs SNat 5 mmol, P < .05), and acetate (SHyd 298 vs SNat 219 mmol, P < .13). There were no significant changes in insulin and glucagon production. Intake of the maltitol-rich diet resulted in less available energy (82.0%) than did intake of the maltose-rich diet (92.6%).

Influence of diet composition on intestinal volatile fatty acid and nutrient absorption in unanesthetized pigs.

Two experiments were conducted to study the effect of the amount and nature of fiber and carbohydrates on nutrient and VFA absorption. Five Large White pigs in each crossover experiment were accustomed to a semisynthetic 14% protein diet containing 6 (LC) or 16% (HC) pure cellulose (Exp. 1) or 22% alfalfa meal (6.3% cellulose, HA) and 22% lactose and 6% pure cellulose (HL; Exp. 2). Each animal was then fitted with catheters in the portal vein and carotid artery and with a flow probe around the portal vein. Eight days after surgery, the absorption of reducing sugars (RS) and amino-N was studied for 12 h and that of VFA for 24 h after intake of a single 800-g meal. The alternate diet was then given for 7 to 10 d and a second series of samplings was performed within the same conditions. In the first experiment, added dietary cellulose decreased efficiency of absorption of RS (LC: 90.4 +/- 7.0%; HC: 81.6 +/- 3.6%) and amino-N (LC: 95.3 +/- 9.1%; HC: 70.3 +/- 2.8%; P less than .05). Daily absorption (24 h) of VFA tended to be larger when the cellulose level rose (LC: 1,184 +/- 85 mmol; HC: 1,429 +/- 216 mmol, NS) and increased (P less than .05) with the length of adaptation (21 to 28 d) to the diet, regardless of cellulose level. In the second experiment, after intake of the alfalfa diet, absorption of RS was high (97.8%), whereas absorption of amino-N (74.3%) and VFA (880 +/- 87 mmol/24 h) were low. Intake of lactose reduced absorption of RS (85.2%), did not alter absorption of N (75.9%) and increased absorption of VFA (1,181 +/- 218 mmol/24 h). Thus, the energy efficiency of the diet was lowered (P less than .05) when cellulose was added to the diet but not when alfalfa meal or lactose were added.