Mer or Axl receptor tyrosine kinase inhibition promotes apoptosis, blocks growth and enhances chemosensitivity of human non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is a prevalent and devastating disease that claims more lives than breast, prostate, colon and pancreatic cancers combined. Current research suggests that standard chemotherapy regimens have been optimized to maximal efficiency. Promising new treatment strategies involve novel agents targeting molecular aberrations present in subsets of NSCLC. We evaluated 88 human NSCLC tumors of diverse histology and identified Mer and Axl as receptor tyrosine kinases (RTKs) overexpressed in 69% and 93%, respectively, of tumors relative to surrounding normal lung tissue. Mer and Axl were also frequently overexpressed and activated in NSCLC cell lines. Ligand-dependent Mer or Axl activation stimulated MAPK, AKT and FAK signaling pathways indicating roles for these RTKs in multiple oncogenic processes. In addition, we identified a novel pro-survival pathway-involving AKT, CREB, Bcl-xL, survivin, and Bcl-2-downstream of Mer, which is differentially modulated by Axl signaling. We demonstrated that short hairpin RNA (shRNA) knockdown of Mer or Axl significantly reduced NSCLC colony formation and growth of subcutaneous xenografts in nude mice. Mer or Axl knockdown also improved in vitro NSCLC sensitivity to chemotherapeutic agents by promoting apoptosis. When comparing the effects of Mer and Axl knockdown, Mer inhibition exhibited more complete blockade of tumor growth while Axl knockdown more robustly improved chemosensitivity. These results indicate that Mer and Axl have complementary and overlapping roles in NSCLC and suggest that treatment strategies targeting both RTKs may be more effective than singly-targeted agents. Our findings validate Mer and Axl as potential therapeutic targets in NSCLC and provide justification for development of novel therapeutic compounds that selectively inhibit Mer and/or Axl.

Pomegranate extract inhibits Staphylococcus aureus growth and subsequent enterotoxin production.

In Brazil, pomegranate (Punica granatum L. (Punicaceae)) is widely used as a phytotherapeutic agent. This study evaluates the effect of pomegranate extract on Staphylococcus aureus FRI 722 growth and subsequent enterotoxin production. Bacterial susceptibility was determined by tube dilution method and production of enterotoxin was assessed using membrane-over-agar (MOA) plates. At a low extract concentration (0.01% v/v) bacterial growth was delayed, while a higher concentration (1% v/v) eliminated bacterial growth. Most interestingly, a 0.05% (v/v) concentration of extract was found to inhibit Staphylococcal enterotoxin (SE) A production. These data further implicate pomegranate extracts as potential antibacterial therapeutics with the added ability to inhibit enterotoxin production.

Effect of pentoxifylline [corrected] on myocutaneous flap viability in pigs.

Partial necrosis of a skin flap can complicate reconstructive surgery. We performed a double-blinded crossover study to determine if pentoxifylline improves perfusion and survival of a myocutaneous flap. Ten 20-kg pigs were fed pentoxifylline (400 mg three times a day) or placebo for 1 week before and after raising a 5 x 30 cm panniculus carnosus flap on one flank. After 1 week of washout, each pig began the opposite drug treatment and the surgery was repeated on the opposite flank. Immediately after surgery, perfusion dermofluorometry and laser Doppler velocimetry demonstrated a significant increase in the perfusion of pentoxifylline-treated flaps compared to control flaps. On postoperative day 7, the mean area of clinical necrosis was 39.7 +/- 4.7 cm2 on the placebo sides and 30.1 +/- 4.6 cm2 on the pentoxifylline sides (t = 2.21, p < 0.05). We conclude that pentoxifylline improves perfusion and survival of myocutaneous flaps in pigs. Clinical trials appear to be indicated on the basis of the findings of this experiment.

Effect of guar gum on mineral balances in NIDDM adults.

The self-selected diet of 16 subjects with non-insulin-dependent diabetes mellitus (NIDDM) was supplemented for 6 mo with either a granolalike bar containing 35.5 g carbohydrate and 6.6 g guar gum/bar or a placebo bar containing carbohydrate but no guar gum. Subjects consumed a mean of 4.8 bars/day. Average guar gum consumption at the end of the study was 31.7 g/day. One week before and at the end of the study, subjects were admitted to a metabolic ward and fed a controlled diet similar to their self-selected diet. Food, feces, and urine were composited for analysis of iron, zinc, copper, calcium, magnesium, and manganese. Eight subjects consuming the guar gum supplement and 6 subjects consuming the placebo bar completed collections for mineral balance. Neither consumption of guar gum nor placebo bar significantly changed apparent mineral balance for iron, copper, zinc, calcium, manganese, or magnesium from prestudy levels to 6-mo levels, and no significant differences were observed between the two groups. With the exception of copper, men consumed significantly more minerals than women. We conclude that consumption of guar gum by patients with NIDDM does not adversely affect apparent mineral balance.

The effects of allopurinol and superoxide dismutase in a rat model of skin flap necrosis.

Oxygen-free radicals have been implicated as mediators of ischemic damage in a number of tissues, including heart, kidney, small intestine, and skin. Superoxide dismutase, a free radical scavenger, and allopurinol, an inhibitor of xanthine oxidase (a catalyst in the formation of superoxide) have been shown separately to decrease ischemic damage to tissue. Sixty-two male Sprague-Dawley rats (220 to 280 g) were divided into five groups: control, superoxide dismutase only, allopurinol only, high-dose combined allopurinol and superoxide dismutase, and low-dose combined allopurinol and superoxide dismutase. An 18-cm2 ventral island skin flap, based on a single inferior epigastric vessel, was raised and replaced. Blood flow was assessed with a perfusion fluorometer immediately after the flap was replaced, and on postoperative days 1 and 3. Gross necrosis was assessed on postoperative day 7. Gross necrosis was reliably reduced in all groups as compared with the control; however, necrosis in any one experimental group was not significantly different from any other experimental group. Necrosis (expressed as a percentage of the area of the random [distal] half of the flap) was as follows for each group: control, 74%; superoxide dismutase, 43%; allopurinol, 43%; high-dose combined, 48%; low-dose combined, 33%. Blood flow, as represented by the dermofluorescence index, was not changed by any of the treatments. Blood flow was also related to the eventual survival or necrosis for any one portion of tissue. All experimental groups survived with significantly less blood flow than the control.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term ingestion of guar gum is not toxic in patients with noninsulin-dependent diabetes mellitus.

The use of diets rich in unabsorbable carbohydrate ("fiber") has been advocated for the treatment of noninsulin-dependent diabetes mellitus (NIDDM). The soluble viscous fibers such as guar gum are most effective in normalizing carbohydrate intolerance in such patients; particulate fibers such as cellulose have little or no effect. While the latter are known to affect many aspects of nutrition when consumed in great quantity, little is known of the toxicity of guar gum. Eight adults with NIDDM are reported here who consumed at least 30 grams of guar gum for at least 16 weeks without any change in hematologic, hepatic, or renal function. Serologic screening revealed no change in lipid, protein or mineral metabolism, and no change in electrolyte balance. It is concluded that consumption of 30 grams of guar gum per day for prolonged periods is without serious consequences.