EGFR-STAT3 signaling promotes formation of malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumors (MPNSTs) develop sporadically or in the context of neurofibromatosis type 1. Epidermal growth factor receptor (EGFR) overexpression has been implicated in MPNST formation, but its precise role and relevant signaling pathways remain unknown. We found that EGFR overexpression promotes mouse neurofibroma transformation to aggressive MPNST (GEM-PNST). Immunohistochemistry demonstrated phosphorylated STAT3 (Tyr705) in both human MPNST and mouse GEM-PNST. A specific JAK2/STAT3 inhibitor FLLL32 delayed MPNST formation in an MPNST xenograft nude mouse model. STAT3 knockdown by shRNA prevented MPNST formation in vivo. Finally, reducing EGFR activity strongly reduced pSTAT3 in vivo. Thus, an EGFR-STAT3 pathway is necessary for MPNST transformation and establishment of MPNST xenografts growth but not for tumor maintenance. Efficacy of the FLLL32 pharmacological inhibitor in delaying MPNST growth suggests that combination therapies targeting JAK/STAT3 might be useful therapeutics.

The etiology of uterine sarcomas: a pooled analysis of the epidemiology of endometrial cancer consortium.

BACKGROUND: Uterine sarcomas are characterised by early age at diagnosis, poor prognosis, and higher incidence among Black compared with White women, but their aetiology is poorly understood. Therefore, we performed a pooled analysis of data collected in the Epidemiology of Endometrial Cancer Consortium. We also examined risk factor associations for malignant mixed mullerian tumours (MMMTs) and endometrioid endometrial carcinomas (EECs) for comparison purposes. METHODS: We pooled data on 229 uterine sarcomas, 244 MMMTs, 7623 EEC cases, and 28,829 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) for risk factors associated with uterine sarcoma, MMMT, and EEC were estimated with polytomous logistic regression. We also examined associations between epidemiological factors and histological subtypes of uterine sarcoma. RESULTS: Significant risk factors for uterine sarcoma included obesity (body mass index (BMI)≥30 vs BMI<25 kg m(-2) (OR: 1.73, 95% CI: 1.22-2.46), P-trend=0.008) and history of diabetes (OR: 2.33, 95% CI: 1.41-3.83). Older age at menarche was inversely associated with uterine sarcoma risk (≥15 years vs <11 years (OR: 0.70, 95% CI: 0.34-1.44), P-trend: 0.04). BMI was significantly, but less strongly related to uterine sarcomas compared with EECs (OR: 3.03, 95% CI: 2.82-3.26) or MMMTs (OR: 2.25, 95% CI: 1.60-3.15, P-heterogeneity=0.01). CONCLUSION: In the largest aetiological study of uterine sarcomas, associations between menstrual, hormonal, and anthropometric risk factors and uterine sarcoma were similar to those identified for EEC. Further exploration of factors that might explain patterns of age- and race-specific incidence rates for uterine sarcoma are needed.

Familial systemic amyloidosis associated with bilateral sensorineural hearing loss and bilateral facial palsies.

The Finnish type of familial amyloid polyneuropathy due to variant gelsolin is a rare form of familial amyloidosis. The subtype was first described in 1969 and is characterized by progressive cranial neuropathies, corneal lattice dystrophy and distal sensorimotor dysfunction. It is extremely uncommon, with only two families known to be affected in the UK. We discuss the case of a 70-year-old woman who presented with bilateral facial nerve palsies, bilateral sensorineural hearing loss and Finnish type familial hereditary amyloidosis. A literature search of the Medline database (1966-2005) was performed, using the keywords 'amyloid', 'hearing loss' and 'facial palsy'; however, this association appears to be a novel finding. We review the current literature and discuss otorhinolaryngological presentations of amyloidosis.

Therapeutic constituents and actions of Rubus species.

Rubus species (family Rosaceae) have been cultivated for centuries for their fruits. These and other parts of the plants have been used traditionally for therapeutic purposes. This article highlights these and the potential they can offer. The constituents reported in the various species and those demonstrated to exhibit pharmacological properties have been reviewed. In the search for biologically active compounds, one of the most frequently documented species of the genus is the raspberry plant R. idaeus, the leaves of which have been used traditionally as a uterine relaxant and stimulant during confinement, for the treatment of diarrhoea and similar enteric disorders and as an astringent. Investigations of other Rubus species have been conducted in the last twenty-five years, and have shown possible application for a wide range of indications, including bacterial infections, anxiety, pain and inflammation.

Analytical structures and analysis of the simplest fuzzy PD controllers.

This paper deals with simplest fuzzy PD controllers which employ only two fuzzy sets on the universe of discourse of each input variable, and three fuzzy sets on the universe of discourse of output variable. First, analytical structures of the simplest fuzzy PD controllers are derived via triangular membership functions for fuzzification, intersection T-norm, Lukasiewicz OR and Zadeh (1965) OR T-conorms, Mamdani's minimum, Larsen's product and drastic product inference methods, and center of area method for defuzzification. Properties of such fuzzy PD controllers are investigated. Based on these properties a comparative study is made on fuzzy controllers derived, and also on the fuzzy controllers and their counterpart-conventional linear PD controller. Finally, sufficient conditions for bounded-input bounded-output stability of fuzzy PD control systems are established using the well known small gain theorem.

Betaine distribution in the Malvaceae.

Aerial parts of 26 taxa, distributed in 18 genera and all 5 tribes of the Malvaceae have been examined for the presence of betaines. Glycinebetaine was obtained in high yield (0.5-4.6%, dry weight) from all the plants studied, except Abelmoschus moschatus, in extracts of which glycinebetaine was not detected. Trigonelline was recorded for 16 of the plants tested, but the yields were low (0.005-0.07%, dry weight). Roots and flowers of a few of the species were also examined for betaines. The same compounds as those found in the aerial parts were usually detected, but the glycinebetaine contents of the roots and flowers were considerably lower.

Measuring prenatal drug exposure.

Prenatal drug exposure is an important pediatric health issue. However, the effects on children are not clear because of limitations in the way drug exposure is typically measured. For example, one cannot say cocaine causes a specific outcome if cocaine exposure is not measured accurately. Before we can determine the developmental outcomes associated with drug exposure, 4 measurement issues must be considered: (1) the amount of exposure varies greatly, such as from 1 to 709 g of crack per month; (2) exposure may vary by trimester; (3) exposure could be to one drug or multiple drugs; and (4) different sources of exposure data can be inconsistent (e.g., toxicology and maternal self-report). We use data from 248 families participating in an ongoing longitudinal study to provide concrete examples of these measurement issues. Both nursing researchers and practitioners must carefully attend to measurement issues when interpreting research on the effects of prenatal drug exposure.

Body mass index, height, and prostate cancer mortality in two large cohorts of adult men in the United States.

Body weight and height have both been associated consistently with postmenopausal breast cancer but less consistently with prostate cancer. The present study examined the relationship between body mass index (BMI), height, and death from prostate cancer in two large American Cancer Society cohorts. Men in the study were selected from the male participants in Cancer Prevention Study I (CPS-I; enrolled in 1959 and followed through 1972) and Cancer Prevention Study II (CPS-II; enrolled in 1982 and followed through 1996). After exclusions, 1,590 prostate cancer deaths remained among 381,638 men in CPS-I and 3,622 deaths among 434,630 men in CPS-II. Cox proportional hazards modeling was used to compute rate ratios (RR) and to adjust for confounders. Prostate cancer mortality rates were significantly higher among obese (BMI, > or =30) than nonobese (BMI, <25) men in both cohorts [adjusted RR, 1.27; 95% confidence interval (CI), 1.04-1.56 in CPS-I; RR, 1.21; 95% CI, 1.07-1.37 in CPS-II]. Prostate cancer mortality rates in the CPS-I cohort were lowest for the shortest men (RR, 0.80; 95% CI, 0.63-1.03 for men <65 inches versus 65-66 inches) and highest for the tallest men (RR, 1.39; 95% CI, 1.11-1.74 for men > or =73 inches tall versus 65-66 inches). Rates remained constant among men 65-72 inches tall. No association between height and prostate cancer mortality was observed in the CPS-II cohort (RR, 1.03; 95% CI, 0.82-1.29 for men > or =75 versus 65-66 inches). These results support the hypothesis that obesity increases risk of prostate cancer mortality. Decreased survival among obese men may be a likely explanation for this association.

Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of US women.

CONTEXT: Postmenopausal estrogen use is associated with increased risk of endometrial and breast cancer, 2 hormone-related cancers. The effect of postmenopausal estrogen use on ovarian cancer is not established. OBJECTIVES: To examine the association between postmenopausal estrogen use and ovarian cancer mortality and to determine whether the association differs according to duration and recency of use. DESIGN AND SETTING: The American Cancer Society's Cancer Prevention Study II, a prospective US cohort study with mortality follow-up from 1982 to 1996. PARTICIPANTS: A total of 211 581 postmenopausal women who completed a baseline questionnaire in 1982 and had no history of cancer, hysterectomy, or ovarian surgery at enrollment. MAIN OUTCOME MEASURE: Ovarian cancer mortality, compared among never users, users at baseline, and former users as well as by total years of use of estrogen replacement therapy (ERT). RESULTS: A total of 944 ovarian cancer deaths were recorded in 14 years of follow-up. Women who were using ERT at baseline had higher death rates from ovarian cancer than never users (rate ratio [RR], 1.51; 95% confidence interval [CI], 1.16-1.96). Risk was slightly but not significantly increased among former estrogen users (RR, 1.16; 95% CI, 0.99-1.37). Duration of use was associated with increased risk in both baseline and former users. Baseline users with 10 or more years of use had an RR of 2.20 (95% CI, 1.53-3.17), while former users with 10 or more years of use had an RR of 1.59 (95% CI, 1.13-2.25). Annual age-adjusted ovarian cancer death rates per 100 000 women were 64.4 for baseline users with 10 or more years of use, 38.3 for former users with 10 or more years of use, and 26.4 for never users. Among former users with 10 or more years of use, risk decreased with time since last use reported at study entry (RR for last use <15 years ago, 2.05; 95% CI, 1.29-3.25; RR for last use >/=15 years ago, 1.31; 95% CI, 0.79-2.17). CONCLUSIONS: In this population, postmenopausal estrogen use for 10 or more years was associated with increased risk of ovarian cancer mortality that persisted up to 29 years after cessation of use.

Vitamin C and vitamin E supplement use and colorectal cancer mortality in a large American Cancer Society cohort.

Some recent epidemiological studies have suggested that use of vitamin C or vitamin E supplements, both of which are important antioxidants, may substantially reduce the risk of colon or colorectal cancer. We examined the association between colorectal cancer mortality and use of individual vitamin C and E supplements in the American Cancer Society's Cancer Prevention Study II cohort. We used proportional hazards modeling to estimate rate ratios among 711,891 men and women in the United States who completed a self-administered questionnaire at study enrollment in 1982, had no history of cancer, and were followed for mortality through 1996. During the 14 years of follow-up, 4404 deaths from colorectal cancer occurred. After adjustment for multiple colorectal cancer risk factors, regular use of vitamin C or E supplements, even long-term use, was not associated with colorectal cancer mortality. The combined-sex rate ratios were 0.89 [95% confidence interval (CI), 0.73-1.09] for 10 or more years of vitamin C use and 1.08 (95% CI, 0.85-1.38) for 10 or more years of vitamin E use. In subgroup analyses, use of vitamin C supplements for 10 or more years was associated with decreased risk of colorectal cancer mortality before age 65 years (rate ratio = 0.48; 95% CI, 0.28-0.81) and decreased risk of rectal cancer mortality at any age (rate ratio = 0.40; 95% CI, 0.20-0.80). Our results do not support a substantial effect of vitamin C or E supplement use on overall colorectal cancer mortality.

Effect of body mass on the association between estrogen replacement therapy and mortality among elderly US women.

In observational studies, estrogen replacement therapy is associated with decreased cardiovascular disease rates and increased breast cancer rates. Recent evidence suggests that the impact of estrogen use on disease outcomes may vary by body mass. In a prospective study of 290,827 postmenopausal US women with no history of cancer or cardiovascular disease at enrollment in 1982, the authors examined the association between postmenopausal estrogen use and all-cause, coronary heart disease, stroke, all-cancer, and breast cancer death rates and whether these associations differed by body mass. After 12 years of follow-up, results from Cox proportional hazards models showed that all-cause death rates were lower among baseline estrogen users than never users (rate ratio (RR) = 0.82, 95% confidence interval (CI): 0.78, 0.87). The lowest relative risk was found for coronary heart disease (RR = 0.66, 95% CI: 0.58, 0.77). The inverse association between estrogen use and coronary heart disease mortality was strongest for thin women (body mass index <22 kg/m2) (RR = 0.49, p for interaction = 0.02). Breast cancer mortality did not increase with estrogen use overall, and no increased risk was observed for thin or heavy women. In this population, the reduction in coronary heart disease mortality among estrogen users was greatest for thinner women. Additional studies are needed to confirm or refute these results.

Multivitamin use and colon cancer mortality in the Cancer Prevention Study II cohort (United States).

OBJECTIVE: Multivitamins contain several nutrients, including folic acid, which are hypothesized to reduce colon cancer risk. Previous epidemiologic studies have suggested that effects of multivitamins containing substantial amounts of folic acid (introduced in 1973) may not be evident until 15 or more years since first use. METHODS: We examined the association between daily multivitamin use and colon cancer mortality among 806,397 US men and women in the Cancer Prevention Study II cohort who completed a questionnaire at enrollment in 1982 and were followed for mortality through 1998. RESULTS: After multivariate adjustment, multivitamin use at enrollment showed little association with colon cancer mortality. After 15 years since first use of a multivitamin potentially containing folic acid, we observed slightly decreased risk of colon cancer mortality (rate ratio (RR) = 0.89, 95% confidence interval (CI) 0.80-0.99). Consistent with previous reports, this association was stronger among participants consuming two or more alcoholic drinks per day (RR = 0.71, 95% CI 0.56-0.91). CONCLUSION: Our results are consistent with a modest reduction in colon cancer mortality associated with use of folic acid-containing multivitamins among moderate to heavy alcohol users.

Antiulcer activity and the mechanism of action of magaldrate in gastric ulceration models of rat.

The present study was undertaken to investigate the mechanism of cytoprotective effects of magaldrate in aspirin plus pylorus-ligation model and ethanol-induced gastric ulcer model in rats. Magaldrate (60 mg/kg, p.o.) produced a significant reduction in the ulcer index and significant increase in mucus content in ethanol-induced gastric ulceration in rats. In aspirin plus pylorus-ligation model magaldrate produced significant decrease in ulcer index, total acidity and protein content (PR). It did not produce any significant change in volume of gastric secretion. However, it produced significant increase in total carbohydrate (TC) level but not in ratio between TC and proteins. It also produced a significant decrease in lipid peroxidation (as expressed by thiobarbituric acid reactive substance). Our data suggests the cytoprotective action of magaldrate on gastric mucosal cells which may be due to protection of gastric mucosa from lipid peroxidation.