Collaborative Group of the Americas on Inherited Gastrointestinal Cancer Position statement on multigene panel testing for patients with colorectal cancer and/or polyposis

Familial Cancer - Multigene panel tests for hereditary cancer syndromes are increasingly utilized in the care of colorectal cancer (CRC) and polyposis patients. However, widespread availability of...     

Benzophenone-3 promotion of mammary tumorigenesis is diet-dependent

Benzophenone-3 is a putative endocrine disrupting chemical and common ingredient in sunscreens. The potential of endocrine disrupting chemicals to act as agonists or antagonists in critical hormonally regulated processes, such as mammary gland development and mammary tumorigenesis, demands evaluation of its potential in promoting breast cancer. This study identifies the effects of BP-3 on mammary tumorigenesis with high-fat diet during puberty versus adulthood in Trp53-null transplant BALB/c mice. Benzophenone-3 exposure yielded levels in urine similar to humans subjected to heavy topical sunscreen exposure. Benzophenone-3 was protective for epithelial tumorigenesis in mice fed lifelong low-fat diet, while promotional for epithelial tumorigenesis in mice fed adult high-fat diet. Benzophenone-3 increased tumor cell proliferation, decreased tumor cell apoptosis, and increased tumor vascularity dependent on specific dietary regimen and tumor histopathology. Even in instances of an ostensibly protective effect, other parameters suggest greater risk. Although benzophenone-3 seemed protective on low-fat diet, spindle cell tumors arising in these mice showed increased proliferation and decreased apoptosis. This points to a need for further studies of benzophenone-3 in both animal models and humans as a potential breast cancer risk factor, as well as a more general need to evaluate endocrine disrupting chemicals in varying dietary contexts.     

Different response of senescent female Sprague-Dawley rats to gemfibrozil and rosiglitazone administration

Eighteen-month-old Sprague-Dawley rats present age-related alterations in lipid and glucose metabolism and are resistant to the effect of PPARalpha-activating hypolipidemic drugs, such as gemfibrozil. We tested if these animals were responsive to the administration of rosiglitazone, an insulin-sensitizer acting on PPARgamma. We determined in 18-month-old female Sprague-Dawley rats treated for 21 days with a daily dose of 3mg gemfibrozil/kg or 3mg rosiglitazone/kg: (i) plasma concentrations of total cholesterol (TC), triglycerides (TG), nonesterified fatty acids (NEFA), glucose, insulin and leptin, (ii) hepatic concentrations of TG, NEFA and cholesteryl esters (CE), and (iii) the liver expression and binding activity of peroxisome proliferator-activated receptor alpha (PPARalpha), and several of its target genes, hepatic nuclear factor-4 (HNF-4), and liver X receptor alpha (LXRalpha). Although gemfibrozil induced mild effects on hepatic PPARalpha, HNF-4, and LXRalpha, only rosiglitazone significantly reduced plasma TG (59%), glucose (19%), insulin (61%), and leptin (66%), and liver TG (43%), CE (49%), and NEFA (27%). These changes were associated to an increased body weight gain and a decrease in visceral fat (8.7-fold and 37% vs. control females, respectively). The beneficial effect of rosiglitazone treatment in 18-month-old female rats could be related to a direct effect on white adipose tissue.     

Improved efficacy of 10-Day sequential treatment for Helicobacter pylori eradication in children: a randomized trial

BACKGROUND & AIMS: The currently recommended first-line eradication treatment of Helicobacter pylori in children is usually successful in about 75%. Recently, in adults, a novel 10-day sequential treatment has achieved an eradication rate of 95%. The aim of the study was to assess the H pylori eradication rate of the sequential treatment regimen compared with conventional triple therapy in children. METHODS: Seventy-eight consecutive children with H pylori infection were randomized to receive either sequential treatment (omeprazole plus amoxicillin for 5 days, followed by omeprazole plus clarithromycin plus tinidazole for another 5 days) (n = 38; 15 boys [39.5%]; median age, 11.0 years [range, 3.3-16 years]) or triple therapy (omeprazole, amoxicillin, and metronidazole) for 1 week (n = 37; 15 boys [40.5%]; median age, 9.9 years [range, 4.3-16 years]). H pylori infection was based on 2 out of 3 positive tests results: 13C-urea breath test, rapid urease test, and histologic analysis. Eradication was assessed by 13C-urea breath test 8 weeks after therapy. RESULTS: Seventy-four patients completed the study. H pylori eradication was achieved in 36 children receiving sequential treatment (97.3%; 95% confidence interval, 86.2-99.5) and 28 children receiving triple therapy (75.7%; 95% confidence interval, 59.8-86.7) (P < .02). Compliance with therapy was good (>95%) in all. CONCLUSIONS: Our study shows, for the first time in children, that 10-day sequential treatment achieves a higher eradication rate than standard triple therapy, which is consistent with the results of adult studies.     

Differential 3,5,3'-triiodothyronine-mediated regulation of uncoupling protein 3 transcription: role of Fatty acids

T(3) regulates energy metabolism by stimulating metabolic rate and decreasing metabolic efficiency. The discovery of mitochondrial uncoupling protein 3 (UCP3), its homology to UCP1, and regulation by T(3) rendered it a possible molecular determinant of the action of T(3) on energy metabolism, but data are controversial. This controversy may in part be attributable to discrepancies observed between the regulation by T(3) of UCP3 expression in rats, humans, and mice. To clarify this issue, we studied 1) the induction kinetics of the UCP3 gene by T(3) in rat skeletal muscle, 2) the influence of fatty acids, and 3) the structure and regulation of the various UCP3 promoters by T(3). Within 8 h of single-dose T(3) administration, hypothyroid rats showed a rise in serum fatty acid levels concomitant with a rapid increase in UCP3 expression in gastrocnemius muscle, followed by inductions of peroxisome proliferator activated receptor delta (PPARdelta) (within 24 h) and PPAR target gene expression (after 24 h). This T(3)-induced early UCP3 expression depended on fatty acid-PPAR signaling because depleting serum fatty acid levels abolished its expression, restorable by administration of the PPARdelta agonist L165,041 (4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]phenoxy]acetic acid). In transfected rat L6 myoblasts, only the rat UCP3 promoter positively responded to T(3) and L165,041 together in the presence of MyoD, thyroid hormone receptor beta1 (TRbeta1), PPARdelta, or PPARdelta plus the TR dimerization partner retinoid X receptor alpha. All promoters share a response element common to TR and PPAR (TRE 1), but the observed species differences may be attributable to different localizations of the MyoD response element, which in the rat maps to exon 1.     

Pathology of calcific aortic stenosis

With the aging of the general population in industrialized nations, calcific aortic stenosis (CAS) is becoming an increasingly important medical problem. The etiology is for the most part, dependent on the age at presentation; the two predominant causes in the western world are calcific aortic valve disease arising in a tricuspid aortic valve and bicuspid aortic valve (BAV). CAS is a progressive disease, exhibiting a spectrum of pathologic findings, ranging from valvular sclerosis to severe nodular calcification. Aortic valve replacement is the recommended treatment for severe disease but tissue valves may also calcify over time. Various atherosclerotic risk factors have been linked to aortic stenosis and there are mechanistic similarities between atherosclerosis and CAS. The precise pathologic mechanisms underlying aortic stenosis are poorly understood.