KRAS testing in metastatic colorectal carcinoma: challenges, controversies, breakthroughs, and beyond

Metastatic colorectal cancer harboring a mutation in codon 12 or 13 of the KRAS gene does not benefit from therapy with antibodies targeting the epidermal growth factor receptor (EGFR). The implementation of community KRAS testing is generating a rapid flow of new data that have implications for the pathologist and testing guidelines, besides the physician. Therefore, it seems timely to draw together the threads of this large body of information in order that pathologists can be knowledgeable partners in the multidisciplinary process of targeted cancer therapy, and to help refine current testing guidelines. This review addresses: (1) the most relevant methodological and technical aspects of KRAS testing in terms of sample site (primary/metastatic), test specimens (resection/biopsy/cytology), and the diverse molecular methods available; (2) issues related to daily practice, namely the timing of the test, its turnaround time and the quality control procedures; and (3) the evidence related to the relationship between KRAS genetic intratumoral heterogeneity, clinical sensitivity of mutational detection tools and anti-EGFR treatment outcome. Hopefully, in the near future, elucidation of the potential of biomarker panels, and of the mechanisms underlying primary and acquired resistance to anti-EGFR therapy will refine even further personalized treatment regimes for patients with metastatic colorectal cancer

Regional brain c-fos activation associated with penile erection and other symptoms induced by the spider toxin Tx2-6

Brain areas expressing c-fos messenger RNA were mapped by quantitative in situ hybridization after 1-2 h of intoxication with 10 mu g/kg Tx2-6, a toxin obtained from the venom of the spider Phoneutria nigriventer. Relative to saline-treated controls, brains from toxin-treated animals showed pronounced c-fos activation in many brain areas, including the supraoptic nucleus, the paraventricular nucleus of the hypothalamus, the motor nucleus of the vagus, area postrema, paraventricular and paratenial nuclei of the thalamus, locus coeruleus, central amydaloid nucleus and the bed nucleus of the stria terminalis. the paraventricular hypothalamus and the bed nucleus of the stria terminalis have been implicated in erectile function in other studies. A possible role for central NO is considered. Acute stress also activates many brain areas activated by Tx2-6 as well as with NOstimulated Fos transcription. Brain areas that appear to be selectively activated by Tx2-6, include the paratenial and paraventricular thalamic nuclei, the bed nucleus of the stria terminalis and the area postrema and the dorsal motor n. of vagus in the medulla. However, direct injections of different doses of the toxin into the paraventricular hypothalamic n. failed to induce penile erection, arguing against CNS involvement in this particular effect. (C) 2011 Elsevier B.V. All rights reserved.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)C.N.Pq. (Brazil)Inst Butantan, Pharmacol Lab, BR-05503900 São Paulo, BrazilInst Butantan, Biochem Lab, BR-05503900 São Paulo, BrazilInst Butantan, Lab Immunochem, BR-05503900 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychobiol, São Paulo, BrazilCtr Addict & Mental Hlth, Neuroimaging Res Sect, Toronto, ON, CanadaUniversidade Federal de São Paulo, Dept Psychobiol, São Paulo, BrazilFAPESP: 94/1214-6CNPq: 200538/95-0Web of Scienc

The effects of dietary counseling on children with food allergy: a prospective, multicenter intervention study.

Although dietary counseling is generally recommended in children with food allergy (FA), its effect on the nutritional status of these patients has not yet been evaluated. Our nonrandomized multicenter prospective intervention study was undertaken to investigate the effects of dietary counseling on children with FA. Anthropometric data, dietary intakes, and laboratory biomarkers of nutritional status were evaluated in children with FA (aged 6 to 36 months) before and after dietary counseling, by multidisciplinary teams composed of pediatricians, dietitians, and nurses. Ninety-one children with FA (49 boys and 42 girls; mean age 18.9 months, 95% CI 16.5 to 21.3) were evaluated; 66 children without FA (41 boys and 25 girls; mean age 20.3 months, 95% CI 17.7 to 22.8) served as controls providing baseline values only. At enrollment, energy and protein intakes were lower in children with FA (91 kcal/kg/day, interquartile range [IQR]=15.1, minimum=55.2, maximum=130.6; and 2.2 g/kg/day, IQR=0.5, minimum=1.5, maximum=2.7, respectively) than in children without FA (96 kcal/kg/day, IQR=6.1, minimum=83.6, maximum=118.0; and 4.6 g/kg/day, IQR=1.2, minimum=2.0, maximum=6.1, respectively; P<0.001). A weight to length ratio <2 standard deviations was more frequent in children with FA than in children without FA (21% vs 3%; P<0.001). At 6 months following dietary counseling, the total energy intake of children with FA was similar to the baseline values of control children. Dietary counseling also resulted in a significant improvement of their anthropometric and laboratory biomarkers of nutritional status. The results of our study support the crucial role of dietary counseling in the clinical management of children with FA

The effects of dietary counseling on children with food allergy: a prospective, multicenter intervention study.

Although dietary counseling is generally recommended in children with food allergy (FA), its effect on the nutritional status of these patients has not yet been evaluated. Our nonrandomized multicenter prospective intervention study was undertaken to investigate the effects of dietary counseling on children with FA. Anthropometric data, dietary intakes, and laboratory biomarkers of nutritional status were evaluated in children with FA (aged 6 to 36 months) before and after dietary counseling, by multidisciplinary teams composed of pediatricians, dietitians, and nurses. Ninety-one children with FA (49 boys and 42 girls; mean age 18.9 months, 95% CI 16.5 to 21.3) were evaluated; 66 children without FA (41 boys and 25 girls; mean age 20.3 months, 95% CI 17.7 to 22.8) served as controls providing baseline values only. At enrollment, energy and protein intakes were lower in children with FA (91 kcal/kg/day, interquartile range [IQR]=15.1, minimum=55.2, maximum=130.6; and 2.2 g/kg/day, IQR=0.5, minimum=1.5, maximum=2.7, respectively) than in children without FA (96 kcal/kg/day, IQR=6.1, minimum=83.6, maximum=118.0; and 4.6 g/kg/day, IQR=1.2, minimum=2.0, maximum=6.1, respectively; P<0.001). A weight to length ratio <2 standard deviations was more frequent in children with FA than in children without FA (21% vs 3%; P<0.001). At 6 months following dietary counseling, the total energy intake of children with FA was similar to the baseline values of control children. Dietary counseling also resulted in a significant improvement of their anthropometric and laboratory biomarkers of nutritional status. The results of our study support the crucial role of dietary counseling in the clinical management of children with FA

Involvement of smad7 in inflammatory diseases of the gut and colon cancer

In physiological conditions, the human intestinal mucosa is massively infiltrated with various subsets of immune cells, the activity of which is tightly regulated by several counter-regulatory factors. One of these factors is transforming growth factor-beta 1 (TGF-beta 1), a cytokine produced by multiple cell types and targeting virtually all the intestinal mucosal cells. Binding of TGF-beta 1 to its receptors triggers Smad2/3 signaling, thus culminating in the attenuation/suppression of immune-inflammatory responses. In patients with Crohn's disease and patients with ulcerative colitis, the major human inflammatory bowel diseases (IBD), and in mice with IBD-like colitis, there is defective TGF-beta 1/Smad signaling due to high levels of the intracellular inhibitor Smad7. Pharmacological inhibition of Smad7 restores TGF-beta 1 function, thereby reducing inflammatory pathways in patients with IBD and colitic mice. On the other hand, transgenic over-expression of Smad7 in T cells exacerbates colitis in various mouse models of IBD. Smad7 is also over-expressed in other inflammatory disorders of the gut, such as refractory celiac disease, necrotizing enterocolitis and cytomegalovirus-induced colitis, even though evidence is still scarce and mainly descriptive. Furthermore, Smad7 has been involved in colon carcinogenesis through complex and heterogeneous mechanisms, and Smad7 polymorphisms could influence cancer prognosis. In this article, we review the data about the expression and role of Smad7 in intestinal inflammation and cancer

Psychological Outcomes in Children and Early Adolescents With Type 1 Diabetes Following Pediatric Diabetes Summer Camp: A 3-Month Follow-Up Study

Objective: The aim of this study was to assess general psychosocial adjustment to diabetes and perceived disease management among patients with type 1 diabetes (T1D) and their parents before and after patients' participation in a diabetes summer camp. Methods: In this follow-up study, 20 children and adolescents with T1D (eight boys; mean age = 11.01 ± 0.94 years; mean diabetes duration = 3.02 ± 2.27) attending a southern Italian diabetic center, along with their parents, were assessed prior to and 3 months after the youths participated in a 1 week camp-based intervention involving didactic and interactive child-centered education and recreational activities. Patients and their parents completed measures assessing patients' quality of life and strategies employed by patients to cope with pain. Patients also completed measures evaluating their diabetes psychosocial adjustment, diabetes self-efficacy management, and illness perception; also, their parents completed measures of caregivers' perceived diabetes burden and treatment satisfaction. Youths' glycated hemoglobin (HbA1c) and standardized body mass index (z-BMI) values were also assessed. Within-subjects repeated-measures analyses of variance evaluated pre- and post-camp changes. Results: Camp attendance showed no beneficial effects on glycemic control, as indicated by HbA1c values both before (7.02%) and after (7.28%) camp being lower than 7.5%. HbA1c values were found to have increased after camp (pre-camp = 7.02%, post-camp = 7.28%; p = 0.010), but since they still fell within an acceptable range, they did not reveal clinically relevant changes in glycemic control. No substantial significant improvement in psychosocial measures was observed in children or parents (all p > 0.05). According to the parents' evaluation, social support-seeking as a patient pain-coping strategy was slightly increased (p = 0.044) after attending the camp. Conclusions: This study does not provide empirical evidence of benefits of participating in a diabetes camp for either patients or their parents. These findings suggest that healthcare providers rethink such camps as an experience for youths with T1D that actively involves parents and that includes both youth- and parent-focused psychological interventions

Lesions associated with mineral deposition in the lymph nodes and lungs of cattle: a case-control study of environmental health hazard.

This report focuses on the state of health of the cattle raised in the district of Taranto - city of Italy rated as environmentally at risk. Representative samples of lungs, bronchial and mediastinal lymph nodes of cattle from district of Taranto's slaughterhouses were collected. After a macroscopic examination, samples with marked lesions were processed for light microscopy. Samples were also observed with polarized light microscopy, scanning electron microscopy and with microanalysis. The macroscopic examination revealed that 60 out of 183 samples showed marked lesions. Lung alterations were characterized by thickening of the alveolar septa and by the latter's modifying action on the alveolar spaces, foci of fibrosis and bronchopulmonary inflammation. For 51 out of the 60 samples observed, the histological examination confirmed the presence of pneumoconiosis and lymph nodal anthracosis. Energy-dispersive X-ray microanalysis of lung samples identified a wide range of elements including silicon, aluminium, titanium, iron, carbon and small amount of the other metals. In the lymph-nodes the same kind of metals with a different levels of distribution was observed. Our survey on cattle farmed in areas at high risk of pollution may be helpful to the estimation of the exposure risk for man to environmental contaminants and to the evaluation of the occurrence of the pathological manifestations as well

Body Image Problems in Individuals with Type 1 Diabetes: A Review of the Literature

Despite type 1 diabetes' (T1D) potential influence on adolescents' physical development, the occurrence of body image problems of adolescents with diabetes remains unclear. No research synthesis has yet addressed this issue. This study aims to systematically evaluate the empirical evidence concerning body image in individuals with T1D in order to provide an overview of the existing literature. Using PRISMA methodology, 51 relevant studies that fulfilled the eligibility criteria were found, the majority of them (N = 48) involving youth. The findings varied across studies: 17 studies indicated that in youth with T1D, body dissatisfaction was common and that body concerns were generally greater in youth with T1D than in controls; nine studies did not find any differences in body image problems between participants with and without T1D; three studies described higher body satisfaction in youth with diabetes than in controls; and three studies reported mixed results. Body concerns in individuals with T1D were often found to be associated with negative medical and psychological functioning. The variability and limits in assessment tools across studies, the overrepresentation of female subjects, and the fact that most research in this field is based on cross-sectional data are stressed in the interpretation of these mixed findings. Future research directions that could improve the understanding of body image concerns and clinical implications are discussed

Characterization of globulin storage proteins of a low prolamin cereal species in relation to celiac disease

Brachypodium distachyon, a small annual grass with seed storage globulins as primary protein reserves was used in our study to analyse the toxic nature of non-prolamin seed storage proteins related to celiac disease. The main storage proteins of B. distachyon are the 7S globulin type proteins and the 11S, 12S seed storage globulins similar to oat and rice. Immunoblot analyses using serum samples from celiac disease patients were carried out followed by the identification of immune-responsive proteins using mass spectrometry. Serum samples from celiac patients on a gluten-free diet, from patients with Crohn's disease and healthy subjects, were used as controls. The identified proteins with intense serum-IgA reactivity belong to the 7S and 11-12S seed globulin family. Structure prediction and epitope predictions analyses confirmed the presence of celiac disease-related linear B cell epitope homologs and the presence of peptide regions with strong HLA-DQ8 and DQ2 binding capabilities. These results highlight that both MHC-II presentation and B cell response may be developed not only to prolamins but also to seed storage globulins. This is the first study of the non-prolamin type seed storage proteins of Brachypodium from the aspect of the celiac disease