Perfluorooctanoic acid exposure triggers oxidative stress in the mouse pancreas

• PFOA triggers focal ductal hyperplasia following 7 day exposure. • PFOA exposure increases 8-iso-PGF2α levels in the pancreas. • Antioxidant gene expression is upregulated in the pancreas following PFOA exposure. , Perfluorooctanoic acid (PFOA) is used in the manufacture of many industrial and commercial products. PFOA does not readily decompose in the environment, and is biologically persistent. Human epidemiologic and animal studies suggest that PFOA exposure elicits adverse effects on the pancreas. While multiple animal studies have examined PFOA-mediated toxicity in the liver, little is known about the potential adverse effects of PFOA on the pancreas. To address this, we treated C57Bl/6 mice with vehicle, or PFOA at doses of 0.5, 2.5 or 5.0 mg/kg BW/day for 7 days. Significant accumulation of PFOA was found in the serum, liver and pancreas of PFOA-treated animals. Histopathologic examination of the pancreas revealed focal ductal hyperplasia in mice treated with 2.5 and 5.0 mg/kg BW/day PFOA, while inflammation was observed only in the high dose group. Elevated serum levels of amylase and lipase were observed in the 2.5 mg/kg BW/day PFOA treatment group. In addition, PFOA exposure resulted in a dose-dependent increase in the level of the lipid peroxidation product 8-iso-PGF2α and induction of the antioxidant response genes Sod1, Sod2, Gpx2 and Nqo1. Our findings provide additional evidence that the pancreas is a target organ for PFOA-mediated toxicity and suggest that oxidative stress may be a mechanism through which PFOA induces histopathological changes in the pancreas

Skin examination behavior: the role of melanoma history, skin type, psychosocial factors, and region of residence in determining clinical and self-conducted skin examination

Objective: To examine the frequency and correlates of skin examination behaviors in an international sample of individuals at varying risk of developing melanoma. Design: A cross-sectional, web-based survey. Setting: Data were collected from the general population over a 20-month period on behalf of the Melanoma Genetics Consortium (GenoMEL). Participants: A total of 8178 adults from Northern (32%), Central (33%), and Southern (14%) Europe, Australia (13%), and the United States (8%). Main outcome measures: Self-reported frequency of skin self-examination (SSE) and clinical skin examination (CSE). Results: After adjustment for age and sex, frequency of skin examination was higher in both Australia (odds ratio [OR]SSE=1.80 [99% CI, 1.49-2.18]; ORCSE=2.68 [99% CI, 2.23-3.23]) and the United States (ORSSE=2.28 [99% CI, 1.76-2.94]; ORCSE=3.39 [99% CI, 2.60-4.18]) than in the 3 European regions combined. Within Europe, participants from Southern Europe reported higher rates of SSE than those in Northern Europe (ORSSE=1.61 [99% CI, 1.31-1.97]), and frequency of CSE was higher in both Central (ORCSE=1.47 [99% CI, 1.22-1.78]) and Southern Europe (ORCSE=3.46 [99% CI, 2.78, 4.31]) than in Northern Europe. Skin examination behavior also varied according to melanoma history: participants with no history of melanoma reported the lowest levels of skin examination, while participants with a previous melanoma diagnosis reported the highest levels. After adjustment for region, and taking into account the role of age, sex, skin type, and mole count, engagement in SSE and CSE was associated with a range of psychosocial factors, including perceived risk of developing melanoma; perceived benefits of, and barriers to, skin examination; perceived confidence in one's ability to engage in screening; and social norms. In addition, among those with no history of melanoma, higher cancer-related worry was associated with greater frequency of SSE. Conclusions: Given the strong association between psychosocial factors and skin examination behaviors, particularly among people with no history of melanoma, we recommend that greater attempts be made to integrate psycho-education into the fabric of public health initiatives and clinical care, with clinicians, researchers, and advocacy groups playing a key role in guiding individuals to appropriate tools and resources

Prevalence of variations in melanoma susceptibility genes among Slovenian melanoma families

<p>Abstract</p> <p>Background</p> <p>Two high-risk genes have been implicated in the development of CM (cutaneous melanoma). Germline mutations of the CDKN2A gene are found in < 25% of melanoma-prone families and there are only seven families with mutation of the <it>CDK4 </it>gene reported to date. Beside those high penetrance genes, certain allelic variants of the <it>MC1R </it>gene modify the risk of developing the disease.</p> <p>The aims of our study were: to determine the prevalence of germline <it>CDKN2A </it>mutations and variants in members of families with familial CM and in patients with multiple primary CM; to search for possible <it>CDK4 </it>mutations, and to determine the frequency of variations in the <it>MC1R </it>gene.</p> <p>Methods</p> <p>From January 2001 until January 2007, 64 individuals were included in the study. The group included 28 patients and 7 healthy relatives belonging to 25 families, 26 patients with multiple primary tumors and 3 children with CM. Additionally 54 healthy individuals were included as a control group. Mutations and variants of the melanoma susceptibility genes were identified by direct sequencing.</p> <p>Results</p> <p>Seven families with CDKN2A mutations were discovered (7/25 or 28.0%). The L94Q mutation found in one family had not been previously reported in other populations. The D84N variant, with possible biological impact, was discovered in the case of patient without family history but with multiple primary CM. Only one mutation carrier was found in the control group. Further analysis revealed that c.540C>T heterozygous carriers were more common in the group of CM patients and their healthy relatives (11/64 vs. 2/54). One p14ARF variant was discovered in the control group and no mutations of the <it>CDK4 </it>gene were found.</p> <p>Most frequently found variants of the <it>MC1R </it>gene were T314T, V60L, V92M, R151C, R160W and R163Q with frequencies slightly higher in the group of patients and their relatives than in the group of controls, but the difference was statistically insignificant.</p> <p>Conclusion</p> <p>The present study has shown high prevalence of p16INK4A mutations in Slovenian population of familial melanoma patients (37%) and an absence of p14ARF or <it>CDK4 </it>mutations.</p

Estimating CDKN2A mutation carrier probability among global familial melanoma cases using GenoMELPREDICT

Background: Although rare in the general population, highly penetrant germline mutations in CDKN2A are responsible for 5%-40% of melanoma cases reported in melanoma-prone families. We sought to determine whether MELPREDICT was generalizable to a global series of families with melanoma and whether performance improvements can be achieved. Methods: In total, 2116 familial melanoma cases were ascertained by the international GenoMEL Consortium. We recapitulated the MELPREDICT model within our data (GenoMELPREDICT) to assess performance improvements by adding phenotypic risk factors and history of pancreatic cancer. We report areas under the curve (AUC) with 95% confidence intervals (CIs) along with net reclassification indices (NRIs) as performance metrics. Results: MELPREDICT performed well (AUC 0.752, 95% CI 0.730-0.775), and GenoMELPREDICT performance was similar (AUC 0.748, 95% CI 0.726-0.771). Adding a reported history of pancreatic cancer yielded discriminatory improvement (P &lt; .0001) in GenoMELPREDICT (AUC 0.772, 95% CI 0.750-0.793, NRI 0.40). Including phenotypic risk factors did not improve performance. Conclusion: The MELPREDICT model functioned well in a global data set of familial melanoma cases. Adding pancreatic cancer history improved model prediction. GenoMELPREDICT is a simple tool for predicting CDKN2A mutational status among melanoma patients from melanoma-prone families and can aid in directing these patients to receive genetic testing or cancer risk counseling

Transforming growth factor-β and breast cancer: Tumor promoting effects of transforming growth factor-β

The transforming growth factor (TGF)-βs are potent growth inhibitors of normal epithelial cells. In established tumor cell systems, however, the preponderant experimental evidence suggests that TGF-βs can foster tumor-host interactions that indirectly support the viability and/or progression of cancer cells. The timing of this 'TGF-β switch' during the progressive transformation of epithelial cells is not clear. More recent evidence also suggests that autocrine TGF-β signaling is operative in some tumor cells, and can also contribute to tumor invasiveness and metastases independent of an effect on nontumor cells. The dissociation of antiproliferative and matrix associated effects of autocrine TGF-β signaling at a transcriptional level provides for a mechanism(s) by which cancer cells can selectively use this signaling pathway for tumor progression. Data in support of the cellular and molecular mechanisms by which TGF-β signaling can accelerate the natural history of tumors will be reviewed in this section

Particulate matter exposure during pregnancy is associated with birth weight, but not gestational age, 1962-1992: a cohort study

<p>Abstract</p> <p>Background</p> <p>Exposure to air pollutants is suggested to adversely affect fetal growth, but the evidence remains inconsistent in relation to specific outcomes and exposure windows.</p> <p>Methods</p> <p>Using birth records from the two major maternity hospitals in Newcastle upon Tyne in northern England between 1961 and 1992, we constructed a database of all births to mothers resident within the city. Weekly black smoke exposure levels from routine data recorded at 20 air pollution monitoring stations were obtained and individual exposures were estimated via a two-stage modeling strategy, incorporating temporally and spatially varying covariates. Regression analyses, including 88,679 births, assessed potential associations between exposure to black smoke and birth weight, gestational age and birth weight standardized for gestational age and sex.</p> <p>Results</p> <p>Significant associations were seen between black smoke and both standardized and unstandardized birth weight, but not for gestational age when adjusted for potential confounders. Not all associations were linear. For an increase in whole pregnancy black smoke exposure, from the 1^st(7.4 μg/m³) to the 25^th(17.2 μg/m³), 50^th(33.8 μg/m³), 75^th(108.3 μg/m³), and 90^th(180.8 μg/m³) percentiles, the adjusted estimated decreases in birth weight were 33 g (SE 1.05), 62 g (1.63), 98 g (2.26) and 109 g (2.44) respectively. A significant interaction was observed between socio-economic deprivation and black smoke on both standardized and unstandardized birth weight with increasing effects of black smoke in reducing birth weight seen with increasing socio-economic disadvantage.</p> <p>Conclusions</p> <p>The findings of this study progress the hypothesis that the association between black smoke and birth weight may be mediated through intrauterine growth restriction. The associations between black smoke and birth weight were of the same order of magnitude as those reported for passive smoking. These findings add to the growing evidence of the harmful effects of air pollution on birth outcomes.</p

Loss of Disabled-2 Expression in Pancreatic Cancer Progression

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer type characterized by rapid metastasis and resistance to chemotherapy, properties that are shared by cancer stem cells (CSCs). In pancreatic cancer, tumor cells which possess the properties of CSCs also phenotypically resemble cells that have undergone epithelial-to-mesenchymal transition or EMT. Disabled-2 (Dab2) is a multifunctional scaffold protein frequently downregulated in cancer that has been linked to the process of EMT. However, the role of Dab2 in pancreatic cancer development and progression remains unclear. Downregulation of Dab2 expression in pancreatic cancer cell lines was found to trigger induction of genes characteristic of EMT and the CSC phenotype, while overexpression of Dab2 in the Panc1 cell line blocked the process of TGFβ-stimulated EMT. In addition, selective inhibition of the TGFβRI/RII receptors was found to reverse genes altered by Dab2 downregulation. Dab2 mRNA expression was found to be decreased in PDAC tumor samples, as compared to levels observed in normal pancreatic tissue. Methylation of the Dab2 gene promoter was demonstrated in Stage I PDAC tumors and in the MiaPaCa2 cell line, suggesting that promoter methylation may silence Dab2 expression early in pancreatic cancer progression. These results suggest that Dab2 may function as a tumor suppressor in pancreatic cancer by modulation of the TGFβ-stimulated EMT and CSC phenotype

Non-Linear Vibrations of a Beam Having Variable Cross Section Under Periodic Lateral Forces : Series C : Vibration, Control Engineering, Engineering for Industry

PURPOSE: Approximately 20-30% of breast cancer tumors overexpress or amplify human epidermal growth factor receptor 2 (HER2). The role of this receptor in the progression of HER2+ breast cancer and resistance to certain anticancer monotherapies was investigated. The results of several pre-clinical and clinical trials, with the aim of determining the most safe and effective course of treatment for HER2+ breast cancer, were also thoroughly examined. METHODS: A thorough search of databases including Pubmed, Springer, and The American Society of Clinical Oncology was performed, and pertinent studies were identified. The most relevant studies were preclinical, phase II, and III clinical trials identifying the function of the HER2 receptor in HER2+ breast cancer progression, as well as studies assessing the efficacy of monotherapy and combination therapy in the treatment of this aggressive form of cancer. RESULTS: The HER2 receptor belongs to a family of receptors that consists of four cell-surface receptors (HER1-4) that share strong homology with the epidermal growth factor receptor (EGFR). All HER receptors interact with specific types of ligands to induce receptor activation, except for HER2, for which no known ligand has yet been identified. HER2 is activated by forming dimers with other HER receptors, and this results in a stronger and more prolonged signal transduction event. When expressed at normal levels, HER2 regulates cell growth, differentiation, and survival. However, under pathological conditions of HER2 overexpression, numerous HER2 heterodimers are formed resulting in aggressive tumor growth. Therefore, the prognosis associated with HER2-positive breast cancer is usually poor. A specific cohort of patients with breast cancer whose tumors test both hormone receptor (estrogen receptor [ER] and progesterone receptor [PR]) and HER2 positive have been found to be resistant to targeted hormone therapy. Studies investigating the etiology of this resistance have found that the cell membrane estrogen receptor communicates with HER2 in promoting the release of ER coactivators that cause the endocrine drug and selective estrogen receptor modulator, tamoxifen, to act as an agonist rather than an antagonist of the hormone estrogen. Thus, research has directed its inquiry toward the development of therapies specifically targeting HER2. The development of trastuzumab, a recombinant monoclonal antibody against HER2, initially proved to be a well-tolerated first line of treatment. However, in the long-term patients, trastuzumab was shown to develop resistance to this monotherapy. Therefore, research on HER2 positive breast cancer has focused on the study of different anti-HER2 combination therapies over the past decade. CONCLUSIONS: While the development and approval of the HER2-targeted recombinant monoclonal antibody trastuzumab (Herceptin) has been efficacious in slowing HER2 cancer progression, combining this and other anti-HER2 therapy with either chemotherapy or endocrine therapy has proven more effective in improving overall and progression free survival

Progression and Treatment of HER2-Positive Breast Cancer

PURPOSE: Approximately 20-30% of breast cancer tumors overexpress or amplify human epidermal growth factor receptor 2 (HER2). The role of this receptor in the progression of HER2+ breast cancer and resistance to certain anticancer monotherapies was investigated. The results of several pre-clinical and clinical trials, with the aim of determining the most safe and effective course of treatment for HER2+ breast cancer, were also thoroughly examined. METHODS: A thorough search of databases including Pubmed, Springer, and The American Society of Clinical Oncology was performed, and pertinent studies were identified. The most relevant studies were preclinical, phase II, and III clinical trials identifying the function of the HER2 receptor in HER2+ breast cancer progression, as well as studies assessing the efficacy of monotherapy and combination therapy in the treatment of this aggressive form of cancer. RESULTS: The HER2 receptor belongs to a family of receptors that consists of four cell-surface receptors (HER1-4) that share strong homology with the epidermal growth factor receptor (EGFR). All HER receptors interact with specific types of ligands to induce receptor activation, except for HER2, for which no known ligand has yet been identified. HER2 is activated by forming dimers with other HER receptors, and this results in a stronger and more prolonged signal transduction event. When expressed at normal levels, HER2 regulates cell growth, differentiation, and survival. However, under pathological conditions of HER2 overexpression, numerous HER2 heterodimers are formed resulting in aggressive tumor growth. Therefore, the prognosis associated with HER2-positive breast cancer is usually poor. A specific cohort of patients with breast cancer whose tumors test both hormone receptor (estrogen receptor [ER] and progesterone receptor [PR]) and HER2 positive have been found to be resistant to targeted hormone therapy. Studies investigating the etiology of this resistance have found that the cell membrane estrogen receptor communicates with HER2 in promoting the release of ER coactivators that cause the endocrine drug and selective estrogen receptor modulator, tamoxifen, to act as an agonist rather than an antagonist of the hormone estrogen. Thus, research has directed its inquiry toward the development of therapies specifically targeting HER2. The development of trastuzumab, a recombinant monoclonal antibody against HER2, initially proved to be a well-tolerated first line of treatment. However, in the long-term patients, trastuzumab was shown to develop resistance to this monotherapy. Therefore, research on HER2 positive breast cancer has focused on the study of different anti-HER2 combination therapies over the past decade. CONCLUSIONS: While the development and approval of the HER2-targeted recombinant monoclonal antibody trastuzumab (Herceptin) has been efficacious in slowing HER2 cancer progression, combining this and other anti-HER2 therapy with either chemotherapy or endocrine therapy has proven more effective in improving overall and progression free survival