Proteomics Profiling of Heterozygous and Homozygous Patients with ABCA1 Gene Mutation: A Tangier Disease Molecular Map

Tangier Disease (TD) is a rare inherited disorder with approximately 100 worldwide identified cases. Alpha-lipoprotein deficiency is the main characteristic of this disease, associated with a virtual absence of High Density Lipoproteins (HDL) in blood. Additional symptoms are mild hypertriglyceridemia, neuropathy and enlarged, orange-colored tonsils. Genetically TD is caused by mutations in the ABCA1 gene, which prevent the release of cholesterol and phospholipids from cells, leading to the accumulation of lipids within cells and body tissues. In this work a TD patient and his parental heterozygous were examined from a proteomics point of view. Plasma as well as proteome and secretome of circulating monocytes were analyzed. Plasma proteins underlined in TD the imbalance of lipid trafficking and metabolism, associated with the stimulation of pro-inflammatory pathways. Proteome and secretome of monocytes highlighted an extensive down regulation of mitochondrial enzymes and vesicular trafficking agents along with a substantial cytoskeletal rearrangement, suggesting a reduced activation state of monocytes from TD homozygous patient. This work is the first proteomics profiling of heterozygous and homozygous TD phenotypes and it suggests a TD case as a model to understand general mechanisms of lipid transport and metabolism and their linkage to inflammatory processes

A case-control study of cancers of the gastric cardia in Italy.

In a case-control study of gastric cancer (GC) in high-risk and low-risk areas in Italy, 923 GCs were reviewed by one pathologist and classified according to anatomic site. There were 68 (7.4%) cancers occurring in the gastric cardia. Compared to other GCs, cardia cancer tended to occur more often in males (sex ratio 2.8 vs 1.7) and as intestinal or unclassified histologic types. Nutritional factors for cardia tumours resembled those of other GCs, showing inverse associations with the consumption of raw vegetables, citrus and other fresh fruit, and ascorbic acid, and positive associations with the intake of traditional soups and meat, protein and cholesterol, and preference for salty foods. Cigarette smoking and wine consumption were unrelated to cardia cancer risk, and there was only a weak association with total alcohol intake. Cardia tumours showed a greater familial occurrence of GC than did other sites, with a 7-fold increase in risk for those reporting two first-degree relatives with GC. The authors discuss these findings in view of the rising incidence of adenocarcinomas of the cardia and lower oesophagus that has been reported in some western countries

Lung ultrasound and BNP to detect hidden pulmonary congestion in euvolemic hemodialysis patients: a single centre experience

Background: Dry weight assessment in hemodialysis (HD) remains a challenge. The aim of the study was to investigate the prevalence of subclinical pulmonary congestion using lung ultrasound (LUS) in maintenance HD patients with no clinical or bioimpedance signs of hyperhydration. The correlation between B-lines Score (BLS) and brain natriuretic peptide (BNP) was also evaluated. Methods: Twenty-four HD patients underwent LUS and BNP dosage at the end of the mid-week HD session, monthly for 6 months. LUS was considered as positive when BLS was >15. Hospitalizations and cardiovascular events were also evaluated in relation to the BLS. Results: LUS+ patients at baseline were 16 (67%), whereas 11 (46%) showed LUS + in at least 50% of the measurements (rLUS+ patients). Only the rLUS+ patients had a higher number of cardiovascular events [p=0.019, OR: 7.4 (CI 95%. 1.32-39.8)] and hospitalizations [p=0.034, OR 5.5 (CI 95% 1.22- 24.89)]. A BNP level of 165 pg/ml was identified as cut-off value for predicting pulmonary congestion, defined by BLS >15. Conclusion: Prevalence of pulmonary congestion as assessed by LUS and persistent or recurrent BLS >15 were quite prevalent findings in euvolemic HD patients. In the patients defined as rLUS+, a higher rate of cardiovascular events and hospital admissions was registered. BNP serum levels > 165 pg/ml resulted predictive of pulmonary congestion at LUS. In the dialysis care, regular LUS examination should be reasonably included among the methods useful to detect subclinical lung congestion and to adjust patients’ dry weight

Genetic susceptibility to malignant pleural mesothelioma and other asbestos-associated diseases.

Exposure to asbestos fibers is a major risk factor for malignant pleuralmesothelioma (MPM), lung cancer, and other non-neoplastic conditions, such as asbestosis and pleural plaques. However, in the last decade many studies have shown that polymorphism in the genes involved in xenobiotic and oxidative metabolism or in DNA repair processes may play an important role in the etiology and pathogenesis of these diseases. To evaluate the association between diseases linked to asbestos and genetic variability we performed a review of studies on this topic included in the PubMed database. One hundred fifty-nine citations were retrieved; 24 of them met the inclusion criteria and were evaluated in the review. The most commonly studied GSTM1 polymorphism showed for all asbestos-linked diseases an increased risk in association with the null genotype, possibly linked to its role in the conjugation of reactive oxygen species. Studies focused on GSTT1 null and SOD2 Ala16Val polymorphisms gave conflicting results, while promising results came from studies on a1-antitrypsin in asbestosis and MPO in lung cancer. Among genetic polymorphisms associated to the risk of MPM, the GSTM1 null genotype and two variant alleles of XRCC1 and XRCC3 showed increased risks in a subset of studies. Results for the NAT2 acetylator status, SOD2 polymorphism and EPHX activity were conflicting. Major limitations in the study design, including the small size of study groups, affected the reliability of these studies. Technical improvements such as the use of high-throughput techniques will help to identify molecular pathways regulated by candidate genes

Comparison of Changes in the Lipid Profile of Postmenopausal Women With Early Stage Breast Cancer Treated With Exemestane or Letrozole

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97162/1/0091270011424153.pd

Cancer mortality in a cohort of asbestos textile workers

A cohort of 889 men and 1077 women employed for at least 1 month between 1946 and 1984 by a former Italian leading asbestos (mainly textile) company, characterised by extremely heavy exposures often for short durations, was followed up to 1996, for a total of 53 024 person-years of observation. Employment data were obtained from factory personnel records, while vital status and causes of death were ascertained through municipality registers and local health units. We observed 222 cancer deaths compared with 116.4 expected (standardized mortality ratio, SMR=191). The highest ratios were found for pleural (SMR=4105), peritoneal (SMR=1817) and lung (SMR=282) cancers. We observed direct relationships with duration of employment for lung and peritoneal cancer, and with time since first employment for lung cancer and mesothelioma. Pleural cancer risk was independent from duration (SMR=3428 for employment <1 year, 7659 for 1–4 years, 2979 for 5–9 years and 2130 for ⩾10 years). Corresponding SMRs for lung cancer were 139, 251, 233 and 531. Nonsignificantly increased ratios were found for ovarian (SMR=261), laryngeal (SMR=238) and oro-pharyngeal (SMR=226) cancers. This study confirms and further quantifies the central role of latency in pleural mesothelioma and of cumulative exposure in lung cancer

PP1γ2 and PPP1R11 Are Parts of a Multimeric Complex in Developing Testicular Germ Cells in which their Steady State Levels Are Reciprocally Related

Mice lacking the protein phosphatase 1 gamma isoforms, PP1γ1 and PP1γ2, are male-sterile due to defective germ cell morphogenesis and apoptosis. However, this deficiency causes no obvious abnormality in other tissues. A biochemical approach was employed to learn how expression versus deficiency of PP1γ2, the predominant PP1 isoform in male germ cells, affects spermatogenesis. Methods used in this study include column chromatography, western blot and northern blot analyses, GST pull-down assays, immunoprecipitation, non-denaturing gel electrophoresis, phosphatase enzyme assays, protein sequencing, and immunohistochemistry. We report for the first time that in wild-type testis, PP1γ2 forms an inactive complex with actin, protein phosphatase 1 regulatory subunit 7 (PPP1R7), and protein phosphatase 1 regulatory subunit 11 (PPP1R11), the latter, a potent PP1 inhibitor. Interestingly, PPP1R11 protein, but not its mRNA level, falls significantly in PP1γ-null testis where mature sperm are virtually absent. Conversely, both mature sperm numbers and the PPP1R11 level increase substantially in PP1γ-null testis expressing transgenic PP1γ2. PPP1R11 also appears to be ubiquitinated in PP1γ-null testis. The levels of PP1γ2 and PPP1R11 were increased in phenotypically normal PP1α-null testis. However, in PP1α-null spleen, where PP1γ2 normally is not expressed, PPP1R11 levels remained unchanged. Our data clearly show a direct reciprocal relationship between the levels of the protein phosphatase isoform PP1γ2 and its regulator PPP1R11, and suggest that complex formation between these polypeptides in testis may prevent proteolysis of PPP1R11 and thus, germ cell apoptosis

Quantification of ETS exposure in hospitality workers who have never smoked

<p>Abstract</p> <p>Background</p> <p>Environmental Tobacco Smoke (ETS) was classified as human carcinogen (K1) by the German Research Council in 1998. According to epidemiological studies, the relative risk especially for lung cancer might be twice as high in persons who have never smoked but who are in the highest exposure category, for example hospitality workers. In order to implement these results in the German regulations on occupational illnesses, a valid method is needed to retrospectively assess the cumulative ETS exposure in the hospitality environment.</p> <p>Methods</p> <p>A literature-based review was carried out to locate a method that can be used for the German hospitality sector. Studies assessing ETS exposure using biological markers (for example urinary cotinine, DNA adducts) or questionnaires were excluded. Biological markers are not considered relevant as they assess exposure only over the last hours, weeks or months. Self-reported exposure based on questionnaires also does not seem adequate for medico-legal purposes. Therefore, retrospective exposure assessment should be based on mathematical models to approximate past exposure.</p> <p>Results</p> <p>For this purpose a validated model developed by Repace and Lowrey was considered appropriate. It offers the possibility of retrospectively assessing exposure with existing parameters (such as environmental dimensions, average number of smokers, ventilation characteristics and duration of exposure). The relative risk of lung cancer can then be estimated based on the individual cumulative exposure of the worker.</p> <p>Conclusion</p> <p>In conclusion, having adapted it to the German hospitality sector, an existing mathematical model appears to be capable of approximating the cumulative exposure. However, the level of uncertainty of these approximations has to be taken into account, especially for diseases with a long latency period such as lung cancer.</p