Digitoxin medication and cancer; case control and internal dose-response studies

BACKGROUND: Digitoxin induces apoptosis in different human malignant cell lines in vitro. In this paper we investigated if patients taking digitoxin for cardiac disease have a different cancer incidence compared to the general population. METHODS: Computer stored data on digitoxin concentrations in plasma from 9271 patients with cardiac disease were used to define a user population. Age and sex matched controls from the Norwegian Cancer Registry were used to calculate the number of expected cancer cases. RESULTS: The population on digitoxin showed a higher incidence of cancer compared to the control population. However, an additional analysis showed that the population on digitoxin had a general increased risk of cancer already, before the start on digitoxin. Leukemia/lymphoma were the cancer types which stood out with the highest risk in the digitoxin population before starting on digitoxin. This indicates that yet unknown risk factors exist for cardiovascular disease and lymphoproliferative cancer. An internal dose-response analysis revealed a relationship between high plasma concentration of digitoxin and a lower risk for leukemia/lymphoma and for cancer of the kidney/urinary tract. CONCLUSION: Morbidity and mortality are high in the population on digitoxin, due to high age and cardiac disease.These factors disturb efforts to isolate an eventual anticancer effect of digitoxin in this setting. Still, the results may indicate an anticancer effect of digitoxin for leukemia/lymphoma and kidney/urinary tract cancers. Prospective clinical cancer trials have to be done to find out if digitoxin and other cardiac glycosides are useful as anticancer agents

Privacy in crowdsourcing:a systematic review

The advent of crowdsourcing has brought with it multiple privacy challenges. For example, essential monitoring activities, while necessary and unavoidable, also potentially compromise contributor privacy. We conducted an extensive literature review of the research related to the privacy aspects of crowdsourcing. Our investigation revealed interesting gender differences and also differences in terms of individual perceptions. We conclude by suggesting a number of future research directions.</p

A human MAP kinase interactome.

Mitogen-activated protein kinase (MAPK) pathways form the backbone of signal transduction in the mammalian cell. Here we applied a systematic experimental and computational approach to map 2,269 interactions between human MAPK-related proteins and other cellular machinery and to assemble these data into functional modules. Multiple lines of evidence including conservation with yeast supported a core network of 641 interactions. Using small interfering RNA knockdowns, we observed that approximately one-third of MAPK-interacting proteins modulated MAPK-mediated signaling. We uncovered the Na-H exchanger NHE1 as a potential MAPK scaffold, found links between HSP90 chaperones and MAPK pathways and identified MUC12 as the human analog to the yeast signaling mucin Msb2. This study makes available a large resource of MAPK interactions and clone libraries, and it illustrates a methodology for probing signaling networks based on functional refinement of experimentally derived protein-interaction maps

Detection of regulator genes and eQTLs in gene networks

Genetic differences between individuals associated to quantitative phenotypic traits, including disease states, are usually found in non-coding genomic regions. These genetic variants are often also associated to differences in expression levels of nearby genes (they are "expression quantitative trait loci" or eQTLs for short) and presumably play a gene regulatory role, affecting the status of molecular networks of interacting genes, proteins and metabolites. Computational systems biology approaches to reconstruct causal gene networks from large-scale omics data have therefore become essential to understand the structure of networks controlled by eQTLs together with other regulatory genes, and to generate detailed hypotheses about the molecular mechanisms that lead from genotype to phenotype. Here we review the main analytical methods and softwares to identify eQTLs and their associated genes, to reconstruct co-expression networks and modules, to reconstruct causal Bayesian gene and module networks, and to validate predicted networks in silico.Comment: minor revision with typos corrected; review article; 24 pages, 2 figure

Circulating markers of arterial thrombosis and late-stage age-related macular degeneration: a case-control study.

PURPOSE: The aim of this study was to examine the relation of late-stage age-related macular degeneration (AMD) with markers of systemic atherothrombosis. METHODS: A hospital-based case-control study of AMD was undertaken in London, UK. Cases of AMD (n=81) and controls (n=77) were group matched for age and sex. Standard protocols were used for colour fundus photography and to classify AMD; physical examination included height, weight, history of or treatment for vascular-related diseases and smoking status. Blood samples were taken for measurement of fibrinogen, factor VIIc (FVIIc), factor VIIIc, prothrombin fragment F1.2 (F1.2), tissue plasminogen activator, and von Willebrand factor. Odds ratios from logistic regression analyses of each atherothrombotic marker with AMD were adjusted for age, sex, and established cardiovascular disease risk factors, including smoking, blood pressure, body mass index, and total cholesterol. RESULTS: After adjustment FVIIc and possibly F1.2 were inversely associated with the risk of AMD; per 1 standard deviation increase in these markers the odds ratio were, respectively, 0.62 (95% confidence interval 0.40, 0.95) and 0.71 (0.46, 1.09). None of the other atherothrombotic risk factors appeared to be related to AMD status. There was weak evidence that aspirin is associated with a lower risk of AMD. CONCLUSIONS: This study does not provide strong evidence of associations between AMD and systematic markers of arterial thrombosis, but the potential effects of FVIIc, and F1.2 are worthy of further investigation

Chronic psychosocial and financial burden accelerates 5-year telomere shortening: findings from the Coronary Artery Risk Development in Young Adults Study.

Leukocyte telomere length, a marker of immune system function, is sensitive to exposures such as psychosocial stressors and health-maintaining behaviors. Past research has determined that stress experienced in adulthood is associated with shorter telomere length, but is limited to mostly cross-sectional reports. We test whether repeated reports of chronic psychosocial and financial burden is associated with telomere length change over a 5-year period (years 15 and 20) from 969 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) Study, a longitudinal, population-based cohort, ages 18-30 at time of recruitment in 1985. We further examine whether multisystem resiliency, comprised of social connections, health-maintaining behaviors, and psychological resources, mitigates the effects of repeated&nbsp;burden on telomere attrition over 5 years. Our results indicate that adults with high chronic burden do not show decreased telomere length over the 5-year period. However, these effects do vary by level of resiliency, as regression results revealed a significant interaction between chronic burden and multisystem resiliency. For individuals with high repeated&nbsp;chronic burden and low multisystem resiliency (1 SD below the mean), there was a significant 5-year shortening in telomere length, whereas no significant relationships between chronic burden and attrition were evident for those at moderate and higher levels of resiliency. These effects apply similarly across the three components of resiliency. Results imply that interventions should focus on establishing strong social connections, psychological resources, and health-maintaining behaviors when attempting to ameliorate stress-related decline in telomere length among at-risk individuals

Disrupted postnatal lung development in heme oxygenase-1 deficient mice

BACKGROUND: Heme oxygenase (HO) degrades cellular heme to carbon monoxide, iron and biliverdin. The HO-1 isoform is both inducible and cyto-protective during oxidative stress, inflammation and lung injury. However, little is known about its precise role and function in lung development. We hypothesized that HO-1 is required for mouse postnatal lung alveolar development and that vascular expression of HO-1 is essential and protective during postnatal alveolar development. METHODS: Neonatal lung development in wildtype and HO-1 mutant mice was evaluated by histological and molecular methods. Furthermore, these newborn mice were treated with postnatal dexamethasone (Dex) till postnatal 14 days, and evaluated for lung development. RESULTS: Compared to wildtype littermates, HO-1 mutant mice exhibited disrupted lung alveolar structure including simplification, disorganization and reduced secondary crest formation. These defects in alveolar development were more pronounced when these mice were challenged with Dex treatment. Expression levels of both vascular endothelial and alveolar epithelial markers were also further decreased in HO-1 mutants after Dex treatment. CONCLUSIONS: These experiments demonstrate that HO-1 is required in normal lung development and that HO-1 disruption and dexamethasone exposure are additive in the disruption of postnatal lung growth. We speculate that HO-1 is involved in postnatal lung development through modulation of pulmonary vascular development

Symptom lead times in lung and colorectal cancers: What are the benefits of symptom-based approaches to early diagnosis?

This is the final version of the article. Available from Cancer Research UK via the DOI in this record.Background: Individuals with undiagnosed lung and colorectal cancers present with non-specific symptoms in primary care more often than matched controls. Increased access to diagnostic services for patients with symptoms generates more early-stage diagnoses, but the mechanisms for this are only partially understood. Methods: We re-analysed a UK-based case-control study to estimate the Symptom Lead Time (SLT) distribution for a range of potential symptom criteria for investigation. Symptom Lead Time is the time between symptoms caused by cancer and eventual diagnosis, and is analogous to Lead Time in a screening programme. We also estimated the proportion of symptoms in lung and colorectal cancer cases that are actually caused by the cancer. Results: Mean Symptom Lead Times were between 4.1 and 6.0 months, with medians between 2.0 and 3.2 months. Symptom Lead Time did not depend on stage at diagnosis, nor which criteria for investigation are adopted. Depending on the criteria, an estimated 27-48% of symptoms in individuals with as yet undiagnosed lung cancer, and 12-32% with undiagnosed colorectal cancer are not caused by the cancer. Conclusions: In most cancer cases detected by a symptom-based programme, the symptoms are caused by cancer. These cases have a short lead time and benefit relatively little. However, in a significant minority of cases cancer detection is serendipitous. This group experiences the benefits of a standard screening programme, a substantial mean lead time and a higher probability of early-stage diagnosis.This work was supported by the National Institute for Health Research (NIHR) Programme Grants for Applied Research Programme, RP-PG-0608-10045

Estimating the workload associated with symptoms-based ovarian cancer screening in primary care: an audit of electronic medical records

BACKGROUND: Ovarian cancer is the most lethal gynaecological malignancy in the United Kingdom (UK). Studies have found that many women with ovarian cancer have symptoms for several months before diagnosis. Using a symptoms-based tool to diagnose ovarian cancer (OC) earlier is appealing, but may increase general practitioner (GP) workload because the symptoms are typically vague and non-specific. This study aimed to provide estimates of the GP workload associated with offering symptoms-based ovarian cancer screening. METHODS: A cross-sectional analysis of electronic records from four general practices in England, UK. We downloaded anonymous data on women aged 45–74 who consulted over one week to estimate the proportion who would be offered ‘screening’ according to the UK National Institute for Health and Care Excellence (NICE) guidelines and a symptoms index (Index 2) over one year. We used previous consultations (censoring women with no prior symptom at the date of their last recorded consultation) to estimate the proportion of women presenting with a new (not recorded in previous 12 months) NICE symptom each year. RESULTS: Data were obtained from 19,558 women. The proportion presenting over one week varied between practices (5%-14%), however, the proportion with an OC symptom was similar (17% overall). Over one year, an estimated 51.8% (95% CI 44.0%-59.7%) would present with an OC symptom, 26.6% (95% CI 19.3%-35.1%) with a NICE symptom and 20.3% (95% CI 13.7%-28.5%) with an Index 2 symptom. Each year, an estimated 11.9% (95% CI 5.0%-18.3%) of women would present with a new NICE symptom. CONCLUSION: One in two women aged 45–74 present to primary care at least once a year with an OC symptom, 11.9% with a new NICE symptom. This would be comparable to 2 to 8 yearly screening (depending on what symptoms triggered testing)