Age-related biological features of germ cell tumors.

Germ cell tumors (GCTs) are rare but clinically and pathologically diverse tumors that occur in an extensive range of age groups, from children to older adults and which include both seminomatous and nonseminomatous tumors. Current clinical management for both male and female teenagers and young adults (TYAs) with GCTs remains inconsistent, alternating between pediatric and adult multidisciplinary oncology teams, based on locally defined age cutoffs. Therefore, we reviewed available literature to determine the biological similarities and differences between GCTs in young children (0-12 years), TYAs (13-24 years), and older adults (>24 years). GCTs arising in pediatric and adult populations in general showed marked molecular biological differences within identical histological subtypes, whereas there was a distinct paucity of available data for GCTs in the TYA population. These findings highlight that clinical management based simply on chronological age may be inappropriate for TYA and suggests that the optimal future management of GCTs should consider specific molecular biological factors in addition to clinical parameters in the context of patient-specific age group rather than medical specialty.This is the accepted manuscript. The final version is available at http://onlinelibrary.wiley.com/doi/10.1002/gcc.22131/abstract

MAGE, BAGE and GAGE: tumour antigen expression in benign and malignant ovarian tissue.

To determine if ovarian cancer patients would be suitable for MAGE-peptide vaccine-based immunotherapy, the frequency of expression of the MAGE-1-4 genes in ovarian tumours was assessed using reverse transcription polymerase chain reaction (RT-PCR) and product verification with digoxigenin-labelled oligonucleotide probes specific for each MAGE gene. In addition, the frequency of expression of more recently discovered tumour antigens (BAGE, GAGE -1, -2 and GAGE -3, -6) was established using RT-PCR and ethidium bromide staining. In this study 1/16 normal ovarian tissue specimens and 11/25 benign lesions expressed MAGE-1. In non-malignant tissue there was preferential expression of MAGE-1 in premenopausal women. A total of 15/27 malignant specimens expressed MAGE-1, including 10/14 serous cystadenocarcinomas. Expression of other tumour antigens was infrequent. The finding of MAGE-1 expression in both benign and malignant tissue questions previous assumptions regarding the role of MAGE genes in carcinogenesis. In addition, preferential MAGE-1 gene expression in non-malignant premenopausal tissue suggests that the MAGE genes may be involved in cellular proliferation as opposed to carcinogenesis or possibly that MAGE gene expression is under cyclical hormonal control. Finally, this study indicates that serous cystadenocarcinomas may be suitable tumours for MAGE-1 peptide immunotherapy

Serum microRNA screening for DICER1-associated pleuropulmonary blastoma.

CT chest scanning has been recommended to screen for pleuropulmonary blastoma (PPB) in babies and young children known to harbor germline DICER1 mutations. However, only a minority of these patients will develop PPB, and the use of CT scans is associated with risks such as secondary malignancy. Recently, we identified a panel of microRNAs that were highly abundant in the serum of a patient with a germline DICER1-mutated PPB, but present at normal levels in healthy relatives carrying the same germline mutation. Consequently, we advocate the addition of serum microRNA profiling to this programme of radiological surveillance, in order to establish its clinical utility as a PPB biomarker. If validated, this blood-based screening-tool may reduce our reliance on CT imaging.This is the accepted manuscript. The final version is available at http://onlinelibrary.wiley.com/doi/10.1002/pbc.25209/abstract

Newtonian Hydrodynamics of the Coalescence of Black Holes with Neutron Stars I: Tidally locked binaries with a stiff equation of state

We present a detailed study of the hydrodynamical interactions in a Newtonian black hole-neutron star binary during the last stages of inspiral. We consider close binaries which are tidally locked, use a stiff equation of state (with an adiabatic index Gamma=3) throughout, and explore the effect of different initial mass ratios on the evolution of the system. We calculate the gravitational radiation signal in the quadrupole approximation. Our calculations are carried out using a Smooth Particle Hydrodynamics (SPH) code.Comment: Replaces previous version which had figures separate from the text of the paper. Now 47 pages long with 19 embedded figures (the figures are the same, they were renumbered) Uses aaspp4.st

Socio-economic status and lifestyle factors are associated with achalasia risk: a population-based case-control study.

AIM: To evaluate the association between various lifestyle factors and achalasia risk. METHODS: A population-based case-control study was conducted in Northern Ireland, including n = 151 achalasia cases and n = 117 age- and sex-matched controls. Lifestyle factors were assessed via a face-to-face structured interview. The association between achalasia and lifestyle factors was assessed by unconditional logistic regression, to produce odds ratios (OR) and 95% confidence interval (CI). RESULTS: Individuals who had low-class occupations were at the highest risk of achalasia (OR = 1.88, 95%CI: 1.02-3.45), inferring that high-class occupation holders have a reduced risk of achalasia. A history of foreign travel, a lifestyle factor linked to upper socio-economic class, was also associated with a reduced risk of achalasia (OR = 0.59, 95%CI: 0.35-0.99). Smoking and alcohol consumption carried significantly reduced risks of achalasia, even after adjustment for socio-economic status. The presence of pets in the house was associated with a two-fold increased risk of achalasia (OR = 2.00, 95%CI: 1.17-3.42). No childhood household factors were associated with achalasia risk. CONCLUSION: Achalasia is a disease of inequality, and individuals from low socio-economic backgrounds are at highest risk. This does not appear to be due to corresponding alcohol and smoking behaviours. An observed positive association between pet ownership and achalasia risk suggests an interaction between endotoxin and viral infection exposure in achalasia aetiology

Warp diffusion in accretion discs: a numerical investigation

In this paper we explore numerically the evolution of a warped accretion disc. Here, we focus here on the regime where the warp evolves diffusively. By comparing the numerical results to a simple diffusion model, we are able to determine the diffusion coefficient of the warp, $\alpha_2$, as a function of the relevant disc parameters. We find that while in general the disc behaviour is well reproduced by the diffusion model and for relatively large viscosities the warp diffusion is well described by the linear theory (in particular confirming that the warp diffusion coefficient is inversely proportional to viscosity), significant non-linear effects are present as the viscosity becomes smaller, but still dominates over wave-propagation effects. In particular, we find that the inverse dependence of the diffusion coefficient on viscosity breaks down at low viscosities, so that $\alpha_2$ never becomes larger than a saturation value $\alpha_{\rm max}$ of order unity. This can have major consequences in the evolution of systems where a warped disc is present. In particular, it affects the location of the warp radius in the Bardeen-Petterson effect and therefore the spin up (or spin down) of supermassive black holes in the nuclei of galaxies. Additionally, we also find that while the rate of warp diffusion does not depend significantly on the detailed viscosity formulation, the rate of internal precession generated by the warp is strongly affected by it. Such effects should be considered with care when modeling the evolution of warped discs. This emphasises the need to test the above results using different numerical schemes, and with higher resolution, in order to investigate the degree to which numerical simulations are able to provide accurate modeling of the complex fluid dynamics of warped discs. (Abridged)Comment: 17 pages, accepted for publication in MNRA

Solid tumors of childhood display specific serum microRNA profiles.

BACKGROUND: Serum biomarkers for diagnosis and risk stratification of childhood solid tumors would improve the accuracy/timeliness of diagnosis and reduce the need for invasive biopsies. We hypothesized that differential expression and/or release of microRNAs (miRNAs) by such tumors may be detected as altered serum miRNA profiles. METHODS: We undertook global quantitative reverse transcription PCR (qRT-PCR) miRNA profiling (n = 741) on RNA from 53 serum samples, representing 33 diagnostic cases of common childhood cancers plus 20 controls. Technical confirmation was performed in a subset of 21 cases, plus four independent samples. RESULTS: We incorporated robust quality control steps for RNA extraction, qRT-PCR efficiency and hemolysis quantification. We evaluated multiple methods to normalize global profiling data and identified the 'global mean' approach as optimal. We generated a panel of six miRNAs that were most stable in pediatric serum samples and therefore most suitable for normalization of targeted miRNA qRT-PCR data. Tumor-specific serum miRNA profiles were identified for each tumor type and selected miRNAs underwent confirmatory testing. We identified a panel of miRNAs (miR-124-3p/miR-9-3p/miR-218-5p/miR-490-5p/miR-1538) of potential importance in the clinical management of neuroblastoma, as they were consistently highly overexpressed in MYCN-amplified high-risk cases (MYCN-NB). We also derived candidate miRNA panels for noninvasive differential diagnosis of a liver mass (hepatoblastoma vs. combined MYCN-NB/NB), an abdominal mass (Wilms tumor vs. combined MYCN-NB/NB), and sarcoma subtypes. CONCLUSIONS: This study describes a pipeline for robust diagnostic serum miRNA profiling in childhood solid tumors, and has identified candidate miRNA profiles for prospective testing. IMPACT: We propose a new noninvasive method with the potential to diagnose childhood solid tumors.RCUK, OtherThis is the Author Accepted Manuscript. The final version is available from AACR at http://cebp.aacrjournals.org/content/24/2/350.lon

Cost analysis of noninvasive blood-based microRNA testing versus CT scans for follow-up in patients with testicular germ-cell tumors

BACKGROUND: Our group has developed a noninvasive blood-based microRNA (miRNA) test for improving diagnosis, disease monitoring, and relapse detection in malignant testicular germ-cell tumors (TGCTs). Performance analysis suggests the test is likely to have comparable sensitivity and specificity in detecting TGCT as computed tomography (CT), thus reducing the need for serial CT scans for follow-up monitoring, with associated reductions in cumulative radiation burden and second cancer risk. To facilitate clinical adoption, we undertook a cost analysis to identify the budget impact of replacing CT scans with miRNA testing within health care systems. METHODS: The TGCT aftercare pathway was mapped out using National Comprehensive Cancer Network guidelines. A Markov model was built to simulate the impact of the miRNA test on TGCT aftercare costs. Incidence, treatment probabilities, relapse rate, and death rate data were collected from published studies to populate the model. RESULTS: Applying our model to the US health care system, the miRNA test has the potential to save up to $69 million per year in aftercare expenses related to TGCT treatment, with exact savings depending on the adoption rate and test price. CONCLUSION: This analysis demonstrates the potential positive budget impact of adopting miRNA testing in place of CT scans in the clinical management of TGCTs