Modeling Somatic Evolution in Tumorigenesis

Tumorigenesis in humans is thought to be a multistep process where certain mutations confer a selective advantage, allowing lineages derived from the mutated cell to outcompete other cells. Although molecular cell biology has substantially advanced cancer research, our understanding of the evolutionary dynamics that govern tumorigenesis is limited. This paper analyzes the computational implications of cancer progression presented by Hanahan and Weinberg in The Hallmarks of Cancer. We model the complexities of tumor progression as a small set of underlying rules that govern the transformation of normal cells to tumor cells. The rules are implemented in a stochastic multistep model. The model predicts that (i) early-onset cancers proceed through a different sequence of mutation acquisition than late-onset cancers; (ii) tumor heterogeneity varies with acquisition of genetic instability, mutation pathway, and selective pressures during tumorigenesis; (iii) there exists an optimal initial telomere length which lowers cancer incidence and raises time of cancer onset; and (iv) the ability to initiate angiogenesis is an important stage-setting mutation, which is often exploited by other cells. The model offers insight into how the sequence of acquired mutations affects the timing and cellular makeup of the resulting tumor and how the cellular-level population dynamics drive neoplastic evolution

Health Coverage History of Local Uninsured PatientsAssessing the Need for an Eligibility Specialist

Abstract: Uninsured Americans are a growing population as insurance premiums climb and fewer employers offer health coverage. Providing medical care to the uninsured often represents a significant financial loss to medical institutions. Our study sought to describe the insurance history and barriers to obtaining health coverage for uninsured patients at the Community Health Center of Burlington, Vermont (CHCB). The potential benefit of adding an insurance eligibility position to the staff at CHCB was also explored. Data were collected by random phone survey from 100 CHCB patients identified as uninsured at their last visit; patients were queried regarding insurance history and interest in enrollment assistance. At the time of survey 66% were currently uninsured, and the majority (87.9%) of these respondents previously held insurance. Loss of insurance was most often due to a change in job status, income or a change in eligibility. Cost was a major barrier to insurance noted by individuals; on average respondents indicated they would be willing to pay around $65 per month for overage. A majority (75.7%) of uninsured respondents also expressed interest in an onsite eligibility worker. These data suggest that the patient population at CHCB would be well served by implementing some form of eligibility staffing. There are a number of different health insurance options in Vermont that could benefit these patients, provided they have assistance with applying. Due to the small sample size of our survey, we recommend that the scope of the eligibility position be determined by closely examining the caseload encountered.https://scholarworks.uvm.edu/comphp_gallery/1025/thumbnail.jp

Bone mineral density and the risk of incident dementia:A meta-analysis

Background: It is not known whether bone mineral density (BMD) measured at baseline or as the rate of decline prior to baseline (prior bone loss) is a stronger predictor of incident dementia or Alzheimer's disease (AD). Methods:We performed a meta-analysis of three longitudinal studies, the Framingham Heart Study (FHS), the Rotterdam Study (RS), and the Rush Memory and Aging Project (MAP), modeling the time to diagnosis of dementia as a function of BMD measures accounting for covariates. We included individuals with one or two BMD assessments, aged ≥60 years, and free of dementia at baseline with follow-up available. BMD was measured at the hip femoral neck using dual-energy X-ray absorptiometry (DXA), or at the heel calcaneus using quantitative ultrasound to calculate estimated BMD (eBMD). BMD at study baseline (“baseline BMD”) and annualized percentage change in BMD prior to baseline (“prior bone loss”) were included as continuous measures. The primary outcome was incident dementia diagnosis within 10 years of baseline, and incident AD was a secondary outcome. Baseline covariates included age, sex, body mass index, ApoE4 genotype, and education. Results: The combined sample size across all three studies was 4431 with 606 incident dementia diagnoses, 498 of which were AD. A meta-analysis of baseline BMD across three studies showed higher BMD to have a significant protective association with incident dementia with a hazard ratio of 0.47 (95% CI: 0.23–0.96; p = 0.038) per increase in g/cm2, or 0.91 (95% CI: 0.84–0.995) per standard deviation increase. We observed a significant association between prior bone loss and incident dementia with a hazard ratio of 1.30 (95% CI: 1.12–1.51; p &lt; 0.001) per percent increase in prior bone loss only in the FHS cohort. Conclusions: Baseline BMD but not prior bone loss was associated with incident dementia in a meta-analysis across three studies.</p

Corporate boards and performance pricing in private debt contracts

This paper investigates the effects of corporate governance on the use of performance pricing in debt contracts on a sample of newly syndicated loans in the U.S. private debt market. While cross-sectional results provide no evidence for the predicted relation between corporate governance quality and the likelihood of using performance pricing in debt contracts, there is evidence for the predicted positive relation between corporate governance quality and the use of interest-increasing performance pricing provisions. Evidence also provides support for the predicted negative relation between corporate governance quality and the use of financial ratio as the measure of performance underlying the provisions. Overall, empirical evidence supports the hypothesis that debt-holders perceive aspects of corporate governance to be beneficial and factor them in their contracting decisions

Validation of the SF-36 in patients with endometriosis.

OBJECTIVES: Endometriosis presents with significant pain as the most common symptom. Generic health measures can allow comparisons across diseases or populations. However, the Medical Outcomes Study Short Form 36 (SF-36) has not been validated for this disease. The goal of this study was to validate the SF-36 (version 2) for endometriosis. METHODS: Using data from two clinical trials (N = 252 and 198) of treatment for endometriosis, a full complement of psychometric analyses was performed. Additional instruments included a pain visual analog scale (VAS); a physician-completed questionnaire based on patient interview (modified Biberoglu and Behrman--B&B); clinical global impression of change (CGI-C); and patient satisfaction with treatment. RESULTS: Bodily pain (BP) and the Physical Component Summary Score (PCS) were correlated with the pain VAS at baseline and over time and the B&B at baseline and end of study. In addition, those who had the greatest change in BP and PCS also reported the greatest change on CGI-C and patient satisfaction with treatment. Other subscales showed smaller, but significant, correlations with change in the pain VAS, CGI-C, and patient satisfaction with treatment. CONCLUSIONS: The SF-36--particularly BP and the PCS--appears to be a valid and responsive measure for endometriosis and its treatment

The receptor tyrosine kinase EphB4 is overexpressed in ovarian cancer, provides survival signals and predicts poor outcome

EphB4 is a member of the largest family of transmembrane receptor tyrosine kinases and plays critical roles in axonal pathfinding and blood vessel maturation. We wanted to determine the biological role of EphB4 in ovarian cancer. We studied the expression of EphB4 in seven normal ovarian specimens and 85 invasive ovarian carcinomas by immunohistochemistry. EphB4 expression was largely absent in normal ovarian surface epithelium, but was expressed in 86% of ovarian cancers. EphB4 expression was significantly associated with advanced stage of disease and the presence of ascites. Overexpression of EphB4 predicted poor survival in both univariate and multivariate analyses. We also studied the biological significance of EphB4 expression in ovarian tumour cells lines in vitro and in vivo. All five malignant ovarian tumour cell lines tested expressed higher levels of EphB4 compared with the two benign cell lines. Treatment of malignant, but not benign, ovarian tumour cell lines with progesterone, but not oestrogen, led to a 90% reduction in EphB4 levels that was associated with 50% reduction in cell survival. Inhibition of EphB4 expression by specific siRNA or antisense oligonucleotides significantly inhibited tumour cell viability by inducing apoptosis via activation of caspase-8, and also inhibited tumour cell invasion and migration. Furthermore, EphB4 antisense significantly inhibited growth of ovarian tumour xenografts and tumour microvasculature in vivo. Inhibition of EphB4 may hence have prognostic and therapeutic utility in ovarian carcinoma

Medical treatment of renal cancer: new horizons.

Renal cell carcinoma (RCC) makes up 2-3% of adult cancers. The introduction of tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin inhibitors in the mid-2000s radically changed the management of RCC. These targeted treatments superseded immunotherapy with interleukin-2 and interferon. The pendulum now appears to be shifting back towards immunotherapy, with the evidence of prolonged overall survival of patients with metastatic RCC on treatment with the anti-programmed cell death 1 ligand monoclonal antibody, nivolumab. Clinical prognostic criteria aid prediction of relapse risk for resected localised disease. Unfortunately, for patients at high risk of relapse, no adjuvant treatment has yet shown benefit, although further trials are yet to report. Clinical prognostic models also have a role in the management of advanced disease; now there is a pressing need for predictive biomarkers to direct therapy. Treatment selection for metastatic disease is currently based on histology, prognostic group and patient preference based on side effect profile. In this article, we review the current medical and surgical management of localised, oligometastatic and advanced RCC, including side effect management and the evidence base for management of poor-risk and non-clear cell disease. We discuss recent results from clinical trials and how these are likely to shape future practice and a renaissance of immunotherapy for renal cell cancer

Human Placental-Specific Epipolymorphism and its Association with Adverse Pregnancy Outcomes

Interindividual variation in DNA-methylation level is widespread in the human genome, despite its critical role in regulating gene expression. The nature of this variation, including its tissue-specific nature, and the role it may play in human phenotypic variation and disease is still poorly characterized. The placenta plays a critical role in regulating fetal growth and development in ways that have lifelong effects on health. To identify genes with a high degree of interindividual DNA methylation variation in the human placenta, we surveyed the human genome using the Illumina GoldenGate Methylation Cancer panel targeting 1505 CpG sites of 807 genes. While many sites show a continuous pattern of methylation levels, WNT2, TUSC3 and EPHB4 were identified to have a polymorphic “on-or-off” pattern of DNA methylation variation at their promoter region which was confirmed by pyrosequencing. Methylation of these genes can be found in 7%–25% of over 100 placentas tested. The methylation state at the promoter of these genes is concordant with mRNA allelic expression. In three informative cases TUSC3 was observed to be methylated on the maternal allele, and it is thus possible this represents a polymorphically imprinted gene. Furthermore, TUSC3 promoter methylation showed evidence for association with preeclampsia. A biological significance of these methylation allelic polymorphisms (MAPs) to human placental diversity is further implied by their placental specificity and absence in mouse. An extended study of blood suggests that MAPs may also be found in other tissues, implicating their utility for tissue-specific association with complex disorders. The identification of such “epipolymorphism” in other tissues and their use in association studies, should improve our understanding of interindividual phenotypic variability and complex disease susceptibility

The molecular phylogeny of eph receptors and ephrin ligands

<p>Abstract</p> <p>Background</p> <p>The tissue distributions and functions of Eph receptors and their ephrin ligands have been well studied, however less is known about their evolutionary history. We have undertaken a phylogenetic analysis of Eph receptors and ephrins from a number of invertebrate and vertebrate species.</p> <p>Results</p> <p>Our findings indicate that Eph receptors form three major clades: one comprised of non-chordate and cephalochordate Eph receptors, a second comprised of urochordate Eph receptors, and a third comprised of vertebrate Eph receptors. Ephrins, on the other hand, fall into either a clade made up of the non-chordate and cephalochordate ephrins plus the urochordate and vertebrate ephrin-Bs or a clade made up of the urochordate and vertebrate ephrin-As.</p> <p>Conclusion</p> <p>We have concluded that Eph receptors and ephrins diverged into A and B-types at different points in their evolutionary history, such that primitive chordates likely possessed an ancestral ephrin-A and an ancestral ephrin-B, but only a single Eph receptor. Furthermore, ephrin-As appear to have arisen in the common ancestor of urochordates and vertebrates, whereas ephrin-Bs have a more ancient bilaterian origin. Ancestral ephrin-B-like ligands had transmembrane domains; as GPI anchors appear to have arisen or been lost at least 3 times.</p

Coexpression of EphB4 and ephrinB2 in tumour advancement of ovarian cancers

EphB4 and ephrinB2 expressions in ovarian cancers were studied to analyse EphB4/ephrinB2 functions against clinical backgrounds. EphB4 and ephrinB2 were dominantly localised in ovarian cancer cells of all cases studied. Both the histoscores and mRNA levels of EphB4 and ephrinB2 significantly increased with clinical stages (I<II<III<IV, P<0.001) in ovarian cancers, although there was no significant difference in EphB4 and ephrinB2 histoscores or in mRNA levels according to histopathological types. EphB4 as well as ephrinB2 histoscores in cancer cells correlated with the corresponding mRNA levels in each case (EphB4, P<0.001; ephrinB2, P<0.001). The 24-month survival rates of the 36 patients with high EphB4 and ephrinB2 expression were poor (25 and 27%, respectively), while for the other 36 patients with low EphB4 and ephrinB2 expression, they were significantly higher (68 and 64%, respectively). Therefore, EphB4/ephrinB2 may function in tumour advancement and coexpression of the Eph/ephrin system may potentiate tumour progression leading to poor survival. Thus, EphB4/ephrinB2 can be recognised as a novel prognostic indicator in the primary tumours of ovarian cancers