Glucuronidation by UGT1A1 Is the Dominant Pathway of the Metabolic Disposition of Belinostat in Liver Cancer Patients

10.1371/journal.pone.0054522PLoS ONE81

Neuroblastoma Cell Lines Contain Pluripotent Tumor Initiating Cells That Are Susceptible to a Targeted Oncolytic Virus

Although disease remission can frequently be achieved for patients with neuroblastoma, relapse is common. The cancer stem cell theory suggests that rare tumorigenic cells, resistant to conventional therapy, are responsible for relapse. If true for neuroblastoma, improved cure rates may only be achieved via identification and therapeutic targeting of the neuroblastoma tumor initiating cell. Based on cues from normal stem cells, evidence for tumor populating progenitor cells has been found in a variety of cancers.Four of eight human neuroblastoma cell lines formed tumorspheres in neural stem cell media, and all contained some cells that expressed neurogenic stem cell markers including CD133, ABCG2, and nestin. Three lines tested could be induced into multi-lineage differentiation. LA-N-5 spheres were further studied and showed a verapamil-sensitive side population, relative resistance to doxorubicin, and CD133+ cells showed increased sphere formation and tumorigenicity. Oncolytic viruses, engineered to be clinically safe by genetic mutation, are emerging as next generation anticancer therapeutics. Because oncolytic viruses circumvent typical drug-resistance mechanisms, they may represent an effective therapy for chemotherapy-resistant tumor initiating cells. A Nestin-targeted oncolytic herpes simplex virus efficiently replicated within and killed neuroblastoma tumor initiating cells preventing their ability to form tumors in athymic nude mice.These results suggest that human neuroblastoma contains tumor initiating cells that may be effectively targeted by an oncolytic virus

Computational analysis of expression of human embryonic stem cell-associated signatures in tumors

<p>Abstract</p> <p>Background</p> <p>The cancer stem cell model has been proposed based on the linkage between human embryonic stem cells and human cancer cells. However, the evidences supporting the cancer stem cell model remain to be collected. In this study, we extensively examined the expression of human embryonic stem cell-associated signatures including core genes, transcription factors, pathways and microRNAs in various cancers using the computational biology approach.</p> <p>Results</p> <p>We used the class comparison analysis and survival analysis algorithms to identify differentially expressed genes and their associated transcription factors, pathways and microRNAs among normal vs. tumor or good prognosis vs. poor prognosis phenotypes classes based on numerous human cancer gene expression data. We found that most of the human embryonic stem cell- associated signatures were frequently identified in the analysis, suggesting a strong linkage between human embryonic stem cells and cancer cells.</p> <p>Conclusions</p> <p>The present study revealed the close linkage between the human embryonic stem cell associated gene expression profiles and cancer-associated gene expression profiles, and therefore offered an indirect support for the cancer stem cell theory. However, many interest issues remain to be addressed further.</p

Maternal and neonatal health expenditure in Mumbai slums (India): A cross sectional study

Background: The cost of maternity care can be a barrier to access that may increase maternal and neonatal mortality risk. We analyzed spending on maternity care in urban slum communities in Mumbai to better understand the equity of spending and the impact of spending on household poverty.Methods: We used expenditure data for maternal and neonatal care, collected during post-partum interviews. Interviews were conducted in 2005-2006, with a sample of 1200 slum residents in Mumbai (India). We analysed expenditure by socio-economic status (SES), calculating a Kakwani Index for a range of spending categories. We also calculated catastrophic health spending both with and without adjustment for coping strategies. This identified the level of catastrophic payments incurred by a household and the prevalence of catastrophic payments in this population. The analysis also gave an understanding of the protection from medical poverty afforded by coping strategies (for example saving and borrowing).Results: A high proportion of respondents spent catastrophically on care. Lower SES was associated with a higher proportion of informal payments. Indirect health expenditure was found to be (weakly) regressive as the poorest were more likely to use wage income to meet health expenses, while the less poor were more likely to use savings. Overall, the incidence of catastrophic maternity expenditure was 41%, or 15% when controlling for coping strategies. We found no significant difference in the incidence of catastrophic spending across wealth quintiles, nor could we conclude that total expenditure is regressive.Conclusions: High expenditure as a proportion of household resources should alert policymakers to the burden of maternal spending in this context. Differences in informal payments, significantly regressive indirect spending and the use of savings versus wages to finance spending, all highlight the heavier burden borne by the most poor. If a policy objective is to increase institutional deliveries without forcing households deeper into poverty, these inequities will need to be addressed. Reducing out-of-pocket payments and better regulating informal payments should have direct benefits for the most poor. Alternatively, targeted schemes aimed at assisting the most poor in coping with maternal spending (including indirect spending) could reduce the household impact of high costs

Discovery of new liver fibrosis markers in hepatitis C patients using proteomics

Introduction: Liver biopsy is the reference standard for assessing liver fibrosis, and no reliable non-invasive diagnostic approach is available to discriminate between the intermediate stages of fibrosis. Therefore suitable serological biomarkers of liver fibrosis are urgently needed.Aim: The objective of this study was to use proteomics to identify novel fibrosis biomarkers in hepatitis C patients with different degrees of liver fibrosis.Method: Proteins in plasma samples from healthy control individuals and patients with hepatitis C virus (HCV) induced cirrhosis were analysed using a proteomics technique—two dimensional gel electrophoresis (2-DE). This technique separated the proteins in plasma samples of control and cirrhotic patients and by visualising the separated proteins we were able to identify proteins which were increasing or decreasing in hepatic cirrhosis. Identified markers were validated across all Ishak stages and compared to the markers used in FibroTest, Enhanced Liver Fibrosis (ELF) test, Hepascore and FIBROSpect by western blotting.Results: 44 candidate biomarkers for hepatic fibrosis were identified of which 20 were novel. western blot validation of all candidate markers using plasma samples from patients across all Ishak fibrosis scores showed that the markers which changed with increasing fibrosis most consistently included lipid transfer inhibitor protein, complement C3d, corticosteroid-binding globulin, apolipoprotein J and apolipoprotein L1. These five novel markers which are secreted in blood showed a promising consistent change with increasing fibrosis stage when compared to the markers used for the FibroTest, ELF test, Hepascore and FIBROSpect.Conclusion: This study identifies 20 novel fibrosis biomarker candidates. The proteins identified by these improved approaches may help to assess hepatic fibrosis and eliminate the need for invasive liver biopsies.</br