Development of a non-transformed human liver cell line with differentiated-hepatocyte and urea-synthetic functions: applicable for bioartificial liver

There is a need to develop human hepatocyte cell lines which retain both replicating capacity and highly differentiated functions to facilitate the development of an efficient bioartificial liver. The present study was undertaken to differentiate, using sodium butyrate, the actively replicating immortalized human liver cell line. The effects of butyrate on cell growth and cell cycle were analyzed, and the albumin synthesis, cytochrome P450 and ammonia-detoxifying activity of the butyrate-treated cells were measured. Butyrate treatment resulted in G2/M arrest of the cell cycle and polygonal changes in the cell morphology. Neither the control nor the butyrate-treated cells showed transformed characteristics. Butyrate treatment increased the amount of albumin secretion, cytochrome P450 activity, and the urea production rate of the cells. The present study provides non-transformed human hepatocytes, which can replicate unlimitedly and then restore differentiated hepatocyte-specific functions by butyrate, and therefore, have applications for the development of an efficient bioartificial liver.     

Multiple imputation technique applied to appropriateness ratings in cataract surgery

Missing data such as appropriateness ratings in clinical research are a common problem and this often yields a biased result. This paper aims to introduce the multiple imputation method to handle missing data in clinical research and to suggest that the multiple imputation technique can give more accurate estimates than those of a complete-case analysis. The idea of multiple imputation is that each missing value is replaced with more than one plausible value. The appropriateness method was developed as a pragmatic solution to problem of trying to assess "appropriate" surgical and medical procedures for patients. Cataract surgery was selected as one of four procedures that were evaluated as a part of the Clinical Appropriateness Initiative. We created mild to high missing rates of 10%, 30% and 50% and compared the performance of logistic regression in cataract surgery. We treated the coefficients in the original data as true parameters and compared them with the other results. In the mild missing rate (10%), the deviation from the true coefficients was quite small and ignorable. After removing the missing data, the complete-case analysis did not reveal any serious bias. However, as the missing rate increased, the bias was not ignorable and it distorted the result. This simulation study suggests that a multiple imputation technique can give more accurate estimates than those of a complete-case analysis, especially for moderate to high missing rates (30 - 50%). In addition, the multiple imputation technique yields better accuracy than a single imputation technique. Therefore, multiple imputation is useful and efficient for a situation in clinical research where there is large amounts of missing data.     

Age-dependent changes of gene expression in the Drosophila head

Previous gene expression profiling studies in Drosophila have provided clues for understanding the aging process at the gene expression level. For a detailed understanding, studies of specific regions of the body are necessary. We therefore employed microarray analysis to examine gene expression changes in the Drosophila head during aging. Six hundred and eighty-four of the 5405 genes present in the microarray showed significant age-dependent changes as determined by significance analysis of microarray (SAM) (q < 0.05). The biological significance of the changes was analyzed using the gene annotations provided by the Gene Ontology Consortium. Major changes involved genes affecting energy metabolism (proton transport, energy pathways, oxidative phosphorylation) and neuronal function, especially responses to light. Genes involved in protein catabolism and several other metabolic processes also showed age-dependent changes. Most of the changes were reductions in gene expression and occurred before day 13 of adult life. After day 13, the age-dependent gene expression changes were relatively smaller than earlier life. Interestingly, the two biological processes of major gene expression changes are related to the two known environmental changes that increase life span in Drosophila: caloric restriction and light reduction. Our findings suggest that light signaling and energy metabolism may be important biological processes affected by aging and be interesting targets for the further investigation related to the longevity in Drosophila.     

Precision Tracing of Household Dengue Spread Using Inter- and Intra-Host Viral Variation Data,Kamphaeng Phet,Thailand

Dengue control approaches are best informed by granular spatial epidemiology of these viruses, yet reconstruction of inter- and intra-household transmissions is limited when analyzing case count, serologic, or genomic consensus sequence data. To determine viral spread on a finer spatial scale, we extended phylogenomic discrete trait analyses to reconstructions of house-to-house transmissions within a prospective cluster study in Kamphaeng Phet, Thailand. For additional resolution and transmission confirmation, we mapped dengue intra-host single nucleotide variants on the taxa of these time-scaled phylogenies. This approach confirmed 19 household transmissions and revealed that dengue disperses an average of 70 m per day between households in these communities. We describe an evolutionary biology framework for the resolution of dengue transmissions that cannot be differentiated based on epidemiologic and consensus genome data alone. This framework can be used as a public health tool to inform control approaches and enable precise tracing of dengue transmissions.     

Costs of Immunization Programs for 10 Vaccines in 94 Low- and Middle-Income Countries From 2011 to 2030

ObjectivesUnderstanding the level of investment needed for the 2021-2030 decade is important as the global community faces the next strategic period for vaccines and immunization programs. To assist with this goal, we estimated the aggregate costs of immunization programs for ten vaccines in 94 low- and middle-income countries from 2011 to 2030.MethodWe calculated vaccine, immunization delivery and stockpile costs for 94 low- and middle-income countries leveraging the latest available data sources. We conducted scenario analyses to vary assumptions about the relationship between delivery cost and coverage as well as vaccine prices for fully self-financing countries.ResultsThe total aggregate cost of immunization programs in 94 countries for 10 vaccines from 2011 to 2030 is $70.8 billion (confidence interval: $56.6-$93.3) under the base case scenario and $84.1 billion ($72.8-$102.7) under an incremental delivery cost scenario, with an increasing trend over two decades. The relative proportion of vaccine and delivery costs for pneumococcal conjugate, human papillomavirus, and rotavirus vaccines increase as more countries introduce these vaccines. Nine countries in accelerated transition phase bear the highest burden of the costs in the next decade, and uncertainty with vaccine prices for the 17 fully self-financing countries could lead to total costs that are 1.3-13.1 times higher than the base case scenario.ConclusionResource mobilization efforts at the global and country levels will be needed to reach the level of investment needed for the coming decade. Global-level initiatives and targeted strategies for transitioning countries will help ensure the sustainability of immunization programs.     

Systemic inflammation response index predicts all-cause mortality in patients with antineutrophil cytoplasmic antibody-associated vasculitis

International Urology and Nephrology - A systemic inflammation response index (SIRI) has been recently introduced as a tool for the assessment of the prognosis of several critical medical...     

Novel second-generation rexinoid induces growth arrest and reduces cancer cell stemness in human neuroblastoma patient-derived xenografts

IntroductionThe poor therapeutic efficacy seen with current treatments for neuroblastoma may be attributed to stem cell-like cancer cells (SCLCCs), a subpopulation of cancer cells associated with poor prognosis and disease recurrence. Retinoic acid (RA) is a differentiating agent used as maintenance therapy for high-risk neuroblastoma but nearly half of children treated with RA relapse. We hypothesized that 6-Methyl-UAB30 (6-Me), a second-generation rexinoid recently developed with a favorable toxicity profile compared to RA, would reduce cancer cell stemness in human neuroblastoma patient-derived xenografts (PDXs).MethodsCells from three neuroblastoma PDXs were treated with 6-Me and proliferation, viability, motility, and cell-cycle progression were assessed. CD133 expression, sphere formation, and mRNA abundance of stemness and differentiation markers were evaluated using flow cytometry, in vitro extreme limiting dilution analysis, and real-time PCR, respectively.ResultsTreatment with 6-Me decreased proliferation, viability, and motility, and induced cell-cycle arrest and differentiation in all three neuroblastoma PDXs. In addition, 6-Me treatment led to decreased CD133 expression, decreased sphere-forming ability, and decreased mRNA abundance of Oct4, Nanog, and Sox2, indicating decreased cancer cell stemness.Conclusions6-Me decreased oncogenicity and reduced cancer cell stemness of neuroblastoma PDXs, warranting further exploration of 6-Me as potential novel therapy for neuroblastoma.     

Clinical Significance of De Novo Malignancy After Liver Transplant: A Single-Center Study

BackgroundSeveral studies have reported that solid organ transplant recipients have a high risk for malignant tumors because the suppressed immune system fails in preventing malignant transformations. De novo malignancy after transplantation is the most common cause of death in the late period after liver transplant (LT). This study investigated the clinical significance of de novo malignancy after LT, and it is the largest study based in Korea to report long-term follow-up results associated with de novo malignancy after LT.MethodsData of 1793 adults who underwent LT in Seoul National University Hospital were retrospectively collected, and medical charts and data from the Ministry of Public Administration and Security were reviewed to examine the causes of death and de novo malignancy status. The Fisher exact test and Kaplan-Meier survival analysis were used to analyze the data.ResultsOf the 1793 recipients, 27 died of de novo malignancies. Of 875 hepatocellular carcinoma (HCC) patients, 12 died, and of 918 non-HCC patients, 15 died. De novo malignancy was the main cause of death at 5 years after LT but was not in the initial 5 years. In Korea the most common cancers that developed after LT were gastric cancer (21.4%) and lymphoma (14.3%). De novo HCC in non-HCC cases was found in 2 patients.ConclusionDe novo malignancy is a key factor affecting long-term survival after LT. Therefore, regular screening and education are important for improving long-term survival and quality of life in these patients after LT.