Systematic Analysis of miR-506-3p Target Genes Identified Key Mediators of Its Differentiation-Inducing Function.

Background/Objectives: miR-506-3p has been demonstrated to be a strong inducer of neuroblastoma cell differentiation, highlighting the potential of applying miR-506-3p mimics to neuroblastoma differentiation therapy. However, the target genes of miR-506-3p that mediate its differentiation-inducing function have not been fully defined. This study aims to comprehensively investigate the targetome of miR-506-3p regarding its role in regulating neuroblastoma cell differentiation. Methods: We combined gene expression profiling and functional high-content screening (HCS) to identify miR-506-3p target genes that have differentiation-modulating functions. For evaluating the potential clinical relevance of the identified genes, we analyzed the correlations of gene expressions with neuroblastoma patient survival. Results: We identified a group of 19 target genes with their knockdown significantly inducing cell differentiation, suggesting that these genes play a key role in mediating the differentiation-inducing activity of miR-506-3p. We observed significant correlations of higher mRNA levels with lower patient survival with 13 of the 19 genes, suggesting that overexpression of these 13 genes plays important roles in promoting neuroblastoma development by disrupting the cell differentiation pathways. Conclusions: Through this study, we identified novel target genes of miR-506-3p that function as strong modulators of neuroblastoma cell differentiation. Our findings represent a significant advancement in understanding the mechanisms by which miR-506-3p induces neuroblastoma cell differentiation. Future investigations of the identified 13 genes are needed to fully define their functions and mechanisms in controlling neuroblastoma cell differentiation, the understanding of which may reveal additional targets for developing novel differentiation therapeutic agents.

Private health insurance in the United States and Sweden: A comparative review.

Background and Aims: The United States of America and Sweden both contain a public and private component to their healthcare systems. While both countries spend a similar amount per capita on public healthcare expenditures, the United States spends significantly more in the private healthcare sector. Sweden has a social democratic model of health care, and given its identity as a welfare state, private health insurance providers have a small and nuanced role. Methods: This paper was completed after searches were queried for "Sweden," "United States," and variants of the words "insurance," "public," "private," "Medicare," "Medicaid," "public," and "costs." A preliminary search in May 2022, yielded 78 articles, of which 45 were ultimately considered relevant for this review. Inclusion criteria consisted of English language articles, topic relevance, and verification of MEDLINE-indexed journals. These searches were performed in PubMed, Google Scholar, Embase, and Cochrane. Summary findings of these searches are compiled in this review. Results: Sweden guarantees low-cost appropriate care to all citizens with equitable access; however, drawbacks of its system include high financial burden, lack of primary care infrastructure, as well as geographical and socioeconomic inequities. On the other hand, the United States' healthcare system is built around the private sector with public health insurance reserved only for the most vulnerable patient populations. Conclusion: Our goal is to provide an overview, compare the role of private health insurance in both countries, and highlight policies that have had beneficial effects in each nation. Possible solutions to the drawbacks of each nation's health insurance policies could be addressed by additional support to Sweden's vulnerable population by developing a program similar to the US' Medicare Advantage program. Conversely, the United States may benefit from increasing access to public health insurance, especially in instances where families face unemployment.

Identification of CDKN3 as a Key Gene that Regulates Neuroblastoma Cell Differentiation.

We conducted a high-content screening (HCS) in neuroblastoma BE(2)-C cells to identify cell cycle regulators that control cell differentiation using a library of siRNAs against cell cycle-regulatory genes. We discovered that knocking down expression of cyclin dependent kinase inhibitor 3 (CDKN3) showed the most potent effect in inducing neurite outgrowth, the morphological cell differentiation marker of neuroblastoma cells. We then demonstrated that CDKN3 knockdown increased expression of neuroblastoma molecular differentiation markers, neuron specific enolase (NSE), ßIII-tubulin and growth associated protein 43 (GAP43). We further showed that CDKN3 knockdown reduced expression of cell proliferation markers Ki67 and proliferating cell nuclear antigen (PCNA), and reduced colony formation of neuroblastoma cells. More importantly, we observed a correlation of high tumor CDKN3 mRNA levels with poor patient survival in the investigation of public neuroblastoma patient datasets. In exploring the mechanisms that regulate CDKN3 expression, we found that multiple strong differentiation-inducing molecules, including miR-506-3p and retinoic acid, down-regulated CDKN3 expression. In addition, we found that N-Myc promoted CDKN3 expression at the transcriptional level by directly binding to the CDKN3 promoter. Furthermore, we found that CDKN3 and two additional differentiation-regulating cell cycle proteins identified in our HCS, CDC6 and CDK4, form an interactive network to promote expression of each other. In summary, we for the first time discovered the function of CDKN3 in regulating neuroblastoma cell differentiation and characterized the transcriptional regulation of CDKN3 expression by N-Myc in neuroblastoma cells. Our findings support that CDKN3 plays a role in modulating neuroblastoma cell differentiation and that overexpression of CDKN3 may contribute to neuroblastoma progression.

Prevalence of Frailty in Older Community-Dwelling Tanzanians According to Comprehensive Geriatric Assessment.

OBJECTIVES: To investigate the prevalence of frailty using a Comprehensive Geriatric Assessment (CGA) in older community-dwelling adults living in rural northern Tanzania. DESIGN: Cross-sectional survey. SETTING: Five randomly selected villages in Hai District, Kilimanjaro region, Tanzania. PARTICIPANTS: All adults aged 60 and older living in the selected villages were eligible to participate, including older adults with cognitive impairment provided a close relative was able to assent on their behalf. All participants were community dwelling because institutionalization is very rare. MEASUREMENTS: Participants were screened using a short frailty screening tool, the Brief Frailty Instrument for Tanzania (B-FIT), comprising an abbreviated test of cognitive function and the Barthel Index, which assesses functional independence. Based on B-FIT score, a frailty-weighted, stratified sample was selected for in-depth assessment using CGA and characterized as frail or not frail. RESULTS: Two hundred thirty-six CGAs were performed in 1,207 people screened, 91 of whom were deemed frail. After adjusting for stratification, the prevalence of frailty was 19.1% (95% confidence interval=15.2-23.1). CONCLUSION: This is the first study in sub-Saharan Africa to report the prevalence of frailty in community-dwelling older adults according to a CGA. The strengths of reporting frailty according to a CGA include the ability to consider likely medical diagnoses based on clinical assessment and to assess individuals' social circumstances and environment.