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We investigated the impacts of chronic conditions on wealth depletion of minority and non-Hispanic white elders during the five-year time period. Along with total wealth depletion, we examined depletion of different sources of wealth, which are financial assets and housing equity. Financial assets are more liquid and may be a better measure of the resources household can promptly use to meet health emergencies. Housing equity is a final resort to household without financial assets available. The influence of chronic conditions on wealth depletion of elders is estimated across minority elders and white elders, by using the data of 4,521 elderly households that participated in both 1993 and 1998 of the Asset and Health Dynamics of the Oldest. In estimation, two major issues were considered in regard to our data: one is attrition, and the other is outliers of dependent variables stemming from mostly measurement errors. The attrition rate of our sample was 25% between the first wave and the third wave for 5 years, which may lead to biased estimates. We examined the impact of attrition and conducted a robust regression analysis to eliminate the impacts of outliners. As dependent variable of this study is the difference in the dollar amount of net worth during the five year time period, there is high possibility that outliers of the dependant variables affect estimates, leading to biased and unrobust estimates. In order to investigate the impact of outliers on estimates, we estimates 3 models using OLS: 1) general sample, 2)1% adjusted sample with changing 1% of extreme absolute values of dependent variable to mean value 3) 5% adjusted sample with changing 5% of extreme absolute values of dependent variable to mean value. We found that the impacts of new severe chronic conditions on wealth depletion and sources for depletion differ across minority and white elders. White elders with new severe chronic conditions depleted total wealth of $5,528 or more than those without those conditions, while new chronic conditions did not exhibit any significant association with minority elder' s wealth depletion. However, minority elders with new severe chronic conditions depleted $2,843 or more of housing equity than those without the conditions, while white elders did not. In contrast, white elders with new severe chronic conditions depleted $3,056 or more of financial wealth those without the conditions, while minority elders did not. These findings indicates that due to the absence of significant financial assets, minority elders tend to use their housing equity to cope with health shock. We can point out some implications from this analysis. First, new severe chronic conditions in later life leaded to wealth depletion of elders through different sources and different magnitude between two race groups: total wealth for white elders and home equity for minority elders. In the policy perspective, this finding indicates that assuming homogenous effects of chronic conditions on all elders are significantly biased and calls for estimating the financial burden of illness for each racial/ethnic group. Second, minority elders used home equity for their main financial source on new severe chronic conditions. This suggests that providing proper information associated with procedures of housing equity need for minority elders and their families. Third, in the analytical perspective, studies to examine the impact of health change on wealth depletion based on aggregated wealth may not grab accurate impacts across race groups. Thus, the analysis based on separate sources of wealth may be more desirable. This study has the following limitations. First, the Hispanic sample is relatively small and thereby we combined Hispanics with African Americans and grouped minority elders. Thus, we could not see separate impact between Hispanics and American African elders. Second, the measurement of chronic conditions' severity did not take into account intra- group differences in diagnostic categories, failing to differentiate the relative magnitude of each condition. The sample size is too small to obtain reliable statistical power of estimates. [ABSTRACT FROM AUTHOR]

This study investigates the effects of new health events and existing chronic health conditions on wealth depletion of the elderly with particular attention to different income levels and types of chronic conditions. A model integrating a life-cycle model of savings and a behavioral model of health care utilization is proposed and estimated using Waves 1 and 2 of the Asset and Health Dynamics of the Oldest Old (AHEAD) data set. Both new health events and existing health conditions significantly influence wealth depletion of elders, but their impacts differ across income levels. A new occurrence of severe chronic conditions brought wealth depletion of middle income elders, while a new occurrence of mild chronic conditions depleted the wealth of only high-income elders. Having existing chronic health conditions was associated with wealth depletion of only high-income elders, but has no impact on other income groups. Poor health, particularly a new health event, leads to considerable wealth depletion of the elderly, especially middle-income elders. Considering the significant impacts of new health events, the public needs to be more informed of potential health events in later life and the associated costs. The unequal burden of chronic conditions across different income levels should be recognized, particularly the critical consequences on middle-income elderly. [ABSTRACT FROM AUTHOR]

Myocyte enhancer factor 2 (MEF2) plays pivotal roles in various biological processes, and its transcriptional activity is regulated by histone acetylation/deacetylation enzymes in a calcium-dependent fashion. A calcineurin-binding protein 1 (Cabin1) has been shown to participate in repression of MEF2 by recruiting mSin3 and its associated histone deacetylases. Here, we report that histone methylation also takes a part in Cabin1-mediated repression of MEF2. Immunoprecipitate of Cabin1 complex can methylate histone H3 by association with SUV39H1. SUV39H1 increased Cabin1-mediated repression of MEF2 transcriptional activity in MEF2-targeting promoters. The SUV39H1 was revealed to bind to the 501-900-amino acid region of Cabin1, which was distinct from its histone deacetylase-recruiting domain. In addition, the Gal4-Cabin1-(501-900) alone repressed a constitutively active Gal4-tk-promoter, indicating that Cabin1 recruits SUV39H1 and represses transcriptional activity. Finally, both SUV39H1 and Cabin1 were shown to bind on the MEF2 target promoter in a calcium-dependent manner. Thus, Cabin1 recruits chromatin-modifying enzymes, both histone deacetylases and a histone methyltransferase, to repress MEF2 transcriptional activity. [ABSTRACT FROM AUTHOR]

Disrupting the eukaryotic translation initiation factor 4F (eIF4F) complex offers an appealing strategy to potentiate the effectiveness of existing cancer therapies and to overcome resistance to drugs such as BRAF inhibitors (BRAFi). Here, we identified and characterized the small molecule SBI-0640756 (SBI- 756), a first-in-class inhibitor that targets eIF4G1 and disrupts the eIF4F complex. SBI-756 impaired the eIF4F complex assembly independently of mTOR and attenuated growth of BRAF-resistant and BRAF-independent melanomas. SBI-756 also suppressed AKT and NF-kB signaling, but small-molecule derivatives were identified that only marginally affected these pathways while still inhibiting eIF4F complex formation and melanoma growth, illustrating the potential for further structural and functional manipulation of SBI-756 as a drug lead. In the gene expression signature patterns elicited by SBI-756, DNA damage, and cell-cycle regulatory factors were prominent, with mutations in melanoma cells affecting these pathways conferring drug resistance. SBI-756 inhibited the growth of NRAS, BRAF, and NF1-mutant melanomas in vitro and delayed the onset and reduced the incidence of Nras/Ink4a melanomas in vivo. Furthermore, combining SBI-756 and a BRAFi attenuated the formation of BRAFi-resistant human tumors. Taken together, our findings show how SBI-756 abrogates the growth of BRAFindependent and BRAFi-resistant melanomas, offering a preclinical rationale to evaluate its antitumor effects in other cancers. [ABSTRACT FROM AUTHOR]

The RING finger E3 ubiquitin ligase Siah2 is implicated in control of diverse cellular biological events, including MAPK signaling and hypoxia. Here we demonstrate that Siah2 is subject to regulation by the deubiquitinating enzyme USP13. Overexpression of USP13 increases Siah2 stability by attenuating its autodegradation. Consequently, the ability of Siah2 to target its substrates prolyl hydroxylase 3 and Spry2 (Sprouty2) for ubiquitin-mediated proteasomal degradation is attenuated. Conversely, inhibition of USP13 expression with corresponding shRNA decreases the stability of both Siah2 and its substrate Spry2. Thus, USP13 limits Siah2 autodegradation and its ubiquitin ligase activity against its target substrates. Strikingly, the effect of USP13 on Siah2 is not mediated by its isopeptidase activity: mutations in its ubiquitin-binding sequences positioned within the ubiquitin-specific processing protease and ubiquitin-binding domains, but not within putative catalytic sites, abolish USP13 binding to and effect on Siah2 autodegradation and targeted ubiquitination. Notably, USP13 expression is attenuated in melanoma cells maintained under hypoxia, thereby relieving Siah2 inhibition and increasing its activity under low oxygen levels. Significantly, on melanoma tissue microarray, high nuclear expression of USP13 coincided with high nuclear expression of Siah2. Overall, this study identifies a new layer of Siah2 regulation mediated by USP13 binding to ubiquitinated Siah2 protein with a concomitant inhibitory effect on its activity under normoxia. [ABSTRACT FROM AUTHOR]

We investigate the impact of health on wealth depletion of African American, Hispanic, and non-Hispanic white elders. Using the data from 4,464 elderly households that participated in both the 1993 Asset and Health Dynamics of the Oldest Old and the 1998 Health and Retirement Study, we find that health problems contribute to wealth depletion differently across elders in different racial and ethnic groups. We draw policy implications from the findings regarding ways to help consumers protect their financial security from health shocks in later life.