The natural product englerin A (EA) binds to and activates protein kinase C-θ (PKCθ). EA-dependent activation of PKCθ induces an insulin resistant phenotype, limiting the access of tumor cells to glucose. At the same time, EA causes PKCθ-mediated phosphorylation and activation of the transcription factor heat shock factor 1, an inducer of glucose dependence. By promoting glucose addiction while simultaneously starving cells of glucose, EA proves to be synthetically lethal to highly glycolytic tumors.
HSF1; englerin A; renal cell cancer; PKCθ; insulin resistance
Asian Americans have the highest incidence of hepatocellular carcinoma (HCC), the major form of primary liver cancer, of all ethnic groups in the United States. Chronic hepatitis B virus (HBV) infection is the most common cause of HCC, and as many as 1 in 10 foreign-born Asian Americans are chronically infected with HBV. We tested the effectiveness of a culturally tailored liver cancer education program for increasing screening for HBV among Chinese, Korean, and Vietnamese Americans residing in the Baltimore–Washington metropolitan area, from November 2009 through June 2010.
We used a cluster randomized controlled trial to recruit volunteer participants from community-based organizations (CBOs) in the Baltimore–Washington metropolitan area. We selected 877 participants by using a pretest survey. People were eligible to participate if they had not attended a hepatitis B–related education program in the past 5 years. The intervention group (n = 441) received a 30-minute educational program, and the control group (n = 436) received an educational brochure. After attending the educational program, the intervention group completed a post-education survey. Six months later, participants in both groups were followed up by telephone. Receipt of HBV screening was the outcome measure.
Approximately 79% (n = 688) of participants completed the 6-month follow-up telephone survey. Among those who had not had HBV screening at baseline (n = 446), the adjusted odds of self-reported receipt of HBV screening at the 6-month follow-up to the educational program were significantly higher for the intervention group than for the control group (odds ratio = 5.13; 95% confidence interval, 3.14–8.39; P < .001). Chinese Americans and Vietnamese Americans had significantly higher odds of having HBV screening in the 6-month period than Korean Americans.
Culturally tailored education programs that increase liver cancer awareness can be effective in increasing HBV screening among underserved Asian American populations.
Parents' employment status is frequently cited as a possible predictor of child weight status. Despite the importance of the topic, only a few studies have been conducted. No longitudinal studies have been conducted in the United States.
A cohort of 1201 girls from the Trial of Activity for Adolescent Girls was used. Height, weight, and percent body fat (PBF) were measured at the 6th and 8th grades. Parents' employment status (measured at 6th grade) was categorized into working full time (reference), part time, unemployed, working or staying at home, and don't know. Mixed-model regression was used to reflect the hierarchical design of our study and adjusted for age, race, parents' education level, free or reduced-price school lunch status, and living arrangement.
Girls whose mothers worked part time or stayed at home had a decreased risk of excess weight gain [relative risk (RR)=0.94, 95% confidence interval (CI) 0.88, 1.00; RR=0.89, 95% CI 0.79, 1.00, respectively] compared to girls whose mothers worked full time. Girls whose fathers were unemployed had a moderately increased risk of excess weight gain (RR=1.13, 95% CI 1.00, 1.26) compared to girls whose fathers worked full time. Having an unemployed mother or part-time or stay-at-home father was not associated with excess weight gain. Parents' employment status was not associated with excess PBF gain.
Our findings suggest that the availability of the mother has a greater influence on the weight of the daughter than the availability of the father. There is a need for a better understanding of how parents' employment status influences excess weight gain in adolescent girls.
Asian Americans have disproportionately high prevalence of chronic hepatitis B virus infection in the United States and yet have low hepatitis B screening and vaccination rates. We developed three photonovels specifically designed for Chinese, Korean, and Vietnamese Americans and evaluated their cultural relevance and effectiveness in increasing self-efficacy and intention to have a hepatitis B screening. Photonovels' storylines were drawn from focus group themes, and lay people from each community played actors/actresses in community settings. Photonovels were pilot tested, revised, and distributed in a hepatitis B intervention. A two-page process evaluation questionnaire was mailed to 441 participants after one month. Descriptive analysis and multiple logistic regressions were conducted to assess the overall evaluation of the photonovel and to assess factors associated with self-efficacy and intention to have hepatitis B screening. Eighty-four percent of participants responded to the process evaluation. The majority of participants either strongly agreed or agreed that the cancer information in the photonovel was helpful, the story was written by someone who knows the community, and the information was easy to understand. Overall, more than 80% of them thought this photonovel was a good teaching tool. Favorable evaluation of the photonovel was associated with both having intention and self-efficacy to have a hepatitis B screening in the next 5 months. When stratified by level of education and income, the associations were stronger among the lower income and education groups. Culturally appropriate photonovels are useful tools to promote hepatitis B screening among Asian Americans, especially among those of lower socioeconomic status.
Asian Americans; community-based participatory research; educational material; hepatitis B; photonovel; screening
The objective of this study is to examine the association between acculturation and BMI among Asian Americans using multiple measures of acculturation. Data of 847 Chinese, Korean and Vietnamese recruited for a health education program in Maryland during 2009 to 2010 were used. Acculturation was measured by the short version of Suinn-Lew Asian Self-Identity Acculturation Scale (SL-ASIA) and its individual components. Height and weight were measured by trained staff. Multiple linear regressions were used to estimate the association between acculturation and BMI. After adjusting for age, gender, education, income, marital status, and ethnicity, SL-ASIA (β = 0.71, SE = 0.28), having education in the US (β = 0.56, SE = 0.28), younger age of arrival (0–5 years: β = 3.32, SE = 0.76, 6–10 years: β = 1.55, SE = 0.78), self identified as Americans (β = 1.51, SE = 0.77) and equal preference of Asian/American food in restaurants (β = 0.92, SE = 0.28) were significantly associated with increased BMI. The association between acculturation and BMI was stronger among men than women, strongest among Chinese and weakest among Vietnamese. Acculturation was moderately associated with increased BMI among Asian Americans and this association varied by measures of acculturation. The association of acculturation and BMI was moderated by sex and ethnicity groups.
BMI; Obesity; Acculturation; Asian Americans
Prevalence of hepatitis B among Asian Americans is higher than for any other ethnic group in the United States. Since more than 50% of liver cancer is hepatitis B related, the burden of morbidity and mortality is extremely high among Asian Americans, highlighting the need for culturally appropriate interventions. We conducted focus groups (n = 8) with a total of 58 Korean, Vietnamese, and Chinese immigrants in Maryland to explore knowledge, awareness and perceived barriers toward hepatitis B screening and vaccinations. Thematic analysis uncovered generally low levels of knowledge and awareness of hepatitis B risks, screening, and vaccination; inter-generational differences; and barriers to prevention. Some differences arose across ethnic groups, particularly toward perceived orientation to preventive activities and the role of religious groups. High rates of hepatitis B infection among Asian Americans highlight the need for tailored interventions. These findings may assist policy strategists in implementing interventions that will facilitate the integration and scale-up of hepatitis B education, screening, and vaccination campaigns.
Hepatitis B risk; HBV screening and vaccinations; Asian Americans; Qualitative; Immigrant health
Our study identifies the prevalence of HBV virus (HBV) screening and vaccination among Asian Americans, and ethnic differences for factors associated with screening and vaccination behaviors. In 2009–2010 we recruited 877 Korean, Chinese, and Vietnamese Americans 18 years of age and above through several community organizations, churches and local ethnic businesses in Maryland for a health education intervention and a self-administered survey. Prevalence of HBV screening, screening result and vaccinations were compared by each ethnic group. We used logistic regression analysis to understand how sociodemographics, familial factors, patient-, provider-, and resource-related barriers are associated with screening and vaccination behaviors, using the total sample and separate analysis for each ethnic group. Forty-seven percent of participants reported that they had received HBV screening and 38% had received vaccinations. Among the three groups, the Chinese participants had the highest screening prevalence, but lowest self-reported infection rate; Vietnamese has the lowest screening and vaccination prevalence. In multivariate analysis, having better knowledge of HBV, and family and physician recommendations was significantly associated with screening and vaccination behaviors. Immigrants who had lived in the US for more than a quarter of their lifetime were less likely to report ever having been screened (OR = 0.39, 95% CI: 0.28–0.55) or vaccinated (OR = 0.62, 95% CI: 0.44–0.88). In ethnic-specific analysis, having a regular physician (OR = 4.46, 95% CI: 1.62–12.25) and doctor's recommendation (OR = 2.11, 95% CI: 1.05–4.22) are significantly associated with Korean's vaccination behaviors. Health insurance was associated with vaccination behaviors only among Vietnamese (OR = 2.66, 95% CI: 1.21–5.83), but not among others.
HBV infection; Asian Americans; HBV prevalence; Health care access barriers
Heat shock protein 90 (Hsp90) is an essential, evolutionarily conserved molecular chaperone. Cancer cells rely on Hsp90 to chaperone mutated and/or activated oncoproteins, and its involvement in numerous signaling pathways makes it an attractive target for drug development. Surprisingly, however, the impact of Hsp90 inhibitors on cancer cells is frequently cytostatic in nature, and efforts to enhance the antitumor activity of Hsp90 inhibitors in the clinic remain a significant challenge. In agreement with previous data obtained using Wee1 siRNA, we show that dual pharmacologic inhibition of Wee1 tyrosine kinase and Hsp90 causes cancer cells to undergo apoptosis in vitro and in vivo. Gene expression profiling revealed that induction of the intrinsic apoptotic pathway by this drug combination coincided with transcriptional downregulation of Survivin and Wee1, an outcome not seen in cells treated separately with either agent. At the translational level, expression of these two proteins, as well as activated Akt, was completely abrogated. These data support the hypothesis that Wee1 inhibition sensitizes cancer cells to Hsp90 inhibitors; they establish combined Wee1/Hsp90 inhibition as a novel therapeutic strategy; and they provide a mechanistic rationale for enhancing the pro-apoptotic activity of Hsp90 inhibitors.
Wee1; apoptosis; cancer; heat shock protein 90; molecular targeted anticancer drugs
Although acculturation may have positive effects for immigrants, including better socioeconomic profiles and increased occupational opportunities, their health profiles deteriorate with longer duration in the U.S. Prior research indicates that increasing acculturation is associated with some poorer health outcomes among immigrants in the U.S. However, most of these studies have used length of stay or English language proficiency as proxies for acculturation, and have mainly examined self-reported “current” health outcomes. This study advances knowledge on associations between acculturation and health among immigrants by explicitly examining self-reported “change” in health since immigration, in relation to acculturation-related variables. We use data from the New Immigrant Survey (NIS; 2003-2004), a cross-sectional study of legal immigrants to the U.S. In addition to testing more conventionally examined proxies of acculturation (length of stay and English proficiency), we also examine English language use and self-reported change in diet. Multivariable logistic regression analyses on 5,982 participants generally supported previous literature indicating a deleterious impact of acculturation, with increasing duration of stay and greater self-reported change in diet being associated with a poorer change in health since moving to the U.S. Although English language proficiency and use were associated with greater odds of reporting a worse change in health when examined individually, they were non-significant in multivariable models including all acculturation measures. Findings from this study suggest that when taking into account multiple measures of acculturation, language may not necessarily indicate unhealthy assimilation and dietary change may be a pathway leading to declines in immigrant health. Increasing duration in the U.S. may also reflect the adoption of unhealthy behaviors, as well as greater exposure to harmful sources of psychosocial stress including racial and anti-immigrant discrimination. Our study suggests that multiple indicators of acculturation may be useful in examining the effect of acculturation on changes in health among immigrants.
Breast cancer incidence and the number of breast cancer survivors have been rapidly increasing among Chinese and Korean women in the United States. However, few data are available regarding quality of life in Asian American breast cancer survivors. This qualitative study aims to describe Asian American women’s perceptions of quality of life and their breast cancer experiences. In-depth interviews with four Chinese and five Korean American breast cancer survivors and three oncologists were conducted in Chinese, Korean, or English. Interviews were recorded and transcripts were translated into English. Qualitative analyses were performed by two independent coders and then discussed and agreed upon by the research team. The respondents reported that the breast cancer experience had affected various domains of quality of life, but women reported having limited resources with which to cope effectively. Depression, anxiety, and stress were commonly reported, but women rarely discussed these issues with family and friends or sought professional help. As immigrants, women’s loneliness and a lack of social support and culturally relevant resources seemed to be major barriers to maintaining good quality of life. Women also expressed interest in learning more about alternative therapies and relaxation skills. These findings can be used to help inform the development of a culturally appropriate intervention for Asian American breast cancer survivors. Future programs may provide information in women’s native languages to teach skills to cope with stress and anxiety, increase women’s self-efficacy within the context of their cultural background, and enhance social support among women from the same ethnic group.
breast cancer; quality of life; survivorship; Asian American; Chinese American; Korean American
HMGN1 is a nuclear protein that binds to nucleosomes and alters the accessibility of regulatory factors to their chromatin targets. To elucidate its biological function and identify specific HMGN1 target genes, we generated Hmgn1−/− mice. DNA microarray analysis of Hmgn1+/+ and Hmgn1−/− embryonic fibroblasts identified N-cadherin as a potential HMGN1 gene target. RT-PCR and western blot analysis confirmed a linkage between HMGN1 expression and N-cadherin levels. In both transformed and primary mouse embryonic fibroblasts (MEFs), HMGN1 acted as negative regulator of N-cadherin expression. Likewise, the N-cadherin levels in early embryos of Hmgn1−/− mice were higher than those of their Hmgn1+/+ littermates. Loss of HMGN1 increased the adhesiveness, motility and aggregation potential of Hmgn1−/− MEFs, a phenotype consistent with increased levels of N-cadherin protein. Re-expression of wildtype HMGN1, but not of the mutant HMGN1 protein that does not bind to chromatin, in Hmgn1−/− MEFs, decreased the levels of N-cadherin and restored the Hmgn1+/+ phenotype. These studies demonstrate a role for HMGN1 in the regulation of specific gene expression. We suggest that in MEFs, and during early mouse development, the interaction of HMGN1 with chromatin down-regulates the expression of N-cadherin.
HMG protein; N-cadherin; chromatin; transcription
Depression represents a growing concern among Asian Americans. This study examined whether discrimination and family dynamics are associated with depression in this population.
Weighted logistic regressions using nationally representative data on Asian American adults (N = 2095) examining associations between discrimination, negative interactions with relatives, family support, and 12-month major depressive disorder (MDD).
Discrimination (odds ratio [OR] = 2.13, 95% confidence interval [CI] = 1.67, 2.71) and negative interactions with relatives (OR = 1.28, 95% CI = 1.03, 1.58) were positively associated with MDD. Family support was associated with lower MDD (OR = 0.73, 95% CI = 0.59, 0.89), and buffered lower levels of discrimination.
Results suggest that discrimination may have negative mental health implications, and also point to the importance of family relationships for depression among Asian Americans. Findings suggest that providers may consider stress experienced at multiple ecological levels to address Asian American mental health needs.
Asian Americans; major depressive disorder; discrimination; family relationships
Interactions between breast cancer patients and their oncologists are important as effective patient-physician communication can facilitate the delivery of quality cancer care. However, little is known about patient-physician communication processes among Asian American breast cancer patients, who may have unique communication needs and challenges. Thus, we interviewed Asian American patients and several oncologists to explore patient-physician communication processes in breast cancer care.
We conducted in-depth interviews with nine Chinese- or Korean American breast cancer patients and three Asian American oncologists who routinely provided care for Asian American patients in the Washington DC metropolitan area in 2010. We conducted patient interviews in Chinese or Korean and then translated into English. We conducted physicians’ interviews in English. We performed qualitative analyses to identify themes.
For women with limited English proficiency, language was the greatest barrier to understanding information and making treatment-related decisions. Both patients and oncologists believed that interpretation provided by patients’ family members may not be accurate, and patients may neglect to ask questions because of their worry of burdening others. We observed cultural differences regarding expectations of the doctor’s role and views of cancer recovery. As expressed by the patients and observed by oncologists, Asian American women are less likely to be assertive and are mostly reliant on physicians to make treatment decisions. However, many patients expressed a desire to be actively involved in the decision-making process.
Findings provide preliminary insight into patient-physician communication and identify several aspects of patient-physician communication that need to be improved for Asian American breast cancer patients. Proper patient education with linguistically and culturally appropriate information and tools may help improve communication and decision-making processes for Asian American women with breast cancer.
Asian American; breast cancer; patient-physician communication; language barrier; cultural difference; treatment decision making
Androgen receptor activity drives incurable castrate-resistant prostate cancer. All approved antiandrogens inhibit androgen receptor-driven transcription, and in addition the second-generation antiandrogen MDV3100 inhibits ligand-activated androgen receptor nuclear translocation, via an unknown mechanism. Here, we report methoxychalcones that lock the heat shock protein 90-androgen receptor complex in the cytoplasm in an androgen-non-responsive state, thus demonstrating a novel chemical scaffold for antiandrogen development and a unique mechanism of antiandrogen activity.
chalcone; antiandrogen; androgen receptor translocation; prostate cancer; Hsp90
Inactivation of the TCA cycle enzyme, fumarate hydratase (FH), drives a metabolic shift to aerobic glycolysis in FH-deficient kidney tumors and cell lines from patients with hereditary leiomyomatosis renal cell cancer (HLRCC), resulting in decreased levels of AMP-activated kinase (AMPK) and p53 tumor suppressor, and activation of the anabolic factors, acetyl-CoA carboxylase and ribosomal protein S6. Reduced AMPK levels leads to diminished expression of the DMT1 iron transporter, and the resulting cytosolic iron deficiency activates the iron regulatory proteins, IRP1 and IRP2, and increases expression of the hypoxia inducible factor HIF-1α, but not HIF-2α. Silencing of HIF-1α or activation of AMPK diminishes invasive activities, indicating that alterations of HIF-1α and AMPK contribute to the oncogenic growth of FH-deficient cells.
Hepatitis B (HBV) screening; Asian Americans; sociocultural factors
The purpose of this community-based study was to apply a Sociocultural Health Behavior Model to determine the association of factors proposed in the model with breast cancer screening behaviors among Asian American women.
A cross-sectional design included a sample of 682 Chinese, Korean, and Vietnamese women aged 40 years and older. The frequency distribution analysis and Chi-square analysis were used for the initial screening of the following variables: sociodemographic, cultural, enabling, environmental, and social support. Univariate and multivariate analyses were conducted on factors for breast cancer screening using multinomial logistic regression analysis.
Correlates to positive breast cancer screening included demographics (ethnicity), cultural factors (living in the United States for 15 years or more, speaking English well), enabling factors (having a regular physician to visit, health insurance covering the screening), and family/social support factors (those who had a family/friend receiving a mammogram).
The results of this study suggest that breast cancer screening programs will be more effective if they include the cultural and health beliefs, enabling, and social support factors associated with breast cancer screening. The use of community organizations may play a role in helping to increase breast cancer screening rates among Asian American women.
breast cancer screening; Vietnamese; Korean; Chinese; breast cancer; Asian American
The objective of this study is to obtain and discuss in-depth information on mental health problems, including the status, barriers, and potential solutions in 1.5 and 2nd generation Asian American young adults. As a part of the Health Needs Assessment project, the researchers conducted two focus groups with 17 young adults (mainly 1.5 or 2nd generation) from eight Asian American communities (Asian Indian, Cambodian, Chinese, Indonesian, Korean, Taiwanese, Thai, and Vietnamese) in Montgomery County, Maryland. We developed a moderator's guide with open-ended questions and used it to collect qualitative data. Using a software, we organized and identified emergent themes by major categories. Participants reported a several common sources of stress that affect the mental health of Asian American young adults including: pressure to meet parental expectations of high academic achievement and live up to the “model minority” stereotype; difficulty of balancing two different cultures and communicating with parents; family obligations based on the strong family values; and discrimination or isolation due to racial or cultural background. Young Asian Americans tend not to seek professional help for their mental health problems; instead they use personal support networks—close friends, significant others, and religious community. Participants suggested that Asian cultural norms that do not consider mental problems important, and associated stigma of seeking professional care might undermine their mental health help seeking behavior. Our findings support a need for delivering culturally appropriate programs to raise awareness of mental health and cultural training for health providers to deliver culturally appropriate care.
Mental health; Asian American; Young adults; Immigrant health; 1.5 generation; 2nd generation
We examined disparities in burn and fire injuries by age and race/ethnicity to identify disparities during the life course.
Burn and fire mortality rates were disaggregated by five-year age groups, gender, and race/ethnicity from 1999 to 2004.
Compared with non-Hispanic white people, Native American and African American people older than 55 years of age experienced a higher risk of death from fires and burns. The rate ratio of burn/fire deaths for African Americans compared with white people was 3.14 (95% confidence interval [CI] 2.98, 3.31) for those aged 55 years and older. The corresponding rate ratio for Native Americans compared with white people was 1.93 (95% CI 1.49, 2.46) for those aged 55 years and older.
The especially heightened risk among minority seniors could reflect living arrangements that place them at higher risk. Heightened fire risks for minority seniors require broad attention and the development of effective interventions.
Swe1 (Saccharomyces WEE1), the only “true” tyrosine kinase in budding yeast, is an Hsp90 client protein. Here we show that Swe1Wee1 phosphorylates a conserved tyrosine residue (Y24 in yeast Hsp90 and Y38 in human Hsp90α) in the N-domain of Hsp90. Phosphorylation is cell cycle-associated and modulates the ability of Hsp90 to chaperone a selected clientele, including v-Src and several other kinases. Non-phosphorylatable mutants have normal ATPase activity, support yeast viability, and productively chaperone the Hsp90 client glucocorticoid receptor. Deletion of SWE1 in yeast increases Hsp90 binding to its inhibitor geldanamycin, and pharmacologic inhibition/silencing of Wee1 sensitizes cancer cells to Hsp90 inhibitor-induced apoptosis. These findings demonstrate that Hsp90 chaperoning of distinct client proteins is differentially regulated by specific post-translational modification of a unique subcellular pool of the chaperone, and they provide a novel strategy to increase the cellular potency of Hsp90 inhibitors.
Liver cancer is one of most commonly diagnosed cancers among Koreans. Chronic hepatitis B virus (HBV) infection is a major risk factor for liver cancer. HBV infection can be prevented by effective screening and vaccination programs. The purpose of this study is to examine the status of HBV infection and the predictors associated with HBV vaccination.
The study population was derived from the 2005 Korea National Cancer Screening Survey (KNCSS). The KNCSS is an annual cross-sectional survey that uses a nationally-representative random sampling to investigate cancer screening rates. A total of 1,786 Koreans over 40 years of age participated in this study.
Of all the participants, 5.9% reported HBV positive (HBsAg+, HBsAb-), 41.8% were HBV negative but protected (HBsAg-, HBsAb+), and 52.3% were unprotected (HBsAg-, HBsAb-). Among unprotected individuals (n = 934), 23.1% reported to have received the vaccination. About half of those who had vaccinations completed the 3-shot vaccine series. In multiple analyses, education, having private cancer insurance, alcohol use, having regular check-up, and doing regular exercise were associated with completed HBV vaccination.
This study result suggests that we need a liver cancer education program to increase HBV awareness and to increase the liver cancer prevention message among low educated populations.
In a previous genomic analysis, using somatic methyltransferase (DNMT) knockout cells, we showed that hypomethylation decreased the expression of as many genes as were observed to increase, suggesting a previously unknown mechanism for epigenetic regulation. To address this idea, the expression of the BAG family genes was used as a model. These genes were used because their expression was decreased in DNMT1−/−, DNMT3B−/−, and double knockout cells and increased in DNMT1-overexpressing and DNMT3B-overexpressing cells. Chromatin immunoprecipitation analysis of the BAG-1 promoter in DNMT1-overexpressing or DNMT3B-overexpressing cells showed a permissive dimethyl-H3-K4/dimethyl-H3-K9 chromatin status associated with DNA-binding of CTCFL/BORIS, as well as increased BAG-1 expression. In contrast, a nonpermissive dimethyl-H3-K4/dimethyl-H3-K9 chromatin status was associated with CTCF DNA-binding and decreased BAG-1 expression in the single and double DNMT knockout cells. BORIS short hairpin RNA knockdown decreased both promoter DNA-binding, as well as BAG-1 expression, and changed the dimethyl-H3-K4/dimethyl-H3-K9 ratio to that characteristic of a nonpermissive chromatin state. These results suggest that DNMT1 and DNMT3B regulate BAG-1 expression via insulator protein DNA-binding and chromatin dynamics by regulating histone dimethylation.
Infrared spectroscopy identifies molecules by detection of vibrational patterns characteristic of molecular bonds. We apply this approach to measure protein acetylation after treatment with histone deacetylase inhibitors. The anticancer activity of histone deacetylase inhibitors (HDACi) is ascribed to the hyperacetylation of both core nucleosomal histones and non-histone proteins critical to the maintenance of the malignant phenotype. 1, 2 After incubating peripheral blood mononuclear cells in vitro with the HDACi SNDX-275, a benzamide drug derivative, vibrational spectral changes in the methyl and methylene stretching mode regions, which reflect concentration-dependent increases in protein acetylation, were detected and quantified. We applied these metrics, based upon spectral differences, to peripheral blood mononuclear cells (PBMCs) from patients treated in vivo with this agent. The data demonstrate a new approach to a sensitive assessment of global molecular modifications that is independent of antibodies, requires minimal cell processing, and is easily adapted to high-throughput screening.
acetylation; histone; vibrational spectroscopy; imaging; epigenetics; cancer
Gain-of-function mutations in the proto-oncogene c-kit that induce constitutive kinase activity of its product, KIT protein, are characteristic of human mast cell disease and are believed to play a central role in mast cell leukemia oncogenesis, proliferation and survival. Nuclear overexpression of the Wnt effector β-catenin and deregulated β-catenin nuclear signaling can promote malignant transformation in solid tumors and hematologic malignancies. However, a role for β-catenin in mast cell leukemia has not been described. Nuclear accumulation of β-catenin is upregulated by its tyrosine phosphorylation, a process that can be exacerbated by de-regulated expression of oncogenic tyrosine kinases. Here, we investigated the relationship between activated KIT and β-catenin signaling in mast cell leukemia. β-catenin was tyrosine-phosphorylated in cells with KIT activated by either gain-of-function mutation or incubation with the KIT ligand stem cell factor. β-catenin tyrosine-phosphorylation depended on KIT activity but not on PI3K-AKT activation. Tyrosine-phosphorylation of β-catenin was associated with its nuclear localization and enhanced transcription of target genes c-myc and cyclin D1. Endogenous KIT and β-catenin were found to associate in mast cell leukemia cells, and in vitro kinase assay demonstrated that active KIT phosphorylates tyrosine residues of β-catenin directly. Aberrant β-catenin-driven transcription caused by de-regulated KIT may represent a significant new target for treatment of mast cell leukemia.
c-kit; mast cell; β-catenin; Tyrosine-phosphorylation
We investigated the relation of educational attainment and annual household income to cognitive function and cognitive decline in community-dwelling women aged 66 years or older. Subjects were 6,314 health professionals participating in the Women’s Health Study, among whom information on education and income was self-reported. From 1998 to 2000, we administered five cognitive tests, measuring general cognition, episodic memory and verbal fluency, using a validated telephone interview. Second cognitive assessments were conducted approximately two years later; information was complete for 5,573 women at the time of analysis, with 94% follow-up. We used linear and logistic regression to calculate multivariate-adjusted mean differences, and odds of cognitive impairment (defined as worst 10% of test distribution) and of substantial decline in performance (worst 10% of distribution), across various levels of education and income. After adjusting for numerous potential confounding factors, we found strong trends of increasing mean cognitive performance with increasing level of education (p-trend<0.0005 on all cognitive measures). Odds of cognitive impairment also consistently decreased with increasing education (eg, on summary score combining all tests, OR=0.6, 95% CI 0.3–0.9 comparing those with a doctoral degree to those with a 3-year associate’s degree). For income, we found significant trends of increasing mean cognitive performance with increasing income on the summary score and on episodic memory (p-trends<0.0001). For example, the OR was 0.6 (95% CI 0.4–0.8) comparing those with the highest income to the lowest income on the summary score. Results were generally similar for cognitive decline over two years, although somewhat weaker. Thus, in these well-educated, professional women, educational attainment and income both predicted cognitive function and decline.
educational attainment; income; cognitive function; cognitive decline