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1.  Boric acid induces cytoplasmic stress granule formation, eIF2α phosphorylation, and ATF4 in prostate DU-145 cells 
Biometals  2014;28:133-141.
Dietary boron intake is associated with reduced prostate and lung cancer risk and increased bone mass. Boron is absorbed and circulated as boric acid (BA) and at physiological concentrations is a reversible competitive inhibitor of cyclic ADP ribose, the endogenous agonist of the ryanodine receptor calcium (Ca+2) channel, and lowers endoplasmic reticulum (ER) [Ca2+]. Low ER [Ca2+] has been reported to induce ER stress and activate the eIF2α/ATF4 pathway. Here we report that treatment of DU-145 prostate cells with physiological levels of BA induces ER stress with the formation of stress granules and mild activation of eIF2α, GRP78/BiP, and ATF4. Mild activation of eIF2α and its downstream transcription factor, ATF4, enables cells to reconfigure gene expression to manage stress conditions and mild activation of ATF4 is also required for the differentiation of osteoblast cells. Our results using physiological levels of boric acid identify the eIF2α/ATF pathway as a plausible mode of action that underpins the reported health effects of dietary boron.
PMCID: PMC4300416  PMID: 25425213
Boron; Boric acid; eIF2α; ATF4; DU-145 cells
2.  Evidence for Ongoing DNA Damage in Multiple Myeloma Cells as Revealed by Constitutive Phosphorylation of H2AX 
Leukemia  2011;25(8):1344-1353.
DNA double strand breaks (DSBs) are deleterious lesions that can lead to chromosomal anomalies, genomic instability and cancer. The histone protein H2AX plays an important role in the DNA damage response (DDR) and the presence of phospho-H2AX (γH2AX) nuclear foci is the hallmark of DSBs. We hypothesize that ongoing DNA damage provides a mechanism by which chromosomal abnormalities and intratumor heterogeneity are acquired in malignant plasma cells (PCs) in patients with multiple myeloma (MM). Therefore, we assessed PCs from patients with the premalignant condition, monoclonal gammopathy of undetermined significance (MGUS) and MM, as well as human MM cell lines (HMCLs) for evidence of DSBs. γH2AX foci were detected in 2/5 MGUS samples, 37/40 MM samples and 6/6 HMCLs. Notably, the DSB response protein 53BP1 colocalized with γH2AX in both MM patient samples and HMCLs. Treatment with wortmannin decreased phosphorylation of H2AX and suggests phosphoinositide (PI) 3-kinases and/or PI3-kinase like family members underlie the presence of γH2AX foci in MM cells. Taken together, these data imply that ongoing DNA damage intensifies across the disease spectrum of MGUS to MM and may provide a mechanism whereby clonal evolution occurs in the monoclonal gammopathies.
PMCID: PMC3940337  PMID: 21566653
Myeloma; H2AX; PI3-kinase; ATR; DNA damage
3.  Increased Expression of Extracellular Matrix Metalloproteinase Inducer (CD147) in Multiple Myeloma: Role in Regulation of Myeloma Cell Proliferation 
Leukemia  2012;26(10):2286-2296.
Multiple myeloma (MM) is preceded by the asymptomatic premalignant state, monoclonal gammopathy of undetermined significance (MGUS). Although MGUS patients may remain stable for years, they are at increased risk of progressing to MM. A better understanding of the relevant molecular changes underlying the transition from an asymptomatic to symptomatic disease state is urgently needed. Our studies show for the first time that the CD147 molecule (extracellular matrix metalloproteinase inducer) may be playing an important biological role in MM. We first demonstrate that CD147 is over-expressed in MM plasma cells (PCs) vs. normal and premalignant PCs. Next, functional studies revealed that the natural CD147 ligand, cyclophilin B, stimulates MM cell growth. Moreover, when MM patient PCs displaying bimodal CD147 expression were separated into CD147bright and CD147dim populations and analyzed for proliferation potential, we discovered that CD147bright PCs displayed significantly higher levels of cell proliferation than did CD147dim PCs. Lastly, CD147 silencing significantly attenuated MM cell proliferation. Taken together, these data suggest that the CD147 molecule plays a key role in MM cell proliferation and may serve as an attractive target for reducing the proliferative compartment of this disease.
PMCID: PMC3915875  PMID: 22460757
CD147; multiple myeloma; cyclophilin B; plasma cells
4.  Psychosocial Distress and Stroke Risk in Older Adults 
To investigate the association of psychosocial distress with risk of stroke mortality and incident stroke in older adults.
Data were from the Chicago Health and Aging Project, a longitudinal population-based study conducted in three contiguous neighborhoods on the south side of Chicago, Illinois. Participants were community-dwelling black and non-Hispanic white adults, age 65 and older (N=4,120 for stroke mortality; N=2,649 for incident stroke). Psychosocial distress was an analytically-derived composite measure of depressive symptoms, perceived stress, neuroticism, and life dissatisfaction. Cox proportional hazards models examined the association of distress with stroke mortality and incident stroke over 6 years of follow-up.
151 stroke deaths and 452 incident strokes were identified. Adjusting for age, race, and sex, the hazard ratio (HR) for each 1-SD increase in distress was 1.47 (95% confidence interval [CI]=1.28–1.70) for stroke mortality and 1.18 (95% CI, 1.07–1.30) for incident stroke. Associations were reduced following adjustment for stroke risk factors and remained significant for stroke mortality (HR=1.29; 95% CI=1.10–1.52) but not for incident stroke (HR=1.09; 95% CI=0.98–1.21). Secondary analyses of stroke subtypes showed that distress was strongly related to incident hemorrhagic strokes (HR=1.70; 95% CI=1.28–2.25) but not ischemic strokes (HR=1.02; 95% CI=0.91–1.15) in fully adjusted models.
Increasing levels of psychosocial distress are related to excess risk of both fatal and nonfatal stroke in older black and white adults. Additional research is needed to examine pathways linking psychosocial distress to cerebrovascular disease risk.
PMCID: PMC3552144  PMID: 23238864
epidemiology; psychosocial stress; risk factors; women & minorities
5.  Effects of a Home-Based Walking Intervention on Mobility and Quality of Life in People With Diabetes and Peripheral Arterial Disease 
Diabetes Care  2011;34(10):2174-2179.
Determine the efficacy of a home-based walking intervention to improve walking ability and quality of life in people with diabetes and peripheral arterial disease (PAD).
We conducted a randomized, controlled, single-blind trial within university-affiliated clinics in our local community. We randomized 145 participants (45 women) with diabetes and PAD to our intervention—a 6-month behavioral intervention targeting levels of readiness to engage in routine walking for exercise—versus attention control. Our primary outcome was 6-month change in maximal treadmill walking distance. Secondary outcomes included 3-month change in maximal walking distance, lower limb function (i.e., walking impairment scores), quality of life (Medical Outcomes Short Form Survey), exercise behaviors, depressive symptoms, and self-efficacy at 3 and 6 months.
The mean age of participants was 66.5 (SD 10.1) years. Intervention and control groups did not differ significantly in 6-month change in maximal treadmill walking distance (average [SE] 24.5 [19.6] meters vs. 39.2 [19.6] meters; P = 0.60). Among secondary outcomes, for the intervention and control groups, respectively, average walking speed scores increased by 5.7 [2.2] units and decreased by 1.9 [2.8] units (P = 0.03); the mental health quality of life subscale score increased by 3.2 [1.5] and decreased by 2.4 [1.5] units (P = 0.01).
A home-based walking intervention did not improve walking distance but did improve walking speed and quality of life in people with diabetes and PAD. Clinicians should consider recommending home-based walking therapy for such patients.
PMCID: PMC3177730  PMID: 21873560
6.  Latent Constructs in Psychosocial Factors Associated with Cardiovascular Disease: An Examination by Race and Sex 
This study examines race and sex differences in the latent structure of 10 psychosocial measures and the association of identified factors with self-reported history of coronary heart disease (CHD). Participants were 4,128 older adults from the Chicago Health and Aging Project. Exploratory factor analysis (EFA) with oblique geomin rotation was used to identify latent factors among the psychosocial measures. Multi-group comparisons of the EFA model were conducted using exploratory structural equation modeling to test for measurement invariance across race and sex subgroups. A factor-based scale score was created for invariant factor(s). Logistic regression was used to test the relationship between the factor score(s) and CHD adjusting for relevant confounders. Effect modification of the relationship by race–sex subgroup was tested. A two-factor model fit the data well (comparative fit index = 0.986; Tucker–Lewis index = 0.969; root mean square error of approximation = 0.039). Depressive symptoms, neuroticism, perceived stress, and low life satisfaction loaded on Factor I. Social engagement, spirituality, social networks, and extraversion loaded on Factor II. Only Factor I, re-named distress, showed measurement invariance across subgroups. Distress was associated with a 37% increased odds of self-reported CHD (odds ratio: 1.37; 95% confidence intervals: 1.25, 1.50; p-value < 0.0001). This effect did not differ by race or sex (interaction p-value = 0.43). This study identified two underlying latent constructs among a large range of psychosocial variables; only one, distress, was validly measured across race–sex subgroups. This construct was robustly related to prevalent CHD, highlighting the potential importance of latent constructs as predictors of cardiovascular disease.
PMCID: PMC3270306  PMID: 22347196
psychosocial; risk factor; cardiovascular disease; factor analysis; race and sex
7.  Clinical Trials – The Art of Enrollment 
Seminars in Oncology Nursing  2008;24(4):262-269.
Enrollment barriers and multidisciplinary approaches to increase cancer trials participation are presented. Recruitment barriers, research in Maryland, and a Best Practice for cancer trials are discussed.
Data Sources
Journal and research articles, web sites.
Clinical trials have produced prevention and care advances for cancer and other diseases. Trial enrollment is lower for minorities and underserved communities. A comprehensive program for addressing enrollment barriers should incorporate research on barriers, multidisciplinary teams, and education and trial infrastructure in community settings.
Implications for Nursing Practice
Health disparities training, including culturally appropriate enrollment approaches for education and retention of underserved communities, should incorporate community stakeholders and nurse/physician researchers.
PMCID: PMC3262589  PMID: 19000600
clinical trials enrollment; barriers; accrual; minority and underserved
8.  Identification of copy-number abnormalities and inactivating mutations in two negative regulators of NF-kB signaling pathways in Waldenström’s Macroglobulinemia 
Cancer research  2009;69(8):3579-3588.
Waldenström’s macroglobulinemia (WM) is a distinct clinico-biological entity defined as a B-cell neoplasm characterized by a lymphoplasmacytic infiltrate in the bone marrow (BM) and immunoglobulin M paraprotein production. Cytogenetic analyses were historically limited by the difficulty in obtaining tumor metaphases and the genetic basis of the disease remains poorly defined. Here we performed a comprehensive analysis in 42 WM patients by using high-resolution, array-based comparative genomic hybridization approach to unravel the genetic mechanisms associated with WM pathogenesis. Overall, 83% of patients have chromosomal abnormalities, with a median of three abnormalities per patient. Gain of 6p was the second most common abnormality (17%) and its presence was always concomitant with 6q loss. A minimal deleted region, including MIRN15A and MIRN16-1, was delineated on 13q14 in 10% of patients. Of interest, we reported biallelic deletions and/or inactivating mutations with uniparental disomy in TRAF3 and TNFAIP3, two negative regulators of the NF-kB signaling pathway. Furthermore, we confirmed the association between TRAF3 inactivation and increased transcriptional activity of NF-kB target genes. Mutational activation of the NF-kB pathway, which is normally activated by ligand-receptor interactions within the BM microenvironment, highlights its biologic importance, and suggests a therapeutic role for inhibitors of NF-kB pathway activation in the treatment of Waldenström’s macroglobulinemia.
PMCID: PMC2782932  PMID: 19351844
Waldenström’s Macroglobulinemia; aCGH; TRAF3; TNFAIP3; NF-kB signaling pathways
9.  Receptor Activated Ca2+ Release Is Inhibited by Boric Acid in Prostate Cancer Cells 
PLoS ONE  2009;4(6):e6009.
The global disparity in cancer incidence remains a major public health problem. We focused on prostate cancer since microscopic disease in men is common, but the incidence of clinical disease varies more than 100 fold worldwide. Ca2+ signaling is a central regulator of cell proliferation, but has received little attention in cancer prevention. We and others have reported a strong dose-dependent reduction in the incidence of prostate and lung cancer within populations exposed to boron (B) in drinking water and food; and in tumor and cell proliferation in animal and cell culture models.
Methods/Principal Findings
We examined the impact of B on Ca2+ stores using cancer and non-cancer human prostate cell lines, Ca2+ indicators Rhod-2 AM and Indo-1 AM and confocal microscopy. In DU-145 cells, inhibition of Ca2+ release was apparent following treatment with Ringers containing RyR agonists cADPR, 4CmC or caffeine and respective levels of BA (50 µM), (1, 10 µM) or (10, 20, 50,150 µM). Less aggressive LNCaP cancer cells required 20 µM BA and the non-tumor cell line PWR1E required 150 µM BA to significantly inhibit caffeine stimulated Ca2+ release. BA (10 µM) and the RyR antagonist dantroline (10 µM) were equivalent in their ability to inhibit ER Ca2+ loss. Flow cytometry and confocal microscopy analysis showed exposure of DU-145 cells to 50 µM BA for 1 hr decreased stored [Ca2+] by 32%.
We show B causes a dose dependent decrease of Ca2+ release from ryanodine receptor sensitive stores. This occurred at BA concentrations present in blood of geographically disparate populations. Our results suggest higher BA blood levels lower the risk of prostate cancer by reducing intracellular Ca2+ signals and storage.
PMCID: PMC2698284  PMID: 19554099
10.  Adapting Evidence-Based Strategies to Increase Physical Activity Among African Americans, Hispanics, Hmong, and Native Hawaiians: A Social Marketing Approach 
Preventing Chronic Disease  2007;4(4):A102.
Using a social marketing approach, we studied how best to adapt proven, evidence-based strategies to increase physical activity for use with underserved racial or ethnic groups.
We conducted focus groups with low-income Hispanic women in Texas, Hmong parents and their children in California, low-income African American women and men in the Mississippi Delta, and Native Hawaiian college students in Hawaii. We also interviewed key leaders of these communities. Topics of discussion were participants' perceptions about 1) the benefits of engaging in physical activity, 2) the proposed evidence-based strategies for increasing each community's level of physical activity, and 3) the benefits and barriers to following the proposed interventions for increasing physical activity. A total of 292 individuals participated in the study.
All groups considered that being physically active was part of their culture, and participants found culturally relevant suggestions for physical activities appealing. Overwhelmingly, strategies that aimed to create or improve social support and increase access to physical activity venues received the most positive feedback from all groups. Barriers to physical activity were not culturally specific; they are common to all underserved people (lack of time, transportation, access, neighborhood safety, or economic resources).
Results indicate that evidence-based strategies to increase physical activity need to be adapted for cultural relevance for each racial or ethnic group. Our research shows that members of four underserved populations are likely to respond to strategies that increase social support for physical activity and improve access to venues where they can be physically active. Further research is needed to test how to implement such strategies in ways that are embraced by community members.
PMCID: PMC2099267  PMID: 17875246

Results 1-10 (10)