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1.  Racial and Gender Disparities in Incidence of Lung and Bronchus Cancer in the United States: A Longitudinal Analysis 
PLoS ONE  2016;11(9):e0162949.
Background
Certain population groups in the United States carry a disproportionate burden of cancer. This work models and analyzes the dynamics of lung and bronchus cancer age-adjusted incidence rates by race (White and Black), gender (male and female), and prevalence of daily smoking in 38 U.S. states, the District of Columbia, and across eight U.S. geographic regions from 1999 to 2012.
Methods
Data, obtained from the U.S. Cancer Statistics Section of the Centers for Disease Control and Prevention, reflect approximately 77% of the U.S. population and constitute a representative sample for making inferences about incidence rates in lung and bronchus cancer (henceforth lung cancer). A longitudinal linear mixed-effects model was used to study lung cancer incidence rates and to estimate incidence rate as a function of time, race, gender, and prevalence of daily smoking.
Results
Between 1999 and 2012, age-adjusted incidence rates in lung cancer have decreased in all states and regions. However, racial and gender disparities remain. Whites continue to have lower age-adjusted incidence rates for this cancer than Blacks in all states and in five of the eight U.S. geographic regions. Disparities in incidence rates between Black and White men are significantly larger than those between Black and White women, with Black men having the highest incidence rate of all subgroups. Assuming that lung cancer incidence rates remain within reasonable range, the model predicts that the gender gap in the incidence rate for Whites would disappear by mid-2018, and for Blacks by 2026. However, the racial gap in lung cancer incidence rates among Black and White males will remain. Among all geographic regions, the Mid-South has the highest overall lung cancer incidence rate and the highest incidence rate for Whites, while the Midwest has the highest incidence rate for Blacks. Between 1999 and 2012, there was a downward trend in the prevalence of daily smokers in both genders. However, males have significantly higher rates of cigarette smoking than females at all time points. The highest and lowest prevalence of daily smoking are found in the Mid-South and New England, respectively. There was a significant correlation between lung cancer incidence rates and smoking prevalence in all geographic regions, indicating a strong influence of cigarette smoking on regional lung cancer incidence rates.
Conclusion
Although age-adjusted incidence rates in lung cancer have decreased throughout the U.S., racial and gender disparities remain. This longitudinal model can help health professionals and policy makers make predictions of age-adjusted incidence rates for lung cancer in the U.S. in the next five to ten years.
doi:10.1371/journal.pone.0162949
PMCID: PMC5042522  PMID: 27685944
2.  Physician Characteristics and the Reported Effect of Evidence-Based Practice Guidelines 
Health Services Research  2008;43(2):569-581.
Objective
To explore characteristics that may contribute to the effect practice guidelines have on the practice of medicine.
Data Sources
From the third round of the Community Tracking Study, Physician Survey, 2000–2001.
Study Design
An ordinal logistic regression model was estimated to capture the full range of responses.
Principal Findings
Recent medical school graduates, women, minorities, ob-gyn specialists, physicians who use computers for information in their practices, and physicians in nonsolo practice types were significantly more likely to state practice guidelines had an effect on their practice.
Conclusions
Many barriers have prevented wide acceptance of practice guidelines among the medical community. Our findings suggest there will be positive results on guideline effects as recent graduates, women, and minorities enter the physician workforce.
doi:10.1111/j.1475-6773.2007.00788.x
PMCID: PMC2442364  PMID: 18484106
Evidence-based practice guidelines; physician characteristics
3.  Chronic Obstructive Pulmonary Disease Self-Management Activation Research Trial (COPD-SMART): Results of Recruitment and Baseline Patient Characteristics 
Contemporary clinical trials  2015;41:192-201.
Objective
To describe the recruitment methods, study participation rate, and baseline characteristics of a representative sample of outpatients with COPD eligible for pulmonary rehabilitation participating in a trial of a lifestyle behavioral intervention to increase physical activity.
Setting and Design
A patient registry was developed for recruitment using an administrative database from primary care and specialty clinics of an academic medical center in northeast Texas for a parallel group randomized trial.
Results
The registry was comprised of 5,582 patients and over the course of the 30 month recruitment period 325 patients were enrolled for an overall study participation rate of 35.1%. After a 6-week COPD self-management education period provided to all enrolled patients, 305 patients were randomized into either Usual Care (UC; n=156) or the Physical Activity Self-Management intervention (PASM; n=149). There were no clinically significant differences in demographics, clinical characteristics, or health status indicators between the randomized groups.
Conclusion
The results of this recruitment process demonstrate the successful use of a patient registry for enrolling a representative sample of outpatients eligible for pulmonary rehabilitation with COPD from primary and specialty care. Moreover, this approach to patient recruitment provides a model for future studies utilizing administrative databases and electronic health records.
doi:10.1016/j.cct.2015.01.018
PMCID: PMC4380855  PMID: 25657053
randomized clinical trial; recruitment; chronic obstructive pulmonary disease; physical activity; self-management
4.  PI3K/AKT/mTOR and sonic hedgehog pathways cooperate together to inhibit human pancreatic cancer stem cell characteristics and tumor growth 
Oncotarget  2015;6(31):32039-32060.
Cancer stem cells (CSCs) play major roles in cancer initiation, progression, and metastasis. It is evident from growing reports that PI3K/Akt/mTOR and Sonic Hedgehog (Shh) signaling pathways are aberrantly reactivated in pancreatic CSCs. Here, we examined the efficacy of combining NVP-LDE-225 (PI3K/mTOR inhibitor) and NVP-BEZ-235 (Smoothened inhibitor) on pancreatic CSCs characteristics, microRNA regulatory network, and tumor growth. NVP-LDE-225 co-operated with NVP-BEZ-235 in inhibiting pancreatic CSC's characteristics and tumor growth in mice by acting at the level of Gli. Combination of NVP-LDE-225 and NVP-BEZ-235 inhibited self-renewal capacity of CSCs by suppressing the expression of pluripotency maintaining factors Nanog, Oct-4, Sox-2 and c-Myc, and transcription of Gli. NVP-LDE-225 co-operated with NVP-BEZ-235 to inhibit Lin28/Let7a/Kras axis in pancreatic CSCs. Furthermore, a superior interaction of these drugs was observed on spheroid formation by pancreatic CSCs isolated from Pankras/p53 mice. The combination of these drugs also showed superior effects on the expression of proteins involved in cell proliferation, survival and apoptosis. In addition, NVP-LDE-225 co-operated with NVP-BEZ-235 in inhibiting EMT through modulation of cadherin, vimentin and transcription factors Snail, Slug and Zeb1. In conclusion, these data suggest that the combined inhibition of PI3K/Akt/mTOR and Shh pathways may be beneficial for the treatment of pancreatic cancer.
PMCID: PMC4741658  PMID: 26451606
pancreatic cancer; PI3K/AKT/mTOR; sonic hedgehog; cancer stem cell; Gli
5.  T Model of Growth and its Application in Systems of Tumor-Immune Dynamics 
In this paper we introduce a new growth model called T growth model. This model is capable of representing sigmoidal growth as well as biphasic growth. This dual capability is achieved without introducing additional parameters. The T model is useful in modeling cellular proliferation or regression of cancer cells, stem cells, bacterial growth and drug dose-response relationships. We recommend usage of the T growth model for the growth of tumors as part of any system of differential equations. Use of this model within a system will allow more flexibility in representing the natural rate of tumor growth. For illustration, we examine some systems of tumor-immune interaction in which the T growth rate is applied. We also apply the model to a set of tumor growth data.
PMCID: PMC4476034  PMID: 23906156
Growth models; tumor-immune dynamics; RNA interference
6.  Clinical Implications of Rabphillin-3A-Like Gene Alterations in Breast Cancer 
PLoS ONE  2015;10(6):e0129216.
For the rabphillin-3A-like (RPH3AL) gene, a putative tumor suppressor, the clinical significance of genetic alterations in breast cancers was evaluated. DNA and RNA were extracted from formalin-fixed, paraffin-embedded (FFPE) cancers and matching normal tissues. DNA samples were assessed for loss of heterozygosity (LOH) at the 17p13.3 locus of RPH3AL and the 17p13.1 locus of the tumor suppressor, TP53. RPH3AL was sequenced, and single nucleotide polymorphisms (SNPs) were genotyped. RNA samples were evaluated for expression of RPH3AL, and FFPE tissues were profiled for its phenotypic expression. Alterations in RPH3AL were correlated with clinicopathological features, LOH of TP53, and patient survival. Of 121 cancers, 80 had LOH at one of the RPH3AL locus. LOH of RHP3AL was associated with nodal metastasis, advanced stage, large tumor size, and poor survival. Although ~50% were positive for LOH at the RPH3AL and TP53 loci, 19 of 105 exhibited LOH only at the RPH3AL locus. Of these, 12 were non-Hispanic Caucasians (Whites), 15 had large tumors, and 12 were older (>50 years). Patients exhibiting LOH at both loci had shorter survival than those without LOH at these loci (log-rank, P = 0.014). LOH at the TP53 locus alone was not associated with survival. Analyses of RPH3AL identified missense point mutations in 19 of 125 cases, a SNP (C>A) in the 5’untranslated region at -25 (5’UTR-25) in 26 of 104, and a SNP (G>T) in the intronic region at 43 bp downstream to exon-6 (intron-6-43) in 79 of 118. Genotype C/A or A/A of the SNP at 5’UTR-25 and genotype T/T of a SNP at intron-6-43 were predominantly in Whites. Low levels of RNA and protein expression of RPH3AL were present in cancers relative to normal tissues. Thus, genetic alterations in RPH3AL are associated with aggressive behavior of breast cancers and with short survival of patients.
doi:10.1371/journal.pone.0129216
PMCID: PMC4466565  PMID: 26070152
7.  Inequalities in vaccination coverage for young females whose parents are informal caregivers 
Human Vaccines & Immunotherapeutics  2014;10(8):2454-2459.
The effects of caregiver strain and stress on preventive health service utilization among adult family members are well-established, but the effects of informal caregiving on children of caregivers are unknown. We aimed to assess whether inequalities in vaccination coverage (specifically human papillomavirus [HPV] and influenza) exist for females aged 9 to 17 years whose parents are informal caregivers (i.e., care providers for family members or others who are not functionally independent) compared with females whose parents are not informal caregivers. Data from the 2009 Behavioral Risk Factor Surveillance System were analyzed using Poisson regression with robust variance to estimate overall and subgroup-specific HPV and influenza vaccination prevalence ratios (PRs) and corresponding 95% confidence limits (CL) comparing females whose parents were informal caregivers with females whose parents were not informal caregivers. Our unweighted study populations comprised 1645 and 1279 females aged 9 to 17 years for the HPV and influenza vaccination analyses, respectively. Overall, both HPV and influenza vaccination coverage were lower among females whose parents were informal caregivers (HPV: PR = 0.72, 95% CL: 0.53, 0.97; Influenza: PR = 0.89, 95% CL: 0.66, 1.2). Our results suggest consistently lower HPV and influenza vaccination coverage for young females whose parents are informal caregivers. Our study provides new evidence about the potential implications of caregiving on the utilization of preventive health services among children of caregivers.
doi:10.4161/hv.29096
PMCID: PMC4896764  PMID: 25424955
informal caregiver; risk perception; strain; human papillomavirus vaccine; influenza vaccination; children; adolescents
8.  Domain-Specific Self-Efficacy Is Associated with Measures of Functional Capacity and Quality of Life among Patients with Moderate to Severe Chronic Obstructive Pulmonary Disease 
Rationale: The relationship between self-efficacy and health behaviors is well established. However, little is known about the relationship between self-efficacy and health-related indicators among patients with chronic obstructive pulmonary disease (COPD).
Objectives: The purpose of this cross-sectional cohort study was to test the hypothesis that the total score and specific subdomain scores of the COPD Self-Efficacy Scale (CSES) are associated with functional capacity and quality of life in a group of patients with moderate to severe COPD.
Methods: Relationships were examined in a cross-sectional study of baseline data collected as part of a randomized trial. Self-efficacy was measured using the five domains of the CSES: negative affect, emotional arousal, physical exertion, weather/environment, and behavioral. Measures of quality of life and functional capacity included SF-12: physical and mental composite scores, Chronic Respiratory Questionnaire dyspnea domain, and the 6-minute-walk test. Statistical analyses included Spearman correlation and categorical analyses of self-efficacy (“confident” vs. “not confident”) using general linear models adjusting for potential confounders.
Measurements and Main Results: There were 325 patients enrolled with a mean age (standard deviation) of 68.5 (9.48) years, 49.5% male, and 91.69% non-Hispanic white. The negative affect, emotional arousal, and physical exertion domains were moderately correlated (range, 0.3–0.7) with the SF-12 mental composite score and Chronic Respiratory Questionnaire dyspnea domain. In models exploring each CSES domain as “confident” versus “not confident” and adjusting for age, sex, race, pack-years, and airflow obstruction severity, there were multiple clinically and statistically significant associations between the negative affect, emotional arousal, and physical exertion domains with functional capacity and quality of life.
Conclusions: The aggregated total CSES score was associated with better quality of life and functional capacity. Our analysis of subdomains revealed that the physical exertion, negative affect, and emotional arousal subdomains had the largest associations with functional capacity and quality of life indicators. These findings suggest that interventions to enhance self-efficacy may improve the functional capacity and quality of life of patients with moderate to severe COPD.
doi:10.1513/AnnalsATS.201308-273BC
PMCID: PMC4028735  PMID: 24447029
COPD; dyspnea; self-efficacy; quality of life
9.  Guillain–Barre syndrome following quadrivalent human papillomavirus vaccination among vaccine-eligible individuals in the United States 
Post-marketing surveillance studies provide conflicting evidence about whether Guillain–Barre syndrome occurs more frequently following quadrivalent human papillomavirus (HPV4) vaccination. We aimed to assess whether Guillain–Barre syndrome is reported more frequently following HPV4 vaccination than other vaccinations among females and males aged 9 to 26 y in the United States. We used adverse event reports received by the United States Vaccine Adverse Event Reporting System (VAERS) between January 1, 2010 and December 31, 2012 to estimate overall, age-, and sex-specific proportional reporting ratios (PRRs) and corresponding Χ2 values for reports of Guillain–Barre syndrome between 5 and 42 d following HPV vaccination. Minimum criteria for a signal using this approach are 3 or more cases, PRR ≥2, and Χ2 ≥ 4. Guillain–Barre syndrome was listed as an adverse event in 45 of 14 822 reports, of which 9 reports followed HPV4 vaccination and 36 reports followed all other vaccines. The overall, age-, and sex-specific PRR estimates were uniformly below 1. In addition, the overall, age-, and sex-specific Χ2 values were uniformly below 3. Our analysis of post-marketing surveillance data does not suggest that Guillain–Barre syndrome is reported more frequently following HPV4 vaccination than other vaccinations among vaccine-eligible females or males in the United States. Our findings may be useful when discussing the risks and benefits of HPV4 vaccination.
doi:10.4161/hv.26292
PMCID: PMC4181024  PMID: 24013368
human papillomavirus; vaccine; post-marketing surveillance; Guillain-Barre syndrome; adverse event; safety
10.  A histological evaluation and in vivo assessment of intratumoral near infrared photothermal nanotherapy-induced tumor regression 
Purpose
Nanoparticle (NP)-enabled near infrared (NIR) photothermal therapy has realized limited success in in vivo studies as a potential localized cancer therapy. This is primarily due to a lack of successful methods that can prevent NP uptake by the reticuloendothelial system, especially the liver and kidney, and deliver sufficient quantities of intravenously injected NPs to the tumor site. Histological evaluation of photothermal therapy-induced tumor regression is also neglected in the current literature. This report demonstrates and histologically evaluates the in vivo potential of NIR photothermal therapy by circumventing the challenges of intravenous NP delivery and tumor targeting found in other photothermal therapy studies.
Methods
Subcutaneous Cal 27 squamous cell carcinoma xenografts received photothermal nanotherapy treatments, radial injections of polyethylene glycol (PEG)-ylated gold nanorods and one NIR 785 nm laser irradiation for 10 minutes at 9.5 W/cm2. Tumor response was measured for 10–15 days, gross changes in tumor size were evaluated, and the remaining tumors or scar tissues were excised and histologically analyzed.
Results
The single treatment of intratumoral nanorod injections followed by a 10 minute NIR laser treatment also known as photothermal nanotherapy, resulted in ~100% tumor regression in ~90% of treated tumors, which was statistically significant in a comparison to the average of all three control groups over time (P<0.01).
Conclusion
Photothermal nanotherapy, or intratumoral nanorod injections followed by NIR laser irradiation of tumors and tumor margins, demonstrate the potential of NIR photothermal therapy as a viable localized treatment approach for primary and early stage tumors, and prevents NP uptake by the reticuloendothelial system.
doi:10.2147/IJN.S60648
PMCID: PMC4227627  PMID: 25395847
photothermal cancer therapy; malignancy; cancer treatment; intratumoral; gold nanorods; nanoparticles; PEGylation; laser therapy
11.  MDA-9/Syntenin regulates differentiation and angiogenesis programs in head and neck squamous cell carcinoma 
Oncoscience  2014;1(11):725-737.
Little is known about the molecular pathways regulating poor differentiation and invasion of head and neck squamous cell carcinoma (HNSCC). In the present study, we aimed to determine the role of MDA-9/Syntenin, a metastasis associated molecule in HNSCC tumorigenesis. Elevated MDA-9/Syntenin expression was evident in 67% (54/81) primary HNSCC tumors (p=0.001-0.002) and 69% (9/13) pre-neoplastic tissues (p=0.02-0.03). MDA-9/Syntenin overexpression was associated with the stage (p=0.001), grade (p=0.001) and lymph node metastasis (p=0.0001). Silencing of MDA-9/Syntenin in 3 poorly differentiated HNSCC cell lines induced squamous epithelial cell differentiation, disrupted angiogenesis and reduced tumor growth in vitro and in vivo. We confirmed SPRR1B and VEGFR1 as the key molecular targets of MDA-9/Syntenin on influencing HNSCC differentiation and angiogenesis respectively. MDA-9/Syntenin disrupted SPRR1B expression interacting through its PDZ1 domain and altered VEGFR1 expression in vitro and in vivo. VEGFR1 co-localized with MDA-9/Syntenin in HNSCC cell lines and primary tumor. Downregulation of growth regulatory molecules CyclinD1, CDK4, STAT3, PI3K and CTNNB1 was also evident in the MDA-9/Syntenin depleted cells, which was reversed following over-expression of MDA-9/Syntenin in immortalized oral epithelial cells. Our results suggest that early induction of MDA-9/Syntenin expression influences HNSCC progression and should be further evaluated for potential biomarker development.
PMCID: PMC4278274  PMID: 25593999
Head and neck suqamous cell carcinoma; MDA-9/Syntenin; differentiation; SPRR1B; VEGFR1
12.  Disparities in Cervical Cancer Mortality Rates as Determined by the Longitudinal Hyperbolastic Mixed-Effects Type II Model 
PLoS ONE  2014;9(9):e107242.
Background
The main purpose of this study was to model and analyze the dynamics of cervical cancer mortality rates for African American (Black) and White women residing in 13 states located in the eastern half of the United States of America from 1975 through 2010.
Methods
The cervical cancer mortality rates of the Surveillance, Epidemiology, and End Results (SEER) were used to model and analyze the dynamics of cervical cancer mortality. A longitudinal hyperbolastic mixed-effects type II model was used to model the cervical cancer mortality data and SAS PROC NLMIXED and Mathematica were utilized to perform the computations.
Results
Despite decreasing trends in cervical cancer mortality rates for both races, racial disparities in mortality rates still exist. In all 13 states, Black women had higher mortality rates at all times. The degree of disparities and pace of decline in mortality rates over time differed among these states. Determining the paces of decline over 36 years showed that Tennessee had the most rapid decline in cervical cancer mortality for Black women, and Mississippi had the most rapid decline for White Women. In contrast, slow declines in cervical cancer mortality were noted for Black women in Florida and for White women in Maryland.
Conclusions
In all 13 states, cervical cancer mortality rates for both racial groups have fallen. Disparities in the pace of decline in mortality rates in these states may be due to differences in the rates of screening for cervical cancers. Of note, the gap in cervical cancer mortality rates between Black women and White women is narrowing.
doi:10.1371/journal.pone.0107242
PMCID: PMC4167327  PMID: 25226583
13.  GANT-61 inhibits pancreatic cancer stem cell growth in vitro and in NOD/SCID/IL2R gamma null mice xenograft 
Cancer letters  2012;330(1):22-32.
Multiple lines of evidence suggest that the Sonic Hedgehog (Shh) signaling pathway is aberrantly reactivated in pancreatic cancer stem cells (CSCs). The objectives of this study were to examine the molecular mechanisms by which GANT-61 (Gli transcription factor inhibitor) regulates stem cell characteristics and tumor growth. Effects of GANT-61 on CSC’s viability, spheroid formation, apoptosis, DNA-binding and transcriptional activities, and epithelial-mesenchymal transition (EMT) were measured. Humanized NOD/SCID/IL2Rgammanull mice were used to examine the effects of GANT-61 on CSC’s tumor growth. GANT-61 inhibited cell viability, spheroid formation, and Gli-DNA binding and transcriptional activities, and induced apoptosis by activation of caspase-3 and cleavage of Poly-ADP ribose Polymerase (PARP). GANT-61 increased the expression of TRAIL-R1/DR4, TRAIL-R2/DR5 and Fas, and decreased expression of PDGFRα and Bcl-2. GANT-61 also suppressed EMT by up-regulating E-cadherin and inhibiting N-cadherin and transcription factors Snail, Slug and Zeb1. In addition, GANT-61 inhibited pluripotency maintaining factors Nanog, Oct4, Sox-2 and cMyc. Suppression of both Gli1 plus Gli2 by shRNA mimicked the changes in cell viability, spheroid formation, apoptosis and gene expression observed in GANT-61-treated pancreatic CSCs. Furthermore, GANT-61 inhibited CSC tumor growth which was associated with up-regulation of DR4 and DR5 expression, and suppression of Gli1, Gli2, Bcl-2, CCND2 and Zeb1 expression in tumor tissues derived from NOD/SCID IL2Rγ null mice. Our data highlight the importance of Shh pathway for self-renewal and metastasis of pancreatic CSCs, and also suggest Gli as a therapeutic target for pancreatic cancer in eliminating CSCs.
doi:10.1016/j.canlet.2012.11.018
PMCID: PMC4153855  PMID: 23200667
Pancreatic cancer stem cells; GANT-61; Sonic hedgehog; Gli transcription factor
14.  A Phase I Clinical Trial of Ad5/3-Δ24, a Novel Serotype-Chimeric, Infectivity-Enhanced, Conditionally-Replicative Adenovirus (CRAd), in Patients with Recurrent Ovarian Cancer 
Gynecologic oncology  2013;130(3):518-524.
Objective
The conditionally replicative adenovirus Ad5/3-Δ24 has a type-3 knob incorporated into the type-5 fiber that facilitates enhanced ovarian cancer infectivity. Preclinical studies have shown that Ad5/3-Δ24 achieves significant oncolysis and antitumor activity in ovarian cancer models. The purpose of this study was to evaluate in a Phase I trial the feasibility and safety of intraperitoneal (IP) Ad5/3-Δ24 in recurrent ovarian cancer patients.
Methods
Eligible patients were treated with IP Ad5/3-Δ24 for 3 consecutive days in one of three dose cohorts ranging 1 × 1010–1 × 1012 vp. Toxicity was assessed utilizing CTC grading and efficacy with RECIST. Ascites, serum, and other samples were obtained to evaluate gene transfer, generation of wildtype virus, viral shedding, and antibody response.
Results
Nine of 10 patients completed treatment per protocol. A total of 15 vector-related adverse events were experienced in 5 patients. These events included fever or chills, nausea, fatigue, and myalgia. All were grade 1–2 in nature, transient, and medically managed. Of the 8 treated patients evaluable for response, six patients had stable disease and 2 patients had progressive disease. Three patients had decreased CA-125 from pretreatment levels one month after treatment. Ancillary biologic studies indicated Ad5/3-Δ24 replication in patients in the higher dose cohorts. All patients experienced an anti-adenoviral neutralizing antibody effect.
Conclusions
This study suggests the feasibility and safety of a serotype chimeric infectivity-enhanced CRAd, Ad5/3-Δ24, as a potential therapeutic option for recurrent ovarian cancer patients.
doi:10.1016/j.ygyno.2013.06.003
PMCID: PMC3748258  PMID: 23756180
CRAd; gene therapy; infectivity-enhanced adenoviral vectors; ovarian cancer
15.  microRNA-29 negatively regulates EMT regulator N-myc interactor in breast cancer 
Molecular Cancer  2014;13:200.
Background
N-Myc Interactor is an inducible protein whose expression is compromised in advanced stage breast cancer. Downregulation of NMI, a gatekeeper of epithelial phenotype, in breast tumors promotes mesenchymal, invasive and metastatic phenotype of the cancer cells. Thus the mechanisms that regulate expression of NMI are of potential interest for understanding the etiology of breast tumor progression and metastasis.
Method
Web based prediction algorithms were used to identify miRNAs that potentially target the NMI transcript. Luciferase reporter assays and western blot analysis were used to confirm the ability of miR-29 to target NMI. Quantitive-RT-PCRs were used to examine levels of miR29 and NMI from cell line and patient specimen derived RNA. The functional impact of miR-29 on EMT phenotype was evaluated using transwell migration as well as monitoring 3D matrigel growth morphology. Anti-miRs were used to examine effects of reducing miR-29 levels from cells. Western blots were used to examine changes in GSK3β phosphorylation status. The impact on molecular attributes of EMT was evaluated using immunocytochemistry, qRT-PCRs as well as Western blot analyses.
Results
Invasive, mesenchymal-like breast cancer cell lines showed increased levels of miR-29. Introduction of miR-29 into breast cancer cells (with robust level of NMI) resulted in decreased NMI expression and increased invasion, whereas treatment of cells with high miR-29 and low NMI levels with miR-29 antagonists increased NMI expression and decreased invasion. Assessment of 2D and 3D growth morphologies revealed an EMT promoting effect of miR-29. Analysis of mRNA of NMI and miR-29 from patient derived breast cancer tumors showed a strong, inverse relationship between the expression of NMI and the miR-29. Our studies also revealed that in the absence of NMI, miR-29 expression is upregulated due to unrestricted Wnt/β-catenin signaling resulting from inactivation of GSK3β.
Conclusion
Aberrant miR-29 expression may account for reduced NMI expression in breast tumors and mesenchymal phenotype of cancer cells that promotes invasive growth. Reduction in NMI levels has a feed-forward impact on miR-29 levels.
doi:10.1186/1476-4598-13-200
PMCID: PMC4169820  PMID: 25174825
N-Myc interactor; EMT; Breast cancer; miR-29
16.  Rural-Urban Disparities in Quality of Life Among Patients With COPD 
Purpose
Limited evidence in the US suggests that among patients with chronic obstructive pulmonary disease (COPD), rural residence is associated with higher hospitalization rates and increased mortality. However, little is known about the reasons for these disparities. This study’s purpose was to describe the health status of rural vs urban residence among patients with COPD and to examine factors associated with differences between these 2 locations.
Methods
This was a cross-sectional study of baseline data from a representative sample of patients with COPD enrolled in a clinical trial. Rural-urban residence was determined from zip code. Health status was measured using the SF-12 and health care utilization. Independent sample t-tests, chi-square tests, and multiple linear and logistic regressions were performed to examine differences between rural and urban patients.
Findings
Rural residence was associated with poorer health status and higher health care utilization. Among rural patients unadjusted physical functioning scores were lower on the SF-12 (30.22 vs 33.49; P = .005) that persisted after adjustment for potential confounders (β = -2.35; P = .04). However, after further adjustment for social and psychological factors only the Body-Mass index, Airflow obstruction, Dyspnea, and Exercise (BODE) Index was significantly associated with health status.
Conclusions
In this representative sample of patients with COPD rural residence was associated with worse health status, primarily associated with greater impairment as measured by BODE index. While rural patients reported a higher dose of smoking, a number of other unmeasured factors associated with rural residence may contribute to these disparities.
doi:10.1111/jrh.12005
PMCID: PMC3752695  PMID: 23944281
COPD; health disparities; health-related quality of life; rural; utilization of health services
17.  The Prognostic Value of microRNAs Varies with Patient Race/Ethnicity and Stage of Colorectal Cancer 
Purpose
MicroRNAs (miRNAs) have potential prognostic value for colorectal cancers (CRCs); however, their value based on patient race/ethnicity and pathologic stage has not been determined. The goal was to ascertain the prognostic value of 5 miRNAs with increased expression in CRCs of African American (Black) and non-Hispanic Caucasian (White) patients.
Experimental Design
TaqMan® qRT-PCR was used to quantify expression of miR-20a, miR-21, miR-106a, miR-181b, and miR-203 in paired normal and tumor CRC archival tissues collected from 106 Black and 239 White patients. The results were correlated with overall survival based on patient race/ethnicity and pathologic stage. Since decisions regarding adjuvant therapy are important for Stage III CRCs, and since miR-181b appeared to have prognostic value only for Stage III Black patients, we assessed its prognostic value in a separate cohort of Stage III CRCs of Blacks.
Results
All 5 miRNAs had higher expression in CRCs (>1.0-fold) than in corresponding normal tissues. High expression of miR-203 was associated with poor survival of Whites with Stage IV CRCs (HR=3.00, 95% CI=1.29–7.53), but in Blacks it was an indicator of poor survival of patients with Stage I and II CRCs (HR=5.63, 95% CI=1.03–30.64). Increased miR-21 expression correlated with poor prognosis for White Stage IV patients (HR=2.50, 95% CI=1.07–5.83). In both test and validation cohorts, high miR-181b expression correlated with poor survival of only Black patients with Stage III CRCs (HR=1.94, 95% CI=1.03–3.67).
Conclusion
These preliminary findings suggest that the prognostic value of miRNAs in CRCs varies with patient race/ethnicity and stage of disease.
doi:10.1158/1078-0432.CCR-12-3302
PMCID: PMC3746330  PMID: 23719259
Race; miRNAs; prognosis; stage; colorectal cancer
18.  Chronic Obstructive Pulmonary Disease Self-Management Activation Research Trial (COPD-SMART): Design and Methods 
Contemporary clinical trials  2013;35(2):77-86.
Background
Treatment of COPD requires multiple pharmacological and non-pharmacological intervention strategies. One target is physical inactivity because it leads to disability and contributes to poor physical and mental health. Unfortunately, less than one percent of eligible patients have access to gold-standard pulmonary rehabilitation.
Methods
A single-site parallel group randomized trial was designed to determine if a self-management lifestyle physical activity intervention would improve physical functioning and dyspnea. During the first six weeks after enrollment patients receive COPD self-management education delivered by a health coach using a workbook and weekly telephone calls. Patients are then randomized to usual care or the physical activity intervention. The 20 week physical activity intervention is delivered by the health coach using a workbook supported by alternating one-on-one telephone counseling and computer assisted telephone calls. Theoretical foundations include social cognitive theory and the transtheoretical model.
Results
Primary outcomes include change in Chronic Respiratory Questionnaire (CRQ) dyspnea domain and 6-minute walk distance measured at 6-, 12-, and 18-months after randomization. Secondary outcomes include other CRQ domains (fatigue, emotion, and mastery), SF-12, and health care utilization. Other measures include process outcomes and clinical characteristics.
Conclusions
This theory driven self-management lifestyle physical activity intervention is designed to reach patients unable to complete center-based pulmonary rehabilitation. Results will advance knowledge and methods for dissemination of a potentially cost-effective program for patients with COPD.
doi:10.1016/j.cct.2013.05.004
PMCID: PMC3703772  PMID: 23680985
chronic obstructive pulmonary disease; self-management; physical activity; lifestyle; pulmonary rehabilitation; randomized trial
19.  Impact of a Community Based Implementation of REACH II Program for Caregivers of Alzheimer's Patients 
PLoS ONE  2014;9(2):e89290.
Background
In 2009 an estimated 5.3 million people in the United States were afflicted with Alzheimer's disease, a degenerative form of dementia. The impact of this disease is not limited to the patient but also has significant impact on the lives and health of their family caregivers. The Resources for Enhancing Alzheimer's Caregiver Health (REACH II) program was developed and tested in clinical studies. The REACH II program is now being delivered by community agencies in several locations. This study examines the impact of the REACH II program on caregiver lives and health in a city in north Texas.
Study design
Family caregivers of Alzheimer's patients were assessed using an instrument covering the multi-item domains of Caregiver Burden, Depression, Self-Care, and Social Support upon enrollment in the program and at the completion of the 6 month intervention. The domain scores were analyzed using a multivariate paired t-test and Bonferroni confidence interval for the differences in pre- and post-service domain scores.
Results
A total of 494 families were enrolled in the program during the period January 1, 2011 through June 30, 2012. Of these families 177 completed the 6 month program and have pre – and post service domain scores. The median age for the caregivers was 62 years. The domain scores for Depression and Caregiver Burden demonstrated statistically significant improvements upon program completion.
Conclusion
The REACH II intervention was successfully implemented by a community agency with comparable impacts to those of the clinical trial warranting wider scale implementation.
doi:10.1371/journal.pone.0089290
PMCID: PMC3937331  PMID: 24586664
20.  Health information technology capacity at federally qualified health centers: a mechanism for improving quality of care 
Background
The adoption of health information technology has been recommended as a viable mechanism for improving quality of care and patient health outcomes. However, the capacity of health information technology (i.e., availability and use of multiple and advanced functionalities), particularly in federally qualified health centers (FQHCs) on improving quality of care is not well understood. We examined associations between health information technology (HIT) capacity at FQHCs and quality of care, measured by the receipt of discharge summary, frequency of patients receiving reminders/notifications for preventive care/follow-up care, and timely appointment for specialty care.
Methods
The analyses used 2009 data from the National Survey of Federally Qualified Health Centers. The study included 776 of the FQHCs that participated in the survey. We examined the extent of HIT use and tested the hypothesis that level of HIT capacity is associated with quality of care. Multivariable logistic regressions, reporting unadjusted and adjusted odds ratios, were used to examine whether ‘FQHCs’ HIT capacity’ is associated with the outcome measures.
Results
The results showed a positive association between health information technology capacity and quality of care. FQHCs with higher HIT capacity were significantly more likely to have improved quality of care, measured by the receipt of discharge summaries (OR=1.43; CI=1.01, 2.40), the use of a patient notification system for preventive and follow-up care (OR=1.74; CI=1.23, 2.45), and timely appointment for specialty care (OR=1.77; CI=1.24, 2.53).
Conclusions
Our findings highlight the promise of HIT in improving quality of care, particularly for vulnerable populations who seek care at FQHCs. The results also show that FQHCs may not be maximizing the benefits of HIT. Efforts to implement HIT must include strategies that facilitate the implementation of comprehensive and advanced functionalities, as well as promote meaningful use of these systems. Further examination of the role of health information systems in clinical decision-making and improvements in patient outcomes are needed to better understand the benefits of HIT in improving overall quality of care.
doi:10.1186/1472-6963-13-35
PMCID: PMC3570359  PMID: 23363660
Health information technology; Federally qualified health centers; Electronic medical records; Quality of care; Patient reminder/notification; Adoption of technology; Meaningful use; Care coordination
21.  Clinical and multiple gene expression variables in survival analysis of breast cancer: Analysis with the hypertabastic survival model 
BMC Medical Genomics  2012;5:63.
Background
We explore the benefits of applying a new proportional hazard model to analyze survival of breast cancer patients. As a parametric model, the hypertabastic survival model offers a closer fit to experimental data than Cox regression, and furthermore provides explicit survival and hazard functions which can be used as additional tools in the survival analysis. In addition, one of our main concerns is utilization of multiple gene expression variables. Our analysis treats the important issue of interaction of different gene signatures in the survival analysis.
Methods
The hypertabastic proportional hazards model was applied in survival analysis of breast cancer patients. This model was compared, using statistical measures of goodness of fit, with models based on the semi-parametric Cox proportional hazards model and the parametric log-logistic and Weibull models. The explicit functions for hazard and survival were then used to analyze the dynamic behavior of hazard and survival functions.
Results
The hypertabastic model provided the best fit among all the models considered. Use of multiple gene expression variables also provided a considerable improvement in the goodness of fit of the model, as compared to use of only one. By utilizing the explicit survival and hazard functions provided by the model, we were able to determine the magnitude of the maximum rate of increase in hazard, and the maximum rate of decrease in survival, as well as the times when these occurred. We explore the influence of each gene expression variable on these extrema. Furthermore, in the cases of continuous gene expression variables, represented by a measure of correlation, we were able to investigate the dynamics with respect to changes in gene expression.
Conclusions
We observed that use of three different gene signatures in the model provided a greater combined effect and allowed us to assess the relative importance of each in determination of outcome in this data set. These results point to the potential to combine gene signatures to a greater effect in cases where each gene signature represents some distinct aspect of the cancer biology. Furthermore we conclude that the hypertabastic survival models can be an effective survival analysis tool for breast cancer patients.
doi:10.1186/1755-8794-5-63
PMCID: PMC3548720  PMID: 23241496
Hypertabastic survival models; Gene expression variables; Breast cancer biomarkers; Seventy gene signature; ErbB2 overexpression; Fibroblast core serum response
22.  Factors associated with attention deficit/hyperactivity disorder among US children: Results from a national survey 
BMC Pediatrics  2012;12:50.
Background
The purpose of this study was to investigate the association between Attention Deficit/Hyperactivity Disorder (ADHD) and various factors using a representative sample of US children in a comprehensive manner. This includes variables that have not been previously studied such as watching TV/playing video games, computer usage, family member’s smoking, and participation in sports.
Methods
This was a cross-sectional study of 68,634 children, 5–17 years old, from the National Survey of Children’s Health (NSCH, 2007–2008). We performed bivariate and multivariate logistic regression analyses with ADHD classification as the response variable and the following explanatory variables: sex, race, depression, anxiety, body mass index, healthcare coverage, family structure, socio-economic status, family members’ smoking status, education, computer usage, watching television (TV)/playing video games, participation in sports, and participation in clubs/organizations.
Results
Approximately 10% of the sample was classified as having ADHD. We found depression, anxiety, healthcare coverage, and male sex of child to have increased odds of being diagnosed with ADHD. One of the salient features of this study was observing a significant association between ADHD and variables such as TV usage, participation in sports, two-parent family structure, and family members’ smoking status. Obesity was not found to be significantly associated with ADHD, contrary to some previous studies.
Conclusions
The current study uncovered several factors associated with ADHD at the national level, including some that have not been studied earlier in such a setting. However, we caution that due to the cross-sectional and observational nature of the data, a cause and effect relationship between ADHD and the associated factors can not be deduced from this study. Future research on ADHD should take into consideration these factors, preferably through a longitudinal study design.
doi:10.1186/1471-2431-12-50
PMCID: PMC3502478  PMID: 22583686
National Survey of Children’s Health; Neurobehavioral disorder; Obesity; Depression; Medication; TV usage; Participation in sports; Smoking status
23.  GEOGRAPHIC DISPARITY IN COPD HOSPITALIZATION RATES AMONG THE TEXAS POPULATION 
Respiratory medicine  2011;105(5):734-739.
Summary
Background
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality caused by cigarette smoking and other environmental exposures. While variation in exposures may affect COPD morbidity and mortality, little is known about geographic variation, a surrogate of exposures. The objective of this manuscript is to explore the geographic variation in COPD hospitalization rates among the Texas population in 2006.
Methods
The study population consisted of all Texas residents with COPD hospitalizations in the 2006 Texas Health Care Information Council (THCIC) data. County population estimates stratified by race, age, gender were linked to THCIC data to calculate county level COPD hospitalization rates per 100,000 admissions. The data were merged with Urban Influence Codes by county, and metropolitan status was determined by United States Department of Agriculture (USDA) criteria. Variation in COPD hospitalization rates were analyzed using Poisson Regression.
Results
Overall, non-Hispanic (NH) Whites had the highest rate of hospitalization, followed by NH Blacks (rate ratio=0.42) and Hispanics (RR=0.17), the 65+ age category had the highest rates of hospitalization. In the metropolitan counties COPD hospitalization rates are lower than non metropolitan counties, however in metropolitan counties the rates of hospitalization are significantly higher (p<0.0001) in females compared to males. The rates were significantly higher in males in public health regions 10 and 11, which are predominantly non-metropolitan counties.
Conclusions
In Texas there is substantial geographic variation in hospitalization rates associated with gender and race/ethnicity. Other factors that may contribute to the variation and require further investigation include differences in smoking and exposure to other environmental risk factors, access to primary care, medical practice patterns, and coding practices.
doi:10.1016/j.rmed.2010.12.019
PMCID: PMC3064740  PMID: 21255991
24.  Safety-net facilities and hospitalization rates of chronic obstructive pulmonary disease: a cross-sectional analysis of the 2007 Texas Health Care Information Council inpatient data 
Purpose
Geographic disparities in hospitalization rates for chronic obstructive pulmonary disease (COPD) have been observed in Texas. However, little is known about the sources of these variations. The purpose of this manuscript is to further explore the geographic disparity of COPD hospitalization rates in Texas by examining county-level factors affecting access to care.
Patients and methods
The study is a cross-sectional analysis of the 2007 Texas Health Care Information Council, Texas, demographer population projections and the 2009 Area Resource File (ARF). The unit of analysis was county-specific hospitalization rate, calculated as the number of discharges of county residents divided by county-level population estimates. Indicators of access to care included: type of safety-net facility and number of pulmonary specialists in a county. Safety-net facilities of interest were federally qualified health centers (FQHCs) and rural health clinics (RHCs).
Results
There was a significant difference (P < 0.05) in hospitalization rates according to health center presence. Counties with only FQHCs had the lowest COPD hospitalization rate (132 per 100,000 observations), and counties with only RHCs had the highest hospitalization rate (229 per 100,000 observations). The presence of a pulmonary specialist was associated with a significant decrease (25%) in hospitalization rates among counties with only FQHCs.
Conclusion
In Texas, counties with only FQHCs were associated with lower COPD hospitalization rates. The presence of a RHC alone may be insufficient to decrease hospitalizations from COPD. There are a number of factors that may contribute to these variations in hospitalization rates, such as racial/ethnic distribution, types and quality of services provided, and the level of rurality, which creates greater distances to care and lower concentration of hospitals and pulmonary specialists.
doi:10.2147/COPD.S26072
PMCID: PMC3224651  PMID: 22135489
health centers; COPD; health disparities
25.  Sociodemographic and geographic characteristics associated with patient visits to osteopathic physicians for primary care 
Background
Health care reform promises to dramatically increase the number of Americans covered by health insurance. Osteopathic physicians (DOs) are recognized for primary care, including a "hands-on" style with an emphasis on patient-centered care. Thus, DOs may be well positioned to deliver primary care in this emerging health care environment.
Methods
We used data from the National Ambulatory Medical Care Survey (2002-2006) to study sociodemographic and geographic characteristics associated with patient visits to DOs for primary care. Descriptive analyses were initially performed to derive national population estimates (NPEs) for overall patient visits, primary care patient visits, and patient visits according to specialty status. Osteopathic and allopathic physician (MD) patient visits were compared using cross-tabulations and multiple logistic regression to compute odds ratios (ORs) and 95% confidence intervals (CIs) for DO patient visits. The latter analyses were also conducted separately for each geographic characteristic to assess the potential for effect modification based on these factors.
Results
Overall, 134,369 ambulatory medical care visits were surveyed, representing 4.6 billion (NPE) ± 220 million (SE) patient visits when patient visit weights were applied. Osteopathic physicians provided 336 million ± 30 million (7%) of these patient visits. Osteopathic physicians provided 217 million ± 21 million (10%) patient visits for primary care services; including 180 million ± 17 million (12%) primary care visits for adults (21 years of age or older) and 37 million ± 5 million (5%) primary care visits for minors. Osteopathic physicians were more likely than MDs to provide primary care visits in family and general medicine (OR, 6.03; 95% CI, 4.67-7.78), but were less likely to provide visits in internal medicine (OR, 0.37; 95% CI, 0.24-0.58) or pediatrics (OR, 0.21; 95% CI, 0.11-0.40). Overall, patients in the pediatric and geriatric ages, Blacks, Hispanics, and persons in the South and West were less likely to utilize DOs, although there was some evidence of effect modification according to United States Census region.
Conclusions
Health care reform provides unprecedented opportunities for DOs to reach historically underserved populations and to overcome the "pediatric primary-care paradox."
doi:10.1186/1472-6963-11-303
PMCID: PMC3238348  PMID: 22053988

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