Association Between Obesity and Therapeutic Goal Attianment in Patients with Concomitant Hypertension and Dyslipidemia

Objective: A retrospective study was conducted to examine the variations in therapeutic {blood pressure (BP) and lipid} goal attainment and medication utilization pattern in patients with concomitant hypertension and dyslipidemia, specifically comparing obese versus non-obese patients. Methods: GE Centricity EMR database containing data from 2004-2011 was utilized. 9,086 patients diagnosed with concomitant hypertension and dyslipidemia were evaluated. Goal attainment and treatment pattern for BP and lipid levels was assessed based on JNC 7 and NCEP ATP III guidelines, respectively. Results: Substantial proportion of patients with concomitant hypertension and dyslipidemia failed to attain BP and lipid goals. Further, in patients with concomitant hypertension and dyslipidemia, obesity appears to be an independent risk factor for the failure to attain BP and dual BP/LDL-C. Conclusions: With increasing prevalence of obesity and inadequate therapeutic goal attainment in these populations, healthcare professionals should use appropriate treatment strategies for improving the management of cardiovascular risk factors (hypertension, dyslipidemia, and obesity)

Impact of Incident Cancer on Coronary Artery Disease-Related Concomitant Medication Adherence, Short-Term Health and Economic Outcomes Among Elderly Medicare Beneficiaries with Coronary Artery Diseas

Coronary artery disease (CAD) is one of the most burdensome chronic conditions in the elderly. The two key goals of long-term management of CAD are (i) to reduce symptoms and ischemia and (ii) prevent myocardial infarction and death, by lowering lipids and blood pressure. Of all the risk reduction strategies, use and adherence to concomitant pharmacotherapy with statins and beta-blockers, angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) have been shown to be highly effective and has become the cornerstone of CAD management. However, adherence to concomitant pharmacotherapy can be influenced by many factors including the development of other life-threatening conditions such as cancer. To date, no real-world study has assessed how incident cancer can affect adherence to concomitant pharmacotherapy and whether concomitant pharmacotherapy can minimize the negative effects of some cancer treatments on CAD-related morbidity and expenditures among individuals with CAD and incident cancer. To fill the knowledge gap, the three related aims of this dissertation were to analyze: 1) the association between incident breast, colorectal, and prostate cancer diagnosis and adherence to statins and/or ACEIs/ARBs/beta-blockers among elderly fee-for-service (FFS) Medicare beneficiaries with pre-existing CAD; 2) the impact of non-adherence to these medication classes on short-term CAD-related hospitalizations in patients with incident cancer diagnosis; and 3) the impact of incident cancer diagnosis on short-term CAD-related inpatient and outpatient healthcare expenditures. The study used a retrospective observational longitudinal cohort study design was conducted among elderly Medicare FFS beneficiaries with pre-existing CAD and those with incident breast cancer (BC), colorectal cancer (CC), or prostate cancer (PC), using multiple years (2005--2012). The study data was derived from the cancer registry data from Surveillance, Epidemiology and End Results (SEER) program linked with the Medicare claims data, the American community survey census-tract files and Area Health Resource Files. Aim 1 and Aim 3 also included 5% non-cancer random sample of Medicare beneficiaries, residing in SEER regions, with pre-existing CAD. Each individual was observed for 48 months with 24-month baseline (for identification of CAD and baseline characteristics) period, 12-month pre-index, and 12-month post-index periods. In the first aim, only 28.9% of the elderly with CAD were adherent to both statins and ACEIs/ARBs/beta-blockers. In the adjusted analyses, women [AOR = 0.70; 95% CI = 0.58, 0.81; P \u3c 0.0001] and men [AOR = 0.63; 95% CI = 0.51, 0.75; P \u3c 0.0001] with CC and men with PC [AOR = 0.92; 95% CI = 0.85, 0.99; P = 0.022] were significantly less likely to be adherent to both medication classes compared to women and men with NC, respectively. No significant differences in adherence to medications were observed among women with BC compared to women with NC. Even among those using single medication class, women [AOR = 0.64; 95% CI = 0.50, 0.79; P \u3c 0.0001] and men with CC [AOR = 0.59; 95% CI = 0.42, 0.76; P \u3c 0.0001] were significantly less likely to be adherent to that medication class compared to women and men with NC. In the second aim, adherence to both statins and ACEIs/ARBs/beta-blockers was estimated at 31.2% during the 120-day period immediately after cancer diagnosis; 13.7% were not adherent to both medication classes during the same period; 27.4% had CAD-related hospitalizations immediately after cancer diagnosis and this percentage declined to 10.6% during the last four months of the post-cancer period. In the adjusted analyses, those not adherent to both statins and ACEIs/ARBs/beta-blockers were more likely to have CAD-related hospitalization compared to those who were adherent to both medication classes [AOR = 1.82; 95% CI = 1.72, 1.92; P \u3c 0.0001]. In the third aim, overall, CAD-related mean healthcare expenditures at pre-index period accounted for about 32.6%--39.5% of total expenditures among women and 41.5% - 46.8% among men. In the adjusted GLMM, all cancer groups had significantly higher CAD-related healthcare expenditures compared to the non-cancer groups. Women with CC 153% higher expenditures compared to women with no cancer [beta = 0.93, P \u3c 0.0001]. Men with CC had 166% higher expenditures compared to men with NC [beta = 0.98, P \u3c 0.0001]. Further, men and women with CC had 57% and 55% higher expenditures compared to men with PC and women with BC, respectively. In summary, the study findings, collectively, suggest that cancer diagnosis negatively impacts adherence to CAD pharmacotherapy. Reduction in adherence was associated with increase in CAD-related hospitalizations and subsequent increase in CAD-related expenditures. This warrants the integration of cardiovascular care in the elderly diagnosed with cancer. Future studies need to explore whether the emerging collaborative care models, such as medical homes, can reduce inpatient use, and consequently, CAD-related expenditures

Design and Synthesis of CDK-5 and MEK-5 Inhibitors and Synthesis towards Tubulysin Analogs

CDK-5 is associated with hyperphosphorylation of the microtubule-associated protein tau, formation of neurofibrillary tangles, and possibly an acceleration of the neurodegenerative progression of Alzheimer\u27s disease. C6-O linked benzimidazoles and C-4 benzamide and phenylacetamide benzimidazoles based on (R)-Roscovitine, a non-selective inhibitor of CDK-5 were designed and synthesized. MEK-5, a member of the MAPK family, phosphorylates ERK-5 permitting cells to survive oxidative stress. MEK-5 is upregulated in tumor cells and activated by mitogens; inhibition of this enzyme is a potential anti-cancer strategy. Scaffolds from the following classes--benzimidazole, diphenylamine, flavones, and ortho-carboxyamide were examined for their capacity to be developed into potent and selective MEK-5 inhibitors. Tubulysin is a natural product that disrupts microtubule dynamics, blocks mitosis, and induces cell death. It has been examined as a potential anti-cancer agent in hollow fiber assays. Simple and reliable procedures were developed for the gram-scale synthesis of Mep-Ile dipeptide and Tup fragments of tubulysin

A systematic review of quality of life instruments in long-term breast cancer survivors

Abstract Background Breast cancer is the most common cancer in women, representing 16% of all female cancers. According to the American Cancer Society, long-term cancer survival is defined as more than five years of survivorship since diagnosis, with approximately 2.5 million breast cancer survivors (BCS) in 2006. The long-term effects from breast cancer and its treatment have been shown to have positive and negative effects on both recovery and survivors' quality of life (QoL). The purpose of the study was to identify QoL instruments that have been validated in long-term BCS and to review the studies that have used the QoL instruments in this population. Methods A systematic literature search was conducted from January 1990 to October 2010 using electronic databases. Instruments validated and used in BCS were included in the review. In addition, QoL studies in long-term BCS using the validated instruments were reviewed. The search was limited to studies in English language. Studies of BCS of less than five years after initial diagnosis, any clinical or review studies were excluded. Results The review identified a total of 12 instruments (10 disease-specific, 2 condition-specific) validated in long-term BCS. According to the QoL framework proposed by Ferrell and colleagues, three instruments (Quality of Life-Cancer Survivors, Quality of Life in Adult Cancer Survivors Scale, and Quality of Life Index-Cancer Version) evaluated all four domains (physical, psychological, social, and spiritual) of QoL. A review of the psychometric evaluation showed that Quality of Life in Adult Cancer Survivors Scale has acceptable reliability, validity, and responsiveness in long-term BCS compared to other disease-specific instruments. The review also yielded 19 studies that used these QoL instruments. The study results indicated that age-group, ethnicity, and type of treatment influenced different aspects of QoL. Conclusions There is a significant impact of breast cancer on QoL in long-term BCS. The review can help researchers and clinicians select the most appropriate instruments to assess the changes in QoL in BCS.</p

Temporal Changes in Cholangiocarcinoma Incidence and Mortality in the United States from 2001 to 2017.

BACKGROUND: Previous studies report increasing cholangiocarcinoma (CCA) incidence up to 2015. This contemporary retrospective analysis of CCA incidence and mortality in the US from 2001-2017 assessed whether CCA incidence continued to increase beyond 2015. PATIENTS AND METHODS: Patients (≥18 years) with CCA were identified in the National Cancer Institute Surveillance, Epidemiology, and End Results 18 cancer registry (International Classification of Disease for Oncology [ICD-O]-3 codes: intrahepatic [iCCA], C221; extrahepatic [eCCA], C240, C241, C249). Cancer of unknown primary (CUP) cases were identified (ICD-O-3: C809; 8140/2, 8140/3, 8141/3, 8143/3, 8147/3) because of potential misclassification as iCCA. RESULTS: Forty-thousand-and-thirty CCA cases (iCCA, n=13,174; eCCA, n=26,821; iCCA and eCCA, n=35) and 32,980 CUP cases were analyzed. From 2001-2017, CCA, iCCA, and eCCA incidence (per 100 000 person-years) increased 43.8% (3.08 to 4.43), 148.8% (0.80 to 1.99), and 7.5% (2.28 to 2.45), respectively. In contrast, CUP incidence decreased 54.4% (4.65 to 2.12). CCA incidence increased with age, with greatest increase among younger patients (18-44 years, 81.0%). Median overall survival from diagnosis was 8, 6, 9, and 2 months for CCA, iCCA, eCCA, and CUP. From 2001-2016, annual mortality rate declined for iCCA (57.1% to 41.2%) and generally remained stable for eCCA (40.9% to 37.0%) and for CUP (64.3% to 68.6%). CONCLUSIONS: CCA incidence continued to increase from 2001-2017, with greater increase in iCCA versus eCCA, whereas CUP incidence decreased. The divergent CUP versus iCCA incidence trends, with overall greater absolute change in iCCA incidence, provide evidence for a true increase in iCCA incidence that may not be wholly attributable to CUP reclassification

Hospital length of stay and all-cause 30-day readmissions among high-risk medicaid beneficiaries

This study examined the association between index hospitalization characteristics and the risk of all-cause 30-day readmission among high-risk Medicaid beneficiaries using multi-level analyses. A retrospective cohort with a baseline and a follow-up period was used. The study population consisted of Medicaid beneficiaries (21-64 years) with selected chronic conditions, continuous fee-for-service enrollment through the observation period, and at least one inpatient encounter during the follow-up period (N=15,806). The outcome of 30-day readmission was measured using inpatient admissions within 30-days from the discharge date of the first observed hospitalization. Key independent variables included length of stay, reason for admission, and month of index hospitalization (seasonality). Multi-level logistic regression that accounted for beneficiaries nested within counties was used to examine this association, after controlling for patient-level and county-level characteristics. In this study population, 16.7% had all-cause 30-day readmissions. Adults with greater lengths of stay during the index hospitalization were more likely to have 30-day readmissions [AOR=1.03, 95% CI 1.02,1.04]. Adults who were hospitalized for cardiovascular conditions [AOR=1.20, 95% CI 1.08,1.33], diabetes [AOR=1.23, 95% CI 1.10,1.39], cancer [AOR=1.55, 95% CI 1.26,1.90], and mental health conditions [AOR=2.17, 95% CI 1.98,2.38] were more likely to have 30-day readmissions compared to those without these conditions

Structure activity relationships of anthranilic acid-based compounds on cellular and in vivo mitogen activated protein kinase-5 signaling pathways

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Novel Diphenylamine Analogs Induce Mesenchymal to Epithelial Transition in Triple Negative Breast Cancer

Epithelial to mesenchymal transition (EMT) is a cellular program that converts non-motile epithelial cells into invasive mesenchymal cells. EMT is implicated in cancer metastasis, chemo-resistance, cancer progression, and generation of cancer stem cells (CSCs). Inducing mesenchymal to epithelial transition (MET), the reverse phenomenon of EMT, is proposed as a novel strategy to target triple negative and tamoxifen-resistant breast cancer. Triple negative breast cancer (TNBC) is characterized by the loss of hormone receptors, a highly invasive mesenchymal phenotype, and a lack of targeted therapy. Estrogen receptor-positive breast cancer can be targeted by tamoxifen, an ER antagonist. However, these cells undergo EMT over the course of treatment and develop resistance. Thus, there is an urgent need to develop therapeutic interventions to target these aggressive cancers. In this study, we examined the role of novel diphenylamine analogs in converting the mesenchymal phenotype of MDA-MB-231 TNBC cells to a lesser aggressive epithelial phenotype. Using analog-based drug design, a series of diphenylamine analogs were synthesized and initially evaluated for their effect on E-cadherin protein expression and changes incell morphology, which was quantified by measuring the spindle index (SI) value. Selected compound 1 from this series increases the expression of E-cadherin, a primary marker for epithelial cells, and decreases the mesenchymal markers SOX2, ZEB1, Snail, and vimentin. The increase in epithelial markers and the decrease in mesenchymal markers are consistent with a phenotypic switch from spindle-like morphology to cobblestone-like morphology. Furthermore, Compound 1 decreases spheroid viability, cell migration, and cell proliferation in triple negative BT-549 and tamoxifen-resistant MCF-7 breast cancer cells