Contextual, organizational and ecological effects on the variations in hospital readmissions of rural Medicare beneficiaries in eight southeastern states.

The enactment of the Patient Protection and Affordable Care Act (ACA) has been expected to improve the coverage of health insurance, particularly as related to the coordination of seamless care and the continuity of elder care among Medicare beneficiaries. The analysis of longitudinal data (2007 through 2013) in rural areas offers a unique opportunity to examine trends and patterns of rural disparities in hospital readmissions within 30 days of discharge among Medicare beneficiaries served by rural health clinics (RHCs) in the eight southeastern states of the Department of Health & Human Services (DHHS) Region 4. The purpose of this study is twofold: first, to examine rural trends and patterns of hospital readmission rates by state and year (before and after the ACA enactment); and second, to investigate how contextual (county characteristic), organizational (clinic characteristic) and ecological (aggregate patient characteristic) factors may influence the variations in repeat hospitalizations. The unit of analysis is the RHC. We used administrative data compiled from multiple sources for the Centers of Medicare and Medicaid Services for a period of seven years. From 2007 to 2008, risk-adjusted readmission rates increased slightly among Medicare beneficiaries served by RHCs. However, the rate declined in 2009 through 2013. A generalized estimating equation of sixteen predictors was analyzed for the variability in risk-adjusted readmission rates. Nine predictors were statistically associated with the variability in risk-adjusted readmission rates of the RHCs pooled from 2007 through 2013 together. The declined rates were associated with by the ACA effect, Georgia, North Carolina, South Carolina, and the percentage of elderly population in a county where RHC is located. However, the increase of risk-adjusted rates was associated with the percentage of African Americans in a county, the percentage of dually eligible patients, the average age of patients, and the average clinical visits by African American patients. The sixteen predictors accounted for 21.52 % of the total variability in readmissions. This study contributes to the literature in health disparities research from the contextual, organizational and ecological perspectives in the analysis of longitudinal data. The synergism of multiple contextual, organizational and ecological factors, as shown in this study, should be considered in the design and implementation of intervention studies to address the problem of hospital readmissions through prevention and enhancement of disease management of rural Medicare beneficiaries.

Penetration and drug delivery of albumin nanoparticles into pancreatic multicellular tumor spheroids.

Albumin-based nanoparticles have been exploited as a useful carrier for the efficient delivery of anti-cancer drugs. In this study, albendazole was encapsulated into bovine serum albumin (BSA)-polycaprolactone (PCL) conjugates and the formed nanoparticles with a size about 100 nm were used to treat pancreatic carcinoma cells. In addition, two more types of albendazole-loaded BSA nanoparticles, 10 nm and 200 nm ones, were prepared using a desolvation method. The albendazole-loaded BSA nanoparticles were evaluated with both 2D cultured AsPC-1 cells and 3D multicellular tumor spheroids (MCTS). Their anti-tumor effects were also compared. BSA-PCL nanoparticles and 200 nm BSA nanoparticles showed noticeable cytotoxicity to 2D cultured AsPC-1 cells when compared to the free drug. The penetration of BSA-PCL nanoparticles and 200 nm BSA nanoparticles, especially the BSA-PCL nanoparticles, enabled effective delivery of albendazole into pancreatic MCTS. BSA-PCL nanoparticles also showed a better inhibition effect on the growth of pancreatic MCTS than the 200 nm counterpart. Although 10 nm BSA nanoparticles inhibited the growth of MCTS, the inhibitory effect was even less than that of free albendazole. In addition, it is also found that SPARC protein facilitates the penetration and drug delivery of albumin nanoparticle since treatment using anti-SPARC antibody decreased the efficacy of drug loaded BSA nanoparticles.

Stabilization of Paclitaxel-Conjugated Micelles by Cross-Linking with Cystamine Compromises the Antitumor Effects against Two- and Three-Dimensional Tumor Cellular Models.

Paclitaxel (PTX)-conjugated micelles provide a promising tool for the treatment of prostate cancer. Core cross-linking by incorporating a disulfide bridge is a useful approach to improving the in vivo stability of polymeric micelles. This paper aims to investigate the effects of different degrees of cross-linking on the antitumor efficacy of micelles formed by poly(ethylene glycol methyl ether acrylate)-b-poly(carboxyethyl acrylate) (POEGMEA-b-PCEA-PTX) block copolymer. Both two-dimensional (2D) and three-dimensional (3D) in vitro prostate tumor cell models were used to evaluate the un-cross-linked and cross-linked micelles. The cytotoxicity decreased with an increase in the degree of cross-linking upon being tested with 2D cultured cells, and all micelles remained less cytotoxic than free PTX. In the 3D prostate MCTS model, however, there was no statistical difference between the performance of un-cross-linked micelles and free PTX, while increasing cross-linking densities led to significantly relevant decreases in the antitumor efficacy of micelles. These results are contradictory to our previous research using an irreversible cross-linker (1,8-diaminooctane) to stabilize POEGMEA-b-PCEA-PTX conjugate micelles where it was shown that cross-linking accelerates and improves the effects of the micelles when compared to those of un-cross-linked micelles. Further studies that aim to investigate the underlying mechanisms of disulfide bonds when micelles are internalized into cells are desired.

Pharmacological blockade of aquaporin-1 water channel by AqB013 restricts migration and invasiveness of colon cancer cells and prevents endothelial tube formation in vitro.

BACKGROUND: Aquaporins (AQP) are water channel proteins that enable fluid fluxes across cell membranes, important for homeostasis of the tissue environment and for cell migration. AQP1 knockout mouse models of human cancers showed marked inhibition of tumor-induced angiogenesis, and in pre-clinical studies of colon adenocarcinomas, forced over-expression of AQP1 was shown to increase angiogenesis, invasion and metastasis. We have synthesized small molecule antagonists of AQP1. Our hypothesis is that inhibition of AQP1 will reduce migration and invasiveness of colon cancer cells, and the migration and tube-forming capacity of endothelial cells in vitro. METHODS: Expression of AQP1 in cell lines was assessed by quantitative (q) PCR, western blot and immunofluorescence, while expression of AQP1 in human colon tumour tissue was assessed by immunohistochemistry. The effect of varying concentrations of the AQP1 inhibitor AqB013 was tested on human colon cancer cell lines expressing high versus low levels of AQP1, using wound closure (migration) assays, matrigel invasion assays, and proliferation assays. The effect of AqB013 on angiogenesis was tested using an endothelial cell tube-formation assay. RESULTS: HT29 colon cancer cells with high AQP1 levels showed significant inhibition of migration compared to vehicle control of 27.9% ± 2.6% (p < 0.0001) and 41.2% ± 2.7 (p <0.0001) treated with 160 or 320 µM AqB013 respectively, whereas there was no effect on migration of HCT-116 cells with low AQP1 expression. In an invasion assay, HT29 cells treated with 160 µM of AqB013, showed a 60.3% ± 8.5% decrease in invasion at 144 hours (p < 0.0001) and significantly decreased rate of invasion compared with the vehicle control (F-test, p = 0.001). Almost complete inhibition of endothelial tube formation (angiogenesis assay) was achieved at 80 µM AqB013 compared to vehicle control (p < 0.0001). CONCLUSION: These data provide good evidence for further testing of the inhibitor as a therapeutic agent in colon cancer.

Core-Cross-Linking Accelerates Antitumor Activities of Paclitaxel-Conjugate Micelles to Prostate Multicellular Tumor Spheroids: A Comparison of 2D and 3D Models.

The 2D monolayer cell culture model is often the first step in the prediction of the success or failure of a nanoparticle-based drug delivery system. However, there is often poor translation between the 2D monolayer in vitro results and the nanoparticle-drug performance in vivo. One possible way of bridging this gap is the use of multicellular tumor spheroids (MCTSs) as an intermediate in vitro model due to its 3D structure. This paper aims to quantify and compare the results obtained from traditional 2D monolayer cell cultures and 3D MCTS by studying the cytotoxic effects of free paclitaxel (PTX) and paclitaxel, which has been conjugated to a poly(ethylene glycol methyl ether acrylate)-b-poly(carboxyethyl acrylate) (POEGMEA-b-PCEA-PTX) block copolymer and self-assembled to give a micellar delivery system. The core of the micelle was cross-linked with a diamino nondegradable cross-linker to compare the effects of micelle stability on the results. Although the 2D prostate tumor cell culture results indicated that all micellar variants (IC50: 193-271 nM) were significantly less toxic than free paclitaxel (IC50: 15.2 nM), the micelles showed faster and higher cytotoxicity than free PTX in the 3D prostate MCTS. The cross-linking of micelles even showed accelerated antitumor activities to the MCTS compared with un-cross-linked micelles. The results indicate that DAO-cross-linked POEGMEA-b-PCEA-PTX conjugate micelles will be a useful nanodrug carrier for prostate cancer therapy. MCTS offers a very promising method of incorporating 3D structures into in vitro testing.

Drug carriers for the delivery of therapeutic peptides.

Peptides take on an increasingly important role as therapeutics in areas including diabetes, oncology, and metabolic, cardiovascular, and infectious diseases. In addition, many peptides such as insulin have been employed for many years. A challenge in the administration of peptide drugs is their often low hydrolytic stability, as well as other problems that are common to any drug treatment such as systemic distribution. There is a significant attention in the literature of protein drugs and their delivery strategies, but not many overviews are specifically dedicated to peptides. In this review, the different approaches to deliver peptides have been summarized where the focus is only on drug carriers based on organic materials. Initial discussion is on different methods of polymer-peptide conjugation before being followed by physical encapsulation techniques, which is divided into surfactant-based techniques and polymer carriers. Surfactant-based techniques are dominated by liposome, microemulsions and solid-lipid nanoparticles. The field widens further in the polymer field. The delivery of peptides has been enhanced using polymer-decorated liposomes, solid microspheres, polyelectrolyte complex, emulsions, hydrogels, and injectable polymers. The aim of this article is to give the reader an overview over the different types of carriers.