Delivery of sorafenib by myofibroblast-targeted nanoparticles for the treatment of renal fibrosis.

Fibrosis is an excessive accumulation of the extracellular matrix within solid organs in response to injury and a common pathway that leads functional failure. No clinically approved agent is available to reverse or even prevent this process. Herein, we report a nanotechnology-based approach that utilizes a drug carrier to deliver a therapeutic cargo specifically to fibrotic kidneys, thereby improving the antifibrotic effect of the drug and reducing systemic toxicity. We first adopted in vitro-in vivo combinatorial phage display technology to identify peptide ligands that target myofibroblasts in mouse unilateral ureteral obstruction (UUO)-induced fibrotic kidneys. We then engineered lipid-coated poly(lactic-co-glycolic acid) nanoparticles (NPs) with fibrotic kidney-homing peptides on the surface and sorafenib, a potent antineoplastic multikinase inhibitor, encapsulated in the core. Sorafenib loaded in the myofibroblast-targeted NPs significantly reduced the infiltration of α-smooth muscle actin-expressing myofibroblasts and deposition of collagen I in UUO-treated kidneys and enhanced renal plasma flow measured by Technetium-99m mercaptoacetyltriglycine scintigraphy. This study demonstrates the therapeutic potential of the newly identified peptide fragments as anchors to target myofibroblasts and represents a strategic advance for selective delivery of sorafenib to treat renal fibrosis. SIGNIFICANCE STATEMENT: Renal fibrosis is a pathological feature accounting for the majority of issues in chronic kidney disease (CKD), which may progress to end-stage renal disease (ESRD). This manuscript describes a myofibroblast-targeting drug delivery system modified with phage-displayed fibrotic kidney-homing peptides. By loading the myofibroblast-targeting nanoparticles (NPs) with sorafenib, a multikinase inhibitor, the NPs could suppress collagen synthesis in cultured human myofibroblasts. When given intravenously to mice with UUO-induced renal fibrosis, sorafenib loaded in myofibroblast-targeting NPs significantly ameliorated renal fibrosis. This approach provides an efficient therapeutic option to renal fibrosis. The myofibroblast-targeting peptide ligands and nanoscale drug carriers may be translated into clinical application in the future.

Lower rates of mortality, readmission and reoperation in patients receiving acupuncture after hip fracture: a population-based analysis.

BACKGROUND: Studies on the effects of acupuncture on mortality and complication rates in hip fracture patients are limited by small sample size and short follow-up time. We aimed to assess the associations of acupuncture use with mortality, readmission and reoperation rates in hip fracture patients using a longitudinal population-based database. METHODS: A retrospective matched cohort study was conducted using data for the years 1996-2012 from Taiwan's National Health Insurance Research Database. Hip fracture patients were divided into an acupuncture group consisting of 292 subjects who received at least 6 acupuncture treatments within 183 days of hip fracture, and a propensity score matched "no acupuncture" group of 876 subjects who did not receive any acupuncture treatment and who functioned as controls. The two groups were compared using survival analysis and competing risk analysis. RESULTS: Compared to non-treated subjects, subjects treated with acupuncture had a lower risk of overall death (hazard ratio (HR): 0.41, 95% confidence interval (CI): 0.24-0.73, p = 0.002), a lower risk of readmission due to medical complications (subdistribution HR (sHR): 0.64, 95% CI: 0.44-0.93, p = 0.019) and a lower risk of reoperation due to surgical complications (sHR: 0.62, 95% CI: 0.40-0.96, p = 0.034). CONCLUSION: This is the first study to suggest that postoperative acupuncture in hip fracture patients is associated with significantly lower mortality, readmission and reoperation rates compared with those of matched controls.

Diet and Rheumatoid Arthritis Symptoms: Survey Results From a Rheumatoid Arthritis Registry.

OBJECTIVE: Patients with rheumatoid arthritis (RA) often ask whether specific foods, popularized as inflammatory or antiinflammatory, can improve or worsen their RA. Patients with RA took a survey on diet and RA symptoms, and the survey data were collected and analyzed. METHODS: A dietary survey was mailed to 300 subjects in a single-center RA registry at a large academic center. Subjects were asked about their consumption of 20 foods and whether these foods make their RA symptoms better, worse, or unchanged. Semiannual registry data include demographics, medications, comorbidities, and disease activity scores. Fisher's exact test and Wilcoxon's rank sum tests evaluated associations between subject characteristics from the most recent registry assessment and changes in RA symptoms from specific foods. RESULTS: Of the 217 subjects (72% response rate), 83% were female; the median RA duration was 17 years (interquartile range 9-27 years), and 58% were taking a biologic disease-modifying antirheumatic drug. Twenty-four percent of subjects reported that foods affect their RA symptoms, with 15% reporting improvement and 19% reporting worsening. Blueberries and spinach were the foods most often reported to improve RA symptoms, while soda with sugar and desserts were those most often reported to worsen RA symptoms. Younger age and noting that sleep, warm room temperature, and vitamin/mineral supplements improve RA were each associated with reporting that foods affect RA symptoms. Medication use, sex, body mass index, smoking, disease duration, disease activity scores, and self-reported RA flares were not associated with reporting that foods affect RA. CONCLUSION: Nearly one-quarter of RA subjects with longstanding disease reported that diet had an effect on their RA symptoms.

Comparative effectiveness of osteoporosis drugs in preventing secondary nonvertebral fractures in Taiwanese women.

CONTEXT: The evidence for relative effectiveness of osteoporosis drugs in secondary prevention of nonvertebral fractures was unclear and could not be extrapolated to the Asian population. OBJECTIVE: The objective of the study was to compare the relative effectiveness of different classes of osteoporosis drugs in secondary prevention of nonvertebral fractures in Taiwanese women. DESIGN: This was a retrospective cohort study from 2003 to 2007, with up to 6 years of follow-up. SETTING: The study included enrollees in Taiwan National Health Insurance. PATIENTS: Patients older than 50 years, with vertebral/hip fracture and were new to osteoporosis therapy, were recruited. INTERVENTION: Patients were classified into the alendronate, calcitonin, or raloxifene group, according to their exposure after follow-up. MAIN OUTCOME MEASURE: The primary outcome of our study was the risk of incident nonvertebral fracture (hip, humerus, or radius fractures). A multivariate Cox proportional hazard model adjusted for fracture risk factors was used to compare the relative fracture risk among three treatment groups under on-treatment scenarios. Propensity score-matched hazard ratios were examined, and interactions between fracture incidence and patients' compliance were investigated as well. RESULTS: There were 19 840, 9534, and 25 483 patients in the alendronate, raloxifene, and calcitonin groups, respectively. The fracture rates were highest in calcitonin recipients (4.57 per 100 person-years), followed by raloxifene and alendronate. Results from Cox analyses showed raloxifene (hazard ratio 1.47; 95% confidence interval 1.29-1.67) and calcitonin (hazard ratio 1.51; 95% confidence interval 1.29-1.75) had higher nonvertebral fracture risks as compared with alendronate. The risk differences were more pronounced in compliant patients. CONCLUSION: We found alendronate users had the lowest secondary nonvertebral fracture risk, as compared with raloxifene and calcitonin users. Consistent results were found in a series of sensitivity analyses.