Citations

The aryl hydrocarbon receptor (AHR) is a nuclear receptor that modulates the response to environmental stimuli. It was recognized historically for its role in toxicology but, in recent decades, it has been increasingly recognized as an important modulator of disease—especially for its role in modulating immune and inflammatory responses. AHR has been implicated in many diseases that are driven by immune/inflammatory processes, including major depressive disorder, multiple sclerosis, rheumatoid arthritis, asthma, and allergic responses, among others. The mechanisms by which AHR has been suggested to impact immune/inflammatory diseases include targeted gene expression and altered immune differentiation. It has been suggested that single nucleotide polymorphisms (SNPs) that are near AHR-regulated genes may contribute to AHR-dependent disease mechanisms/pathways. Further, we have found that SNPs that are outside of nuclear receptor binding sites (i.e., outside of AHR response elements (AHREs)) may contribute to AHR-dependent gene regulation in a SNP- and ligand-dependent manner. This review will discuss the evidence and mechanisms of AHR contributions to immune/inflammatory diseases and will consider the possibility that SNPs that are outside of AHR binding sites might contribute to AHR ligand-dependent inter-individual variation in disease pathophysiology and response to pharmacotherapeutics.

SummaryIbrutinib, a Bruton tyrosine kinase inhibitor, is approved for treatment of various B‐cell malignancies. In ibrutinib clinical studies, low‐grade haemorrhage was common, whereas major haemorrhage (MH) was infrequent. We analysed the incidence of and risk factors for MH from 15 ibrutinib clinical studies (N = 1768), including 4 randomised controlled trials (RCTs). Rates of any‐grade bleeding were similar for single‐agent ibrutinib and ibrutinib combinations (39% and 40%). Low‐grade bleeding was more common in ibrutinib‐treated than comparator‐treated patients (35% and 15%), and early low‐grade bleeding was not associated with MH. The proportion of MH in RCTs was higher with ibrutinib than comparators (4.4% vs. 2.8%), but after adjusting for longer exposure with ibrutinib (median 13 months vs. 6 months), the incidence of MH was similar (3.2 vs. 3.1 per 1000 person‐months). MH led to treatment discontinuation in 1% of all ibrutinib‐treated patients. Use of anticoagulants and/or antiplatelets (AC/AP) during the study was common (~50% of patients) and had an increased exposure‐adjusted relative risk for MH in both the total ibrutinib‐treated population (1.9; 95% confidence interval, 1.2–3.0) and RCT comparator‐treated patients (2.4; 95% confidence interval, 1.0–5.6), indicating that ibrutinib may not alter the effect of AC/AP on the risk of MH in B‐cell malignancies.

Background Automated individualized risk prediction tools linked to electronic health records ( EHR s) are not available for management of patients with peripheral arterial disease. The goal of this study was to create a prognostic tool for patients with peripheral arterial disease using data elements automatically extracted from an EHR to enable real‐time and individualized risk prediction at the point of care. Methods and Results A previously validated phenotyping algorithm was deployed to an EHR linked to the Rochester Epidemiology Project to identify peripheral arterial disease cases from Olmsted County, MN, for the years 1998 to 2011. The study cohort was composed of 1676 patients: 593 patients died over 5‐year follow‐up. The c‐statistic for survival in the overall data set was 0.76 (95% confidence interval [CI], 0.74–0.78), and the c‐statistic across 10 cross‐validation data sets was 0.75 (95% CI, 0.73–0.77). Stratification of cases demonstrated increasing mortality risk by subgroup (low: hazard ratio, 0.35 [95% CI, 0.21–0.58]; intermediate‐high: hazard ratio, 2.98 [95% CI, 2.37–3.74]; high: hazard ratio, 8.44 [95% CI, 6.66–10.70], all P <0.0001 versus the reference subgroup). An equation for risk calculation was derived from Cox model parameters and β estimates. Big data infrastructure enabled deployment of the real‐time risk calculator to the point of care via the EHR . Conclusions This study demonstrates that electronic tools can be deployed to EHR s to create automated real‐time risk calculators to predict survival of patients with peripheral arterial disease. Moreover, the prognostic model developed may be translated to patient care as an automated and individualized real‐time risk calculator deployed at the point of care.

As a follow‐up to genome‐wide association analysis of common variants associated with ovarian carcinoma (cancer), our study considers seven well‐known ovarian cancer risk factors and their interactions with 28 genome‐wide significant common genetic variants. The interaction analyses were based on data from 9971 ovarian cancer cases and 15,566 controls from 17 case–control studies. Likelihood ratio and Wald tests for multiplicative interaction and for relative excess risk due to additive interaction were used. The top multiplicative interaction was noted between oral contraceptive pill (OCP) use (ever vs. never) and rs13255292 (p value = 3.48 × 10−4). Among women with the TT genotype for this variant, the odds ratio for OCP use was 0.53 (95% CI = 0.46–0.60) compared to 0.71 (95%CI = 0.66–0.77) for women with the CC genotype. When stratified by duration of OCP use, women with 1–5 years of OCP use exhibited differential protective benefit across genotypes. However, no interaction on either the multiplicative or additive scale was found to be statistically significant after multiple testing correction. The results suggest that OCP use may offer increased benefit for women who are carriers of the T allele in rs13255292. On the other hand, for women carrying the C allele in this variant, longer (5+ years) use of OCP may reduce the impact of carrying the risk allele of this SNP. Replication of this finding is needed. The study presents a comprehensive analytic framework for conducting gene–environment analysis in ovarian cancer.

AbstractBiodegradable drug‐eluting stents (DESs) are used today to treat atherosclerotic arteries and as vehicles to deliver inhibitors to suppress restenosis, with potential applications also in localized cancer therapy. Here the development of a series of drug‐eluting poly(glycerol sebacate) (PGS) coils that may find possible use as DESs is reported. PGS is a tough, biodegradable, and biocompatible elastomer that has adjustable mechanical properties thanks to careful control of the fabrication process. Specifically, 3D PGS coils featuring superior mechanical and fracture‐resistance properties are fabricated. The surface erosion profile of PGS is designed to further reduce the risk of fragmentation and non‐target embolization during the degradation process. A dual‐encapsulation mechanism is applied, first poly(ε‐caprolactone) microparticles loaded with an anticancer drug Doxorubicin followed by dispersion of these microparticles in the PGS coils, to prolong the release of drug molecules from the interior. Systematic evaluations of the mechanical properties of the PGS coils and their drug release behaviors are conducted. It is anticipated that, these PGS coils may enable minimally invasive delivery using standard endovascular catheters, for achieving localized and sustained release of chemotherapy to tumors, as well as conventional applications in treating vascular disorders.

Replacement of the exocrine parenchyma by fibrous tissue is a main characteristic of chronic pancreatitis. Understanding the mechanisms of pancreatic fibrogenesis is critical for the development of preventive and therapeutic interventions. Cyclooxygenase-2 (COX-2), a rate-limiting enzyme for prostaglandin synthesis, is expressed in patients with chronic pancreatitis. However, it is unknown whether COX-2 can cause chronic pancreatitis. To investigate the roles of pancreatic acinar COX-2 in fibrogenesis and the development of chronic pancreatitis, COX-2 was ectopically expressed specifically in pancreatic acinar cells in transgenic mice. Histopathological changes and expression levels of several profibrogenic factors related to chronic pancreatitis were evaluated. COX-2 was expressed in the pancreas of the transgenic mice, as detected by Western blot analysis. Immunohistochemical staining showed COX-2 was specifically expressed in pancreatic acinar cells. COX-2 expression led to progressive changes in the pancreas, including pancreas megaly, persistent inflammation, collagen deposition, and acinar-to-ductal metaplasia. Quantitative RT-PCR and immunostaining showed that profibrogenic factors were upregulated and pancreatic stellate cells were activated in the COX-2 transgenic mice. Expression of COX-2 in pancreatic acinar cells is sufficient to induce chronic pancreatitis. Targeting this pathway may be valuable in the prevention of chronic pancreatitis. NEW & NOTEWORTHY COX-2 expression is observed in pancreatic tissues of human chronic pancreatitis. In this study, we showed that COX-2 expression caused the development of chronic pancreatitis in transgenic mice, supporting the idea that COX-2 inhibition may be an effective preventive and therapeutic strategy.

Abstract Incorporation of hydroxyapatite (HA) into polymer networks is a promising strategy to enhance the mechanical properties and osteoinductivity of the composite scaffolds for bone tissue engineering. In this study, we designed a group of nanocomposite scaffolds based on cross‐linkable poly(propylene fumarate) (PPF) and 30 wt % strontium‐hydroxyapatite (Sr‐HA) nanoparticles. Four different Sr contents [Sr:(Sr + Ca), molar ratio] in the Sr‐HA particles were studied: 0% (HA), 5% (Sr5‐HA), 10% (Sr10‐HA), and 20% (Sr20‐HA). Two‐dimensional (2D) disks were prepared using a thermal crosslinking method. The structure and surface morphology of different Sr‐HA and PPF/Sr‐HA composites were characterized using scanning electron microscopy (SEM), energy‐dispersive X‐ray spectroscopy (EDS), transmission electron microscopy (TEM), and atomic force microscopy (AFM). To detect cellular responses in vitro, MC3T3‐E1 cells were seeded and cultured on the different PPF/Sr‐HA composite disks. Cell morphology after 24 h and 5 days were imaged using Live/Dead live cell staining and SEM, respectively. Cell proliferation was quantified using an MTS assay at 1, 4, and 7 days. Osteogenic differentiation of the cells was examined by alkaline phosphatase (ALP) staining at 10 days and quantified using ALP activity and osteocalcin assays at 7, 14, and 21 days. The sizes of the HA, Sr5‐HA, Sr10‐HA, and Sr20‐HA particles were mainly between 10 × 20 nm and 10 × 250 nm, and these nanoparticles were dispersed or clustered in the composite scaffolds. in vitro cell studies showed that the PPF/Sr10‐HA scaffold was significantly better than the other three groups (PPF/HA, PPF/Sr5‐HA, and PPF/Sr20‐HA) in supporting MC3T3‐E1 cell adhesion, proliferation, and differentiation. PPF/Sr10‐HA may, therefore, serve as a promising scaffold material for bone tissue engineering. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 631–642, 2019.