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Arrestin translocation and signaling have come to the fore of the G protein-coupled receptor molecular pharmacology field. Some receptor-arrestin interactions are relatively well understood and considered responsible for specific therapeutic or adverse outcomes. Coupling of arrestins with cannabinoid receptors 1 (CB ) and 2 (CB ) has been reported, though the majority of studies have not systematically characterized the differential ligand dependence of this activity. In addition, many prior studies have utilized bovine (rather than human) arrestins, and the most widely applied assays require reporter-tagged receptors, which prevent meaningful comparison between receptor types. We have employed a bioluminescence resonance energy transfer (BRET) method that does not require the use of tagged receptors and thereby allows comparisons of arrestin translocation between receptor types, as well as with cells lacking the receptor of interest - an important control. The ability of a selection of CB and CB agonists to stimulate cell surface translocation of human and bovine β-arrestin-1 and -2 was assessed. We find that some CB ligands induce moderate β-arrestin-2 translocation in comparison with vasopressin V receptor (a robust arrestin recruiter); however, CB coupling with β-arrestin-1 and CB with either arrestin elicited low relative efficacies. A range of efficacies between ligands was evident for both receptors and arrestins. Endocannabinoid 2-arachidonoylglycerol stood out as a high efficacy ligand for translocation of β-arrestin-2 via CB . Δ -tetrahydrocannabinol was generally unable to elicit translocation of either arrestin subtype via CB or CB ; however, control experiments revealed translocation in cells not expressing CB /CB , which may assist in explaining some discrepancy with the literature. Overexpression of GRK2 had modest influence on CB /CB -induced arrestin translocation. Results with bovine and human arrestins were largely analogous, but a few instances of inconsistent rank order potencies/efficacies between bovine and human arrestins raise the possibility that subtle differences in receptor conformation stabilized by these ligands manifest in disparate affinities for the two arrestin species, with important potential consequences for interpretation in ligand bias studies. As well as contributing important information regarding CB /CB ligand-dependent arrestin coupling, our study raises a number of points for consideration in the design and interpretation of arrestin recruitment assays.

Background Although barriers to trial accrual are well‐reported, few studies have explored trial eligibility and trial offers as potential drivers of disparities in cancer clinical trial enrollment. Methods We identified patients with gastrointestinal (GI) or head/neck (HN) malignancies who were seen as new patients at the University of Michigan Health Rogel Cancer Center in 2016. By exhaustive review of the electronic medical record, we assessed the primary outcomes: (1) eligibility for, (2) documented offer of, and (3) enrollment in a clinical trial. All 41 of the clinical trials available to these patients were considered. Independent variables included clinical and non‐clinical patient‐related factors. We assessed associations between these variables and the primary outcomes using multivariable regression. Results Of 1446 patients, 43% were female, 15% were over age 75, 6% were Black. 305 (21%) patients were eligible for a clinical trial. Among eligible patients, 154 (50%) had documentation of a trial offer and 90 (30%) enrolled. Among the GI cohort, bivariate analyses demonstrated that older age was associated with decreased trial eligibility. Bivariate analyses also demonstrated that Black race was associated with increased trial offer. After adjustment, patients 75 or older were less likely to be eligible for a clinical trial in the GI cohort; however, we found no significant associations between race and any of the outcomes after adjustment. Among eligible GI patients, we found no significant associations between non‐clinical factors and enrollment. Among the HN cohort, bivariate analyses demonstrated that female sex, older age, Black race, and unpartnered marital status were associated with decreased likelihood of trial offer; however, we found no significant associations between race, age, and marital status and any of the outcomes after adjustment. We found no significant associations between non‐clinical factors and eligibility after adjustment; however, women were less likely to be offered and to enroll in a clinical trial in the HN cohort. Conclusion Factors associated with eligibility, documented offer, and enrollment differed between disease site cohorts at our institution. Future work is needed to ensure the equitable inclusion of women and elderly patients in clinical trials. A thorough review assessing the clinical trial eligibility of individual cancer patients seen at an academic center demonstrates that only 21% of patients were eligible for any trials, and only half of these eligible patients had documented evidence of clinical trial offer. Specific demographic groups were less likely to receive a trial offer. Interventions in the clinical encounter are needed to improve recognition of trial eligibility and facilitate trial offer if we hope to improve accrual to cancer clinical trials.

Purpose Although many studies clearly demonstrate disparities in cancer clinical trial enrollment, there is a lack of consensus on potential causes. Furthermore, virtually nothing is known about associations between patients’ decision-making style and their participation in clinical trials. Methods Women with newly diagnosed, stage 0–II breast cancer reported to the Georgia and Los Angeles County Surveillance, Epidemiology, and End Results (SEER) registries in 2013–2014 were surveyed approximately seven months after diagnosis. We investigated two primary outcome variables: (1) invitation to participate in a clinical trial, (2) participation in a clinical trial. We evaluated bivariate associations using Chi-squared tests and used multivariable logistic regression models to investigate associations between patient variables, including decision-making style, and the primary outcomes. Results 2578 patients responded (71% response rate); 30% were > age 65, 18% were black, 18% were Latina, 29% had ≤ high school education. 10% of patients reported invitation to participate in a clinical trial; 5% reported participation in a clinical trial. After adjustment younger age, receipt of chemotherapy or radiation, disease stage, and a more rational (versus more intuitive) decision-making style were associated with a higher odds of invitation to participate. Being married was associated with a higher odds of participation; having an annual family income ≥ $40,000 was associated with a lower odds of participation. Conclusions 10% of patients reported invitation to participate in a clinical trial, and half of these reported participation. Invitation to participate varied by age and decision-making style, and participation varied by marital status and income.

The literature reports no randomized trial in chronic coronary artery disease (CAD) of a comprehensive management strategy integrating intense lifestyle management, maximal medical treatment to specific goals and high precision quantitative cardiac positron emission tomography (PET) for identifying high mortality risk patients needing essential invasive procedures. We hypothesize that this comprehensive strategy achieves greater risk factor reduction, lower major adverse cardiovascular events and fewer invasive procedures than standard practice. The CENTURY Study (NCT00756379) is a randomized-controlled-trial study in patients with stable or at high risk for CAD. Patients are randomized to standard of care (Standard group) or intense comprehensive lifestyle-medical treatment to targets and PET guided interventions (Comprehensive group). Comprehensive Group patients are regularly consulted by the CENTURY team implementing diet/lifestyle/exercise program and medical treatment to target risk modification. Cardiac PET at baseline, 24-, and 60-months quantify the physiologic severity of CAD and guide interventions in the Comprehensive group while patients and referring physicians of the Standard group are blinded to PET results. The primary end-point is the CENTURY risk score reduction during 5 years follow-up. The secondary endpoint is a composite of death, non-fatal myocardial infarction, stroke, and coronary revascularization. The CENTURY Study is the first study in stable CAD to test the incremental benefit of a comprehensive strategy integrating intense lifestyle modification, medical treatment to specific goals, and high-precision quantitative myocardial perfusion imaging to guide revascularization. A total of 1028 patients have been randomized, and the 5 years follow-up will conclude in 2022.

Excessive fibrosis and resultant poor control of intraocular pressure (IOP) reduce the efficacy of glaucoma surgeries. Historically, corticosteroids and anti-fibrotic agents, such as mitomycin C (MMC) and 5-fluorouracil (5-FU), have been used to mitigate post-surgical fibrosis, but these have unpredictable outcomes. Therefore, there is a need to develop novel treatments which provide increased effectiveness and specificity. This review aims to provide insight into the pathophysiology behind wound healing in glaucoma surgery, as well as the current and promising future wound healing agents that are less toxic and may provide better IOP control.

The rapid structural evolution and emergence of novel synthetic cannabinoid receptor agonists (SCRAs) in the recreational market remains a key public health concern. Despite representing one of the largest classes of new psychoactive substances, pharmacological data on new SCRAs is limited, particularly at the cannabinoid CB2 receptor (CB2). Hence, the current study aimed to characterize the molecular pharmacology of a structurally diverse panel of SCRAs at CB2, including 4‐cyano MPP‐BUT7AICA, 4F‐MDMB‐BUTINACA, AMB‐FUBINACA, JWH‐018, MDMB‐4en‐PINACA, and XLR‐11. The activity of SCRAs was assessed in a battery of in vitro assays in CB2‐expressing HEK 293 cells: G protein activation (Gαi3 and GαoB), phosphorylation of ERK1/2, and β‐arrestin 1/2 translocation. The activity profiles of the ligands were further evaluated using the operational analysis to identify ligand bias. All SCRAs activated the CB2 signaling pathways in a concentration‐dependent manner, although with varying potencies and efficacies. Despite the detection of numerous instances of statistically significant bias, compound activities generally appeared only subtly distinct in comparison with the reference ligand, CP55940. In contrast, the phytocannabinoid THC exhibited an activity profile distinct from the SCRAs; most notably in the translocation of β‐arrestins. These findings demonstrate that CB2 is able to accommodate a structurally diverse array of SCRAs to generate canonical agonist activity. Further research is required to elucidate whether the activation of CB2 contributes to the toxicity of these compounds.

In August–September 2006, as part of the Second Texas Air Quality Study, NO2 and SO2 emissions from the Houston Ship Channel and Texas City industrial areas were quantified using mobile mini‐differential optical absorption spectroscopy instruments. The measured NO2 emissions from the Houston Ship Channel and Texas City industrial areas were 2542 and 452 kg h−1, respectively, yielding NOx emissions 70% and 43%, respectively, above the reported inventory values. Quantified SO2 emissions from the Houston Ship Channel area were 1749 kg h−1 and were found to be 34% above the values reported in the inventory. Short‐term variability of NO2 and SO2 emissions was found at the Houston Ship Channel. On 31 August 2006, a plume was detected at the HSC during three consecutive measurements, yielding a HCHO flux of 481 kg h−1. This event has been mainly attributed to photochemical production.

Herpes zoster is caused by a reactivation of the varicella-zoster virus after primary manifestation during childhood as chicken pox, commonly occurring in elderly and immunosuppressed patients. Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) is defined by the unsuppressed release of antidiuretic hormone (ADH) from the pituitary gland, with impaired water excretion causing hyponatremia. Though limited, literature supports herpes zoster infection inducing SIADH, through a proposed mechanism of alteration of the ADH regulator pathway due to viral infection of the dorsal root ganglion (DRG). Our case is distinct in that our patient presented elements of hypovolemic hyponatremia with concomitant SIADH.