Cystic fibrosis macrophage function and clinical outcomes after elexacaftor/tezacaftor/ivacaftor.

BACKGROUND: Abnormal macrophage function caused by dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) is a critical contributor to chronic airway infections and inflammation in people with cystic fibrosis (PWCF). Elexacaftor/tezacaftor/ivacaftor (ETI) is a new CFTR modulator therapy for PWCF. Host-pathogen and clinical responses to CFTR modulators are poorly described. We sought to determine how ETI impacts macrophage CFTR function, resulting effector functions and relationships to clinical outcome changes. METHODS: Clinical information and/or biospecimens were obtained at ETI initiation and 3, 6, 9 and 12 months post-ETI in 56 PWCF and compared with non-CF controls. Peripheral blood monocyte-derived macrophages (MDMs) were isolated and functional assays performed. RESULTS: ETI treatment was associated with increased CF MDM CFTR expression, function and localisation to the plasma membrane. CF MDM phagocytosis, intracellular killing of CF pathogens and efferocytosis of apoptotic neutrophils were partially restored by ETI, but inflammatory cytokine production remained unchanged. Clinical outcomes including increased forced expiratory volume in 1 s (+10%) and body mass index (+1.0 kg·m-2) showed fluctuations over time and were highly individualised. Significant correlations between post-ETI MDM CFTR function and sweat chloride levels were observed. However, MDM CFTR function correlated with clinical outcomes better than sweat chloride. CONCLUSION: ETI is associated with unique changes in innate immune function and clinical outcomes.

Intraperitoneal nanotherapy for metastatic ovarian cancer based on siRNA-mediated suppression of DJ-1 protein combined with a low dose of cisplatin.

Herein, we report an efficient combinatorial therapy for metastatic ovarian cancer based on siRNA-mediated suppression of DJ-1 protein combined with a low dose of cisplatin. DJ-1 protein modulates, either directly or indirectly, different oncogenic pathways that support and promote survival, growth, and invasion of ovarian cancer cells. To evaluate the potential of this novel therapy, we have engineered a cancer-targeted nanoplatform and validated that DJ-1 siRNA delivered by this nanoplatform after intraperitoneal injection efficiently downregulates the DJ-1 protein in metastatic ovarian cancer tumors and ascites. In vivo experiments revealed that DJ-1 siRNA monotherapy outperformed cisplatin alone by inhibiting tumor growth and increasing survival of mice with metastatic ovarian cancer. Finally, three cycles of siRNA-mediated DJ-1 therapy in combination with a low dose of cisplatin completely eradicated ovarian cancer tumors from the mice, and there was no cancer recurrence detected for the duration of the study, which lasted 35 weeks.

Detecting aberrant opioid behavior in the emergency department: a prospective study using the screener and Opioid Assessment for Patients with Pain-Revised (SOAPP®-R), Current Opioid Misuse Measure (COMM)™, and provider gestalt.

Emergency department (ED) providers have limited time to evaluate patients at risk for opioid misuse. A validated tool to assess the risk for aberrant opioid behavior may mitigate adverse sequelae associated with prescription opioid misuse. We sought to determine if SOAPP-R, COMM, and provider gestalt were able to identify patients at risk for prescription opioid misuse as determined by pharmacy records at 12 months. We conducted a prospective observational study of adult patients in a high volume US ED. Patients completed the SOAPP-R and COMM, and treating EM providers evaluated patients' opioid misuse risk. We performed variable-centered, person-centered, and hierarchical cluster analyses to determine whether provider gestalt, SOAPP-R, or COMM, or a combination, predicted higher misuse risk. The primary outcome was the number of opioid prescriptions at 12 months according to pharmacy records. For 169 patients (mean age 43 years, 51% female, 73% white), correlation analysis showed a strong relationship between SOAPP-R and COMM with predicting the number of opioid prescriptions dispensed at 12 months. Provider scores estimating opioid misuse were not related to SOAPP-R and only weakly associated with COMM. In our adjusted regression models, provider gestalt and SOAPP-R uniquely predicted opioid prescriptions at 6 and 12 months. Using designated cutoff scores, only SOAPP-R detected a difference in the number of opioid prescriptions. Cluster analysis revealed that provider gestalt, SOAPP-R, and COMM scores jointly predicted opioid prescriptions. Provider gestalt and self-report instruments uniquely predicted the number of opioid prescriptions in ED patients. A combination of gestalt and self-assessment scores can be used to identify at-risk patients who otherwise miss the cutoff scores for SOAPP-R and COMM.

A polypill for all? Critical review of the polypill literature for primary prevention of cardiovascular disease and stroke.

OBJECTIVE: To evaluate the efficacy and safety of the polypill for prevention of cardiovascular disease (CVD) and stroke and to present literature related to the polypill components (statin, aspirin, antihypertensive) for primary prevention of CVD and stroke. DATA SOURCES: A literature search was conducted in MEDLINE (1948-January 2011) and EMBASE (1974-January 2011) using the terms polypill and Polycap. When limited to clinical trials, systematic reviews, or meta-analyses, 7 studies were identified. Bibliographies of pertinent review articles and studies were scanned for additional references. A similar search was conducted to identify literature related to the use of polypill components for primary prevention of CVD and stroke. STUDY SELECTION AND DATA EXTRACTION: Studies that evaluated the hypothetical benefits of a polypill and controlled trials that assessed a formulation of the polypill related to prevention of CVD and stroke were included. Studies were assessed for efficacy, safety, drug interactions, and clinical pharmacokinetics. DATA SYNTHESIS: An initial study to predict benefit estimated that a hypothetical polypill would reduce diastolic blood pressure by 11 mm Hg and low-density lipoprotein cholesterol (LDL-C) by 70 mg/dL, thus reducing the relative risks of CVD and stroke by 88% and 80%, respectively. One clinical trial in patients at low risk for CVD and stroke found that diastolic blood pressure was reduced by 1.6 mm Hg and LDL-C was reduced by 17.7 mg/dL, correlating with 44% and 21% reduction in the relative risks of CVD and stroke, respectively. Studies in higher risk patients reported reductions in systolic blood pressure of up to 28.8 mm Hg and in LDL-C of up to 54 mg/dL, correlating with 62% and 60% relative reduction in risks of CVD and stroke, respectively. CONCLUSIONS: Polypill study results have been more modest than originally theorized. However, results show promise in patients at higher risk for CVD and stroke.

Effect of intraperitoneal and intravenous administration of cholecystokinin-8 and apolipoprotein AIV on intestinal lymphatic CCK-8 and apo AIV concentration.

CCK and apolipoprotein AIV (apo AIV) are gastrointestinal satiety signals whose synthesis and secretion by the gut are stimulated by fat absorption. Intraperitoneally administered CCK-8 is more potent in suppressing food intake than a similar dose administered intravenously, but the reason for this disparity is unclear. In contrast, both intravenous and intraperitoneally administered apo AIV are equally as potent in inhibiting food intake. When we compared the lymphatic concentration of CCK-8 and apo AIV, we found that neither intraperitoneally nor intravenously administered CCK-8 or apo AIV altered lymphatic flow rate. Interestingly, intraperitoneal administration of CCK-8 produced a significantly higher lymphatic concentration at 15 min than did intravenous administration. Intraperitoneal injection of apo AIV also yielded a higher lymphatic concentration at 30 min than did intravenous administration. Intraperitoneal administration of CCK-8 and apo AIV also resulted in a much longer period of elevated CCK-8 and apo AIV peptide concentration in lymph than intravenous administration. Furthermore, enzymatic activity of dipeptidyl peptidase IV (DPPIV) and aminopeptidase was higher in plasma than in lymph during fasting, and so, satiation peptides, such as CCK-8 and apo AIV in the lymph, are protected from degradation by the significantly lower DPPIV and aminopeptidase activity levels in lymph than in plasma. Therefore, the higher potency of intraperitoneally administered CCK-8 compared with intravenously administered CCK-8 in inhibiting food intake may be explained by both its higher concentration in lymph and the prolonged duration of its presence in the lamina propria.

Brain apolipoprotein E: an important regulator of food intake in rats.

OBJECTIVE: The worldwide prevalence of obesity is increasing at an alarming rate, along with the associated increased rates of type 2 diabetes, heart disease, and some cancers. While efforts to address environmental factors responsible for the recent epidemic must continue, investigation into the anorectic functions of potential molecules we present here, such as apolipoprotein (apo)E, offers exciting possibilities for future development of successful anti-obesity therapies. RESEARCH DESIGN AND METHODS: Changes in feeding behavior after intracerebroventricular injection of apoE, the regulation of hypothalamic apoE gene expression by energy status, and the interaction of hypothalamic apoE with other neuropeptides were studied. RESULTS: Intracerebroventricular apoE significantly decreased food intake without causing malaise, whereas intracerebroventricular infusion of apoE antiserum stimulated feeding, implying that endogenous apoE tonically inhibits food intake. Consistent with this, apoE was present in the hypothalamus, a brain site intimately involved in the integration of signals for energy homeostasis. Fasted rats exhibited significantly decreased apoE gene expression in the hypothalamus, and refeeding of these rats for 4 h evoked a significant increase of hypothalamic apoE mRNA levels. Both genetically obese (ob/ob) mice and rats with high-fat diet-induced obesity had significantly reduced hypothalamic apoE mRNA levels compared with their lean control counterparts, suggesting that decreased apoE may contribute to hyperphagia in these obese animals. Additionally, apoE-stimulated hypothalamic proopiomelanocortin gene expression and SHU9119, a melanocortin 3/4 receptor antagonist, attenuated the inhibitory function of apoE on feeding. CONCLUSIONS: These data demonstrate that apoE suppresses food intake via a mechanism enhancing melanocortin signaling in the hypothalamus.