Risk of Clinically Relevant Pharmacokinetic-Based Drug-Drug Interactions with Drugs Approved by the U.S. Food and Drug Administration Between 2013 and 2016.

A total of 103 drugs (including 14 combination drugs) were approved by the U.S. Food and Drug Administration from 2013 to 2016.

Ion Channel Dysfunctions in Dilated Cardiomyopathy in Limb-Girdle Muscular Dystrophy.

Background: Limb-Girdle muscular dystrophies (LGMD) are a heritable group of genetically determined disorders with a primary involvement of the pelvic or shoulder girdle musculature with partially cardiac manifestation, such as dilated cardiomyopathy (DCM) and life-threatening tachyarrhythmia. We report here that human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes from a patient with LGMD2I and DCM associated with recurrent ventricular tachycardia displayed ion channel dysfunction and abnormality of calcium homeostasis.

Methods: Dermal fibroblasts obtained from a patient with LGMD2I harboring a fukutin-related protein gene mutation (826C>A; Leu276Ile) and 3 healthy donors were reprogrammed to hiPSCs.

Bronchial extracellular matrix from COPD patients induces altered gene expression in repopulated primary human bronchial epithelial cells.

Chronic obstructive pulmonary disease (COPD) is a serious global health problem characterized by chronic airway inflammation, progressive airflow limitation and destruction of lung parenchyma. Remodeling of the bronchial airways in COPD includes changes in both the bronchial epithelium and the subepithelial extracellular matrix (ECM). To explore the impact of an aberrant ECM on epithelial cell phenotype in COPD we developed a new ex vivo model, in which normal human bronchial epithelial (NHBE) cells repopulate and differentiate on decellularized human bronchial scaffolds derived from COPD patients and healthy individuals.

Higher CYP2E1 Activity Correlates with Hepatocarcinogenesis Induced by Diethylnitrosamine.

Hepatocellular carcinoma (HCC) is one of the most common types of primary liver cancer and the third most frequent cause of cancer death worldwide. Diethylnitrosamine (DEN) is one of the recognized risk factors for hepatocarcinogenesis likely due to CYP2E1-mediated metabolic activation. However, CYP2E1-mediated DEN metabolic activity in non-neoplastic liver tissue from HCC patients has not been determined; the role of CYP2E1 activity, in particular CYP2E1 constitutive activity and CYP2E1 inhibited activity, with respect to the hepatocarcinogenesis induced by DEN is not yet clear.

Cardioprotective Role of Myeloid-Derived Suppressor Cells in Heart Failure.

Background: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that expand in cancer, inflammation, and infection and negatively regulate inflammation and the immune response. Heart failure (HF) is a complex clinical syndrome wherein inflammation induction and incomplete resolution can potentially contribute to HF development and progression. However, the role of MDSCs in HF remains unclear.

Reduced methanol input induces increased protein output by AOX1 promoter in a trans-acting elements engineered Pichia pastoris.

High oxygen consumption and heat release caused by methanol catabolism usually bring difficulties to industrial scale-up and cost for protein expression driven by methanol-induced AOX1 promoter in Pichia pastoris. Here, reduced methanol feeding levels were investigated for expression of insulin precursor in a trans-acting elements engineered P. pastoris strain MF1-IP.

Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer.

Background: Osimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations. We compared osimertinib with standard EGFR-TKIs in patients with previously untreated, EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC).

Methods: In this double-blind, phase 3 trial, we randomly assigned 556 patients with previously untreated, EGFR mutation-positive (exon 19 deletion or L858R) advanced NSCLC in a 1:1 ratio to receive either osimertinib (at a dose of 80 mg once daily) or a standard EGFR-TKI (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily).

Effects of Nano-Aluminum Nitride on the Performance of an Ultrahigh-Temperature Inorganic Phosphate Adhesive Cured at Room Temperature.

Based on the optimal proportion of resin and curing agent, an ultrahigh-temperature inorganic phosphate adhesive was prepared with aluminum dihydric phosphate, aluminium oxide ( α -Al₂O₃), etc. and cured at room temperature (RT). Then, nano-aluminum nitride (nano-AlN), nano-Cupric oxide (nano-CuO), and nano-titanium oxide (nano-TiO₂) were added into the adhesive.

Enjoyment of Spicy Flavor Enhances Central Salty-Taste Perception and Reduces Salt Intake and Blood Pressure.

High salt intake is a major risk factor for hypertension and is associated with cardiovascular events. Most countries exhibit a traditionally high salt intake; thus, identification of an optimal strategy for salt reduction at the population level may have a major impact on public health. In this multicenter, random-order, double-blind observational and interventional study, subjects with a high spice preference had a lower salt intake and blood pressure than subjects who disliked spicy food.

Hidden Lineage Complexity of Glycan-Dependent HIV-1 Broadly Neutralizing Antibodies Uncovered by Digital Panning and Native-Like gp140 Trimer.

Germline precursors and intermediates of broadly neutralizing antibodies (bNAbs) are essential to the understanding of humoral response to HIV-1 infection and B-cell lineage vaccine design. Using a native-like gp140 trimer probe, we examined antibody libraries constructed from donor-17, the source of glycan-dependent PGT121-class bNAbs recognizing the N332 supersite on the HIV-1 envelope glycoprotein. To facilitate this analysis, a digital panning method was devised that combines biopanning of phage-displayed antibody libraries, 900 bp long-read next-generation sequencing, and heavy/light (H/L)-paired antibodyomics.

Pharmacokinetic and pharmacodynamics of intravenous dexmedetomidine in morbidly obese patients undergoing laparoscopic surgery.

Background: This study was designed to investigate the pharmacokinetics and pharmacodynamics of dexmedetomidine in morbidly obese patients undergoing laparoscopic surgery.

Methods: Morbidly obese (body mass index ≥40 kg/m) and normal weight patients scheduled for elective laparoscopic surgery were included (n = 8, each group). After baseline hemodynamic measurement, dexmedetomidine 1 μg/kg was administered over 10 min.

Trimester-Specific Weight Gain and Midpregnancy Diastolic Blood Pressure Rebound During Normotensive Pregnancy.

The longitudinal exposure-response relationship between trimester-specific gestational weight gain (GWG) and blood pressure (BP) during pregnancy is not well understood. We retrospectively assessed 1112 uncomplicated, normotensive pregnant women whose body weight and BP were measured from 12 to 40 weeks of gestation from a hospital-based cohort. By using growth curve modeling, a J-shaped pattern dominated diastolic BP (DBP) changing dynamics, with a midpregnancy drop at 20 to 22 weeks followed by a rebound.

ARHGAP18 Protects Against Thoracic Aortic Aneurysm Formation by Mitigating the Synthetic and Proinflammatory Smooth Muscle Cell Phenotype.

Rationale: Thoracic aortic aneurysm (TAA) is a potentially lethal condition, which can affect individuals of all ages. TAA may be complicated by the sudden onset of life-threatening dissection or rupture. The underlying mechanisms leading to TAA formation, particularly in the nonsyndromal idiopathic group of patients, are not well understood.

Small Intracranial Aneurysms: Diagnostic Accuracy of CT Angiography.

Purpose To assess the accuracy of computed tomographic (CT) angiography for diagnosis of cerebral aneurysms 5 mm or smaller, with digital subtraction angiography (DSA) as the reference standard, in a large patient cohort Materials and Methods This retrospective study was approved by the local institutional review board with a waiver of written informed consent. A total of 1366 patients who underwent cerebral CT angiography followed by DSA were included. The performance of CT angiography for depiction of aneurysms was evaluated by two readers on a per-patient and per-aneurysm basis and based on size of aneurysm, location, and status of rupture.

Y-shaped methoxy poly (ethylene glycol)-block-poly (epsilon-caprolactone)-based micelles for skin delivery of ketoconazole: in vitro study and in vivo evaluation.

Ketoconazole is a hydrophobic broad-spectrum antifungal agent for skin infection therapy. In order to develop topical formulation of ketoconazole for improving its selective skin deposition and water-solubility, ketoconazole-loaded Y-shaped monomethoxy poly(ethylene glycol)-block-poly(ɛ-caprolactone) micelles were prepared through thin-film hydration method with high entrapment efficiency (96.1±0.

Validation and comparison of four models to calculate pretest probability of obstructive coronary artery disease in a Chinese population: A coronary computed tomographic angiography study.

Objective: We sought to compare the performance of the updated Diamond-Forrester method (UDFM), Duke clinical score (DCS), Genders clinical model (GCM) and Genders extended model (GEM) in a Chinese population referred to coronary computed tomography angiography (coronary CTA).

Background: The reliability of existing models to calculate the pretest proability (PTP) of obstructive coronary artery disease (CAD) have not been fully investigated, especially in a Chinese population.

Methods: We identified 5743 consecutive patients with suspected stable CAD who underwent coronary calcium scoring (CCS) and coronary CCTA.

Impact of Coagulant and Flocculant Addition to an Anaerobic Dynamic Membrane Bioreactor (AnDMBR) Treating Waste-Activated Sludge.

In this work, we investigated the effects of flocculation aid (FA) addition to an anaerobic dynamic membrane bioreactor (AnDMBR) (7 L, 35 °C) treating waste-activated sludge (WAS). The experiment consisted of three distinct periods. In period 1 (day 1-86), the reactor was operated as a conventional anaerobic digester with a solids retention time (SRT) and hydraulic retention time (HRT) of 24 days.

Sex Differences in Inflammatory Markers and Health Status Among Young Adults With Acute Myocardial Infarction: Results From the VIRGO (Variation in Recovery: Role of Gender on Outcomes of Young Acute Myocardial Infarction Patients) Study.

Background: Young women (≤55 years of age) with acute myocardial infarction (AMI) have higher mortality risk than similarly aged men. Elevated inflammatory markers are associated with an increased risk of cardiovascular outcomes after AMI, but little is known about whether young women have higher inflammatory levels after AMI compared with young men.

Methods And Results: We assessed sex differences in post-AMI inflammatory markers and whether such differences account for sex differences in 12-month health status, using data from 2219 adults with AMI, 18 to 55 years of age, in the United States.

A UPLC/MS/MS method for determination of protosappanin B in rat plasma and its application of a pharmacokinetic and bioavailability study.

Caesalpinia sappan L. is a traditional medicinal plant which is used for promoting blood circulation and cerebral apoplexy therapy in China. Previous reports showed that the extracts of Caesalpinia sappan L.

Two Trichome Birefringence-Like Proteins Mediate Xylan Acetylation, Which Is Essential for Leaf Blight Resistance in Rice.

Acetylation is a ubiquitous modification on cell wall polymers, which play a structural role in plant growth and stress defenses. However, the mechanisms for how crop plants accomplish cell wall polymer O-acetylation are largely unknown. Here, we report on the isolation and characterization of two trichome birefringence-like (tbl) mutants in rice (Oryza sativa), which are affected in xylan O-acetylation.

Src Kinases Regulate Glutamatergic Input to Hypothalamic Presympathetic Neurons and Sympathetic Outflow in Hypertension.

The elevated sympathetic outflow associated with hypertension is maintained by increased N-methyl-d-aspartate receptor (NMDAR) activity in the paraventricular nucleus (PVN) of the hypothalamus. Synaptic NMDAR activity is tightly regulated by protein kinases, including the Src family of tyrosine kinases. We determined whether Src kinases play a role in increased NMDAR activity of PVN neurons projecting to the rostral ventrolateral medulla and in elevated sympathetic vasomotor tone in spontaneously hypertensive rats (SHRs).

Genetic and Pharmacologic Inhibition of the Chemokine Receptor CXCR2 Prevents Experimental Hypertension and Vascular Dysfunction.

Background: The recruitment of leukocytes to the vascular wall is a key step in hypertension development. Chemokine receptor CXCR2 mediates inflammatory cell chemotaxis in several diseases. However, the role of CXCR2 in hypertension development and the underlying mechanisms remain unknown.

Effect of Estimated Glomerular Filtration Rate Decline on the Efficacy and Safety of Clopidogrel With Aspirin in Minor Stroke or Transient Ischemic Attack: CHANCE Substudy (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events).

Background And Purpose: Patients with chronic kidney disease (CKD) are at a particularly high risk for ischemic and bleeding events. Limited data exist as to the efficacy and safety of clopidogrel in stroke patients with renal dysfunction. Therefore, we sought to assess the impact of decreased kidney function on clinical outcomes for stroke patients on clopidogrel-aspirin treatment.

Mnk1 (Mitogen-Activated Protein Kinase-Interacting Kinase 1) Deficiency Aggravates Cardiac Remodeling in Mice.

Identifying the key factor involved in cardiac remodeling is critically important for developing novel strategies to protect against heart failure. Here, the role of Mnk1 (mitogen-activated protein kinase-interacting kinase 1) in cardiac remodeling was clarified. Cardiac remodeling was induced by transverse aortic constriction in Mnk1-knockout mice and their wild-type control mice.

MicroRNA-21 Lowers Blood Pressure in Spontaneous Hypertensive Rats by Upregulating Mitochondrial Translation.

Background: Excessive reactive oxygen species generated in mitochondria has been implicated as a causal event in hypertensive cardiomyopathy. Multiple recent studies suggest that microRNAs (miRNAs) are able to translocate to mitochondria to modulate mitochondrial activities, but the medical significance of such a new miRNA function has remained unclear. Here, we characterized spontaneous hypertensive rats (SHRs) in comparison with Wistar rats, finding that micro RNA-21 (miR-21) was dramatically induced in SHRs relative to Wistar rats.