Citations

Background Calcitonin gene-related peptide plays an important role in migraine pathophysiology. Erenumab, a human monoclonal antibody that inhibits the calcitonin gene-related peptide receptor, is being evaluated for migraine prevention. Methods In this randomized, double-blind, placebo-controlled, phase 3 study, 577 adults with episodic migraine were randomized to placebo or 70 mg erenumab; 570 patients were included in efficacy analyses. Primary endpoint was change in monthly migraine days. Secondary endpoints were ≥50% reduction in monthly migraine days, change in acute migraine-specific medication treatment days, and ≥5-point reduction in Physical Impairment and Impact on Everyday Activities domain scores measured by the Migraine Physical Function Impact Diary. All endpoints assessed change from baseline at month 3. Results Patients receiving erenumab experienced −2.9 days change in monthly migraine days, compared with −1.8 days for placebo, least-squares mean (95% CI) treatment difference of −1.0 (−1.6, −0.5) ( p < 0.001). A ≥ 50% reduction in monthly migraine days was achieved by 39.7% (erenumab) and 29.5% (placebo) of patients (OR:1.59 (95% CI: 1.12, 2.27) ( p = 0.010). Migraine-specific medication treatment days were reduced by −1.2 (erenumab) and −0.6 (placebo) days, a treatment difference of −0.6 (−1.0, −0.2) ( p = 0.002). The ≥5-point reduction rates in Migraine Physical Function Impact Diary – Physical Impairment were 33.0% and 27.1% (OR:1.33 (0.92, 1.90) ( p = 0.13) and in Migraine Physical Function Impact Diary – Everyday Activities were 40.4% and 35.8% (OR:1.22 (0.87, 1.71) ( p = 0.26). Safety and adverse event profiles of erenumab were similar to placebo. Most frequent adverse events were upper respiratory tract infection, injection site pain, and nasopharyngitis. Conclusions As a preventive treatment of episodic migraine, erenumab at a dosage of 70 mg monthly significantly reduced migraine frequency and acute migraine-specific medication use. (Funded by Amgen). Trial registration ClinicalTrials.gov, NCT02483585.

Objective To assess stroke/systemic embolism, major bleeding and other outcomes, and treatment effect of apixaban versus warfarin, in patients with atrial fibrillation (AF) and different types of valvular heart disease (VHD), using data from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial. Methods There were 14 793 patients with known VHD status, categorised as having moderate or severe mitral regurgitation (MR) (n=3382), aortic regurgitation (AR) (n=842) or aortic stenosis (AS) (n=324); patients with moderate or severe mitral stenosis were excluded from the trial. Baseline characteristics, efficacy and safety outcomes were compared between each type and no significant VHD. Treatment effect was assessed using an adjusted model. Results Patients with MR or AR had similar rates of stroke/systemic embolism and bleeding compared with patients without MR or AR, respectively. Patients with AS had significantly higher event rates (presented as rate per 100 patient-years of follow-up) of stroke/systemic embolism (3.47 vs 1.36; adjusted HR (adjHR) 2.21, 95% CI 1.35 to 3.63), death (8.30 vs 3.53; adjHR 1.92, 95% CI 1.41 to 2.61), major bleeding (5.31 vs 2.53; adjHR 1.80, 95% CI 1.19 to 2.75) and intracranial bleeding (1.29 vs 0.51; adjHR 2.54, 95% CI 1.08 to 5.96) than patients without AS. The superiority of apixaban over warfarin on stroke/systemic embolism was similar in patients with versus without MR (HR 0.69, 95% CI 0.46 to 1.04 vs HR 0.79, 95% CI 0.63 to 1.00; interaction P value 0.52), with versus without AR (HR 0.57, 95% CI 0.27 to 1.20 vs HR 0.78, 95% CI 0.63 to 0.96; interaction P value 0.52), and with versus without AS (HR 0.44, 95% CI 0.17 to 1.13 vs HR 0.79, 95% CI 0.64 to 0.97; interaction P value 0.19). For each of the primary and secondary efficacy and safety outcomes, there was no evidence of a different effect of apixaban over warfarin in patients with any VHD subcategory. Conclusions In anticoagulated patients with AF, AS is associated with a higher risk of stroke/systemic embolism, bleeding and death. The efficacy and safety benefits of apixaban compared with warfarin were consistent, regardless of presence of MR, AR or AS. Clinical trial registration ARISTOTLE clinical trial number NCT00412984.

Intrahepatic cholangiocarcinoma remains a highly heterogeneous malignancy that has eluded effective patient stratification to date. The extent to which such heterogeneity can be influenced by individual driver mutations remains to be evaluated. Here, we analyzed genomic (whole‐exome sequencing, targeted exome sequencing) and epigenomic data from 496 patients and used the three most recurrently mutated genes to stratify patients ( IDH , KRAS , TP53 , “undetermined”). Using this molecular dissection approach, each subgroup was determined to possess unique mutational signature preferences, comutation profiles, and enriched pathways. High‐throughput drug repositioning in seven patient‐matched cell lines, chosen to reflect the genetic alterations specific for each patient group, confirmed in silico predictions of subgroup‐specific vulnerabilities linked to enriched pathways. Intriguingly, patients lacking all three mutations (“undetermined”) harbored the most extensive structural alterations, while isocitrate dehydrogenase mutant tumors displayed the most extensive DNA methylome dysregulation, consistent with previous findings. Conclusion : Stratification of intrahepatic cholangiocarcinoma patients based on occurrence of mutations in three classifier genes ( IDH , KRAS , TP53 ) revealed unique oncogenic programs (mutational, structural, epimutational) that influence pharmacologic response in drug repositioning protocols; this genome dissection approach highlights the potential of individual mutations to induce extensive molecular heterogeneity and could facilitate advancement of therapeutic response in this dismal disease. (H epatology 2018).

Eosinophil peroxidase (EPO), a cationic protein found in eosinophils, has been reported to be cytotoxic independent of its peroxidase activity. This study investigated with electrophysiological methods whether EPO is toxic to mammalian urinary bladder epithelium. Results indicate that EPO, when added to the mucosal solution, increases apical membrane conductance of urinary bladder epithelium only when the apical membrane potential is cell interior negative. The EPO-induced conductance was concentration dependent, with a maximum conductance of 411 μS/cm2 and a Michaelis-Menten constant of 113 nM. The EPO-induced conductance was nonselective for K+ and Cl−. The conductance was partially reversed using voltage but not by removal of EPO from the bulk solution. Mucosal Ca2+reversed the EPO-induced conductance by a mechanism involving reversible block of the conductance. Prolonged exposure (up to 1 h) to EPO was toxic to the urinary bladder epithelium, as indicated by an irreversible increase in transepithelial conductance. These results suggest that EPO is indeed toxic to urinary bladder epithelium via a mechanism that involves an increase in membrane permeability.

The eosinophil granule protein major basic protein (MBP) is toxic to a wide variety of cell types, by a poorly understood mechanism. To determine whether the action of MBP involves an alteration in membrane permeability, we tested purified MBP on rabbit urinary bladder epithelium using transepithelial voltage-clamp techniques. Addition of nanomolar concentrations of MBP to the mucosal solution caused an increase in apical membrane conductance only when the voltage across the apical membrane was cell interior negative. The magnitude of the MBP-induced conductance was a function of MBP concentration, and the rate of the initial increase in conductance was a function of the transepithelial voltage. The MBP-induced conductance was nonselective for K+ and Cl−. Mucosal Ca2+ reversed the induced conductance, whereas mucosal Mg2+partially blocked the induced conductance and slowed the rate of the increase in conductance. The induced conductance was partially reversed by changing the voltage gradient across the apical membrane to cell interior positive. Prolonged exposure resulted in an irreversible loss of the barrier function of the urinary bladder epithelium. These results suggest that an increase in cell membrane ion permeability is an initial step in MBP-induced loss of barrier function.

Hepatocytes do not express Bcl-2, a repressor of apoptosis. In contrast, cholangiocytes, which are in direct contact with bile, do express Bcl-2. Because cholestasis results in the retention of bile within hepatocytes, we reasoned cholestasis may induce hepatocellular expression of Bcl-2. Thus our aim was to determine whether hepatocytes express Bcl-2 or alter expression of other Bcl-2 family members in cholestasis using the bile duct-ligated (BDL) rat as a model of cholestasis. De novo Bcl-2 expression was observed in hepatocytes of BDL rats assessed by reverse transcriptase-polymerase chain reaction and immunoblot analysis. Immunohistochemistry demonstrated that Bcl-2 expression in hepatocytes was greater in periportal hepatocytes than pericentral hepatocytes. Expression of Bcl-x (an antiapoptotic Bcl-2 family protein) was not altered by bile duct ligation, whereas expression of Bax (a proapoptotic Bcl-2 family protein) increased slightly as determined by Northern and Western blot analyses. Bcl-2-positive hepatocytes isolated from BDL rats were resistant to induction of apoptosis by 50 microM glycochenodeoxycholate. Our results demonstrate, for the first time, expression of Bcl-2 by hepatocytes during cholestasis. We suggest that hepatocellular expression of Bcl-2 during cholestasis is an adaptive phenomenon to resist apoptosis by toxic bile salts.

Estrogen replacement increases risk of venous thrombosis. In this study, we determined responses in vitro to platelets and platelet products in veins from adult male and intact and ovariectomized female pigs. When contracted with prostaglandin F2α, platelets (25,000 platelets/μl) caused relaxation in veins with endothelium. Higher numbers of platelets caused contraction in veins with and without endothelium. In veins without endothelium, contractions were greater in veins from male than in veins from female pigs, and contractions in intact female pig veins were greater than in ovariectomized females pig veins. Platelet products 5-hydroxytryptamine and thromboxane (analog U-46619) caused comparable contractions in all veins; contractions to prostacyclin were less in veins from intact female pigs. ADP caused comparable endothelium-dependent relaxations in all groups. These relaxations were increased by indomethacin in veins from intact males and females; with inhibition of nitric oxide, relaxations were comparable in all groups. These results suggest that venous responses to platelets vary with sex and presence of ovaries in female pigs. These variations reflect differences in type and quantity of substances released from platelets as well as the sensitivity of the smooth muscle to some vasoactive substances. In addition, products of cyclooxygenase may reduce endothelium-dependent relaxations in veins.

The aim of this study was to evaluate the potential mechanisms underlying the improved contractility of the diaphragm (Dia) in adult intact male hamsters after nandrolone (Nan) administration, given subcutaneously over 4 wk via a controlled-release capsule (initial dose: 4.5 mg ⋅ kg−1 ⋅ day−1; with weight gain, final dose: 2.7 mg ⋅ kg−1 ⋅ day−1). Control (Ctl) animals received blank capsules. Isometric contractile properties of the Dia were determined in vitro after 4 wk. The maximum velocity of unloaded shortening ( V o) was determined in vitro by means of the slack test. Dia fibers were classified histochemically on the basis of myofibrillar ATPase staining and fiber cross-sectional area (CSA), and the relative interstitial space was quantitated. Ca2+-activated myosin ATPase activity was determined by quantitative histochemistry in individual diaphragm fibers. Myosin heavy chain (MHC) isoforms were identified electrophoretically, and their proportions were determined by using scanning densitometry. Peak twitch and tetanic forces, as well as V o, were significantly greater in Nan animals compared with Ctl. The proportion of type IIa Dia fibers was significantly increased in Nan animals. Nan increased the CSA of all fiber types (26–47%), whereas the relative interstitial space decreased. The relative contribution of fiber types to total costal Dia area was preserved between the groups. Proportions of MHC isoforms were similar between the groups. There was a tendency for increased expression of MHC2B with Nan. Ca2+-activated myosin ATPase activity was increased 35–39% in all fiber types in Nan animals. We conclude that, after Nan administration, the increase in Dia specific force results from the relatively greater Dia CSA occupied by hypertrophied muscle fibers, whereas the increased ATPase activity promotes a higher rate of cross-bridge turnover and thus increased V o. We speculate that Nan in supraphysiological doses have the potential to offset or ameliorate conditions associated with enhanced proteolysis and disordered protein turnover.