Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

BACKGROUND Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. METHODS In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2-F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2-F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. FINDINGS Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1-F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2-F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1-F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). INTERPRETATION Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes. FUNDING Intercept Pharmaceuticals

Role of A Novel Angiogenesis FKBPL-CD44 Pathway in Preeclampsia Risk Stratification and Mesenchymal Stem Cell Treatment

Context: Preeclampsia is a leading cardiovascular complication in pregnancy lacking effective diagnostic and treatment strategies.Objective: To investigate the diagnostic and therapeutic target potential of the angiogenesis proteins, FK506-binding protein like (FKBPL) and CD44.Design and intervention: FKBPL and CD44 plasma concentration or placental expression were determined in women pre- or postdiagnosis of preeclampsia. Trophoblast and endothelial cell function was assessed following mesenchymal stem cell (MSC) treatment and in the context of FKBPL signaling.Settings and participants: Human samples prediagnosis (15 and 20 weeks of gestation; n ≥ 57), or postdiagnosis (n = 18 for plasma; n = 4 for placenta) of preeclampsia were used to determine FKBPL and CD44 levels, compared to healthy controls. Trophoblast or endothelial cells were exposed to low/high oxygen, and treated with MSC-conditioned media (MSC-CM) or a FKBPL overexpression plasmid.Main outcome measures: Preeclampsia risk stratification and diagnostic potential of FKBPL and CD44 were investigated. MSC treatment effects and FKBPL-CD44 signaling in trophoblast and endothelial cells were assessed.Results: The CD44/FKBPL ratio was reduced in placenta and plasma following clinical diagnosis of preeclampsia. At 20 weeks of gestation, a high plasma CD44/FKBPL ratio was independently associated with the 2.3-fold increased risk of preeclampsia (odds ratio = 2.3, 95% confidence interval [CI] 1.03-5.23, P = 0.04). In combination with high mean arterial blood pressure (>82.5 mmHg), the risk further increased to 3.9-fold (95% CI 1.30-11.84, P = 0.016). Both hypoxia and MSC-based therapy inhibited FKBPL-CD44 signaling, enhancing cell angiogenesis.Conclusions: The FKBPL-CD44 pathway appears to have a central role in the pathogenesis of preeclampsia, showing promising utilities for early diagnostic and therapeutic purposes.</p

Determination of radioactivity levels in Akhisar, Gordes, Golmarmara and Sindirgi regions, Western Turkey

WOS: 000330780800008In this study, radioactivity measurements in the environment of Akhisar, Golmarmara, Gordes and Sindirgi regions in Western Turkey were investigated in order to evaluate the implications of any excess radioactivity in the environment of geological formation. The radioactivity concentrations of K-40, U-238 and Th-232 radionuclides in the soil samples were measured by a NaI(Tl) gamma spectrometer system, and the radium activity concentrations in the water samples were also analyzed by an ZnS(Ag) alpha counter by the collector chamber method. The radioactivity of K-40, U-238 and Th-232 in soils ranged 2.80-2,347.77, 9.90-256.19 and 9.66-106.53 Bq kg(-1), respectively. The activity of Ra-226 in the water samples ranged from 0.03 Bq L-1 (0.89pCi/L) to 0.80 Bq L-1 (21.58pCi/L). In addition, the external terrestrial gamma dose rate in air (nGy h(-1)), annual effective dose rate (mSv year(-1)) and radium equivalent activity (Bq kg(-1)) were calculated and compared with international standard values.Celal Bayar University Scientific Research Projects Coordination (BAP)Celal Bayar University [2010/10]In this study, Celal Bayar University Scientific Research Projects Coordination (BAP) No. 2010/10 with the Project is supported

Radioactivity levels and heavy metals in the urban soil of Central Serbia

Radioactivity concentrations and heavy metal content were measured in soil samples collected from the area of Kragujevac, one of the largest cities in Serbia. The specific activities of Ra-226, Th-232, K-40 and Cs-137 in 30 samples were measured by gamma spectrometry using an HPGe semiconductor detector. The average values +/- standard deviations were 33.5 +/- 8.2, 50.3 +/- 10.6, 425.8 +/- 75.7 and 40.2 +/- 26.3 Bq kg(-1), respectively. The activity concentrations of Ra-226, Th-232 and Cs-137 have shown normal distribution. The annual effective doses, radium equivalent activities, external hazard indexes and excess lifetime cancer risk were also estimated. A RAD7 device was used for measuring radon exhalation rates from several samples with highest content of Ra-226. The concentrations of As, Co, Cr, Cu, Mn, Ni, Pb and Zn were measured, as well as their EDTA extractable concentrations. Wide ranges of values were obtained, especially for Cr, Mn, Ni, Pb and Zn. The absence of normal distribution indicates anthropogenic origin of Cr, Ni, Pb and Zn. Correlations between radionuclide activities, heavy metal contents and physicochemical properties of analysed soil were determined by Spearman correlation coefficient. Strong positive correlation between Ra-226 and Th-232 was found