Antitumor activity in preclinical models and a phase I study of patients with dedifferentiated liposarcoma (DD-LPS) was observed with selinexor. We evaluated the clinical benefit of selinexor in ...patients with previously treated DD-LPS whose sarcoma progressed on approved agents.
SEAL was a phase II-III, multicenter, randomized, double-blind, placebo-controlled study. Patients age 12 years or older with advanced DD-LPS who had received two-five lines of therapy were randomly assigned (2:1) to selinexor (60 mg) or placebo twice weekly in 6-week cycles (crossover permitted). The primary end point was progression-free survival (PFS). Patients who received at least one dose of study treatment were included for safety analysis (ClinicalTrials.gov identifier: NCT02606461).
Two hundred eighty-five patients were enrolled (selinexor, n = 188; placebo, n = 97). PFS was significantly longer with selinexor versus placebo: hazard ratio (HR) 0.70 (95% CI, 0.52 to 0.95; one-sided
= .011; medians 2.8
2.1 months), as was time to next treatment: HR 0.50 (95% CI, 0.37 to 0.66; one-sided
< .0001; medians 5.8
3.2 months). With crossover, no difference was observed in overall survival. The most common treatment-emergent adverse events of any grade versus grade 3 or 4 with selinexor were nausea (151 80.7%
11 5.9), decreased appetite (113 60.4%
14 7.5%), and fatigue (96 51.3%
12 6.4%). Four (2.1%) and three (3.1%) patients died in the selinexor and placebo arms, respectively. Exploratory RNA sequencing analysis identified that the absence of
expression was associated with longer PFS with selinexor compared with placebo (median 6.9
2.2 months; HR, 0.19;
= .001).
Patients with advanced, refractory DD-LPS showed improved PFS and time to next treatment with selinexor compared with placebo. Supportive care and dose reductions mitigated side effects of selinexor. Prospective validation of
expression as a predictive biomarker for selinexor in DD-LPS is warranted.
Abstract Introduction Gastrokine-1 (GKN1) is a secreted auto-/paracrine protein, described to be expressed in the gastric mucosa. In gastric cancers GKN1 expression is commonly down-regulated. While ...current research focusses on the exploration of tumor-suppressive properties of GKN1 with regard to its potential clinical use in the treatment of gastroenterologic tumor disease, nothing is known about GKN1 expression and function in other organ systems. We investigated GKN1 expression in placental tissue and cells. Materials and methods GKN1 was localized using immunohistochemistry in first and third trimester placental tissue, hydatidiform moles and various gestational trophoblastic neoplasias. We determined the expression of GKN1 in immunomagnetic bead-separated term placental cells and in choriocarcinoma cell lines. The role of GKN1 for JEG-3 migration was studied using live cell imaging. E-cadherin, MMP-2 and -9, TIMP-1 and -2, as well as urokinase (uPA) expression levels were determined. Results GKN1 is expressed in healthy third trimester placentas. Its expression is specifically limited to the extravillous trophoblast (EVT). GKN1 expression is significantly reduced in choriocarcinoma cell lines and gestational trophoblastic neoplasias. GKN1 attenuates the migration of JEG-3 choriocarcinoma cells in vitro, possibly via AKT-mediated induction of E-cadherin. GKN1 treatment reduced MMP-9 expression in JEG-3. Discussion Besides its role in gastric physiology our results clearly indicate regulatory functions of GKN1 in the EVT at the feto-maternal interface during pregnancy. Based on our findings in the JEG-3 choriocarcinoma cell line, an auto-/paracrine role of GKN1 for EVT motility and villous anchorage at the basal plate is conceivable. Thus, the tumor suppressor GKN1 is expressed in placental EVT and might contribute to the regulation of EVT migration/invasion.
A
bstract
The production of beauty and charm quarks in
ep
interactions has been studied with the ZEUS detector at HERA for exchanged four-momentum squared 5
< Q
2
<
1000 GeV
2
using an integrated ...luminosity of 354 pb
−1
. The beauty and charm content in events with at least one jet have been extracted using the invariant mass of charged tracks associated with secondary vertices and the decay-length significance of these vertices. Differential cross sections as a function of
Q
2
, Bjorken
x
, jet trans- verse energy and pseudorapidity were measured and compared with next-to-leading-order QCD calculations. The beauty and charm contributions to the proton structure functions were extracted from the double-differential cross section as a function of
x
and
Q
2
. The running beauty-quark mass,
m
b
at the scale
m
b
, was determined from a QCD fit at next-to-leading order to HERA data for the first time and found to be
m
b
(
m
b
) = 4.07 ± 0.14 (fit)
− 0.07
+ 0.01
(mod.)
− 0.00
+ 0.05
(param.)
− 0.05
+ 0.08
(theo.) GeV.
Development of a practical asymmetric synthesis of a glucagon receptor antagonist drug candidate for the treatment of type 2 diabetes is described. The antagonist consists of a ...1,1,2,2-tetrasubstituted ethane core substituted with a propyl and three aryl groups including a fluoro-indole. The key steps to construct the ethane core and the two stereogenic centers involved a ketone arylation, an asymmetric hydrogenation via dynamic kinetic resolution, and an anti-selective Friedel–Crafts alkylation of a fluoro-indole with a chiral α-phenyl benzyl cation. We also developed two new efficient syntheses of the fluoro-indole, including an unusual Larock-type indole synthesis and a Sugasawa-heteroannulation route. The described convergent synthesis was used to prepare drug substance in 52% overall yield and 99% ee on multikilogram scales.
The X-ray Telescope (XRT) for the SWIFT mission, built by the international consortium from Pennsylvania State University (US), University of Leicester (UK) and Osservatorio Astronomico di Brera ...(Italy), is already installed on the SWIFT spacecraft. The XRT has two key functions on SWIFT; to determine locations of GRBs to better than 5 arc seconds within 100 seconds of initial detection of a burst and to measure spectra and light curves of the X-ray afterglow over around four orders of magnitude of decay in the afterglow intensity. This paper summarises the XRT performance, operating modes and sensitivity for the detection of prompt and extended X-ray afterglows from gamma-ray bursts. The performance characteristics have been determined from data taken during the ground calibration campaign at MPE's Panter facility in September 2002.
PDF
