Arginine depletion is a putative target in hepatocellular carcinoma (HCC). HCC often lacks argininosuccinate synthetase, a citrulline to arginine-repleting enzyme. ADI-PEG 20 is a cloned arginine ...degrading enzyme—arginine deiminase—conjugated with polyethylene glycol. The goal of this study was to evaluate this agent as a potential novel therapeutic for HCC after first line systemic therapy.
Patients with histologically proven advanced HCC and Child-Pugh up to B7 with prior systemic therapy, were randomized 2 : 1 to ADI-PEG 20 18 mg/m2 versus placebo intramuscular injection weekly. The primary end point was overall survival (OS), with 93% power to detect a 4–5.6 months increase in median OS (one-sided α = 0.025). Secondary end points included progression-free survival, safety, and arginine correlatives.
A total of 635 patients were enrolled: median age 61, 82% male, 60% Asian, 52% hepatitis B, 26% hepatitis C, 76% stage IV, 91% Child-Pugh A, 70% progressed on sorafenib and 16% were intolerant. Median OS was 7.8 months for ADI-PEG 20 versus 7.4 for placebo (P = 0.88, HR = 1.02) and median progression-free survival 2.6 months versus 2.6 (P = 0.07, HR = 1.17). Grade 3 fatigue and decreased appetite occurred in <5% of patients. Two patients on ADI-PEG 20 had ≥grade 3 anaphylactic reaction. Death rate within 30 days of end of treatment was 15.2% on ADI-PEG 20 versus 10.4% on placebo, none related to therapy. Post hoc analyses of arginine assessment at 4, 8, 12 and 16 weeks, demonstrated a trend of improved OS for those with more prolonged arginine depletion.
ADI-PEG 20 monotherapy did not demonstrate an OS benefit in second line setting for HCC. It was well tolerated. Strategies to enhance prolonged arginine depletion and synergize the effect of ADI-PEG 20 are underway.
www.clinicaltrials.gov (NCT 01287585).
Hopping Hotspots: Global Shifts in Marine Biodiversity Renema, W.; Bellwood, D. R.; Braga, J. C. ...
Science (American Association for the Advancement of Science),
08/2008, Letnik:
321, Številka:
5889
Journal Article
Recenzirano
Hotspots of high species diversity are a prominent feature of modern global biodiversity patterns. Fossil and molecular evidence is starting to reveal the history of these hotspots. There have been ...at least three marine biodiversity hotspots during the past 50 million years. They have moved across almost half the globe, with their timing and locations coinciding with major tectonic events. The birth and death of successive hotspots highlights the link between environmental change and biodiversity patterns. The antiquity of the taxa in the modern Indo-Australian Archipelago hotspot emphasizes the role of pre-Pleistocene events in shaping modern diversity patterns.
•The progress in energy resolution of monochromated STEM-EELS is reviewed, up to the present 4.2 meV resolution record.•Surveyed applications include the new and very rich field of vibrational ...spectroscopy in the electron microscope, as well as specific examples such as damage-free identification of isotopic substitution in biological materials.•Likely future developments are summarized.
Electron energy loss spectroscopy (EELS) in the electron microscope has progressed remarkably in the last five years. Advances in monochromator and spectrometer design have improved the energy resolution attainable in a scanning transmission electron microscope (STEM) to 4.2 meV, and new applications of ultrahigh energy resolution EELS have not lagged behind. They include vibrational spectroscopy in the electron microscope, a field that did not exist 5 years ago but has now grown very substantially. Notable examples include vibrational mapping with about 1 nm spatial resolution, analyzing the momentum dependence of vibrational states in very small volumes, determining the local temperature of the sample from the ratio of energy gains to energy losses, detecting hydrogen and analyzing its bonding, probing radiation-sensitive materials with minimized damage by aloof spectroscopy and leap-frog scanning, and identifying biological molecules with different isotopic substitutions. We review the instrumentation advances, provide a summary of key applications, and chart likely future directions.
By the end of 2018, 42 years after the landing of the two Viking seismometers on Mars, InSight will deploy onto Mars’ surface the SEIS (
S
eismic
E
xperiment for
I
nternal
S
tructure) instrument; a ...six-axes seismometer equipped with both a long-period three-axes Very Broad Band (VBB) instrument and a three-axes short-period (SP) instrument. These six sensors will cover a broad range of the seismic bandwidth, from 0.01 Hz to 50 Hz, with possible extension to longer periods. Data will be transmitted in the form of three continuous VBB components at 2 sample per second (sps), an estimation of the short period energy content from the SP at 1 sps and a continuous compound VBB/SP vertical axis at 10 sps. The continuous streams will be augmented by requested event data with sample rates from 20 to 100 sps. SEIS will improve upon the existing resolution of Viking’s Mars seismic monitoring by a factor of
∼
2500
at 1 Hz and
∼
200
000
at 0.1 Hz. An additional major improvement is that, contrary to Viking, the seismometers will be deployed via a robotic arm directly onto Mars’ surface and will be protected against temperature and wind by highly efficient thermal and wind shielding. Based on existing knowledge of Mars, it is reasonable to infer a moment magnitude detection threshold of
M
w
∼
3
at
40
∘
epicentral distance and a potential to detect several tens of quakes and about five impacts per year. In this paper, we first describe the science goals of the experiment and the rationale used to define its requirements. We then provide a detailed description of the hardware, from the sensors to the deployment system and associated performance, including transfer functions of the seismic sensors and temperature sensors. We conclude by describing the experiment ground segment, including data processing services, outreach and education networks and provide a description of the format to be used for future data distribution.
Context. The protoplanetary disk around the F-type star HD 135344B (SAO 206462) is in a transition stage and shows many intriguing structures both in scattered light and thermal (sub-)millimeter ...emission which are possibly related to planet formation processes. Aims. We aim to study the morphology and surface brightness of the disk in scattered light to gain insight into the innermost disk regions, the formation of protoplanets, planet-disk interactions traced in the surface and midplane layers, and the dust grain properties of the disk surface. Methods. We have carried out high-contrast polarimetric differential imaging (PDI) observations with VLT/SPHERE and obtained polarized scattered light images with ZIMPOL in the R and I-bands and with IRDIS in the Y and J-bands. The scattered light images and surface brightness profiles are used to study in detail structures in the disk surface and brightness variations. We have constructed a 3D radiative transfer model to support the interpretation of several detected shadow features. Results. The scattered light images reveal with unprecedented angular resolution and sensitivity the spiral arms as well as the 25 au cavity of the disk. Multiple shadow features are discovered on the outer disk with one shadow only being present during the second observation epoch. A positive surface brightness gradient is observed in the stellar irradiation corrected (r2-scaled) images in southwest direction possibly due to an azimuthally asymmetric perturbation of the temperature and/or surface density by the passing spiral arms. The disk integrated polarized flux, normalized to the stellar flux, shows a positive trend towards longer wavelengths which we attribute to large (2πa ≳ λ) aggregate dust grains in the disk surface. Part of the non-azimuthal polarization signal in the Uφ image of the J-band observation can be attributed to multiple scattering in the disk. Conclusions. The detected shadow features and their possible variability have the potential to provide insight into the structure of and processes occurring in the innermost disk regions. Possible explanations for the presence of the shadows include a 22° misaligned inner disk, a warped disk region that connects the inner disk with the outer disk, and variable or transient phenomena such as a perturbation of the inner disk or an asymmetric accretion flow. The spiral arms are best explained by one or multiple protoplanets in the exterior of the disk although no gap is detected beyond the spiral arms up to 1.′′0.
PDF
