In an extension of a basket trial focusing on triple-negative breast cancer, patients who received sacituzumab govitecan, an antibody–drug conjugate, had a 33.3% response rate for a median of 7.7 ...months. Myelotoxic effects and diarrhea were major adverse reactions.
Neurons tightly regulate firing rate and a failure to do so leads to multiple neurological disorders. Therefore, a fundamental question in neuroscience is how neurons produce reliable activity ...patterns for decades to generate behavior. Neurons have built-in feedback mechanisms that allow them to monitor their output and rapidly stabilize firing rate. Most work emphasizes the role of a dominant feedback system within a neuronal population for the control of moment-to-moment firing. In contrast, we find that respiratory motoneurons use 2 activity-dependent controllers in unique combinations across cells, dynamic activation of an Na+ pump subtype, and rapid potentiation of Kv7 channels. Both systems constrain firing rate by reducing excitability for up to a minute after a burst of action potentials but are recruited by different cellular signals associated with activity, increased intracellular Na+ (the Na+ pump), and membrane depolarization (Kv7 channels). Individual neurons do not simply contain equal amounts of each system. Rather, neurons under strong control of the Na+ pump are weakly regulated by Kv7 enhancement and vice versa along a continuum. Thus, each motoneuron maintains its characteristic firing rate through a unique combination of the Na+ pump and Kv7 channels, which are dynamically regulated by distinct feedback signals. These results reveal a new organizing strategy for stable circuit output involving multiple fast activity sensors scaled inversely across a neuronal population.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Women with advanced endometrial cancer that progressed during platinum-containing therapy were randomly assigned to lenvatinib plus pembrolizumab or physician’s choice of chemotherapy (doxorubicin or ...paclitaxel). The median progression-free survival was 7.2 months with lenvatinib plus pembrolizumab and 3.8 months with chemotherapy; the median overall survival was 18.3 months and 11.4 months, respectively.
Squid gelatin obtained from inner and outer tunics was hydrolysed with Alcalase to isolate antioxidant peptide sequences. The ACE-inhibitory activity of the isolated peptides was also evaluated. ...After fractionation by ultrafiltration and size-exclusion chromatography into four fractions, the antioxidant activity of the peptide fractions was determined by radical scavenging ability and ferric reducing power. Fraction FIII showed the highest antioxidant activity, although slight differences could be expected in the antioxidant activity of the different fractions based on the amino acid composition. FIII was subjected to liquid chromatography and tandem mass spectrometry (LC–MS/MS) and two major compounds were identified: the compound with
m/
z 952.42, which could be mostly comprised by the carbohydrate fucose, and the peptide with
m/
z 1410.63. Three possible sequences were proposed and synthesised for this peptide, and the contribution of Leu or Hyp residues to the antioxidant and ACE-inhibitory activities of the resulting sequence was evaluated. The presence of Leu residues in the peptide sequence in replacement of Hyp seems to play an important role in the antioxidant and ACE-inhibitory activity.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Sacituzumab govitecan (SG), a trophoblast cell surface antigen-2 (Trop-2)-directed antibody-drug conjugate, has demonstrated antitumor efficacy and acceptable tolerability in a phase I/II multicenter ...trial (NCT01631552) in patients with advanced epithelial cancers. This report summarizes the safety data from the overall safety population (OSP) and efficacy data, including additional disease cohorts not published previously.
Patients with refractory metastatic epithelial cancers received intravenous SG (8, 10, 12, or 18 mg/kg) on days 1 and 8 of 21-day cycles until disease progression or unacceptable toxicity. Endpoints for the OSP included safety and pharmacokinetic parameters with investigator-evaluated objective response rate (ORR per RECIST 1.1), duration of response, clinical benefit rate, progression-free survival, and overall survival evaluated for cohorts (n > 10 patients) of small-cell lung, colorectal, esophageal, endometrial, pancreatic ductal adenocarcinoma, and castrate-resistant prostate cancer.
In the OSP (n = 495, median age 61 years, 68% female; UGT1A1∗28 homozygous, n = 46; 9.3%), 41 (8.3%) permanently discontinued treatment due to adverse events (AEs). Most common treatment-related AEs were nausea (62.6%), diarrhea (56.2%), fatigue (48.3%), alopecia (40.4%), and neutropenia (57.8%). Most common treatment-related serious AEs (n = 75; 15.2%) were febrile neutropenia (4.0%) and diarrhea (2.8%). Grade ≥3 neutropenia and febrile neutropenia occurred in 42.4% and 5.3% of patients, respectively. Neutropenia (all grades) was numerically more frequent in UGT1A1∗28 homozygotes (28/46; 60.9%) than heterozygotes (69/180; 38.3%) or UGT1A1∗1 wild type (59/177; 33.3%). There was one treatment-related death due to an AE of aspiration pneumonia. Partial responses were seen in endometrial cancer (4/18, 22.2% ORR) and small-cell lung cancer (11/62, 17.7% ORR), and one castrate-resistant prostate cancer patient had a complete response (n = 1/11; 9.1% ORR).
SG demonstrated a toxicity profile consistent with previous published reports. Efficacy was seen in several cancer cohorts, which validates Trop-2 as a broad target in solid tumors.
•Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate with a hydrolyzable linker and an SN-38 payload.•The most frequent treatment-related adverse events (TRAEs) were nausea, diarrhea, neutropenia, alopecia, and fatigue.•Grade ≥3 TRAEs were infrequent except for treatment-related grade ≥3 neutropenia; discontinuation due to AEs was 8.3%.•AEs with SG parallel those of chemotherapy and can be managed with proactive intervention per established guidelines.•Objective response rates, coupled with disease control, are apparent across small disease cohorts, warranting further study.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Digital contact tracing is a relevant tool to control infectious disease outbreaks, including the COVID-19 epidemic. Early work evaluating digital contact tracing omitted important features and ...heterogeneities of real-world contact patterns influencing contagion dynamics. We fill this gap with a modeling framework informed by empirical high-resolution contact data to analyze the impact of digital contact tracing in the COVID-19 pandemic. We investigate how well contact tracing apps, coupled with the quarantine of identified contacts, can mitigate the spread in real environments. We find that restrictive policies are more effective in containing the epidemic but come at the cost of unnecessary large-scale quarantines. Policy evaluation through their efficiency and cost results in optimized solutions which only consider contacts longer than 15-20 minutes and closer than 2-3 meters to be at risk. Our results show that isolation and tracing can help control re-emerging outbreaks when some conditions are met: (i) a reduction of the reproductive number through masks and physical distance; (ii) a low-delay isolation of infected individuals; (iii) a high compliance. Finally, we observe the inefficacy of a less privacy-preserving tracing involving second order contacts. Our results may inform digital contact tracing efforts currently being implemented across several countries worldwide.
Advanced recurrent ovarian cancer (ROC) is the leading cause of gynecologic cancer-related death in developed countries and new treatments are needed. Previous studies of immune checkpoint blockade ...showed low objective response rates (ORR) in ROC with no identified predictive biomarker.
This phase II study of pembrolizumab (NCT02674061) examined two patient cohorts with ROC: cohort A received one to three prior lines of treatment with a platinum-free interval (PFI) or treatment-free interval (TFI) between 3 and 12months and cohort B received four to six prior lines with a PFI/TFI of ≥3months. Pembrolizumab 200mg was administered intravenously every 3weeks until cancer progression, toxicity, or completion of 2years. Primary end points were ORR by Response Evaluation Criteria in Solid Tumors version 1.1 per blinded independent central review by cohort and by PD-L1 expression measured as combined positive score (CPS). Secondary end points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.
Cohort A enrolled 285 patients; the first 100 served as the training set for PD-L1 biomarker analysis. Cohort B enrolled 91 patients. ORR was 7.4% for cohort A and 9.9% for cohort B. Median DOR was 8.2months for cohort A and not reached for cohort B. DCR was 37.2% and 37.4%, respectively, in cohorts A and B. Based on the training set analysis, CPS 1 and 10 were selected for evaluation in the confirmation set. In the confirmation set, ORR was 4.1% for CPS<1, 5.7% CPS ≥1, and 10.0% for CPS ≥10. PFS was 2.1months for both cohorts. Median OS was not reached for cohort A and was 17.6months for cohort B. Toxicities were consistent with other single-agent pembrolizumab trials.
Single-agent pembrolizumab showed modest activity in patients with ROC. Higher PD-L1 expression was correlated with higher response.
Clinicaltrials.gov, NCT02674061
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Anyons occur in two-dimensional electron systems as excitations with fractional charge in the topologically ordered states of the fractional quantum Hall effect (FQHE). Their dynamics are of utmost ...importance for topological quantum phases and possible decoherence-free quantum information approaches, but observing these dynamics experimentally is challenging. Here, we report on a dynamical property of anyons: the long-predicted Josephson relation
=
*
/
for charges
* =
/3 and
/5, where
is the charge of the electron and
is Planck's constant. The relation manifests itself as marked signatures in the dependence of photo-assisted shot noise (PASN) on voltage
when irradiating contacts at microwaves frequency
The validation of FQHE PASN models indicates a path toward realizing time-resolved anyon sources based on levitons.
Revisiting Proxima with ESPRESSO Suárez Mascareño, A.; Faria, J. P.; Figueira, P. ...
Astronomy and astrophysics (Berlin),
07/2020, Volume:
639
Journal Article
Peer reviewed
Open access
Context.
The discovery of Proxima b marked one of the most important milestones in exoplanetary science in recent years. Yet the limited precision of the available radial velocity data and the ...difficulty in modelling the stellar activity calls for a confirmation of the Earth-mass planet.
Aims.
We aim to confirm the presence of Proxima b using independent measurements obtained with the new ESPRESSO spectrograph, and refine the planetary parameters taking advantage of its improved precision.
Methods.
We analysed 63 spectroscopic ESPRESSO observations of Proxima (Gl 551) taken during 2019. We obtained radial velocity measurements with a typical radial velocity photon noise of 26 cm s
−1
. We combined these data with archival spectroscopic observations and newly obtained photometric measurements to model the stellar activity signals and disentangle them from planetary signals in the radial velocity (RV) data. We ran a joint Markov chain Monte Carlo analysis on the time series of the RV and full width half maximum of the cross-correlation function to model the planetary and stellar signals present in the data, applying Gaussian process regression to deal with the stellar activity signals.
Results.
We confirm the presence of Proxima b independently in the ESPRESSO data and in the combined ESPRESSO+ HARPS+UVES dataset. The ESPRESSO data on its own shows Proxima b at a period of 11.218 ± 0.029 days, with a minimum mass of 1.29 ± 0.13
M
⊕
. In the combined dataset we measure a period of 11.18427 ± 0.00070 days with a minimum mass of 1.173 ± 0.086
M
⊕
. We get a clear measurement of the stellar rotation period (87 ± 12 d) and its induced RV signal, but no evidence of stellar activity as a potential cause for the 11.2 days signal. We find some evidence for the presence of a second short-period signal, at 5.15 days with a semi-amplitude of only 40 cm s
−1
. If caused by a planetary companion, it would correspond to a minimum mass of 0.29 ± 0.08
M
⊕
. We find that forthe case of Proxima, the full width half maximum of the cross-correlation function can be used as a proxy for the brightness changes and that its gradient with time can be used to successfully detrend the RV data from part of the influence of stellar activity. The activity-induced RV signal in the ESPRESSO data shows a trend in amplitude towards redder wavelengths. Velocities measured using the red end of the spectrograph are less affected by activity, suggesting that the stellar activity is spot dominated. This could be used to create differential RVs that are activity dominated and can be used to disentangle activity-induced and planetary-induced signals. The data collected excludes the presence of extra companions with masses above 0.6
M
⊕
at periods shorter than 50 days.
Full text
Available for:
FMFMET, NUK, UL, UM, UPUK
Context.
The bright star
π
Men was chosen as the first target for a radial velocity follow-up to test the performance of ESPRESSO, the new high-resolution spectrograph at the European Southern ...Observatory’s Very Large Telescope. The star hosts a multi-planet system (a transiting 4
M
⊕
planet at ~0.07 au and a sub-stellar companion on a ~2100-day eccentric orbit), which is particularly suitable for a precise multi-technique characterization.
Aims.
With the new ESPRESSO observations, which cover a time span of 200 days, we aim to improve the precision and accuracy of the planet parameters and search for additional low-mass companions. We also take advantage of the new photometric transits of
π
Men c observed by TESS over a time span that overlaps with that of the ESPRESSO follow-up campaign.
Methods.
We analysed the enlarged spectroscopic and photometric datasets and compared the results to those in the literature. We further characterized the system by means of absolute astrometry with H
IPPARCOS
and
Gaia
. We used the high-resolution spectra of ESPRESSO for an independent determination of the stellar fundamental parameters.
Results.
We present a precise characterization of the planetary system around
π
Men. The ESPRESSO radial velocities alone (37 nightly binned data with typical uncertainty of 10 cm s
−1
) allow for a precise retrieval of the Doppler signal induced by
π
Men c. The residuals show a root mean square of 1.2 m s
−1
, which is half that of the HARPS data; based on the residuals, we put limits on the presence of additional low-mass planets (e.g. we can exclude companions with a minimum mass less than ~2
M
⊕
within the orbit of
π
Men c). We improve the ephemeris of
π
Men c using 18 additional TESS transits, and, in combination with the astrometric measurements, we determine the inclination of the orbital plane of
π
Men b with high precision (
i
b
=45.8
−1.1
+1.4
deg). This leads to the precise measurement of its absolute mass
m
b
=14.1
−0.4
+0.5
M
Jup
, indicating that
π
Men b can be classified as a brown dwarf.
Conclusions.
The
π
Men system represents a nice example of the extreme precision radial velocities that can be obtained with ESPRESSO for bright targets. Our determination of the 3D architecture of the
π
Men planetary system and the high relative misalignment of the planetary orbital planes put constraints on and challenge the theories of the formation and dynamical evolution of planetary systems. The accurate measurement of the mass of
π
Men b contributes to make the brown dwarf desert a bit greener.
Full text
Available for:
FMFMET, NUK, UL, UM, UPUK
PDF
