61 research outputs found
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Nivolumab plus ipilimumab in the treatment of advanced melanoma.
Advanced melanoma has historically been a difficult disease to treat due to few effective systemic treatment options. However, over the past few years, scientific advancements in immune checkpoint inhibition have resulted in several novel approaches that have changed front-line management of advanced melanoma. Despite these exciting developments, there remains room for improvement in treatment outcomes. Combination immunotherapy, in particular combined cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) blockade, represents an important first step in this direction
Phase II Trial of IL-12 Plasmid Transfection and PD-1 Blockade in Immunologically Quiescent Melanoma.
PurposeTumors with low frequencies of checkpoint positive tumor-infiltrating lymphocytes (cpTIL) have a low likelihood of response to PD-1 blockade. We conducted a prospective multicenter phase II trial of intratumoral plasmid IL-12 (tavokinogene telseplasmid; "tavo") electroporation combined with pembrolizumab in patients with advanced melanoma with low frequencies of checkpoint positive cytotoxic lymphocytes (cpCTL).Patients and methodsTavo was administered intratumorally days 1, 5, and 8 every 6 weeks while pembrolizumab (200 mg, i.v.) was administered every 3 weeks. The primary endpoint was objective response rate (ORR) by RECIST, secondary endpoints included duration of response, overall survival and progression-free survival. Toxicity was evaluated by the CTCAE v4. Extensive correlative analysis was done.ResultsThe combination of tavo and pembrolizumab was well tolerated with adverse events similar to those previously reported with pembrolizumab alone. Patients had a 41% ORR (n = 22, RECIST 1.1) with 36% complete responses. Correlative analysis showed that the combination enhanced immune infiltration and sustained the IL-12/IFNγ feed-forward cycle, driving intratumoral cross-presenting dendritic cell subsets with increased TILs, emerging T cell receptor clones and, ultimately, systemic cellular immune responses.ConclusionsThe combination of tavo and pembrolizumab was associated with a higher than expected response rate in this poorly immunogenic population. No new or unexpected toxicities were observed. Correlative analysis showed T cell infiltration with enhanced immunity paralleling the clinical activity in low cpCTL tumors
Nivolumab plus ipilimumab in the treatment of advanced melanoma
Advanced melanoma has historically been a difficult disease to treat due to few effective systemic treatment options. However, over the past few years, scientific advancements in immune checkpoint inhibition have resulted in several novel approaches that have changed front-line management of advanced melanoma. Despite these exciting developments, there remains room for improvement in treatment outcomes. Combination immunotherapy, in particular combined cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) blockade, represents an important first step in this direction
Research into the efficacy and cost-effectiveness of brief, free of charge and anonymous sex counselling to improve (mental) health in youth: Design of a randomised controlled trial
<p>Abstract</p> <p>Background</p> <p>The capacity to form romantic relationships and sexual health of adolescents in the Netherlands are compromised by several factors, including young age of first intercourse and adolescent depression. Several thresholds like own expenses, trust and embarrassment prevent adolescents to seek help for their sexual problems. To overcome these thresholds, brief sex counselling has been developed. It has been used since 2006 within the Rotterdam-Rijnmond Public Health Service, but there is lack of information about the (cost-) effectiveness. In the current study we will evaluate the (cost-) effectiveness of brief sex counselling for sexual problems in adolescents and young adults between 18 and 25 years of age.</p> <p>Methods</p> <p>In a randomised controlled trial we will compare (1) brief sex counselling with (2) intensive sexological treatment, and (3) delayed treatment (waiting list). Embedded in this RCT will be a trial-based economic evaluation, looking at the cost-effectiveness and cost-utility of brief sex counselling versus the two other interventions. Four hundred fifty adolescents (aged 18-25) with sexual problems will be recruited among the persons who visit the Public Health Service (PHS) and through various websites. After a screening procedure, eligible participants will be randomly allocated to one of the three intervention groups. Primary outcome measure of the clinical evaluation is the severity of sexual problems. Other outcomes include psychological distress, especially depression. The economic evaluation will be performed from a societal perspective. Costs will be assessed continuously by a retrospective questionnaire covering the last 3 month. All outcome assessments (including those for the economic evaluation) will take place via the internet at baseline, and at 3, 6, 9, and 12 months after baseline.</p> <p>Discussion</p> <p>The proposed research project will be the first study to provide preliminary data about the effect and cost-effectiveness of brief sex counselling in youth in comparison with intensive sexological treatment and delayed treatment. It is anticipated that positive results in (cost-) effectiveness of the proposed intervention will contribute to the improvement of sexual health care for adolescents and young adults.</p> <p>Trial registration</p> <p>The study has been registered at the Netherlands Trial Register, part of the Dutch Cochrane Centre (NTR1952)</p
Early Release Science of the Exoplanet WASP-39b with JWST NIRSpec G395H
Measuring the abundances of carbon and oxygen in exoplanet atmospheres is
considered a crucial avenue for unlocking the formation and evolution of
exoplanetary systems. Access to an exoplanet's chemical inventory requires
high-precision observations, often inferred from individual molecular
detections with low-resolution space-based and high-resolution ground-based
facilities. Here we report the medium-resolution (R600) transmission
spectrum of an exoplanet atmosphere between 3-5 m covering multiple
absorption features for the Saturn-mass exoplanet WASP-39b, obtained with JWST
NIRSpec G395H. Our observations achieve 1.46x photon precision, providing an
average transit depth uncertainty of 221 ppm per spectroscopic bin, and present
minimal impacts from systematic effects. We detect significant absorption from
CO (28.5) and HO (21.5), and identify SO as the
source of absorption at 4.1 m (4.8). Best-fit atmospheric models
range between 3 and 10x solar metallicity, with sub-solar to solar C/O ratios.
These results, including the detection of SO, underscore the importance of
characterising the chemistry in exoplanet atmospheres, and showcase NIRSpec
G395H as an excellent mode for time series observations over this critical
wavelength range.Comment: 44 pages, 11 figures, 3 tables. Resubmitted after revision to Natur
Early Release Science of the exoplanet WASP-39b with JWST NIRCam
Measuring the metallicity and carbon-to-oxygen (C/O) ratio in exoplanet
atmospheres is a fundamental step towards constraining the dominant chemical
processes at work and, if in equilibrium, revealing planet formation histories.
Transmission spectroscopy provides the necessary means by constraining the
abundances of oxygen- and carbon-bearing species; however, this requires broad
wavelength coverage, moderate spectral resolution, and high precision that,
together, are not achievable with previous observatories. Now that JWST has
commenced science operations, we are able to observe exoplanets at previously
uncharted wavelengths and spectral resolutions. Here we report time-series
observations of the transiting exoplanet WASP-39b using JWST's Near InfraRed
Camera (NIRCam). The long-wavelength spectroscopic and short-wavelength
photometric light curves span 2.0 - 4.0 m, exhibit minimal systematics,
and reveal well-defined molecular absorption features in the planet's spectrum.
Specifically, we detect gaseous HO in the atmosphere and place an upper
limit on the abundance of CH. The otherwise prominent CO feature at 2.8
m is largely masked by HO. The best-fit chemical equilibrium models
favour an atmospheric metallicity of 1-100 solar (i.e., an enrichment
of elements heavier than helium relative to the Sun) and a sub-stellar
carbon-to-oxygen (C/O) ratio. The inferred high metallicity and low C/O ratio
may indicate significant accretion of solid materials during planet formation
or disequilibrium processes in the upper atmosphere.Comment: 35 pages, 13 figures, 3 tables, Nature, accepte
Photochemically-produced SO in the atmosphere of WASP-39b
Photochemistry is a fundamental process of planetary atmospheres that
regulates the atmospheric composition and stability. However, no unambiguous
photochemical products have been detected in exoplanet atmospheres to date.
Recent observations from the JWST Transiting Exoplanet Early Release Science
Program found a spectral absorption feature at 4.05 m arising from SO
in the atmosphere of WASP-39b. WASP-39b is a 1.27-Jupiter-radii, Saturn-mass
(0.28 M) gas giant exoplanet orbiting a Sun-like star with an equilibrium
temperature of 1100 K. The most plausible way of generating SO in
such an atmosphere is through photochemical processes. Here we show that the
SO distribution computed by a suite of photochemical models robustly
explains the 4.05 m spectral feature identified by JWST transmission
observations with NIRSpec PRISM (2.7) and G395H (4.5). SO
is produced by successive oxidation of sulphur radicals freed when hydrogen
sulphide (HS) is destroyed. The sensitivity of the SO feature to the
enrichment of the atmosphere by heavy elements (metallicity) suggests that it
can be used as a tracer of atmospheric properties, with WASP-39b exhibiting an
inferred metallicity of 10 solar. We further point out that
SO also shows observable features at ultraviolet and thermal infrared
wavelengths not available from the existing observations.Comment: 39 pages, 14 figures, accepted to be published in Natur
Photochemically produced SO2 in the atmosphere of WASP-39b
Photochemistry is a fundamental process of planetary atmospheres that regulates the atmospheric composition and stability1. However, no unambiguous photochemical products have been detected in exoplanet atmospheres so far. Recent observations from the JWST Transiting Exoplanet Community Early Release Science Program2,3 found a spectral absorption feature at 4.05 μm arising from sulfur dioxide (SO2) in the atmosphere of WASP-39b. WASP-39b is a 1.27-Jupiter-radii, Saturn-mass (0.28 MJ) gas giant exoplanet orbiting a Sun-like star with an equilibrium temperature of around 1,100 K (ref. 4). The most plausible way of generating SO2 in such an atmosphere is through photochemical processes5,6. Here we show that the SO2 distribution computed by a suite of photochemical models robustly explains the 4.05-μm spectral feature identified by JWST transmission observations7 with NIRSpec PRISM (2.7σ)8 and G395H (4.5σ)9. SO2 is produced by successive oxidation of sulfur radicals freed when hydrogen sulfide (H2S) is destroyed. The sensitivity of the SO2 feature to the enrichment of the atmosphere by heavy elements (metallicity) suggests that it can be used as a tracer of atmospheric properties, with WASP-39b exhibiting an inferred metallicity of about 10× solar. We further point out that SO2 also shows observable features at ultraviolet and thermal infrared wavelengths not available from the existing observations
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