Despite the completion of numerous phase II studies, a standard of care treatment has yet to be defined for metastatic uveal melanoma (mUM). To determine benchmarks of progression free survival (PFS) ...and overall survival (OS), we carried out a meta-analysis using individual patient level trial data.
Individual patient variables and survival outcomes were requested from 29 trials published from 2000 to 2016. Univariable and multivariable analysis were carried out for prognostic factors. The variability between trial arms and between therapeutic agents on PFS and OS was investigated.
OS data were available for 912 patients. The median PFS was 3.3months (95% CI 2.9–3.6) and 6-month PFS rate was 27% (95% CI 24–30). Univariable analysis showed male sex, elevated (i.e. > versus ≤ upper limit of normal) lactate dehydrogenase (LDH), elevated alkaline phosphatase (ALP) and diameter of the largest liver metastasis (≥3cm versus <3cm) to be substantially associated with shorter PFS. Multivariable analysis showed male sex, elevated LDH and elevated ALP were substantially associated with shorter PFS. The most substantial factors associated with 6-month PFS rate, on both univariable and multivariable analysis were elevated LDH and ALP. The median OS was 10.2months (95% CI 9.5–11.0) and 1year OS was 43% (95% CI 40–47). The most substantial prognostic factors for shorter OS by univariable and multivariable analysis were elevated LDH and elevated ALP. Patients treated with liver directed treatments had statistically significant longer PFS and OS.
Benchmarks of 6-month PFS and 1-year OS rates were determined accounting for prognostic factors. These may be used to facilitate future trial design and stratification in mUM.
Purpose In this work, we tested the hypothesis that microneedles provide a minimally invasive method to inject particles into the suprachoroidal space for drug delivery to the back of the eye. ...Methods A single, hollow microneedle was inserted into the sclera, and infused nanoparticle and microparticle suspensions into the suprachoroidal space. Experiments were performed on whole rabbit, pig, and human eyes ex vivo. Particle delivery was imaged using brightfield and fluorescence microscopy as well as microcomputed tomography. Results Microneedles were shown to deliver sulforhodamine B as well as nanoparticle and microparticle suspensions into the suprachoroidal space of rabbit, pig, and human eyes. Volumes up to 35 μL were administered consistently. Optimization of the delivery device parameters showed that microneedle length, pressure, and particle size played an important role in determining successful delivery into the suprachoroidal space. Needle lengths of 800-1,000 μm and applied pressures of 250-300 kPa provided most reliable delivery. Conclusions Microneedles were shown for the first time to deliver nanoparticle and microparticle suspensions into the suprachoroidal space of rabbit, pig and human eyes. This shows that microneedles may provide a minimally invasive method for controlled drug delivery to the back of the eye.
Patients with chronic heart failure and a reduced ejection fraction were randomly assigned to the soluble guanylate cyclase stimulator vericiguat or placebo, in addition to guideline-based medical ...therapy. The incidence of death from cardiovascular causes or first hospitalization for heart failure was lower among patients who received vericiguat.
Inertial confinement fusion (ICF) has existed as a field of study since the 1970s, but the field was born out of the Cold War. In the decades since the 1960s, pioneering research developing the ...principles and technologies of ICF has culminated in the creation of three major Department of Energy facilities that still exist today: the National Ignition Facility (NIF) at Lawrence Livermore National Laboratory, the OMEGA laser at the Laboratory for Laser Energetics, and the Z pulsed power facility at Sandia National Laboratories. While the technology of ICF facilities themselves is interesting, this review concentrates upon the physics principles of the targets fielded on U.S. ICF facilities and upon results from the last decade of research. While there have been periods of frustration on the road to ICF ignition, recent research has demonstrated great leaps in understanding what aspects of the implosions need more control. Tangible progress in ICF is evident as burning plasmas and ignited plasmas have recently been generated, repeatedly, on the NIF stemming from decades of science and engineering understanding generated from work at the three previously mentioned facilities and in the international community.
Endocannabinoids are released 'on-demand' on the basis of physiological need, and can be pharmacologically augmented by inhibiting their catabolic degradation. The endocannabinoid anandamide is ...degraded by the catabolic enzyme fatty acid amide hydrolase (FAAH). Anandamide is implicated in the mediation of fear behaviors, including fear extinction, suggesting that selectively elevating brain anandamide could modulate plastic changes in fear. Here we first tested this hypothesis with preclinical experiments employing a novel, potent and selective FAAH inhibitor, AM3506 (5-(4-hydroxyphenyl)pentanesulfonyl fluoride). Systemic AM3506 administration before extinction decreased fear during a retrieval test in a mouse model of impaired extinction. AM3506 had no effects on fear in the absence of extinction training, or on various non-fear-related measures. Anandamide levels in the basolateral amygdala were increased by extinction training and augmented by systemic AM3506, whereas application of AM3506 to amygdala slices promoted long-term depression of inhibitory transmission, a form of synaptic plasticity linked to extinction. Further supporting the amygdala as effect-locus, the fear-reducing effects of systemic AM3506 were blocked by intra-amygdala infusion of a CB1 receptor antagonist and were fully recapitulated by intra-amygdala infusion of AM3506. On the basis of these preclinical findings, we hypothesized that variation in the human FAAH gene would predict individual differences in amygdala threat-processing and stress-coping traits. Consistent with this, carriers of a low-expressing FAAH variant (385A allele; rs324420) exhibited quicker habituation of amygdala reactivity to threat, and had lower scores on the personality trait of stress-reactivity. Our findings show that augmenting amygdala anandamide enables extinction-driven reductions in fear in mouse and may promote stress-coping in humans.
ABSTRACT We report on radio and X-ray observations of the only known repeating Fast Radio Burst (FRB) source, FRB 121102. We have detected six additional radio bursts from this source: five with the ...Green Bank Telescope at 2 GHz, and one at 1.4 GHz with the Arecibo Observatory, for a total of 17 bursts from this source. All have dispersion measures consistent with a single value (∼559 pc cm−3) that is three times the predicted maximum Galactic contribution. The 2 GHz bursts have highly variable spectra like those at 1.4 GHz, indicating that the frequency structure seen across the individual 1.4 and 2 GHz bandpasses is part of a wideband process. X-ray observations of the FRB 121102 field with the Swift and Chandra observatories show at least one possible counterpart; however, the probability of chance superposition is high. A radio imaging observation of the field with the Jansky Very Large Array at 1.6 GHz yields a 5 upper limit of 0.3 mJy on any point-source continuum emission. This upper limit, combined with archival Wide-field Infrared Survey Explorer 22 m and IPHAS H surveys, rules out the presence of an intervening Galactic H ii region. We update our estimate of the FRB detection rate in the PALFA survey to be FRBs sky−1 day−1 (95% confidence) for peak flux density at 1.4 GHz above 300 mJy. We find that the intrinsic widths of the 12 FRB 121102 bursts from Arecibo are, on average, significantly longer than the intrinsic widths of the 13 single-component FRBs detected with the Parkes telescope.
Quinazolines are an important class of heterocyclic compounds that have proven their significance, especially in the field of organic synthesis and medicinal chemistry because of their wide range of ...biological and pharmacological properties. Thus, numerous synthetic methods have been developed for the synthesis of quinazolines and their derivatives. This review article briefly outlines the new synthetic methods for compounds containing the quinazoline scaffold employing transition metal-catalyzed reactions.
A series of pyrazolo(dihydro)pyridines was synthesized and evaluated for antileishmanial efficacy against experimental visceral leishmaniasis (VL). Among all compounds, 6d and 6j exhibited better ...activity than miltefosine against intracellular amastigotes. Compound 6j (50 mg/kg/day) was further studied against Leishmania donovani/BALB/c mice via the intraperitoneal route for 5 days and displayed >91 and >93% clearance of splenic and liver parasitic burden, respectively. Combination treatment of 6j with a subcurative dose of miltefosine (5 mg/kg) in BALB/c mice almost completely ameliorated the disease (>97% inhibition) by augmenting nitric oxide generation and shifting the immune response toward Th1. Furthermore, investigating the effect of 6j on Leishmania promastigotes revealed that it induced molecular events, such as a loss in mitochondrial membrane potential, externalization of phosphatidylserine, and DNA fragmentation, that ultimately resulted in the programmed cell death of the parasite. These results along with pharmacokinetic studies suggest that 6j could be a promising lead for treating VL as an adjunct therapy with miltefosine.
Atovaquone belongs to a naphthoquinone class of drugs and is used in combination with proguanil (Malarone) for the treatment of acute, uncomplicated malaria caused by Plasmodium falciparum (including ...chloroquine-resistant P. falciparum/P. vivax). Numerous quinone-derived compounds have attracted considerable attention in the last few decades due to their potential in antimalarial drug discovery. Several semi-synthetic derivatives of natural quinones, synthetic quinones (naphtho-/benzo-quinone, anthraquinones, thiazinoquinones), and quinone-based hybrids were explored for their in vitro and in vivo antimalarial activities. A careful literature survey revealed that this topic has not been compiled as a review article so far. Therefore, we herein summarise the recent discovery (the year 2009–2020) of quinone based antimalarial compounds in chronological order. This compilation would be very useful towards the exploration of novel quinone-derived compounds against malarial parasites with promising efficacy and lesser side effects.
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•Quinone derivatives exhibit potent antimalarial activities against drug-sensitive and MDR-resistant P. falciparum strains.•This review covers the recent studies of in vitro and in vivo antimalarial activity (2009-2020) of quinone-based compounds.•This describes structural modifications at specified positions on quinones and their impact on antimalarial activity.•Toxicity and bioavailability issues suffered by quinones need to be addressed for the development of effective drugs.
A blind, randomised, prospective, bilateral study to investigate the efficacy of riboflavin/ultraviolet A corneal collagen cross-linkage to halt the progression of keratoconus.
24 patients with ...early/moderate bilateral keratoconus with recent progression were recruited. One eye was randomly assigned to undergo collagen cross-linkage following epithelial removal with riboflavin 0.1% and ultraviolet A (370 nm at 3 mW/cm(2)). The other remained untreated as a control. The follow-up was 18 months in 22 patients.
At 18 months, Orbscan II 3 mm, 5 mm keratometry and simulated astigmatism and cone apex power and wave-front measurements (Keraton Scout), including root mean square, coma and pentafoil showed significant reductions from baseline in treated compared with untreated eyes (p=0.04). In treated eyes at 18 months, the best spectacle-corrected acuity improved (p=0.01), and Orbscan II-simulated keratometry (p<0.001), 3 mm keratometry (p=0.008), simulated astigmatism (p=0.007), cone apex power (p=0.002), root mean square, coma, spherical aberration, secondary astigmatism and pentafoil (p=0.05) decreased from baseline. One treated eye experienced transient recurrent corneal erosions; otherwise there were no complications attributable to the treatment.
Corneal collagen cross-linkage appears to be an effective and safe modality to halt the progression of keratoconus. Improvements in visual and topographic parameters are seen in some eyes.
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