Biodegradable PEG-poly(ω-pentadecalactone- co - p -dioxanone) nanoparticles for enhanced and sustained drug delivery to treat brain tumors

Intracranial delivery of therapeutic agents is limited by penetration beyond the blood-brain barrier (BBB) and rapid metabolism of the drugs that are delivered. Convection-enhanced delivery (CED) of drugloaded nanoparticles (NPs) provides for local administration, control of distribution, and sustained drug release. While some investigators have shown that repeated CED procedures are possible, longer periods of sustained release could eliminate the need for repeated infusions, which would enhance safety and translatability of the approach. Here, we demonstrate that nanoparticles formed from poly(ethylene glycol)-poly(u-pentadecalactone-co-p-dioxanone) block copolymers [PEG-poly(PDL-co- DO)] are highly efficient nanocarriers that provide long-term release: small nanoparticles (less than 100 nm in diameter) continuously released a radiosensitizer (VE822) over a period of several weeks in vitro, provided widespread intracranial drug distribution during CED, and yielded significant drug retention within the brain for over 1 week. One advantage of PEG-poly(PDL-co-DO) nanoparticles is that hydrophobicity can be tuned by adjusting the ratio of hydrophobic PDL to hydrophilic DO monomers, thus making it possible to achieve a wide range of drug release rates and drug distribution profiles. When administered by CED to rats with intracranial RG2 tumors, and combined with a 5-day course of fractionated radiation therapy, VE822-loaded PEG-poly(PDL-co-DO) NPs significantly prolonged survival when compared to free VE822. Thus, PEG-poly(PDL-co-DO) NPs represent a new type of versatile nanocarrier system with potential for sustained intracranial delivery of therapeutic agents to treat brain tumors

Tropospheric Ozone Assessment Report : Present-day ozone distribution and trends relevant to human health

This study quantifies the present-day global and regional distributions (2010–2014) and trends (2000–2014) for five ozone metrics relevant for short-term and long-term human exposure. These metrics, calculated by the Tropospheric Ozone Assessment Report, are: 4th highest daily maximum 8-hour ozone (4MDA8); number of days with MDA8 > 70 ppb (NDGT70), SOMO35 (annual Sum of Ozone Means Over 35 ppb) and two seasonally averaged metrics (3MMDA1; AVGMDA8). These metrics were explored at ozone monitoring sites worldwide, which were classified as urban or non-urban based on population and nighttime lights data.Present-day distributions of 4MDA8 and NDGT70, determined predominantly by peak values, are similar with highest levels in western North America, southern Europe and East Asia. For the other three metrics, distributions are similar with North–South gradients more prominent across Europe and Japan. Between 2000 and 2014, significant negative trends in 4MDA8 and NDGT70 occur at most US and some European sites. In contrast, significant positive trends are found at many sites in South Korea and Hong Kong, with mixed trends across Japan. The other three metrics have similar, negative trends for many non-urban North American and some European and Japanese sites, and positive trends across much of East Asia. Globally, metrics at many sites exhibit non-significant trends. At 59% of all sites there is a common direction and significance in the trend across all five metrics, whilst 4MDA8 and NDGT70 have a common trend at ~80% of all sites. Sensitivity analysis shows AVGMDA8 trends differ with averaging period (warm season or annual). Trends are unchanged at many sites when a 1995–2014 period is used; although fewer sites exhibit non-significant trends. Over the longer period 1970–2014, most Japanese sites exhibit positive 4MDA8/SOMO35 trends. Insufficient data exist to characterize ozone trends for the rest of Asia and other world regions

Linker-extended native cyanovirin-N facilitates PEGylation and potently inhibits HIV-1 by targeting the glycan ligand

Cyanovirin-N (CVN) potently inhibits human immunodeficiency virus type 1 (HIV-1) infection, but both cytotoxicity and immunogenicity have hindered the translation of this protein into a viable therapeutic. A molecular docking analysis suggested that up to 12 residues were involved in the interaction of the reverse parallel CVN dimer with the oligosaccharide targets, among which Leu-1 was the most prominent hot spot residue. This finding provided a possible explanation for the lack of anti-HIV-1 activity observed with N-terminal PEGylated CVN. Therefore, linker-CVN (LCVN) was designed as a CVN derivative with a flexible and hydrophilic linker (Gly4Ser)3 at the N-terminus. The N-terminal α-amine of LCVN was PEGylated to create 10 K PEG-aldehyde (ALD)-LCVN. LCVN and 10 K PEG-ALD-LCVN retained the specificity and affinity of CVN for high mannose N-glycans. Moreover, LCVN exhibited significant anti-HIV-1 activity with attenuated cytotoxicity in the HaCaT keratinocyte cell line and MT-4 T lymphocyte cell lines. 10 K PEG-ALD-LCVN also efficiently inactivated HIV-1 with remarkably decreased cytotoxicity and pronounced cell-to-cell fusion inhibitory activity in vitro. The linker-extended CVN and the mono-PEGylated derivative were determined to be promising candidates for the development of an anti-HIV-1 agent. This derivatization approach provided a model for the PEGylation of biologic candidates without introducing point mutations. © 2014 Chen et al

Tropospheric Ozone Assessment Report: present-day tropospheric ozone distribution and trends relevant to vegetation

This Tropospheric Ozone Assessment Report (TOAR) on the current state of knowledge of ozone metrics of relevance to vegetation (TOAR-Vegetation) reports on present-day global distribution of ozone at over 3300 vegetated sites and the long-term trends at nearly 1200 sites. TOAR-Vegetation focusses on three metrics over vegetation-relevant time-periods across major world climatic zones: M12, the mean ozone during 08:00–19:59; AOT40, the accumulation of hourly mean ozone values over 40 ppb during daylight hours, and W126 with stronger weighting to higher hourly mean values, accumulated during 08:00–19:59. Although the density of measurement stations is highly variable across regions, in general, the highest ozone values (mean, 2010–14) are in mid-latitudes of the northern hemisphere, including southern USA, the Mediterranean basin, northern India, north, north-west and east China, the Republic of Korea and Japan. The lowest metric values reported are in Australia, New Zealand, southern parts of South America and some northern parts of Europe, Canada and the USA. Regional-scale assessments showed, for example, significantly higher AOT40 and W126 values in East Asia (EAS) than Europe (EUR) in wheat growing areas (p < 0.05), but not in rice growing areas. In NAM, the dominant trend during 1995–2014 was a significant decrease in ozone, whilst in EUR it was no change and in EAS it was a significant increase. TOAR-Vegetation provides recommendations to facilitate a more complete global assessment of ozone impacts on vegetation in the future, including: an increase in monitoring of ozone and collation of field evidence of the damaging effects on vegetation; an investigation of the effects on peri-urban agriculture and in mountain/upland areas; inclusion of additional pollutant, meteorological and inlet height data in the TOAR dataset; where not already in existence, establishing new region-specific thresholds for vegetation damage and an innovative integration of observations and modelling including stomatal uptake of the pollutant

Search for a new scalar resonance decaying to a pair of Z bosons in proton-proton collisions at √s=13 TeV

A search for a new scalar resonance decaying to a pair of Z bosons is performed in the mass range from 130 GeV to 3 TeV, and for various width scenarios. The analysis is based on proton-proton collisions recorded by the CMS experiment at the LHC in 2016, corresponding to an integrated luminosity of 35.9 fb⁻¹ at a center-of-mass energy of 13 TeV. The Z boson pair decays are reconstructed using the 4ℓ, 2ℓ2q, and 2ℓ2ν final states, where ℓ = e or μ. Both gluon fusion and electroweak production of the scalar resonance are considered, with a free parameter describing their relative cross sections. A dedicated categorization of events, based on the kinematic properties of associated jets, and matrix element techniques are employed for an optimal signal and background separation. A description of the interference between signal and background amplitudes for a resonance of an arbitrary width is included. No significant excess of events with respect to the standard model expectation is observed and limits are set on the product of the cross section for a new scalar boson and the branching fraction for its decay to ZZ for a large range of masses and widths. Keywords: Hadron-Hadron scattering (experiments); Higgs physic

Search for Pair-Produced Resonances Decaying to Quark Pairs in Proton-Proton Collisions at √s = 13 TeV

A general search for the pair production of resonances, each decaying to two quarks, is reported. The search is conducted separately for heavier resonances (masses above 400 GeV), where each of the four final-state quarks generates a hadronic jet resulting in a four-jet signature, and for lighter resonances (masses between 80 and 400 GeV), where the pair of quarks from each resonance is collimated and reconstructed as a single jet resulting in a two-jet signature. In addition, a b-tagged selection is applied to target resonances with a bottom quark in the final state. The analysis uses data collected with the CMS detector at the CERN LHC, corresponding to an integrated luminosity of 35.9  fb⁻¹, from proton-proton collisions at a center-of-mass energy of 13 TeV. The mass spectra are analyzed for the presence of new resonances, and are found to be consistent with standard model expectations. The results are interpreted in the framework of R-parity-violating supersymmetry assuming the pair production of scalar top quarks decaying via the hadronic coupling λ′′312 or λ′′323 and upper limits on the cross section as a function of the top squark mass are set. These results probe a wider range of masses than previously explored at the LHC, and extend the top squark mass limits in the ˜t→qq′ scenario

Green Pathways for the Enzymatic Synthesis of Furan-Based Polyesters and Polyamides

The attention towards the utilization of sustainable feedstocks for polymer synthesis has grown exponentially in recent years. One of the spotlighted monomers derived from renewable resources is 2,5-furandicarboxylic acid (FDCA), one of the most promising bio-based monomers, due to its resemblance to petroleum-based terephthalic acid. Very interesting synthetic routes using this monomer have been reported in the last two decades. Combining the use of bio-based monomers and non-toxic chemicals via enzymatic polymerizations can lead to a robust and favorable approach towards a greener technology of bio-based polymer production. In this chapter, a brief introduction to FDCA-based monomers and enzymatic polymerizations is given, particularly focusing on furan-based polymers and their polymerization. In addition, an outline of the recent developments in the field of enzymatic polymerizations is discussed. </p

Search for resonances in the mass spectrum of muon pairs produced in association with b quark jets in proton-proton collisions at root 8 and 13 TeV

A search for resonances in the mass range 12-70 GeV produced in association with a b quark jet and a second jet, and decaying to a muon pair, is reported. The analysis is based on data from proton-proton collisions at center-of-mass energies of 8 and 13 TeV, collected with the CMS detector at the LHC and corresponding to integrated luminosities of 19.7 and 35.9 fb(-1), respectively. The search is carried out in two mutually exclusive event categories. Events in the first category are required to have a b quark jet in the central region (|| 2.4) and at least one jet in the forward region (|| > 2.4). Events in the second category are required to have two jets in the central region, at least one of which is identified as a b quark jet, no jets in the forward region, and low missing transverse momentum. An excess of events above the background near a dimuon mass of 28 GeV is observed in the 8 TeV data, corresponding to local significances of 4.2 and 2.9 standard deviations for the first and second event categories, respectively. A similar analysis conducted with the 13 TeV data results in a mild excess over the background in the first event category corresponding to a local significance of 2.0 standard deviations, while the second category results in a 1.4 standard deviation deficit. The fiducial cross section measurements and 95% confidence level upper limits on those for a resonance consistent with the 8 TeV excess are provided at both collision energies

Combination therapy with oral treprostinil for pulmonary arterial hypertension. A double-blind placebo-controlled clinical trial

Rationale: Oral treprostinil improves exercise capacity in patients with pulmonary arterial hypertension (PAH), but the effect on clinical outcomes was unknown. Objectives: To evaluate the effect of oral treprostinil compared with placebo on time to first adjudicated clinical worsening event in participants with PAH who recently began approved oral monotherapy. Methods: In this event-driven, double-blind study, we randomly allocated 690 participants (1:1 ratio) with PAH to receive placebo or oral treprostinil extended-release tablets three times daily. Eligible participants were using approved oral monotherapy for over 30 days before randomization and had a 6-minute-walk distance 150 m or greater. The primary endpoint was the time to first adjudicated clinical worsening event: death; hospitalization due to worsening PAH; initiation of inhaled or parenteral prostacyclin therapy; disease progression; or unsatisfactory long-term clinical response. Measurements and Main Results: Clinical worsening occurred in 26% of the oral treprostinil group compared with 36% of placebo participants (hazard ratio, 0.74; 95% confidence interval, 0.56–0.97; P = 0.028). Key measures of disease status, including functional class, Borg dyspnea score, and N-terminal pro–brain natriuretic peptide, all favored oral treprostinil treatment at Week 24 and beyond. A noninvasive risk stratification analysis demonstrated that oral treprostinil–assigned participants had a substantially higher mortality risk at baseline but achieved a lower risk profile from Study Weeks 12–60. The most common adverse events in the oral treprostinil group were headache, diarrhea, flushing, nausea, and vomiting. Conclusions: In participants with PAH, addition of oral treprostinil to approved oral monotherapy reduced the risk of clinical worsening. Clinical trial registered with www.clinicaltrials.gov (NCT01560624)