Highlights ► Recent technology advances in DNA vaccines research have led to enhanced immunepotency of this platform. ► In vivo electroporation (EP) has increased DNA antigen delivery upto a 1000 ...fold over naked DNA alone. ► Immune responses and protection from disease challenge with DNA-EP are shown to be comparable or superior to well studied vaccine platforms – viral vectors and live/attenuated/inactivated virus vaccines. ► The prospects for DNA-EP vaccine approach to impact diverse cancer and infectious disease targets are promising.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Millions of individuals have used illicit anabolic-androgenic steroids (AAS), but the long-term cardiovascular associations of these drugs remain incompletely understood.
Using a cross-sectional ...cohort design, we recruited 140 experienced male weightlifters 34 to 54 years of age, comprising 86 men reporting ≥2 years of cumulative lifetime AAS use and 54 nonusing men. Using transthoracic echocardiography and coronary computed tomography angiography, we assessed 3 primary outcome measures: left ventricular (LV) systolic function (left ventricular ejection fraction), LV diastolic function (early relaxation velocity), and coronary atherosclerosis (coronary artery plaque volume).
Compared with nonusers, AAS users demonstrated relatively reduced LV systolic function (mean±SD left ventricular ejection fraction = 52±11% versus 63±8%;
<0.001) and diastolic function (early relaxation velocity = 9.3±2.4 cm/second versus 11.1±2.0 cm/second;
<0.001). Users currently taking AAS at the time of evaluation (N=58) showed significantly reduced LV systolic (left ventricular ejection fraction = 49±10% versus 58±10%;
<0.001) and diastolic function (early relaxation velocity = 8.9±2.4 cm/second versus 10.1±2.4 cm/second;
=0.035) compared with users currently off-drug (N=28). In addition, AAS users demonstrated higher coronary artery plaque volume than nonusers (median interquartile range 3 0, 174 mL
versus 0 0, 69 mL
;
=0.012). Lifetime AAS dose was strongly associated with coronary atherosclerotic burden (increase 95% confidence interval in rank of plaque volume for each 10-year increase in cumulative duration of AAS use: 0.60 SD units 0.16-1.03 SD units;
=0.008).
Long-term AAS use appears to be associated with myocardial dysfunction and accelerated coronary atherosclerosis. These forms of AAS-associated adverse cardiovascular phenotypes may represent a previously underrecognized public-health problem.
•PVC was subjected to hydrothermal carbonization.•Quantitative hydrodechlorination was observed beyond temperatures of ∼235°C.•An array of PAHs and O-functionalized breakdown products was ...detected.•The sorption potential of the hydrochar for organic sorbates proved very low.
Poly(vinyl chloride) (PVC) was subjected to hydrothermal carbonization in subcritical water at 180–260°C. Dehydrochlorination increased with increasing reaction temperature. The release of chlorine was almost quantitative above ∼235°C. The fraction of organic carbon (OC) recovered in the hydrochar decreased with increasing operating temperature from 93% at 180°C to 75% at 250°C. A wide array of polycyclic aromatic hydrocarbons (PAHs) could be detected in the aqueous phase, but their combined concentration amounted to only ∼140μgg−1 PVC-substrate at 240°C. A pathway for the formation of cyclic hydrocarbons and O-functionalized organics was proposed. Chlorinated hydrocarbons including chlorophenols could only be identified at trace levels (low ppb). Polychlorinated dibenzodioxins (PCDDs) and dibenzofurans (PCDFs) could not be detected. The sorption potential of the hydrochar turned out to be very low, in particular for polar organic pollutants. Our results provide strong evidence that hydrothermal carbonization of household organic wastes which can be tied to co-discarded PVC-plastic residues is environmentally sound regarding the formation of toxic organic products. Following these findings, hydrothermal treatment of PVC-waste beyond operating temperatures of ∼235°C to allow complete release of organic chlorine should be further pursued.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Mutations in sunlight-induced melanoma arise from cyclobutane pyrimidine dimers (CPDs), DNA photoproducts that are typically created picoseconds after an ultraviolet (UV) photon is absorbed at ...thymine or cytosine. We found that in melanocytes, CPDs are generated for >3 hours after exposure to UVA, a major component of the radiation in sunlight and in tanning beds. These ``dark CPDs'' constitute the majority of CPDs and include the cytosine-containing CPDs that initiate UV-signature C→T mutations. Dark CPDs arise when UV-induced reactive oxygen and nitrogen species combine to excite an electron in fragments of the pigment melanin. This creates a quantum triplet state that has the energy of a UV photon but induces CPDs by energy transfer to DNA in a radiation-independent manner. Melanin may thus be carcinogenic as well as protective against cancer. These findings also validate the long-standing suggestion that chemically generated excited electronic states are relevant to mammalian biology.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Changes in prostate cancer screening practices in the United States have led to recent declines in overall incidence, but it is unknown whether relaxed screening has led to changes in the incidence ...of advanced and metastatic prostate cancer at diagnosis.
We identified all men diagnosed with prostate cancer in the National Cancer Data Base (2004-2013) at 1089 different health-care facilities in the United States. Joinpoint regressions were used to model annual percentage changes (APCs) in the incidence of prostate cancer based on stage relative to that of 2004.
The annual incidence of metastatic prostate cancer increased from 2007 to 2013 (Joinpoint regression: APC: 7.1%, P<0.05) and in 2013 was 72% more than that of 2004. The incidence of low-risk prostate cancer decreased from years 2007 to 2013 (APC: -9.3%, P<0.05) to 37% less than that of 2004. The greatest increase in metastatic prostate cancer was seen in men aged 55-69 years (92% increase from 2004 to 2013).
Beginning in 2007, the incidence of metastatic prostate cancer has increased especially among men in the age group thought most likely to benefit from definitive treatment for prostate cancer. These data highlight the continued need for nationwide refinements in prostate cancer screening and treatment.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We show that measures of star formation rates (SFRs) for infrared galaxies using either single-band 24 is a subset of m or extinction-corrected Pa alpha luminosities are consistent in the total ...infrared luminosity = L(TIR) ~ 1010 L range. MIPS 24 is a subset of m photometry can yield SFRs accurately from this luminosity upward: SFR(M yr-1) = 7.8 X 10-10 L(24 is a subset of m, L ) from L(TIR) = 5X 109 L to 1011 L and SFR = 7.8 X 10-10 L(24 is a subset of m, L )(7.76 X 10-11 L(24))0.048 for higher L(TIR). For galaxies with L(TIR) >= 1010 L , these new expressions should provide SFRs to within 0.2 dex. For L(TIR) >= 1011 L , we find that the SFR of infrared galaxies is significantly underestimated using extinction-corrected Pa alpha (and presumably using any other optical or near-infrared recombination lines). As a part of this work, we constructed spectral energy distribution templates for eleven luminous and ultraluminous purely star forming infrared galaxies and over the spectral range 0.4 is a subset of m to 30 cm. We use these templates and the SINGS data to construct average templates from 5 is a subset of m to 30 cm for infrared galaxies with L(TIR) = 5X 109 to 1013 L . All of these templates are made available online.
Of several dozen galaxies observed spectroscopically that are candidates for having a redshift (z) in excess of seven, only five have had their redshifts confirmed via Lyman α emission, at z = 7.008, ...7.045, 7.109, 7.213 and 7.215 (refs 1-4). The small fraction of confirmed galaxies may indicate that the neutral fraction in the intergalactic medium rises quickly at z > 6.5, given that Lyman α is resonantly scattered by neutral gas. The small samples and limited depth of previous observations, however, makes these conclusions tentative. Here we report a deep near-infrared spectroscopic survey of 43 photometrically-selected galaxies with z > 6.5. We detect a near-infrared emission line from only a single galaxy, confirming that some process is making Lyman α difficult to detect. The detected emission line at a wavelength of 1.0343 micrometres is likely to be Lyman α emission, placing this galaxy at a redshift z = 7.51, an epoch 700 million years after the Big Bang. This galaxy's colours are consistent with significant metal content, implying that galaxies become enriched rapidly. We calculate a surprisingly high star-formation rate of about 330 solar masses per year, which is more than a factor of 100 greater than that seen in the Milky Way. Such a galaxy is unexpected in a survey of our size, suggesting that the early Universe may harbour a larger number of intense sites of star formation than expected.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Premature termination codons (PTCs) are responsible for 10-15% of all inherited disease. PTC suppression during translation offers a promising approach to treat a variety of genetic disorders, yet ...small molecules that promote PTC read-through have yielded mixed performance in clinical trials. Here we present a high-throughput, cell-based assay to identify anticodon engineered transfer RNAs (ACE-tRNA) which can effectively suppress in-frame PTCs and faithfully encode their cognate amino acid. In total, we identify ACE-tRNA with a high degree of suppression activity targeting the most common human disease-causing nonsense codons. Genome-wide transcriptome ribosome profiling of cells expressing ACE-tRNA at levels which repair PTC indicate that there are limited interactions with translation termination codons. These ACE-tRNAs display high suppression potency in mammalian cells, Xenopus oocytes and mice in vivo, producing PTC repair in multiple genes, including disease causing mutations within cystic fibrosis transmembrane conductance regulator (CFTR).
Antibody immunotherapy is revolutionizing modern medicine. The field has advanced dramatically over the past 40 years, driven in part by major advances in isolation and manufacturing technologies ...that have brought these important biologics to the forefront of modern medicine. However, the global uptake of monoclonal antibody (mAb) biologics is impeded by biophysical and biochemical liabilities, production limitations, the need for cold-chain storage and transport, as well as high costs of manufacturing and distribution. Some of these hurdles may be overcome through transient in vivo gene delivery platforms, such as non-viral synthetic plasmid DNA and messenger RNA vectors that are engineered to encode optimized mAb genes. These approaches turn the body into a biological factory for antibody production, eliminating many of the steps involved in bioprocesses and providing several other significant advantages, and differ from traditional gene therapy (permanent delivery) approaches. In this review, we focus on nucleic acid delivery of antibody employing synthetic plasmid DNA vector platforms, and RNA delivery, these being important approaches that are advancing simple, rapid, in vivo expression and having an impact in animal models of infectious diseases and cancer, among others.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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