The rapid advancement of nanotechnology has created a vast array of engineered nanomaterials (ENMs) which have unique physical (size, shape, crystallinity, surface charge) and chemical (surface ...coating, elemental composition and solubility) attributes. These physicochemical properties of ENMs can produce chemical conditions to induce a pro-oxidant environment in the cells, causing an imbalanced cellular energy system dependent on redox potential and thereby leading to adverse biological consequences, ranging from the initiation of inflammatory pathways through to cell death. The present study was designed to evaluate size-dependent cellular interactions of known biologically active silver nanoparticles (NPs, Ag-15nm, Ag-30nm, and Ag-55nm). Alveolar macrophages provide the first defense and were studied for their potential role in initiating oxidative stress. Cell exposure produced morphologically abnormal sizes and adherence characteristics with significant NP uptake at high doses after 24 h. Toxicity evaluations using mitochondrial and cell membrane viability along with reactive oxygen species (ROS) were performed. After 24 h of exposure, viability metrics significantly decreased with increasing dose (10−75 μg/mL) of Ag-15nm and Ag-30nm NPs. A more than 10-fold increase of ROS levels in cells exposed to 50 μg/mL Ag-15nm suggests that the cytotoxicity of Ag-15nm is likely to be mediated through oxidative stress. In addition, activation of the release of traditional inflammatory mediators were examined by measuring levels of cytokines/chemokines, including tumor necrosis factor (TNF-α), macrophage inhibitory protein (MIP-2), and interleukin-6 (IL-6), released into the culture media. After 24 h of exposure to Ag-15nm nanoparticles, a significant inflammatory response was observed by the release of TNF-α, MIP-2, and IL-1β. However, there was no detectable level of IL-6 upon exposure to silver nanoparticles. In summary, a size-dependent toxicity was produced by silver nanoparticles, and one predominant mechanism of toxicity was found to be largely mediated through oxidative stress.
This study targeted the fungal communities in the phyllosphere of Quercus macrocarpa and compared the fungal species richness, diversity and community composition among trees located within and ...outside a small urban center using recently developed 454 sequencing and DNA tagging. The results indicate that the fungal phyllosphere communities are extremely diverse and strongly dominated by ascomycetes, with Microsphaeropsis two Operational Taxonomic Units (OTUs); 23.6%, Alternaria (six OTUs; 16.1%), Epicoccum (one OTU; 6.0%) and Erysiphe (two OTUs; 5.9%) as the most abundant genera. Although the sequencing effort averaged 1000 reads per tree and detected nearly 700 distinct molecular OTUs at 95% internal transcribed spacer 1 similarity, the richness of the hyperdiverse phyllosphere communities could not be reliably estimated as nearly one-half of the molecular OTUs were singletons. The fungal communities within and outside the urban center differed in richness and diversity, which were lower within the urban development. The two land-use types contained communities that were distinct and more than 10% of the molecular OTUs differed in their frequency.
This paper presents the first plasmid DNA irradiations carried out with Very High Energy Electrons (VHEE) over 100-200 MeV at the CLEAR user facility at CERN to determine the Relative Biological ...Effectiveness (RBE) of VHEE. DNA damage yields were measured in dry and aqueous environments to determine that ~ 99% of total DNA breaks were caused by indirect effects, consistent with other published measurements for protons and photons. Double-Strand Break (DSB) yield was used as the biological endpoint for RBE calculation, with values found to be consistent with established radiotherapy modalities. Similarities in physical damage between VHEE and conventional modalities gives confidence that biological effects of VHEE will also be similar-key for clinical implementation. Damage yields were used as a baseline for track structure simulations of VHEE plasmid irradiation using GEANT4-DNA. Current models for DSB yield have shown reasonable agreement with experimental values. The growing interest in FLASH radiotherapy motivated a study into DSB yield variation with dose rate following VHEE irradiation. No significant variations were observed between conventional and FLASH dose rate irradiations, indicating that no FLASH effect is seen under these conditions.
Fluorination of conjugated molecules has been established as an effective structural modification strategy to influence properties and has attracted extensive attention in organic solar cells (OSCs). ...Here, we have investigated optoelectronic and photovoltaic property changes of OSCs made of polymer donors with the non-fullerene acceptors (NFAs) ITIC and IEICO and their fluorinated counterparts IT-4F and IEICO-4F. Device studies show that fluorinated NFAs lead to reduced V oc but increased J sc and fill-factor (FF), and therefore, the ultimate influence to efficiency depends on the compensation of V oc loss and gains of J sc and FF. Fluorination lowers energy levels of NFAs, reduces their electronic band gaps, and red-shifts the absorption spectra. The impact of fluorination on the molecular order depends on the specific NFA, and the conversion of ITIC to IT-4F reduces the structural order, which can be reversed after blending with the donor PBDB-T. Contrastingly, IEICO-4F presents stronger π–π stacking after fluorination from IEICO, and this is further strengthened after blending with the donor PTB7-Th. The photovoltaic blends universally present a donor-rich surface region which can promote charge transport and collection toward the anode in inverted OSCs. The fluorination of NFAs, however, reduces the fraction of donors in this donor-rich region, consequently encouraging the intermixing of donor/acceptor for efficient charge generation.
NRG1 fusion-positive lung cancers have emerged as potentially actionable events in lung cancer, but clinical support is currently limited and no evidence of efficacy of this approach in cancers ...beyond lung has been shown.
Here, we describe two patients with advanced cancers refractory to standard therapies. Patient 1 had lung adenocarcinoma and patient 2 cholangiocarcinoma. Whole-genome and transcriptome sequencing were carried out for these cases with select findings validated by fluorescence in situ hybridization.
Both tumors were found to be positive for NRG1 gene fusions. In patient 1, an SDC4–NRG1 gene fusion was detected, similar gene fusions having been described in lung cancers previously. In patient 2, a novel ATP1B1–NRG1 gene fusion was detected. Cholangiocarcinoma is not a disease type in which NRG1 fusions had been described previously. Integrative genome analysis was used to assess the potential functional significance of the detected genomic events including the gene fusions, prioritizing therapeutic strategies targeting the HER-family of growth factor receptors. Both patients were treated with the pan HER-family kinase inhibitor afatinib and both displayed significant and durable response to treatment. Upon progression sites of disease were sequenced. The lack of obvious genomic events to describe the disease progression indicated that broad transcriptomic or epigenetic mechanisms could be attributed to the lack of prolonged response to afatinib.
These observations lend further support to the use of pan HER-tyrosine kinase inhibitors for the treatment of NRG1 fusion-positive in both cancers of lung and hepatocellular origin and indicate more broadly that cancers found to be NRG1 fusion-positive may benefit from such a clinical approach regardless of their site of origin.
Personalized Oncogenomics (POG) Program of British Columbia: Utilization of Genomic Analysis to Better Understand Tumour Heterogeneity and Evolution (NCT02155621).
The fungal richness, diversity and community composition in the Quercus macrocarpa phyllosphere were compared across a growing season in trees located in six stands within and outside a small urban ...center using 454-sequencing and DNA tagging. The approaches did not differentiate between endophytic and epiphytic fungal communities. Fungi accumulated in the phyllosphere rapidly and communities were temporally dynamic, with more than a third of the analyzed operational taxonomic units (OTUs) and half of the BLAST-inferred genera showing distinct seasonal patterns. The seasonal patterns could be explained by fungal life cycles or environmental tolerances. The communities were hyperdiverse and differed between the urban and nonurban stands, albeit not consistently across the growing season. Foliar macronutrients (nitrogen (N), potassium (K) and sulfur (S)), micronutrients (boron (B), manganese (Mn) and selenium (Se)) and trace elements (cadmium (Cd), lead (Pb) and zinc (Zn)) were enriched in the urban trees, probably as a result of anthropogenic activities. Because of correlations with the experimental layout, these chemical elements should not be considered as community drivers without further empirical studies. We suggest that a combination of mechanisms leads to differences between urban and nonurban communities. Among those are stand isolation and size, nutrient and pollutant accumulation plus stand management, including fertilization and litter removal.
The association of BK virus infection with hemorrhagic cystitis in blood and marrow transplant (BMT) recipients was first demonstrated two decades ago. During this time, therapeutic interventions ...focused on supportive measures such as hyperhydration, continuous bladder irrigation and topical administration of agents that alter the mucosal surface of the bladder wall. In recent years, PCR amplification of viral DNA in the urine and plasma has solidified the association of BK virus infection with hemorrhagic cystitis, demonstrating that higher urine and plasma viral loads occur in the setting of disease. The evaluation of virus-specific therapy has lagged behind assessment of the viral load and theories of pathogenesis. Extrapolating from successes in the treatment of BK virus nephropathy in the renal transplant population, cidofovir and leflunomide are identified as potential effective agents for the treatment of BK virus-associated hemorrhagic cystitis. The fluoroquinolone antibiotics may prove to be effective as prophylactic agents. Given the manifestation of BK virus infection in organs outside of the urinary tract in an increasing immunocompromised patient population and the availability of potential antiviral agents, therapeutic trials need to progress beyond the small case series in order to improve the morbidity and mortality caused by BK virus-associated hemorrhagic cystitis in the BMT population.
There is increasing recognition of an important contribution of chemokines and their receptors in the pathology of atherosclerosis and related cardiovascular disease. The chemokine receptor CCR5 was ...initially known for its role as a co‐receptor for HIV infection of macrophages and is the target of the recently approved CCR5 antagonist maraviroc. However, evidence is now emerging supporting a role for CCR5 and its ligands CCL3 (MIP‐1α), CCL4 (MIP‐1β) and CCL5 (RANTES) in the initiation and progression of atherosclerosis. Specifically, the CCR5 deletion polymorphism CCR5delta32, which confers resistance to HIV infection, has been associated with a reduced risk of cardiovascular disease and both CCR5 antagonism and gene deletion reduce atherosclerosis in mouse models of the disease. Antagonism of CCL5 has also been shown to reduce atherosclerotic burden in these animal models. Crucially, CCR5 and its ligands CCL3, CCL4 and CCL5 have been identified in human and mouse vasculature and have been detected in human atherosclerotic plaque. Not unexpectedly, CC chemokines have also been linked to saphenous vein graft disease, which shares similarity to native vessel atherosclerosis. Distinct roles for chemokine–receptor systems in atherogenesis have been proposed, with CCR5 likely to be critical in recruitment of monocytes to developing plaques. With an increased burden of cardiovascular disease observed in HIV‐infected individuals, the potential cardiovascular‐protective effects of drugs that target the CCR5 receptor warrant greater attention. The availability of clinically validated antagonists such as maraviroc currently provides an advantage for targeting of CCR5 over other chemokine receptors.
To determine an effective and tolerable dose of a novel oral calcitonin gene-related peptide (CGRP) receptor antagonist, MK-0974, for the acute treatment of migraine.
Randomized, double-blind, ...parallel-group, clinical trial with a two-stage, adaptive, dose-ranging design. Patients were allocated to treat a moderate or severe migraine attack with MK-0974 (25, 50, 100, 200, 300, 400, or 600 mg), rizatriptan 10 mg, or placebo taken orally. The primary endpoint was pain relief (reduction to mild or none) 2 hours after dosing. Secondary endpoints included pain freedom at 2 hours and sustained pain relief at 24 hours. A prespecified, blinded, automated interim analysis was used to discontinue randomization to less effective doses.
Per the adaptive study design, the four lowest MK-0974 groups (25, 50, 100, 200 mg) were discontinued due to insufficient efficacy. For the remaining treatment groups, the estimated pain relief proportions at 2 hours were 300 mg (n = 38) 68.1%, 400 mg (n = 45) 48.2%, 600 mg (n = 40) 67.5%, rizatriptan 10 mg (n = 34) 69.5%, and placebo (n = 115) 46.3%. The prespecified primary efficacy hypothesis test, which compared the average 2-hour pain relief response proportion of the combined 300, 400, and 600 mg MK-0974 groups to placebo, was significant (P = 0.015). A generally similar efficacy pattern was seen for other endpoints. MK-0974 was generally well tolerated and there did not appear to be an increase in adverse events with increasing dose.
The novel, orally administered calcitonin gene-related peptide (CGRP) receptor antagonist, MK-0974, was effective and generally well tolerated for the acute treatment of migraine.
A diet rich in dairy and calcium (Ca) has been variably associated with improvements in body composition and decreased risk of type 2 diabetes. Our objective was to determine if a dietary pattern ...high in dairy and Ca improves weight loss and subjective appetite to a greater extent than a low dairy/Ca diet during energy restriction in overweight and obese adults with metabolic syndrome.
A total of 49 participants were randomized to one of two treatment groups: Control (low dairy, ≈ 700 mg/day Ca, -500 kcal/day) or Dairy/Ca (high dairy, ≈ 1400 mg/day Ca, -500 kcal/day) for 12 weeks. Body composition, subjective ratings of appetite, food intake, plasma satiety hormones, glycemic response and inflammatory cytokines were measured.
Control (-2.2 ± 0.5 kg) and Dairy/Ca (-3.3 ± 0.6 kg) had similar weight loss. Based on self-reported energy intake, the percentage of expected weight loss achieved was higher with Dairy/Ca (82.1 ± 19.4%) than Control (32.2 ± 7.7%; P=0.03). Subjects in the Dairy/Ca group reported feeling more satisfied (P=0.01) and had lower dietary fat intake (P=0.02) over 12 weeks compared with Control. Compared with Control, Dairy/Ca had higher plasma levels of peptide tyrosine tyrosine (PYY, P=0.01) during the meal tolerance test at week 12. Monocyte chemoattractant protein-1 was reduced at 30 min with Dairy/Ca compared with Control (P=0.04).
In conclusion, a dairy- and Ca-rich diet was not associated with greater weight loss than control. Modest increases in plasma PYY concentrations with increased dairy/Ca intake, however, may contribute to enhanced sensations of satisfaction and reduced dietary fat intake during energy restriction.
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