A germline mutation in the 3′-untranslated region of KRAS (rs61764370, KRAS-variant: TG/GG) has previously been associated with altered patient outcome and drug resistance/sensitivity in various ...cancers. We examined the prognostic and predictive significance of this variant in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).
We conducted a retrospective study of 103 HNSCCs collected from three completed clinical trials. KRAS-variant genotyping was conducted for these samples and 8 HNSCC cell lines. p16 expression was determined in a subset of 26 oropharynx tumors by immunohistochemistry. Microarray analysis was also utilized to elucidate differentially expressed genes between KRAS-variant and non-variant tumors. Drug sensitivity in cell lines was evaluated to confirm clinical findings.
KRAS-variant status was determined in 95/103 (92%) of the HNSCC tumor samples and the allelic frequency of TG/GG was 32% (30/95). Three of the HNSCC cell lines (3/8) studied had the KRAS-variant. No association between KRAS-variant status and p16 expression was observed in the oropharynx subset (Fisher's exact test, P = 1.0). With respect to patient outcome, patients with the KRAS-variant had poor progression-free survival when treated with cisplatin (log-rank P = 0.002). Conversely, KRAS-variant patients appeared to experience some improvement in disease control when cetuximab was added to their platinum-based regimen (log-rank P = 0.04).
The TG/GG rs61764370 KRAS-variant is a potential predictive biomarker for poor platinum response in R/M HNSCC patients.
NCT00503997, NCT00425750, NCT00003809.
Phosphodiesterases (PDEs) shape local cAMP gradients to underpin the specificity of receptor function. Key to this process is the highly defined nature of the intra-cellular location of PDEs in the ...cell. PDE4A5 is a PDE isoform that specifically degrades cAMP and is known to associate with the p75 neurotrophin receptor (p75NTR) where it modulates cAMP signalling cascades that regulate extracellular matrix remodelling in the lungs. Here we map and validate novel protein-protein interaction sites that are important for formation of the PDE4A5-p75NTR complex and show, for the first time, that phosphorylation of PDE4A5 by MAPKAPK2 enhances PDE4A5 interaction with p75NTR and that this, in turn, serves to attenuate fibrin degradation.
We have recently performed the characterization of alternative splicing events (ASEs) in head and neck squamous cell carcinoma, which allows dysregulation of protein expression common for cancer ...cells. Such analysis demonstrated a high ASE prevalence among tumor samples, including tumor-specific alternative splicing in the GSN gene.In vitro studies confirmed that overall expression of either ASE-GSN or wild-type GSN (WT-GSN) isoform inversely correlated with cell proliferation, whereas the high ratio of ASE-GSN to WT-GSN correlated with increased cellular invasion. Additionally, a change in expression of either isoform caused compensatory changes in expression of the other isoform. Our results suggest that the overall expression and the balance between GSN isoforms are mediating factors in proliferation, while increased overall expression of ASE-GSN is specific to cancer tissues. As a result, we propose ASE-GSN can serve not only as a biomarker of disease and disease progression, but also as a neoantigen for head and neck squamous cell carcinoma treatment, for which only a limited number of disease-specific targeted therapies currently exist.
Stable nitrogen isotopes (delta(15)N) in bioindicators are increasingly employed to identify nitrogen sources in many ecosystems and biological characteristics of the eastern oyster (Crassostrea ...virginica) make it an appropriate species for this purpose. To assess nitrogen isotopic fractionation associated with assimilation and baseline variations in oyster mantle, gill, and muscle tissue delta(15)N, manipulative fieldwork in Chesapeake Bay and corresponding modeling exercises were conducted. This study (1) determined that five individuals represented an optimal sample size; (2) verified that delta(15)N in oysters from two locations converged after shared deployment to a new location reflecting a change in nitrogen sources; (3) identified required exposure time and temporal integration (four months for muscle, two to three months for gill and mantle); and (4) demonstrated seasonal delta(15)N increases in seston (summer) and oysters (winter). As bioindicators, oysters can be deployed for spatial interpolation of nitrogen sources, even in areas lacking extant populations.
Objective. The HLA 8.1 ancestral haplotype (HLA-B*08/DRB1*03/DQA1*05/DQB1*02) is associated with adult/juvenile idiopathic inflammatory myopathy (IIM), but confers a greater strength of association ...in patients possessing anti-Jo-1 or anti-PM-Scl antibodies. The HLA–DPB1 gene is centromeric to other HLA class II loci and separated by a recombination hotspot. We investigated whether HLA–DPB1 associations differ between anti-Jo-1 and anti-PM-Scl antibody-positive IIM cases. Methods. Two hundred and thirty-three adult IIM patients (73% females, 49.4 ± 13.6 years) with PM (n = 89), DM (n = 88) and myositis associated with another CTD (n = 55) and 85 juvenile DM patients (75% females, 6.2 ± 3.6 years) were compared with 678 UK Caucasian controls. Patients/controls were genotyped for HLA–DPB1 and DRB1 alleles. Myositis-specific and associated antibodies were identified in cases using immunoprecipitation. Results. HLA–DPB1*0101 was associated with IIM overall 22 vs 13% controls, corrected probability (Pcorr) = 2 × 10−03; odds ratio (OR) 2.0; 95% CI 1.4, 2.9, PM (Pcorr = 7 × 10−03; OR 2.5; 95% CI 1.5, 4.4) and anti-Jo-1 (Pcorr = 3 × 10−5; OR 4.1; 95% CI 2.1, 7.8). No significant DPB1*0101 difference was present between anti-PM-Scl cases and controls. The HLA–DPB1*0101 association in IIM overall cases was dependent on the presence of DRB1*03. A number of HLA–DRB1*03/DPB1 haplotypes were identified, but only DRB1*03/DPB1*0101 was associated with anti-Jo-1 antibody-positive cases. Conclusions. The HLA–DRB1*03/DPB1*0101 haplotype is a risk factor for anti-Jo-1 antibody-positive IIM. Thus, although DRB1*03 is strongly associated with possession of either anti-Jo-1 or anti-PM-Scl, differing antibody associations are observed at the HLA–DPB1 locus.
This paper compares the performance of the Local Ensemble Transform Kalman Filter (LETKF) with the Physical-Space Statistical Analysis System (PSAS) under a perfect model scenario. PSAS is a 3D-Var ...assimilation system used operationally in the Goddard Earth Observing System Data Assimilation System (GEOS-4 DAS). The comparison is carried out using simulated winds and geopotential height observations and the finite volume Global Circulation Model with 72 grid points zonally, 46 grid points meridionally and 55 vertical levels. With forty ensemble members, the LETKF obtains analyses and forecasts with significantly lower RMS errors than those from PSAS, especially over the Southern Hemisphere and oceans. This observed advantage of the LETKF over PSAS is due to the ability of the 40-member ensemble LETKF to capture flow-dependent errors and thus create a good estimate of the evolving background uncertainty. An initial decrease of the forecast errors in the Northern Hemisphere observed in the PSAS but not in the LETKF suggests that the LETKF analysis is more balanced.
Precise temporal control of gene expression in neuronal progenitors is necessary for correct regulation of neurogenesis and cell fate specification. However, the cellular heterogeneity of the ...developing CNS has posed a major obstacle to identifying the gene regulatory networks that control these processes. To address this, we used single-cell RNA sequencing to profile ten developmental stages encompassing the full course of retinal neurogenesis. This allowed us to comprehensively characterize changes in gene expression that occur during initiation of neurogenesis, changes in developmental competence, and specification and differentiation of each major retinal cell type. We identify the NFI transcription factors (Nfia, Nfib, and Nfix) as selectively expressed in late retinal progenitor cells and show that they control bipolar interneuron and Müller glia cell fate specification and promote proliferative quiescence.
•Mouse retinal development was profiled using single-cell RNA-seq•Early and late-stage retinal progenitors are distinct•Primary and neurogenic retinal progenitors are distinct•NFI factors control cell-cycle exit and generation of late-born retinal cell types
We use single-cell RNA-seq analysis to comprehensively profile gene expression during mouse retinal development. We find major differences between early and late-stage, as well as primary and neurogenic, progenitors. We also find that NFI factors control cell-cycle exit and generation of late-born cell types.
In many marine environments, a voltage gradient exists across the water sediment interface resulting from sedimentary microbial activity. Here we show that a fuel cell consisting of an anode embedded ...in marine sediment and a cathode in overlying seawater can use this voltage gradient to generate electrical power in situ. Fuel cells of this design generated sustained power in a boat basin carved into a salt marsh near Tuckerton, New Jersey, and in the Yaquina Bay Estuary near Newport, Oregon. Retrieval and analysis of the Tuckerton fuel cell indicates that power generation results from at least two anode reactions: oxidation of sediment sulfide (a by-product of microbial oxidation of sedimentary organic carbon) and oxidation of sedimentary organic carbon catalyzed by microorganisms colonizing the anode. These results demonstrate in real marine environments a new form of power generation that uses an immense, renewable energy reservoir (sedimentary organic carbon) and has near-immediate application.
Stable nitrogen isotopes (δ15N) in bioindicators are increasingly employed to identify nitrogen sources in many ecosystems and biological characteristics of the eastern oyster (Crassostrea virginica) ...make it an appropriate species for this purpose. To assess nitrogen isotopic fractionation associated with assimilation and baseline variations in oyster mantle, gill, and muscle tissue δ15N, manipulative fieldwork in Chesapeake Bay and corresponding modeling exercises were conducted. This study (1) determined that five individuals represented an optimal sample size; (2) verified that δ15N in oysters from two locations converged after shared deployment to a new location reflecting a change in nitrogen sources; (3) identified required exposure time and temporal integration (four months for muscle, two to three months for gill and mantle); and (4) demonstrated seasonal δ15N increases in seston (summer) and oysters (winter). As bioindicators, oysters can be deployed for spatial interpolation of nitrogen sources, even in areas lacking extant populations.
We present the first frequency-dependent analyses of the geographic smoothing of wind power’s variability, analyzing the interconnected measured output of 20 wind plants in Texas. Reductions in ...variability occur at frequencies corresponding to times shorter than ∼24
h and are quantified by measuring the departure from a Kolmogorov spectrum. At a frequency of 2.8×10
−4
Hz (corresponding to 1
h), an 87% reduction of the variability of a single wind plant is obtained by interconnecting 4 wind plants. Interconnecting the remaining 16 wind plants produces only an additional 8% reduction. We use step change analyses and correlation coefficients to compare our results with previous studies, finding that wind power ramps up faster than it ramps down for each of the step change intervals analyzed and that correlation between the power output of wind plants 200
km away is half that of co-located wind plants. To examine variability at very low frequencies, we estimate yearly wind energy production in the Great Plains region of the United States from automated wind observations at airports covering 36 years. The estimated wind power has significant inter-annual variability and the severity of wind drought years is estimated to be about half that observed nationally for hydroelectric power.
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