While mutations in the KRAS oncogene are among the most prevalent in human cancer, there are few successful treatments to target these tumors. It is also likely that heterogeneity in KRAS-mutant ...tumor biology significantly contributes to the response to therapy. We hypothesized that the presence of commonly co-occurring mutations in STK11 and TP53 tumor suppressors may represent a significant source of heterogeneity in KRAS-mutant tumors. To address this, we utilized a large cohort of resected tumors from 442 lung adenocarcinoma patients with data including annotation of prevalent driver mutations (KRAS and EGFR) and tumor suppressor mutations (STK11 and TP53), microarray-based gene expression and clinical covariates, including overall survival (OS). Specifically, we determined impact of STK11 and TP53 mutations on a new KRAS mutation-associated gene expression signature as well as previously defined signatures of tumor cell proliferation and immune surveillance responses. Interestingly, STK11, but not TP53 mutations, were associated with highly elevated expression of KRAS mutation-associated genes. Mutations in TP53 and STK11 also impacted tumor biology regardless of KRAS status, with TP53 strongly associated with enhanced proliferation and STK11 with suppression of immune surveillance. These findings illustrate the remarkably distinct ways through which tumor suppressor mutations may contribute to heterogeneity in KRAS-mutant tumor biology. In addition, these studies point to novel associations between gene mutations and immune surveillance that could impact the response to immunotherapy.
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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
The SWI SNF complex and cancer REISMAN, D; GLAROS, S; THOMPSON, E. A
Oncogene,
04/2009, Volume:
28, Issue:
14
Journal Article
Peer reviewed
Open access
The mammalian SWI/SNF complexes mediate ATP-dependent chromatin remodeling processes that are critical for differentiation and proliferation. Not surprisingly, loss of SWI/SNF function has been ...associated with malignant transformation, and a substantial body of evidence indicates that several components of the SWI/SNF complexes function as tumor suppressors. This review summarizes the evidence that underlies this conclusion, with particular emphasis upon the two catalytic subunits of the SWI/SNF complexes, BRM, the mammalian ortholog of SWI2/SNF2 in yeast and brahma in Drosophila, and Brahma-related gene-1 (BRG1).
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We present a statistical method for identifying species hybrids using data on multiple, unlinked markers. The method does not require that allele frequencies be known in the parental species nor that ...separate, pure samples of the parental species be available. The method is suitable for both markers with fixed allelic differences between the species and markers without fixed differences. The probability model used is one in which parentals and various classes of hybrids (F(1)'s, F(2)'s, and various backcrosses) form a mixture from which the sample is drawn. Using the framework of Bayesian model-based clustering allows us to compute, by Markov chain Monte Carlo, the posterior probability that each individual belongs to each of the distinct hybrid classes. We demonstrate the method on allozyme data from two species of hybridizing trout, as well as on two simulated data sets.
Understanding drop size distribution (DSD) variability has important implications for remote sensing and numerical modeling applications. Twelve disdrometer datasets across three latitude bands are ...analyzed in this study, spanning a broad range of precipitation regimes: light rain, orographic, deep convective, organized midlatitude, and tropical oceanic. Principal component analysis (PCA) is used to reveal comprehensive modes of global DSD spatial and temporal variability. Although the locations contain different distributions of individual DSD parameters, all locations are found to have the same modes of variability. Based on PCA, six groups of points with unique DSD characteristics emerge. The physical processes that underpin these groups are revealed through supporting radar observations. Group 1 (group 2) is characterized by high (low) liquid water content (LWC), broad (narrow) distribution widths, and large (small) median drop diameters D
0
. Radar analysis identifies group 1 (group 2) as convective (stratiform) rainfall. Group 3 is characterized by weak, shallow radar echoes and large concentrations of small drops, indicative of warm rain showers. Group 4 identifies heavy stratiform precipitation. The low latitudes exhibit distinct bimodal distributions of the normalized intercept parameter N
w
, LWC, and D
0
and are found to have a clustering of points (group 5) with high rain rates, large N
w
, and moderate D
0
, a signature of robust warm rain processes. A distinct group associated with ice-based convection (group 6) emerges in the midlatitudes. Although all locations exhibit the same covariance of parameters associated with these groups, it is likely that the physical processes responsible for shaping the DSDs vary as a function of location.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Iron-catalyzed graphitization of biomass Thompson, E; Danks, A E; Bourgeois, L ...
Green chemistry : an international journal and green chemistry resource : GC,
01/2015, Volume:
17, Issue:
1
Journal Article
Peer reviewed
This paper reports the direct transformation of raw lignocellulosic biomass into nanostructured graphitic carbon in a single step. Catalytic iron carbide nanoparticles are generated in situ by ...thermal decomposition of absorbed iron nitrate followed by carbothermal reduction. The Fe sub(3)C particles then etch through the biomass to generate intertwined graphitic tubules through catalytic graphitization. The materials are mesoporous with the pore size dependant on the iron content. Conversion of raw biomass into stable graphitic carbon at relatively low temperatures (800 degree C) offers a promising route to large-scale and sustainable synthesis of carbons for electrode or filtration applications. This facile method can also be used to produce nanocomposites of Fe sub(3)C/graphite combined with nanoparticles of metal oxides such as CaO or MgO, again from a one-pot precursor, giving potential for a wide range of applications.
Citrullination of proteins, a post-translational conversion of arginine residues to citrulline, is recognized in rheumatoid arthritis, but largely undocumented in cancer. Here we show that ...citrullination of the extracellular matrix by cancer cell derived peptidylarginine deiminase 4 (PAD4) is essential for the growth of liver metastases from colorectal cancer (CRC). Using proteomics, we demonstrate that liver metastases exhibit higher levels of citrullination and PAD4 than unaffected liver, primary CRC or adjacent colonic mucosa. Functional significance for citrullination in metastatic growth is evident in murine models where inhibition of citrullination substantially reduces liver metastatic burden. Additionally, citrullination of a key matrix component collagen type I promotes greater adhesion and decreased migration of CRC cells along with increased expression of characteristic epithelial markers, suggesting a role for citrullination in promoting mesenchymal-to-epithelial transition and liver metastasis. Overall, our study reveals the potential for PAD4-dependant citrullination to drive the progression of CRC liver metastasis.
► SKPFM provided information about galvanic interactions existing in Mg alloys. ► Galvanic interactions depended on the Volta potential differences of the alloy constituents. ► The Volta potential ...differences of the constituents depended on their composition. ► The as-cast ZE41 alloy presented strong galvanic corrosion. ► No evidence of galvanic corrosion by RE-containing phases was observed in WEXX alloys.
Four commercially produced rare-earth-magnesium alloys, as-cast ZE41, sand-cast WE43-T6, and wrought WE43-T6 and WE54-T6, were studied by scanning Kelvin probe force microscopy (SKPFM) in order to evaluate the role of their micro-constituent phases on potential galvanic interactions. Such interactions were then examined by immersion of the alloys in 3.5
wt% NaCl solution. The results confirmed that SKPFM was a powerful tool to determine the corrosion mechanism of magnesium alloys, where the intensity of the corrosion attack depended on the relative Volta potential differences of the micro-constituents, as well as their amounts, compositions and distributions within the alloys.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background. During the 2012-2013 influenza season, there was cocirculation of influenza A(H3N2) and 2 influenza lineage viruses in the United States. Methods. Patients with acute cough illness for ≤7 ...days were prospectively enrolled and had swab samples obtained at outpatient clinics in 5 states. Influenza vaccination dates were confirmed by medical records. The vaccine effectiveness (VE) was estimated as 100% × (1 - adjusted odds ratio) for vaccination in cases versus test-negative controls. Results. Influenza was detected in 2307 of 6452 patients (36%); 1292 (56%) had influenza A(H3N2), 582 (25%) had influenza B/Yamagata, and 303 (13%) had influenza B/Victoria. VE was 49% (95% confidence interval CI, 43%-55%) overall, 39% (95% CI, 29%-47%) against influenza A(H3N2), 66% (95% CI, 58%-73%) against influenza B/Yamagata (vaccine lineage), and 51% (95% CI, 36%-63%) against influenza B/Victoria. VE against influenza A(H3N2) was highest among persons aged 50-64 years (52%; 95% CI, 33%-65%) and persons aged 6 months-8 years (51%; 95% CI, 32%-64%) and lowest among persons aged ≥65 years (11%; 95% CI, -41% to 43%). In younger age groups, there was evidence of residual protection from receipt of the 2011-2012 vaccine 1 year earlier. Conclusions. The 2012-2013 vaccines were moderately effective in most age groups. Cross-lineage protection and residual effects from prior vaccination were observed and warrant further investigation.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Objective
To explore the separate effects of being ‘at risk’ of gestational diabetes mellitus (GDM) and screening for GDM, and of raised fasting plasma glucose (FPG) and clinical diagnosis of GDM, on ...the risk of late stillbirth.
Design
Prospective case–control study.
Setting
Forty‐one maternity units in the UK.
Population
Women who had a stillbirth ≥28 weeks of gestation (n = 291) and women with an ongoing pregnancy at the time of interview (n = 733).
Methods
Causal mediation analysis explored the joint effects of (i) ‘at risk’ of GDM and screening for GDM and (ii) raised FPG (≥5.6 mmol/l) and clinical diagnosis of GDM on the risks of late stillbirth. Adjusted odds ratios (aOR) were estimated by logistic regression adjusted for confounders identified by directed acyclic graphs.
Main outcome measures
Screening for GDM and FPG levels
Results
Women ‘at risk’ of GDM, but not screened, experienced 44% greater risk of late stillbirth than those not ‘at risk’ (aOR 1.44, 95% CI 1.01–2.06). Women ‘at risk’ of GDM who were screened experienced no such increase (aOR 0.98, 95% CI 0.70–1.36). Women with raised FPG not diagnosed with GDM experienced four‐fold greater risk of late stillbirth than women with normal FPG (aOR 4.22, 95% CI 1.04–17.02). Women with raised FPG who were diagnosed with GDM experienced no such increase (aOR 1.10, 95% CI 0.31–3.91).
Conclusions
Optimal screening and diagnosis of GDM mitigate the higher risks of late stillbirth in women ‘at risk’ of GDM and/or with raised FPG. Failure to diagnose GDM leaves women with raised FPG exposed to avoidable risk of late stillbirth.
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Risk of #stillbirth in gestational diabetes is mitigated by effective screening and diagnosis.
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Risk of #stillbirth in gestational diabetes is mitigated by effective screening and diagnosis.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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