An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors.

To address the biological heterogeneity of lung cancer, we studied 199 lung adenocarcinomas by integrating genome-wide data on copy number alterations and gene expression with full annotation for major known somatic mutations in this cancer. This showed non-random patterns of copy number alterations significantly linked to EGFR and KRAS mutation status and to distinct clinical outcomes, and led to the discovery of a striking association of EGFR mutations with underexpression of DUSP4, a gene within a broad region of frequent single-copy loss on 8p. DUSP4 is involved in negative feedback control of EGFR signaling, and we provide functional validation for its role as a growth suppressor in EGFR-mutant lung adenocarcinoma. DUSP4 loss also associates with p16/CDKN2A deletion and defines a distinct clinical subset of lung cancer patients. Another novel observation is that of a reciprocal relationship between EGFR and LKB1 mutations. These results highlight the power of integrated genomics to identify candidate driver genes within recurrent broad regions of copy number alteration and to delineate distinct oncogenetic pathways in genetically complex common epithelial cancers

Hip abductors and thigh muscles strength ratios and their relation to electromyography amplitude during split squat and walking lunge exercises

Background: The hip abductors (HAB), quadriceps (Q) and hamstrings (H) reciprocal strength ratios are predictors of electromyography (EMG) amplitude during load carrying walking at moderate intensity. Therefore, these strength ratios might predict also the EMG during the exercises as walking lunge (WL) or split squat (SSq) at submaximal intensity. Objective: To determine whether the EMG amplitude of vastus mediali (VM), vastus laterali (VL), biceps femoris (BF) and gluteus medius (Gmed) is associated with muscle strength ratio during SSqs and WLs. To determine whether the EMG amplitude differs between individuals with HAB/H ratio above and below one and between individuals with H/Q or HAB/Q ratio above and below 0.5 during SSqs and WLs. Methods: 17 resistance-trained men (age 29.6 ± 4.6 years) with at least 3 years of strength training performed in cross-sectional design 5 s maximal voluntary isometric contractions (MVIC) on an isokinetic dynamometer for knee extension, knee flexion, and hip abduction. The MVIC was used to normalize the EMG signal and estimate the individual strength ratios. Than participants performed WL and SSq for a 5 repetition maximum, to find out muscle activity at submaximal intensity of exercise. Results: The H/Q ratio was associated by Kendall’s tau (τ) with VM (τ = .33) and BF (τ = -.71) amplitude, HAB/Q ratio was associated with BF (τ = -.43) and Gmed (τ = .38) amplitude, as well as HAB/H was associated with VM (τ = -.41) and Gmed (τ = .74) amplitude. ANOVA results showed significant differences between SSq and WL (F(4, 79) = 10, p \u3c .001, ηp2 = .34) in Gmed amplitude, where WL resulted in higher Gmed amplitude compared to SSq. Other significant differences were found between H/Q groups (F(4, 29) = 3, p = .04, ηp2 = .28) in VM and Gmed amplitude, where group with H/Q \u3e 0.5 showed higher VMO amplitude and lower Gmed amplitude. Furthermore, significant difference was found for HAB/H groups (F(4, 29) = 4, p = .02, ηp2 = .34) in VM amplitude, where group with HAB/H \u3c 1 showed higher VM amplitude. Conclusions: The ratios of HAB, H and Q are able to predict Gmed, VM and BF activity during WL and SSq. WL resulted in higher activity level of Gmed than SSq, because WL includes the impact forces as part of lunge movement. WL should be used in resistance-training programme, if the strengthening of Gmed or VM is the aim

Bisimulation of Labeled State-to-Function Transition Systems of Stochastic Process Languages

Labeled state-to-function transition systems, FuTS for short, admit multiple transition schemes from states to functions of finite support over general semirings. As such they constitute a convenient modeling instrument to deal with stochastic process languages. In this paper, the notion of bisimulation induced by a FuTS is proposed and a correspondence result is proven stating that FuTS-bisimulation coincides with the behavioral equivalence of the associated functor. As generic examples, the concrete existing equivalences for the core of the process algebras ACP, PEPA and IMC are related to the bisimulation of specific FuTS, providing via the correspondence result coalgebraic justification of the equivalences of these calculi.Comment: In Proceedings ACCAT 2012, arXiv:1208.430

Compound heterozygosity for lossâ ofâ function GARS variants results in a multisystem developmental syndrome that includes severe growth retardation

Aminoacylâ tRNA synthetases (ARSs) are ubiquitously expressed enzymes that ligate amino acids onto tRNA molecules. Genes encoding ARSs have been implicated in myriad dominant and recessive disease phenotypes. Glycylâ tRNA synthetase (GARS) is a bifunctional ARS that charges tRNAGly in the cytoplasm and mitochondria. GARS variants have been associated with dominant Charcotâ Marieâ Tooth disease but have not been convincingly implicated in recessive phenotypes. Here, we describe a patient from the NIH Undiagnosed Diseases Program with a multisystem, developmental phenotype. Wholeâ exome sequence analysis revealed that the patient is compound heterozygous for one frameshift (p.Glu83Ilefs*6) and one missense (p.Arg310Gln) GARS variant. Using in vitro and in vivo functional studies, we show that both GARS variants cause a lossâ ofâ function effect: the frameshift variant results in depleted protein levels and the missense variant reduces GARS tRNA charging activity. In support of GARS variant pathogenicity, our patient shows striking phenotypic overlap with other patients having ARSâ related recessive diseases, including features associated with variants in both cytoplasmic and mitochondrial ARSs; this observation is consistent with the essential function of GARS in both cellular locations. In summary, our clinical, genetic, and functional analyses expand the phenotypic spectrum associated with GARS variants.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138288/1/humu23287-sup-0001-text.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138288/2/humu23287.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138288/3/humu23287_am.pd