Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma.

We characterized the mutational landscape of melanoma, the form of skin cancer with the highest mortality rate, by sequencing the exomes of 147 melanomas. Sun-exposed melanomas had markedly more ultraviolet (UV)-like C>T somatic mutations compared to sun-shielded acral, mucosal and uveal melanomas. Among the newly identified cancer genes was PPP6C, encoding a serine/threonine phosphatase, which harbored mutations that clustered in the active site in 12% of sun-exposed melanomas, exclusively in tumors with mutations in BRAF or NRAS.

MDM4 is a key therapeutic target in cutaneous melanoma.

The inactivation of the p53 tumor suppressor pathway, which often occurs through mutations in TP53 (encoding tumor protein 53) is a common step in human cancer. However, in melanoma-a highly chemotherapy-resistant disease-TP53 mutations are rare, raising the possibility that this cancer uses alternative ways to overcome p53-mediated tumor suppression. Here we show that Mdm4 p53 binding protein homolog (MDM4), a negative regulator of p53, is upregulated in a substantial proportion (∼65%) of stage I-IV human melanomas and that melanocyte-specific Mdm4 overexpression enhanced tumorigenesis in a mouse model of melanoma induced by the oncogene Nras.

Raloxifene attenuates Pseudomonas aeruginosa pyocyanin production and virulence.

There has been growing interest in disrupting bacterial virulence mechanisms as a form of infectious disease control through the use of 'anti-infective' drugs. Pseudomonas aeruginosa is an opportunistic pathogen noted for its intrinsic antibiotic resistance that causes serious infections requiring new therapeutic options. In this study, an analysis of the P.

Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion.

Drug resistance presents a challenge to the treatment of cancer patients. Many studies have focused on cell-autonomous mechanisms of drug resistance. By contrast, we proposed that the tumour micro-environment confers innate resistance to therapy.

Glucose deprivation activates a metabolic and signaling amplification loop leading to cell death.

The altered metabolism of cancer can render cells dependent on the availability of metabolic substrates for viability. Investigating the signaling mechanisms underlying cell death in cells dependent upon glucose for survival, we demonstrate that glucose withdrawal rapidly induces supra-physiological levels of phospho-tyrosine signaling, even in cells expressing constitutively active tyrosine kinases. Using unbiased mass spectrometry-based phospho-proteomics, we show that glucose withdrawal initiates a unique signature of phospho-tyrosine activation that is associated with focal adhesions.

Preexisting MEK1 exon 3 mutations in V600E/KBRAF melanomas do not confer resistance to BRAF inhibitors.

Unlabelled: BRAF inhibitors (BRAFi) induce antitumor responses in nearly 60% of patients with advanced V600E/KBRAF melanomas. Somatic activating MEK1 mutations are thought to be rare in melanomas, but their potential concurrence with V600E/KBRAF may be selected for by BRAFi. We sequenced MEK1/2 exon 3 in melanomas at baseline and upon disease progression.

Rational design of a new class of polycyclic organic bases bearing two superbasic sites and their applications in the CO2 capture and activation process.

A new type of polycyclic organic superbases is reported with very high proton affinities in the gas phase and the pK(a) upto 45.8 units in acetonitrile. They have exhibited the 2nd pK(a) upto 44.

Receptor tyrosine kinases in cancer escape from BRAF inhibitors.

The BRAF inhibitors (BRAFi) induce anti-tumor responses in nearly 60% of patients with advanced -mutant melanomas but only 5% of patients with -mutant colorectal carcinomas. Earlier studies of how a subset of melanoma that initially responds to BRAFi but later acquires drug resistance pointed to the importance of receptor tyrosine kinases (RTKs) in drug escape. In a pair of recent reports, this RTK-mediated mechanism of acquired BRAFi resistance in melanoma is re-surfacing in the context of innate or primary BRAFi resistance in -mutant colorectal carcinomas, suggesting potential upfront therapeutic strategies to prevent BRAFi resistance.

The course of unilateral intracranial arteriopathy in young adults with arterial ischemic stroke.

Background And Purpose: Unilateral intracranial focal nonprogressive arteriopathy is often found in children with arterial ischemic stroke. We aimed to investigate the course of unilateral intracranial arteriopathy in young adults.

Methods: We searched the Utrecht Stroke Database for patients between 16 and 50 years of age diagnosed with anterior circulation arterial ischemic stroke and a nonatherosclerotic, unilateral intracranial large-artery arteriopathy between 1991 and 2005.

Radioembolization after portal vein embolization in a patient with multifocal hepatocellular carcinoma.

Radioembolization is an effective locoregional therapy for patients with intermediate or advanced stage hepatocellular carcinoma (HCC). It has been shown that radioembolization is safe in patients with portal vein thrombosis. This case report describes safe radioembolization after portal vein embolization in a patient with multifocal HCC.

Predicting missing biomarker data in a longitudinal study of Alzheimer disease.

Objective: To investigate predictors of missing data in a longitudinal study of Alzheimer disease (AD).

Methods: The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a clinic-based, multicenter, longitudinal study with blood, CSF, PET, and MRI scans repeatedly measured in 229 participants with normal cognition (NC), 397 with mild cognitive impairment (MCI), and 193 with mild AD during 2005-2007. We used univariate and multivariable logistic regression models to examine the associations between baseline demographic/clinical features and loss of biomarker follow-ups in ADNI.

Influence of DNA-dye complex stability on separation resolution in microchip electrophoresis.

Background: Different markers have been used to label DNA for sample detection in gel electrophoresis. Intercalating dyes, (e.g.

Melanoma whole-exome sequencing identifies (V600E)B-RAF amplification-mediated acquired B-RAF inhibitor resistance.

The development of acquired drug resistance hampers the long-term success of B-RAF inhibitor therapy for melanoma patients. Here we show (V600E)B-RAF copy-number gain as a mechanism of acquired B-RAF inhibitor resistance in 4 out of 20 (20%) patients treated with B-RAF inhibitor. In cell lines, (V600E)B-RAF overexpression and knockdown conferred B-RAF inhibitor resistance and sensitivity, respectively.

Incidence and clinical predictors of low defibrillation safety margin at time of implantable defibrillator implantation.

Background: Determination of the defibrillation safety margin (DSM) is the most common method of testing device effectiveness at the time of implantation of implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy defibrillator (CRTD). Low DSM remains a problem in clinical practice.

Objective: The purpose of this study is to ascertain the incidence and clinical predictors of low DSM and the treatment strategies for low DSM in ICD or CRTD recipients.

In vivo gene expression in Mannheimia haemolytica A1 during a time-course trial in the bovine host.

The objective of this study is to examine the expression of Mannheimia haemolytica genes over time during the early stage of infection. In addition, gene expression at different sites of infection in the bovine host was examined. A time-course experiment was designed to collect pharyngeal swabs and lung washings from the same animals over two time points.

Establishment of motor neuron-V3 interneuron progenitor domain boundary in ventral spinal cord requires Groucho-mediated transcriptional corepression.

Background: Dorsoventral patterning of the developing spinal cord is important for the correct generation of spinal neuronal types. This process relies in part on cross-repressive interactions between specific transcription factors whose expression is regulated by Sonic hedgehog. Groucho/transducin-like Enhancer of split (TLE) proteins are transcriptional corepressors suggested to be recruited by at least certain Sonic hedgehog-controlled transcription factors to mediate the formation of spatially distinct progenitor domains within the ventral spinal cord.

The HSP90 inhibitor XL888 overcomes BRAF inhibitor resistance mediated through diverse mechanisms.

Purpose: The clinical use of BRAF inhibitors is being hampered by the acquisition of drug resistance. This study shows the potential therapeutic use of the HSP90 inhibitor (XL888) in six different models of vemurafenib resistance.

Experimental Design: The ability of XL888 to inhibit growth and to induce apoptosis and tumor regression of vemurafenib-resistant melanoma cell lines was shown in vitro and in vivo.

RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors.

Background: Cutaneous squamous-cell carcinomas and keratoacanthomas are common findings in patients treated with BRAF inhibitors.

Methods: We performed a molecular analysis to identify oncogenic mutations (HRAS, KRAS, NRAS, CDKN2A, and TP53) in the lesions from patients treated with the BRAF inhibitor vemurafenib. An analysis of an independent validation set and functional studies with BRAF inhibitors in the presence of the prevalent RAS mutation was also performed.

Reversing melanoma cross-resistance to BRAF and MEK inhibitors by co-targeting the AKT/mTOR pathway.

Background: The sustained clinical activity of the BRAF inhibitor vemurafenib (PLX4032/RG7204) in patients with BRAF(V600) mutant melanoma is limited primarily by the development of acquired resistance leading to tumor progression. Clinical trials are in progress using MEK inhibitors following disease progression in patients receiving BRAF inhibitors. However, the PI3K/AKT pathway can also induce resistance to the inhibitors of MAPK pathway.

A proteomic analysis of the regulon of the NarP two-component regulatory system response regulator in the bovine pathogen Mannheimia haemolytica A1.

Background: The response of the NarQP two-component signal transduction system regulon in response to the presence of nitrate for the bovine pathogen Mannheimia haemolytica A1 was investigated by proteomic analysis. Total proteins from a narP mutant and the parent SH1217 grown with or without NaNO3 supplement were examined by ISO-DALT 2D electrophoresis and liquid chromatography-mass spectrometry.

Results: Seventeen proteins were differentially expressed in the parent strain SH1217 in response to the addition of NaNO3 to the growth media.

RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E).

Activated RAS promotes dimerization of members of the RAF kinase family. ATP-competitive RAF inhibitors activate ERK signalling by transactivating RAF dimers. In melanomas with mutant BRAF(V600E), levels of RAS activation are low and these drugs bind to BRAF(V600E) monomers and inhibit their activity.

Sites of ubiquitin attachment in Saccharomyces cerevisiae.

Sites of ubiquitin modification have been identified by mass spectrometry based on the increase in molecular mass of a tryptic peptide carrying two additional glycine residues from the ubiquitin moiety. However, such peptides with GG shifts have been difficult to discover. We identify 870 unique sites of ubiquitin attachment on 438 different proteins of the yeast Saccharomyces cerevisiae.

A snap-shot of Mannheimia hemolytica A1 gene expression during infection in the bovine host.

It is expected that Mannheimia hemolytica A1 expresses a particular collection of genes during infection in the host. The bacterial gene products are produced in the in vivo environment to facilitate growth and survival. Here, we examined gene expression by M.