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https://www.readbyqxmd.com/read/28550454/oncogenic-roles-of-the-pi3k-akt-mtor-axis
#1
Masahiro Aoki, Teruaki Fujishita
The PI3K/AKT/mTOR pathway is frequently activated in various human cancers and has been considered a promising therapeutic target. Many of the positive regulators of the PI3K/AKT/mTOR axis, including the catalytic (p110α) and regulatory (p85α), of class IA PI3K, AKT, RHEB, mTOR, and eIF4E, possess oncogenic potentials, as demonstrated by transformation assays in vitro and by genetically engineered mouse models in vivo. Genetic evidences also indicate their roles in malignancies induced by activation of the upstream oncoproteins including receptor tyrosine kinases and RAS and those induced by the loss of the negative regulators of the PI3K/AKT/mTOR pathway such as PTEN, TSC1/2, LKB1, and PIPP...
May 28, 2017: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/28550340/heat-and-bleach-a-cost-efficient-method-for-extracting-microplastics-from-return-activated-sludge
#2
Surya Sujathan, Ann-Kathrin Kniggendorf, Arun Kumar, Bernhard Roth, Karl-Heinz Rosenwinkel, Regina Nogueira
The extraction of plastic microparticles, so-called microplastics, from sludge is a challenging task due to the complex, highly organic material often interspersed with other benign microparticles. The current procedures for microplastic extraction from sludge are time consuming and require expensive reagents for density separation as well as large volumes of oxidizing agents for organic removal, often resulting in tiny sample sizes and thus a disproportional risk of sample bias. In this work, we present an improved extraction method tested on return activated sludge (RAS)...
May 26, 2017: Archives of Environmental Contamination and Toxicology
https://www.readbyqxmd.com/read/28550183/somatic-mutation-spectrum-in-monoclonal-gammopathy-of-undetermined-significance-indicates-a-less-complex-genomic-landscape-compared-to-multiple-myeloma
#3
Aneta Mikulasova, Christopher P Wardell, Alexander Murison, Eileen M Boyle, Graham H Jackson, Jan Smetana, Zuzana Kufova, Ludek Pour, Viera Sandecka, Martina Almasi, Pavla Vsianska, Evzen Gregora, Petr Kuglik, Roman Hajek, Faith E Davies, Gareth J Morgan, Brian A Walker
Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant precursor of multiple myeloma with a 1% risk of progression per year. Although targeted analyses have shown the presence of specific genetic abnormalities such as IGH translocations, RB1 deletion, 1q gain, hyperdiploidy or RAS genes mutations, little is known about the molecular mechanism of malignant transformation. We have performed whole exome sequencing together with CGH+SNP array analysis in 33 flow-cytometry separated abnormal plasma cell samples from MGUS patients to describe somatic gene mutations and chromosome changes at the genome-wide level...
May 26, 2017: Haematologica
https://www.readbyqxmd.com/read/28550141/role-of-dynamin-src-and-ras-in-the-protein-kinase-c-mediated-activation-of-erk-by-gonadotropin-releasing-hormone
#4
Outhiriaradjou Benard, Zvi Naor, Rony Seger
No abstract text is available yet for this article.
May 26, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28550040/kras-g12d-expression-in-lung-resident-myeloid-cells-promotes-pulmonary-lch-like-neoplasm-sensitive-to-statin-treatment
#5
Tamihiro Kamata, Susan Giblett, Catrin Pritchard
Langerhans cell histiocytosis (LCH) is a rare histiocytic neoplasm associated with somatic mutations in the genes involved in the RAF/MEK/ERK signaling pathway. Recently, oncogenic mutations in NRAS/KRAS, upstream regulators of the RAF/MEK/ERK pathway, have been reported in pulmonary, but not in non-pulmonary, LCH cases, suggesting organ-specific contribution of oncogenic RAS to LCH pathogenesis. Using a mouse model expressing KRAS(G12D) in the lung by nasal delivery of adenoviral Cre, here we show that KRAS(G12D) expression in lung-resident myeloid cells induces pulmonary LCH-like neoplasms comprised of pathogenic CD11c(high)F4/80+CD207+ cells...
May 26, 2017: Blood
https://www.readbyqxmd.com/read/28549900/four-decades-of-ocular-renin-angiotensin-and-kallikrein-kinin-systems-1977-2017
#6
REVIEW
Rajko Igić
This review offers a contemporary history of the renin-angiotensin (RAS) and kallikrein-kinin (KKS) systems with emphasis on how these complex systems affect the eye. It describes the types of communication (cross-talk) between the two systems and evaluates their potential role in the development of diabetic retinopathy, diabetic macular edema, age-related macular degeneration, glaucoma, and uveitis. In addition to detailing the important physiological actions of components of the RAS and KKS, possibilities are suggested for new therapeutic avenues in the treatment of common ocular diseases...
May 23, 2017: Experimental Eye Research
https://www.readbyqxmd.com/read/28549012/ras-mutation-clinical-risk-score-to-predict-survival-after-resection-of-colorectal-liver-metastases
#7
Kristoffer W Brudvik, Robert P Jones, Felice Giuliante, Junichi Shindoh, Guillaume Passot, Michael H Chung, Juhee Song, Liang Li, Vegar J Dagenborg, Åsmund A Fretland, Bård Røsok, Agostino M De Rose, Francesco Ardito, Bjørn Edwin, Elena Panettieri, Luigi M Larocca, Suguru Yamashita, Claudius Conrad, Thomas A Aloia, Graeme J Poston, Bjørn A Bjørnbeth, Jean-Nicolas Vauthey
OBJECTIVE: To determine the impact of RAS mutation status on the traditional clinical score (t-CS) to predict survival after resection of colorectal liver metastases (CLM). BACKGROUND: The t-CS relies on the following factors: primary tumor nodal status, disease-free interval, number and size of CLM, and carcinoembryonic antigen level. We hypothesized that the addition of RAS mutation status could create a modified clinical score (m-CS) that would outperform the t-CS...
May 25, 2017: Annals of Surgery
https://www.readbyqxmd.com/read/28548933/kir2dl5-mutation-and-loss-underlies-sporadic-dermal-neurofibroma-pathogenesis-and-growth
#8
Corina Anastasaki, Sonika Dahiya, David H Gutmann
Dermal neurofibromas (DNFs) are benign peripheral nerve sheath tumors thought to originate from Schwann cell progenitors. These tumors represent one of the hallmarks of the neurofibromatosis type 1 (NF1) tumor predisposition syndrome, where they can number in the thousands. While NF1-DNFs arise due to mutations in the NF1 gene, the vast majority of DNFs occur sporadically (sp-DNFs), where the genetic etiology is currently unknown. Herein, we employed whole-exome sequencing of sp-DNFs to identify a recurrent mutation in the KIR2DL5 gene, which codes for a protein suppressor of natural killer (NK) cell activity...
May 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28548879/ras-and-rho-gtpase-regulation-of-pol-ii-transcription-a-shortcut-model-revisited
#9
Zhi-Liang Zheng
Transcriptional control is critical in relaying signals mediated by Ras and Rho family small GTPases to effect gene expression. In the classical model, signaling components such as MAP kinase target sequence-specific transcription factors, which in turn recruit RNA polymerase (Pol) II holoenzyme to the promoter and activate transcription. Findings in recent years have led to the proposal of a shortcut model in which the mediator components of the Pol II holoenzyme are regulated by signaling pathways. A very recent finding shows that an evolutionarily conserved Rho GTPase signaling pathway can directly modulate the Pol II C-terminal domain (CTD) phosphorylation by inhibiting the CTD phosphatase in yeast and Arabidopsis...
May 26, 2017: Transcription
https://www.readbyqxmd.com/read/28548091/cellular-interplay-via-cytokine-hierarchy-causes-pathological-cardiac-hypertrophy-in-raf1-mutant-noonan-syndrome
#10
Jiani C Yin, Mathew J Platt, Xixi Tian, Xue Wu, Peter H Backx, Jeremy A Simpson, Toshiyuki Araki, Benjamin G Neel
Noonan syndrome (NS) is caused by mutations in RAS/ERK pathway genes, and is characterized by craniofacial, growth, cognitive and cardiac defects. NS patients with kinase-activating RAF1 alleles typically develop pathological left ventricular hypertrophy (LVH), which is reproduced in Raf1(L613V/+) knock-in mice. Here, using inducible Raf1(L613V) expression, we show that LVH results from the interplay of cardiac cell types. Cardiomyocyte Raf1(L613V) enhances Ca(2+) sensitivity and cardiac contractility without causing hypertrophy...
May 26, 2017: Nature Communications
https://www.readbyqxmd.com/read/28546426/guanine-nucleotide-exchange-factor-epac2-dependent-activation-of-the-gtp-binding-protein-rap2a-mediates-camp-dependent-growth-arrest-in-neuroendocrine-cells
#11
Andrew C Emery, Wenqin Xu, Maribeth V Eiden, Lee E Eiden
First messenger-dependent activation of MAPKs in neuronal and endocrine cells is critical for cell differentiation and function and requires guanine nucleotide exchange factor (GEF)- mediated activation of downstream Ras-family small GTPases, which ultimately lead to ERK, JNK, and p38 phosphorylation. Because there are numerous GEFs and also a host of Ras-family small GTPases, it is important to know which specific GEF-small GTPase dyad functions in a given cellular process. Here, we investigated the upstream activators and downstream effectors of signaling via the GEF Epac2 in the neuroendocrine NS-1 cell line...
May 25, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28545687/synergistic-effect-of-mek-inhibitor-and-metformin-combination-in-low-grade-serous-ovarian-cancer
#12
Ismail Mert, Jasdeep Chhina, Ghassan Allo, Jing Dai, Shelly Seward, Mark S Carey, Marta Llaurado, Shailendra Giri, Ramandeep Rattan, Adnan R Munkarah
OBJECTIVE: Low-grade serous ovarian cancer (LGSOC) constitutes 5-8% of epithelial ovarian cancers and is refractory to chemotherapy. We and others have shown metformin to cause significant growth inhibition in high-grade ovarian cancer both in vitro and in vivo. Here, we aimed to analyze if metformin was effective in inhibiting proliferation of LGSOC alone and in combination with MEK inhibitor. METHODS: Three LGSOC lines (VOA1056, VOA1312 and VOA5646) were treated with metformin, trametinib or 2-deoxyglucose (2DG) alone or in combination with metformin...
May 22, 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28545219/new-species-for-the-biomitigation-of-a-super-intensive-marine-fish-farm-effluent-combined-use-of-polychaete-assisted-sand-filters-and-halophyte-aquaponics
#13
Bruna Marques, Ricardo Calado, Ana I Lillebø
The main objective of this study was to test an innovative biomitigation approach, where polychaete-assisted (Hediste diversicolor) sand filters were combined with the production of Halimione portulacoides in aquaponics, to remediate an organic-rich effluent generated by a super intensive fish farm operating a land-based RAS (Recirculating aquaculture system). The set up included four different experimental combinations that were periodically monitored for 5months. After this period, polychaete-assisted sand filters reduced in 70% the percentage of OM and the average densities increased from ≈400ind...
May 21, 2017: Science of the Total Environment
https://www.readbyqxmd.com/read/28544747/k-ras-mutation-and-amplification-status-is-predictive-of-resistance-and-high-basal-pakt-is-predictive-of-sensitivity-to-everolimus-in-biliary-tract-cancer-cell-lines
#14
Yvonne Yeung, David K Lau, Fiona Chionh, Hoanh Tran, Janson W T Tse, Andrew J Weickhardt, Mehrdad Nikfarjam, Andrew M Scott, Niall C Tebbutt, John M Mariadason
Advanced biliary tract cancer (BTC) has a poor prognosis and limited treatment options. The PI3K/Akt/mTOR signaling pathway is hyperactivated in a subset of BTCs and clinical activity to the mTOR inhibitor everolimus has been observed in some BTC patients. The goal of this study was to identify biomarkers predictive of everolimus response. Twenty BTC cell lines were assessed for everolimus sensitivity with a spectrum of growth inhibitory responses observed. Molecular biomarkers of sensitivity and resistance were identified by interrogation of the activation status of the Ras/MAPK and PI3K/Akt/mTOR pathways...
May 24, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28544128/a-pediatric-trial-of-radiation-cetuximab-followed-by-irinotecan-cetuximab-in-newly-diagnosed-diffuse-pontine-gliomas-and-high-grade-astrocytomas-a-pediatric-oncology-experimental-therapeutics-investigators-consortium-study
#15
Margaret E Macy, Mark W Kieran, Susan N Chi, Kenneth J Cohen, Tobey J MacDonald, Amy A Smith, Michael M Etzl, Michele C Kuei, Andrew M Donson, Lia Gore, Jennifer DiRenzo, Tanya M Trippett, Irina Ostrovnaya, Aru Narendran, Nicholas K Foreman, Ira J Dunkel
BACKGROUND: Diffuse intrinsic pontine gliomas (DIPGs) and high-grade astrocytomas (HGA) continue to have dismal prognoses. The combination of cetuximab and irinotecan was demonstrated to be safe and tolerable in a previous pediatric phase 1 combination study. We developed this phase 2 trial to investigate the safety and efficacy of cetuximab given with radiation therapy followed by adjuvant cetuximab and irinotecan. METHODS: Eligible patients of age 3-21 years had newly diagnosed DIPG or HGA...
May 24, 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28543912/association-study-of-interleukin-1-family-interleukin-6-and-its-receptor-gene-polymorphisms-in-patients-with-recurrent-aphthous-stomatitis
#16
Lydie Izakovicova Holla, Simona Valova, Petra Borilova Linhartova, Jirina Bartova, Jitka Petanova, Pavel Kuklinek, Antonin Fassmann
BACKGROUND: Recurrent aphthous stomatitis (RAS) is one of the most common oral chronic ulcerative disease in which proinflammatory cytokines such as interleukin 1 (IL-1) and interleukin 6 (IL-6) are thought to play an important role. The aim of this study was to investigate the possible association between polymorphisms in the IL-1 cytokine family, IL-6 or its receptor and RAS in the Czech population. METHODS: A total of 248 subjects, 184 healthy controls and 64 patients with RAS were genotyped for IL-1A-889C>T, IL-1B-511C>T, IL-1B+3953C>T, IL-1RN86 bp variable number of tandem repeats (VNTR) in intron 2, IL-6-597G>A, IL-6-572G>C, IL-6-174G>C and IL-6R+48992A>C by polymerase chain reaction (PCR) methods...
May 20, 2017: Journal of Oral Pathology & Medicine
https://www.readbyqxmd.com/read/28543352/effect-of-albiglutide-on-cholecystokinin-induced-gallbladder-emptying-in-healthy-individuals-a-randomized-crossover-study
#17
Bonnie C Shaddinger, Malcolm A Young, Julia Billiard, David A Collins, Azra Hussaini, Antonio Nino
The glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) exenatide and lixisenatide reduce cholecystokinin (CCK)-induced gallbladder emptying in healthy subjects. It is unknown if all GLP-1 RAs share this effect; therefore, the effect of the GLP-1 RA albiglutide on gallbladder function was assessed. In this randomized, double-blind, 2-way crossover study, a single dose of subcutaneous albiglutide 50 mg or placebo was administered to 17 healthy subjects, and CCK-induced gallbladder contractility was measured by ultrasonography...
May 19, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28542501/a-rho-associated-coiled-coil-containing-kinases-rock-inhibitor-y-27632-enhances-adhesion-viability-and-differentiation-of-human-term-placenta-derived-trophoblasts-in-vitro
#18
Kenichiro Motomura, Naoko Okada, Hideaki Morita, Mariko Hara, Masato Tamari, Keisuke Orimo, Go Matsuda, Ken-Ichi Imadome, Akio Matsuda, Takeshi Nagamatsu, Mikiya Fujieda, Haruhiko Sago, Hirohisa Saito, Kenji Matsumoto
Although human term placenta-derived primary cytotrophoblasts (pCTBs) represent a good human syncytiotrophoblast (STB) model, in vitro culture of pCTBs is not always easily accomplished. Y-27632, a specific inhibitor of Rho-associated coiled-coil containing kinases (ROCK), reportedly prevented apoptosis and improved cell-to-substrate adhesion and culture stability of dissociated cultured human embryonic stem cells and human corneal endothelial cells. The Rho kinase pathway regulates various kinds of cell behavior, some of which are involved in pCTB adhesion and differentiation...
2017: PloS One
https://www.readbyqxmd.com/read/28542095/magnetization-transfer-magnetic-resonance-imaging-noninvasively-detects-renal-fibrosis-in-swine-atherosclerotic-renal-artery-stenosis-at-3-0-t
#19
Kai Jiang, Christopher M Ferguson, John R Woollard, Xiangyang Zhu, Lilach O Lerman
OBJECTIVES: Renal fibrosis is a useful biomarker for diagnosis and evaluation of therapeutic interventions of renal diseases but often requires invasive testing. Magnetization transfer magnetic resonance imaging (MT-MRI), which evaluates the presence of macromolecules, offers a noninvasive tool to probe renal fibrosis in murine renal artery stenosis (RAS) at 16.4 T. In this study, we aimed to identify appropriate imaging parameters for collagen detection at 3.0 T MRI and to test the utility of MT-MRI in measuring renal fibrosis in a swine model of atherosclerotic RAS (ARAS)...
May 24, 2017: Investigative Radiology
https://www.readbyqxmd.com/read/28540724/pde%C3%AE-binding-to-ras-isoforms-provides-a-route-to-proper-membrane-localization
#20
Serena Muratcioglu, Hyunbum Jang, Attila Gursoy, Ozlem Keskin, Ruth Nussinov
To signal, Ras isoforms must be enriched at the plasma membrane (PM). It was suggested that phosphodiesterase-δ (PDEδ) can bind and shuttle some farnesylated Ras isoforms to the PM - but not all. Among these, interest focused on K-Ras4B, the most abundant oncogenic Ras isoform. To study PDEδ/Ras interactions, we modeled and simulated the PDEδ/K-Ras4B complex. We obtained structures which were similar to two subsequently determined crystal structures. We next modeled and simulated complexes of PDEδ with the farnesylated hypervariable regions (HVRs) of K-Ras4A and N-Ras...
May 25, 2017: Journal of Physical Chemistry. B
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