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https://www.readbyqxmd.com/read/28728003/evaluation-of-the-effects-of-low-energetic-microwave-irradiation-on-anaerobic-digestion
#1
Bert Bastiaens, Rob Van den Broeck, Lise Appels, Raf Dewil
The present study investigates the effects of microwave irradiation on the performance of anaerobic digestion processes. A first set of experiments is performed to distinguish the upper limit of the applied energy levels. Secondly, the effects of these treatments on the performance of the digestion process are evaluated in 3 experimental setups: (i) monitoring the acetic acid degradation, (ii) performing a biological methane potential (BMP) assay and (iii) conducting a specific methanogenic activity (SMA) test...
July 17, 2017: Journal of Environmental Management
https://www.readbyqxmd.com/read/28724936/an-engineered-protein-antagonist-of-k-ras-b-raf-interaction
#2
Monique J Kauke, Michael W Traxlmayr, Jillian A Parker, Jonathan D Kiefer, Ryan Knihtila, John McGee, Greg Verdine, Carla Mattos, K Dane Wittrup
Ras is at the hub of signal transduction pathways controlling cell proliferation and survival. Its mutants, present in about 30% of human cancers, are major drivers of oncogenesis and render tumors unresponsive to standard therapies. Here we report the engineering of a protein scaffold for preferential binding to K-Ras G12D. This is the first reported inhibitor to achieve nanomolar affinity while exhibiting specificity for mutant over wild type (WT) K-Ras. Crystal structures of the protein R11.1.6 in complex with K-Ras WT and K-Ras G12D offer insight into the structural basis for specificity, highlighting differences in the switch I conformation as the major defining element in the higher affinity interaction...
July 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28724666/braf-inhibitors-amplify-the-pro-apoptotic-activity-of-mek-inhibitors-by-inducing-er-stress-in-nras-mutant-melanoma
#3
Heike Niessner, Tobias Sinnberg, Corinna Kosnopfel, Keiran S M Smalley, Daniela Beck, Christian Praetorius, Marion Mai, Stefan Beissert, Dagmar Kulms, Martin Schaller, Claus Garbe, Keith T Flaherty, Dana Westphal, Ines Wanke, Friedegund Meier
<p>NRAS mutations in malignant melanoma are associated with aggressive disease requiring rapid antitumor intervention, but there is no approved targeted therapy for this subset of patients. In clinical trials, the MEK inhibitor (MEKi) binimetinib displayed modest antitumor activity, making combinations a requisite. In a previous study, the BRAF inhibitor (BRAFi) vemurafenib was shown to induce endoplasmic reticulum (ER) stress that together with inhibition of the RAF-MEK-ERK (MAPK) pathway amplified its pro-apoptotic activity in BRAF-mutant melanoma...
July 19, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28724426/high-expression-of-ets2-predicts-poor-prognosis-in-acute-myeloid-leukemia-and-may-guide-treatment-decisions
#4
Lin Fu, Huaping Fu, Qingyun Wu, Yifan Pang, Keman Xu, Lei Zhou, Jianlin Qiao, Xiaoyan Ke, Kailin Xu, Jinlong Shi
BACKGROUND: ETS2 is a downstream effector of the RAS/RAF/ERK pathway, which plays a critical role in the development of malignant tumor. However, the clinical impact of ETS2 expression in AML remains unknown. METHODS: In this study, we evaluated the prognostic significance of ETS2 expression using two relatively large cohorts of AML patients. RESULTS: In the first cohort, compared to low expression of ETS2 (ETS2 (low)), high expression of ETS2 (ETS2 (high)) showed significant shorter OS, EFS and RFS in the current treatments including the allogeneic HCT group (n = 72) and the chemotherapy group (n = 100)...
July 19, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/28724377/combination-therapy-for-melanoma-with-braf-mek-inhibitor-and-immune-checkpoint-inhibitor-a-mathematical-model
#5
Xiulan Lai, Avner Friedman
BACKGROUND: The B-raf gene is mutated in up to 66% of human malignant melanomas, and its protein product, BRAF kinase, is a key part of RAS-RAF-MEK-ERK (MAPK) pathway of cancer cell proliferation. BRAF-targeted therapy induces significant responses in the majority of patients, and the combination BRAF/MEK inhibitor enhances clinical efficacy, but the response to BRAF inhibitor and to BRAF/MEK inhibitor is short lived. On the other hand, treatment of melanoma with an immune checkpoint inhibitor, such as anti-PD-1, has lower response rate but the response is much more durable, lasting for years...
July 19, 2017: BMC Systems Biology
https://www.readbyqxmd.com/read/28723153/understanding-the-reactivity-of-co3-%C3%A2-and-no2-%C3%A2-radicals-towards-s-containing-and-aromatic-amino-acids
#6
Sharmistha Karmakar, Ayan Datta
The reactivity of CO3-(.) and NO2(.) radicals towards six amino acid side chains namely, cysteine (Cys), methionine (Met), phenylalanine (Phe), tyrosine (Tyr), histidine (His) and tryptophan (Trp), has been explored using state-of-art density functional theory (DFT) and transition state theory (TST). Three reaction mechanisms, namely hydrogen atom abstraction (HAT), radical adduct formation (RAF) and single electron transfer (SET) have been considered for detailed study. While CO3-(.) radical is highly reactive towards majority of amino acids, the reactivity of NO2(...
July 19, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28722501/pediatric-endonasal-dacryocystorhinostomy-a-multicenter-series-of-116-cases
#7
WengOnn Chan, Geoff Wilcsek, Raf Ghabrial, Robert Alan Goldberg, Peter Dolman, Dinesh Selva, Raman Malhotra
We report our experience with pediatric endonasal dacryocystorhinostomy (DCR). Multicenter, retrospective, noncomparative study. Cases of pediatric endonasal DCR during 2006-2011 were included from six oculoplastic units. Patients over the age of 16 years were excluded. The outcomes of pediatric endonasal DCR are presented. Indication for surgery, demographics, previous interventions, intraoperative or postoperative complications, follow-up duration, and success rate (defined as significant improvement of epiphora) were evaluated...
July 19, 2017: Orbit
https://www.readbyqxmd.com/read/28720574/fructose-1-6-bisphosphatase-inhibits-erk-activation-and-bypasses-gemcitabine-resistance-in-pancreatic-cancer-by-blocking-iqgap1-mapk-interaction
#8
Xin Jin, Yunqian Pan, Liguo Wang, Tao Ma, Lizhi Zhang, Amy H Tang, Daniel D Billadeau, Heshui Wu, Haojie Huang
Dysregulation of the mitogen-activated protein kinase (MAPK) pathway correlates with progression of pancreatic ductal adenocarcinoma (PDAC) progression. IQ motif containing GTPase activating protein 1 (IQGAP1) is a MAPK scaffold that directly regulates the activation of RAF, MEK, and extracellular signaling-regulated kinases (ERK). Fructose-1,6-bisphosphatase (FBP1), a key enzyme in gluconeogenesis, is transcriptionally downregulated in various cancers, including PDAC. Here we demonstrate that FBP1 acts as a negative modulator of the IQGAP1-MAPK signaling axis in PDAC cells...
July 18, 2017: Cancer Research
https://www.readbyqxmd.com/read/28720517/transient-receptor-potential-trpm3-channels-pharmacology-signaling-and-biological-functions
#9
REVIEW
Gerald Thiel, Sandra Rubil, Andrea Lesch, Lisbeth A Guethlein, Oliver G Rössler
The transient receptor potential melastatin-3 (TRPM3) channel belongs to the family of transient receptor potential (TRP) cation channels that are expressed in a variety of tissues and cell types, including dorsal root ganglia, cardiomyocytes and pancreatic beta-cells. Although its natural ligands are currently unknown, TRPM3 channels can be activated by the neurosteroid pregnenolone sulfate, the synthetic ligand CIM0216, and by noxious heat. TRPM3 channels are regulated by phosphoinositides, and perhaps by calmodulin...
July 15, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28720430/oncogenic-pathways-that-affect-antitumor-immune-response-and-immune-checkpoint-blockade-therapy
#10
REVIEW
Xianda Zhao, Subbaya Subramanian
Mechanistic insights of cancer immunology have led to the development of immune checkpoint blockade therapy (ICBT), which has elicited a remarkable clinical response in some cancer patients. Increasing evidence suggests that activation of oncogenic pathways, such as RAS/RAF/MAPK and PI3K signaling, impairs the antitumor immune response. Such oncogenic signaling, in turn, activates many inhibitory factors, including expression of immune checkpoint genes-allowing active infiltration of immunosuppressive cells into the tumor environment and inducing resistance against T-cell killing...
July 15, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28719152/a-first-in-human-phase-i-multicenter-open-label-dose-escalation-study-of-the-oral-raf-vegfr-2-inhibitor-raf265-in-locally-advanced-or-metastatic-melanoma-independent-from-braf-mutation-status
#11
Benjamin Izar, William Sharfman, F Stephen Hodi, Donald Lawrence, Keith T Flaherty, Ravi Amaravadi, Kevin B Kim, Igor Puzanov, Jeffrey Sosman, Reinhard Dummer, Simone M Goldinger, Lyhping Lam, Shefali Kakar, Zhongwen Tang, Oliver Krieter, David F McDermott, Michael B Atkins
To establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety profile, and anti-tumor efficacy of RAF265. We conducted a multicenter, open-label, phase-I, dose-escalation trial of RAF265, an orally available RAF kinase/VEGFR-2 inhibitor, in patients with advanced or metastatic melanoma. Pharmacokinetic (PK) analysis, pharmacodynamics (PD) and tumor response assessment were conducted. We evaluated metabolic tumor response by 18[F]-fluorodeoxyglucose-positron-emission tomography (FDG-PET), tissue biomarkers using immunohistochemistry (IHC), and modulators of angiogenesis...
July 18, 2017: Cancer Medicine
https://www.readbyqxmd.com/read/28718440/selective-targeting-of-rsk-isoforms-in-cancer
#12
REVIEW
Kimberly A Casalvieri, Christopher J Matheson, Donald S Backos, Philip Reigan
The p90 ribosomal S6 kinase family (RSK1-4) is a group of highly conserved Ser/Thr kinases that act as downstream effectors of the Ras/Raf/MEK/ERK signaling pathway. The RSKs phosphorylate a range of substrates involved in transcription, translation, cell cycle regulation, and cell survival. Although the RSKs have a high degree of sequence homology, their functional differences in cancer are of great interest. Current RSK inhibitors target more than one RSK isoform, and this may limit their efficacy as anticancer agents...
April 2017: Trends in Cancer
https://www.readbyqxmd.com/read/28717400/treatment-of-nras-mutated-advanced-or-metastatic-melanoma-rationale-current-trials-and-evidence-to-date
#13
REVIEW
Amélie Boespflug, Julie Caramel, Stephane Dalle, Luc Thomas
The disease course of BRAF (v-raf murine sarcoma viral oncogene homolog B1)-mutant melanoma has been drastically improved by the arrival of targeted therapies. NRAS (neuroblastoma RAS viral oncogene homolog)-mutated melanoma represents 15-25% of all metastatic melanoma patients. It currently does not have an approved targeted therapy. Metastatic patients receive immune-based therapies as first-line treatments, then cytotoxic chemotherapy like carboplatin/paclitaxel (C/P), dacarbazine (DTIC) or temozolomide (TMZ) as a second-line treatment...
July 2017: Therapeutic Advances in Medical Oncology
https://www.readbyqxmd.com/read/28714990/an-approach-to-suppress-the-evolution-of-resistance-in-braf-v600e-mutant-cancer
#14
Yaohua Xue, Luciano Martelotto, Timour Baslan, Alberto Vides, Martha Solomon, Trang Thi Mai, Neelam Chaudhary, Greg J Riely, Bob T Li, Kerry Scott, Fabiola Cechhi, Ulrika Stierner, Kalyani Chadalavada, Elisa de Stanchina, Sarit Schwartz, Todd Hembrough, Gouri Nanjangud, Michael F Berger, Jonas Nilsson, Scott W Lowe, Jorge S Reis-Filho, Neal Rosen, Piro Lito
The principles that govern the evolution of tumors exposed to targeted therapy are poorly understood. Here we modeled the selection and propagation of an amplification in the BRAF oncogene (BRAF(amp)) in patient-derived tumor xenografts (PDXs) that were treated with a direct inhibitor of the kinase ERK, either alone or in combination with other ERK signaling inhibitors. Single-cell sequencing and multiplex fluorescence in situ hybridization analyses mapped the emergence of extra-chromosomal amplification in parallel evolutionary trajectories that arose in the same tumor shortly after treatment...
July 17, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28708103/pharmacogenomics-of-targeted-agents-for-personalization-of-colorectal-cancer-treatment
#15
REVIEW
Alessia Bignucolo, Elena De Mattia, Erika Cecchin, Rossana Roncato, Giuseppe Toffoli
The use of targeted agents in the treatment of metastatic colorectal cancer (CRC) has improved patient outcomes. Anti-epidermal growth factor receptor (anti-EGFR) agents (cetuximab and panitumumab) and antiangiogenic molecules (bevacizumab, regorafeninb, ramucirumab, and aflibercept) have been successfully integrated into clinical practice. Other drugs have been designed to target additional deregulated pathways in CRC, such as MAPK (mitogen-activated protein kinase)/PI3K-AKT (phosphatidylinositol-3-kinase-AKT serine/threonine kinase)/mTOR (mammalian target of rapamycin), HER-2 and 3 ( human epidermal growth factor receptor-2 and -3), and BRAF...
July 14, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28705542/effect-of-coronary-artery-disease-risk-snps-on-serum-cytokine-levels-and-cytokine-imbalance-in-premature-coronary-artery-disease
#16
Wafa M Ansari, Steve E Humphries, Abdul K Naveed, Omer J Khan, Dilshad A Khan, Ejaz Hassan Khattak
BACKGROUND: Premature Coronary Artery Disease (PCAD) occurs almost a decade earlier in the South Asian population as compared to the West. Inclusion of genetic information can prove to be a robust measure to improve early risk prediction of PCAD. Aim was to estimate the genotypic distribution and risk allele frequencies of 13 Coronary Artery Disease (CAD) risk Single Nucleotide Polymorphisms in loci identified by the CARDIoGRAMplusC4D consortium namely MIA3 rs17465637; 9p21 rs10757274; CXCL12 rs1746048; APOA5 rs662799; APOB rs1042031; LPA rs3798220; LPA 10455872; MRAS rs9818870; LPL rs328; SORT1 rs646776; PCSK9 rs11591147; APOE rs429358; APOE rs7412 in Pakistani PCAD patients and controls...
July 10, 2017: Cytokine
https://www.readbyqxmd.com/read/28700341/survival-of-metastatic-melanoma-patients-after-dendritic-cell-vaccination-correlates-with-expression-of-leukocyte-phosphatidylethanolamine-binding-protein-1-raf-kinase-inhibitory-protein
#17
Sonja I Buschow, Matteo Ramazzotti, Inge M J Reinieren-Beeren, Lucie M Heinzerling, Harm Westdorp, Irene Stefanini, Luca Beltrame, Stanleyson V Hato, Eva Ellebaek, Stefanie Gross, Van Anh Nguyen, Georg Weinlich, Jiannis Ragoussis, Dilair Baban, Beatrice Schuler-Thurner, Inge M Svane, Nikolaus Romani, Jonathan M Austyn, I Jolanda M De Vries, Gerold Schuler, Duccio Cavalieri, Carl G Figdor
Immunotherapy for metastatic melanoma offers great promise but, to date, only a subset of patients have responded. There is an urgent need to identify ways of allocating patients to the most beneficial therapy, to increase survival and decrease therapy-associated morbidity and costs. Blood-based biomarkers are of particular interest because of their straightforward implementation in routine clinical care. We sought to identify markers for dendritic cell (DC) vaccine-based immunotherapy against metastatic melanoma through gene expression analysis of peripheral blood mononuclear cells...
June 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28698230/chromoendoscopy-versus-narrow-band-imaging-in-uc-a-prospective-randomised-controlled-trial
#18
Raf Bisschops, Talat Bessissow, Joseph A Joseph, Filip Baert, Marc Ferrante, Vera Ballet, Hilde Willekens, Ingrid Demedts, Karel Geboes, Gert De Hertogh, Séverine Vermeire, Paul Rutgeerts, Gert Van Assche
BACKGROUND: Patients with long-standing UC have an increased risk for the development of colonic neoplastic lesions. Chromoendoscopy (CE) has been proven to enhance neoplasia detection while the role of virtual chromoendoscopy (VC) is still to be defined. OBJECTIVE: To compare the performance of CE to VC for the detection of neoplastic lesions in patients with long-standing UC. DESIGN: A multicentre prospective randomised controlled trial...
July 11, 2017: Gut
https://www.readbyqxmd.com/read/28694330/phosphorylation-of-the-c-raf-n-region-promotes-raf-dimerization
#19
Maho Takahashi, Yanping Li, Tara J Dillon, Yumi Kariya, Philip J S Stork
Activation of Raf kinases by the small GTPase Ras requires two major sets of phosphorylations. One set lies within the activation loop and the other lies within the N-terminal acidic region (N-region). In the most abundant isoform of Raf, C-Raf, N-region phosphorylations occur on serine 338 (S338) and tyrosine 341 (Y341), and are thought to provide allosteric activation of the Raf dimer. We show that the phosphorylation of these N-region sites does not require C-Raf dimerization, but rather, they precede dimerization...
July 10, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28693379/incidence-of-osteonecrosis-of-the-jaw-in-patients-with-bone-metastases-treated-sequentially-with-bisphosphonates-and-denosumab
#20
Tine Loyson, Thomas Van Cann, Patrick Schöffski, Paul M Clement, Oliver Bechter, Isabel Spriet, Ruxandra Coropciuc, Constantinus Politis, Raf O Vandeweyer, Joseph Schoenaers, Herlinde Dumez, Patrick Berteloot, Patrick Neven, Kristiaan Nackaerts, Feng J S H Woei-A-Jin, Kevin Punie, Hans Wildiers, Benoit Beuselinck
OBJECTIVES: Osteonecrosis of the jaw (ONJ) is a serious adverse event of bone resorption inhibitors (BRIs), such as bisphosphonates and denosumab. Bisphosphonates and denosumab inhibit osteoclast function through different pharmacological effects and bisphosphonates are retained in bone for several months to years. Sequential treatment with bisphosphonates and denosumab might lead to an overlapping treatment effect, due to the addition of the effect of denosumab on the residual bisphosphonate effect...
July 10, 2017: Acta Clinica Belgica
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