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https://www.readbyqxmd.com/read/28098945/frequency-of-cnksr2-mutation-in-the-x-linked-epilepsy-aphasia-spectrum
#1
John A Damiano, Rosemary Burgess, Sara Kivity, Tally Lerman-Sagie, Zaid Afawi, Ingrid E Scheffer, Samuel F Berkovic, Michael S Hildebrand
Synaptic proteins are critical to neuronal function in the brain, and their deficiency can lead to seizures and cognitive impairments. CNKSR2 (connector enhancer of KSR2) is a synaptic protein involved in Ras signaling-mediated neuronal proliferation, migration and differentiation. Mutations in the X-linked gene CNKSR2 have been described in patients with seizures and neurodevelopmental deficits, especially those affecting language. In this study, we sequenced 112 patients with phenotypes within the epilepsy-aphasia spectrum (EAS) to determine the frequency of CNKSR2 mutation within this complex set of disorders...
January 18, 2017: Epilepsia
https://www.readbyqxmd.com/read/28098907/synergistic-combination-of-ys-1-and-adriamycin-inhibits-human-renal-cancer-through-erk1-2-signaling-pathway-in%C3%A2-vitro-and-in%C3%A2-vivo
#2
Xiaowen Yu, Qingqing Yang, Sensen Lin, Shengtao Yuan, Li Sun
Adriamycin (ADM) is a principal drug for the treatment of renal cell cancer (RCC). Due to its limited response and high renal and cardiac toxicity, synergistic effects of ADM in combination with other drugs have been widely researched. In this study, we found the combination between YS-1 and ADM, performed higher anticancer activity on 786-O human RCC cells in vitro and in vivo, than that reported on its anti-angiogenesis effect compared with monotherapy of ADM. Our data showed that when combined with ADM, YS-1 promoted the sensitivity of 786-O cells to ADM...
January 16, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28098884/renin-angiotensin-system-activation-accelerates-atherosclerosis-in-experimental-renal-failure-by-promoting-endoplasmic-reticulum-stress-related-inflammation
#3
Jia Yang, Xi Zhang, Xinyi Yu, Weixue Tang, Hua Gan
In this study, we investigated the association between the renin-angiotensin system (RAS), endoplasmic reticulum (ER) stress and atherosclerosis (AS) in uremic apolipoprotein E knockout (apoE-/-) mice. Mild uremia was induced by a 5/6 nephrectomy (5/6 Nx) in 10-week-old apoE-/- mice. Four weeks after nephrectomy, the mice received losartan or no treatment for 16 weeks. Sham-operated mice served as the controls. We found that uremia accelerated AS at the aortic root. The activation of ER stress and the significant upregulation of pro-inflammatory cytokines and chemokines were observed in the uremic mice...
January 12, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28098870/mir-148a-increases-the-sensitivity-to-cisplatin-by-targeting-rab14-in-renal-cancer-cells
#4
Eun-Ae Kim, Tae Ghab Kim, Eon-Gi Sung, In-Hwan Song, Joo-Young Kim, Kyung-Oh Doh, Tae-Jin Lee
MicroRNA (miR) can exert various biological functions by targeting oncogenes or tumor suppressor genes in numerous human malignancies. Recent evidence has shown that miR-148a increases the drug sensitivity of various cancer cells. Herein, we show that ectopic expression of miR-148a induces apoptosis, reduces clonogenicity, and increases the sensitivity to TRAIL and cisplatin in renal cancer cells. The luciferase reporter assay showed that miR-148a negatively regulated ras-related protein 14 (Rab14) expression by binding to the miR-148a binding site in the 3' untranslated region (3'UTR) of Rab14...
January 17, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28098823/integrative-mirna-gene-expression-analysis-enables-refinement-of-associated-biology-and-prediction-of-response-to-cetuximab-in-head-and-neck-squamous-cell-cancer
#5
Loris De Cecco, Marco Giannoccaro, Edoardo Marchesi, Paolo Bossi, Federica Favales, Laura D Locati, Lisa Licitra, Silvana Pilotti, Silvana Canevari
This paper documents the process by which we, through gene and miRNA expression profiling of the same samples of head and neck squamous cell carcinomas (HNSCC) and an integrative miRNA-mRNA expression analysis, were able to identify candidate biomarkers of progression-free survival (PFS) in patients treated with cetuximab-based approaches. Through sparse partial least square-discriminant analysis (sPLS-DA) and supervised analysis, 36 miRNAs were identified in two components that clearly separated long- and short-PFS patients...
January 14, 2017: Genes
https://www.readbyqxmd.com/read/28098151/juvenile-myelomonocytic-leukemia-associated-variants-are-associated-with-neo-natal-lethal-noonan-syndrome
#6
Heather Mason-Suares, Diana Toledo, Jean Gekas, Katherine A Lafferty, Naomi Meeks, M Cristina Pacheco, David Sharpe, Thomas E Mullen, Matthew S Lebo
Gain-of-function variants in some RAS-MAPK pathway genes, including PTPN11 and NRAS, are associated with RASopathies and/or acquired hematological malignancies, most notably juvenile myelomonocytic leukemia (JMML). With rare exceptions, the spectrum of germline variants causing RASopathies does not overlap with the somatic variants identified in isolated JMML. Studies comparing these variants suggest a stronger gain-of-function activity in the JMML variants. As JMML variants have not been identified as germline defects and have a greater impact on protein function, it has been speculated that they would be embryonic lethal...
January 18, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28096419/stromal-cues-regulate-the-pancreatic-cancer-epigenome-and-metabolome
#7
Mara H Sherman, Ruth T Yu, Tiffany W Tseng, Cristovao M Sousa, Sihao Liu, Morgan L Truitt, Nanhai He, Ning Ding, Christopher Liddle, Annette R Atkins, Mathias Leblanc, Eric A Collisson, John M Asara, Alec C Kimmelman, Michael Downes, Ronald M Evans
A fibroinflammatory stromal reaction cooperates with oncogenic signaling to influence pancreatic ductal adenocarcinoma (PDAC) initiation, progression, and therapeutic outcome, yet the mechanistic underpinning of this crosstalk remains poorly understood. Here we show that stromal cues elicit an adaptive response in the cancer cell including the rapid mobilization of a transcriptional network implicated in accelerated growth, along with anabolic changes of an altered metabolome. The close overlap of stroma-induced changes in vitro with those previously shown to be regulated by oncogenic Kras in vivo suggests that oncogenic Kras signaling-a hallmark and key driver of PDAC-is contingent on stromal inputs...
January 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28096188/erk1-2-phosphorylate-gab2-to-promote-a-negative-feedback-loop-that-attenuates-pi3k-akt-signaling
#8
Xiaocui Zhang, Geneviève Lavoie, Antoine Méant, Léo Aubert, Marie Cargnello, André Haman, Trang Hoang, Philippe P Roux
The scaffolding adapter protein Gab2 (Grb2-associated binder) promotes cell proliferation, survival and motility by engaging several signaling pathways downstream of growth factor and cytokine receptors. In particular, Gab2 plays essential roles in mast cells as it is required for PI3K (phosphoinositide 3-kinase) activation in response to Kit and the high-affinity IgE receptor. While the positive role of Gab2 in PI3K signaling is well documented, very little is known about the mechanisms that attenuate its function...
January 17, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28096034/twelve-months-effect-of-self-referral-to-inpatient-treatment-on-patient-activation-recovery-symptoms-and-functioning-a-randomized-controlled-study
#9
I E O Moljord, M L Lara-Cabrera, Ø Salvesen, M B Rise, D Bjørgen, D Ø Antonsen, T M Olsø, G H Evensen, C B Gudde, O M Linaker, A Steinsbekk, L Eriksen
OBJECTIVE: To investigate the effect of having a contract for self-referral to inpatient treatment (SRIT) in patients with severe mental disorders. METHODS: A randomized controlled trial with 53 adult patients; 26 participants received a SRIT contract, which they could use to refer themselves into a Community Mental Health Centre up to five days for each referral without contacting a doctor in advance. Outcomes were assessed after 12 months with the self-report questionnaires Patient Activation Measure (PAM-13), Recovery Assessment Scale (RAS), and the Behavior and Symptom Identification Scale (BASIS-32) and analyzed using linear mixed and regression models...
January 11, 2017: Patient Education and Counseling
https://www.readbyqxmd.com/read/28093501/discrete-cytosolic-macromolecular-braf-complexes-exhibit-distinct-activities-and-composition
#10
Britta Diedrich, Kristoffer Tg Rigbolt, Michael Röring, Ricarda Herr, Stephanie Kaeser-Pebernard, Christine Gretzmeier, Robert F Murphy, Tilman Brummer, Jörn Dengjel
As a central element within the RAS/ERK pathway, the serine/threonine kinase BRAF plays a key role in development and homeostasis and represents the most frequently mutated kinase in tumors. Consequently, it has emerged as an important therapeutic target in various malignancies. Nevertheless, the BRAF activation cycle still raises many mechanistic questions as illustrated by the paradoxical action and side effects of RAF inhibitors. By applying SEC-PCP-SILAC, we analyzed protein-protein interactions of hyperactive BRAF(V)(600E) and wild-type BRAF (BRAF(WT))...
January 16, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28093232/phospholipase-c%C3%AE%C2%B5-deficiency-delays-the-early-stage-of-cutaneous-wound-healing-and-attenuates-scar-formation-in-mice
#11
Xiaolong Zhu, Yue Sun, Xin Mu, Pan Guo, Fei Gao, Jing Zhang, Yunjuan Zhu, Xianzhi Zhang, Lingling Chen, Zhiwei Ning, Yunfeng Bai, Jiling Ren, Maoqiang Man, Peimei Liu, Lizhi Hu
This study aimed to investigate the role of phospholipase Cε (PLCε) in the skin wound healing process. PLCε, an effect factor of Ras/Rap small G protein, plays a crucial role in skin inflammation by regulating inflammatory cytokines. Inflammatory responses are closely associated with wound healing. Full-thickness skin wounds were made in the PLCε knockout (KO) and wild-type (WT) mice, and the healing process was analyzed. The macroscopic wound closure rate declined in the PLCε KO mice on days 3, 4, and 5 after wounding, following the decreased expression of interleukin (IL)-6, chemokine (C-X-C motif) ligand (Cxcl)-1, Cxcl-2, and chemokine (C-C motif) ligand (Ccl) 20...
January 13, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28092671/pde4d-promotes-fak-mediated-cell-invasion-in-braf-mutated-melanoma
#12
J Delyon, A Servy, F Laugier, J André, N Ortonne, M Battistella, S Mourah, A Bensussan, C Lebbé, N Dumaz
The cyclic AMP (cAMP) signaling pathway is critical in melanocyte biology for regulating differentiation. It is downregulated by phosphodiesterase (PDE) enzymes, which degrade cAMP itself. In melanoma evidence suggests that inhibition of the cAMP pathway by PDE type 4 (PDE4) favors tumor progression. For example, in melanomas harboring RAS mutations, the overexpression of PDE4 is crucial for MAPK pathway activation and proliferation induced by oncogenic RAS. Here we showed that PDE4D is overexpressed in BRAF-mutated melanoma cell lines, constitutively disrupting the cAMP pathway activation...
January 16, 2017: Oncogene
https://www.readbyqxmd.com/read/28091615/pirfenidone-controls-the-feedback-loop-of-the-at1r-p38-mapk-renin-angiotensin-system-axis-by-regulating-liver-x-receptor-%C3%AE-in-myocardial-infarction-induced-cardiac-fibrosis
#13
Chunmei Li, Rui Han, Le Kang, Jianping Wang, Yonglin Gao, Yanshen Li, Jie He, Jingwei Tian
Pirfenidone (PFD), an anti-fibrotic small molecule drug, is used to treat fibrotic diseases, but its effects on myocardial infarction (MI)-induced cardiac fibrosis are unknown. The aim of this study was to determine the effects of PFD on MI-induced cardiac fibrosis and the possible underlying mechanisms in rats. After establishment of the model, animals were administered PFD by gavage for 4 weeks. During the development of MI-induced cardiac fibrosis, we found activation of a positive feedback loop between the angiotensin II type 1 receptor (AT1R)/phospho-p38 mitogen-activated protein kinase (p38 MAPK) pathway and renin-angiotensin system (RAS), which was accompanied by down-regulation of liver X receptor-α (LXR-α) expression...
January 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28090762/use-of-ace-inhibition-and-blood-pressure-management-in-deferring-dialysis-initiation
#14
Lucia Del Vecchio, Ugo Teatini, Francesco Locatelli
Elevated blood pressure is one of the most significant risk factor for the development of chronic kidney disease (CKD); its treatment is a milestone in CKD management. While it is accepted that a stricter blood pressure control is indicated in patients with proteinuria or microalbuminuria, the exact degree of blood pressure reduction to be obtained in CKD patients is still under debate. Following more recent interpretation of old trials, a BP target for < 140/90 mmHg is suggested for non-proteinuric CKD patients...
January 13, 2017: Panminerva Medica
https://www.readbyqxmd.com/read/28090674/ns5b-promotes-degradation-of-the-nore1a-tumor-suppressor-to-facilitate-hepatitis-c-virus-replication
#15
Payal Arora, Amartya Basu, M Lee Schmidt, Geoffrey J Clark, Howard Donninger, Daniel B Nichols, Diego F Calvisi, Neerja Kaushik-Basu
: Hepatitis C infection is a common risk factor for the development of liver cancer. The molecular mechanisms underlying this effect are only partially understood. Here we show that the HCV protein NS5B directly binds to the tumor suppressor NORE1A (RASSF5) and promotes its proteosomal degradation. In addition, we show that NORE1A co-localizes to sites of HCV viral replication and suppresses the process. Thus, NORE1A has anti-viral activity which is specifically antagonized by NS5B. Moreover, the suppression of NORE1A protein levels correlated almost perfectly with elevation of Ras activity in primary human samples...
January 16, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28088467/stat3-signaling-mediates-tumour-resistance-to-egfr-targeted-therapeutics
#16
Ahmad A Zulkifli, Fiona H Tan, Tracy L Putoczki, Stanley S Stylli, Rodney B Luwor
Several EGFR inhibitors are currently undergoing clinical assessment or are approved for the clinical management of patients with varying tumour types. However, treatment often results in a lack of response in many patients. The majority of patients that initially respond eventually present with tumours that display acquired resistance to the original therapy. A large number of receptor tyrosine and intracellular kinases have been implicated in driving signaling that mediates this tumour resistance to anti-EGFR targeted therapy, and in a few cases these discoveries have led to overall changes in prospective tumour screening and clinical practice (K-RAS in mCRC and EGFR T790M in NSCLC)...
January 11, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28087344/up-regulation-of-the-active-form-of-small-gtpase-rab13-promotes-macroautophagy-in-vascular-endothelial-cells
#17
Lu Zhang, Fang Dai, LiuQing Cui, Bo Zhou, YuQi Guo
The importance of macroautophagy (hereafter referred to as autophagy) in vascular endothelial cell (VEC) biology and dysfunction is increasingly recognized, but the molecular mechanisms of autophagy in VECs in the presence of serum are still poorly understood. Previously, we identified pterostilbene as a potent autophagy inducer of VECs in the presence of serum. In this study, we used pterostilbene as a tool to induce VEC autophagy and identified the differentially expressed genes using high-throughput DAN microarray...
January 10, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28087255/unknown-face-of-known-drugs-what-else-can-we-expect-from-angiotensin-converting-enzyme-inhibitors
#18
REVIEW
Anna Wzgarda, Robert Kleszcz, Monika Prokop, Katarzyna Regulska, Milosz Regulski, Jaroslaw Paluszczak, Beata J Stanisz
The renin-angiotensin system (RAS) is one of important systems among homeostatic mechanisms that controls the function of cardiovascular, renal and adrenal systems. As RAS has a very complex nature, it has been also found as related to the control of cell migration and apoptosis. Angiotensin-converting enzyme inhibitors (ACEI) are drugs most commonly used in the modulation of RAS activity. ACEI have been extensively described as effective in the treatment of hypertension among adults, but also as drugs delaying progression in diabetic nephropathy and reducing mortality in left ventricular dysfunction and congestive heart failure...
January 10, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28086882/differential-effects-of-glucagon-like-peptide-1-receptor-agonists-on-heart-rate
#19
REVIEW
Martin Lorenz, Francesca Lawson, David Owens, Denis Raccah, Christine Roy-Duval, Anne Lehmann, Riccardo Perfetti, Lawrence Blonde
While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are known to increase heart rate (HR), it is insufficiently recognized that the extent varies greatly between the various agonists and is affected by the assessment methods employed. Here we review published data from 24-h time-averaged HR monitoring in healthy individuals and subjects with type 2 diabetes mellitus (T2DM) treated with either short-acting GLP-1 RAs, lixisenatide or exenatide, or long-acting GLP-1 RAs, exenatide LAR, liraglutide, albiglutide, or dulaglutide (N = 1112; active-treatment arms)...
January 13, 2017: Cardiovascular Diabetology
https://www.readbyqxmd.com/read/28079954/conformational-sers-classification-of-k-ras-point-mutations-for-cancer-diagnostics
#20
Judit Morla-Folch, Patricia Gisbert-Quilis, Matteo Masetti, Eduardo Garcia-Rico, Ramon A Alvarez-Puebla, Luca Guerrini
Point mutations in Ras oncogenes are routinely screened for diagnostics and treatment of tumors (especially in colorectal cancer). Here, we develop an optical approach based on direct SERS coupled with chemometrics for the study of the specific conformations that single-point mutations impose on a relatively large fragment of the K-Ras gene (141 nucleobases). Results obtained offer the unambiguous classification of different mutations providing a potentially useful insight for diagnostics and treatment of cancer in a sensitive, fast, direct and inexpensive manner...
January 12, 2017: Angewandte Chemie
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