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https://www.readbyqxmd.com/read/28918459/hla-class-i-expression-predicts-prognosis-and-therapeutic-benefits-from-tyrosine-kinase-inhibitors-in-metastatic-renal-cell-carcinoma-patients
#1
Jiajun Wang, Li Liu, Yang Qu, Wei Xi, Yu Xia, Qi Bai, Ying Xiong, Qilai Long, Jiejie Xu, Jianming Guo
PURPOSE: Classical HLA class I antigen is highly involved in antigen presentation and adaptive immune response against tumor. In this study, we explored its predictive value for treatment response and survival in metastatic renal-cell carcinoma (mRCC) patients. EXPERIMENTAL DESIGN: A TKI cohort of 111 mRCC patients treated with sunitinib or sorafenib and a non-TKI cohort of 160 mRCC patients treated with interleukin-2 or interferon-α-based immunotherapy at a single institution were retrospectively enrolled...
September 16, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28918311/structural-basis-for-the-potent-and-selective-binding-of-ldn-212854-to-the-bmp-receptor-kinase-alk2
#2
Eleanor Williams, Alex N Bullock
Individuals with the rare developmental disorder fibrodysplasia ossificans progressiva (FOP) experience disabling heterotopic ossification caused by a gain of function mutation in the intracellular region of the BMP type I receptor kinase ALK2, encoded by the gene ACVR1. Small molecule BMP type I receptor inhibitors that block this ossification in FOP mouse models have been derived from the pyrazolo[1,5-a]pyrimidine scaffold of dorsomorphin. While the first derivative LDN-193189 exhibited pan inhibition of BMP receptors, the more recent compound LDN-212854 has shown increased selectivity for ALK2...
September 12, 2017: Bone
https://www.readbyqxmd.com/read/28918096/a-comprehensive-review-on-aurora-kinase-small-molecule-inhibitors-and-clinical-trial-studies
#3
REVIEW
Ankit C Borisa, Hardik G Bhatt
Aurora kinase belongs to serine/threonine kinase family which controls cell division. Therapeutic inhibition of Aurora kinase showed great promise as probable anticancer regime because of its important role during cell division. Here, in this review, we have carried out exhaustive study of various synthetic molecules reported as Aurora kinase inhibitors and developed as lead molecule at various stages of clinical trials from its discovery in 1995 to till date. We reported details of small molecules, specifically inhibiting all 3 types of Aurora kinases, which includes extensive literature search in various database like various scientific journals, patents, scifinder and PubMed database, internet resources, books, etc...
August 24, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28918051/lrrk2-antisense-oligonucleotides-ameliorate-%C3%AE-synuclein-inclusion-formation-in-a-parkinson-s-disease-mouse-model
#4
Hien Tran Zhao, Neena John, Vedad Delic, Karli Ikeda-Lee, Aneeza Kim, Andreas Weihofen, Eric E Swayze, Holly B Kordasiewicz, Andrew B West, Laura A Volpicelli-Daley
No treatments exist to slow or halt Parkinson's disease (PD) progression; however, inhibition of leucine-rich repeat kinase 2 (LRRK2) activity represents one of the most promising therapeutic strategies. Genetic ablation and pharmacological LRRK2 inhibition have demonstrated promise in blocking α-synuclein (α-syn) pathology. However, LRRK2 kinase inhibitors may reduce LRRK2 activity in several tissues and induce systemic phenotypes in the kidney and lung that are undesirable. Here, we test whether antisense oligonucleotides (ASOs) provide an alternative therapeutic strategy, as they can be restricted to the CNS and provide a stable, long-lasting reduction of protein throughout the brain...
September 15, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28917508/insulin-dependent-metabolic-and-inotropic-responses-in-the-heart-are-modulated-by-hydrogen-peroxide-from-nadph-oxidase-isoforms-nox2-and-nox4
#5
Benjamin Steinhorn, Juliano L Sartoretto, Andrea Sorrentino, Natalia Romero, Hermann Kalwa, E Dale Abel, Thomas Michel
RATIONALE: Hydrogen peroxide (H2O2) is a stable reactive oxygen species (ROS) that has long been implicated in insulin signal transduction in adipocytes. However, H2O2's role in mediating insulin's effects on the heart are unknown. OBJECTIVE: We investigated the role of H2O2 in activating insulin-dependent changes in cardiac myocyte metabolic and inotropic pathways. The sources of insulin-dependent H2O2 generation were also studied. METHODS AND RESULTS: In addition to the canonical role of insulin in modulating cardiac metabolic pathways, we found that insulin also inhibited beta adrenergic-induced increases in cardiac contractility...
September 13, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28917447/cell-penetrating-peptides-to-dissect-host-pathogen-protein-protein-interactions-in-theileria-transformed-leukocytes
#6
REVIEW
Malak Haidar, Perle Latré de Laté, Eileen J Kennedy, Gordon Langsley
One powerful application of cell penetrating peptides is the delivery into cells of molecules that function as specific competitors or inhibitors of protein-protein interactions. Ablating defined protein-protein interactions is a refined way to explore their contribution to a particular cellular phenotype in a given disease context. Cell-penetrating peptides can be synthetically constrained through various chemical modifications that stabilize a given structural fold with the potential to improve competitive binding to specific targets...
September 7, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28917156/tgf%C3%AE-1-synergizes-with-flt3-ligand-to-induce-chemoresistant-quiescence-in-acute-lymphoblastic-leukemia-with-mll-gene-rearrangements
#7
M Tamai, Y Furuichi, S Kasai, N Ando, D Harama, K Goi, T Inukai, K Kagami, M Abe, H Ichikawa, K Sugita
Fms-like tyrosine kinase 3 (FLT3) is highly expressed in mixed-lineage leukemia (MLL) gene-rearranged acute lymphoblastic leukemia (MLL+ALL) with a dismal prognosis. We previously reported that FLT3 ligand (FL) stimulation induced cell cycle arrest in MLL+ALL cells leading to resistance against anti-leukemic agents. Given that FL stimulation enhanced transforming growth factor (TGF)β1 mRNA levels in MLL+ALL cells, we extensively examined the effect of TGFβ1 on the cell cycle progression and chemosensitivity in MLL+ALL cells, and found that TGFβ1 stimulation induced MLL+ALL cells into cell cycle arrest resistant to arabinosyl cytosine; its effect was markedly enhanced in synergy with FL...
September 13, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28917151/a-novel-self-nanoemulsifying-formulation-for-sunitinib-evaluation-of-anticancer-efficacy
#8
R Nazari-Vanani, N Azarpira, H Heli, K Karimian, N Sattarahmady
Breast cancer is the top cancer and a main cause of death among women. The incidence of this cancer is increasing in the world. Sunitinib maleate is an oral, small-molecule, multi-targeted receptor tyrosine kinase inhibitor that inhibits tumor cell proliferation and angiogenesis, and has been administrated as an anticancer drug. Self-nanoemulsifying drug delivery system (SNEDDS) is an isotopic mixture of an oil, a surfactant and usually a co-surfactant, which can spontaneously form fine oil-in-water nanoemulsion in aqueous media...
September 7, 2017: Colloids and Surfaces. B, Biointerfaces
https://www.readbyqxmd.com/read/28917142/reactions-of-tobacco-genotypes-with-different-antioxidant-capacities-to-powdery-mildew-and-tobacco-mosaic-virus-infections
#9
Gábor Gullner, Csilla Juhász, Adél Németh, Balázs Barna
The interactions of powdery mildew (Golovinomyces orontii) and Tobacco mosaic virus (TMV) with tobacco lines having down or upregulated antioxidants were investigated. Xanthi-nc, its salicylic acid-deficient NahG mutant, a paraquat-sensitive Samsun (PS) and its paraquat tolerant (PT) mutant were used. Cell membrane damage caused by H2O2 was significantly higher in NahG than Xanthi, whereas it was lower in PT than in PS. Leakage of ions from PT was reduced by the powdery mildew infection. On the other hand TMV inoculation led to a 6-fold and 2-fold elevation of ion leakage from hypersensitive resistant NahG and Xanthi leaves, respectively, whereas ion leakage increased slightly from susceptible PS leaves...
September 8, 2017: Plant Physiology and Biochemistry: PPB
https://www.readbyqxmd.com/read/28916818/identification-of-4-phenylquinolin-2-1h-one-as-a-specific-allosteric-inhibitor-of-akt
#10
Bill X Huang, Kenny Newcomer, Karl Kevala, Elena Barnaeva, Wei Zheng, Xin Hu, Samarjit Patnaik, Noel Southall, Juan Marugan, Marc Ferrer, Hee-Yong Kim
Akt plays a major role in tumorigenesis and the development of specific Akt inhibitors as effective cancer therapeutics has been challenging. Here, we report the identification of a highly specific allosteric inhibitor of Akt through a FRET-based high-throughput screening, and characterization of its inhibitory mechanism. Out of 373,868 compounds screened, 4-phenylquinolin-2(1H)-one specifically decreased Akt phosphorylation at both T308 and S473, and inhibited Akt kinase activity (IC50 = 6 µM) and downstream signaling...
September 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28916781/6-bromo-indirubin-3-oxime-6bio-a-glycogen-synthase-kinase-3%C3%AE-inhibitor-activates-cytoprotective-cellular-modules-and-suppresses-cellular-senescence-mediated-biomolecular-damage-in-human-fibroblasts
#11
Aimilia D Sklirou, Nicolas Gaboriaud-Kolar, Issidora Papassideri, Alexios-Leandros Skaltsounis, Ioannis P Trougakos
As genetic interventions or extended caloric restriction cannot be applied in humans, many studies have been devoted to the identification of natural products that can prolong healthspan. 6-bromoindirubin-3'-oxime (6BIO), a hemi-synthetic derivative of indirubins found in edible mollusks and plants, is a potent inhibitor of Glycogen synthase kinase 3β (Gsk-3β). This pleiotropic kinase has been implicated in various age-related diseases including tumorigenesis, neurodegeneration and diabetes. Accordingly, 6BIO has shown anti-tumor and anti-neurodegenerative activities; nevertheless, the potential role of 6BIO in normal human cells senescence remains largely unknown...
September 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28916723/fibroblast-growth-factor-2-fgf2-regulates-cytoglobin-expression-and-activation-of-human-hepatic-stellate-cells-via-jnk-signaling
#12
Misako Sato-Matsubara, Tsutomu Matsubara, Atsuko Daikoku, Yoshinori Okina, Lisa Longato, Krista Rombouts, Le Thi Thanh Thuy, Jun Adachi, Takeshi Tomonaga, Kazuo Ikeda, Katsutoshi Yoshizato, Massimo Pinzani, Norifumi Kawada
Cytoglobin (CYGB) belongs to the mammalian globin family and is exclusively expressed in hepatic stellate cells (HSCs) in the liver. In addition to its gas-binding ability, CYGB is relevant to hepatic inflammation, fibrosis, and cancer because of its antioxidative properties; however, the regulation of CYGB gene expression remains unknown. Here, we sought to identify factors that induce CYGB expression in HSCs and to clarify the molecular mechanism involved. We used the human HSC cell line HHSteC and primary human HSCs isolated from intact human liver tissues...
September 15, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28916704/delayed-neutrophil-apoptosis-enhances-net-formation-in-cystic-fibrosis
#13
Robert D Gray, Gareth Hardisty, Kate H Regan, Maeve Smith, Calum T Robb, Rodger Duffin, Annie Mackellar, Jennifer M Felton, Lily Paemka, Brian N McCullagh, Christopher D Lucas, David A Dorward, Edward F McKone, Gordon Cooke, Seamas C Donnelly, Pradeep K Singh, David A Stoltz, Christopher Haslett, Paul B McCray, Moira K B Whyte, Adriano G Rossi, Donald J Davidson
BACKGROUND: Cystic fibrosis (CF) lung disease is defined by large numbers of neutrophils and associated damaging products in the airway. Delayed neutrophil apoptosis is described in CF although it is unclear whether this is a primary neutrophil defect or a response to chronic inflammation. Increased levels of neutrophil extracellular traps (NETs) have been measured in CF and we aimed to investigate the causal relationship between these phenomena and their potential to serve as a driver of inflammation...
September 15, 2017: Thorax
https://www.readbyqxmd.com/read/28916471/the-pyk2-mcu-pathway-in-the-rat-middle-cerebral-artery-occlusion-model-of-ischemic-stroke
#14
Kun Zhang, Jiajia Yan, Liang Wang, Xinying Tian, Tong Zhang, Li Guo, Bin Li, Wang Wang, Xiaoyun Liu
Mitochondrial dysfunction caused by Ca(2+) overload plays an important role in ischemia-induced brain damage. Mitochondrial calcium uniporter (MCU), located on the mitochondrial inner membrane, is the major channel responsible for mitochondrial Ca(2+) uptake. Activated proline-rich tyrosine kinase 2 (Pyk2) can directly phosphorylate MCU, which enhances mitochondrial Ca(2+) uptake in cardiomyocytes. It has been suggested that the Pyk2/MCU pathway may be a novel therapeutic target in stress-induced cellular apoptosis...
September 12, 2017: Neuroscience Research
https://www.readbyqxmd.com/read/28916378/clinical-pharmacology-of-anti-angiogenic-drugs-in-oncology
#15
REVIEW
P Gougis, J Wassermann, J P Spano, N Keynan, C Funck-Brentano, J E Salem
Abnormal vasculature proliferation is one of the so-called hallmarks of cancer. Angiogenesis inhibitor therapies are one of the major breakthroughs in cancer treatment in the last two decades. Two types of anti-angiogenics have been approved: monoclonal antibodies and derivatives, which are injected and target the extracellular part of a receptor, and protein kinase inhibitors, which are orally taken small molecules targeting the intra-cellular Adenosine Triphosphate -pocket of different kinases. They have become an important part of some tumors' treatment, both in monotherapy or in combination...
September 1, 2017: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/28916338/structure-activity-relationship-study-of-small-molecule-inhibitors-of-the-deptor-mtor-interaction
#16
Jihye Lee, Yijiang Shi, Mario Vega, Yonghui Yang, Joseph Gera, Michael E Jung, Alan Lichtenstein
DEPTOR is a 48kDa protein that binds to mTOR and inhibits this kinase within mTORC1 and mTORC2 complexes. Over-expression of DEPTOR specifically occurs in the multiple myeloma (MM) tumor model and DEPTOR knockdown is cytotoxic to MM cells, suggesting it is a potential therapeutic target. Since mTORC1 paralysis protects MM cells against DEPTOR knockdown, it indicates that the protein-protein interaction between DEPTOR and mTOR is key to MM viability vs death. In a previous study, we used a yeast two-hybrid screen of a small inhibitor library to identify a compound that inhibited DEPTOR/mTOR binding in yeast...
September 6, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28916223/bet-bromodomain-inhibitors-modulate-epigenetic-patterns-at-the-diacylglycerol-kinase-alpha-enhancer-associated-with-radiation-induced-fibrosis
#17
Gintvile Valinciute, Christoph Weigel, Marlon R Veldwijk, Christopher C Oakes, Carsten Herskind, Frederik Wenz, Christoph Plass, Peter Schmezer, Odilia Popanda
BACKGROUND AND PURPOSE: Fibrosis is a frequent adverse effect of radiotherapy and no effective treatments are currently available to prevent or reverse fibrotic disease. We have previously identified altered epigenetic patterns at a gene enhancer of the diacylglycerol kinase alpha (DGKA) locus in normal skin fibroblasts derived from fibrosis patients. An open chromatin pattern related to radiation-inducibility of DGKA is associated with onset of radiation-induced fibrosis. Here, we explore epigenetic modulation of DGKA as a way to mitigate predisposition to fibrosis...
September 12, 2017: Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology
https://www.readbyqxmd.com/read/28916199/erk-and-rock-functionally-interact-in-a-signaling-network-that-is-compensationally-upregulated-in-spinal-muscular-atrophy
#18
Niko Hensel, Svetlana Baskal, Lisa Marie Walter, Hella Brinkmann, Manuela Gernert, Peter Claus
Spinal Muscular Atrophy (SMA) is a motoneuron disease caused by low levels of functional survival of motoneuron protein (SMN). Molecular disease mechanisms downstream of functional SMN loss are still largely unknown. Previous studies suggested an involvement of Rho kinase (ROCK) as well as the extracellular signal-regulated kinases (ERK) pathways in the pathomechanism. Both pathways are bi-directionally linked and inhibit each other. Thus, we hypothesize that both pathways regulate SMA pathophysiology in vivo in a combined manner rather than acting separately...
September 12, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28916198/treatment-outcome-and-quality-of-life-of-1239-patients-with-advanced-non-small-cell-lung-cancer-final-results-from-the-prospective-german-tlk-cohort-study
#19
Ulla von Verschuer, Roland Schnell, Hans Werner Tessen, Jochen Eggert, Adrian Binninger, Lisa Spring, Martina Jänicke, Norbert Marschner
OBJECTIVES: Real-life data on advanced non-small cell lung cancer (NSCLC) are centrally important to complement the results from clinical trials and to improve the standard of care. We present data on the choice of systemic first- and second-line treatment, number of treatment lines, survival and longitudinal data on health-related quality of life (HRQOL) of patients treated by medical oncologists in Germany. MATERIALS AND METHODS: 1239 patients with advanced NSCLC were recruited at start of first-line therapy into the prospective German clinical cohort study TLK (Tumour Registry Lung Cancer) by 107 sites between February 2010 and December 2013 and followed-up until January 2016...
August 22, 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28916166/antagomir-613-protects-neuronal-cells-from-oxygen-glucose-deprivation-re-oxygenation-via-increasing-sphk2-expression
#20
Guangfu Di, Zhichun Wang, Wenming Wang, Feng Cheng, Hua Liu
Oxygen glucose deprivation (OGD)/re-oxygenation (OGDR) causes damages to neuronal cells. Sphingosine kinase 2 (SphK2) expression could exert neuroprotective functions. Here, we aim to induce SphK2 expression via inhibiting the anti-SphK2 microRNA: microRNA-613 ("miR-613"). In both SH-SY5Y neuronal cells and primary murine hippocampal neurons, transfection of the miR-613's specific inhibitor, antagomiR-613 ("antamiR-613"), induced miR-613 depletion and SphK2 expression. Reversely, forced over-expression of miR-613 caused SphK2 downregulation in SH-SY5Y cells...
September 12, 2017: Biochemical and Biophysical Research Communications
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