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https://www.readbyqxmd.com/read/29228388/caspase-inhibition-reduces-hepatic-tissue-factor-driven-coagulation-in-vitro-and-in-vivo
#1
Anna K Kopec, Alfred P Spada, Patricia C Contreras, Nigel Mackman, James P Luyendyk
Tissue factor (TF) is the primary activator of the blood coagulation cascade. Liver parenchymal cells (i.e., hepatocytes) express TF in a molecular state that lacks procoagulant activity. Hepatocyte apoptosis is an important feature of acute and chronic liver diseases, and Fas-induced apoptosis increases hepatocyte TF procoagulant activity in vitro. We determined the impact of a pan-caspase inhibitor, IDN-7314, on hepatocyte TF activity in vitro and TF-mediated coagulation in vivo. Treatment of primary mouse hepatocytes with the Fas death receptor ligand (Jo2, 0...
December 7, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29228101/spironolactone-and-resistant-hypertension-in-heart-failure-with-preserved-ejection-fraction
#2
P Rossignol, B Claggett, J Liu, O Vardeny, B Pitt, F Zannad, S Solomon
Background: Recent evidence suggests that the mineralocorticoid receptor antagonist spironolactone should be the preferred fourth line antihypertensive treatment in resistant hypertension (RHTN). Whether spironolactone improves blood pressure (BP) control in heart failure with preserved ejection fraction (HFpEF) and RHTN is unknown. Methods: We identified patients with RHTN, defined as baseline systolic blood pressure (SBP) between 140 and 160 mmHg on 3 or more medications, in the Americas cohort of the TOPCAT trial, in which patients with HFpEF were randomized to spironolactone vs...
December 7, 2017: American Journal of Hypertension
https://www.readbyqxmd.com/read/29227965/human-longevity-25-genetic-loci-associated-in-389-166-uk-biobank-participants
#3
Luke C Pilling, Chia-Ling Kuo, Kamil Sicinski, Jone Tamosauskaite, George A Kuchel, Lorna W Harries, Pamela Herd, Robert Wallace, Luigi Ferrucci, David Melzer
We undertook a genome-wide association study (GWAS) of parental longevity in European descent UK Biobank participants. For combined mothers' and fathers' attained age, 10 loci were associated (p<5*10-8), including 8 previously identified for traits including survival, Alzheimer's and cardiovascular disease. Of these, 4 were also associated with longest 10% survival (mothers age ≥90 years, fathers ≥87 years), with 2 additional associations including MC2R intronic variants (coding for the adrenocorticotropic hormone receptor)...
December 6, 2017: Aging
https://www.readbyqxmd.com/read/29227909/navigating-the-no-man-s-land-of-tki-failed-egfr-mutated-non-small-cell-lung-cancer-nsclc-a-review
#4
REVIEW
Bryan Oronsky, Patrick Ma, Tony R Reid, Pedro Cabrales, Michelle Lybeck, Arnold Oronsky, Neil Oronsky, Corey A Carter
As the leading cause of cancer-related mortality, lung cancer is a worldwide health issue that is overwhelmingly caused by smoking. However, a substantial minority (~25%) of patients with non-small cell lung cancer (NSCLC) has never smoked. In these patients, activating mutations of the epidermal growth factor receptor (EGFR) are more likely, which render their tumors susceptible for a finite period to treatment with EGFR tyrosine kinase inhibitors (TKIs) and confer a better prognosis than EGFR wild-type NSCLC...
December 8, 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/29227475/an-alox12-12-hete-gpr31-signaling-axis-is-a-key-mediator-of-hepatic-ischemia-reperfusion-injury
#5
Xiao-Jing Zhang, Xu Cheng, Zhen-Zhen Yan, Jing Fang, Xiaozhan Wang, Weijun Wang, Zhen-Yu Liu, Li-Jun Shen, Peng Zhang, Pi-Xiao Wang, Rufang Liao, Yan-Xiao Ji, Jun-Yong Wang, Song Tian, Xue-Yong Zhu, Yan Zhang, Rui-Feng Tian, Lin Wang, Xin-Liang Ma, Zan Huang, Zhi-Gang She, Hongliang Li
Hepatic ischemia-reperfusion (IR) injury is a common clinical issue lacking effective therapy and validated pharmacological targets. Here, using integrative 'omics' analysis, we identified an arachidonate 12-lipoxygenase (ALOX12)-12-hydroxyeicosatetraenoic acid (12-HETE)-G-protein-coupled receptor 31 (GPR31) signaling axis as a key determinant of the hepatic IR process. We found that ALOX12 was markedly upregulated in hepatocytes during ischemia to promote 12-HETE accumulation and that 12-HETE then directly binds to GPR31, triggering an inflammatory response that exacerbates liver damage...
December 11, 2017: Nature Medicine
https://www.readbyqxmd.com/read/29226970/a-dominant-interfering-camta3-mutation-compromises-primary-transcriptional-outputs-mediated-by-both-cell-surface-and-intracellular-immune-receptors-in-arabidopsis-thaliana
#6
Florence Jacob, Barbara Kracher, Akira Mine, Carolin Seyfferth, Servane Blanvillain-Baufumé, Jane E Parker, Kenichi Tsuda, Paul Schulze-Lefert, Takaki Maekawa
Pattern recognition receptors (PRRs) and nucleotide-binding domain and leucine-rich repeat (LRR)-containing proteins (NLRs) initiate pattern-triggered immunity (PTI) and effector-triggered immunity (ETI), respectively, each associated with the activation of an overlapping set of defence genes. The regulatory mechanism behind this convergence of PTI- and ETI-mediated defence gene induction remains elusive. We generated transgenic Arabidopsis plants that enable conditional NLR activation without pathogen infection to dissect NLR- and PRR-mediated transcriptional signals...
December 11, 2017: New Phytologist
https://www.readbyqxmd.com/read/29226626/randomized-clinical-study-of-safety-pharmacokinetics-and-pharmacodynamics-of-ripk1-inhibitor-gsk2982772-in-healthy-volunteers
#7
Kathleen Weisel, Nicola E Scott, Debra J Tompson, Bartholomew J Votta, Sujith Madhavan, Kat Povey, Allen Wolstenholme, Monica Simeoni, Todd Rudo, Lauren Richards-Peterson, Tarjinder Sahota, J Gene Wang, John Lich, Joshua Finger, Adeline Verticelli, Michael Reilly, Peter J Gough, Philip A Harris, John Bertin, Mei-Lun Wang
GSK2982772 is a highly selective inhibitor of receptor-interacting protein kinase 1 (RIPK1) being developed to treat chronic inflammatory diseases. This first-in-human study evaluated safety, tolerability, pharmacokinetics (PK), and exploratory pharmacodynamics (PD) of GSK2982772 administered orally to healthy male volunteers. This was a Phase I, randomized, placebo-controlled, double-blind study. In Part A, subjects received single ascending doses of GSK2982772 (0.1-120 mg) or placebo in a crossover design during each of 4 treatment periods...
December 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/29225694/non-small-cell-lung-cancer-treatment-r-evolution-ten-years-of-advances-and-more-to-come
#8
REVIEW
Luca Toschi, Sabrina Rossi, Giovanna Finocchiaro, Armando Santoro
Diagnostic and treatment algorithms in non-small cell lung cancer (NSCLC) are evolving at a never-before-seen pace. Histological subtyping to maximise treatment efficacy and avoid toxicity has marked the beginning of the revolution, opening the way to molecular characterisation to guide genomically driven treatments with targeted agents, led by Epidermal Growth Factor Receptor (EGFR) and Anaplastic Lymphoma Kinase (ALK) inhibitors. More recently, agents against the Program Death 1 receptor (PD-1) and ligand 1 (PD-L1) have entered the clinical arena, offering new hope to NSCLC patients, although several uncertainties remain to be elucidated...
2017: Ecancermedicalscience
https://www.readbyqxmd.com/read/29225183/ca2-mediates-axotomy-induced-necrosis-and-apoptosis-of-satellite-glial-cells-remote-from-the-transection-site-in-the-isolated-crayfish-mechanoreceptor
#9
Andrey Khaitin, Mikhail Rudkovskii, Anatoly Uzdensky
Severe nerve injury such as axotomy induces neuron degeneration and death of surrounding glial cells. Using a crayfish stretch receptor that consists of a single mechanoreceptor neuron enveloped by satellite glia, we showed that axotomy not only mechanically injures glial cells at the transection location, but also induces necrosis or apoptosis of satellite glial cells remote from the transection site. We studied Ca2+role in spontaneous or axotomy-induced death of remote glial cells. Stretch receptors were isolated using the original technique that kept the neuron connected to the ventral cord ganglion (control preparations)...
December 7, 2017: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/29225166/apatinib-inhibits-migration-and-invasion-as-well-as-pd-l1-expression-in-osteosarcoma-by-targeting-stat3
#10
Bingxin Zheng, Tingting Ren, Yi Huang, Wei Guo
The cure rate of osteosarcoma has not improved in the past 30 years. The new treatments and drugs is urgently needed, especially for metastatic osteosarcoma. Anti-angiogenesis therapy and immunotherapy has got promising anti-tumor effects in various tumors. It is hypothesised that combining checkpoint inhibitor immunotherapies with antiangiogenic treatment may have a synergistic effect and enhance the efficacy of both treatments. However, its underlying mechanism remain largely uninvestigated. To investigate the clinical significance of vascular endothelial growth factor receptor-2 (VEGFR2) and programmed death ligand-1 (PD-L1) in osteosarcoma, we analyzes their expression levels in 93 osteosarcoma specimens by immunohistochemistry...
December 7, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29224824/circulating-tumour-cell-pd-l1-test-for-head-and-neck-cancers
#11
Arutha Kulasinghe, Liz Kenny, Chamindie Punyadeera
Immune checkpoint inhibitors have gained traction over the last few years in the treatment of metastatic/recurrent head and neck squamous cell carcinoma (HNSCC) patients. Monoclonal antibodies that block the programmed death 1 (PD-1) receptor and its major ligand, PD-L1, have shown durable responses and low toxicity profiles. There are currently no validated predictive biomarkers to select patients likely to respond to anti-PD-1/PD-L1 therapy to avoid unwanted side effects and to reduce healthcare expenditure...
December 2017: Oral Oncology
https://www.readbyqxmd.com/read/29224649/efficacy-and-safety-of-potent-platelet-p2y12-receptor-inhibitors-in-elderly-versus-nonelderly-patients-with-acute-coronary-syndrome-a-systematic-review-and-meta-analysis
#12
Giuseppe Tarantini, Daisuke Ueshima, Gianpiero D'Amico, Giulia Masiero, Giuseppe Musumeci, Gregg W Stone, Sorin J Brener
BACKGROUND: The use of the potent oral P2Y12 inhibitors prasugrel and ticagrelor in patients with acute coronary syndromes (ACS) has a favorable net clinical effect compared with clopidogrel and is recommended as first-line therapy. However, the impact of these agents on ischemic and bleeding events in elderly ACS patients is not well defined. METHODS: We performed a systematic review of articles comparing potent P2Y12 inhibitors to clopidogrel in elderly and nonelderly patients (defined according to each study) with ACS in terms of efficacy (composite of cardiovascular death, myocardial infarction, or stroke) and safety (major bleeding) end points...
January 2018: American Heart Journal
https://www.readbyqxmd.com/read/29223745/buparlisib-plus-fulvestrant-in-postmenopausal-women-with-hormone-receptor-positive-her2-negative-advanced-breast-cancer-progressing-on-or-after-mtor-inhibition-belle-3-a-randomised-double-blind-placebo-controlled-phase-3-trial
#13
Angelo Di Leo, Stephen Johnston, Keun Seok Lee, Eva Ciruelos, Per E Lønning, Wolfgang Janni, Ruth O'Regan, Marie-Ange Mouret-Reynier, Dimitar Kalev, Daniel Egle, Tibor Csőszi, Roberto Bordonaro, Thomas Decker, Vivianne C G Tjan-Heijnen, Sibel Blau, Alessio Schirone, Denis Weber, Mona El-Hashimy, Bharani Dharan, Dalila Sellami, Thomas Bachelot
BACKGROUND: Activation of the PI3K/AKT/mTOR pathway occurs frequently in breast cancer that is resistant to endocrine therapy. Approved mTOR inhibitors effectively inhibit cell growth and proliferation but elicit AKT phosphorylation via a feedback activation pathway, potentially leading to resistance to mTOR inhibitors. We evaluated the efficacy and safety of buparlisib plus fulvestrant in patients with advanced breast cancer who were pretreated with endocrine therapy and mTOR inhibitors...
December 6, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/29223163/neuroprotective-properties-of-endocannabinoids-n-arachidonoyl-dopamine-and-n-docosahexaenoyl-dopamine-examined-in-neuronal-precursors-derived-from-human-pluripotent-stem-cells
#14
E V Novosadova, E L Arsenyeva, E S Manuilova, L G Khaspekov, M Yu Bobrov, V V Bezuglov, S N Illarioshkin, I A Grivennikov
Neuroprotective properties of endocannabinoids N-arachidonoyl dopamine (NADA) and N-docosahexaenoyl dopamine (DHDA) were examined in neuronal precursor cells differentiated from human induced pluripotent stem cells and subjected to oxidative stress. Both compounds exerted neuroprotective activity, which was enhanced by elevating the concentration of the endocannabinoids within the 0.1-10 µM range. However, both agents at 10 µM concentration showed a marked toxic effect resulting in death of ~30% of the cells...
November 2017: Biochemistry. Biokhimii︠a︡
https://www.readbyqxmd.com/read/29222605/the-endocannabinoid-system-in-cardiovascular-function-novel-insights-and-clinical-implications
#15
REVIEW
Salvador Sierra, Natasha Luquin, Judith Navarro-Otano
RATIONALE: Cardiovascular disease is now recognized as the number one cause of death in the world, and the size of the population at risk continues to increase rapidly. The dysregulation of the endocannabinoid (eCB) system plays a central role in a wide variety of conditions including cardiovascular disorders. Cannabinoid receptors, their endogenous ligands, as well as enzymes conferring their synthesis and degradation, exhibit overlapping distributions in the cardiovascular system. Furthermore, the pharmacological manipulation of the eCB system has effects on blood pressure, cardiac contractility, and endothelial vasomotor control...
December 8, 2017: Clinical Autonomic Research: Official Journal of the Clinical Autonomic Research Society
https://www.readbyqxmd.com/read/29222530/seizure-rates-in-enzalutamide-treated-men-with-metastatic-castration-resistant-prostate-cancer-and-risk-of-seizure-the-upward-study
#16
Susan Slovin, William Clark, Joan Carles, Andrew Krivoshik, Jung Wook Park, Fong Wang, Daniel George
Importance: The androgen receptor inhibitor enzalutamide prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC). In controlled clinical studies, 0.5% (10 of 2051) of patients experienced seizure, but patients with a history of or risk factors for seizure were excluded. Men with mCRPC and seizure risk factors have an estimated seizure rate of 2.8 per 100 patient-years without enzalutamide exposure. Objective: To assess seizure incidence in patients with seizure risk factors who were receiving enzalutamide for mCRPC...
December 7, 2017: JAMA Oncology
https://www.readbyqxmd.com/read/29222312/harnessing-the-power-of-the-immune-system-in-non-hodgkin-lymphoma-immunomodulators-checkpoint-inhibitors-and-beyond
#17
REVIEW
Stephen M Ansell
Non-Hodgkin lymphoma is a malignancy of B lymphocytes that typically infiltrate sites of disease, including the lymph nodes, spleen, and bone marrow. Beyond the presence of malignant cells, many immune cells are also present within the tumor microenvironment. Although these immune cells have the potential to regulate the growth of malignant B cells, intratumoral immune cells are unable to eradicate lymphoma cells and most patients with lymphoma have clinical evidence of disease progression. Recent data have identified some of the mechanisms that account for the suppressed antitumor immune response and have created opportunities for treatment to overcome the deficiencies...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/29222290/chronic-organ-failure-in-adult-sickle-cell-disease
#18
REVIEW
Elliott Vichinsky
Sickle cell disease is now a chronic adult illness characterized by progressive multiorgan failure, particularly involving the brain and kidney. The etiology is multifactorial; it includes hemolysis and nitric oxide deficiency. As patients age, most experience neurologic insult. Twenty-five percent of older adults have had a clinical stroke and at least half of the population have had a silent infarct, cortical atrophy, and neurocognitive impairment. Periodic screening with neuroimaging and neurocognitive testing is recommended...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/29221175/trpm8-is-required-for-survival-and-radioresistance-of-glioblastoma-cells
#19
Dominik Klumpp, Stephanie C Frank, Lukas Klumpp, Efe C Sezgin, Marita Eckert, Lena Edalat, Martin Bastmeyer, Daniel Zips, Peter Ruth, Stephan M Huber
TRPM8 is a Ca2+-permeable nonselective cation channel belonging to the melastatin sub-group of the transient receptor potential (TRP) family. TRPM8 is aberrantly overexpressed in a variety of tumor entities including glioblastoma multiforme where it reportedly contributes to tumor invasion. The present study aimed to disclose further functions of TRPM8 in glioma biology in particular upon cell injury by ionizing radiation. To this end, TCGA data base was queried to expose the TRPM8 mRNA abundance in human glioblastoma specimens and immunoblotting was performed to analyze the TRPM8 protein abundance in primary cultures of human glioblastoma...
November 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29221131/hoxa5-increases-mitochondrial-apoptosis-by-inhibiting-akt-mtorc1-s6k1-pathway-in-mice-white-adipocytes
#20
Fei Feng, Qian Ren, Song Wu, Muhammad Saeed, Chao Sun
Homeobox A5(Hoxa5), a member of the Hox family, plays a important role in the regulation of proliferation and apoptosis in cancer cells. The dysregulation of the adipocyte apoptosis in vivo leads to obesity and metabolic disorders. However, the effects of Hoxa5 on adipocyte apoptosis are still unknown. In this study, palmitic acid (PA) significantly increased the mRNA level of Hoxa5 and triggered white adipocyte apoptosis in vivo and in vitro. Further analysis revealed that Hoxa5 enhanced the early and late apoptotic cells and fragmentation of genomic DNA in adipocytes from inguinal white adipose tissue (iWAT) of mice...
November 10, 2017: Oncotarget
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