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Findings from a phase I/II study indicate a higher response rate among patients with BRAF-mutant metastatic colorectal cancer treated with an EGFR inhibitor alongside dual, as opposed to single-level, MAPK blockade. Panitumumab combined with trametinib and dabrafenib only modestly increased median progression-free survival, however; a short-lived decrease in responders' BRAF V600E mutant allele fraction and the emergence of RAS mutations may have been contributing factors.
October 21, 2016: Cancer Discovery
Marty D Spranger, Jasdeep Kaur, Javier A Sala-Mercado, Abhinav C Krishnan, Rania Abu-Hamdah, Alberto Alvarez, Tiago M Machado, Robert A Augustyniak, Donal S O'Leary
Increases in myocardial oxygen consumption during exercise mainly occur via increases in coronary blood flow (CBF) as cardiac oxygen extraction is high even at rest. However, sympathetic coronary constrictor tone can limit increases in CBF. Increased sympathetic nerve activity (SNA) during exercise is, in part, a function of muscle metaboreflex activation (MMA). As SNA is heightened even at rest in subjects with hypertension (HTN), we tested whether HTN causes exaggerated coronary vasoconstriction during mild treadmill exercise with MMA (elicited by reducing hindlimb blood flow by ~60%) thereby limiting increases in CBF and ventricular performance...
October 21, 2016: American Journal of Physiology. Heart and Circulatory Physiology
Toby N Weingarten, Tasha L Welch, Tamara L Moore, Gulshat F Walters, Joni L Whipple, Alexandre Cavalcante, Irina Bancos, William F Young, Lucinda M Gruber, Muhammad Z Shah, Travis J McKenzie, Darrell R Schroeder, Juraj Sprung
OBJECTIVE: To determine whether, despite pharmacologic adrenergic receptor blockade, higher preoperative levels of catecholamines and metanephrines (adrenergic activity) are associated with increased intraoperative complications. METHODS: Records of patients undergoing paraganglioma and pheochromocytoma (PGL-PCC) resection from January 1, 2000, through June 31, 2015, were reviewed for preoperative levels of adrenergic activity, intraoperative variability in blood pressure and heart rate (range), and postoperative outcomes (hypotension requiring treatment)...
October 18, 2016: Urology
J Chee, B W S R Robinson, R A Holt, J Creaney
Harnessing the immune system to fight cancer is an exciting advancement in lung cancer therapy. Anti-tumor immunity can be augmented by checkpoint blockade therapy, which removes the inhibition/brakes imposed on the immune system by the tumor. Checkpoint blockade therapy with anti-PD1/anti-PDL1 antibodies causes tumor regression in around 25% of lung cancer patients. In another approach, the immune system is forced or accelerated to attack the tumour, via augmentation of the anti-tumour response against mutations carried by each lung tumour...
October 18, 2016: Chest
Mei Han, Chengyan Wang, Yinchun Ji, Zilan Song, Li Xing, Yi Su, Xisheng Wang, Ao Zhang, Jing Ai, Meiyu Geng
A metabolism-based fine-tuning structure-optimization was conducted to address the oxidative metabolism and hERG blockade of our early ALK inhibitor. Compound 8 was identified showing high potency against both ALK wild type and gatekeeper mutant. In addition to the optimal PK properties and significant cell antiproliferative effects, 8 showed complete tumor growth inhibition at doses of 50 or 10mg/kg once daily in the Karpas299 xenograft model. All these results encouraged the further development of 8 as a potent and orally bioavailable ALK inhibitor...
October 14, 2016: Bioorganic & Medicinal Chemistry Letters
Qian Chen, Ligeng Xu, Chao Liang, Chao Wang, Rui Peng, Zhuang Liu
A therapeutic strategy that can eliminate primary tumours, inhibit metastases, and prevent tumour relapses is developed herein by combining adjuvant nanoparticle-based photothermal therapy with checkpoint-blockade immunotherapy. Indocyanine green (ICG), a photothermal agent, and imiquimod (R837), a Toll-like-receptor-7 agonist, are co-encapsulated by poly(lactic-co-glycolic) acid (PLGA). The formed PLGA-ICG-R837 nanoparticles composed purely by three clinically approved components can be used for near-infrared laser-triggered photothermal ablation of primary tumours, generating tumour-associated antigens, which in the presence of R837-containing nanoparticles as the adjuvant can show vaccine-like functions...
October 21, 2016: Nature Communications
Y Kimura, J Maeda, M Yamada, K Takahata, K Yokokawa, Y Ikoma, C Seki, H Ito, M Higuchi, T Suhara
RATIONALE: The beneficial effects of psychostimulant drugs in the treatment of psychiatric disorders occur because they increase the extracellular dopamine concentration by inhibiting re-uptake of extracellular dopamine at dopamine transporters. However, the psychological effects at low dopamine transporter occupancy have not been well demonstrated. OBJECTIVES: The purpose of the study was to evaluate the psychological effects, dopamine transporter occupancy, and dopamine release induced by a single oral administration of a clinical dose of mazindol...
October 20, 2016: Psychopharmacology
Jay S Mishra, Gary D Hankins, Sathish Kumar
INTRODUCTION: Blood pressure is lower in females than males. Angiotensin II type-2 receptor (AT2R) induces vasodilation. This study determined whether sex differences in vascular AT2R expression occur and if androgens exert control on AT2R expression in the vasculature. METHODS: AT2Rs in the aorta of male and female Sprague-Dawley rats were examined following alteration in androgen levels by gonadectomy or hormone supplementation. RESULTS: AT2R mRNA and protein expression levels were lower in the aortas of males than females...
October 2016: Journal of the Renin-angiotensin-aldosterone System: JRAAS
Marco Tucci, Stefania Stucci, Anna Passarelli, Stella D'Oronzo, Franco Silvestris
Interleukin-17A (IL-17A) promotes the osteoclast (OC)-like differentiation of dendritic cells (DCs) in multiple myeloma (MM), and contributes to the pathogenesis of myeloma bone disease (MBD). In our study, EVR significantly abrogated the in vitro OC-like activity of DCs from 12 MM patients. Exploring the EVR effects, we found that the inhibition of the osteo-erosive activity of OC-DCs was mostly due to the blockade of signals driven by the IL-17A receptor toward CEBPbeta/MAFB axis Therefore, MM patients with MBD would probably benefit from mTOR inhibition...
October 17, 2016: Experimental Hematology
Ana M Contreras-Sandoval, María Merino, Marcos Vasquez, Iñaki F Trocóniz, Pedro Berraondo, María J Garrido
Blockade of PD-L1 with specific monoclonal antibodies (anti-PD-L1) represents a therapeutic strategy to increase the capability of the immune system to modulate the tumor immune-resistance. The relationship between anti-PD-L1 tumor exposition and anti-tumor effect represents a challenge that has been addressed in this work through the identification of certain biomarkers implicated in the antibody's mechanism of action, using a syngeneic melanoma mouse model. The development of an in-vitro/in-vivo platform has allowed us to investigate the PD-L1 behavior after its blockage with anti-PD-L1 at cellular level and in animals...
October 18, 2016: Oncotarget
Lauren Brasile, Nicholas Henry, Bart Stubenitsky
BACKGROUND: We have previously reported on a novel organ-specific immunomodifying therapy that provides protection from early allograft rejection in the absence of systemic immunosuppressive drugs. This novel therapy is a nano-barrier membrane called ImmunoCloak, consisting of a matrix of laminin, proteoglycans, fibronectin and collagens. The membrane "immunocloaks" the luminal surfaces within the renal vasculature by covering the point of contact between donor vascular endothelial cells and the recipient's immune cells; without adversely affecting renal function...
October 19, 2016: Transplantation
Naoto Fujii, Maya Sarah Singh, Lyra Halili, Jeffrey C Louie, Glen P Kenny
During exercise, cutaneous vasodilation and sweating responses occur, whereas these responses rapidly decrease during postexercise recovery. We hypothesized that the activation of endothelin A (ETA) receptors, but not endothelin B (ETB) receptors, attenuate cutaneous vasodilation during high-intensity exercise and contribute to the subsequent postexercise suppression of cutaneous vasodilation. We also hypothesized that both receptors increase sweating during and following high-intensity exercise. Eleven males (24 ± 4 years) performed an intermittent cycling protocol consisting of two 30-min bouts of moderate- (40% VO2peak) and high- (75% VO2peak) intensity exercise in the heat (35°C), each separated by a 20- and 40-min recovery period, respectively...
October 7, 2016: Journal of Applied Physiology
Alice C Wyse-Jackson, Sarah L Roche, Ana M Ruiz-Lopez, Jennifer N Moloney, Ashleigh M Byrne, Thomas G Cotter
Retinitis pigmentosa (RP) is a degenerative retinal disease leading to photoreceptor cell loss. In 2011, our group identified the synthetic progesterone 'Norgestrel' as a potential treatment for RP. Subsequent research showed Norgestrel to work through progesterone receptor membrane component 1 (PGRMC1) activation and upregulation of neuroprotective basic fibroblast growth factor (bFGF). Using trophic factor deprivation of 661W photoreceptor-like cells, we aimed to further elucidate the mechanism leading to Norgestrel-induced neuroprotection...
October 20, 2016: European Journal of Neuroscience
Davide Cattano, Carlos Artime
No abstract text is available yet for this article.
October 20, 2016: Minerva Anestesiologica
Jing Zhang, Ya-Qin Tan, Ming-Hui Wei, Xiao-Jing Ye, Guan-Ying Chen, Rui Lu, Ge-Fei Du, Gang Zhou
Oral lichen planus (OLP) is a T-cell-mediated autoimmune mucocutaneous disease affected by the interactions among the keratinocytes, CD4(+) T cells and CD8(+) T cells. B7-H1 induced by Toll-like receptors (TLRs), can suppress T cell immune reaction, thereby resulting in immune tolerance. However, the role of TLRs-mediated B7-H1 on keratinocytes in the immune response of OLP is still unknown. The present study showed that TLR4 could induce time-coursed B7-H1 expression on oral keratinocytes, and blocking NF-κB or PI3K/mTOR pathway down-regulated B7-H1 transcriptional expression...
October 20, 2016: Experimental Dermatology
Nicola Tufton, Kirun Gunganah, Shazia Hussain, Maralyn Druce, Robert Carpenter, Michael Ashby, William M Drake, Scott A Akker
We read with interest the article on whether patients with hormonally functioning phaeochromocytomas and paragangliomas receive proper adrenoreceptor blockade (1). Since the removal of intravenous phenoxybenzamine (Goldshield) from the UK formulae due to worldwide lack of availability, providing patients with adequate alpha adrenoreceptor blockade has become more challenging. We conducted a small retrospective audit in our department to investigate the efficacy of oral Phenoxybenzamine compared to intravenous Phenoxybenzamine as we had formed the clinical impression that that pre-operative preparation is currently less safe than it used to be...
October 19, 2016: Clinical Endocrinology
Faramarz Mosaffa, Seyed Amir Mohajerani, Reza Aminnejad, Ali Solhpour, Shideh Dabir, Gholam Reza Mohseni
BACKGROUND: Preemptive analgesia is the blocking of pain perception afferent pathways before noxious painful stimuli. Clonidine is an alpha agonist drug that is partially selective for α-2 adrenoreceptors. Clonidine is used as anti-anxiety medication and an, analgesic, and it prolongs the duration of the block in the brachial plexus block. OBJECTIVES: To compare the effect of preemptive clonidine with midazolam on intraoperative sedation, duration of block, and postoperative pain scores...
June 2016: Anesthesiology and Pain Medicine
J Hefner, H Csef
The last ten years have seen hardly any improvement in the prognosis of ovarian carcinoma. There is a great need for new treatment strategies, and a recent retrospective study showing a survival advantage with the use of beta blockers met with a very positive response. This systematic review summarizes the current state of knowledge and research on the topic: A database analysis identified six clinical studies showing inconsistent results with respect to the administration of beta blockers and disease course...
October 2016: Geburtshilfe und Frauenheilkunde
Shigeru Shibata, Kenichi Ishizawa, Shunya Uchida
The kidney has a central role in long-term control of blood pressure, and decreased kidney function is a common but difficult-to-treat cause of hypertension. Conversely, elevated blood pressure contributes to the progression of chronic kidney disease. Steroid hormone aldosterone and its receptor mineralocorticoid receptor (MR) contribute to hypertension by increasing renal salt reabsorption and promote kidney dysfunction through direct effects on renal parenchymal cells. Accumulating data indicate that various mechanisms affect aldosterone-MR signaling...
October 20, 2016: Hypertension Research: Official Journal of the Japanese Society of Hypertension
Tetsuo Mitsui, Maho Ishida, Michi Izawa, Jun Arita
Estrogen binds to nuclear estrogen receptors (ERs) to modulate transcription of target genes in estrogen-responsive cells. However, recent studies have shown that estrogen also binds to cytoplasmic membrane ERs to modulate protein kinase signaling cascades, leading to non-genomic actions. We investigated whether either nuclear or membrane ERs, including G protein-coupled estrogen receptor 1 (Gper1), mediate the inhibitory action of estrogen on insulin-like growth factor-1 (IGF-1)-induced proliferation of pituitary lactotrophs in primary culture...
October 19, 2016: Endocrine Journal
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