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Alexandre Bozec, Nathalie Ebran, Nina Radosevic-Robin, Emmanuel Chamorey, Hedi Ben Yahia, Serge Marcie, Mathieu Gautier, Frédérique Penault-Llorca, Gérard Milano
BACKGROUND: The purpose of this study was to investigate the effects of combining the phosphotidylinositol-3-kinase (PI3K) inhibitor buparlisib (BKM)120 with the anti-epidermal growth factor receptor (EGFR) agent cetuximab and radiotherapy (RT) on an orthotopic model of head and neck squamous cell carcinoma (HNSCC). METHODS: We evaluated the antitumor efficacy of BKM120, cetuximab, and RT, administered alone or in combination, using the human PIK3CA-mutated HNSCC cell line, CAL33, injected into the floor of the mouth of nude mice...
August 10, 2016: Head & Neck
Jessica L Geiger, Julie E Bauman, Michael K Gibson, William E Gooding, Prakash Varadarajan, Athanasios Kotsakis, Daniel Martin, Jorge Silvio Gutkind, Matthew L Hedberg, Jennifer R Grandis, Athanassios Argiris
BACKGROUND: Patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) demonstrate aberrant activation of the phosphotidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. We examined the efficacy of everolimus, an mTOR inhibitor, in patients with recurrent or metastatic HNSCC. METHODS: This single-arm phase II study enrolled biomarker-unselected patients with recurrent or metastatic HNSCC who failed at least 1 prior therapy...
May 27, 2016: Head & Neck
Daniel W Bowles, Mark Kochenderfer, Allen Cohn, Lucas Sideris, Nghia Nguyen, Vivian Cline-Burkhardt, Ian Schnadig, Minsig Choi, Lisle Nabell, Arvind Chaudhry, Robert Ruxer, Antonio Ucar, Diana Hausman, Luke Walker, Alexander Spira, Antonio Jimeno
BACKGROUND: The phosphotidylinositol-3 kinase (PI3K)/serine-threonine kinase/mammalian target of rapamycin signaling pathway is frequently altered in colorectal cancer (CRC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. This randomized phase II study evaluated cetuximab with or without PX-866 in patients with metastatic, anti-epidermal growth factor receptor-naive, KRAS codon 12 and 13 wild-type CRC. PATIENTS AND METHODS: Patients with metastatic CRC who had received both oxaliplatin and irinotecan were randomized (1:1) to cetuximab (400 mg/m(2) loading then 250 mg/m(2) weekly) with or without PX-866 (8 mg orally daily; arms A and B, respectively)...
March 31, 2016: Clinical Colorectal Cancer
Bénédicte Rysman, François Mouawad, Abigaëlle Gros, Amélie Lansiaux, Dominique Chevalier, Samuel Meignan
Human epidermal growth factor receptor 3 (HER3) is a member of the human epidermal growth factor receptor (HER) family. The main characteristic of HER3 is that it does not possess tyrosine kinase activity, unlike other HERs. The role of HER3 in tumorigenesis has now been recognized, particularly in head and neck squamous cell carcinomas (HNSCCs). Despite conflicting studies, HER3 was found to be overexpressed in HNSCC samples, and correlates with disease progression and poor survival, especially when it is coexpressed with other HERs...
April 2016: Head & Neck
Xiao-Jun Li, Su-Juan Dai, Shao-Wei Liu, Jia-Meng Liu, Li Chen, Lin Hu, Cheng-Hang Sun
A novel actinomycete, designated strain S6R2A4-9T, was isolated from a soil sample collected from a karst cave in Henan Province, China and subjected to a polyphasic taxonomic study. This isolate grew optimally at 25-28℃, pH 6.5‒8.0 and in the absence of NaCl. The substrate mycelia of the isolate were well developed with irregular branches. Aerial mycelia fragmented into long rod-shaped elements. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain S6R2A4-9T resided in the cluster of genus Tenggerimyces within the family Nocardioidaceae and shared the highest 16S rRNA gene sequence similarity (98...
January 19, 2016: International Journal of Systematic and Evolutionary Microbiology
I K H Hadem, R Sharma
Insulin-like growth factor-1 (IGF-1), a key mediator of growth hormone action in mammals, plays an important role in the regulation of cellular and tissue functions. In the present investigation, the normal age-dependent and effect of dietary restriction on the expression levels of serum IGF-1, phosphotidylinositol 3-kinase (PI3K), and protein kinase B (PKB/Akt) in the liver, kidney and skeletal muscles of 1-, 9-, and 21-month-old female mice were ascertained using ELISA and Western blot analysis. Results showed that serum IGF-1 peaks at 9-month-old and decreases in older age...
March 2016: Hormone and Metabolic Research, Hormon- und Stoffwechselforschung, Hormones et Métabolisme
Hong-Min Sun, Tao Zhang, Yu-Zhen Wei, Hong-Yu Liu, Li-Yan Yu, Yu-Qin Zhang
A novel aerobic actinomycete, designated strain I12A-02601T, was isolated from a desert soil crusts sample collected from the Shapotou region of Tengger Desert, north-west China. The substrate mycelia of this isolate were well-developed and branched, but not fragmented. The maturity aerial mycelia formed short chains of small, rod-shaped spores. The strain contained ll-diaminopimelic acid, dd-diaminopimelic acid, galactose, glucose, ribose and xylose in its whole-cell hydrolysates. The polar lipids consisted of diphosphatidylglycerol, N-acetylglucosamine-containing phospholipids, phosphatidylinositolmannoside and glycolipids...
October 2015: International Journal of Systematic and Evolutionary Microbiology
C Zhu, S Wang, B Wang, F Du, C Hu, H Li, Y Feng, R Zhu, M Mo, Y Cao, A Li, X Yu
Human age-related retinal diseases, such as age-related macular degeneration (AMD), are intimately associated with decreased tissue oxygenation and hypoxia. Different antioxidants have been investigated to reverse AMD. In the present study, we describe the antioxidant 17β-estradiol (βE2) and investigate its protective effects on retinal neurons. Fourteen days after ovariectomy, adult Sprague-Dawley rats were exposed to 8000-lux light for 12h to induce retinal degeneration. Reactive oxygen species (ROS) levels were assessed by confocal fluorescence microscopy using 2,7-dichlorofluorescein diacetate...
September 24, 2015: Neuroscience
Jun Feng, Blake Mertz
Focal adhesion kinase (FAK) is a protein tyrosine kinase that is ubiquitously expressed, recruited to focal adhesions, and engages in a variety of cellular signaling pathways. Diverse cellular responses, such as cell migration, proliferation, and survival, are regulated by FAK. Prior to activation, FAK adopts an autoinhibited conformation in which the FERM domain binds the kinase domain, blocking access to the activation loop and substrate binding site. Activation of FAK occurs through conformational change, and acidic phospholipids such as phosphatidylinositol 4,5-bisphosphate (PIP2) are known to facilitate this process...
2015: PloS One
E I Tyulkova, L A Vataeva, O V Vetrovoy, D Yu Romanovsky
The present study was aimed at the analysis of spatial learning abilities in the Morris water maze (working memory) as well as hippocampal levels of phosphatidylinositol 4,5-diphosphates (TPI), phosphatidylinositol 4-phosphates (DPI), phosphotidylinositols (MPI), and expression of the type 1 inositol 1,4,5-trisphosphate receptor (IR3R1) in rats exposed to severe hypobaric hypoxia (ascent to 11 km, 3 h) on prenatal days 14-16 (group 1) or 17-19 (group 2). Exposure to severe hypoxia led to significant elevation of TP 1 and DPI hippocampal levels in juvenile and adult rats in the group 1, however these changes were more pronounced in juvenile rats than in adults...
March 2015: Zhurnal Evoliutsionnoĭ Biokhimii i Fiziologii
Yue Wang, Xiu Long Niu, Xiao Qin Guo, Jing Yang, Ling Li, Ye Qu, Cun Xiu Hu, Li Qun Mao, Dan Wang
About 40-60% of ovarian cancer (OVCA) cases express ERα, but only a small proportion of patients respond clinically to anti-estrogen treatment with estrogen receptor (ER) antagonist tamoxifen (TAM). The mechanism of TAM resistance in the course of OVCA progression remains unclear. However, IL6 plays a critical role in the development and progression of OVCA. Our recent results indicated that IL6 secreted by OVCA cells may promote the resistance of these cells to TAM via ER isoforms and steroid hormone receptor coactivator-1...
June 2015: Journal of Molecular Endocrinology
Hong Wang, Aileen X Wang, Kevin Aylor, Eugene J Barrett
AIMS/HYPOTHESIS: As insulin entry into muscle interstitium is rate-limiting for its overall peripheral action, defining the route and regulation of its entry is critical. Caveolin-1 is required for caveola formation in vascular endothelial cells (ECs) and for EC insulin uptake. Whether this requirement reflects simply the need for caveola availability or involves a more active role for caveolae/caveolin-1 is not known. Here, we examined the role of insulin-stimulated tyrosine 14 (Tyr(14))-caveolin-1 phosphorylation in mediating EC insulin uptake and the role of cellular Src-kinase (cSrc), TNF-α/IL-6 and high fat diet (HFD) in regulating this process...
June 2015: Diabetologia
Yi Xie, Takeo Nakanishi, Karthika Natarajan, Lowell Safren, Anne W Hamburger, Arif Hussain, Douglas D Ross
Phosphorylated cyclic-AMP (cAMP) response element binding protein (p-CREB) is a downstream effector of a variety of important signaling pathways. We investigated whether the human BCRP promoter contains a functional cAMP response element (CRE). 8Br-cAMP, a cAMP analogue, increased the activity of a BCRP promoter reporter construct and BCRP mRNA in human carcinoma cells. Epidermal growth factor receptor (EGFR) pathway activation also led to an increase in p-CREB and in BCRP promoter reporter activity via two major downstream EGFR signaling pathways: the phosphotidylinositol-3-kinase (PI3K)/AKT pathway and the mitogen-activated protein kinase (MAPK) pathway...
March 2015: Biochimica et Biophysica Acta
Antonio Jimeno, Julie E Bauman, Charles Weissman, Douglas Adkins, Ian Schnadig, Patrice Beauregard, Daniel W Bowles, Alexander Spira, Benjamin Levy, Nagashree Seetharamu, Diana Hausman, Luke Walker, Charles M Rudin, Keisuke Shirai
INTRODUCTION: The phosphotidylinositol-3 kinase (PI3K)/serine-threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is frequently altered in head and neck squamous cell cancer (HNSCC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. Preclinical models revealed synergy with docetaxel and a phase 1 trial demonstrated tolerability of this combination. This randomized phase 2 study evaluated PX-866 combined with docetaxel in patients with advanced, refractory HNSCC...
April 2015: Oral Oncology
A Jimeno, K Shirai, M Choi, J Laskin, M Kochenderfer, A Spira, V Cline-Burkhardt, E Winquist, D Hausman, L Walker, R B Cohen
BACKGROUND: The phosphotidylinositol-3 kinase (PI3K)/serine-threonine kinase/mammalian target of rapamycin signaling pathway is frequently altered in head and neck squamous cell cancer (HNSCC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. A phase I trial demonstrated tolerability of this combination. This randomized phase II study evaluated PX-866 combined with cetuximab in patients with advanced, refractory HNSCC. METHODS: Patients with recurrent or metastatic HNSCC who had received at least one and no more than two prior systemic treatment regimens were randomized (1 : 1) to cetuximab with or without PX-866 (8 mg p...
March 2015: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Liang Ge, Min Zhang, Randy Schekman
Formation of the autophagosome requires significant membrane input from cellular organelles. However, no direct evidence has been developed to link autophagic factors and the mobilization of membranes to generate the phagophore. Previously, we established a cell-free LC3 lipidation reaction to identify the ER-Golgi intermediate compartment (ERGIC) as a membrane source for LC3 lipidation, a key step of autophagosome biogenesis (Ge et al., eLife 2013; 2:e00947). We now report that starvation activation of autophagic phosphotidylinositol-3 kinase (PI3K) induces the generation of small vesicles active in LC3 lipidation...
2014: ELife
R Majeed, A Hamid, P L Sangwan, P K Chinthakindi, S Koul, S Rayees, G Singh, D M Mondhe, M J Mintoo, S K Singh, S K Rath, A K Saxena
Betulinic acid (BA) is a pentacyclic triterpenoid natural product reported to inhibit cell growth in a variety of cancers. However, the further clinical development of BA got hampered because of poor solubility and pharmacological properties. Interestingly, this molecule offer several hotspots for structural modifications in order to address its associated issues. In our endeavor, we selected C-3 position for the desirable chemical modification in order to improve its cytotoxic and pharmacological potential and prepared a library of different triazoline derivatives of BA...
2014: Cell Death & Disease
Jingying Liu, Xiuran Wang, Meina Li, Qian Du, Qiyun Li, Pengda Ma
A Gram-positive, aerobic, rod-shaped, motile, endospore-forming bacterium, designated strain A12(T), was isolated from a saline and alkali soil samples in Baicheng City, western of Jilin Province, China. Growth occurred in 15-45 °C (optimum, 30 °C) and at pH 7.0-11.5 (optimum, pH 9.0) and in the presence of 0-10 % (w/v) NaCl [optimum, 1-3 % (w/v) NaCl]. Meso-DAP was present in the peptidoglycan. The predominant menaquinone was MK-7. The major polar lipid profile was phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, phosphatidyl inositol-methyl and phosphotidylinositol dimannosid...
January 2015: Archives of Microbiology
Francesco Perri, Roberto Pacelli, Giuseppina Della Vittoria Scarpati, Laura Cella, Mario Giuliano, Francesco Caponigro, Stefano Pepe
Head and neck squamous cell carcinoma (HNSCC) is strongly associated with alcohol and tobacco consumption. Lately, the incidence of human papillomavirus (HPV)-related tumors has shown a significant increase, and HPV-related tumors show distinctive features if compared with the HPV-negative counterpart. Locally advanced HNSCC can be treated with concomitant chemoradiotherapy, but early recurrences sometimes occur. Relapses are often related to an intrinsic radioresistance of the tumors. Alterations in intracellular pathways, primarily involved in cell proliferation, apoptosis, and DNA repair, can lead to radioresistance...
May 2015: Head & Neck
Bing-Huo Zhang, Juan Cheng, Wei Chen, Han-Quan Li, Jian-Yuan Yang, Dong-Jin Park, Chang-Jin Kim, Rui Shen, Yan-Qin Duan, Wen-Jun Li
Strain JXJ 0135(T), an anti-cyanobacterial actinomycete, was isolated from a soil sample collected from Lushan Mountain, south China, and identified by using polyphasic approach. Phylogenetic analysis of the near-complete 16S rRNA gene sequence indicated that strain JXJ 0135(T) belongs to the genus Streptomyces and exhibited distinct subclade and also highest similarity (98.6%) to Streptomyces scopuliridis RB72(T). The strain developed well-branched substrate and aerial mycelia, and produced spiral spore chains...
January 2015: Journal of Antibiotics
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