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https://www.readbyqxmd.com/read/28645941/a-first-time-in-human-study-of-gsk2636771-a-phosphoinositide-3-kinase-beta-selective-inhibitor-in-patients-with-advanced-solid-tumors
#1
Joaquin Mateo, Gopinath Ganji, Charlotte Lemech, Howard A Burris, Sae-Won Han, Karen E Swales, Shaun Decordova, Maurice P DeYoung, Deborah A Smith, Shanker Kalyana-Sundaram, Jiuhua Wu, Monica Motwani, Rakesh Kumar, Jerry M Tolson, Sun Young Rha, Hyun Cheol Chung, Joseph Paul Eder, Sunil Sharma, Yung-Jue Bang, Jeffrey R Infante, Li Yan, Johann S de Bono, Hendrik-Tobias Arkenau
The phosphoinositide 3 kinase (PI3K)/protein kinase B (AKT) pathway is commonly activated in several tumor types. Selective targeting of p110β could result in successful pathway inhibition while avoiding the on and off target effects of pan-PI3K inhibitors. GSK2636771 is a potent, orally bioavailable, adenosine triphosphate-competitive, selective inhibitor of PI3Kβ.<br /><br />Experimental Design: <p>We evaluated the safety, pharmacokinetics, pharmacodynamics and antitumor activity of GSK2636771 to define the recommended Phase II dose (RP2D)...
June 23, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28645850/biomechanical-analysis-using-fea-and-experiments-of-a-standard-plate-method-versus-three-cable-methods-for-fixing-acetabular-fractures-with-simultaneous-tha
#2
Mina S R Aziz, Omar Dessouki, Saeid Samiezadeh, Habiba Bougherara, Emil H Schemitsch, Radovan Zdero
Acetabular fractures potentially account for up to half of all pelvic fractures, while pelvic fractures potentially account for over one-tenth of all human bone fractures. This is the first biomechanical study to assess acetabular fracture fixation using plates versus cables in the presence of a total hip arthroplasty, as done for the elderly. In Phase 1, finite element (FE) models compared a standard plate method versus 3 cable methods for repairing an acetabular fracture (type: anterior column plus posterior hemi-transverse) subjected to a physiological-type compressive load of 2207N representing 3 x body weight for a 75kg person during walking...
June 20, 2017: Medical Engineering & Physics
https://www.readbyqxmd.com/read/28645776/selective-inhibition-of-flt3-by-gilteritinib-in-relapsed-or-refractory-acute-myeloid-leukaemia-a-multicentre-first-in-human-open-label-phase-1-2-study
#3
Alexander E Perl, Jessica K Altman, Jorge Cortes, Catherine Smith, Mark Litzow, Maria R Baer, David Claxton, Harry P Erba, Stan Gill, Stuart Goldberg, Joseph G Jurcic, Richard A Larson, Chaofeng Liu, Ellen Ritchie, Gary Schiller, Alexander I Spira, Stephen A Strickland, Raoul Tibes, Celalettin Ustun, Eunice S Wang, Robert Stuart, Christoph Röllig, Andreas Neubauer, Giovanni Martinelli, Erkut Bahceci, Mark Levis
BACKGROUND: Internal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia. METHODS: In this phase 1-2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment...
June 20, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28642717/the-lactate-minimum-test-concept-methodological-aspects-and-insights-for-future-investigations-in-human-and-animal-models
#4
REVIEW
Leonardo H D Messias, Claudio A Gobatto, Wladimir R Beck, Fúlvia B Manchado-Gobatto
In 1993, Uwe Tegtbur proposed a useful physiological protocol named the lactate minimum test (LMT). This test consists of three distinct phases. Firstly, subjects must perform high intensity efforts to induce hyperlactatemia (phase 1). Subsequently, 8 min of recovery are allowed for transposition of lactate from myocytes (for instance) to the bloodstream (phase 2). Right after the recovery, subjects are submitted to an incremental test until exhaustion (phase 3). The blood lactate concentration is expected to fall during the first stages of the incremental test and as the intensity increases in subsequent stages, to rise again forming a "U" shaped blood lactate kinetic...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28642030/cyclic-mog35-55-ameliorates-clinical-and-neuropathological-features-of-experimental-autoimmune-encephalomyelitis
#5
Athanasios Lourbopoulos, George Deraos, Minos-Timotheos Matsoukas, Olga Touloumi, Aggeliki Giannakopoulou, Hubert Kalbacher, Nikolaos Grigoriadis, Vasso Apostolopoulos, John Matsoukas
EAE is induced to susceptible mice using linear peptides of myelin proteins of the central nervous system. Specific peptide motifs within the peptide-binding groove of the MHC peptide-complex determines the affinity of the peptide in each animal and the consequent T-cell receptor recognition and activation of the cell. Altered peptide ligand (APL) vaccination is a novel approach based on an effort to induce T-cell tolerance or alter cytokine profile from pro-inflammatory to anti-inflammatory. In the present study we synthesized the MOG35-55 peptide and altered its 3-dimensional conformation to make it a cyclic one (c-MOG35-55)...
June 7, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28637840/promoting-sleep-oscillations-and-their-functional-coupling-by-transcranial-stimulation-enhances-memory-consolidation-in-mild-cognitive-impairment
#6
Julia Ladenbauer, Josef Ladenbauer, Nadine Külzow, Rebecca de Boor, Elena Avramova, Ulrike Grittner, Agnes Flöel
Alzheimer's disease (AD) not only involves loss of memory functions but also prominent deterioration of sleep physiology, already evident in the stage of mild cognitive impairment (MCI). Cortical slow oscillations (SO, 0.5-1 Hz) and thalamo-cortical spindle activity (12-15 Hz) during sleep, and their temporal coordination, are considered critical for memory formation. We investigated the potential of slow oscillatory transcranial direct current stimulation (so-tDCS), applied during a daytime nap in a sleep state-dependent manner, to modulate these activity patterns and sleep-related memory consolidation in 9 male and 7 female human patients with MCI...
June 21, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28628884/proteomics-profiling-reveals-inflammatory-biomarkers-of-antidepressant-treatment-response-findings-from-the-co-med-trial
#7
Bharathi S Gadad, Manish K Jha, Bruce D Grannemann, Taryn L Mayes, Madhukar H Trivedi
Animal and human studies suggest an association between depression and aberrant immune response. Further, common inflammatory markers may change during the course of antidepressant treatment in patients. The objective of this study was to evaluate changes in inflammatory markers and clinical outcomes from subjects enrolled in the Combining Medications to Enhance Depression Outcome (CO-MED) trial. At baseline and week 12 (treatment completion), plasma samples of 102 participants were analyzed via a multiplex assay comprised of inflammatory markers using a 27-plex standard assay panel plus a 4-plex human acute phase xMAP technology based platform...
May 26, 2017: Journal of Psychiatric Research
https://www.readbyqxmd.com/read/28627713/process-development-of-human-multipotent-stromal-cell-microcarrier-culture-using-an-automated-high-throughput-microbioreactor
#8
Qasim A Rafiq, Mariana P Hanga, Thomas R J Heathman, Karen Coopman, Alvin W Nienow, David J Williams, Christopher J Hewitt
Microbioreactors play a critical role in process development as they reduce reagent requirements and can facilitate high-throughput screening of process parameters and culture conditions. Here we have demonstrated and explained in detail, for the first time, the amenability of the automated ambr15 cell culture microbioreactor system for the development of scalable adherent human mesenchymal multipotent stromal/stem cell (hMSC) microcarrier culture processes. This was achieved by first improving suspension and mixing of the microcarriers and then improving cell attachment thereby reducing the initial growth lag phase...
June 19, 2017: Biotechnology and Bioengineering
https://www.readbyqxmd.com/read/28625777/safety-and-tolerability-of-subcutaneous-trastuzumab-for-the-adjuvant-treatment-of-human-epidermal-growth-factor-receptor-2-positive-early-breast-cancer-safeher-phase-iii-study-s-primary-analysis-of-2573-patients
#9
J Gligorov, B Ataseven, M Verrill, M De Laurentiis, K H Jung, H A Azim, N Al-Sakaff, S Lauer, M Shing, X Pivot
AIM: To assess the safety and tolerability of adjuvant subcutaneous trastuzumab (Herceptin(®) SC, H SC), delivered from an H SC Vial via hand-held syringe (Cohort A) or single-use injection device (Cohort B), with or without chemotherapy, for human epidermal growth factor receptor 2 (HER2)-positive stage I to IIIC early breast cancer (EBC) in the phase III SafeHer study (NCT01566721). METHODS: Patients received 600 mg fixed-dose H SC every 3 weeks for 18 cycles...
June 15, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28624695/first-in-human-phase-i-study-of-oral-s49076-a-unique-met-axl-fgfr-inhibitor-in-advanced-solid-tumours
#10
Jordi Rodon, Sophie Postel-Vinay, Antoine Hollebecque, Paolo Nuciforo, Analia Azaro, Valérie Cattan, Lucie Marfai, Isabelle Sudey, Karl Brendel, Audrey Delmas, Stéphanie Malasse, Jean-Charles Soria
BACKGROUND AND OBJECTIVES: S49076 is a novel ATP-competitive tyrosine kinase inhibitor of MET, AXL and FGFR with a unique selectivity profile. A phase I open-label study was undertaken to establish the tolerability profile and determine the recommended dose (RD) and administration schedule. MATERIALS AND METHODS: Patients with advanced solid tumours received S49076 orally once-daily (qd) or twice-daily (bid) in continuous 21-day cycles at escalating doses guided by a 3 + 3 design and followed by an expansion phase at the RD...
June 15, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28623830/identification-characteristics-and-human-exposure-assessments-of-triclosan-bisphenol-a-and-four-commonly-used-organic-uv-filters-in-indoor-dust-collected-from-shanghai-china
#11
Junjie Ao, Tao Yuan, Yuning Ma, Li Gao, Ni Ni, Dan Li
Indoor dust is a very significant medium to understand human exposure of emerging contaminants. A novel and robust analytical method to measure the amounts of six personal care products (PCPs) (triclosan, bisphenol-A and four commonly used organic ultraviolet (UV) filters) simultaneously in indoor dust is developed in this paper. Target analytes were extracted using accelerated solvent extraction. After sample cleanup by solid-phase extraction (SPE), the extracts were derivatized and analyzed using gas chromatography-tandem mass spectrometry...
June 9, 2017: Chemosphere
https://www.readbyqxmd.com/read/28618005/bace1-inhibitor-lanabecestat-azd3293-in-a-phase-1-study-of-healthy-japanese-subjects-pharmacokinetics-and-effects-on-plasma-and-cerebrospinal-fluid-a%C3%AE-peptides
#12
Kei Sakamoto, Shunji Matsuki, Kyoko Matsuguma, Tatsuya Yoshihara, Naoki Uchida, Fumihiko Azuma, Muir Russell, Glen Hughes, Samantha Budd Haeberlein, Robert C Alexander, Susanna Eketjäll, Alan R Kugler
Lanabecestat (AZD3293; LY3314814) is an orally active potent inhibitor of human β-secretase 1 in clinical development for the treatment of Alzheimer disease. In this first Japanese clinical study for an Alzheimer disease intervention to include cerebrospinal fluid (CSF) sampling in Japanese elderly healthy subjects, we report the pharmacokinetics and effects on plasma and CSF amyloid-β (Aβ) peptides of lanabecestat in a phase 1 study involving 40 healthy Japanese subjects (NCT02005211). No safety and tolerability concerns were identified in healthy Japanese subjects exposed to lanabecestat up to the highest doses given, which is consistent with observations in a US phase 1 study of lanabecestat...
June 15, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28614791/human-vaccination-against-plasmodium-vivax-duffy-binding-protein-induces-strain-transcending-antibodies
#13
Ruth O Payne, Sarah E Silk, Sean C Elias, Kathryn H Milne, Thomas A Rawlinson, David Llewellyn, A Rushdi Shakri, Jing Jin, Geneviève M Labbé, Nick J Edwards, Ian D Poulton, Rachel Roberts, Ryan Farid, Thomas Jørgensen, Daniel Gw Alanine, Simone C de Cassan, Matthew K Higgins, Thomas D Otto, James S McCarthy, Willem A de Jongh, Alfredo Nicosia, Sarah Moyle, Adrian Vs Hill, Eleanor Berrie, Chetan E Chitnis, Alison M Lawrie, Simon J Draper
BACKGROUND: Plasmodium vivax is the most widespread human malaria geographically; however, no effective vaccine exists. Red blood cell invasion by the P. vivax merozoite depends on an interaction between the Duffy antigen receptor for chemokines (DARC) and region II of the parasite's Duffy-binding protein (PvDBP_RII). Naturally acquired binding-inhibitory antibodies against this interaction associate with clinical immunity, but it is unknown whether these responses can be induced by human vaccination...
June 15, 2017: JCI Insight
https://www.readbyqxmd.com/read/28612710/yc-1-induces-g0-g1-phase-arrest-and-mitochondria-dependent-apoptosis-in-cisplatin-resistant-human-oral-cancer-car-cells
#14
Miau-Rong Lee, Chingju Lin, Chi-Cheng Lu, Sheng-Chu Kuo, Je-Wei Tsao, Yu-Ning Juan, Hong-Yi Chiu, Fang-Yu Lee, Jai-Sing Yang, Fuu-Jen Tsai
Oral cancer is a serious and fatal disease. Cisplatin is the first line of chemotherapeutic agent for oral cancer therapy. However, the development of drug resistance and severe side effects cause tremendous problems clinically. In this study, we investigated the pharmacologic mechanisms of YC-1 on cisplatin-resistant human oral cancer cell line, CAR. Our results indicated that YC-1 induced a concentration-dependent and time-dependent decrease in viability of CAR cells analyzed by MTT assay. Real-time image analysis of CAR cells by IncuCyte™ Kinetic Live Cell Imaging System demonstrated that YC-1 inhibited cell proliferation and reduced cell confluence in a time-dependent manner...
June 2017: BioMedicine
https://www.readbyqxmd.com/read/28606591/safety-and-immunogenicity-of-the-rvsv%C3%A2-g-zebov-gp-ebola-virus-vaccine-candidate-in-healthy-adults-a-phase-1b-randomised-multicentre-double-blind-placebo-controlled-dose-response-study
#15
D Gray Heppner, Tracy L Kemp, Brian K Martin, William J Ramsey, Richard Nichols, Emily J Dasen, Charles J Link, Rituparna Das, Zhi Jin Xu, Eric A Sheldon, Teresa A Nowak, Thomas P Monath
BACKGROUND: The 2014 Zaire Ebola virus outbreak highlighted the need for a safe, effective vaccine with a rapid onset of protection. We report the safety and immunogenicity of the recombinant vesicular stomatitis virus-Zaire Ebola virus envelope glycoprotein vaccine (rVSV∆G-ZEBOV-GP) across a 6 log10 dose range in two sequential cohorts. METHODS: In this phase 1b double-blind, placebo-controlled, dose-response study we enrolled and randomly assigned healthy adults (aged 18-61 years) at eight study sites in the USA to receive a single injection of vaccine or placebo, administered by intramuscular injection...
June 9, 2017: Lancet Infectious Diseases
https://www.readbyqxmd.com/read/28596304/pcsk9-inhibition-and-atherosclerotic-cardiovascular-disease-prevention-does-reality-match-the-hype
#16
REVIEW
Savvas Hadjiphilippou, Kausik K Ray
Within this review we look at whether the potential provided by proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition for prevention of atherosclerotic cardiovascular disease matches the excitement generated. Two fully human monoclonal antibodies to PCSK9 are currently licenced for clinical use both in the USA and the European Union: evolocumab and alirocumab. These reduce low-density lipoprotein cholesterol by over 50% across a range of populations and were generally found to have a safety profile comparable with placebo...
June 8, 2017: Heart: Official Journal of the British Cardiac Society
https://www.readbyqxmd.com/read/28595074/protective-effect-of-arthrospira-platensis-extracts-against-ultraviolet-b-induced-cellular-senescence-through-inhibition-of-dna-damage-and-matrix-metalloproteinase-1-expression-in-human-dermal-fibroblasts
#17
Jeong-Ju Lee, Ki Bbeum Kim, Jina Heo, Dae-Hyun Cho, Hee-Sik Kim, Song Hee Han, Kyu Joong Ahn, In-Sook An, Sungkwan An, Seunghee Bae
Ultraviolet (UV) light exposure causes skin photoaging, which is known to be preventable and controllable by application of UV-protective agents. In this study, we demonstrated, for the first time, that the extract of microalgae Arthrospira platensis has a reverse effect on UV-induced photodamage such as loss of cell viability, cellular senescence, DNA damage, and collagen destruction in dermal fibroblasts. Forty-eight extracts were prepared from the cell biomass by controlling culture light conditions, extract solvents, and disruption methods...
May 31, 2017: Journal of Photochemistry and Photobiology. B, Biology
https://www.readbyqxmd.com/read/28594750/blockade-of-hla-antibody-triggered-classical-complement-activation-in-sera-from-subjects-dosed-with-the-anti-c1s-monoclonal-antibody-tnt009-results-from-a-randomized-first-in-human-phase-1-trial
#18
Jakob Mühlbacher, Bernd Jilma, Markus Wahrmann, Johann Bartko, Farsad Eskandary, Christian Schörgenhofer, Michael Schwameis, Graham C Parry, James C Gilbert, Sandip Panicker, Georg A Böhmig
BACKGROUND: Complement may play a key role in antibody-mediated rejection (ABMR). A promising therapeutic approach may be classical pathway (CP) inhibition at the level of early component C1. METHODS: In this first-in-human, double-blind, randomized placebo-controlled phase 1 trial, we evaluated the safety and complement inhibitory effect of TNT009, a humanized monoclonal anti-C1s antibody. Sixty-four adult healthy volunteers received either single (n=48; 7 consecutive cohorts: 0...
June 7, 2017: Transplantation
https://www.readbyqxmd.com/read/28588020/enasidenib-in-mutant-idh2-relapsed-or-refractory-acute-myeloid-leukemia
#19
Eytan M Stein, Courtney D DiNardo, Daniel A Pollyea, Amir T Fathi, Gail J Roboz, Jessica K Altman, Richard M Stone, Daniel J DeAngelo, Ross L Levine, Ian W Flinn, Hagop M Kantarjian, Robert Collins, Manish R Patel, Arthur E Frankel, Anthony Stein, Mikkael A Sekeres, Ronan T Swords, Bruno C Medeiros, Christophe Willekens, Paresh Vyas, Alessandra Tosolini, Qiang Xu, Robert D Knight, Katharine E Yen, Sam Agresta, Stéphane de Botton, Martin S Tallman
Recurrent mutations in isocitrate dehydrogenase 2 (IDH2) occur in ~12% of patients with acute myeloid leukemia (AML). Mutated IDH2 proteins neomorphically synthesize 2-hydroxyglutarate resulting in DNA and histone hypermethylation, leading to blocked cellular differentiation. Enasidenib (AG-221/CC-90007) is a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes. This first-in-human, phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in patients with mutant-IDH2 advanced myeloid malignancies...
June 6, 2017: Blood
https://www.readbyqxmd.com/read/28587465/clarifying-the-catalytic-mechanism-of-human-glutamine-synthetase-a-qm-mm-study
#20
Cátia Moreira, Maria João Ramos, Pedro A Fernandes
Glutamine synthetase (GS) is a crucial enzyme responsible for the elimination of both neurotoxic glutamate and toxic ammonium, by combining them into glutamine. Alterations on the GS activity are associated with severe liver and neurodegenerative diseases and its absence or malformation results in death. In this work, the catalytic mechanism of human GS has been investigated with high-level QM/MM calculations, showing a two-phase reaction cycle. During phase 1, GS activates the reactants (NH4(+) and glutamate) with extreme efficiency, through NH4(+) deprotonation by E305 and glutamate phosphorylation by ATP, in two spontaneous and barrierless reactions...
June 6, 2017: Journal of Physical Chemistry. B
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