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First-in-human phase 1 study

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https://www.readbyqxmd.com/read/27910704/the-safety-of-nivolumab-for-the-treatment-of-advanced-non-small-cell-lung-cancer
#1
Giulio Metro, Biagio Ricciuti, Marta Brambilla, Sara Baglivo, Irene Soli, Elisa Minenza, Giulia Costanza Leonardi, Alessandro D'Arpino, Daniela Colabrese, Marco Tazza, Daniela Zicari, Vincenzo Minotti, Rita Chiari
Immune checkpoint blockaders (ICBs) act by unbalancing the immune system, thus favoring the development of an immune-mediated antitumor effect. ICBs targeting the programmed cell death receptor-1 (PD-1) have recently been investigated in a number of advanced tumors, including non-small cell lung cancer (NSCLC). Nivolumab, a fully human IgG4 kappa directed against PD-1, has been the first ICB to be approved for second-line treatment of advanced NSCLC. Areas covered: In this review we focus on the clinical development of nivolumab for the treatment of advanced NSCLC, with an emphasis on its safety profile...
December 2, 2016: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/27908155/a-new-algorithm-for-estimating-the-rod-volume-fraction-and-the-trabecular-thickness-from-in-vivo-computed-tomography
#2
Felix Sebastian Leo Thomsen, Jaime Andrés Peña, Yongtao Lu, Gerd Huber, Michael Morlock, Claus-Christian Glüer, Claudio Augusto Delrieux
PURPOSE: Existing microstructure parameters are able to predict vertebral in vitro failure load, but for noisy in vivo data more complex algorithms are needed for a robust assessment. METHODS: A new algorithm is proposed for the microstructural analysis of trabecular bone under in vivo quantitative computed tomography (QCT). Five fractal parameters are computed: (1) the average local fractal dimension FD, (2) its standard deviation FD.SD, (3) the fractal rod volume ratio fRV/BV, (4) the average fractal trabecular thickness fTb...
December 2016: Medical Physics
https://www.readbyqxmd.com/read/27906070/subretinal-adipose-tissue-derived-mesenchymal-stem-cell-implantation-in-advanced-stage-retinitis-pigmentosa-a-phase-i-clinical-safety-study
#3
Ayse Oner, Z Burcin Gonen, Neslihan Sinim, Mustafa Cetin, Yusuf Ozkul
BACKGROUND: This prospective clinical case series aimed to investigate the safety of subretinal adipose tissue-derived mesenchymal stem cell (ADMSC) implantation in advanced stage retinitis pigmentosa (RP). METHODS: This study included 11 patients with end-stage RP who received subretinal implantation of ADMSCs. All patients had a total visual field defect and five of them only had light perception. The best corrected visual acuity (BCVA) in the study was 20/2000...
December 1, 2016: Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/27902470/phase-i-study-of-qlnc120-a-novel-egfr-and-her2-kinase-inhibitor-in-pre-treated-patients-with-her2-overexpressing-advanced-breast-cancer
#4
Tongtong Zhang, Qing Li, Shanshan Chen, Yang Luo, Ying Fan, Binghe Xu
This study evaluated the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetic profile, and preliminary antitumor activity of QLNC120, an inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), in HER2 overexpressing advanced breast cancer patients. In addition, the prognostic biomarkers of QLNC120 were investigated. QLNC120 was administered as a single dose, followed by 7 days observation, and then once daily consecutively. Scheduled dose escalation was 450mg, 750mg, 1000mg and 1250mg...
November 25, 2016: Oncotarget
https://www.readbyqxmd.com/read/27900021/inhibition-of-pttg1-expression-by-microrna-suppresses-proliferation-and-induces-apoptosis-of-malignant-glioma-cells
#5
Xing Su, Jianguo Chen, Lanchun Ni, Wei Shi, Jinlong Shi, Xiaojiang Liu, Yu Zhang, Peipei Gong, Hui Zhu, Qingfeng Huang
The present study aimed to investigate the role of pituitary tumor-transforming gene 1 (PTTG1) in the proliferation, invasion and apoptosis of human malignant glioma U251 cells. Firstly, 2 microRNAs (miRNAs) targeting PTTG1 messenger (m)RNA were ligated into a pcDNA6.2-GW/EmGFP-miR expression vector. The recombinant plasmids, miRNA-1 and miRNA-2 (miR-2), were transfected into U251 cells using the liposome method. PTTG1 mRNA and protein levels were evaluated using quantitative polymerase chain reaction and western blot analysis...
November 2016: Oncology Letters
https://www.readbyqxmd.com/read/27899892/age-dependent-hepatic-udp-glucuronosyltransferase-gene-expression-and-activity-in-children
#6
Elizabeth Neumann, Huma Mehboob, Jacqueline Ramírez, Snezana Mirkov, Min Zhang, Wanqing Liu
UDP-glucuronosyltransferases (UGTs) are important phase II drug metabolism enzymes. The aim of this study was to explore the relationship between age and changes in mRNA expression and activity of major human hepatic UGTs, as well as to understand the potential regulatory mechanism underlying this relationship. Using previously generated data, we investigated age-dependent mRNA expression levels of 11 hepatic UGTs (UGT1A1, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A9, UGT2B4, UGT2B7, UGT2B10, UGT2B15, and UGT2B17) and 16 transcription factors (AHR, AR, CAR, ESR2, FXR, GCCR, HNF1a, HNF3a, HNF3b, HNF4a, PPARA, PPARG, PPARGC, PXR, SP1, and STAT3) in liver tissue of donors (n = 38) ranging from 0 to 25 years of age...
2016: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/27898309/diverging-temporal-trends-of-human-exposure-to-bisphenols-and-plastizisers-such-as-phthalates-caused-by-substitution-of-legacy-edcs
#7
Irina Gyllenhammar, Anders Glynn, Bo A G Jönsson, Christian H Lindh, Per Ola Darnerud, Kettil Svensson, Sanna Lignell
Phthalates and phenolic substances were investigated in urine samples from first-time mothers in Uppsala, Sweden, collected between 2009 and 2014. These substances have a comparably fast metabolism and urinary metabolites are predominantly analysed. The main aim was to investigate if measures to decrease production and use of certain phthalates and bisphenol A (BPA) have resulted in decreased human exposure, and to determine if exposures to replacement chemicals have increased. Temporal trends were evaluated for metabolites (n=13) of seven phthalates, a phthalate replacer, four different bisphenols, triclosan, one organophosphate-based flame retardant, and for two pesticides...
November 26, 2016: Environmental Research
https://www.readbyqxmd.com/read/27895800/a-novel-curcumin-analogue-is-a-potent-chemotherapy-candidate-for-human-hepatocellular-carcinoma
#8
Ji-An Zhao, Mei-Xiang Sang, Cui-Zhi Geng, Shi-Jie Wang, Bao-En Shan
Curcumin (CUR) has been demonstrated to protect against carcinogenesis and to prevent tumor development in cancer; however, the clinical application of CUR is limited by its instability and poor metabolic properties. The present study offers an strategy for a novel CUR analogue, (1E,4E)-1,5-bis(2-bromophenyl)penta-1,4-dien-3-one (GL63), to be used as a potential therapeutic agent for hepatocellular carcinoma (HCC) in vitro and in vivo. The current study demonstrated that GL63 exhibited more potent inhibition of proliferation of HCC cells than CUR...
November 2016: Oncology Letters
https://www.readbyqxmd.com/read/27894277/human-limb-skeletal-muscle-wasting-and-architectural-remodeling-during-five-to-ten-days-intubation-and-ventilation-in-critical-care-an-observational-study-using-ultrasound
#9
Peter Turton, Richard Hay, Jonathon Taylor, Jamie McPhee, Ingeborg Welters
BACKGROUND: Critically ill patients frequently suffer muscle weakness whilst in critical care. Ultrasound can reliably track loss of muscle size, but also quantifies the arrangement of the muscle fascicles, known as the muscle architecture. We sought to measure both pennation angle and fascicle length, as well as tracking changes in muscle thickness in a population of critically ill patients. METHODS: On days 1, 5 and 10 after admission to critical care, muscle thickness was measured in ventilated critically ill patients using bedside ultrasound...
November 29, 2016: BMC Anesthesiology
https://www.readbyqxmd.com/read/27886407/first-in-human-assessment-of-prx002-an-anti-%C3%AE-synuclein-monoclonal-antibody-in-healthy-volunteers
#10
Dale B Schenk, Martin Koller, Daniel K Ness, Sue G Griffith, Michael Grundman, Wagner Zago, Jay Soto, George Atiee, Susanne Ostrowitzki, Gene G Kinney
BACKGROUND: α-Synuclein is a major component of pathologic inclusions that characterize Parkinson's disease. PRX002 is an antibody that targets α-synuclein, and its murine parent antibody 9E4 has been shown in preclinical studies to reduce α-synuclein pathology and to protect against cognitive and motor deteriorations and progressive neurodegeneration in human α-synuclein transgenic mice. METHODS: This first-in-human, randomized, double-blind, placebo-controlled, phase 1 study assessed the impact of PRX002 administered to 40 healthy participants in 5 ascending-dose cohorts (n = 8/cohort) in which participants were randomly assigned to receive a single intravenous infusion of study drug (0...
November 25, 2016: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/27878237/inhibition-of-the-growth-of-human-melanoma-cells-by-methionine-enkephalin
#11
Dong-Mei Wang, Guang-Chuan Wang, Jing Yang, Nicolas P Plotnikoff, Noreen Griffin, Yu-Man Han, Rui-Qun Qi, Xing-Hua Gao, Feng-Ping Shan
Melanoma is an aggressive cancer, the incidence of which is increasing worldwide. Limited therapies are currently available, particularly following metastasis. The aim of the present study was to investigate the inhibiting effect of methionine enkephalin (MENK) on human melanoma via opioid receptors. The results of the present study revealed that MENK markedly regulates the proliferation of A375 cells, causing cell cycle arrest in G0/G1 phase and a decrease in the percentage of cells in S and G2/M phases. Reverse transcription‑quantitative polymerase chain reaction demonstrated that MENK treatment increased opioid receptor expression in A375 cells...
November 14, 2016: Molecular Medicine Reports
https://www.readbyqxmd.com/read/27878105/spread-of-human-immunodeficiency-virus-1-among-men-who-have-sex-with-men-is-emerging-as-a-genuine-social-concern-and-affecting-the-general-populace-case-reports-from-eastern-india
#12
Aroni Chatterjee, Agniswar Sarkar, Sabbir Ansari, Sattik Siddhanta, Siwalik Banerjee, Rathindranath Sarkar, Nilanjan Chakraborty
Human immunodeficiency virus (HIV) infection among men who have sex with men (MSM) has increased to a drastic proportion throughout India in the last couple of years due to a lack of productive identification and management framework. In apprehension of social disgrace these men attempt to live a normal hetero conjugal life and, in the process, act as a bridge in spreading the virus to their women partners. In this case report we have highlighted two cases which clearly distinguished the adequacy of HIV treatment among MSM when they are diagnosed during early or late phases of infection...
November 12, 2016: World Journal of Virology
https://www.readbyqxmd.com/read/27876223/monitoring-of-organochlorine-pesticides-in-blood-of-women-with-uterine-cervix-cancer
#13
Ángel G Polanco Rodríguez, M Inmaculada Riba López, T Ángel DelValls Casillas, J Alfredo Araujo León, Olfa Mahjoub, Anjan Kumar Prusty
In Yucatan, Mexico, chronic exposure of Mayan population to pesticides is expected as about 30 per cent are drinking polluted water. Residues of organochlorine pesticides (OCP) were monitored in 18 municipalities of Yucatan with high mortality rates due to uterine cervix cancer. 70 blood samples collected from Mayan women living in livestock, agricultural and metropolitan area were analyzed for OCP. Solid Phase Extraction was performed on C18 cartridges and analyzed by Gas Chromatography with Electron Capture Detector...
November 18, 2016: Environmental Pollution
https://www.readbyqxmd.com/read/27872580/untargeted-polar-metabolomics-of-transformed-mda-mb-231-breast-cancer-cells-expressing-varying-levels-of-human-arylamine-n-acetyltransferase-1
#14
Samantha M Carlisle, Patrick J Trainor, Xinmin Yin, Mark A Doll, Marcus W Stepp, J Christopher States, Xiang Zhang, David W Hein
INTRODUCTION: Human arylamine N-acetyltransferase 1 (NAT1) is a phase II xenobiotic metabolizing enzyme found in almost all tissues. Expression of NAT1 is elevated in several cancers including breast cancer. However, the exact mechanism by which NAT1 expression affects cancer risk and progression remains unclear. OBJECTIVE: This study explored polar metabolome differences between MDA-MB-231 breast cancer cells expressing varying levels of NAT1 activity using an untargeted approach...
July 2016: Metabolomics: Official Journal of the Metabolomic Society
https://www.readbyqxmd.com/read/27872130/a-first-in-human-phase-i-study-of-the-atp-competitive-akt-inhibitor-ipatasertib-gdc-0068-demonstrates-robust-and-safe-targeting-of-akt-in-patients-with-solid-tumors
#15
Cristina Saura, Desamparados Roda, Susana Roselló, Mafalda Oliveira, Teresa Macarulla, José Alejandro Pérez-Fidalgo, Rafael Morales-Barrera, Juan Manuel Sanchis-García, Luna Musib, Nageshwar Budha, Jin Zhu, Michelle Nannini, Wai Y Chan, Sandra M Sanabria Bohórquez, Raymond D Meng, Kui Lin, Yibing Yan, Premal Patel, José Baselga, Josep Tabernero, Andres Cervantes
Activation of Akt signaling by PTEN loss or PIK3CA mutations occurs frequently in human cancers but targeting Akt has been difficult due to the mechanism-based toxicities of inhibitors that target the inactive conformation of Akt. Ipatasertib (GDC‑0068) is a novel selective ATP-competitive small molecule inhibitor of Akt that preferentially targets active phosphorylated Akt and is potent in cell lines with evidence of Akt activation. In this Phase I study, ipatasertib was well-tolerated; most adverse events were gastrointestinal and Grade 1-2 in severity...
November 21, 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27871720/-guidelines-for-the-prescription-of-mood-stabilizers-for-adolescents-a-literature-review
#16
G Munch, N Godart
INTRODUCTION: Adolescence is a unique phase of the human developmental process. In adolescents, psychotropic medications may have different efficacy and tolerance profiles compared to those at other stages of the lifespan. Mood stabilizers are a complex pharmacological category including lithium, some anticonvulsants, and some second generation antipsychotics. Focusing on this class of pharmacological agents, we aim to answer the following questions: in which indications and according to which modalities should mood stabilizers be prescribed during adolescence? METHODS: Information was sought from the websites of the French Haute Autorité de santé (HAS) and Agence nationale de sécurité du médicament et des produits de santé (ANSM), the American Food and Drug Administration (FDA) and the British National Institute for Health and Clinical Excellence (NICE)...
November 18, 2016: L'Encéphale
https://www.readbyqxmd.com/read/27870574/evaluation-of-bgj398-a-fibroblast-growth-factor-receptor-1-3-kinase-inhibitor-in-patients-with-advanced-solid-tumors-harboring-genetic-alterations-in-fibroblast-growth-factor-receptors-results-of-a-global-phase-i-dose-escalation-and-dose-expansion-study
#17
Lucia Nogova, Lecia V Sequist, Jose Manuel Perez Garcia, Fabrice Andre, Jean-Pierre Delord, Manuel Hidalgo, Jan H M Schellens, Philippe A Cassier, D Ross Camidge, Martin Schuler, Ulka Vaishampayan, Howard Burris, G Gary Tian, Mario Campone, Zev A Wainberg, Wan-Teck Lim, Patricia LoRusso, Geoffrey I Shapiro, Katie Parker, Xueying Chen, Somesh Choudhury, Francois Ringeisen, Diana Graus-Porta, Dale Porter, Randi Isaacs, Reinhard Buettner, Jürgen Wolf
Purpose This two-part, first-in-human study was initiated in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors (FGFRs) to determine the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), and the schedule, safety, pharmacokinetics, pharmacodynamics, and antitumor activity of oral BGJ398, a selective FGFR1-3 tyrosine kinase inhibitor. Patients and Methods Adult patients were treated with escalating dosages of BGJ398 5 to 150 mg once daily or 50 mg twice daily continuously in 28-day cycles...
November 21, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/27863806/pharmacokinetics-safety-and-tolerability-of-single-and-multiple-doses-of-abt-493-a-first-in-human-study
#18
Chih-Wei Lin, Sandeep Dutta, Armen Asatryan, Yi-Lin Chiu, Haoyu Wang, Jack Clifton, Andrew Campbell, Wei Liu
ABT-493 is a hepatitis C virus nonstructural protein 3/4A protease inhibitor with pangenotypic antiviral activity. This study investigated the pharmacokinetics, safety, and tolerability of single and multiple ascending doses of ABT-493 and the effect of food and ritonavir coadministration on ABT-493 pharmacokinetics in healthy adults. In the blinded, randomized, placebo-controlled phase 1 single- and multiple-dose portions of the study, ABT-493 25-800 mg were evaluated as single doses, and 200, 400, and 800 mg were evaluated as multiple doses...
November 15, 2016: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/27852956/preparation-for-a-first-in-man-lentivirus-trial-in-patients-with-cystic-fibrosis
#19
Eric W F W Alton, Jeffery M Beekman, A Christopher Boyd, June Brand, Marianne S Carlon, Mary M Connolly, Mario Chan, Sinead Conlon, Heather E Davidson, Jane C Davies, Lee A Davies, Johanna F Dekkers, Ann Doherty, Sabrina Gea-Sorli, Deborah R Gill, Uta Griesenbach, Mamoru Hasegawa, Tracy E Higgins, Takashi Hironaka, Laura Hyndman, Gerry McLachlan, Makoto Inoue, Stephen C Hyde, J Alastair Innes, Toby M Maher, Caroline Moran, Cuixiang Meng, Michael C Paul-Smith, Ian A Pringle, Kamila M Pytel, Andrea Rodriguez-Martinez, Alexander C Schmidt, Barbara J Stevenson, Stephanie G Sumner-Jones, Richard Toshner, Shu Tsugumine, Marguerite W Wasowicz, Jie Zhu
We have recently shown that non-viral gene therapy can stabilise the decline of lung function in patients with cystic fibrosis (CF). However, the effect was modest, and more potent gene transfer agents are still required. Fuson protein (F)/Hemagglutinin/Neuraminidase protein (HN)-pseudotyped lentiviral vectors are more efficient for lung gene transfer than non-viral vectors in preclinical models. In preparation for a first-in-man CF trial using the lentiviral vector, we have undertaken key translational preclinical studies...
November 16, 2016: Thorax
https://www.readbyqxmd.com/read/27846891/cytokine-and-chemokine-alterations-in-tissue-csf-and-plasma-in-early-presymptomatic-phase-of-experimental-allergic-encephalomyelitis-eae-in-a-rat-model-of-multiple-sclerosis
#20
Nozha Borjini, Mercedes Fernández, Luciana Giardino, Laura Calzà
BACKGROUND: Experimental allergic encephalomyelitis (EAE) is the most commonly used experimental animal model for human multiple sclerosis (MS) that has been used so far to study the acute and remission-relapsing phases of the disease. Despite the vast literature on neuroinflammation onset and progression in EAE, important questions are still open regarding in particular the early asymptomatic phase between immunization and clinical onset. METHODS: In this study, we performed a time-course investigation of neuroinflammation and demyelination biomarkers in the spinal cord (SC), cerebrospinal fluid (CSF), and blood in EAE induced in dark agouti (DA) female rats compared to the controls and adjuvant-injected rats, using high-throughput technologies for gene expression and protein assays and focusing on the time-course between immunization, clinical onset (1, 5, 8 days post-immunization (DPI)), and progression (11 and 18 DPI)...
November 15, 2016: Journal of Neuroinflammation
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