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Proof of concept phase I

Calum A MacRae, Gerry Boss, Matthew Brenner, Robert E Gerszten, Sari Mahon, Randall T Peterson
We have developed an integrated pipeline for countermeasure discovery that, under the auspices of the National Institutes of Health Countermeasures Against Chemical Threats network, is one of the few efforts within academia that by design spans the spectrum from discovery to phase I. The successful implementation of this approach for cyanide would enable efficient proof-of-concept studies that would lay the foundation for a generalizable strategy for parallel mechanistic studies and accelerated countermeasure development in the face of new and emerging chemical threats...
August 2016: Annals of the New York Academy of Sciences
Yoann Duffier, Audrey Lorthiois, Pau Cisteró, Florian Dupuy, Grégory Jouvion, Laurence Fiette, Dominique Mazier, Alfredo Mayor, Catherine Lavazec, Alicia Moreno Sabater
The development of new drugs to disrupt malaria transmission requires the establishment of an in vivo model to address the biology of Plasmodium falciparum sexual stages (gametocytes). Herein we show that chemically immune-modulated NSG mice grafted with human erythrocytes support complete sexual development of P. falciparum parasites and generate high gametocytemia. Immunohistochemistry and RT-qPCR analyses indicate an enrichment of immature gametocytes in the bone marrow and the spleen, suggesting a sequestration mechanism reminiscent to that observed in humans...
October 12, 2016: Scientific Reports
Claire Roiland, Gaelle Trippé-Allard, Khaoula Jemli, Bruno Alonso, Jean-Claude Ameline, Régis Gautier, Thierry Bataille, Laurent Le Pollès, Emmanuelle Deleporte, Jacky Even, Claudine Katan
We report on (207)Pb, (79)Br, (14)N, (1)H, (13)C and (2)H NMR experiments for studying the local order and dynamics in hybrid perovskite lattices. (207)Pb NMR experiments conducted at room temperature on a series of MAPbX3 compounds (MA = CH3NH3(+); X = Cl, Br and I) showed that the isotropic (207)Pb NMR shift is strongly dependent on the nature of the halogen ions. Therefore (207)Pb NMR appears to be a very promising tool for the characterisation of local order in mixed halogen hybrid perovskites. (207)Pb NMR on MAPbBr2I served as a proof of concept...
October 5, 2016: Physical Chemistry Chemical Physics: PCCP
F Husseini, J-P Delord, C Fournel-Federico, J Guitton, P Erbs, M Homerin, C Halluard, C Jemming, C Orange, J-M Limacher, J-E Kurtz
BACKGROUND: TG4023 is a modified vaccinia virus Ankara (MVA) containing the yeast-originated transgene FCU1, expressing cytosine deaminase and uracil phosphoribosyltransferase enzymes that transform the prodrug flucytosine (5-FC) into cytotoxic 5-fluorouracil (5-FU) and 5-fluorouridine-5'-monophosphate (5-FUMP), respectively. This first-in-human study aimed to assess the maximum tolerated dose (MTD) of intra-tumoral (IT) TG4023 and the safety, feasibility, and proof-of-concept (PoC) of TG4023/5-FC combination to deliver high 5-FU concentrations in tumors...
September 29, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Ralph E Parchment, James H Doroshow
Analyzing the molecular interplay between malignancies and therapeutic agents is rarely a straightforward process, but we hope that this special issue of Seminars has highlighted the clinical value of such endeavors as well as the relevant theoretical and practical considerations. Here, we conclude with both an overview of the various high-value applications of clinical pharmacodynamics (PD) in developmental therapeutics and an outline of the framework for incorporating PD analyses into the design of clinical trials...
August 2016: Seminars in Oncology
H F Martins, K Shi, B C Thomsen, S Martin-Lopez, M Gonzalez-Herraez, S J Savory
A major cause of faults in optical communication links is related to unintentional third party intrusions (normally related to civil/agricultural works) causing fiber breaks or cable damage. These intrusions could be anticipated and avoided by monitoring the dynamic strain recorded along the cable. In this work, a novel technique is proposed to implement real-time distributed strain sensing in parallel with an operating optical communication channel. The technique relies on monitoring the Rayleigh backscattered light from optical communication data transmitted using standard modulation formats...
September 19, 2016: Optics Express
Pamela Blair Allen, Leo I Gordon
INTRODUCTION: Classical Hodgkin's Lymphoma (cHL) is characterized by genetic reliance on the PD-1 pathway. Rapid accumulation of data describing the role and efficacy of PD-1 and its blockade warrants a focused review. AREAS COVERED: In this article, we will review the unique biologic features that predispose cHL to PD-1 inhibition, current data regarding the safety and efficacy of PD-1 inhibitors in the treatment of cHL, biomarkers of immune response, ongoing clinical trials with PD-1 inhibitors, as well as areas of uncertainty...
October 2016: Expert Review of Hematology
Laura Rammazzo, Dimitris Kikidis, Amal Anwer, Nora Macdonald, Efthymios Kyrodimos, Christoph Maurer, Floris Wuyts, Linda Luxon, Athanasios Bibas, Doris-Eva Bamiou
BACKGROUND: Balance problems are caused by multiple factors and often lead to falls and related fractures, bringing large socio-economic costs. The complexity of balance control mechanisms, the lack of medical expertise, and the absence of specialised equipment contribute to the delayed or incorrect diagnosis and management ofthese patients. Advances in computer science have allowed the development of computer systems that support clinical diagnosis and treatment decisions based on individualised patient data...
2016: Trials
A Tan, K Fujisawa, Y Yukawa, Y T Matsunaga
We developed a robust bottom-up approach to construct open-ended, tubular co-culture constructs that simulate the human vascular morphology and microenvironment. By design, these three-dimensional artificial vessels mimic the basic architecture of an artery: a collagen-rich extracellular matrix (as the tunica externa), smooth muscle cells (SMCs) (as the tunica media), and an endothelial cell (EC) lining (as the tunica interna). A versatile needle-based fabrication technique was employed to achieve controllable arterial layouts within a PDMS-hosted collagen microchannel scaffold (330 ± 10 μm in diameter): (direct co-culture) a SMC/EC bilayer to follow the structure of an arteriole-like segment; and (encapsulated co-culture) a lateral SMC multilayer covered by an EC monolayer lining to simulate the architecture of a larger artery...
October 20, 2016: Biomaterials Science
Mariko Ago, Siqi Huan, Maryam Borghei, Janne Raula, Esko I Kauppinen, Orlando J Rojas
An aerosol flow reactor was used for the first time for high-throughput, high yield synthesis of spherical lignin particles with given inherent hydrophilicity, depending on the precursor biomolecule. In situ fractionation via Berner type impactor afforded populations with characteristic sizes ranging from ∼30 nm to 2 μm. The as-produced, dry lignin particles displayed excellent mechanical integrity, even after redispersion under high shear in either mineral oil or water. They were effective in the stabilization of oil-in-water (O/W) Pickering emulsions with tunable droplet size, depending on the dimension of the lignin particles used for emulsification...
September 7, 2016: ACS Applied Materials & Interfaces
E McGrath, C Espie, A Power, A Murphy, J Newell, C Kelly, N Duffy, P Gunning, I Gibson, M O'Donnell
OBJECTIVE: Impaired sleep quality is common, and is associated with an increased risk of cardiovascular disease and death, thought to be mediated by adverse effects on established vascular risk factors, particularly hypertension. The aim of this study was to determine if a web-delivered sleep intervention reduces blood pressure compared to vascular risk factor education alone (standard care), through modification of sleep quality. DESIGN AND METHOD: HASH(0x49bfa00) DESIGN/SETTING/PARTICIPANTS: A Phase II, proof-of-concept, randomised, blinded controlled trial of 134 community-based participants with sleep impairment and systolic blood pressure (130-160 mmHg) and diastolic blood pressure (<110 mmHg) without cardiovascular disease...
September 2016: Journal of Hypertension
Vipul Jairath, Barrett G Levesque, Niels Vande Casteele, Reena Khanna, Mahmoud Mosli, Pieter Hindryckx, Simon Travis, Marjolejn Duijvenstein, Jordi Rimola, Julian Panes, Geert D'Haens, William J Sandborn, Brian G Feagan
The highest attrition rates during drug development programmes occur at the proof of concept stage. Given the large number of molecules under development for Crohn's disease, a need exists to improve the efficiency of early drug development by fast-tracking promising agents and terminating ineffective ones. Multiple opportunities are available to achieve these goals, including the use of more responsive outcome measures, and the incorporation of sophisticated pharmacokinetic modelling and/or highly specific pharmacodynamic markers into exposure-based dosing regimens and novel trial designs...
August 3, 2016: Journal of Crohn's & Colitis
Jason P Stopyra, Samuel I Ritter, Jennifer Beatty, James C Johnson, Douglas M Kleiner, James E Winslow, Alison R Gardner, William P Bozeman
INTRODUCTION: Despite research demonstrating the overall safety of Conducted Electrical Weapons (CEWs), commonly known by the brand name TASER(®), concerns remain regarding cardiac safety. The addition of cardiac biomonitoring capability to a CEW could prove useful and even lifesaving in the rare event of a medical crisis by detecting and analyzing cardiac rhythms during the period immediately after CEW discharge. OBJECTIVE: To combine an electrocardiogram (ECG) device with a CEW to detect and store ECG signals while still allowing the CEW to perform its primary function of delivering an incapacitating electrical discharge...
October 2016: Journal of Forensic and Legal Medicine
Thomas Fovet, Natasza Orlov, Miriam Dyck, Paul Allen, Klaus Mathiak, Renaud Jardri
Auditory-verbal hallucinations (AVHs) are frequent and disabling symptoms, which can be refractory to conventional psychopharmacological treatment in more than 25% of the cases. Recent advances in brain imaging allow for a better understanding of the neural underpinnings of AVHs. These findings strengthened transdiagnostic neurocognitive models that characterize these frequent and disabling experiences. At the same time, technical improvements in real-time functional magnetic resonance imaging (fMRI) enabled the development of innovative and non-invasive methods with the potential to relieve psychiatric symptoms, such as fMRI-based neurofeedback (fMRI-NF)...
2016: Frontiers in Psychiatry
Carlo Zambonelli, Antu K Dey, Susan Hilt, Samuel Stephenson, Eden P Go, Daniel F Clark, Mark Wininger, Celia Labranche, David Montefiori, Hua-Xin Liao, Ronald I Swanstrom, Heather Desaire, Barton F Haynes, Andrea Carfi, Susan W Barnett
The viral envelope glycoprotein (Env) is the major target for antibody (Ab)-mediated vaccine development against the Human Immunodeficiency Virus type 1 (HIV-1). Although several recombinant Env antigens have been evaluated in clinical trials, only the surface glycoprotein, gp120, (from HIV-1 subtype B, MN, and subtype CRF_01AE, A244) used in the ALVAC prime-AIDSVAX gp120 boost RV144 Phase III HIV vaccine trial was shown to contribute to protective efficacy, although modest and short-lived. Hence, for clinical trials in southern Africa, a bivalent protein boost of HIV-1 subtype C gp120 antigens composed of two complementary gp120s, from the TV1...
2016: PloS One
Alexey Belogurov, Konstantin Zakharov, Yakov Lomakin, Kirill Surkov, Sergey Avtushenko, Peter Kruglyakov, Ivan Smirnov, Gleb Makshakov, Curtis Lockshin, Gregory Gregoriadis, Dmitry Genkin, Alexander Gabibov, Evgeniy Evdoshenko
Previously, we showed that CD206-targeted liposomal delivery of co-encapsulated immunodominant myelin basic protein (MBP) sequences MBP46-62, MBP124-139 and MBP147-170 (Xemys) suppressed experimental autoimmune encephalomyelitis in dark Agouti rats. The objective of this study was to assess the safety of Xemys in the treatment of patients with relapsing-remitting multiple sclerosis (MS) and secondary progressive MS, who failed to achieve a sustained response to first-line disease-modifying therapies. In this phase I, open-label, dose-escalating, proof-of-concept study, 20 patients with relapsing-remitting or secondary progressive MS received weekly subcutaneously injections with ascending doses of Xemys up to a total dose of 2...
June 20, 2016: Neurotherapeutics: the Journal of the American Society for Experimental NeuroTherapeutics
Cor H J Lamers, Yarne Klaver, Jan W Gratama, Stefan Sleijfer, Reno Debets
We studied safety and proof of concept of a phase I/II trial with chimeric antigen receptor (CAR) T-cells in patients with metastatic renal cell carcinoma (mRCC). The CAR was based on the G250 mAb that recognized an epitope of carboxy-anhydrase-IX (CAIX). Twelve patients with CAIX+ mRCC were treated in three cohorts with a maximum of 10 daily infusions of 2×10(7) to 2×10(9) CAR T-cells. Circulating CAR T-cells were transiently detectable in all patients and maintained antigen-specific immune functions following their isolation post-treatment...
June 15, 2016: Biochemical Society Transactions
Jianping Gao, Yingchang Zou, Yonggang Wang, Feng Wang, Lang Lang, Ping Wang, Yong Zhou, Kejing Ying
A number of multiresistant pathogens including Acinetobacter baumannii (A. baumannii) place a heavy burden on ventilator-associated pneumonia (VAP) patients in intensive care units (ICU). It is critically important to differentiate between bacterial infection and colonization to avoid prescribing unnecessary antibiotics. Quantitative culture of lower respiratory tract (LRT) specimens, however, requires invasive procedures. Nowadays, volatile organic compounds (VOCs) have been studied in vitro and in vivo to identify pathogen-derived biomarkers...
June 2016: Journal of Breath Research
Yuelin Song, Qingqing Song, Jun Li, Jiao Zheng, Chun Li, Yuan Zhang, Lingling Zhang, Yong Jiang, Pengfei Tu
Direct analysis is of great importance to understand the real chemical profile of a given sample, notably biological materials, because either chemical degradation or diverse errors and uncertainties might be resulted from sophisticated protocols. In comparison with biofluids, it is still challenging for direct analysis of solid biological samples using high performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Herein, a new analytical platform was configured by online hyphenating pressurized liquid extraction (PLE), turbulent flow chromatography (TFC), and LC-MS/MS...
July 8, 2016: Journal of Chromatography. A
Andrew Hughes, Donal Landers, Hendrik-Tobias Arkenau, Saj Shah, Richard Stephens, Amrik Mahal, Matthew Simmons, Charlotte Lemech, Jennifer Royle
INTRODUCTION: During early clinical testing of a new medication, it is critical to understand and characterise patient tolerability. However, in early clinical studies, it is difficult for patients to contribute directly to the sponsors' understanding of a new compound. Patient reported opinions about clinical tolerability (PROACT) provides a new, simple and innovative way in which patients can collaborate using an application downloaded to a mobile computer or smartphone. METHODS: PROACT was designed with special consideration given to patient confidentiality, patient engagement and data security...
June 2016: Advances in Therapy
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