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Proof of concept phase I

Emily E Pocock, Richard J Mandle, John W Goodby
Liquid crystalline phases with a spontaneous twist-bend modulation are most commonly observed for dimers and bimesogens with nonamethylene spacers. In order to redress this balance we devised a simple chemical intermediate that can be used to prepare unsymmetrical bimesogens; as a proof of concept we prepared and studied eleven novel materials with all found to exhibit the twist-bend phase and exhibit a linear relationship between TN-I and TTB-N. A computational study of the conformational landscape reveals the octamethyleneoxy spacer to have a broader distribution of bend-angles than the nonamethylene equivalent, leading to reductions in the thermal stability of the TB phase...
March 12, 2018: Soft Matter
Lea M Gerischer, Andreas Fehlner, Theresa Köbe, Kristin Prehn, Daria Antonenko, Ulrike Grittner, Jürgen Braun, Ingolf Sack, Agnes Flöel
Dementia due to Alzheimer's Disease (AD) is a neurodegenerative disease for which treatment strategies at an early stage are of great clinical importance. So far, there is still a lack of non-invasive diagnostic tools to sensitively detect AD in early stages and to predict individual disease progression. Magnetic resonance elastography (MRE) of the brain may be a promising novel tool. In this proof-of-concept study, we investigated whether multifrequency-MRE (MMRE) can detect differences in hippocampal stiffness between patients with clinical diagnosis of dementia due to AD and healthy controls (HC)...
2018: NeuroImage: Clinical
Muhammad Faraz Shaikh, Zoran Salcic, Kevin I-Kai Wang, Aiguo Patrick Hu
Electrical stimulators are often prescribed to correct foot drop walking. However, commercial foot drop stimulators trigger inappropriately under certain non-gait scenarios. Past researches addressed this limitation by defining stimulation control based on automaton of a gait cycle executed by foot drop of affected limb/foot only. Since gait is a collaborative activity of both feet, this research highlights the role of normal foot for robust gait detection and stimulation triggering. A novel bipedal gait model is proposed where gait cycle is realized as an automaton based on concurrent gait sub-phases (states) from each foot...
March 10, 2018: Medical & Biological Engineering & Computing
Alfredo I Hernández, Diego Pérez, Delphine Feuerstein, Corinne Loiodice, Laurence Graindorge, Gustavo Guerrero, Nadège Limousin, Frédéric Gagnadoux, Yves Dauvilliers, Renaud Tamisier, Arnaud Prigent, Philippe Mabo, Amel Amblard, Lotfi Senhadji, Jean-Louis Pépin
Obstructive sleep apnea (OSA) occurs when the upper airway narrows or collapses due to the loss of upper airway muscle activation at sleep onset. This study investigated the effectiveness of triggered kinesthetic stimulation in patients with OSA. This proof-of-concept, open-label, multicenter prospective study was conducted on 24 patients with severe OSA. During a one night evaluation, kinesthetic stimulation was intermittently delivered in 30 minute periods. The duration of apneas and hypopneas during Stim on and Stim off periods were compared...
February 15, 2018: Scientific Reports
Jung-Min Lee, Jayakumar Nair, Alexandra Zimmer, Stanley Lipkowitz, Christina M Annunziata, Maria J Merino, Elizabeth M Swisher, Maria I Harrell, Jane B Trepel, Min-Jung Lee, Mohammad H Bagheri, Dana-Adriana Botesteanu, Seth M Steinberg, Lori Minasian, Irene Ekwede, Elise C Kohn
BACKGROUND: High-grade serous ovarian carcinoma is characterised by TP53 mutations, DNA repair defects, and genomic instability. We hypothesised that prexasertib (LY2606368), a cell cycle checkpoint kinase 1 and 2 inhibitor, would be active in BRCA wild-type disease. METHODS: In an open-label, single-centre, two-stage, proof-of-concept phase 2 study, we enrolled women aged 18 years or older with measurable, recurrent high-grade serous or high-grade endometrioid ovarian carcinoma...
January 17, 2018: Lancet Oncology
Rodabe N Amaria, Peter A Prieto, Michael T Tetzlaff, Alexandre Reuben, Miles C Andrews, Merrick I Ross, Isabella C Glitza, Janice Cormier, Wen-Jen Hwu, Hussein A Tawbi, Sapna P Patel, Jeffrey E Lee, Jeffrey E Gershenwald, Christine N Spencer, Vancheswaran Gopalakrishnan, Roland Bassett, Lauren Simpson, Rosalind Mouton, Courtney W Hudgens, Li Zhao, Haifeng Zhu, Zachary A Cooper, Khalida Wani, Alexander Lazar, Patrick Hwu, Adi Diab, Michael K Wong, Jennifer L McQuade, Richard Royal, Anthony Lucci, Elizabeth M Burton, Sangeetha Reddy, Padmanee Sharma, James Allison, Phillip A Futreal, Scott E Woodman, Michael A Davies, Jennifer A Wargo
BACKGROUND: Dual BRAF and MEK inhibition produces a response in a large number of patients with stage IV BRAF-mutant melanoma. The existing standard of care for patients with clinical stage III melanoma is upfront surgery and consideration for adjuvant therapy, which is insufficient to cure most patients. Neoadjuvant targeted therapy with BRAF and MEK inhibitors (such as dabrafenib and trametinib) might provide clinical benefit in this high-risk p opulation. METHODS: We undertook this single-centre, open-label, randomised phase 2 trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA)...
January 17, 2018: Lancet Oncology
Albert To, Liana O Medina, Kenji O Mfuh, Michael M Lieberman, Teri Ann S Wong, Madhuri Namekar, Eileen Nakano, Chih-Yun Lai, Mukesh Kumar, Vivek R Nerurkar, Axel T Lehrer
Following the 2015 Zika virus (ZIKV) outbreaks in the South Pacific, Caribbean, and Americas, ZIKV has emerged as a serious threat due to its association with infantile microcephaly and other neurologic disorders. Despite an international effort to develop a safe and effective vaccine to combat congenital Zika syndrome and ZIKV infection, only DNA and mRNA vaccines encoding the precursor membrane (prM) and envelope (E) proteins, an inactivated-ZIKV vaccine, and a measles virus-based ZIKV vaccine are currently in phase I or II (prM/E DNA) clinical trials...
January 2018: MSphere
I Tanarro, B Alemán, P de Vicente, J D Gallego, J R Pardo, G Santoro, K Lauwaet, F Tercero, A Díaz-Pulido, E Moreno, M Agúndez, J R Goicoechea, J M Sobrado, J A López, L Martínez, J L Doménech, V J Herrero, J M Hernández, R J Peláez, J A López-Pérez, J Gómez-González, J L Alonso, E Jiménez, D Teyssier, K Makasheva, M Castellanos, C Joblin, J A Martín-Gago, J Cernicharo
We present a proof of concept on the coupling of radio astronomical receivers and spectrometers with chemical reactors and the performances of the resulting setup for spectroscopy and chemical simulations in laboratory astrophysics. Several experiments including cold plasma generation and UV photochemistry were performed in a 40 cm long gas cell placed in the beam path of the Aries 40 m radio telescope receivers operating in the 41-49 GHz frequency range interfaced with fast Fourier transform spectrometers providing 2 GHz bandwidth and 38 kHz resolution...
January 2018: Astronomy and Astrophysics
Christa C Chrovian, Akinola Soyode-Johnson, Alexander A Peterson, Christine F Gelin, Xiaohu Deng, Curt A Dvorak, Nicholas I Carruthers, Brian Lord, Ian Fraser, Leah Aluisio, Kevin J Coe, Brian Scott, Tatiana Koudriakova, Freddy Schoetens, Kia Sepassi, David J Gallacher, Anindya Bhattacharya, Michael A Letavic
A single pot dipolar cycloaddition reaction/Cope elimination sequence was developed to access novel 1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine P2X7 antagonists that contain a synthetically challenging chiral center. The structure-activity relationships of the new compounds are described. Two of these compounds, (S)-(2-fluoro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone (compound 29) and (S)-(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone (compound 35), were found to have robust P2X7 receptor occupancy at low doses in rat with ED50 values of 0...
January 11, 2018: Journal of Medicinal Chemistry
Janice A Lansita, Kirsten M Mease, Haiyan Qiu, Ted Yednock, Sethu Sankaranarayanan, Susan Kramer
ANX005 is a humanized immunoglobulin G4 recombinant antibody against C1q that inhibits its function as the initiating molecule of the classical complement cascade. The safety and tolerability of ANX005 are currently being evaluated in a phase I trial in healthy volunteers ( Identifier: NCT03010046). Inhibition of C1q can be applied therapeutically in a broad spectrum of diseases, including acute antibody-mediated autoimmune disease, such as Guillain-Barré syndrome (GBS), and in chronic diseases of the central nervous system involving complement-mediated neurodegeneration, such as Alzheimer's disease (AD)...
November 2017: International Journal of Toxicology
Ricardo Alexandre Toniolo, Michelle Silva, Francy de Brito Ferreira Fernandes, José Antonio de Mello Siqueira Amaral, Rodrigo da Silva Dias, Beny Lafer
Depressive episodes are a major cause of morbidity and dysfunction in individuals suffering from bipolar disorder. Currently available treatments for this condition have limited efficacy and new therapeutic options are needed. Extensive research in the pathophysiology of bipolar disorder points to the existence of mitochondrial and bioenergetic dysfunction. We hypothesized that creatine monohydrate, a nutraceutical that works as a mitochondrial modulator, would be effective as an adjunctive therapy for bipolar depression...
February 2018: Journal of Neural Transmission
Massimiliano M Villone, Pasquale Memmolo, Francesco Merola, Martina Mugnano, Lisa Miccio, Pier Luca Maffettone, Pietro Ferraro
We report a reliable full-angle tomographic phase microscopy (FA-TPM) method for flowing quasi-spherical cells along microfluidic channels. This method lies in a completely passive optical system, i.e. mechanical scanning or multi-direction probing of the sample is avoided. It exploits the engineered rolling of cells while they are flowing along a microfluidic channel. Here we demonstrate significant progress with respect to the state of the art of in-flow TPM by showing a general extension to cells having almost spherical shapes while they are flowing in suspension...
December 19, 2017: Lab on a Chip
Rohini M Nair, Murali Ms Balla, Imran Khan, Ravi Kiran Reddy Kalathur, Paturu Kondaiah, Geeta K Vemuganti
BACKGROUND: Retinoblastoma (Rb), the most common childhood intraocular malignant tumor, is reported to have cancer stem cells (CSCs) similar to other tumors. Our previous investigation in primary tumors identified the small sized cells with low CD133 (Prominin-1) and high CD44 (Hyaluronic acid receptor) expression to be putative Rb CSCs using flow cytometry (FSClo /SSClo /CD133lo /CD44hi ). With this preliminary data, we have now utilized a comprehensive approach of in vitro characterization of Y79 Rb cell line following CSC enrichment using CD133 surface marker and subsequent validation to confirm the functional properties of CSCs...
November 21, 2017: BMC Cancer
Christopher H Evans, Steven Craig Ghivizzani, Paul D Robbins
Most forms of arthritis are incurable, difficult to treat and a major cause of disability in western countries. Better local treatment of arthritis is impaired by the pharmacokinetics of the joint that make it very difficult to deliver drugs to joints at sustained, therapeutic concentrations. This is especially true of biologic drugs, such as proteins and RNA, many of which show great promise in pre-clinical studies. Gene transfer provides a strategy for overcoming this limitation. The basic concept is to deliver cDNAs encoding therapeutic products by direct intra-articular injection, leading to sustained, endogenous synthesis of the gene products within the joint...
November 21, 2017: Human Gene Therapy
Pan Zheng, Bahari Belaton, Iman Yi Liao, Zainul Ahmad Rajion
Landmarks, also known as feature points, are one of the important geometry primitives that describe the predominant characteristics of a surface. In this study we proposed a self-contained framework to generate landmarks on surfaces extracted from volumetric data. The framework is designed to be a three-fold pipeline structure. The pipeline comprises three phases which are surface construction, crest line extraction and landmark identification. With input as a volumetric data and output as landmarks, the pipeline takes in 3D raw data and produces a 0D geometry feature...
2017: PloS One
Paul C Lyon, Lucy F Griffiths, Jenni Lee, Daniel Chung, Robert Carlisle, Feng Wu, Mark R Middleton, Fergus V Gleeson, Constantin C Coussios
Background: TARDOX is a Phase I single center study of ultrasound triggered targeted drug delivery in adult oncology patients with incurable liver tumours. This proof of concept study is designed to demonstrate the safety and feasibility of targeted drug release and enhanced delivery of doxorubicin from thermally sensitive liposomes (ThermoDox®) triggered by mild hyperthermia induced by focused ultrasound in liver tumours. A key feature of the study is the direct quantification of the doxorubicin concentration before and after ultrasound exposure from tumour biopsies, using high performance liquid chromatography (HPLC)...
2017: Journal of Therapeutic Ultrasound
Ahmed I A Chowdhury, Jason I Gerhard, David Reynolds, Denis M O'Carroll
This study proposes and proves (in concept) a novel approach of combining electrokinetic (EK)-assisted delivery of an oxidant, persulfate (PS), and low temperature electrical resistivity heating (ERH), to activate PS, to achieve remediation of contaminated, low permeability soil. This unique combination is able to overcome existing challenges in remediating low permeability materials, particularly associated with delivering remediants. A further benefit of the approach is the use of the same electrodes for both EK and ERH phases...
November 10, 2017: Environmental Science & Technology
Rod Knight, Mohammad Karamouzian, Travis Salway, Mark Gilbert, Jean Shoveller
INTRODUCTION: Globally, young gay, bisexual and other men who have sex with men (gbMSM) continue to experience disproportionately high rates of HIV and other sexually transmitted and blood-borne infections (STBBIs). As such, there are strong public health imperatives to evaluate innovative prevention, treatment and care interventions, including online interventions. This study reviewed and assessed the status of published research (e.g. effectiveness; acceptability; differential effects across subgroups) involving online interventions that address HIV/STBBIs among young gbMSM...
November 2017: Journal of the International AIDS Society
Jaitip Tipanee, Yoke Chin Chai, Thierry VandenDriessche, Marinee K Chuah
Transposons derived from Sleeping Beauty (SB), piggyBac (PB), or Tol2 typically require cotransfection of transposon DNA with a transposase either as an expression plasmid or mRNA. Consequently, this results in genomic integration of the potentially therapeutic gene into chromosomes of the desired target cells, and thus conferring stable expression. Non-viral transfection methods are typically preferred to deliver the transposon components into the target cells. However, these methods do not match the efficacy typically attained with viral vectors and are sometimes associated with cellular toxicity evoked by the DNA itself...
December 22, 2017: Bioscience Reports
Chang Yi Wang, Pei-Ning Wang, Ming-Jang Chiu, Connie L Finstad, Feng Lin, Shugene Lynn, Yuan-Hung Tai, Xin De Fang, Kesheng Zhao, Chung-Ho Hung, Yiting Tseng, Wen-Jiun Peng, Jason Wang, Chih-Chieh Yu, Be-Sheng Kuo, Paul A Frohna
INTRODUCTION: A novel amyloid β (Aβ) synthetic peptide vaccine (UB-311) has been evaluated in a first-in-human trial with patients of mild-to-moderate Alzheimer's disease. We describe translational research covering vaccine design, preclinical characterization, and phase-I clinical trial with supportive outcome that advances UB-311 into an ongoing phase-II trial. METHODS: UB-311 is constructed with two synthetic Aβ1-14-targeting peptides (B-cell epitope), each linked to different helper T-cell peptide epitopes (UBITh(®)) and formulated in a Th2-biased delivery system...
June 2017: Alzheimer's & Dementia: Translational Research & Clinical Interventions
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