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First-in-human phase 1 study

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https://www.readbyqxmd.com/read/28449038/real-time-imaging-of-single-neuronal-cell-apoptosis-in-patients-with-glaucoma
#1
Maria F Cordeiro, Eduardo M Normando, M Jorge Cardoso, Serge Miodragovic, Seham Jeylani, Benjamin M Davis, Li Guo, Sebastien Ourselin, Roger A'Hern, Philip A Bloom
Retinal cell apoptosis occurs in many ocular neurodegenerative conditions including glaucoma-the major cause of irreversible blindness worldwide. Using a new imaging technique that we have called DARC (detection of apoptosing retinal cells), which until now has only been demonstrated in animal models, we assessed if annexin 5 labelled with fluorescent dye DY-776 (ANX776) could be used safely in humans to identify retinal cell apoptosis. Eight patients with glaucomatous neurodegeneration and evidence of progressive disease, and eight healthy subjects were randomly assigned to intravenous ANX776 doses of 0...
April 26, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28444181/allogeneic-human-mesenchymal-stem-cell-infusions-for-aging-frailty
#2
Samuel Golpanian, Darcy L DiFede, Aisha Khan, Ivonne Hernandez Schulman, Ana Marie Landin, Bryon A Tompkins, Alan W Heldman, Roberto Miki, Bradley J Goldstein, Muzammil Mushtaq, Silvina Levis-Dusseau, John J Byrnes, Maureen Lowery, Makoto Natsumeda, Cindy Delgado, Russell Saltzman, Mayra Vidro-Casiano, Marietsy V Pujol, Moisaniel Da Fonseca, Anthony A Oliva, Geoff Green, Courtney Premer, Audrey Medina, Krystalenia Valasaki, Victoria Florea, Erica Anderson, Jill El-Khorazaty, Adam Mendizabal, Pascal J Goldschmidt-Clermont, Joshua M Hare
Background: Impaired endogenous stem cell repair capacity is hypothesized to be a biologic basis of frailty. Therapies that restore regenerative capacity may therefore be beneficial. This Phase 1 study evaluated the safety and potential efficacy of intravenous, allogeneic, human mesenchymal stem cell (allo-hMSC)-based therapy in patients with aging frailty. Methods: In this nonrandomized, dose-escalation study, patients received a single intravenous infusion of allo-hMSCs: 20-million (n = 5), 100-million (n = 5), or 200-million cells (n = 5)...
April 21, 2017: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
https://www.readbyqxmd.com/read/28433558/spatial-relationship-of-organized-rotational-and-focal-sources-in-human-atrial-fibrillation-to-autonomic-ganglionated-plexi
#3
Tina Baykaner, Theodoros A Zografos, Junaid A B Zaman, Ioannis Pantos, Mahmood Alhusseini, Rachita Navara, David E Krummen, Sanjiv M Narayan, Demosthenes G Katritsis
BACKGROUND: One approach to improve ablation for atrial fibrillation (AF) is to focus on physiological targets including focal or rotational sources or ganglionic plexi (GP). However, the spatial relationship between these potential mechanisms has never been studied. We tested the hypothesis that rotors and focal sources for AF may co-localize with ganglionated plexi (GP). METHODS: We prospectively identified locations of AF rotors and focal sources, and correlated these to GP sites in 97 consecutive patients (age 59...
April 19, 2017: International Journal of Cardiology
https://www.readbyqxmd.com/read/28432051/impact-of-study-outcome-on-submission-and-acceptance-metrics-for-peer-reviewed-medical-journals-six-year-retrospective-review-of-all-completed-glaxosmithkline-human-drug-research-studies
#4
Gary Evoniuk, Bernadette Mansi, Barbara DeCastro, Jennie Sykes
Objectives To determine whether the outcome of drug studies influenced submission and/or acceptance rates for publication in peer reviewed medical journals.Design A six year retrospective review of publication status by study outcome for all human drug research studies conducted by a single industry sponsor (GlaxoSmithKline) that completed from 1 January 2009 to 30 June 2014 and were therefore due for manuscript submission (per the sponsor's policy) to peer reviewed journals within 18 months of study completion-that is, 31 December 2015...
April 21, 2017: BMJ: British Medical Journal
https://www.readbyqxmd.com/read/28425192/soluble-hla-e-a-follow-up-biomarker-in-takayasu-arteritis-independent-of-hla-e-genotype
#5
Ruchika Goel, Jayakanthan Kabeerdoss, Hindhumathi Mohan, Sumita Danda, Visali Jayaseelan, T Sathish Kumar, John Jude, Paul Bacon, George Joseph, Debashish Danda
AIM: Disease activity assessment in Takayasu arteritis (TA) is challenging. Human leukocyte antigen E (HLA-E) is shed from endothelium into serum as a soluble molecule (sHLA-E) in response to inflammation. We aimed to study: (i) utility of sHLA-E as a biomarker of disease activity; and (ii) association of HLA-E polymorphism rs1264457 with clinical disease in Asian-Indian TA patients. MATERIALS AND METHODS: In phase-1, sHLA-E levels were estimated in sera of 50 consecutive TA patients at baseline visit and 27 healthy controls...
April 19, 2017: International Journal of Rheumatic Diseases
https://www.readbyqxmd.com/read/28424162/pembrolizumab-in-patients-with-chronic-lymphocytic-leukemia-with-richter-s-transformation-and-relapsed-cll
#6
Wei Ding, Betsy R LaPlant, Timothy G Call, Sameer A Parikh, Jose F Leis, Rong He, Tait D Shanafelt, Sutapa Sinha, Jennifer Le-Rademacher, Andrew L Feldman, Thomas M Habermann, Thomas E Witzig, Gregory A Wiseman, Yi Lin, Erik Asmus, Grzegorz S Nowakowski, Michael J Conte, Deborah A Bowen, Casey N Aitken, Daniel L Van Dyke, Patricia T Greipp, Xin Liu, Xiaosheng Wu, Henan Zhang, Charla R Secreto, Shulan Tian, Esteban Braggio, Linda E Wellik, Ivana Micallef, David S Viswanatha, Huihuang Yan, Asher A Chanan-Khan, Neil E Kay, Haidong Dong, Stephen M Ansell
CLL patients progressed early on ibrutinib often develop Richter's transformation (RT) with short survival about 4 months. Preclinical studies suggest that programmed death 1 (PD-1) pathway is critical to inhibit immune surveillance in CLL. This phase 2 study MC1485 (NCT02332980) was designed to test the efficacy and safety of pembrolizumab, a humanized PD-1-blocking antibody, at a dose of 200 mg every 3 weeks in relapsed and transformed CLL. Twenty-five patients including 16 relapsed CLL and 9 RT (all proven diffuse large cell lymphoma) patients were enrolled and 60% received prior ibrutinib...
April 19, 2017: Blood
https://www.readbyqxmd.com/read/28422758/first-in-human-trial-of-multikinase-vegf-inhibitor-regorafenib-and-anti-egfr-antibody-cetuximab-in-advanced-cancer-patients
#7
Vivek Subbiah, Muhammad Rizwan Khawaja, David S Hong, Behrang Amini, Jiang Yungfang, Hui Liu, Adrienne Johnson, Alexa B Schrock, Siraj M Ali, James X Sun, David Fabrizio, Sarina Piha-Paul, Siqing Fu, Apostolia M Tsimberidou, Aung Naing, Filip Janku, Daniel D Karp, Michael Overman, Cathy Eng, Scott Kopetz, Funda Meric-Bernstam, Gerald S Falchook
BACKGROUND: The combination of multikinase VEGF inhibitor regorafenib and anti-EGFR antibody cetuximab overcomes intrinsic and acquired resistance in both EGFR-sensitive and EGFR-resistant preclinical models of colorectal cancer (CRC). METHODS: Utilizing a standard 3+3 design, a phase I study was designed to determine safety, maximum tolerated dose (MTD), and dose-limiting toxicities (DLTs) of the regorafenib plus cetuximab combination among patients with advanced cancer including CRC...
April 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28420859/ultrastructural-and-physico-chemical-characterization-of-saliva-during-menstrual-cycle-in-perspective-of-ovulation-in-human
#8
Ganesan Saibaba, Mahalingam Srinivasan, Archunan Priya Aarthy, Velliyangiri Silambarasan, Govindaraju Archunan
Human saliva is a potential diagnostic fluid and any alteration in body might be reflected in saliva so that saliva is considered as "mirror of the body". Variations in salivary hormone level, ultra structure, pH, flow rate, buffering capacity and electrolytes level are found during menstrual cycle in regard to ovulation. Thirty healthy volunteers were used for the assessment of physico-chemical changes in saliva. Reproductive cycle was categorized as pre-ovulation phase (5 to 12 days), ovulation phase (13 or 14 days) and post-ovulation phase (15 to 25 days) according to salivary arborization test and hormonal analysis...
April 14, 2017: Drug Discoveries & Therapeutics
https://www.readbyqxmd.com/read/28413662/phase-i-study-of-nanoparticle-albumin-bound-paclitaxel-carboplatin-and-trastuzumab-in-women-with-human-epidermal-growth-factor-receptor-2-overexpressing-breast-cancer
#9
Kenji Tezuka, Tsutomu Takashima, Shinichiro Kashiwagi, Hidemi Kawajiri, Shinya Tokunaga, Seika Tei, Shigehiko Nishimura, Shigehito Yamagata, Satoru Noda, Takeo Nishimori, Yoko Mizuyama, Takeshi Sunami, Katsumi Ikeda, Yoshinari Ogawa, Naoyoshi Onoda, Tetsuro Ishikawa, Shinzoh Kudoh, Minoru Takada, Kosei Hirakawa
Although the concurrent use of anthracycline-containing chemotherapy and taxane with trastuzumab are considered the treatment of choice for the primary systemic therapy of human epidermal growth factor receptor 2 (HER2)-overexpressing early breast cancer, non-anthracycline regimens, such as concurrent administration of docetaxel and carboplatin with trastuzumab, exhibited similar efficacies in a previous study. In addition, tri-weekly treatment with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) resulted in significantly higher response rates and a favorable safety profile compared with standard paclitaxel for metastatic breast cancer patients in another phase III study...
April 2017: Molecular and Clinical Oncology
https://www.readbyqxmd.com/read/28408839/dnmt1-regulates-human-endometrial-carcinoma-cell-proliferation
#10
Xinjing Wang, Bilan Li
Endometrial carcinoma (EC) is the most common gynecologic malignancy, but the molecular events involved in the development and progression of EC remain unclear. This study aimed to investigate the role of DNA methyltransferase 1 (DNMT1), a member of DNA methyltransferases, in EC. AN3CA cells were transfected with DNMT1 siRNA. The proliferation, cell cycle, and apoptosis of AN3CA cells were evaluated by Cell Counting Kit-8 (CCK-8) assay and flow cytometry. The expression of related genes was detected by polymerase chain reaction and Western blot analysis...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28402544/angiotensin-1-7-in-human-follicular-fluid-correlates-with-oocyte-maturation
#11
Ines K Cavallo, Cynthia Dela Cruz, Marilene L Oliveira, Helen L Del Puerto, Júlia A Dias, Veronica N Lobach, Maíra Casalechi, Maria G Camargos, Adelina M Reis, Robson A Santos, Fernando M Reis
STUDY QUESTION: Do angiotensin (Ang)-(1-7) levels in human ovarian follicular fluid (FF) correlate with the number and proportion of mature oocytes obtained for IVF? SUMMARY ANSWER: The present study shows for the first time that Ang-(1-7) levels in human FF correlate with the proportion of mature oocytes collected upon ovarian stimulation for IVF. WHAT IS KNOWN ALREADY: Ang-(1-7) is an active peptide of the renin-angiotensin system that stimulates oocyte maturation in isolated rabbit and rat ovaries...
April 10, 2017: Human Reproduction
https://www.readbyqxmd.com/read/28399873/influence-of-functional-task-oriented-mental-practice-on-the-gait-of-transtibial-amputees-a-randomized-clinical-trial
#12
Rodrigo Gontijo Cunha, Paulo José Guimarães Da-Silva, Clarissa Cardoso Dos Santos Couto Paz, Ana Carolina da Silva Ferreira, Carlos Julio Tierra-Criollo
BACKGROUND: Mental practice (MP) through motor imagery is a cognitive training strategy used to improve locomotor skills during rehabilitation programs. Recent works have used MP tasks to investigate the neurophysiology of human gait; however, its effect on functional performance has not been evaluated. In the present study, the influence of gait-oriented MP tasks on the rehabilitation process of gait in transtibial amputees was investigated by assessing the vertical (V), anterior-posterior (AP), and medio-lateral (ML) ground reaction forces (GRFs) and the time duration of the support phase of the prosthetic limb...
April 11, 2017: Journal of Neuroengineering and Rehabilitation
https://www.readbyqxmd.com/read/28399226/biology-of-triatoma-sherlocki-hemiptera-reduviidae-under-laboratory-conditions-biological-cycle-and-resistance-to-starvation
#13
Vanessa Lima-Neiva, Teresa C M Gonçalves, Leonardo S Bastos, Marcia Gumiel, Nathália C Correia, Catia C Silva, Carlos E Almeida, Jane Costa
Triatoma sherlocki Papa, Jurberg, Carcavallo, Cerqueira & Barata was described in 2002, based on specimens caught in the wild in the municipality of Gentio do Ouro, Bahia, Brazil. In 2009, nymphs and adults were detected inside homes and sylvatic specimens were positive for Trypanosoma cruzi (Chagas). No information on the bionomics of T. sherlocki exists, although such data are considered essential to estimate its vector and colonization potential in domestic environments. Herein, the biological cycle of T...
March 30, 2017: Journal of Medical Entomology
https://www.readbyqxmd.com/read/28393481/comparative-study-of-therapeutic-antibody-candidates-derived-from-mini-pool-and-clonal-cell-lines
#14
Lianchun Fan, Giovanni Rizzi, Kathleen Bierilo, Jun Tian, Joon Chong Yee, Reb Russel, Tapan Das
The long journey of developing a drug from initial discovery target identification to regulatory approval often leaves many patients with missed window of opportunities. Both regulatory agencies and biopharmaceutical industry continue to develop creative approaches to shorten the time of new drug development in order to deliver life-saving medicine to patients. Historically, drug substance materials to support the toxicology and early phase clinical study can only be manufactured after creating the final Master Cell Bank (MCB) of the clonally-derived cell line, which normally takes 1-2 years...
April 10, 2017: Biotechnology Progress
https://www.readbyqxmd.com/read/28392469/susceptibility-and-initial-immune-response-of-tupaia-belangeri-cells-to-dengue-virus-infection
#15
Mohammad Enamul Hoque Kayesh, Bouchra Kitab, Takahiro Sanada, Daisuke Hayasaka, Kouichi Morita, Michinori Kohara, Kyoko Tsukiyama-Kohara
Dengue is an emerging disease of great public health significance worldwide. The lack of a suitable infection model has hampered dengue virus (DENV) pathogenesis study, and developing a suitable small animal model has been a long-standing challenge. The aim of this study was to develop a feasible experimental model of DENV infection using Tupaia belangeri. The susceptibility of tupaia to DENV infection and characteristics of its innate immune response were examined in vitro. We found that tupaia fibroblast cells support replication of DENV serotypes 1-4 with a linear increase in viral load 24-96h post-infection in both cells and culture supernatants...
April 6, 2017: Infection, Genetics and Evolution
https://www.readbyqxmd.com/read/28392419/early-phase-dynamics-of-traceable-mcherry-fluorescent-protein-carrying-hiv-1-infection-in-human-peripheral-blood-mononuclear-cells-transplanted-nod-scid-jak3-mice
#16
Nobuyo Higashi-Kuwata, Hiromi Ogata-Aoki, Shin-Ichiro Hattori, Hironori Hayashi, Matthew Danish, Manabu Aoki, Chiemi Shiotsu, Tatsuyoshi Kawamura, Hironobu Ihn, Hisataka Kobayashi, Seiji Okada, Hiroaki Mitsuya
We attempted to elucidate early-phase dynamics of HIV-1 infection using replication-competent, red-fluorescent-protein (mCherry)-labeled HIV-1JR-FL (HIVJR-FL(mC)) and NOD/SCID/Jak3(-/-) mice transplanted with Individual-A's human peripheral blood mononuclear cells (hPBMC)(hNOJ mice). On day 7 following HIVJR-FL(mC) inoculation, mCherry-signal-emitting infection foci were readily identified in the subserosa of 10 of 10 HIVJR-FL(mC)-inoculated hNOJ mice, although infection foci were not located without the mCherry signal in unlabeled HIV-1JR-FL-inoculated mice (n = 6)...
April 6, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28391859/flow-method-based-on-liquid-liquid-extraction-using-deep-eutectic-solvent-for-the-spectrofluorimetric-determination-of-procainamide-in-human-saliva
#17
Lawrence Nugbienyo, Andrey Shishov, Sergei Garmonov, Leonid Moskvin, Vasil Andruch, Andrey Bulatov
In the current study, liquid-liquid extraction, using deep eutectic solvent (DES) as a "green" extraction solvent, was coupled with a stepwise injection system for the first time. The suggested approach was applied for the development of spectrofluorimetric method for procainamide determination. The method is based on aspiration of saliva sample and DES (choline chloride with glycerol at a 1:2M ratio) solution into the mixing chamber of a flow system, followed by injection of acetonitrile into the mixed DES-sample solution...
June 1, 2017: Talanta
https://www.readbyqxmd.com/read/28391576/phase-i-trial-and-pharmacokinetic-study-of-tanibirumab-a-fully-human-monoclonal-antibody-to-vascular-endothelial-growth-factor-receptor-2-in-patients-with-refractory-solid-tumors
#18
Su Jin Lee, Seon Young Lee, Weon Sup Lee, Jin San Yoo, Jong-Mu Sun, Jeeyun Lee, Se Hoon Park, Joon Oh Park, Myung-Ju Ahn, Ho Yeong Lim, Won Ki Kang, Young Suk Park
Background Tanibirumab is a fully human monoclonal antibody to vascular endothelial growth factor receptor 2 (VEGFR-2). We conducted a first-in-human phase I study of tanibirumab in patients with solid tumors refractory to standard chemotherapy. Primary endpoints were evaluating safety, pharmacokinetics (PKs), estimating maximum-tolerated dose (MTD) and recommended phase II dose (RP2D). Methods We designed our study to escalate tanibirumab at 9 different dose levels with a 3 + 3 method and tanibirumab (1-28 mg/kg) was administered intravenously on D1, 8, 15 in 28-day courses...
April 8, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28391399/infant-avoidance-training-alters-cellular-activation-patterns-in-prefronto-limbic-circuits-during-adult-avoidance-learning-i-cellular-imaging-of-neurons-expressing-the-synaptic-plasticity-early-growth-response-protein-1-egr1
#19
Nicole Gröger, Anja Mannewitz, Jörg Bock, Tony Fernando de Schultz, Katja Guttmann, Gerd Poeggel, Katharina Braun
Both positive feedback learning and negative feedback learning are essential for adapting and optimizing behavioral performance. There is increasing evidence in humans and animals that the ability of negative feedback learning emerges postnatally. Our work in rats, using a two-way active avoidance task (TWA) as an experimental paradigm for negative feedback learning, revealed that medial and lateral prefrontal regions of infant rats undergo dramatic synaptic reorganization during avoidance training, resulting in improved avoidance learning in adulthood...
April 8, 2017: Brain Structure & Function
https://www.readbyqxmd.com/read/28387940/the-bial-10-2474-phase-1-study-a-drug-development-perspective-and-recommendations-for-future-first-in-human-trials
#20
REVIEW
Philip Chaikin
BIA 10-2474 (a fatty acid amide hydrolase inhibitor) was evaluated in a first-in-human phase 1 study in normal volunteers to assess safety/tolerability, pharmacokinetics, pharmacodynamics, and food effect. The dose-escalation process consisted of a single-ascending-dose phase (SAD) and multiple-ascending-dose phase (MAD). Prospective determination of the starting dose and maximal escalated dose was consistent with the usual clinical pharmacology principles for extrapolation of preclinical toxicology data to human equivalent doses...
April 7, 2017: Journal of Clinical Pharmacology
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