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Proof of concept trials

Evangelos G Papanikolaou, Hakan Yarali, Evi Timotheou, Michael Grynberg, Odysseas Zafeiratis, Herman Tournaye, Robert Najdecki
Introduction: A drawback of gonadotropin-releasing hormone (GnRH) antagonist protocols in in vitro fertilization (IVF) is that they have limited flexibility in cycle programming. This proof of concept study explored the efficacy of a single-dose, long-acting GnRH antagonist IVF protocol. Trial registration number is NCT03240159, retrospectively registered on March 08, 2017. Materials and methods: The efficacy of a single-dose long-acting antagonist, degarelix, was explored initially in healthy donors and subsequently in infertile patients...
2018: Frontiers in Endocrinology
Júlia Perera-Bel, Barbara Hutter, Christoph Heining, Annalen Bleckmann, Martina Fröhlich, Stefan Fröhling, Hanno Glimm, Benedikt Brors, Tim Beißbarth
BACKGROUND: A comprehensive understanding of cancer has been furthered with technological improvements and decreasing costs of next-generation sequencing (NGS). However, the complexity of interpreting genomic data is hindering the implementation of high-throughput technologies in the clinical context: increasing evidence on gene-drug interactions complicates the task of assigning clinical significance to genomic variants. METHODS: Here we present a method that automatically matches patient-specific genomic alterations to treatment options...
March 15, 2018: Genome Medicine
Yuchi Han, Paul R Forfia, Anjali Vaidya, Jeremy A Mazurek, Myung H Park, Gautam Ramani, Stephen Y Chan, Aaron B Waxman
Introduction: A major determining factor on outcomes in patients with pulmonary arterial hypertension (PAH) is right ventricular (RV) function. Ranolazine, which is currently approved for chronic stable angina, has been shown to improve RV function in an animal model and has been shown to be safe in small human studies with PAH. We aim to study the effect of ranolazine on RV function using cardiovascular magnetic resonance (CMR) in patients with pulmonary hypertension (non-group 2 patients) and monitor the effect of ranolazine on metabolism using metabolic profiling and changes of microRNA...
2018: Open Heart
Congxiu Ye, David Brand, Song G Zheng
Regulatory T cells (Treg) play a crucial role in maintaining immune homeostasis since Treg dysfunction in both animals and humans is associated with multi-organ autoimmune and inflammatory disease. While IL-2 is generally considered to promote T-cell proliferation and enhance effector T-cell function, recent studies have demonstrated that treatments that utilize low-dose IL-2 unexpectedly induce immune tolerance and promote Treg development resulting in the suppression of unwanted immune responses and eventually leading to treatment of some autoimmune disorders...
2018: Signal Transduction and Targeted Therapy
Anna Zuk, Paul M Palevsky, Linda Fried, Frank E Harrell, Samina Khan, Dianne B McKay, Luke Devey, Lakhmir Chawla, Mark de Caestecker, James S Kaufman, B Taylor Thompson, Anupam Agarwal, Tom Greene, Mark Douglas Okusa, Joseph V Bonventre, Laura M Dember, Kathleen D Liu, Benjamin D Humphreys, Daniel Gossett, Yining Xie, Jenna M Norton, Paul L Kimmel, Robert A Star
AKI is a complex clinical condition associated with high mortality, morbidity, and health care costs. Despite improvements in methodology and design of clinical trials, and advances in understanding the underlying pathophysiology of rodent AKI, no pharmacologic agent exists for the prevention or treatment of AKI in humans. To address the barriers that affect successful clinical translation of drug targets identified and validated in preclinical animal models of AKI in this patient population, the National Institute of Diabetes and Digestive and Kidney Diseases convened the "AKI Outcomes: Overcoming Barriers in AKI" workshop on February 10-12, 2015...
March 9, 2018: Clinical Journal of the American Society of Nephrology: CJASN
Gilles Defer, Florian Le Caignec, Sophie Fedrizzi, François Montastruc, Damien Chevanne, Jean-Jacques Parienti, Laure Peyro-Saint-Paul
BACKGROUND: The reporting of adverse drug reactions (ADR) by patients represents an interesting challenge in the field of pharmacovigilance, but the reporting system is not adequately implemented in France. In 2015, only 20 MS patients in France reported ADR due to first-line disease-modifying drugs (DMD), while more than 3000 patients were initiated on DMD. The aim of this study is to validate a proof-of-concept as to whether the use of a mobile application (App) increases ADR reporting among patients with relapsing-remitting multiple sclerosis (RR-MS) receiving DMD...
March 9, 2018: Trials
V G Deepagan, Hyewon Ko, Seunglee Kwon, N Vijayakameswara Rao, Sang Kyoon Kim, Wooram Um, Sohee Lee, Jiwoong Min, Jeongjin Lee, Ki Young Choi, Sol Shin, Minah Suh, Jae Hyung Park
Conventional cancer targeting with nanoparticles has been based on the assumed enhanced permeability and retention (EPR) effect. The data obtained in clinical trials to date, however, have rarely supported the presence of such an effect. To address this challenge, we formulated intracellular nitric oxide-generating nanoparticles (NO-NPs) for the tumor site-specific delivery of NO, a well-known vasodilator, with the intention of boosting EPR. These nanoparticles are self-assembled under aqueous conditions from amphiphilic copolymers of poly(ethylene glycol) and nitrated dextran, which possesses inherent NO release properties in the reductive environment of cancer cells...
March 9, 2018: Nano Letters
Johannes M Werzowa, Marcus D Säemann, Alexander Mohl, Michael Bergmann, Christopher C Kaltenecker, Wolfgang Brozek, Andreas Thomas, Michael Haidinger, Marlies Antlanger, Johannes J Kovarik, Chantal Kopecky, Peter X K Song, Klemens Budde, Julio Pascual, Manfred Hecking
Treating hyperglycemia in previously non-diabetic individuals with exogenous insulin immediately after kidney transplantation reduced the odds of developing Posttransplantation Diabetes Mellitus (PTDM) in our previous proof-of-concept clinical trial. We hypothesized that insulin-pump therapy with maximal insulin dosage during the afternoon would improve glycemic control compared to basal insulin and standard-of-care. In a multi-center, randomized, controlled trial testing insulin isophane for PTDM prevention, we added a third study arm applying continuous subcutaneous insulin lispro infusion (CSII) treatment...
2018: PloS One
Mehran Makvandi, Austin Pantel, Lauren Schwartz, Erin Schubert, Kuiying Xu, Chia-Ju Hsieh, Catherine Hou, Hyoung Kim, Chi-Chang Weng, Harrison Winters, Robert Doot, Michael D Farwell, Daniel A Pryma, Roger A Greenberg, David A Mankoff, Fiona Simpkins, Robert H Mach, Lilie L Lin
BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitors are effective in a broad population of ovarian cancer patients, however resistance caused by low enzyme expression of the drug target, poly(ADP-ribose) polymerase 1 (PARP-1), remains to be clinically evaluated in this context. We hypothesize that PARP-1 expression is variable in ovarian cancer and can be quantified in primary and metastatic disease using a novel positron emitting tomography (PET) imaging agent. METHODS: We used a translational approach to describe the significance of PET imaging of PARP-1 in ovarian cancer...
March 6, 2018: Journal of Clinical Investigation
Aleš Tomek, Václav Matʼoška, Alena Frýdmanová, Hana Magerová, Martin Šrámek, Jaroslava Paulasova-Schwabová, Tereza Růžičková, Petr Janský, Ivana Šarbochová, Ivana Hadačová, Vojtěch Kaplan, Zuzana Lacinová, Luděk Táborský, Victor Serebruany
BACKGROUND: Variable response after clopidogrel is well documented and may affect major adverse clinical events after stroke. Impact of CYP2C19 genetic polymorphisms is an established marker linked to variable response after clopidogrel. However, the association of certain genetic polymorphisms with prediction of major adverse clinical events following stroke still remains controversial, especially in Caucasians. STUDY QUESTION: The primary aim was to evaluate the impact of CYP2C19 allele *2 in heterozygote form on major adverse clinical events in Caucasian poststroke survivors treated with clopidogrel...
March 2018: American Journal of Therapeutics
Christopher R Nesler, Tim A Swift, Elliott J Rouse
Substantial device mass and control complexity can hinder the impact of wearable robotic technologies, such as exoskeletons. Thus, despite promising previous research, the development of a simple, lightweight actuator for these systems has not yet been fully realized. The purpose of this study was to derive and demonstrate a proof-of-concept for a pneumatic interference actuator (PIA)-a lightweight, soft actuator able to produce torque by the self-intersection of a fabric balloon that arises from changes in physical geometry...
March 2, 2018: Soft Robotics
Walid I Essayed, Prashin Unadkat, Ahmed Hosny, Sarah Frisken, Marcio S Rassi, Srinivasan Mukundan, James C Weaver, Ossama Al-Mefty, Alexandra J Golby, Ian F Dunn
OBJECTIVE Endoscopic endonasal approaches are increasingly performed for the surgical treatment of multiple skull base pathologies. Preventing postoperative CSF leaks remains a major challenge, particularly in extended approaches. In this study, the authors assessed the potential use of modern multimaterial 3D printing and neuronavigation to help model these extended defects and develop specifically tailored prostheses for reconstructive purposes. METHODS Extended endoscopic endonasal skull base approaches were performed on 3 human cadaveric heads...
March 2, 2018: Journal of Neurosurgery
Silvia Gregori, Maria Grazia Roncarolo
T regulatory cells, a specialized subset of T cells, are key players in modulating antigen (Ag)-specific immune responses in vivo . Inducible T regulatory type 1 (Tr1) cells are characterized by the co-expression of CD49b and lymphocyte-activation gene 3 (LAG-3) and the ability to secrete IL-10, TGF-β, and granzyme (Gz) B, in the absence of IL-4 and IL-17. The chief mechanisms by which Tr1 cells control immune responses are secretion of IL-10 and TGF-β and killing of myeloid cells via GzB. Tr1 cells, first described in peripheral blood of patients who developed tolerance after HLA-mismatched fetal liver hematopoietic stem cell transplantation, have been proven to modulate inflammatory and effector T cell responses in several immune-mediated diseases...
2018: Frontiers in Immunology
Isabelle Ingrand, Marcello Solinas, Pierre Ingrand, Emilie Dugast, Pierre-Jean Saulnier, Marie-Christine Pérault-Pochat, Claire Lafay-Chebassier
A recent pre-clinical study has shown that brain-penetrating statins can reduce risks of relapse to cocaine and nicotine addiction in rats. Based on this information, we conducted a randomized, double-blind, placebo-controlled, proof-of-concept trial to assess the efficacy of simvastatin in smoking cessation. After informed consent, 118 participants received behavioral cessation support and were randomly assigned to a 3-month treatment with simvastatin or placebo. The primary outcome was biochemically verified abstinence or smoking reduction at 3-month post-target quit date (TQD)...
March 1, 2018: Scientific Reports
Melissa J Chen, Jennifer K Hsia, Mitchell D Creinin
OBJECTIVE: We evaluated a novel concept of initiating the etonogestrel implant as a "back-up" method in women who desire using combined oral contraceptives (COC) but want to decrease their risk of unintended pregnancy with a more effective method. STUDY DESIGN: In this prospective cohort study, we planned to include 20 women as a proof-of-concept. We enrolled both new COC starters and continuing COC users and placed an etonogestrel implant. Participants completed daily bleeding diaries and attended follow-up visits at 1, 3, and 6 months...
February 26, 2018: Contraception
Steven M Smith, Kathryn McAuliffe, Jaclyn M Hall, Caitrin W McDonough, Matthew J Gurka, Temple O Robinson, Ralph L Sacco, Carl Pepine, Elizabeth Shenkman, Rhonda M Cooper-DeHoff
INTRODUCTION: Hypertension is highly prevalent in Florida, but surveillance through the Behavioral Risk Factor Surveillance System (BRFSS) is limited to self-reported hypertension and does not capture data on undiagnosed hypertension or measure blood pressure. We aimed to characterize the hypertensive population in the OneFlorida Clinical Research Consortium by using electronic health records and provide proof-of-concept for using routinely collected clinical data to augment surveillance efforts...
March 1, 2018: Preventing Chronic Disease
Jo Ishizawa, Kenji Nakamaru, Takahiko Seki, Koichi Tazaki, Kensuke Kojima, Dhruv Chachad, Ran Zhao, Lauren E Heese, Wencai Ma, Man Chun John Ma, Courtney D DiNardo, Sherry A Pierce, Keyur P Patel, Archie Tse, R Eric Davis, Arvind Rao, Michael Andreeff
Early clinical trials using murine double minute 2 (MDM2) inhibitors demonstrated proof-of-concept of p53-induced apoptosis by MDM2 inhibition in cancer cells, however, not all wild-type TP53 tumors are sensitive to MDM2 inhibition. Therefore, more potent inhibitors and biomarkers predictive of tumor sensitivity are needed. The novel MDM2 inhibitor DS-3032b is 10-fold more potent than the first-generation inhibitor nutlin-3a. TP53 mutations were predictive of resistance to DS-3032b, and allele frequencies of TP53 mutations were negatively correlated with sensitivity to DS-3032b...
February 28, 2018: Cancer Research
Gianfranco Caselli, Albino Bonazzi, Marco Lanza, Flora Ferrari, Daniele Maggioni, Cristian Ferioli, Roberto Giambelli, Eleonora Comi, Silvia Zerbi, Marco Perrella, Ornella Letari, Elena Di Luccio, Milena Colovic, Stefano Persiani, Tiziano Zanelli, Laura Mennuni, Tiziana Piepoli, Lucio Claudio Rovati
BACKGROUND: Prostaglandin E2 (PGE2 ) acts via its EP4 receptor as a cytokine amplifier (e.g., interleukin [IL]-6) and induces the differentiation and expansion of inflammatory T-helper (Th) lymphocytes. These mechanisms play a key role in the onset and progression of rheumatoid arthritis (RA). We present the pharmacological characterisation of CR6086, a novel EP4 receptor antagonist, and provide evidence for its potential as a disease-modifying anti-rheumatic drug (DMARD). METHODS: CR6086 affinity and pharmacodynamics were studied in EP4-expressing HEK293 cells by radioligand binding and cyclic adenosine monophosphate (cAMP) production, respectively...
March 1, 2018: Arthritis Research & Therapy
Débora Arruda Frommenwiler, Jonghwan Kim, Chang-Soo Yook, Thi Thu Trang Tran, Salvador Cañigueral, Eike Reich
The quality of herbal drugs is usually controlled using several tests recommended in a monograph. HPTLC is the method of choice for identification in many pharmacopoeias. If combined with a suitable reference material for comparison, HPTLC can provide information beyond identification and thus may simplify quality control. This paper describes, as a proof of concept, how HPTLC can be applied to define specifications for an herbal reference material and to control the quality of an herbal drug according to these specifications...
February 28, 2018: Planta Medica
Nouchine Hadjikhani, Jakob Åsberg Johnels, Amandine Lassalle, Nicole R Zürcher, Loyse Hippolyte, Christopher Gillberg, Eric Lemonnier, Yehezkel Ben-Ari
We recently showed that constraining eye contact leads to exaggerated increase of amygdala activation in autism. Here, in a proof of concept pilot study, we demonstrate that administration of bumetanide (a NKCC1 chloride importer antagonist that restores GABAergic inhibition) normalizes the level of amygdala activation during constrained eye contact with dynamic emotional face stimuli in autism. In addition, eye-tracking data reveal that bumetanide administration increases the time spent in spontaneous eye gaze during in a free-viewing mode of the same face stimuli...
February 26, 2018: Scientific Reports
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