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Proof of concept clinical trial

B Barboni, V Russo, P Berardinelli, A Mauro, L Valbonetti, H Sanyal, A Canciello, L Greco, A Muttini, V Gatta, L Stuppia, M Mattioli
The field of regenerative medicine is moving toward clinical practice in veterinary science. In this context, placenta-derived stem cells isolated from domestic animals have covered a dual role, acting both as therapies for patients and as a valuable cell source for translational models. The biological properties of placenta-derived cells, comparable among mammals, make them attractive candidates for therapeutic approaches. In particular, stemness features, low immunogenicity, immunomodulatory activity, multilineage plasticity, and their successful capacity for long-term engraftment in different host tissues after autotransplantation, allo-transplantation, or xenotransplantation have been demonstrated...
January 2018: Cell Transplantation
Jolien Fleur Leijenaar, Geert Jan Groeneveld, Wiesje Maria van der Flier, Philip Scheltens, Erica Surya Klaassen, Henry Chanoch Weinstein, Geert Jan Biessels, Frederik Barkhof, Niels Daniël Prins
BACKGROUND: People with vascular cognitive impairment (VCI) constitute a clinically heterogeneous group, but previous symptomatic drug trials in VCI did not take this clinical heterogeneity into account. Executive dysfunction and memory impairment are the cognitive domains that are most frequently impaired in VCI, and these impairments are likely to reflect vascular damage to specific neurotransmitter systems, which opens the possibility for targeted symptomatic treatment directed at specific neurotransmitters...
March 20, 2018: JMIR Research Protocols
John R Best, Janice J Eng, Jennifer C Davis, Robin Hsiung, Peter A Hall, Laura E Middleton, Peter Graf, Charles H Goldsmith, Teresa Liu-Ambrose
INTRODUCTION: Cerebrovascular disease-such as stroke-is the second most common cause of dementia (ie, vascular dementia). Specifically, a stroke increases one's risk for dementia by a factor of two. Thus, stroke survivors represent a target population in need of intervention strategies to promote cognitive function and prevent dementia. The current standard of care in stroke rehabilitation does not adequately address the significant cognitive consequences of stroke, especially for those who are in the chronic phase (ie, >12 months since an index stroke)...
March 17, 2018: BMJ Open
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
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
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
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
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
Rodrigo B Mansur, Yena Lee, Mehala Subramaniapillai, Elisa Brietzke, Roger S McIntyre
Major depressive disorder and bipolar disorder are highly prevalent and disabling conditions. Cognition is considered a core domain of their psychopathology and a principle mediator of psychosocial impairment, disproportionately accounting for overall illness-associated costs. There are few interventions with replicated evidence of efficacy in treating cognitive deficits in mood disorders. Evidence also indicates that cognitive deficits are associated with obesity and involve significant impairment across multiple domains...
February 23, 2018: Neuropharmacology
Seán Walsh, Erik Roelofs, Peter Kuess, Yvonka van Wijk, Ben Vanneste, Andre Dekker, Philippe Lambin, Bleddyn Jones, Dietmar Georg, Frank Verhaegen
We present a methodology which can be utilized to select proton or photon radiotherapy in prostate cancer patients. Four state-of-the-art competing treatment modalities were compared (by way of an in silico trial) for a cohort of 25 prostate cancer patients, with and without correction strategies for prostate displacements. Metrics measured from clinical image guidance systems were used. Three correction strategies were investigated; no-correction, extended-no-action-limit, and online-correction. Clinical efficacy was estimated via radiobiological models incorporating robustness (how probable a given treatment plan was delivered) and stability (the consistency between the probable best and worst delivered treatments at the 95% confidence limit)...
February 18, 2018: Cancers
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