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Proof of concept clinical trial

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https://www.readbyqxmd.com/read/28330821/beyond-precision-surgery-molecularly-motivated-precision-care-for-gastric-cancer
#1
REVIEW
Y Y Choi, J-H Cheong
Gastric cancer is one of the leading causes of cancer-related deaths worldwide. Despite the high disease prevalence, gastric cancer research has not gained much attention. Recently, genome-scale technology has made it possible to explore the characteristics of gastric cancer at the molecular level. Accordingly, gastric cancer can be classified into molecular subtypes that convey more detailed information of tumor than histopathological characteristics, and these subtypes are associated with clinical outcomes...
March 1, 2017: European Journal of Surgical Oncology
https://www.readbyqxmd.com/read/28328012/free-fatty-acid-receptor-1-ffar1-as-an-emerging-therapeutic-target-for-type-2-diabetes-mellitus-recent-progress-and-prevailing-challenges
#2
REVIEW
Zheng Li, Xue Xu, Wenlong Huang, Hai Qian
The free fatty acid receptor 1 (FFAR1/GPR40) amplifies glucose-dependent insulin secretion; therefore, it has attracted widespread attention as a promising antidiabetic target. Current clinical proof of concept also indicates that FFAR1 agonists achieve the initially therapeutic endpoint for the treatment of type 2 diabetes mellitus (T2DM) without the hypoglycemic risk. Thus, many pharmaceutical companies and academic institutes are competing to develop FFAR1 agonists. However, several candidates have been discontinued in clinical trials, often without reporting the underlying reasons...
March 22, 2017: Medicinal Research Reviews
https://www.readbyqxmd.com/read/28325150/managing-expectations-in-the-transition-to-proof-of-concept-studies
#3
Thomas Kieber-Emmons, Issam Makhoul, Angela Pennisi, Eric R Siegel, Peter D Emanuel, Bejotaloh Monzavi-Karbassi, Zenon Steplewski, J Thaddeus Beck, Laura F Hutchins
BACKGROUND: As we are moving away from the traditional chemotherapy era to targeted therapy, the validity of old assessment paradigms associated with therapeutics are being raised in the context of immunotherapy. The old paradigm required elaborate assessment of toxicity with no expectation of efficacy in early phase trials. Safety data from Phase 1 and 2 studies with many immunotherapeutics show that they display limited toxicities and draw attention to the need to demonstrate efficacy in the early evaluation of new agents...
March 21, 2017: Reviews on Recent Clinical Trials
https://www.readbyqxmd.com/read/28319444/retro-orbital-venous-sinus-delivery-of-raav9-mediates-high-level-transduction-of-brain-and-retina-compared-with-temporal-vein-delivery-in-neonatal-mouse-pups
#4
Alisha M Gruntman, Lin Su, Terence R Flotte
In order to pursue a clinical gene therapy for a human neurologic disease, it is often necessary to perform proof-of-concept trials in mouse models of that disease. In order to demonstrate a potential clinical efficacy, one must be able to select an appropriate vector and route of delivery for the appropriate age group in the disease model. Since many diseases require correction early in life, investigators often need to deliver recombinant adeno-associated viral (rAAV) vectors to neonatal mice. Herein, general central nervous system expression patterns of nuclear GFP following delivery of rAAV by three different routes are reported...
March 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28318816/use-of-electromyography-to-optimize-lokomat-%C3%A2-settings-for-subject-specific-gait-rehabilitation-in-post-stroke-hemiparetic-patients-a-proof-of-concept-study
#5
Yosra Cherni, Mickael Begon, Hicham Chababe, Florent Moissenet
OBJECTIVES: While generic protocols exist for gait rehabilitation using robotic orthotics such as the Lokomat(®), several settings - guidance, body-weight support (BWS) and velocity - may be adjusted to individualize patient training. However, no systematic approach has yet emerged. Our objective was to assess the feasibility and effects of a systematic approach based on electromyography to determine subject-specific settings with application to the strengthening of the gluteus maximus muscle in post-stroke hemiparetic patients...
March 16, 2017: Neurophysiologie Clinique, Clinical Neurophysiology
https://www.readbyqxmd.com/read/28318420/bayesian-penalized-log-likelihood-ratio-approach-for-dose-response-clinical-trial-studies
#6
Yuanyuan Tang, Chunyan Cai, Liangrui Sun, Jianghua He
In literature, there are a few unified approaches to test proof of concept and estimate a target dose, including the multiple comparison procedure using modeling approach, and the permutation approach proposed by Klingenberg. We discuss and compare the operating characteristics of these unified approaches and further develop an alternative approach in a Bayesian framework based on the posterior distribution of a penalized log-likelihood ratio test statistic. Our Bayesian approach is much more flexible to handle linear or nonlinear dose-response relationships and is more efficient than the permutation approach...
February 13, 2017: Journal of Biopharmaceutical Statistics
https://www.readbyqxmd.com/read/28314707/biometrics-and-policing-a-protocol-for-multichannel-sensor-data-collection-and-exploratory-analysis-of-contextualized-psychophysiological-response-during-law-enforcement-operations
#7
Robert D Furberg, Travis Taniguchi, Brian Aagaard, Alexa M Ortiz, Meghan Hegarty-Craver, Kristin H Gilchrist, Ty A Ridenour
BACKGROUND: Stress experienced by law enforcement officers is often extreme and is in many ways unique among professions. Although past research on officer stress is informative, it is limited, and most studies measure stress using self-report questionnaires or observational studies that have limited generalizability. We know of no research studies that have attempted to track direct physiological stress responses in high fidelity, especially within an operational police setting. The outcome of this project will have an impact on both practitioners and policing researchers...
March 17, 2017: JMIR Research Protocols
https://www.readbyqxmd.com/read/28314411/small-molecule-inhibition-of-interleukin-1-receptor-associated-kinase-4-irak4
#8
N E Genung, K M Guckian
In recent years, interleukin-1 receptor-associated kinase 4, IRAK4, has become an attractive target for many medicinal chemistry programmes. Target inhibition is of potential therapeutic value in areas including autoimmune disorders, cancer, inflammatory diseases, and possibly neurodegenerative diseases. Results from high-throughput screening efforts have led, in conjunction with structure-based drug design, to the identification of highly potent and selective small molecule IRAK4 inhibitors from many diverse chemical series...
2017: Progress in Medicinal Chemistry
https://www.readbyqxmd.com/read/28294453/a-translational-approach-for-nmda-receptor-profiling-as-a-vulnerability-biomarker-for-depression-and-schizophrenia
#9
Handan Gunduz-Bruce, Joshua Kenney, Suravi Changlani, Aldo Peixoto, Ralitza Gueorguieva, Cheryl Leone, Nina Stachenfeld
Altered N-methyl-D-aspartate (NMDA) receptor activity and glutamate signaling may underlie the pathogenesis of both schizophrenia and depression in subgroups of patients. In schizophrenia, pharmacologic modeling, postmortem and imaging data suggest reduced NMDA signaling. In contrast, recent clinical trials demonstrating the efficacy of the NMDA antagonist ketamine in severely depressed patients suggest increased NMDA receptor signaling. We conducted a proof of concept study to assess whether there is any in vivo evidence for an inverse association in depression and schizophrenia with respect to the NMDA receptor function...
March 13, 2017: Experimental Physiology
https://www.readbyqxmd.com/read/28289776/-research-funding-for-rare-diseases-in-germany
#10
Frank Wissing, Leena Bruckner-Tuderman
There is high need for more research in the field of rare diseases. Not only must the causes and mechanisms of the numerous and often heterogeneous diseases be delineated, but criteria must also be defined for optimal stratification of patients for individualized therapies. In this context, research and innovative diagnostics are linked together more closely than in other fields of medicine. The early stages of disease-oriented research can be performed in individual institutions but, due to low numbers of patients, late translation and transfer into clinics requires multicentric and international collaboration...
March 13, 2017: Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz
https://www.readbyqxmd.com/read/28287872/development-of-a-modular-automated-system-for-maintenance-and-differentiation-of-adherent-human-pluripotent-stem-cells
#11
Duncan E Crombie, Maciej Daniszewski, Helena H Liang, Tejal Kulkarni, Fan Li, Grace E Lidgerwood, Alison Conquest, Damian Hernández, Sandy S Hung, Katherine P Gill, Elisabeth De Smit, Lisa S Kearns, Linda Clarke, Valentin M Sluch, Xitiz Chamling, Donald J Zack, Raymond C B Wong, Alex W Hewitt, Alice Pébay
Patient-specific induced pluripotent stem cells (iPSCs) have tremendous potential for development of regenerative medicine, disease modeling, and drug discovery. However, the processes of reprogramming, maintenance, and differentiation are labor intensive and subject to intertechnician variability. To address these issues, we established and optimized protocols to allow for the automated maintenance of reprogrammed somatic cells into iPSCs to enable the large-scale culture and passaging of human pluripotent stem cells (PSCs) using a customized TECAN Freedom EVO...
March 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28259495/effects-of-diaphragmatic-breathing-patterns-on-balance-a-preliminary-clinical-trial
#12
Rylee J Stephens, Mitchell Haas, William L Moore, Jordan R Emmil, Jayson A Sipress, Alex Williams
OBJECTIVE: The purpose of this study was to determine the feasibility of performing a larger study to determine if training in diaphragmatic breathing influences static and dynamic balance. METHODS: A group of 13 healthy persons (8 men, 5 women), who were staff, faculty, or students at the University of Western States participated in an 8-week breathing and balance study using an uncontrolled clinical trial design. Participants were given a series of breathing exercises to perform weekly in the clinic and at home...
March 1, 2017: Journal of Manipulative and Physiological Therapeutics
https://www.readbyqxmd.com/read/28247316/selecting-potential-pharmacological-interventions-in-sarcopenia
#13
Amanda J Kilsby, Avan A Sayer, Miles D Witham
Sarcopenia of age is prevalent and costly and proven pharmacological interventions are currently lacking. The pathophysiology of sarcopenia is incompletely understood but appears to involve multiple pathways, including inflammation, hormonal dysregulation, impaired regeneration, mitochondrial dysfunction and denervation. There are several ways in which we might select potential pharmacological interventions for testing in clinical trials. These include a 'bottom-up' approach using basic science to elucidate the molecular processes involved and identify potential targets from this knowledge-a strategy that has led to the development of myostatin inhibitors...
April 2017: Drugs & Aging
https://www.readbyqxmd.com/read/28245243/serelaxin-as-a-potential-treatment-for-renal-dysfunction-in-cirrhosis-preclinical-evaluation-and-results-of-a-randomized-phase-2-trial
#14
Victoria K Snowdon, Neil J Lachlan, Anna M Hoy, Patrick W F Hadoke, Scott I Semple, Dilip Patel, Will Mungall, Timothy J Kendall, Adrian Thomson, Ross J Lennen, Maurits A Jansen, Carmel M Moran, Antonella Pellicoro, Prakash Ramachandran, Isaac Shaw, Rebecca L Aucott, Thomas Severin, Rajnish Saini, Judy Pak, Denise Yates, Neelesh Dongre, Jeremy S Duffield, David J Webb, John P Iredale, Peter C Hayes, Jonathan A Fallowfield
BACKGROUND: Chronic liver scarring from any cause leads to cirrhosis, portal hypertension, and a progressive decline in renal blood flow and renal function. Extreme renal vasoconstriction characterizes hepatorenal syndrome, a functional and potentially reversible form of acute kidney injury in patients with advanced cirrhosis, but current therapy with systemic vasoconstrictors is ineffective in a substantial proportion of patients and is limited by ischemic adverse events. Serelaxin (recombinant human relaxin-2) is a peptide molecule with anti-fibrotic and vasoprotective properties that binds to relaxin family peptide receptor-1 (RXFP1) and has been shown to increase renal perfusion in healthy human volunteers...
February 2017: PLoS Medicine
https://www.readbyqxmd.com/read/28241420/antiosteoporotic-activity-of-genistein-aglycone-in-postmenopausal-women-evidence-from-a-post-hoc-analysis-of-a-multicenter-randomized-controlled-trial
#15
Vincenzo Arcoraci, Marco Atteritano, Francesco Squadrito, Rosario D'Anna, Herbert Marini, Domenico Santoro, Letteria Minutoli, Sonia Messina, Domenica Altavilla, Alessandra Bitto
Genistein has a preventive role against bone mass loss during menopause. However, experimental data in animal models of osteoporosis suggest an anti-osteoporotic potential for this isoflavone. We performed a post-hoc analysis of a previously published trial investigating the effects of genistein in postmenopausal women with low bone mineral density. The parent study was a randomized, double-blind, placebo-controlled trial involving postmenopausal women with a femoral neck (FN) density <0.795 g/cm². A cohort of the enrolled women was, in fact, identified at the baseline as osteoporotic (n = 121) on the basis of their T-score and analyzed thereafter for the 24 months' treatment with either 1000 mg of calcium and 800 IU vitamin D3 (placebo; n = 59); or calcium, vitamin D3, and Genistein aglycone (54 mg/day; genistein; n = 62)...
February 22, 2017: Nutrients
https://www.readbyqxmd.com/read/28228578/proof-of-concept-randomized-trial-of-the-monoclonal-antibody-gsk249320-versus-placebo-in-stroke-patients
#16
Steven C Cramer, Lori A Enney, Colleen K Russell, Monica Simeoni, Thomas R Thompson
BACKGROUND AND PURPOSE: One class of poststroke restorative therapy focuses on promoting axon outgrowth by blocking myelin-based inhibitory proteins such as myelin-associated glycoprotein. The purpose of the current study was to extend preclinical and clinical findings of GSK249320, a humanized monoclonal antibody to myelin-associated glycoprotein with disabled Fc region, to explore effects on motor outcomes poststroke. METHODS: In this phase IIb double-blind, randomized, placebo-controlled study, patients at 30 centers with ischemic stroke 24 to 72 hours prior and gait deficits were randomized to 2 IV infusions of GSK249320 or placebo...
March 2017: Stroke; a Journal of Cerebral Circulation
https://www.readbyqxmd.com/read/28225767/interferon-%C3%AE-1a-for-the-treatment-of-ebola-virus-disease-a-historically-controlled-single-arm-proof-of-concept-trial
#17
Mandy Kader Konde, Darren P Baker, Fode Amara Traore, Mamadou Saliou Sow, Alioune Camara, Alpha Amadou Barry, Doussou Mara, Abdoulaye Barry, Moussa Cone, Ibrahima Kaba, Amento Ablam Richard, Abdoul Habib Beavogui, Stephan Günther, Melania Pintilie, Eleanor N Fish
To date there are no approved antiviral drugs for the treatment of Ebola virus disease (EVD). Based on our in vitro evidence of antiviral activity of interferon (IFN)-ß activity against Ebola virus, we conducted a single arm clinical study in Guinea to evaluate the safety and therapeutic efficacy of IFN β-1a treatment for EVD. Nine individuals infected with Ebola virus were treated with IFN β-1a and compared retrospectively with a matched cohort of 21 infected patients receiving standardized supportive care only during the same time period at the same treatment unit...
2017: PloS One
https://www.readbyqxmd.com/read/28220753/high-performance-communication-by-people-with-paralysis-using-an-intracortical-brain-computer-interface
#18
Chethan Pandarinath, Paul Nuyujukian, Christine H Blabe, Brittany L Sorice, Jad Saab, Francis R Willett, Leigh R Hochberg, Krishna V Shenoy, Jaimie M Henderson
Brain-computer interfaces (BCIs) have the potential to restore communication for people with tetraplegia and anarthria by translating neural activity into control signals for assistive communication devices. While previous pre-clinical and clinical studies have demonstrated promising proofs-of-concept (Serruya et al., 2002; Simeral et al., 2011; Bacher et al., 2015; Nuyujukian et al., 2015; Aflalo et al., 2015; Gilja et al., 2015; Jarosiewicz et al., 2015; Wolpaw et al., 1998; Hwang et al., 2012; Spüler et al...
February 21, 2017: ELife
https://www.readbyqxmd.com/read/28220124/in-vivo-efficacy-of-umbilical-cord-blood-stem-cell-derived-nk-cells-in-the-treatment-of-metastatic-colorectal-cancer
#19
John P Veluchamy, Silvia Lopez-Lastra, Jan Spanholtz, Fenna Bohme, Nina Kok, Daniëlle A M Heideman, Henk M W Verheul, James P Di Santo, Tanja D de Gruijl, Hans J van der Vliet
Therapeutic monoclonal antibodies against the epidermal growth factor receptor (EGFR) act by inhibiting EGFR downstream signaling and by eliciting a natural killer (NK) cell-mediated antitumor response. The IgG1 mAb cetuximab has been used for treatment of RAS(wt) metastatic colorectal cancer (mCRC) patients, showing limited efficacy. In the present study, we address the potential of adoptive NK cell therapy to overcome these limitations investigating two allogeneic NK cell products, i.e., allogeneic activated peripheral blood NK cells (A-PBNK) and umbilical cord blood stem cell-derived NK cells (UCB-NK)...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28215711/biomarkers-for-cystic-fibrosis-drug-development
#20
REVIEW
Marianne S Muhlebach, J P Clancy, Sonya L Heltshe, Assem Ziady, Tom Kelley, Frank Accurso, Joseph Pilewski, Nicole Mayer-Hamblett, Elizabeth Joseloff, Scott D Sagel
PURPOSE: To provide a review of the status of biomarkers in cystic fibrosis drug development, including regulatory definitions and considerations, a summary of biomarkers in current use with supportive data, current gaps, and future needs. METHODS: Biomarkers are considered across several areas of CF drug development, including cystic fibrosis transmembrane conductance regulator modulation, infection, and inflammation. RESULTS: Sweat chloride, nasal potential difference, and intestinal current measurements have been standardized and examined in the context of multicenter trials to quantify CFTR function...
November 2016: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
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