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First-in-human clinical studies

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https://www.readbyqxmd.com/read/28817680/human-alpha-defensin-5-is-a-candidate-biomarker-to-delineate-inflammatory-bowel-disease
#1
Amanda D Williams, Olga Y Korolkova, Amos M Sakwe, Timothy M Geiger, Samuel D James, Roberta L Muldoon, Alan J Herline, J Shawn Goodwin, Michael G Izban, Mary K Washington, Duane T Smoot, Billy R Ballard, Maria Gazouli, Amosy E M'Koma
Inability to distinguish Crohn's colitis from ulcerative colitis leads to the diagnosis of indeterminate colitis. This greatly effects medical and surgical care of the patient because treatments for the two diseases vary. Approximately 30 percent of inflammatory bowel disease patients cannot be accurately diagnosed, increasing their risk of inappropriate treatment. We sought to determine whether transcriptomic patterns could be used to develop diagnostic biomarker(s) to delineate inflammatory bowel disease more accurately...
2017: PloS One
https://www.readbyqxmd.com/read/28817637/genetic-diversity-of-the-o-antigens-of-proteus-species-and-the-development-of-a-suspension-array-for-molecular-serotyping
#2
Xiang Yu, Agnieszka Torzewska, Xinjie Zhang, Zhiqiu Yin, Dominika Drzewiecka, Hengchun Cao, Bin Liu, Yuriy A Knirel, Antoni Rozalski, Lei Wang
Proteus species are well-known opportunistic pathogens frequently associated with skin wound and urinary tract infections in humans and animals. O antigen diversity is important for bacteria to adapt to different hosts and environments, and has been used to identify serotypes of Proteus isolates. At present, 80 Proteus O-serotypes have been reported. Although the O antigen structures of most Proteus serotypes have been identified, the genetic features of these O antigens have not been well characterized. The O antigen gene clusters of Proteus species are located between the cpxA and secB genes...
2017: PloS One
https://www.readbyqxmd.com/read/28817288/in-silico-modeling-approach-for-the-evaluation-of-gastrointestinal-dissolution-supersaturation-and-precipitation-of-posaconazole
#3
Bart Hens, Shriram M Pathak, Amitava Mitra, Nikunjkumar Patel, Bo Liu, Sanjaykumar Patel, Masoud Jamei, Joachim Brouwers, Patrick Augustijns, David B Turner
The aim of this study was to evaluate gastrointestinal (GI) dissolution, supersaturation, and precipitation of posaconazole, formulated as an acidified (pH 1.6) and neutral (pH 7.1) suspension. A physiologically-based pharmacokinetic (PBPK) modeling and simulation tool was applied to simulate GI and systemic concentration-time profiles of posaconazole which were directly compared with intraluminal and systemic data measured in humans. The Advanced Dissolution Absorption and Metabolism (ADAM) model of the Simcyp® Simulator correctly simulated incomplete gastric dissolution and saturated duodenal concentrations of posaconazole in the duodenal fluids following administration of the neutral suspension...
August 17, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28816234/novel-mutations-of-tcirg1-cause-a-malignant-and-mild-phenotype-of-autosomal-recessive-osteopetrosis-aro-in-four-chinese-families
#4
Xiao-Ya Zhang, Jin-Wei He, Wen-Zhen Fu, Chun Wang, Zhen-Lin Zhang
Human autosomal recessive osteopetrosis (ARO), also known as infantile malignant osteopetrosis, is a rare genetic bone disorder that often causes death. Mutations in T-cell immune regulator 1 (TCIRG1) are a frequent cause of human ARO. Six additional genes (TNFSF11, TNFRSF11A, CLCN7, OSTM1, SNX10, PLEKHM1) were also found to be associated with human ARO. In order to expand the mutation spectrum and clinical diversity for a better understanding of the ARO phenotype and to further investigate the clinical characteristics of benign subjects with ARO, we here report five individuals with ARO from four unrelated Chinese families...
August 17, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28815810/proteome-characterization-of-human-pancreatic-cyst-fluid-from-intraductal-papillary-mucinous-neoplasm-by-lc-ms-ms
#5
Joonho Park, Dohyun Han, Misol Do, Jongmin Woo, Joseph I Wang, Youngmin Han, Wooil Kwon, Sun-Whe Kim, Jin-Young Jang, Youngsoo Kim
RATIONALE: In recent years, the molecular components of pancreatic cyst fluid has been used for diagnosis and prognosis. Because the protein markers that are currently used in clinical tests are unreliable, proteomic studies to find new protein markers are being conducted. However, such researches have been limited due to the complexity of pancreatic cyst fluid and the immaturity of proteomic techniques. METHODS: To overcome these limitations and provide a pancreatic cyst proteome dataset, we examined cyst fluid proteome with tandem mass spectrometry...
August 15, 2017: Rapid Communications in Mass Spectrometry: RCM
https://www.readbyqxmd.com/read/28815639/safety-tolerability-and-pharmacokinetic-characteristics-of%C3%A2-a-novel-nonopioid-analgesic-vvz-149-injections-in-healthy-volunteers-a-first-in-class-first-in-human-study
#6
Jaeseong Oh, SeungHwan Lee, Anhye Kim, Jangsoo Yoon, Kyungho Jang, Doo H Lee, Sunyoung Cho, Sang Rim Lee, Kyung-Sang Yu, Jae-Yong Chung
VVZ-149, a dual antagonist of GlyT2 and 5HT2 A receptors, is an investigational analgesic with a novel mechanism of action that is currently under early-stage clinical development as an injectable agent for the treatment of postoperative pain. Here, the safety, tolerability, and pharmacokinetics of VVZ-149 injections in healthy male volunteers were explored in a randomized, double-blind, single- and multiple-ascending-dose (SAD and MAD, respectively), placebo-controlled clinical study. Subjects randomly received a 4-hour intravenous infusion of 0...
August 16, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28815147/triangulating-methodologies-from-software-medicine-and-human-factors-industries-to-measure-usability-and-clinical-efficacy-of-medication-data-visualization-in-an-electronic-health-record-system
#7
Bora Chang, Manoj Kanagaraj, Ben Neely, Noa Segall, Erich Huang
Within the last decade, use of Electronic Health Record (EHR) systems has become intimately integrated into healthcare practice in the United States. However, large gaps remain in the study of clinical usability and require rigorous and innovative approaches for testing usability principles. In this study, validated tools from the core functions that EHRs serve-software, medicine and human factors-were combined to holistically understand and objectively measure usability of medication data displays. The first phase of this study included 132 medical trainee participants who were randomized to one of two simulated EHR environments with either a medication list or a medication timeline visualization...
2017: AMIA Summits on Translational Science Proceedings
https://www.readbyqxmd.com/read/28814881/elevated-expression-of-neuropilin-2-associated-with-unfavorable-prognosis-in-hepatocellular-carcinoma
#8
Xiaogang Dong, Wenjia Guo, Shizhen Zhang, Tianchun Wu, Zhongquan Sun, Sheng Yan, Shusen Zheng
Neuropilin-2 (NRP2) is a single-pass transmembrane glycoprotein and has recently been detected in several human cancer cells. However, its clinical relevance in hepatocellular carcinoma (HCC) remains unclear. This study aimed at evaluating NRP2 expression and clinicopathological significance in HCC patients. Tissue microarray of 190 HCC patients from the First Affiliated Hospital of Zhejiang University was established, and immunohistochemical staining was performed for NRP2. The Kaplan-Meier analysis and Cox proportional hazard model were used to analyze the survival rate...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28814754/unveiling-cerebral-leishmaniasis-parasites-and-brain-inflammation-in-leishmania-donovani-infected-mice
#9
Guilherme D Melo, Sophie Goyard, Laurence Fiette, Alexandre Boissonnas, Christophe Combadiere, Gisele F Machado, Paola Minoprio, Thierry Lang
Visceral leishmaniasis (VL) is a systemic disease with multifaceted clinical manifestations, including neurological signs, however, the involvement of the nervous system during VL is underestimated. Accordingly, we investigated both brain infection and inflammation in a mouse model of VL. Using bioluminescent Leishmania donovani and real-time 2D-3D imaging tools, we strikingly detected live parasites in the brain, where we observed a compartmentalized dual-phased inflammation pattern: an early phase during the first two weeks post-infection, with the prompt arrival of neutrophils and Ly6C(high) macrophages in an environment presenting a variety of pro-inflammatory mediators (IFN-γ, IL-1β, CXCL-10/CXCR-3, CCL-7/CCR-2), but with an intense anti-inflammatory response, led by IL-10; and a re-inflammation phase three months later, extremely pro-inflammatory, with novel upregulation of mediators, including IL-1β, TNF-α and MMP-9...
August 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28814432/minimal-to-no-transfer-of-certolizumab-pegol-into-breast-milk-results-from-cradle-a-prospective-postmarketing-multicentre-pharmacokinetic-study
#10
Megan Eb Clowse, Frauke Förger, Caroline Hwang, John Thorp, Radboud Jem Dolhain, Astrid van Tubergen, Laura Shaughnessy, Jeff Simpson, Marie Teil, Nathalie Toublanc, Maggie Wang, Thomas W Hale
BACKGROUND: Women with chronic inflammatory diseases face uncertainty regarding the safety of biologics during breast feeding. CRADLE was the first industry-sponsored study to evaluate certolizumab pegol (CZP) concentrations in human breast milk and estimate average daily infant dose (ADID) of maternal CZP. METHODS: CRADLE (NCT02154425) was a pharmacokinetic study of lactating mothers receiving CZP. After ≥3 CZP doses, breast milk samples were collected across one dosing period (14 days for 200 mg every 2 weeks [Q2W]; 28 days for 400 mg every 4 weeks [Q4W])...
August 16, 2017: Annals of the Rheumatic Diseases
https://www.readbyqxmd.com/read/28813466/comprehensive-comparison-of-neonate-and-adult-human-platelet-transcriptomes
#11
Eva Caparrós-Pérez, Raúl Teruel-Montoya, Mª José López-Andreo, Mª Carmen Llanos, José Rivera, Verónica Palma-Barqueros, Jose E Blanco, Vicente Vicente, Constantino Martínez, Francisca Ferrer-Marín
Understanding the underlying mechanisms of the well-substantiated platelet hyporeactivity in neonates is of interest given their implications for the clinical management of newborns, a population at higher bleeding risk than adults (especially sick and preterm infants), as well as for gaining insight into the regulatory mechanisms of platelet biology. Transcriptome analysis is useful in identifying mRNA signatures affecting platelet function. However, human fetal/neonatal platelet transcriptome analysis has never before been reported...
2017: PloS One
https://www.readbyqxmd.com/read/28812035/bioabsorbable-versus-metal-screw-in-the-fixation-of-tibial-tubercle-transfer-a-cadaveric-biomechanical-study
#12
Janne T Nurmi, Ari Itälä, Raine Sihvonen, Petri Sillanpää, Pekka Kannus, Harri Sievänen, Teppo L N Järvinen
BACKGROUND: In tibial tubercle transfer (TTT) procedures, the osteotomized and transferred tibial tubercle is usually fixed into the host bone using metal screws. PURPOSE: To compare the strength of fixation provided by a single bioabsorbable screw versus a metal screw for TTT. STUDY DESIGN: Controlled laboratory study. METHODS: Twenty-two pairs of human cadaveric tibiae were used to compare the fixation strength of a single 4...
July 2017: Orthopaedic Journal of Sports Medicine
https://www.readbyqxmd.com/read/28811347/tifa-signaling-in-gastric-epithelial-cells-initiates-the-cag-type-4-secretion-system-dependent-innate-immune-response-to-helicobacter-pylori-infection
#13
Alevtina Gall, Ryan G Gaudet, Scott D Gray-Owen, Nina R Salama
Helicobacter pylori is a bacterial pathogen that colonizes the human stomach, causing inflammation which, in some cases, leads to gastric ulcers and cancer. The clinical outcome of infection depends on a complex interplay of bacterial, host genetic, and environmental factors. Although H. pylori is recognized by both the innate and adaptive immune systems, this rarely results in bacterial clearance. Gastric epithelial cells are the first line of defense against H. pylori and alert the immune system to bacterial presence...
August 15, 2017: MBio
https://www.readbyqxmd.com/read/28811325/ppar%C3%AE-ligand-induced-annexin-a1-expression-determines-chemotherapy-response-via-deubiquitination-of-death-domain-kinase-rip-in-triple-negative-breast-cancers
#14
Luxi Chen, Yi Yuan, Shreya Kar, Madhu M Kanchi, Suruchi Arora, Ji E Kim, Pei F Koh, Einas Yousef, Ramar P Samy, Muthu K Shanmugam, Tuan Z Tan, Sung W Shin, Frank Arfuso, Han M Shen, Henry Yang, Boon C Goh, Joo I Park, Louis Gaboury, Peter E Lobie, Gautam Sethi, Lina Hk Lim, Alan P Kumar
Metastatic breast cancer is still remain incurable so far, new specifically targeted and more effective therapies for triple negative breast cancer (TNBC) are required in the clinic. In this study, our clinical data has established that basal and claudin-low subtypes of breast cancer (TNBC types) express significantly higher levels of Annexin A1 (ANXA1) with poor survival outcomes. Using human cancer cell lines which model the TNBC subtype, we observed a strong positive correlation between expression of ANXA1 and Peroxisome Proliferator-Activated Receptor gamma (PPARγ)...
August 15, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28811194/immunogenetic-studies-of-the-hepatitis-c-virus-infection-in-an-era-of-pan-genotype-antiviral-therapies-effective-treatment-is-coming
#15
Joel Henrique Ellwanger, Valéria de Lima Kaminski, Jacqueline Maria Valverde-Villegas, Daniel Simon, Vagner Ricardo Lunge, José Artur Bogo Chies
What are the factors that influence human hepatitis C virus (HCV) infection, hepatitis status establishment, and disease progression? Firstly, one has to consider the genetic background of the host and HCV genotypes. The immunogenetic host profile will reflect how each infected individual deals with infection. Secondly, there are environmental factors that drive susceptibility or resistance to certain viral strains. These will dictate (I) the susceptibility to infection; (II) whether or not an infected person will promote viral clearance; (III) the immune response and the response profile to therapy; and (IV) whether and how long it would take to the development of HCV-associated diseases, as well as their severity...
August 12, 2017: Infection, Genetics and Evolution
https://www.readbyqxmd.com/read/28810711/whole-rna-sequencing-and-transcriptome-assembly-of-candida-albicans-and-candida-africana-under-chlamydospore-inducing-conditions
#16
Domenico Giosa, Maria Rosa Felice, Travis J Lawrence, Megha Gulati, Fabio Scordino, Letterio Giuffrè, Carla Lo Passo, Enrico D'Alessandro, Giuseppe Criseo, David H Ardell, Aaron D Hernday, Clarissa J Nobile, Orazio Romeo
Candida albicans is the most common cause of life-threatening fungal infections in humans, especially in immunocompromised individuals. Crucial to its success as an opportunistic pathogen is the considerable dynamism of its genome, which readily undergoes genetic changes generating new phenotypes and shaping the evolution of new strains. Candida africana is an intriguing C. albicans biovariant strain that exhibits remarkable genetic and phenotypic differences when compared with standard C. albicans isolates...
July 1, 2017: Genome Biology and Evolution
https://www.readbyqxmd.com/read/28809472/real-time-tracking-the-synthesis-and-degradation-of-albumin-in-complex-biological-systems-with-a-near-infrared-fluorescent-probe
#17
Qiang Jin, Lei Feng, Shui-Jun Zhang, Dan-Dan Wang, Fangjun Wang, Yi Zhang, Jing-Nan Cui, Wen-Zhi Guo, Guang-Bo Ge, Ling Yang
In this study, a novel fluorescent detection system for biological sensing of human albumin (HA) was developed on the basis of the pseudo-esterase activity and substrate preference of HA. The designed near-infrared (NIR) fluorescent probe (DDAP) could be effectively hydrolyzed by HA, accompanied with significant changes in both colour and fluorescence spectrum. The sensing mechanism was fully investigated by fluorescence spectroscopy, NMR and mass spectra. DDAP exhibited excellent selectivity and sensitivity toward HA over a variety of human plasma proteins, hydrolases, and abundant biomolecules found in human body...
August 15, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28809115/an-intuitive-approach-for-predicting-potential-human-health-risk-with-the-tox21-10k-library
#18
Nisha S Sipes, John F Wambaugh, Robert Pearce, Scott S Auerbach, Barbara Anne Wetmore, Jui-Hua Hsieh, Andrew J Shapiro, Daniel Svoboda, Michael J DeVito, Stephen S Ferguson
In vitro-in vivo extrapolation (IVIVE) analyses translating high-throughput screening (HTS) data to human relevance have been limited. This study represents the first report applying IVIVE approaches and exposure comparisons using the entirety of the Tox21 federal collaboration chemical screening data, incorporating assay response efficacy and quality of concentration-response fits, and providing quantitative anchoring to first address the likelihood of human in vivo interactions with Tox21 compounds. This likelihood was assessed using a maximum blood concentration to in vitro response ratio approach (Cmax/AC50), analogous to decision-making methods for clinical drug-drug interactions...
August 15, 2017: Environmental Science & Technology
https://www.readbyqxmd.com/read/28808818/first-in-human-study-of-the-epichaperome-inhibitor-pu-h71-clinical-results-and-metabolic-profile
#19
Giovanna Speranza, Larry Anderson, Alice P Chen, Khanh Do, Michelle Eugeni, Marcie Weil, Larry Rubinstein, Eva Majerova, Jerry Collins, Yvonne Horneffer, Lamin Juwara, Jennifer Zlott, Rachel Bishop, Barbara A Conley, Howard Streicher, Joseph Tomaszewski, James H Doroshow, Shivaani Kummar
Background Molecular chaperone targeting has shown promise as a therapeutic approach in human cancers of various histologies and genetic backgrounds. The purine-scaffold inhibitor PU-H71 (NSC 750424), selective for Hsp90 in epichaperome networks, has demonstrated antitumor activity in multiple preclinical cancer models. The present study was a first in-human trial of PU-H71 aimed at establishing its safety and tolerability and characterizing its pharmacokinetic (PK) profile on a weekly administration schedule in human subjects with solid tumors refractory to standard treatments...
August 12, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28807605/adjuvant-hpv-vaccination-for-anal-cancer-prevention-in-hiv-positive-men-who-have-sex-with-men-the-time-is-now
#20
Ashish A Deshmukh, Scott B Cantor, Elisabeth Fenwick, Elizabeth Y Chiao, Alan G Nyitray, Elizabeth A Stier, Stephen E Goldstone, Timothy Wilkin, Jagpreet Chhatwal
IMPORTANCE: Outcomes of treating high-grade squamous intraepithelial lesions (HSIL), a precursor to anal cancer, remain uncertain. Emerging evidence shows that post HSIL treatment adjuvant quadrivalent human papillomavirus (qHPV) vaccination improves the effectiveness of treatment. However, no recommendations exist regarding the use of qHPV vaccine as an adjuvant form of therapy. Our objective was to determine whether post-treatment adjuvant vaccination should be adopted in HIV-infected MSM (individuals at highest risk for anal cancer) on the basis of cost-effectiveness determined using existing evidence or whether future research is needed...
August 11, 2017: Vaccine
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