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Maiko Nomoto, Jim Ferry, Ziad Hussein
Avatrombopag, a c-Mpl agonist, has been developed to provide an alternative therapy to standard platelet transfusion care for the treatment of thrombocytopenia. The main objectives of this article were to describe the pharmacokinetics (PK) of avatrombopag, to characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship between plasma avatrombopag concentrations and platelet count, and to identify potential intrinsic and extrinsic factors affecting PK or PK/PD in patients with chronic liver disease (CLD)...
June 15, 2018: Journal of Clinical Pharmacology
Mangala Rao, Sayali Onkar, Kristina K Peachman, Yohann White, Hung V Trinh, Ousman Jobe, Yingjun Zhou, Peter Dawson, Michael A Eller, Gary R Matyas, Carl R Alving
Background: In the RV144 trial, HIV-1 gp120 V1V2 antibodies correlated inversely with risk of HIV-1 infection; however the titers waned quickly. We hypothesized that a more potent adjuvant might enhance the magnitude and durability of V1V2 antibodies. Methods: We examined archived sera from a phase I randomized, double blind placebo-controlled trial, conducted in HIV-1 uninfected individuals, vaccinated with HIV-1SF-2 rgp120 either adsorbed to aluminum hydroxide (aluminum hydroxide arm) or encapsulated in liposomes containing monophosphoryl lipid A (MPL®) and then adsorbed to aluminum hydroxide (liposomal arm)...
June 9, 2018: Journal of Infectious Diseases
Hideki Miyachi, James W Reinhardt, Satoru Otsuru, Shuhei Tara, Hidetaka Nakayama, Tai Yi, Yong-Ung Lee, Shinka Miyamoto, Toshihiro Shoji, Tadahisa Sugiura, Christopher K Breuer, Toshiharu Shinoka
BACKGROUND: Acute thrombosis is a crucial cause of bioresorbable vascular graft (BVG) failure. Bone marrow-derived mononuclear cell (BM-MNC)-seeded BVGs demonstrated high graft patency, however, the effect of seeded BM-MNCs against thrombosis remains to be elucidated. Thus, we evaluated an antithrombotic effect of BM-MNC-seeding and utilized platelet-depletion mouse models to evaluate the contribution of platelets to acute thrombosis of BVGs. METHODS AND RESULTS: BVGs were composed of poly(glycolic acid) mesh sealed with poly(l-lactideco-ε-caprolactone)...
September 1, 2018: International Journal of Cardiology
Eun-Ju Ko, Youri Lee, Young-Tae Lee, Yu-Jin Kim, Ki-Hye Kim, Sang-Moo Kang
Annual vaccination is not effective in conferring cross-protection against antigenically different influenza viruses. Therefore, it is of high priority to improve the cross protective efficacy of influenza vaccines. We investigated the adjuvant effects of monophosphoryl lipid A (MPL) and oligodeoxynucleotide CpG (CpG) on promoting homologous protection and cross-protection after vaccination of C57BL/6 and BALB/c mice with inactivated split virus. Combination adjuvant effects of MPL and CpG on improving homologous and cross protective vaccine efficacy were evident as shown by higher levels of homologous and cross-reactive binding IgG and hemagglutination inhibiting antibodies...
June 6, 2018: Antiviral Research
Rushit N Lodaya, Luis A Brito, Tom Y H Wu, Andrew T Miller, Gillis R Otten, Manmohan Singh, Derek T O'Hagan
Adjuvants are required to enhance immune responses to typically poorly immunogenic recombinant antigens. Toll like receptor agonists (TLRa) have been widely evaluated as adjuvants, since they activate the innate immune system. Currently, licensed vaccines adjuvanted with TLRa include the TLR4 agonist Monophosphoryl Lipid (MPL), while additional TLRa are in clinical development. Unfortunately, naturally derived TLRa are often complex and heterogeneous entities, which brings formulation challenges. Consequently, the use of synthetic small molecule TLRa has significant advantages, since they are well-defined discreet molecules, which can be chemically modified to modulate their physicochemical properties...
June 5, 2018: Journal of Pharmaceutical Sciences
M V Bor, I-L Søtang Jacobsen, J B Gram, J J Sidelmann
Background Phadia/EliA fluorescence enzyme immunoassays are widely used automated assays for anticardiolipin (aCL) and anti-β2-glycoprotein I (aβ2GPI) antibodies. To date, cut-off values for these assays have not been evaluated systematically and the evidence behind manufacturer's recommended cut-off values is not clear. Objective To determine Phadia/EliA cut-off values for antiphospholipid antibodies (aPL) according to the procedures suggested by guidelines. Methods A total of 266 blood donors (135 females and 131 males) were included...
January 1, 2018: Lupus
Karina Calvopiña, Matthew B Avison
The hyperproduction of chromosomally encoded β-lactamases is a key method of acquired resistance to ceftazidime, aztreonam, and when seen in backgrounds having reduced envelope permeability, carbapenems. Here we show that loss of Mpl, a UDP-muramic acid/peptide ligase, is a common and previously overlooked cause of chromosomally encoded β-lactamase hyperproduction in clinical isolates of Stenotrophomonas maltophilia and Pseudomonas aeruginosa , important pathogens notorious for their β-lactam resistant phenotypes...
May 29, 2018: Antimicrobial Agents and Chemotherapy
Giuseppe Del Giudice, Rino Rappuoli, Arnaud M Didierlaurent
After decades of slow progress, the last years have seen a rapid acceleration of the development of adjuvanted vaccines which have lately been approved for human use. These adjuvants consist of different components, e.g. aluminium salts, emulsions such as MF59 and AS03, Toll-like receptor (TLR) agonists (CpG ormonophosphoryl lipid A (MPL) adsorbed on aluminium salts as in AS04) or combination of immunopotentiators (QS-21 and MPL in AS01). Despite their distinctive features, most of these adjuvants share some key characteristics...
May 22, 2018: Seminars in Immunology
Miao Xu, June Li, Miguel Antonio Dias Neves, Guangheng Zhu, Naadiya Carrim, Ruoying Yu, Sahil Gupta, John Marshall, Ori Rotstein, Jun Peng, Ming Hou, Shinji Kunishima, Jerry Ware, Donald R Branch, Alan Lazarus, Zaverio M Ruggeri, John Freedman, Heyu Ni
Thrombopoietin (TPO), a hematopoietic growth factor produced predominately by the liver is essential for thrombopoiesis. Prevailing theory posits circulating TPO levels are maintained through its clearance by platelets and megakaryocytes via surface c-Mpl receptor internalization. Interestingly, we found in GPIbα-/- mice, a 2-3-fold decrease in circulating TPO compared to wild-type (WT) controls, which was consistent in GPIbα-deficient human Bernard-Soulier Syndrome (BSS) patients. We showed that lower TPO levels in GPIbα-deficient conditions was not due to increased TPO clearance by GPIbα-/- platelets, but rather through decreased hepatic TPO mRNA transcription and production...
May 24, 2018: Blood
Scott M Baliban, Brittany Curtis, Deanna Toema, Sharon M Tennant, Myron M Levine, Marcela F Pasetti, Raphael Simon
In sub-Saharan Africa, invasive nontyphoidal Salmonella (iNTS) infections with serovars S. Enteritidis, S. Typhimurium and I 4,[5],12:i:- are widespread in children < 5 years old. Development of an efficacious vaccine would provide an important public health tool to prevent iNTS disease in this population. Glycoconjugates of S. Enteritidis core and O-polysaccharide (COPS) coupled to the homologous serovar phase 1 flagellin protein (FliC) were previously shown to be immunogenic and protected adult mice against death following challenge with a virulent Malian S...
May 23, 2018: PLoS Neglected Tropical Diseases
Usha Gutti, Jaswant Kumar Komati, Aneesh Kotipalli, Raja Gopal Venakata Saladi, Ravi Kumar Gutti
BACKGROUND: Hepatoprotective activity along with improved survival percentage and hematological parameters prior to whole body irradiation were reported with Justicia adhatoda extracts. PURPOSE: To evaluate the thrombopoietic potential of Justicia adhatoda L. leaf extract in megakaryocyte differentiation METHODS: Ethanol extracts were prepared using soxhlet extraction method, and IC50 value was determined. The effect of ethanol extracts obtained from Justicia adhatoda on megakaryocyte maturation and development in megakaryocytic Dami cell lines was tested...
April 1, 2018: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Hiraku Takei, Yoko Edahiro, Shuichi Mano, Nami Masubuchi, Yoshihisa Mizukami, Misa Imai, Soji Morishita, Kyohei Misawa, Tomonori Ochiai, Satoshi Tsuneda, Hiroshi Endo, Sou Nakamura, Koji Eto, Akimichi Ohsaka, Marito Araki, Norio Komatsu
Somatic mutations in the calreticulin (CALR) gene have been found in most patients with JAK2- and MPL-unmutated Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). It has recently been shown that mutant CALR constitutively activates the thrombopoietin receptor MPL and, thus, plays a causal role in the development of MPNs. However, the roles of mutant CALR in human haematopoietic cell differentiation remain predominantly elusive. To examine the impact of the 5-base insertion mutant CALR gene (Ins5) on haematopoietic cell differentiation, we generated induced pluripotent stem cells from an essential thrombocythaemia (ET) patient harbouring a CALR-Ins5 mutation and from a healthy individual (WT)...
May 9, 2018: British Journal of Haematology
Jennifer M O'Sullivan, Claire N Harrison
Myelofibrosis is one of the BCR-ABL-negative clonal disorders that collectively are known as myeloproliferative neoplasms (MPNs). It is caused by the proliferation of clonal hematopoietic stem cells, which over time leads to characteristic clinical features. The disease presentation is heterogeneous, however, with 30% of patients initially asymptomatic. This variation in clinical phenotype warrants careful risk stratification to guide appropriate management, and prognostic risk scores are continually being refined...
February 2018: Clinical Advances in Hematology & Oncology: H&O
Andrés I Tkachenko-Bril, Harald Jagoš, Veronika David, Katharina Pils, Jakob Gaudernak, Dietmar Rafolt
BACKGROUND: Patient compliance with lower limb partial weight bearing (PWB) instructions during post-surgical early mobilization is often low and many are unable to adhere to the prescribed limits without the implementation of concurrent biofeedback. OBJECTIVES: A real-time feedback system based on eSHOE instrumented insoles was tested in order to preliminarily quantify its efficiency at improving geriatric patients' compliance. METHODS: In order to gain a proof of concept, measurements with one patient after a hip fracture were carried out...
2018: Studies in Health Technology and Informatics
Yan-Bo Nie, Meng Sun, Colin K He, Man-Kai Ju, Fu-Ling Zhou, San-Yun Wu, Yi Zhou, Li Liu, Hui Shen, Ting-Ting Huang, Pan Liu, Ying Xu, Liang Shao, Xue-Lan Zuo
Essential thrombocythemia (ET) is characterized by thrombotic and hemorrhagic events. The association of clinical characteristics of Chinese ET patients and additional sex combs like 1 (ASXL1) mutations in these patients has remained to be elucidated. In the present study, 72 newly diagnosed Chinese ET patients were enrolled to determine ASXL1 mutations. Mutations in ASXL1, Janus kinase (JAK)2, calreticulin (CALR) and myeloproliferative leukemia (MPL) genes were detected using Sanger sequencing, and data were statistically analyzed...
May 2018: Experimental and Therapeutic Medicine
Yimeng Song, Bo Huang, Jixuan Cai, Bin Chen
A growing body of evidence has proven that urban greenspace is beneficial to improve people's physical and mental health. However, knowledge of population exposure to urban greenspace across different spatiotemporal scales remains unclear. Moreover, the majority of existing environmental assessments are unable to quantify how residents enjoy their ambient greenspace during their daily life. To deal with this challenge, we proposed a dynamic method to assess urban greenspace exposure with the integration of mobile-phone locating-request (MPL) data and high-spatial-resolution remote sensing images...
April 13, 2018: Science of the Total Environment
Satoru Monzen, Shunta Kimura, Masaru Yamaguchi, Ikuo Kashiwakura
A thrombopoiesis-stimulating protein, the myeloproliferative leukemia virus protooncogene (Mpl) ligand romiplostim (RP), is currently approved as a therapeutic agent for idiopathic thrombocytopenic purpura in many countries. Although the action of the initial MPL ligand thrombopoietin (TPO) on human megakaryocytic regeneration from irradiated human hematopoietic stem cells has been examined, there are few reports on the action of RP. In the present study, freshly prepared nonirradiated and 2-Gy X-irradiated human CD34 positive (CD34+ ) cells from placental umbilical cord blood were cultured with a combination of RP and various cytokines...
April 30, 2018: Journal of Interferon & Cytokine Research
Vivaswath S Ayyar, Siddharth Sukumaran, Debra C DuBois, Richard R Almon, Jun Qu, William J Jusko
A multiscale pharmacodynamic model was developed to characterize the receptor-mediated, transcriptomic, and proteomic determinants of corticosteroid (CS) effects on clinically relevant hepatic processes following a single dose of methylprednisolone (MPL) given to adrenalectomized (ADX) rats. The enhancement of tyrosine aminotransferase (TAT) mRNA, protein, and enzyme activity were simultaneously described. Mechanisms related to the effects of MPL on glucose homeostasis, including the regulation of CCAAT-enhancer binding protein-beta (C/EBPβ) and phosphoenolpyruvate carboxykinase (PEPCK) as well as insulin dynamics were evaluated...
April 27, 2018: Journal of Pharmacokinetics and Pharmacodynamics
Farzad Khademi, Ramezan Ali Taheri, Amir Abbas Momtazi-Borojeni, Gholamreza Farnoosh, Thomas P Johnston, Amirhossein Sahebkar
The weakness of the BCG vaccine and its highly variable protective efficacy in controlling tuberculosis (TB) in different age groups as well as in different geographic areas has led to intense efforts towards the development and design of novel vaccines. Currently, there are several strategies to develop novel TB vaccines. Each strategy has its advantages and disadvantages. However, the most important of these strategies is the development of subunit vaccines. In recent years, the use of cationic liposome-based vaccines has been considered due to their capacity to elicit strong humoral and cellular immune responses against TB infections...
April 27, 2018: Reviews of Physiology, Biochemistry and Pharmacology
Jiyong Wang, Emre Gürdal, Anke Horneber, Simon Dickreuter, Sergei Kostcheev, Alfred J Meixner, Monika Fleischer, Pierre-Michel Adam, Dai Zhang
We systematically investigate the metallic photoluminescence (MPL) emitted from plasmonic nanoparticles (NPs) upon excitation with ultrafast laser pulses using a scanning confocal optical microscope (SCOM). By comparing the emission spectra of Au NPs of varying dimensions with the corresponding dark-field scattering spectra, indications are found that MPL encompasses two emission channels: the particle plasmons (PPs) and the electron-hole (e-h) pair recombination. The plasmons can be interpreted to play a twofold role: in the excitation process they provide the local field enhancement, and in the emission process they offer extra radiation channels...
May 3, 2018: Nanoscale
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