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https://www.readbyqxmd.com/read/28339166/pharmacokinetics-pharmacodynamics-pharmacogenomics-safety-and-tolerability-of-avatrombopag-in-healthy-japanese-and-white-subjects
#1
Maiko Nomoto, Gina Pastino, Bhaskar Rege, Jagadeesh Aluri, Jim Ferry, David Han
Avatrombopag, an orally administered, small-molecule thrombopoietin receptor (c-Mpl) agonist, is currently in clinical development for the potential treatment of severe thrombocytopenia in patients with chronic liver disease undergoing an elective procedure. The objectives of this study were to characterize and compare the pharmacokinetics (including the food effect) and pharmacodynamics (platelet count) of avatrombopag following single doses in Japanese and white subjects. Following single dosing under fasted and fed conditions, mean peak concentrations occurred at 5 to 8 hours and subsequently declined with a half-life of 16 to 18 hours in Japanese and white subjects...
March 24, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28335073/clinical-characteristics-and-whole-exome-transcriptome-sequencing-of-coexisting-chronic-myeloid-leukemia-and-myelofibrosis
#2
Malathi Kandarpa, Yi-Mi Wu, Dan Robinson, Patrick William Burke, Arul M Chinnaiyan, Moshe Talpaz
Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell (HSC) disorders that can be classified on the basis of genetic, clinical, phenotypic features. Genetic lesions such as JAK2 mutations and BCR-ABL translocation are often mutually exclusive in MPN patients and lead to essential thrombocythemia, polycythemia vera or myelofibrosis (ET/PV/MF) or chronic myeloid leukemia, respectively. Nevertheless, coexistence of these genetic aberrations in the same patient has been reported. Whether these aberrations occur in the same stem cell or a different cell is unclear, but an unstable genome in the HSCs seems to be the common antecedent...
March 23, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28332377/hb-heathrow-%C3%AE-103-g5-phe%C3%A2-leu-a-first-report-in-an-asian-patient-with-erythrocytosis
#3
Sang Yong Shin, Hyun Young Kim, Hee Jin Kim, Hoon Gu Kim
Congenital erythrocytosis (CE) is a rare and heterogeneous disease. The high oxygen affinity hemoglobin (Hb) variants are the most common cause of CE. Herein, we report a Korean patient with isolated erythrocytosis. A 25-year-old man was referred to our hospital for evaluation of high Hb level (Hb 20.4 g/dL, hematocrit 58%, reticulocyte count 2.90%, white blood cell count 6.83×10⁹/L, and platelet count 195×10⁹/L). Bone marrow biopsy revealed normocellular marrow without myeloproliferative features. JAK2 (V617F, exon 12), CALR (exon 9), and MPL W515K/L mutations were not detected...
May 2017: Yonsei Medical Journal
https://www.readbyqxmd.com/read/28321217/a-vaccine-therapy-for-canine-visceral-leishmaniasis-promoted-significant-improvement-of-clinical-and-immune-status-with-reduction-in-parasite-burden
#4
Bruno Mendes Roatt, Rodrigo Dian de Oliveira Aguiar-Soares, Levi Eduardo Soares Reis, Jamille Mirelle de Oliveira Cardoso, Fernando Augusto Siqueira Mathias, Rory Cristiane Fortes de Brito, Sydnei Magno da Silva, Nelder De Figueiredo Gontijo, Sidney de Almeida Ferreira, Jesus G Valenzuela, Rodrigo Corrêa-Oliveira, Rodolfo Cordeiro Giunchetti, Alexandre Barbosa Reis
Herein, we evaluated the treatment strategy employing a therapeutic heterologous vaccine composed of antigens of Leishmania braziliensis associated with MPL adjuvant (LBMPL vaccine) for visceral leishmaniasis (VL) in symptomatic dogs naturally infected by Leishmania infantum. Sixteen dogs received immunotherapy with MPL adjuvant (n = 6) or with a vaccine composed of antigens of L. braziliensis associated with MPL (LBMPL vaccine therapy, n = 10). Dogs were submitted to an immunotherapeutic scheme consisting of 3 series composed of 10 subcutaneous doses with 10-day interval between each series...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28315483/functional-proteomic-analysis-of-corticosteroid-pharmacodynamics-in-rat-liver-relationship-to-hepatic-stress-signaling-energy-regulation-and-drug-metabolism
#5
Vivaswath S Ayyar, Richard R Almon, Debra C DuBois, Siddharth Sukumaran, Jun Qu, William J Jusko
Corticosteroids (CS) are anti-inflammatory agents that cause extensive pharmacogenomic and proteomic changes in multiple tissues. An understanding of the proteome-wide effects of CS in liver and its relationships to altered hepatic and systemic physiology remains incomplete. Here, we report the application of a functional pharmacoproteomic approach to gain integrated insight into the complex nature of CS responses in liver in vivo. An in-depth functional analysis was performed using rich pharmacodynamic (temporal-based) proteomic data measured over 66h in rat liver following a single dose of methylprednisolone (MPL)...
March 14, 2017: Journal of Proteomics
https://www.readbyqxmd.com/read/28289389/understanding-physiology-in-the-continuum-integration-of-information-from-multiple-omics-levels
#6
Kubra Kamisoglu, Alison Acevedo, Richard R Almon, Susette Coyle, Siobhan Corbett, Debra C Dubois, Tung T Nguyen, William J Jusko, Ioannis P Androulakis
In this paper, we discuss approaches for integrating biological information reflecting diverse physiologic levels. In particular, we explore statistical and model-based methods for integrating transcriptomic, proteomic and metabolomics data. Our case studies reflect responses to a systemic inflammatory stimulus and in response to an anti-inflammatory treatment. Our paper serves partly as a review of existing methods and partly as a means to demonstrate, using case studies related to human endotoxemia and response to methylprednisolone (MPL) treatment, how specific questions may require specific methods, thus emphasizing the non-uniqueness of the approaches...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28281740/comparison-of-laparoendoscopic-single-site-less-and-multiport-laparoscopic-radical-nephrectomy-for-clinical-t1b-and-t2a-renal-masses
#7
Abd-El R Hassan, Omer A Raheem, Sean Berquist, Alp T Beksac, Aaron Bloch, Charles Field, Hak J Lee, Reza Mehrazin, Marc Holden, Michelle McDONALD, Zachary Hamilton, Michael Liss, Ithaar H Derweesh
BACKGROUND: To compare outcomes of Laparoendoscopic single-site surgery (LESS) and multiport laparoscopic (MPL) Radical Nephrectomy (RN) for clinical T1b/T2a renal masses, as concerns continue regarding suitability and benefit of LESS for larger renal masses. METHODS: Retrospective single-surgeon comparison of LESS- and MPL-RN between 7/2005 and 11/2014. 63 patients underwent LESS-RN (44 cT1b/19 cT2a); 133 underwent MPL (83 cT1b/50 cT2a). All patients were managed with a standardized care pathway...
March 10, 2017: Minerva Urologica e Nefrologica, the Italian Journal of Urology and Nephrology
https://www.readbyqxmd.com/read/28273188/-treatment-options-and-limitations-in-the-management-of-myelofibrosis
#8
Gábor Körösmezey, Gabriella Gyõri, Gábor Rudas, Hanna Eid, Zsolt Nagy, Judit Demeter
Primary myelofibrosis has the worst outcome among classical chronic myeloproliferative neoplasms. The past decade has brought numerous discoveries elucidating the role of proliferative mutations in disease pathogenesis. Mutations of the genes JAK2, MPL and CALR are present in about 90 percent of all primary myelofibrosis cases. The prognosis of myelofibrosis is considered heterogeneous, the expected survival of patients may range from one year to more than a decade based on several prognostic factors. Estimated survival can be assessed based on clinical prognostic scores...
March 8, 2017: Magyar Onkologia
https://www.readbyqxmd.com/read/28273187/-the-role-of-driver-and-subclonal-mutations-in-pathogenesis-of-primary-myelofibrosis
#9
Réka Mózes, Ambrus Gángó, Zsófia Boha, Judit Csomor, Csaba Bödör
Primary myelofibrosis (PMF) is a Philadelphia chromosome negative, clonal myeloproliferative neoplasm characterised by a progressive nature. Morphologically, the bone marrow biopsy shows features of abnormal proliferation of terminally differentiated megakaryocytes and subsequent bone marrow fibrosis. The molecular landscape of PMF includes phenotypic driver mutations (JAK2 V617F, CALR and MPL) which represent major diagnostic criteria, and subclonal mutations that also occur in several other myeloid diseases, but have a prognostic value in disease progression of MF...
March 8, 2017: Magyar Onkologia
https://www.readbyqxmd.com/read/28258153/rationalized-design-of-a-mucosal-vaccine-protects-against-mycobacterium-tuberculosis-challenge-in-mice
#10
Mushtaq Ahmed, Hongmei Jiao, Racquel Domingo-Gonzalez, Shibali Das, Kristin L Griffiths, Javier Rangel-Moreno, Uma M Nagarajan, Shabaana A Khader
Pulmonary tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is a leading cause of global morbidity and mortality. The only licensed TB vaccine, Mycobacterium bovis bacillus Calmette-Guerin (BCG), has variable efficacy in protecting against pulmonary TB. Thus, the development of more effective TB vaccines is critical to control the TB epidemic. Specifically, vaccines delivered through the mucosal route are known to induce Th17 responses and provide superior protection against Mtb infection. However, already tested Th17-inducing mucosal adjuvants, such as heat-labile enterotoxins and cholera toxins, are not considered safe for use in humans...
March 3, 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/28255578/neuropil-pruning-in-early-course-schizophrenia-immunological-clinical-and-neurocognitive-correlates
#11
Konasale M Prasad, Ashley M Burgess, Matcheri S Keshavan, Vishwajit L Nimgaonkar, Jeffrey A Stanley
INTRODUCTION: Neuropathological studies suggest neuropil reduction in schizophrenia. Altered synaptic pruning is proposed to underlie neuropil reduction. Underlying factors and clinical correlates of synaptic pruning are poorly understood. Using phosphorus magnetic resonance spectroscopy ((31)P MRS), it is feasible to assess membrane phospholipid (MPL) metabolites in the brain that specifically and sensitively reflect neuropil expansion (elevated MPL precursors) or contraction (elevated MPL catabolites)...
November 2016: Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
https://www.readbyqxmd.com/read/28246554/splanchnic-vein-thrombosis-in-myeloproliferative-neoplasms-pathophysiology-and-molecular-mechanisms-of-disease
#12
REVIEW
Joan How, Amy Zhou, Stephen T Oh
Myeloproliferative neoplasms (MPNs) are the most common underlying prothrombotic disorder found in patients with splanchnic vein thrombosis (SVT). Clinical risk factors for MPN-associated SVTs include younger age, female sex, concomitant hypercoagulable disorders, and the JAK2 V617F mutation. These risk factors are distinct from those associated with arterial or deep venous thrombosis (DVT) in MPN patients, suggesting disparate disease mechanisms. The pathophysiology of SVT is thought to derive from local interactions between activated blood cells and the unique splanchnic endothelial environment...
March 2017: Therapeutic Advances in Hematology
https://www.readbyqxmd.com/read/28245393/-mutation-of-calr-gene-in-patients-with-chronic-myeloproliferative-neoplasm-and-its-clinical-significance
#13
Qin Tang, Xiu-Wen Zhang, Lei Xia, Nai-Ke Jiang
OBJECTIVE: To analyze the CARL gene mutation in the patients with chronic myeloproliferative neoplasm(MPN) and to explore the clinical significance of CALR mutation. METHODS: The peripheral blood of patients was collected and the genomic DNA was exacted, the 9 exon of CALR gene and the fragment of human thrombopoetic receptor(MPL) gene were amplified by PCR, the mutation of CALR and MPL genes was detected by using the direct sequencing, the JAK2 V617F mutation was detected by using allele spicific PCR...
February 2017: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/28235674/thrombopoietin-contributes-to-the-formation-and-the-maintenance-of-hematopoietic-progenitor-containing-cell-clusters-in-the-aorta-gonad-mesonephros-region
#14
Kaho Harada, Ikuo Nobuhisa, Maha Anani, Kiyoka Saito, Tetsuya Taga
In the midgestation mouse embryo, hematopoietic cell clusters containing hematopoietic stem/progenitor cells arise in the aorta-gonad-mesonephros (AGM) region. We have previously reported that forced expression of the Sox17 transcription factor in CD45(low)c-Kit(high) AGM cells, which are the hematopoietic cellular component of the cell clusters, and subsequent coculture with OP9 stromal cells in the presence of three cytokines, stem cell factor (SCF), interleukin-3 (IL-3), and thrombopoietin (TPO), led to the formation and the maintenance of cell clusters with cells at an undifferentiated state in vitro...
February 21, 2017: Cytokine
https://www.readbyqxmd.com/read/28228587/prophylactic-herpes-simplex-virus-2-hsv-2-vaccines-adjuvanted-with-stable-emulsion-and-toll-like-receptor-9-agonist-induce-a-robust-hsv-2-specific-cell-mediated-immune-response-protect-against-symptomatic-disease-and-reduce-the-latent-viral-reservoir
#15
Michael T Hensel, Jason D Marshall, Michael R Dorwart, Darren S Heeke, Eileen Rao, Padmaja Tummala, Li Yu, Gary H Cohen, Roselyn J Eisenberg, Derek D Sloan
Several prophylactic vaccines targeting HSV-2 have failed in the clinic to demonstrate a sustained depression in viral shedding or protection from recurrences. Although these vaccines have generated high titers of neutralizing antibodies, their induction of robust CD8 T cells has largely been unreported, even though evidence for the importance of HSV-2 antigen-specific CD8 T cells is mounting in animal models and in translational studies involving subjects with active HSV-2-specific immune responses. We developed a subunit vaccine composed of the neutralizing antibody (nAb) targets gD and gB, the novel T cell antigen and tegument protein UL40, and we compared this to a whole-inactivated virus vaccine (FI-HSV-2)...
February 22, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28219221/-the-clinical-characteristics-gene-mutations-and-prognosis-of-chronic-neutrophilic-leukemia
#16
Y J Cui, Q Jiang, J Q Liu, B Li, Z F Xu, T J Qin, Y Zhang, W Y Cai, H L Zhang, L W Fang, L J Pan, N B Hu, S Q Qu, Z J Xiao
Objective: To investigate the clinical manifestation, cytogenetics, gene mutations and prognostic factors of chronic neutrophilic leukemia (CNL) . Methods: 16 CNL cases, according to WHO (2016) -definition, were reviewed retrospectively. Identifications of the CSF3R, ASXL1, SETBP1, CALR and MPL mutations were performed by direct sequencing. JAK2 V617F mutation was detected by AS-PCR. Results: Of the 16 CNL patients, the median age was 64 (43-80) years with a male predominance of 75% (12/16) . The median hemoglobin was 114 (81-154) g/L, with median WBC of 41...
January 14, 2017: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/28219062/the-impact-on-allergy-related-cells-of-a-birch-pollen-allergoid-with-and-without-monophosphoryl-lipid-a-in-comparison-with-the-native-equivalent
#17
Margitta Worm, Dennis Ernst, Markus Kraller, Magda Babina
BACKGROUND: The clinical efficacy and safety of allergoid immunotherapy have been demonstrated in clinical trials. However, simultaneous monitoring of the immunological changes by allergoids versus allergens in the cells of the same individual has not been extensively performed, and the impact of concurrent Toll-like receptor 4 (TLR4) ligation has not been specified. METHODS: Three types of birch allergen were utilized: glutaraldehyde-treated allergoid (extract A), the same allergoid plus monophosphoryl lipid A (MPL), i...
2017: International Archives of Allergy and Immunology
https://www.readbyqxmd.com/read/28213022/prevalence-genetic-diversity-and-antimicrobial-resistance-of-listeria-monocytogenes-isolated-from-fresh-and-smoked-fish-in-poland
#18
Kinga Wieczorek, Jacek Osek
A total of 57 out of 301 (18.9%) fresh and smoked fish samples in Poland were positive for Listeria monocytotgenes. The bacteria were most frequently identified in fresh and smoked salmon (32.0% and 33.8% respectively) as well as in fresh cod (31.8%). Only three samples of smoked salmon were contaminated with the bacteria above 100 CFU/g. Four molecular serogroups were identified and the most prevalent, 1/2a-3a (40 isolates; 70.2%), was present in samples from both marine (33 strains; 71.7%) and freshwater fish (7 isolates; 63...
June 2017: Food Microbiology
https://www.readbyqxmd.com/read/28211153/the-prognostic-relevance-of-serum-lactate-dehydrogenase-and-mild-bone-marrow-reticulin-fibrosis-in-essential-thrombocythemia
#19
Mythri Mudireddy, Daniela Barraco, Curtis A Hanson, Animesh Pardanani, Naseema Gangat, Ayalew Tefferi
The 2016 World Health Organization (WHO) diagnostic criteria for myeloproliferative neoplasms (MPN) underscore the prognostically-relevant distinction between essential thrombocythemia (ET) and prefibrotic primary myelofibrosis (pre-PMF). In addition, leukocytosis has been identified as an important prognostic marker in otherwise WHO-defined ET. However, controversy remains regarding the objectivity of morphologic criteria in distinguishing ET from pre-PMF and the precise prognostic cutoff values for leukocytosis...
February 17, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28185911/transcriptome-analysis-of-monozygotic-twin-brothers-with-childhood-primary-myelofibrosis
#20
Nan Ding, Zhaojun Zhang, Wenyu Yang, Lan Ren, Yingchi Zhang, Jingliao Zhang, Zhanqi Li, Peihong Zhang, Xiaofan Zhu, Xiaojuan Chen, Xiangdong Fang
Primary myelofibrosis (PMF) is a chronic myeloproliferative disorder in human bone marrow. Over 50% of patients with myelofibrosis have mutations in JAK2, MPL, or CALR. However, these mutations are rarely detected in children, suggesting a difference in the pathogenesis of childhood PMF. In this study, we investigated the response to drug treatment of a monozygotic twin pair with typical childhood PMF. The twin exhibited different clinical outcomes despite following the same treatment regimen. The transcriptomic profiles of patient samples after drug treatment (E2 and Y2) were significantly different between the twin pair, which is consistent with the observation that the drug treatment was effective only in the younger brother, despite the twin being genetically identical...
February 2017: Genomics, Proteomics & Bioinformatics
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