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https://www.readbyqxmd.com/read/28819248/a-portable-microfluidic-platform-for-rapid-molecular-diagnostic-testing-of-patients-with-myeloproliferative-neoplasms
#1
Hua Wang, Xinju Zhang, Xiao Xu, Qunfeng Zhang, Hengliang Wang, Dong Li, Zhihua Kang, Zhiyuan Wu, Yigui Tang, Zhenhua An, Ming Guan
The ability to simultaneously detect JAK2 V617F and MPL W515K/L mutations would substantially improve the early diagnosis of myeloproliferative neoplasms (MPNs) and decrease the risk of arterial thrombosis. The goal of this study is to achieve a point of care testing platform for simultaneous analysis of major genetic alterations in MPN. Here, we report a microfluidic platform including a glass capillary containing polypropylene matrix that extracts genomic DNA from a drop of whole blood, a microchip for simultaneous multi-gene mutation screening, and a handheld battery-powered heating device...
August 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28782256/risk-factors-and-a-prognostic-model-for-post-splenectomy-survival-in-myelofibrosis
#2
Ayalew Tefferi, Mythri Mudireddy, Naseema Gangat, Curtis A Hanson, Rhett P Ketterling, Animesh Pardanani, David M Nagorney
Palliative treatment in myelofibrosis (MF) includes transfusion support, JAK2 inhibitors, involved field radiotherapy and splenectomy. In order to assist in selecting patients who are likely to benefit from splenectomy, we looked into risk factors for post-splenectomy survival, in 120 consecutive cases (median age 66 years); at the time of splenectomy, 61% displayed red cell transfusion need, 49% platelet count <100 x 10(9)/L, 25% leukocyte count >25 x 10(9)/L, 60% constitutional symptoms and 13% circulating blasts ≥5%; dynamic international prognostic scoring system risk categories were 21% high, 55% intermediate-2, 21% intermediate-1 and 3% low...
August 7, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28767426/human-papillomavirus-16l1-58l2-chimeric-virus-like-particles-elicit-durable-neutralizing-antibody-responses-against-a-broad-spectrum-of-human-papillomavirus-types
#3
Xue Chen, Hongyang Liu, Zhirong Wang, Shuo Wang, Ting Zhang, Meili Hu, Liang Qiao, Xuemei Xu
The neutralizing antibodies elicited by human papillomavirus (HPV) major capsid protein L1 virus-like particle (VLP)-based vaccines are largely type-specific. An HPV vaccine inducing cross-neutralizing antibodies broadly will be cost-effective and of great value. To this end, we constructed HPV16L1-58L2 chimeric VLP (cVLP) by displaying HPV58 L2 aa.16-37 on the DE surface region of HPV16 L1. We found that vaccination with the HPV16L1-58L2 cVLP formulated with alum plus monophosphoryl lipid A (Alum-MPL) adjuvant elicited robust neutralizing antibodies in both mice and rabbits against all tested HPV types including HPV16/31/33/35/52/58 (genus α9), HPV18/39/45/59/68 (genus α7), HPV6/11 (genus α10), HPV2/27/57 (genus α4), and HPV5 (genus β1)...
July 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28751721/evidence-for-a-role-of-trib3-in-the-regulation-of-megakaryocytopoiesis
#4
Lee Butcher, Maninder Ahluwalia, Tiit Örd, Jessica Johnston, Roger H Morris, Endre Kiss-Toth, Tõnis Örd, Jorge D Erusalimsky
Megakaryocytopoiesis is a complex differentiation process driven by the hormone thrombopoietin by which haematopoietic progenitor cells give rise to megakaryocytes, the giant bone marrow cells that in turn break down to form blood platelets. The Tribbles Pseudokinase 3 gene (TRIB3) encodes a pleiotropic protein increasingly implicated in the regulation of cellular differentiation programmes. Previous studies have hinted that TRIB3 could be also involved in megakaryocytopoiesis but its role in this process has so far not been investigated...
July 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28744010/the-jak2v617f-bearing-vascular-niche-promotes-clonal-expansion-in-myeloproliferative-neoplasms
#5
H Zhan, C H S Lin, Y Segal, K Kaushansky
The acquired kinase mutation JAK2V617F plays a central role in myeloproliferative neoplasms (MPNs). However, the mechanisms responsible for the malignant hematopoietic stem/progenitor cell (HSPC) expansion seen in patients with MPNs are not fully understood, limiting the effectiveness of current treatment. Endothelial cells (ECs) are an essential component of the hematopoietic niche, and they have been shown to express the JAK2V617F mutation in patients with MPNs. We show that the JAK2V617F-bearing vascular niche promotes the expansion of the JAK2V617F HSPCs in preference to JAK2WT HSPCs, potentially contributing to poor donor cell engraftment and disease relapse following stem cell transplantation...
July 24, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28741795/a-novel-molecular-mechanism-of-cellular-transformation-via-a-mutant-molecular-chaperone-in-myeloproliferative-neoplasms
#6
REVIEW
Marito Araki, Norio Komatsu
Deregulation of the cytokine-receptor signaling pathway plays a significant role in tumorigenesis. Such deregulation is frequently caused by alterations in the genes involved in the signaling pathway. At the end of 2013, recurrent somatic mutations in the calreticulin (CALR) gene that encodes a molecular chaperone were identified in a subset of patients with Philadelphia-chromosome negative myeloproliferative neoplasms (MPNs). This review focuses on the role of CALR mutations in the oncogenic transformations observed in MPNs...
July 25, 2017: Cancer Science
https://www.readbyqxmd.com/read/28729456/mechanistic-multi-tissue-modeling-of-gilz-regulation-integrating-circadian-gene-expression-with-receptor-mediated-corticosteroid-pharmacodynamics
#7
Vivaswath S Ayyar, Debra C DuBois, Richard R Almon, William J Jusko
The glucocorticoid-induced leucine zipper (GILZ) is an important mediator of anti-inflammatory corticosteroid action. The pharmacokinetic/pharmacodynamic/pharmacogenomic effects of acute and chronic methylprednisolone (MPL) dosing on the tissue-specific dynamics of GILZ expression were examined in rats. A mechanism-based model was developed to investigate and integrate the role of MPL and circadian rhythms on the transcriptional enhancement of GILZ in multiple tissues. Animals received a single 50 mg/kg intramuscular bolus or a seven-day 0...
July 20, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28725653/calr-positive-myeloproliferative-disorder-in-a-patient-with-ph-positive-chronic-myeloid-leukemia-in-durable-treatment-free-remission-a-case-report
#8
Irene Dogliotti, Carmen Fava, Anna Serra, Enrico Gottardi, Filomena Daraio, Francesca Carnuccio, Emilia Giugliano, Monica Bocchia, Giuseppe Saglio, Giovanna Rege-Cambrin
Current diagnostic criteria for Philadelphia-negative myeloproliferative neoplasia (MPN) have been redefined by the discovery of Janus kinase 2 (JAK2), myeloproliferative leukemia (MPL) and calreticulin (CALR) genetic alterations. Only few cases of coexistence of CALR-mutated MPN and Philadelphia-positive chronic myeloid leukemia (CML) have been described so far. Here we report the case of a patient with CML diagnosed in 2001, treated with imatinib and pegylated interferon (IFN) frontline. She reached complete molecular remission (CMR) and discontinued imatinib, maintaining treatment free remission...
2017: Stem Cell Investigation
https://www.readbyqxmd.com/read/28714945/impact-of-molecular-residual-disease-post-allografting-in-myelofibrosis-patients
#9
C Wolschke, A Badbaran, T Zabelina, M Christopeit, F Ayuk, I Triviai, A Zander, H Alchalby, U Bacher, B Fehse, N Kröger
We screened 136 patients with myelofibrosis and a median age of 58 years who underwent allogeneic stem cell transplantation (AHSCT) for molecular residual disease for JAKV617F (n=101), thrombopoietin receptor gene (MPL) (n=4) or calreticulin (CALR) (n=31) mutation in peripheral blood on day +100 and +180 after AHSCT. After a median follow-up of 78 months, the 5-year estimated overall survival was 60% (95% confidence interval (CI): 50-70%) and the cumulative incidence of relapse at 5 years was 26% (95% CI: 18-34%) for the entire study population...
July 17, 2017: Bone Marrow Transplantation
https://www.readbyqxmd.com/read/28711819/differentiation-potential-of-synoviocytes-derived-from-joints-with-cranial-cruciate-ligament-rupture-and-medial-patella-luxation-in-dogs
#10
H M Suranji Wijekoon, Kazuhide Toyota, Sangho Kim, Jing Fang, Eugene C Bwalya, Kenji Hosoya, Masahiro Okumura
The objective of this study was to assess the differentiation capability of synoviocytes derived from dogs with inflammatory joint conditions. Cranial cruciate ligament ruptured (CCLr) (n=12) and medial patella luxated (MPL) (n=10) knee joints of the dogs were used to collect the synovial membrane (SM). Synoviocytes were enzymatically released from the SM and analyzed by flow cytometry for specific cellular markers (CD44 and CD90) of mesenchymal stem cells (MSCs), while doing histopathology from another part of SM sections...
July 9, 2017: Research in Veterinary Science
https://www.readbyqxmd.com/read/28702378/thioredoxin-a-is-essential-for-motility-and-contributes-to-host-infection-of-listeria-monocytogenes-via-redox-interactions
#11
Changyong Cheng, Zhimei Dong, Xiao Han, Hang Wang, Li Jiang, Jing Sun, Yongchun Yang, Tiantian Ma, Chunyan Shao, Xiaodu Wang, Zhongwei Chen, Weihuan Fang, Nancy E Freitag, Huarong Huang, Houhui Song
Microbes employ the thioredoxin system to defend against oxidative stress and ensure correct disulfide bonding to maintain protein function. Listeria monocytogenes has been shown to encode a putative thioredoxin, TrxA, but its biological roles and underlying mechanisms remain unknown. Here, we showed that expression of L. monocytogenes TrxA is significantly induced in bacteria treated with the thiol-specific oxidizing agent, diamide. Deletion of trxA markedly compromised tolerance of the pathogen to diamide, and mainly impaired early stages of infection in human intestinal epithelial Caco-2 cells...
2017: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/28701187/nucdiff-in-depth-characterization-and-annotation-of-differences-between-two-sets-of-dna-sequences
#12
Ksenia Khelik, Karin Lagesen, Geir Kjetil Sandve, Torbjørn Rognes, Alexander Johan Nederbragt
BACKGROUND: Comparing sets of sequences is a situation frequently encountered in bioinformatics, examples being comparing an assembly to a reference genome, or two genomes to each other. The purpose of the comparison is usually to find where the two sets differ, e.g. to find where a subsequence is repeated or deleted, or where insertions have been introduced. Such comparisons can be done using whole-genome alignments. Several tools for making such alignments exist, but none of them 1) provides detailed information about the types and locations of all differences between the two sets of sequences, 2) enables visualisation of alignment results at different levels of detail, and 3) carefully takes genomic repeats into consideration...
July 12, 2017: BMC Bioinformatics
https://www.readbyqxmd.com/read/28697167/congenital-amegakaryocytic-thrombocytopenia-a-case-series-indicating-2-founder-variants-in-the-mississippi-band-of-choctaw-indians
#13
Laura A Newman, Meghan A Luter, Dereck B Davis, Omar A Abdul-Rahman, Juantina M Johnson, Gail C Megason
Congenital amegakaryocytic thrombocytopenia is a rare disorder causing thrombocytopenia that progresses to pancytopenia and bone marrow failure if untreated. It is caused by variants in the MPL gene which encodes the thrombopoeitin receptor. In this report, we review 5 cases of congenital amegakaryocytic thrombocytopenia, all of whom belong to the Mississippi Band of Choctaw Indians. There are 2 common variants in these cases: R90X and R537W. One variant was previously reported only once and had unclear significance at that time...
July 10, 2017: Journal of Pediatric Hematology/oncology
https://www.readbyqxmd.com/read/28690250/simultaneous-determination-of-felodipine-and-metoprolol-in-beagle-dog-plasma-by-online-spe-lc-ms-ms-and-its-application-in-a-pharmacokinetic-study
#14
Meiling Chen, Jiezhao Zhou, Le Mei, Fanglin Yu, Xiangyang Xie, Yan Liu, Yang Yang, Ying Li, Xingguo Mei
In order to overcome deficiencies for simultaneously determining felodipine (FDP) and metoprolol (MPL) with low recovery and low sensitivity, a new online SPE coupled with the liquid chromatography-tandem mass spectrometry (SPE-LC-MS/MS) method for the simultaneous quantitative determination of FDP and MPL in beagle dog plasma was established. The SPE extraction of FDP and MPL was performed on a Retain PEP Javelin column (10 × 2.1 mm, 5 μm), while the chromatographic separation was achieved on a ZORBAX SB-C18 (50 × 2...
2017: Analytical Sciences: the International Journal of the Japan Society for Analytical Chemistry
https://www.readbyqxmd.com/read/28687060/safety-limit-warning-levels-for-the-avoidance-of-excessive-sound-amplification-to-protect-against-further-hearing-loss
#15
Earl E Johnson
OBJECTIVE: To determine safe output sound pressure levels (SPL) for sound amplification devices to preserve hearing sensitivity after usage. DESIGN: A mathematical model consisting of the Modified Power Law (MPL) (Humes & Jesteadt, 1991 ) combined with equations for predicting temporary threshold shift (TTS) and subsequent permanent threshold shift (PTS) (Macrae, 1994b ) was used to determine safe output SPL. STUDY SAMPLE: The study involves no new human subject measurements of loudness tolerance or threshold shifts...
July 7, 2017: International Journal of Audiology
https://www.readbyqxmd.com/read/28677265/epigenetics-in-myeloproliferative-neoplasms
#16
REVIEW
Suzanne McPherson, Mary Frances McMullin, Ken Mills
A decade on from the description of JAK2 V617F, the MPNs are circumscribed by an increasingly intricate landscape. There is now evidence that they are likely the result of combined genetic dysregulation, with several mutated genes involved in the regulation of epigenetic mechanisms. Epigenetic changes are not due to a change in the DNA sequence but are reversible modifications that dictate the way in which genes may be expressed (or silenced). Among the epigenetic mechanisms, DNA methylation is probably the best described...
July 4, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28675510/the-co-regulatory-networks-of-tumor-suppressor-genes-oncogenes-and-mirnas-in-colorectal-cancer
#17
Martha L Slattery, Jennifer S Herrick, Lila E Mullany, Wade S Samowitz, John R Sevens, Lori Sakoda, Roger K Wolff
Tumor suppressor genes (TSGs) and oncogenes (OG) are involved in carcinogenesis. MiRNAs also contribute to cellular pathways leading to cancer. We use data from 217 colorectal cancer (CRC) cases to evaluate differences in TSGs and OGs expression between paired CRC and normal mucosa and evaluate how TSGs and OGs are associated with miRNAs. Gene expression data from RNA-Seq and miRNA expression data from Agilent Human miRNA Microarray V19.0 were used. We focus on genes most strongly associated with CRC (fold change (FC) of ≥1...
July 4, 2017: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/28675499/ultra-short-course-booster-is-effective-in-recurrent-grass-pollen-induced-allergic-rhinitis
#18
O Pfaar, S Lang, U Pieper-Fürst, A Astvatsatourov, F Gerich, L Klimek, M F Kramer, Y Reydelet, K Shah-Hosseini, R Mösges
BACKGROUND: A relevant proportion of allergic rhinitis (AR) patients experience recurrent symptoms after successfully completing allergen immunotherapy (AIT). This prospective, controlled, non-interventional study used internationally standardised instruments to determine the clinical effects of a preseasonal, ultra-short-course booster AIT on clinical outcome parameters. METHODS: This two-arm study included patients aged ≥12 years with recurrent grass pollen-induced seasonal AR who had completed a successful course of any grass pollen AIT at least five years before enrolment...
July 4, 2017: Allergy
https://www.readbyqxmd.com/read/28673392/mechanisms-of-resistance-to-jak2-inhibitors-in-myeloproliferative-neoplasms
#19
REVIEW
Sara C Meyer
Myeloproliferative neoplasms are driven by activated JAK2 signaling due to somatic mutations in JAK2, the thrombopoietin receptor MPL or the chaperone calreticulin in hematopoietic stem/progenitor cells. JAK2 inhibitors have been developed, but despite clinical benefits, they do not signficantly reduce the mutant clone. Loss of response to JAK2 inhibitors occurs and several mechanisms of resistance, genetic and functional, have been identified. Resistance mutations have not been reported in MPN patients suggesting incomplete target inhibition...
August 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/28662951/cd11a-and-cd49d-enhance-the-detection-of-antigen-specific-t-cells-following-human-vaccination
#20
Allison F Christiaansen, Upasna Gaur Dixit, Rhea N Coler, Anna Marie Beckmann, Steven G Reed, Patricia L Winokur, M Bridget Zimmerman, Steven M Varga, Mary E Wilson
BACKGROUND: Determining the efficacy of human vaccines that induce antigen-specific protective CD4 T cell responses against pathogens can be particularly challenging to evaluate. Surface expression of CD11a and CD49d has been shown to identify antigen-specific CD4 T cells against viral pathogens in mice. We hypothesized that CD11a and CD49d would also serve as markers of human antigen-specific T cells responding to vaccination. METHODS: A phase I vaccine trial enabled us to evaluate a novel gating strategy based on surface expression of CD11a and CD49d as a means of detecting antigen-specific, cytokine producing CD4 and CD8 T cells induced after vaccination of naïve individuals against leishmaniasis...
July 24, 2017: Vaccine
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