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https://www.readbyqxmd.com/read/28538171/proliferation-drives-aging-related-functional-decline-in-a-subpopulation-of-the-hematopoietic-stem-cell-compartment
#1
Kristina Kirschner, Tamir Chandra, Vladimir Kiselev, David Flores-Santa Cruz, Iain C Macaulay, Hyun Jun Park, Juan Li, David G Kent, Rupa Kumar, Dean C Pask, Tina L Hamilton, Martin Hemberg, Wolf Reik, Anthony R Green
Aging of the hematopoietic stem cell (HSC) compartment is characterized by lineage bias and reduced stem cell function, the molecular basis of which is largely unknown. Using single-cell transcriptomics, we identified a distinct subpopulation of old HSCs carrying a p53 signature indicative of stem cell decline alongside pro-proliferative JAK/STAT signaling. To investigate the relationship between JAK/STAT and p53 signaling, we challenged HSCs with a constitutively active form of JAK2 (V617F) and observed an expansion of the p53-positive subpopulation in old mice...
May 23, 2017: Cell Reports
https://www.readbyqxmd.com/read/28537924/genetic-defects-of-the-irf1-mediated-major-histocompatibility-complex-class-i-antigen-presentation-pathway-occur-prevalently-in-the-jak2-gene-in-non-small-cell-lung-cancer
#2
Tao Shen, Zhengming Chen, Zhizhuang Joe Zhao, Jie Wu
Recognition of major histocompatibility complex (MHC) class I antigens on tumor cells by cytotoxic T cells is involved in T cell-mediated tumor immune surveillance and immune checkpoint therapy. The interferon-γ (IFNγ)-IRF1 signaling pathway regulates MHC class I antigen presentation. To examine genetic defects of the IFNγ-IRF1 pathway in non-small cell lung cancer (NSCLC), we analyzed The Cancer Genome Atlas (TCGA) lung adenocarcinoma (LuAd) and lung squamous cell carcinoma (LuSc) data. Loss-of-function (LOF) genetic alterations of the IFNγ-IRF1 pathway genes (IFNGR1, IFNGR2, JAK1, JAK2, STAT1, IRF1) were found in 64 (6...
May 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28533538/proteomic-analysis-of-jak2v617f-induced-changes-identifies-potential-new-combinatorial-therapeutic-approaches
#3
S Pearson, A J K Williamson, R Blance, T C P Somervaille, S Taylor, N Azadbakht, A D Whetton, A Pierce
In excess of 90% of patients with polycythemia vera express a mutated form of JAK2, JAK2V617F. Such aberrant proteins offer great potential for the treatment of these diseases however inhibitors to JAK2 have had limited success in the clinic in terms of curing the disease. To understand the effects of this oncogene in hematopoietic cells with the aim of improving treatment strategies we undertook a systematic evaluation of the effects of JAK2V617F expression using proteomics. The effects of JAK2V617F on over 5000 proteins and 2000 nuclear phosphopeptides sites were relatively quantified using either SILAC or eight channel iTRAQ mass spectrometry...
May 23, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28529954/%C3%AE-7-nicotinic-acetylcholine-receptor-stimulation-attenuates-neuroinflammation-through-jak2-stat3-activation-in-murine-models-of-intracerebral-hemorrhage
#4
Paul R Krafft, Devin McBride, William B Rolland, Tim Lekic, Jerry J Flores, John H Zhang
Accounting for high mortality and morbidity rates, intracerebral hemorrhage (ICH) remains one of the most detrimental stroke subtypes lacking a specific therapy. Neuroinflammation contributes to ICH-induced brain injury and is associated with unfavorable outcomes. This study aimed to evaluate whether α7 nicotinic acetylcholine receptor (α7nAChR) stimulation ameliorates neuroinflammation after ICH. Male CD-1 mice and Sprague-Dawley were subjected to intracerebral injection of autologous blood or bacterial collagenase...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28528355/increased-retinol-free-rbp4-contributes-to-insulin-resistance-in-gestational-diabetes-mellitus
#5
Yanmin Chen, Ping Lv, Mengkai Du, Zhaoxia Liang, Menglin Zhou, Danqing Chen
PURPOSE: Retinol-binding protein 4 (RBP4) is a circulating retinol transporter that is strongly associated with insulin resistance. The aim of this study was to evaluate the RBP4 and retinol level in rat model of gestational diabetes mellitus and the relationship between retinol-free RBP4 (apo-RBP4), retinol-bound RBP4 (holo-RBP4) and insulin resistance. METHODS: Pregnant rats were administered streptozotocin to induce diabetes. The RBP4 and retinol levels were evaluated in GDM and normal pregnant rats...
May 20, 2017: Archives of Gynecology and Obstetrics
https://www.readbyqxmd.com/read/28526849/interleukin-22-attenuated-angiotensin-ii-induced-acute-lung-injury-through-inhibiting-the-apoptosis-of-pulmonary-microvascular-endothelial-cells
#6
Zhiyong Wu, Zhipeng Hu, Xin Cai, Wei Ren, Feifeng Dai, Huagang Liu, Jinxing Chang, Bowen Li
Apoptosis of pulmonary microvascular endothelial cells (PMVECs) was considered to be closely related to the pathogenesis of acute lung injury (ALI). We aim to investigate whether IL-22 plays protective roles in lung injury through inhibiting the apoptosis of PMVECs. ALI model was induced through subcutaneous infusion of angiotensin II (Ang II). Lung injury and infiltration of inflammatory cells were evaluated by determining the PaO2/FiO2, calculation of dry to weight ratio in lung, and immunohistochemisty analysis...
May 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28522550/suppression-of-microrna-135b-5pprotects-againstmyocardial-ischemia-reperfusion-injury-by-activatingjak2-stat3-signaling-pathway-in-mice-duringsevofluraneanesthesia
#7
Xiao-Juan Xie, Dong-Mei Fan, Kai Xi, Ya-Wei Chen, Peng-Wei Qi, Qian-Hui Li, Liang Fang, Li-Gang Ma
The study aims to explore the effects of miR-135b-5p on myocardial ischemia/reperfusion (I/R) injuries by regulating JAK2/STAT signaling pathway by mediating inhalation anesthesia with sevoflurane. A sum of 120 healthy Wistar male mice was assigned into six groups. Left ventricular ejection fraction (LVEF) and left ventricular shortening fraction (LVSF) were detected. Cardiomyocyte apoptosis was determined by TUNEL assay. MiR-135b-5p expression, mRNA and protein expression of p-STAT3, p-JAK2, STAT3, JAK2, Bcl2 and Bax were detected by qRT-PCR and Western blotting...
May 18, 2017: Bioscience Reports
https://www.readbyqxmd.com/read/28513614/recurrent-somatic-jak-stat-pathway-variants-within-a-runx1-mutated-pedigree
#8
Kiran Tawana, Jun Wang, Péter A Király, Krisztián Kállay, Gábor Benyó, Marianna Zombori, Judit Csomor, Ahad Al Seraihi, Ana Rio-Machin, András Matolcsy, Claude Chelala, Jamie Cavenagh, Jude Fitzgibbon, Csaba Bödör
Germline variants within the transcription factor RUNX1 are associated with familial platelet disorder and acute leukemia in over 40% of carriers. At present, the somatic events triggering leukemic transformation appear heterogeneous and profiles of leukemia initiation across family members are poorly defined. We report a new RUNX1 family where three sisters harboring a germline nonsense RUNX1 variant, c.601C>T (p.(Arg201*)), developed acute myelomonocytic leukemia (AML) at 5 years of age. Whole-exome sequencing of tumor samples revealed all three siblings independently acquired variants within the JAK-STAT pathway, specifically targeting JAK2 and SH2B3 (a negative regulator of JAK2), while also sharing the 46/1 haplotype linked with sporadic JAK2-positive myeloproliferative neoplasms...
May 17, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28509339/comparison-of-jak2-v617f-positive-essential-thrombocythaemia-and-early-primary-myelofibrosis-the-impact-of-mutation-burden-and-histology
#9
Roberto Latagliata, Nicola Polverelli, Alessia Tieghi, Giuseppe Alberto Palumbo, Massimo Breccia, Elena Sabattini, Loredana Villari, Mara Riminucci, Riccardo Valli, Lucia Catani, Giuliana Alimena, Emanuela Ottaviani, Angelo Fama, Giovanni Martinelli, Margherita Perricone, Marco Spinsanti, Michele Cavo, Nicola Vianelli, Francesca Palandri
An accurate histological diagnosis may distinguish essential thrombocythaemia (ET) from early primary myelofibrosis (early-PMF), which is associated with worse outcome. Outcome of ET is also negatively affected by the presence of the JAK2(V617F) mutation. To investigate the impact of JAK2(V617F) mutation burden and histology on outcome, we collected 475 WHO-diagnosed ET (69.2%) or early-PMF JAK2(V617F) -positive patients followed in 4 Italian haematology centers. JAK2(V617F) allele burden was ≤50% in 90% and 87% of ET and early-PMF patients, respectively (P = ...
May 16, 2017: Hematological Oncology
https://www.readbyqxmd.com/read/28504607/innate-inflammatory-gene-expression-profiling-in-potential-brain-dead-donors-detailed-investigation-of-the-effect-of-common-corticosteroid-therapy
#10
Reza Gholamnezhadjafari, Nader Tajik, Reza Falak, Reza Aflatoonian, Sanaz Dehghan, Abbas Rezaei
Our study aimed to assess the influence of common methylprednisolone therapy on innate inflammatory factors in potential brain-dead organ donors (BDDs). The study groups consisted of 50 potential BDDs who received 15 mg/kg/d methylprednisolone and 25 live organ donors (LDs) as control group. Innate immunity gene expression profiling was performed by RT-PCR array. Soluble serum cytokines and chemokines, complement components, heat shock protein 70 (HSP70) and high mobility group box-1 (HMGB1) were measured by ELISA...
January 1, 2017: Innate Immunity
https://www.readbyqxmd.com/read/28503969/essential-thrombocythemia-a-review-of-the-clinical-features-diagnostic-challenges-and-treatment-modalities-in-the-era-of-molecular-discovery
#11
Sarah Chuzi, Brady L Stein
Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm that is associated with diminished quality of life, thrombohemorrhagic complications, and transformation to myelofibrosis (MF) and acute leukemia (AML). The important recent discoveries of driver mutations, including the calreticulin gene in addition to JAK2 and MPL, have led to a greater understanding of disease pathogenesis and set the stage for the advent of more sophisticated prognostic, diagnostic, and therapeutic strategies. In this paper we summarize recent studies describing the molecular basis of ET...
May 15, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28502479/megakaryocytes-in-myeloproliferative-neoplasms-have-unique-somatic-mutations
#12
Belinda B Guo, Richard J Allcock, Bob Mirzai, Jacques A Malherbe, Fizzah A Choudry, Mattia Frontini, Hun Chuah, James Liang, Simon E Kavanagh, Rebecca Howman, Willem H Ouwehand, Kathryn A Fuller, Wendy N Erber
Myeloproliferative neoplasms (MPNs) are a group of related clonal hemopoietic stem cell disorders associated with hyperproliferation of myeloid cells. They are driven by mutations in the hemopoietic stem cell, most notably JAK2(V617F), CALR, and MPL. Clinically, they have the propensity to progress to myelofibrosis and transform to acute myeloid leukemia. Megakaryocytic hyperplasia with abnormal features are characteristic, and it is thought that these cells stimulate and drive fibrotic progression. The biological defects underpinning this remain to be explained...
May 11, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28501635/determining-the-role-of-inflammation-in-the-selection-of-jak2-mutant-cells-in-myeloproliferative-neoplasms
#13
Jie Zhang, Angela G Fleischman, Dominik Wodarz, Natalia L Komarova
Myeloproliferative neoplasm (MPN) is a hematologic malignancy characterized by the clonal outgrowth of hematopoietic cells with a somatically acquired mutation most commonly in JAK2 (JAK2(V617F)). This mutation endows upon myeloid progenitors cytokine independent growth and consequently leads to excessive production of myeloid lineage cells. It has been previously suggested that inflammation may play a role in the clonal evolution of JAK2(V617F) mutants. In particular, it is possible that one or more cellular kinetic parameters of hematopoietic stem cells (HSCs) are affected by inflammation, such as division or death rates of cells, and the probability of HSC differentiation...
May 10, 2017: Journal of Theoretical Biology
https://www.readbyqxmd.com/read/28500170/jak2-inhibitors-for-myeloproliferative-neoplasms-what-is-next
#14
Prithviraj Bose, Srdan Verstovsek
Since its approval in 2011, the Janus kinase (JAK) 1/2 inhibitor ruxolitinib has evolved to become the centerpiece of therapy for myelofibrosis (MF), and its use in patients with hydroxyurea resistant/intolerant polycythemia vera (PV) is steadily increasing. A number of other JAK2 inhibitors have entered clinical testing, but none has been approved yet, and many discontinued. Importantly, the activity of these agents is not restricted to patients with JAK2 V617F or exon 12 mutations. Although JAK2 inhibitors provide substantial clinical benefit, their disease-modifying activity is limited, and rational combinations with other targeted agents are needed, particularly in MF, where survival is short...
May 12, 2017: Blood
https://www.readbyqxmd.com/read/28499193/stachydrine-ameliorates-isoproterenol-induced-cardiac-hypertrophy-and-fibrosis-by-suppressing-inflammation-and-oxidative-stress-through-inhibiting-nf-%C3%AE%C2%BAb-and-jak-stat-signaling-pathways-in-rats
#15
Lingling Zhao, Dawei Wu, Mengru Sang, Yiming Xu, Zhaoguo Liu, Qinan Wu
Cardiac hypertrophy (CH), as one of the major causes of morbidity and mortality in the world, has become an independent and predictive risk factor for adverse cardiovascular events. However, progress in treatment remains sluggish in recent years. Therefore, compounds derived from non-toxic nature plants are urgently needed. Stachydrine (STA), which is isolated from Leonurus, has various activities, including resistance to cardiovascular disease, but little is known about its effect on CH or the mechanisms. We herein investigated the effect of STA on isoproterenol-induced CH and the underlying mechanisms...
May 9, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28498917/the-new-genomics-what-molecular-databases-can-tell-us-about-human-population-variation-and-endocrine-disease
#16
Peter Rotwein
Major recent advances in genetics and genomics present unique opportunities for enhancing our understanding of human physiology and disease predisposition. Here I demonstrate how analysis of genomic information can provide new understanding of endocrine systems, using the human growth hormone (GH) signaling pathway as an illustrative example. GH is essential for normal postnatal growth in children, and plays important roles in other biological processes throughout life. GH actions are mediated by the GH receptor, primarily via the JAK2 protein tyrosine kinase and the STAT5B transcription factor, and inactivating mutations in this pathway all lead to impaired somatic growth...
May 11, 2017: Endocrinology
https://www.readbyqxmd.com/read/28497580/the-evaluation-of-the-relevance-of-thrombin-generation-and-procoagulant-activity-in-thrombotic-risk-assessment-in-bcr-abl-negative-myeloproliferative-neoplasm-patients
#17
H Baccouche, M Ben Jemaa, A Chakroun, S Chadi, S Mahjoub, I Sfar, Y Gorgi, N Ben Romdhane
INTRODUCTION: It has been recently suggested that microparticles (MP) play a role in the pathogenesis of thrombotic complications. This study aimed to assess the contribution of procoagulant activity expressed by circulating MP in thrombotic events in MPN patients. METHODS: Seventy-four MPN patients were enrolled in a trans-sectional study. The MP procoagulant activity was measured using two assays: (i) the thrombin generation (TG) assay used in different conditions with the addition of both tissue factor (TF) and phospholipids (PL) and with the addition of TF or PL alone and (ii) the PROCOAG-PPL assay...
May 12, 2017: International Journal of Laboratory Hematology
https://www.readbyqxmd.com/read/28495456/crosstalk-between-stat5-activation-and-pi3k-akt-functions-in-normal-and-transformed-mammary-epithelial-cells
#18
REVIEW
Patrick D Rädler, Barbara L Wehde, Kay-Uwe Wagner
Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) have been shown to function downstream of several peptide hormones and cytokines that are required for postnatal development and secretory function of the mammary gland. As part of an extended network, these signal transducers can engage in crosstalk with other pathways to facilitate synergistic, and sometimes antagonistic, actions of different growth factors. Specifically, signaling through the JAK2/STAT5 cascade has been demonstrated to be indispensable for the specification, proliferation, differentiation, and survival of secretory mammary epithelial cells...
May 8, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28495324/biology-of-the-somatotroph-axis-after-the-pituitary
#19
Ron G Rosenfeld, Vivian Hwa
Normal growth requires that pituitary-secreted growth hormone (GH) bind to its specific receptor and activate a complex signaling cascade, leaving to production of insulin-like growth factor-I (IGF-I), which, in turn, activates its own receptor (IGF1R). The GH receptor (GHR) is preformed as a dimer and is transported in a nonligand bound state to the cell surface. Binding of GH to the GHR dimer, results in a conformational change of the dimer, activation of the intracellular Janus Kinase 2 (JAK2) and phosphorylation of signal transducer and activator of transcription (STAT) 5B...
May 8, 2017: Annales D'endocrinologie
https://www.readbyqxmd.com/read/28494868/interferon-receptor-signaling-pathways-regulating-pd-l1-and-pd-l2-expression
#20
Angel Garcia-Diaz, Daniel Sanghoon Shin, Blanca Homet Moreno, Justin Saco, Helena Escuin-Ordinas, Gabriel Abril Rodriguez, Jesse M Zaretsky, Lu Sun, Willy Hugo, Xiaoyan Wang, Giulia Parisi, Cristina Puig Saus, Davis Y Torrejon, Thomas G Graeber, Begonya Comin-Anduix, Siwen Hu-Lieskovan, Robert Damoiseaux, Roger S Lo, Antoni Ribas
PD-L1 and PD-L2 are ligands for the PD-1 immune inhibiting checkpoint that can be induced in tumors by interferon exposure, leading to immune evasion. This process is important for immunotherapy based on PD-1 blockade. We examined the specific molecules involved in interferon-induced signaling that regulates PD-L1 and PD-L2 expression in melanoma cells. These studies revealed that the interferon-gamma-JAK1/JAK2-STAT1/STAT2/STAT3-IRF1 axis primarily regulates PD-L1 expression, with IRF1 binding to its promoter...
May 9, 2017: Cell Reports
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