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https://www.readbyqxmd.com/read/29226168/risks-of-ruxolitinib-in-stat1-gain-of-function-associated-severe-fungal-disease
#1
Ofer Zimmerman, Berenice Rösler, Christa S Zerbe, Lindsey B Rosen, Amy P Hsu, Gulbu Uzel, Alexandra F Freeman, Elizabeth P Sampaio, Sergio D Rosenzwieg, Hye Sun Kuehn, Tiffany Kim, Kristina M Brooks, Parag Kumar, Xiaowen Wang, Mihai G Netea, Frank L van de Veerdonk, Steven M Holland
Heterozygous STAT1 gain-of-function (GOF) mutations are associated with chronic mucocutaneous candidiasis and a broad spectrum of infectious, inflammatory, and vascular manifestations. We describe therapeutic failures with the Janus Kinase (JAK) inhibitor ruxolitinib in 2 STAT1 GOF patients with severe invasive or cutaneous fungal infections.
2017: Open Forum Infectious Diseases
https://www.readbyqxmd.com/read/29225558/vulvar-squamous-cell-carcinoma-aggressiveness-is-associated-with-differential-expression-of-collagen-and-stat1
#2
Emily R Holthoff, Stephanie D Byrum, Samuel G Mackintosh, Thomas Kelly, Alan J Tackett, Charles M Quick, Steven R Post
Background: Vulvar squamous cell carcinoma (vSCC) is a rare but debilitating disease. One vSCC variant comprises tumor cells that grow and expand as a cohesive sheet of cells that "pushes" and compresses the associated lymphoplasmacytic (LPC) stroma. Another vSCC variant features tumor cells that grow in loose association with one another and infiltrate the associated fibromyxoid (FMX) stroma consisting mainly of extracellular matrix. Clinically, infiltrative vSCC with FMX stroma (Inf/FMX) is significantly associated with lymph node metastases and recurrence...
2017: Clinical Proteomics
https://www.readbyqxmd.com/read/29225517/intestinally-restricted-janus-kinase-inhibition-a-potential-approach-to-maximize-the-therapeutic-index-in-inflammatory-bowel-disease-therapy
#3
David T Beattie, M Teresa Pulido-Rios, Fei Shen, Melissa Ho, Eva Situ, Pam R Tsuruda, Patrick Brassil, Melanie Kleinschek, Sharath Hegde
Background: An unmet need remains for safe and effective treatments to induce and maintain remission in inflammatory bowel disease (IBD) patients. The Janus kinase (JAK) inhibitor, tofacitinib, has demonstrated robust efficacy in ulcerative colitis patients although, like other systemic immunosuppressants, there may be safety concerns associated with its use. This preclinical study evaluated whether modulating intestinal inflammation via local JAK inhibition can provide efficacy without systemic immunosuppression...
2017: Journal of Inflammation
https://www.readbyqxmd.com/read/29225170/dihydromyricetin-sensitizes-human-acute-myeloid-leukemia-cells-to-retinoic-acid-induced-myeloid-differentiation-by-activating-stat1
#4
Ming-Hui He, Qiang Zhang, Gang Shu, Ju-Chun Lin, Ling Zhao, Xiao-Xia Liang, Lizi Yin, Fei Shi, Hua-Lin Fu, Zhi-Xiang Yuan
The success of all-trans retinoic acid (ATRA) in differentiation therapy for patients with acute promyelocytic leukemia (APL) highly encourages researches to apply a new combination therapy based on ATRA. Therefore, research strategies to further sensitize cells to retinoids are urgently needed. In this study, we showed that Dihydromyricetin (DMY), a 2,3-dihydroflavonol compound, exhibited a strong synergy with ATRA to promote APL NB4 cell differentiation. We observed that DMY sensitized the NB4 cells to ATRA-induced cell growth inhibition, CD11b expression, NBT reduction and myeloid regulator expression...
December 7, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29221114/interferon-%C3%AF-increases-bola-i-for-implantation-during-early-pregnancy-in-dairy-cows
#5
Zhe Zhu, Binbin Li, Yue Wu, Xiao Wang, GanZhen Deng
Interferon-τ (IFN-τ) signals pregnancy recognition in ruminants. We investigated the effects of IFN-τ produced by embryo trophoblastic cells (ETCs) on expression of bovine leukocyte antigen-I (BoLA-I), a bovine analogue of human MHC-I, in endometrial luminal epithelial cells (EECs) during early pregnancy in dairy cows. Expression of IFN-τ and BoLA-I was increased in endometrial tissues during early pregnancy. Expression of the anti-inflammatory cytokine IL-10 was increased in endometrial tissues, while expression of the pro-inflammatory cytokine IL-6 was decreased, indicating immunosuppression...
November 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29217193/regulation-of-inflammatory-gene-expression-in-macrophages-by-epithelial-stromal-interaction-1-epsti1
#6
Young-Hoon Kim, Jae-Rin Lee, Myong-Joon Hahn
Epithelial-stromal interaction 1 (EPSTI1) was first discovered as a gene induced in breast cancer epithelial cells by co-cultured stromal fibroblasts. There are many reports on the role of Epsti1 in cancer malignancy. Epsti1 is now well known in regulating cancer. Recently, the role of Epsti1 in the immune response has been reported; these reports suggest the role of Epsti1 in immune function, immune privilege, and autoimmune diseases. Furthermore, they show that Epsti1 is expressed in various types of immune cells...
December 4, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29207093/potential-inhibitory-effects-of-the-traditional-herbal-prescription-hyangso-san-against-skin-inflammation-via-inhibition-of-chemokine-production-and-inactivation-of-stat1-in-hacat-keratinocytes
#7
Hye-Sun Lim, Sae-Rom Yo, Mee-Young Lee, Chang-Seob Seo, Hyeun-Kyoo Shin, Soo-Jin Jeong
Inflammatory skin disease are caused by multiple factors, including susceptibility genes, and immunologic and environmental factors, and are characterized by an increase in epidermal thickness and the infiltration of macrophages, keratinocytes, mast cells, eosinophils and other inflammatory cells. Keratinocytes may serve an important role in the pathogenesis of inflammatory skin diseases. The traditional herbal decoction Hyangso‑san (HSS) has been used to treat symptoms of the common cold, including headache, pantalgia, fever and chills...
November 28, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29202461/il-7-dependent-stat1-activation-limits-homeostatic-cd4-t-cell-expansion
#8
Cecile Le Saout, Megan A Luckey, Alejandro V Villarino, Mindy Smith, Rebecca B Hasley, Timothy G Myers, Hiromi Imamichi, Jung-Hyun Park, John J O'Shea, H Clifford Lane, Marta Catalfamo
IL-7 regulates homeostatic mechanisms that maintain the overall size of the T cell pool throughout life. We show that, under steady-state conditions, IL-7 signaling is principally mediated by activation of signal transducers and activators of transcription 5 (STAT5). In contrast, under lymphopenic conditions, there is a modulation of STAT1 expression resulting in an IL-7-dependent STAT1 and STAT5 activation. Consequently, the IL-7-induced transcriptome is altered with enrichment of IFN-stimulated genes (ISGs)...
November 16, 2017: JCI Insight
https://www.readbyqxmd.com/read/29202299/repression-of-interferon-%C3%AE-regulated-cytokines-by-the-jak1-2-inhibitor-ruxolitinib-in-inflammatory-human-macrophages
#9
Marie Febvre-James, Valérie Lecureur, Yu Augagneur, Abdullah Mayati, Olivier Fardel
Ruxolitinib is a Janus kinase (JAK) 1/2 inhibitor, currently used in the treatment of myeloproliferative neoplasms. It exerts potent anti-inflammatory activity, but the involved molecular and cellular mechanisms remain poorly understood. In order to gain insights about this point, ruxolitinib effects towards expression of main inflammatory cytokines were studied in human macrophages, which constitute a key-cell type implicated in inflammation. Analysis of mRNA expression of cytokines (n=84) by PCR array indicated that, among those induced by the pro-inflammatory stimulus lipopolysaccharide (LPS) (n=44), 61...
December 1, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/29198037/gene-expression-profile-and-long-non-coding-rna-analysis-using-rna-seq-in-chicken-embryonic-fibroblast-cells-infected-by-avian-leukosis-virus-j
#10
Xuming Hu, Shihao Chen, Chongxin Jia, Songlei Xue, Chunfeng Dou, Zhenqing Dai, Hui Xu, Zhen Sun, Tuoyu Geng, Hengmi Cui
Avian leukosis virus J (ALVJ) infection induces hematopoietic malignancy in myeloid leukemia and hemangioma in chickens. However, little is known about the mechanisms underpinning the unique pathogenesis of ALVJ. In this study, we investigated the gene expression profiles of ALVJ-infected chicken cells and performed a comprehensive analysis of the long non-coding RNAs (lncRNAs) in CEF cells using RNA-Seq. As a result, 36 differentially expressed lncRNAs and 91 genes (FC > 2 and q-values < 0.05) were identified...
December 2, 2017: Archives of Virology
https://www.readbyqxmd.com/read/29196213/ifngr1-and-stat1-mediated-canonical-ifn-%C3%AE-signaling-drives-nigrostriatal-degeneration
#11
Michael R Strickland, Emily J Koller, Doris Z Deng, Carolina Ceballos-Diaz, Todd E Golde, Paramita Chakrabarty
Brain expression of AAV-Ifn-γ leads to reactive gliosis, nigrostriatal degeneration and midbrain calcification in wild type mice. This mouse model phenocopies idiopathic basal ganglia calcification which is associated with Parkinsonian symptoms. To understand how the nigro-striatal pathway is selectively vulnerable to Ifn-γ, we determined if the phenotype is driven by canonical signaling intermediates, Ifngr1 and Stat1. Using focused bioinformatic analysis and rotarod testing, we show that neuroinflammation and motor abnormalities precede the appearance of midbrain neuropathologies in the brains of Ifn-γ mouse model...
November 28, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/29196212/axl-activation-attenuates-neuroinflammation-by-inhibiting-the-tlr-traf-nf-%C3%AE%C2%BAb-pathway-after-mcao-in-rats
#12
Guangyong Wu, Devin W McBride, John H Zhang
BACKGROUND AND PURPOSE: Ischemic stroke activates Toll-like receptors (TLRs), triggering rapid inflammatory cytokine production. Axl signaling has multiple roles, including regulating cytokine secretion, clearing apoptotic cells, and maintaining cell survival, however, its role in inflammation after ischemic stroke has not been examined. We hypothesized that activation of Axl by recombinant Growth-arrest-specific protein 6 (rGas6) attenuates neuroinflammation by inhibiting the TLR/TRAF/NF-κB pathway after middle cerebral artery occlusion (MCAO) in rats...
November 28, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/29194722/the-rna-genome-of-hepatitis-e-virus-robustly-triggers-antiviral-interferon-response
#13
Wenshi Wang, Yijin Wang, Changbo Qu, Shan Wang, Jianhua Zhou, Wanlu Cao, Lei Xu, Buyun Ma, Mohamad S Hakim, Yuebang Yin, Tiancheng Li, Maikel P Peppelenbosch, Jingmin Zhao, Qiuwei Pan
The outcomes of hepatitis E virus (HEV) infection are diverse, ranging from asymptomatic carrier, self-limiting acute infection, fulminant hepatitis to persistent infection. This is closely associated with the immunological status of the host. This study aims to understand the innate cellular immunity as the first-line defense mechanisms in response to HEV infection. Phosphorylation of STAT1, a hallmark of the activation of antiviral interferon (IFN) response, was observed in the liver tissues of majority of HEV infected patients, but not in the liver of uninfected individuals...
December 1, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29193197/signaling-profiles-of-blood-leukocytes-in-sepsis-and-in-acute-pancreatitis-in-relation-to-disease-severity
#14
Krista Kuuliala, Anne K Penttilä, Kirsi-Maija Kaukonen, Harri Mustonen, Antti Kuuliala, Jani Oiva, Mari Hämäläinen, Eeva Moilanen, Ville Pettilä, Pauli Puolakkainen, Leena Kylänpää, Heikki Repo
Intracellular signaling in blood leukocytes shows multiple aberrations in acute pancreatitis (AP) complicated by organ dysfunction (OD). We studied whether the aberrations associate with severity of AP and occur in sepsis complicated by OD. Study comprises 14 sepsis patients (11 with shock), 18 AP patients (9 mild; 6 moderately severe; 3 severe), and 28 healthy volunteers. Within 48 hours after admission to hospital, phosphorylation of nuclear factor-ĸB (NF-ĸB), signal transducers and activators of transcription (STATs) 1,3, and extracellular signal-regulated kinases 1/2 was measured from stimulated or non-stimulated leukocytes using phosphospecific whole blood flow cytometry...
November 29, 2017: Scandinavian Journal of Immunology
https://www.readbyqxmd.com/read/29187603/defining-the-distinct-intrinsic-properties-of-the-novel-type-i-interferon-epsilon
#15
Sebastian A Stifter, Antony Y Matthews, Niamh E Mangan, Ka Yee Fung, Alexander Drew, Michelle D Tate, Tatiana P Soares da Costa, Daniel Hampsey, Jemma Mayall, Phil M Hansbro, Albert Garcia Minambres, Sahar G Eid, Johnson Mak, Judy Scoble, George Lovrecz, Nicole A de Weerd, Paul J Hertzog
The type I interferons (IFNs) are a family of cytokines with diverse biological activities including antiviral, antiproliferative, and immunoregulatory functions. The discovery of the hormonally regulated, constitutively expressed IFNϵ has suggested a function for IFNs in reproductive tract homeostasis and protection from infections, but its intrinsic activities are untested. We report here the expression, purification, and functional characterization of murine IFNϵ (mIFNϵ). Recombinant mIFNϵ (rmIFNϵ) exhibited an α-helical fold characteristic of type I IFNs and bound to IFN alpha/beta receptor 1 (IFNAR1) and IFNAR2, but, unusually, it had a preference for IFNAR1...
November 29, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29186193/rig-i-like-receptor-activation-by-dengue-virus-drives-follicular-t-helper-cell-formation-and-antibody-production
#16
Joris K Sprokholt, Tanja M Kaptein, John L van Hamme, Ronald J Overmars, Sonja I Gringhuis, Teunis B H Geijtenbeek
Follicular T helper cells (TFH) are fundamental in orchestrating effective antibody-mediated responses critical for immunity against viral infections and effective vaccines. However, it is unclear how virus infection leads to TFH induction. We here show that dengue virus (DENV) infection of human dendritic cells (DCs) drives TFH formation via crosstalk of RIG-I-like receptor (RLR) RIG-I and MDA5 with type I Interferon (IFN) signaling. DENV infection leads to RLR-dependent IKKε activation, which phosphorylates IFNα/β receptor-induced STAT1 to drive IL-27 production via the transcriptional complex ISGF3...
November 29, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/29185487/cross-reactivity-of-antibodies-against-interferon-beta-in-multiple-sclerosis-patients-and-interference-of-the-jak-stat-signaling-pathway
#17
Isaac Hurtado-Guerrero, Maria Jesus Pinto-Medel, Patricia Urbaneja, Jose Luis Rodriguez-Bada, Jesús Ortega-Pinazo, Pedro Serrano, Óscar Fernández, Laura Leyva, Begoña Oliver-Martos
Interferon beta (IFNβ) therapy has immunogenic properties and induces the development of neutralizing antibodies (NAbs). From the extensive literature focused in the development of NAbs in multiple sclerosis (MS) patients, their ability to cross-react has been deficiently evaluated, despite having important consequences in the clinical practice. Here, the relation between the cross-reactivity and the NAbs titers has been evaluated in MS patients, by inhibition of the antiviral activity of IFNβ by bioassay and through the interference with the activation of the IFNß pathway (JAK-STAT), by phosphoflow...
November 29, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29182760/expression-patterns-of-tnf%C3%AE-madcam1-and-stat3-in-intestinal-and-skin-manifestations-of-inflammatory-bowel-disease
#18
Stephan R Vavricka, Jose A Galván, Heather Dawson, Alex Soltermann, Luc Biedermann, Michael Scharl, Alain M Schoepfer, Gerhard Rogler, Mareike B Prinz Vavricka, Luigi Terracciano, Alexander Navarini, Inti Zlobec, Alessandro Lugli, Thomas Greuter
Background: Pathogenesis of cutaneous extraintestinal manifestations (EIM) in inflammatory bowel disease (IBD) remains elusive. Efficacy of anti-TNF agents suggests TNF-dependent mechanisms. The role of other biologics such as anti-integrins or JAK-inhibitors is not yet clear. Methods: We performed immunohistochemistry for TNFα, NFκB, STAT1/STAT3, MAdCAM1, CD20/68, caspase 3/9, IFNγ, Hsp-27/70 on 240 intestinal (55 controls, 185 IBD) and 64 skin biopsies (11 controls, 18 Erythema nodosum (EN), 13 Pyoderma gangenosum (PG), 22 psoriasis)...
November 22, 2017: Journal of Crohn's & Colitis
https://www.readbyqxmd.com/read/29181006/protective-effect-of-panax-notoginseng-root-water-extract-against-influenza-a-virus-infection-by-enhancing-antiviral-interferon-mediated-immune-responses-and-natural-killer-cell-activity
#19
Jang-Gi Choi, Young-Hee Jin, Heeeun Lee, Tae Woo Oh, Nam-Hui Yim, Won-Kyung Cho, Jin Yeul Ma
Influenza is an acute respiratory illness caused by the influenza A virus, which causes economic losses and social disruption mainly by increasing hospitalization and mortality rates among the elderly and people with chronic diseases. Influenza vaccines are the most effective means of preventing seasonal influenza, but can be completely ineffective if there is an antigenic mismatch between the seasonal vaccine virus and the virus circulating in the community. In addition, influenza viruses resistant to antiviral drugs are emerging worldwide...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29180417/snx8-mediates-ifn%C3%AE-triggered-noncanonical-signaling-pathway-and-host-defense-against-listeria-monocytogenes
#20
Jin Wei, Wei Guo, Huan Lian, Qing Yang, Heng Lin, Shu Li, Hong-Bing Shu
IFNγ is a cytokine that plays a key role in host defense against intracellular pathogens. In addition to the canonical JAK-STAT1 pathway, IFNγ also activates an IKKβ-mediated noncanonical signaling pathway that is essential for induction of a subset of downstream effector genes. The molecular mechanisms and functional significance of this IFNγ-triggered noncanonical pathway remains enigmatic. Here, we identified sorting nexin 8 (SNX8) as an important component of the IFNγ-triggered noncanonical signaling pathway...
November 27, 2017: Proceedings of the National Academy of Sciences of the United States of America
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