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https://www.readbyqxmd.com/read/28749573/il-6-stat3-signaling-as-a-promising-target-to-improve-the-efficacy-of-cancer-immunotherapy
#1
REVIEW
Hidemitsu Kitamura, Yosuke Ohno, Yujiro Toyoshima, Junya Ohtake, Shigenori Homma, Hideki Kawamura, Norihiko Takahashi, Akinobu Taketomi
Overcoming the immunosuppressive state in tumor microenvironments is a critical issue to improve the efficacy of cancer immunotherapy. Interleukin (IL)-6, a pleiotropic cytokine, is highly produced in the tumor-bearing host. Previous studies have indicated that IL-6 suppresses the antigen presentation ability of dendritic cells (DCs) through activation of signal transducer and activator of transcription 3 (STAT3). Thus, we focused on the precise effect of the IL-6/STAT3 signaling cascade on human DCs and the subsequent induction of antitumor T cell immune responses...
July 27, 2017: Cancer Science
https://www.readbyqxmd.com/read/28749311/reconstitution-of-the-peripheral-immune-repertoire-following-withdrawal-of-fingolimod
#2
Mahtab Ghadiri, Leslie Fitz-Gerald, Ayman Rezk, Rui Li, Mukanthu Nyirenda, David Haegert, Paul Steven Giacomini, Amit Bar-Or, Jack Antel
BACKGROUND: Following fingolimod cessation, immune reconstitution or lack thereof may have consequences for disease rebound or safety of commencing alternative therapies. OBJECTIVE: To examine the degree and profile of peripheral blood lymphocyte reconstitution following fingolimod withdrawal. METHODS: Total lymphocyte counts (TLC) and CD4+/CD8+ T-cell counts were measured in 18 multiple sclerosis (MS) patients pre-treatment, on fingolimod, and up to 8-9 months post-cessation...
August 2017: Multiple Sclerosis: Clinical and Laboratory Research
https://www.readbyqxmd.com/read/28748582/extravasal-albumin-concentration-modulates-contractile-responses-of-renal-afferent-arterioles
#3
Xiang Gao, Zhi Zhao Liu, Hayar Mohammed, Zhengbing Zhuge, Ming Liu, En Yin Lai, Leif Jansson, Mattias Carlström, Andreas Patzak, A Erik G Persson
AIM: Afferent arterioles (AA) hold a key position in the regulation of renal blood flow and glomerular filtration rate. Being the effector site of tubuloglomerular feedback the afferent arteriole contributes to the renal handling of sodium and fluid. Dehydration goes along with increased renal interstitial protein concentration. Here, the hypothesis was tested that extravasal protein concentration directly modulates afferent arteriolar tone; a mechanism which may contribute to body fluid volume control...
July 27, 2017: Acta Physiologica
https://www.readbyqxmd.com/read/28747670/pkc-%C3%B1-is-dispensable-for-ox40l-induced-tcr-independent-treg-proliferation-but-contributes-by-enabling-il-2-production-from-effector-t-cells
#4
Khaled Alharshawi, Alejandra Marinelarena, Prabhakaran Kumar, Osama El-Sayed, Palash Bhattacharya, Zuoming Sun, Alan L Epstein, Ajay V Maker, Bellur S Prabhakar
We have previously shown that OX40L/OX40 interaction is critical for TCR-independent selective proliferation of Foxp3(+) Tregs, but not Foxp3(-) effector T-cells (Teff), when CD4(+) T-cells are co-cultured with GM-CSF derived bone marrow dendritic cells (G-BMDCs). Events downstream of OX40L/OX40 interaction in Tregs responsible for this novel mechanism are not understood. Earlier, OX40L/OX40 interaction has been shown to stimulate CD4(+) T-cells through the formation of a signalosome involving TRAF2/PKC-Ѳ leading to NF-kB activation...
July 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28747644/active-nuclear-transcriptome-analysis-reveals-inflammasome-dependent-mechanism-for-early-neutrophil-response-to-mycobacterium-marinum
#5
Amy Kenyon, Daria Gavriouchkina, Jernej Zorman, Giorgio Napolitani, Vincenzo Cerundolo, Tatjana Sauka-Spengler
The mechanisms governing neutrophil response to Mycobacterium tuberculosis remain poorly understood. In this study we utilise biotagging, a novel genome-wide profiling approach based on cell type-specific in vivo biotinylation in zebrafish to analyse the initial response of neutrophils to Mycobacterium marinum, a close genetic relative of M. tuberculosis used to model tuberculosis. Differential expression analysis following nuclear RNA-seq of neutrophil active transcriptomes reveals a significant upregulation in both damage-sensing and effector components of the inflammasome, including caspase b, NLRC3 ortholog (wu: fb15h11) and il1β...
July 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28747424/ilc2s-regulate-adaptive-th2-cell-functions-via-pd-l1-checkpoint-control
#6
Christian Schwartz, Adnan R Khan, Achilleas Floudas, Sean P Saunders, Emily Hams, Hans-Reimer Rodewald, Andrew N J McKenzie, Padraic G Fallon
Group 2 innate lymphoid cells (ILC2s) are important effector cells driving the initiation of type 2 immune responses leading to adaptive T helper 2 (Th2) immunity. Here we show that ILC2s dynamically express the checkpoint inhibitor molecule PD-L1 during type 2 pulmonary responses. Surprisingly, PD-L1:PD-1 interaction between ILC2s and CD4(+) T cells did not inhibit the T cell response, but PD-L1-expressing ILC2s stimulated increased expression of GATA3 and production of IL-13 by Th2 cells both in vitro and in vivo...
July 26, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28747383/ischemia-reperfusion-induces-interferon-stimulated-gene-expression-in-microglia
#7
Ashley McDonough, Richard V Lee, Shahani Noor, Chungeun Lee, Thu Le, Michael Iorga, Jessica L H Phillips, Sean Murphy, Thomas Möller, Jonathan R Weinstein
Innate immune signaling is important in the pathophysiology of ischemia/reperfusion (stroke) induced injury and recovery. Several lines of evidence support a central role for microglia in these processes. Recent work has identified Toll-like receptors (TLRs) and type I interferon (IFN) signaling in both ischemia/reperfusion-induced brain injury and ischemic preconditioning-mediated neuroprotection. To determine the effects of 'ischemia/reperfusion-like' conditions on microglia we carried out genomic analyses on wild-type (WT) and TLR4(-/-) cultured microglia following sequential exposure to hypoxia/hypoglycemia and normoxia/normoglycemia (H/H-N/N)...
July 26, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28747315/renal-tubular-cell-derived-extracellular-vesicles-accelerate-the-recovery-of-established-renal-ischemia-reperfusion-injury
#8
Jesus H Dominguez, Yunlong Liu, Hongyu Gao, James M Dominguez, Danhui Xie, K J Kelly
Ischemic renal injury is a complex syndrome; multiple cellular abnormalities cause accelerating cycles of inflammation, cellular damage, and sustained local ischemia. There is no single therapy that effectively resolves the renal damage after ischemia. However, infusions of normal adult rat renal cells have been a successful therapy in several rat renal failure models. The sustained broad renal benefit achieved by relatively few donor cells led to the hypothesis that extracellular vesicles (EV, largely exosomes) derived from these cells are the therapeutic effector in situ We now show that EV from adult rat renal tubular cells significantly improved renal function when administered intravenously 24 and 48 hours after renal ischemia in rats...
July 26, 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/28746882/a-landscape-of-therapeutic-cooperativity-in-kras-mutant-cancers-reveals-principles-for-controlling-tumor-evolution
#9
Grace R Anderson, Peter S Winter, Kevin H Lin, Daniel P Nussbaum, Merve Cakir, Elizabeth M Stein, Ryan S Soderquist, Lorin Crawford, Jim C Leeds, Rachel Newcomb, Priya Stepp, Catherine Yip, Suzanne E Wardell, Jennifer P Tingley, Moiez Ali, Mengmeng Xu, Meagan Ryan, Shannon J McCall, Autumn J McRee, Christopher M Counter, Channing J Der, Kris C Wood
Combinatorial inhibition of effector and feedback pathways is a promising treatment strategy for KRAS mutant cancers. However, the particular pathways that should be targeted to optimize therapeutic responses are unclear. Using CRISPR/Cas9, we systematically mapped the pathways whose inhibition cooperates with drugs targeting the KRAS effectors MEK, ERK, and PI3K. By performing 70 screens in models of KRAS mutant colorectal, lung, ovarian, and pancreas cancers, we uncovered universal and tissue-specific sensitizing combinations involving inhibitors of cell cycle, metabolism, growth signaling, chromatin regulation, and transcription...
July 25, 2017: Cell Reports
https://www.readbyqxmd.com/read/28746851/the-unique-protein-to-protein-carotenoid-transfer-mechanism
#10
Eugene G Maksimov, Nikolai N Sluchanko, Yury B Slonimskiy, Kirill S Mironov, Konstantin E Klementiev, Marcus Moldenhauer, Thomas Friedrich, Dmitry A Los, Vladimir Z Paschenko, Andrew B Rubin
Orange Carotenoid Protein (OCP) is known as an effector and regulator of cyanobacterial photoprotection. This 35 kDa water-soluble protein provides specific environment for blue-green light absorbing keto-carotenoids, which excitation causes dramatic but fully reversible rearrangements of the OCP structure, including carotenoid translocation and separation of C- and N-terminal domains upon transition from the basic orange to photoactivated red OCP form. Although recent studies greatly improved our understanding of the OCP photocycle and interaction with phycobilisomes and the fluorescence recovery protein, the mechanism of OCP assembly remains unclear...
July 25, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28746799/lack-of-il-6-in-the-tumor-microenvironment-augments-type-1-immunity-and-increases-the-efficacy-of-cancer-immunotherapy
#11
Yosuke Ohno, Yujiro Toyoshima, Hideaki Yurino, Norikazu Monma, Huihui Xiang, Kentaro Sumida, Shun Kaneumi, Satoshi Terada, Shinichi Hashimoto, Kazuho Ikeo, Shigenori Homma, Hideki Kawamura, Norihiko Takahashi, Akinobu Taketomi, Hidemitsu Kitamura
Conquering immunosuppression in tumor microenvironments is crucial for effective cancer immunotherapy. It is well known that interleukin (IL)-6, a pleiotropic cytokine, is produced in the tumor-bearing state. In this study, we investigated the precise effects of IL-6 on antitumor immunity and the subsequent tumorigenesis in tumor-bearing hosts. CT26 cells, a murine colon cancer cell line, were intradermally injected into wild-type and IL-6-deficient mice. As a result, we found that tumor growth was decreased significantly in IL-6-deficient mice compared with wild-type mice and the reduction was abrogated by depletion of CD8(+) T cells...
July 26, 2017: Cancer Science
https://www.readbyqxmd.com/read/28746369/single-and-combined-effect-of-retinoic-acid-and-rapamycin-modulate-the-generation-activity-and-homing-potential-of-induced-human-regulatory-t-cells
#12
Enzo Candia, Paz Reyes, Camila Covian, Francisco Rodriguez, Nicolas Wainstein, Jorge Morales, Claudio Mosso, Mario Rosemblatt, Juan Alberto Fierro
Adoptive transfer of CD4+CD25+FOXP3+ regulatory T cells (Treg cells) has been successfully utilized to treat graft versus host disease and represents a promising strategy for the treatment of autoimmune diseases and transplant rejection. The aim of this study was to evaluate the effects of all-trans retinoic acid (atRA) and rapamycin (RAPA) on the number, phenotype, homing markers expression, DNA methylation, and function of induced human Treg cells in short-term cultures. Naive T cells were polyclonally stimulated and cultured for five days in the presence of different combinations of IL-2, TGF-β1, atRA and RAPA...
2017: PloS One
https://www.readbyqxmd.com/read/28745326/defective-positioning-in-granulomas-but-not-lung-homing-limits-cd4-t-cell-interactions-with-mycobacterium-tuberculosis-infected-macrophages-in-rhesus-macaques
#13
K D Kauffman, M A Sallin, S Sakai, O Kamenyeva, J Kabat, D Weiner, M Sutphin, D Schimel, L Via, C E Barry, T Wilder-Kofie, I Moore, R Moore, D L Barber
Protection against Mycobacterium tuberculosis (Mtb) infection requires CD4 T cells to migrate into the lung and interact with infected macrophages. In mice, less-differentiated CXCR3(+) CD4 T cells migrate into the lung and suppress growth of Mtb, whereas CX3CR1(+) terminally differentiated Th1 cells accumulate in the blood vasculature and do not control pulmonary infection. Here we examine CD4 T-cell differentiation and lung homing during primary Mtb infection of rhesus macaques. Mtb-specific CD4 T cells simultaneously appeared in the airways and blood ∼21-28 days post exposure, indicating that recently primed effectors are quickly recruited into the lungs after entering circulation...
July 26, 2017: Mucosal Immunology
https://www.readbyqxmd.com/read/28745269/hepatitis-b-virus-prevents-excessive-viral-production-via-reduction-of-cell-death-inducing-dff45-like-effectors
#14
Jun Yasumoto, Hirotake Kasai, Kentaro Yoshimura, Teruhime Otoguro, Koichi Watashi, Takaji Wakita, Atsuya Yamashita, Tomohisa Tanaka, Sen Takeda, Kohji Moriishi
The relationship between hepatitis B virus (HBV) infection and lipid accumulation remains largely unknown. In this study, we investigated the effect of HBV propagation on lipid droplet growth in HBV-infected cells and HBV-producing cell lines, HepG2.2.15 and HBV-inducible Hep38.7-Tet. The amount of intracellular triglycerides was significantly reduced in HBV-infected and HBV-producing cells compared with HBV-lacking control cells. Electron and immunofluorescent microscopic analyses showed that the average size of a single lipid droplet (LD) was significantly less in the HBV-infected and HBV-producing cells than in the HBV-lacking control cells...
July 2017: Journal of General Virology
https://www.readbyqxmd.com/read/28744797/reconstructing-the-immune-system-with-lentiviral-vectors
#15
REVIEW
Henning Olbrich, Constanze Slabik, Renata Stripecke
Lentiviral vectors (LVs) developed in the past two decades for research and pre-clinical purposes have entered clinical trials with remarkable safety and efficacy performances. Development and clinical testing of LVs for improvement of human immunity showed major advantages in comparison to other viral vector systems. Robust and persisted transduction efficiency of blood cells with LVs, resulted into a broad range of target cells for immune therapeutic approaches: from hematopoietic stem cells and precursor cells for correction of immune deficiencies, up to effector lymphoid and myeloid cells...
July 25, 2017: Virus Genes
https://www.readbyqxmd.com/read/28744785/the-distribution-of-miniature-impala-elements-and-six-genes-in-the-fusarium-genus-is-suggestive-of-horizontal-gene-transfer
#16
Peter van Dam, Martijn Rep
The mimp family of miniature inverted-repeat transposable elements was previously found only in genomes of Fusarium oxysporum and is contextually associated with virulence genes in this species. Through extensive comparative analysis of 83 F. oxysporum and 52 other Fusarium genomes, we uncovered the distribution of different mimp families throughout the genus. We show that (i) mimps are not exclusive to F. oxysporum; (ii) pathogenic isolates generally possess more mimps than non-pathogenic strains and (iii) two isolates of F...
July 25, 2017: Journal of Molecular Evolution
https://www.readbyqxmd.com/read/28743812/horizontal-gene-transfer-of-functional-type-vi-killing-genes-by-natural-transformation
#17
Jacob Thomas, Samit S Watve, William C Ratcliff, Brian K Hammer
Horizontal gene transfer (HGT) can have profound effects on bacterial evolution by allowing individuals to rapidly acquire adaptive traits that shape their strategies for competition. One strategy for intermicrobial antagonism often used by Proteobacteria is the genetically encoded contact-dependent type VI secretion system (T6SS), a weapon used to kill heteroclonal neighbors by direct injection of toxic effectors. Here, we experimentally demonstrate that Vibrio cholerae can acquire new T6SS effector genes via horizontal transfer and utilize them to kill neighboring cells...
July 25, 2017: MBio
https://www.readbyqxmd.com/read/28743803/the-glucocorticoid-angptl4-ceramide-axis-induces-insulin-resistance-through-pp2a-and-pkc%C3%AE
#18
Tzu-Chieh Chen, Daniel I Benjamin, Taiyi Kuo, Rebecca A Lee, Mei-Lan Li, Darryl J Mar, Damian E Costello, Daniel K Nomura, Jen-Chywan Wang
Chronic glucocorticoid exposure is associated with the development of insulin resistance. We showed that glucocorticoid-induced insulin resistance was attenuated upon ablation of Angptl4, a glucocorticoid target gene encoding the secreted protein angiopoietin-like 4, which mediates glucocorticoid-induced lipolysis in white adipose tissue. Through metabolomic profiling, we revealed that glucocorticoid treatment increased hepatic ceramide concentrations by inducing enzymes in the ceramide synthetic pathway in an Angptl4-dependent manner...
July 25, 2017: Science Signaling
https://www.readbyqxmd.com/read/28743721/mind-directly-interacts-with-ftsz-at-h10-helix-suggests-a-model-for-robust-activation-of-minc-to-destabilize-ftsz-polymers
#19
Ashoka Chary Taviti, Tushar Kant Beuria
Cell division in bacteria is a highly controlled and regulated process. FtsZ, a bacterial cytoskeletal protein, forms a ring like structure known as the Z-ring and recruits more than a dozen of proteins to it. The min system oscillates between the poles and inhibits the Z-ring formation at the poles by perturbing FtsZ assembly. This leads to an increase in the FtsZ concentration at the mid cell and helps in Z-ring positioning. MinC, the effector protein, interferes with Z-ring formation through two different mechanisms mediated by its two domains with the help of MinD...
July 25, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28743631/molecular-characterization-and-functional-analysis-of-the-hepcidin-gene-from-roughskin-sculpin-trachidermus-fasciatus
#20
Yingying Liu, Xiaodi Han, Xuezhao Chen, Shanshan Yu, Yingmei Chai, Tongjie Zhai, Qian Zhu
Hepcidin is a kind of cysteine-rich antimicrobial peptide that plays a vital role in host innate immune activity and iron regulation. Here, we report the molecular characterization and functional analysis of a novel hamp1 hepcidin isoforms Tf-Hep from roughskin sculpin, Trachidermus fasciatus. A cDNA fragment of 988 bp with an ORF of 273 bp was obtained. The coding sequence encodes for a signal peptide of 24 amino acids coupled with a prodomain of 40 amino acids and a mature peptide of 26 amino acids. Tissue distribution analysis indicated that Tf-Hep was most abundant in the liver...
July 22, 2017: Fish & Shellfish Immunology
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