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Laura R Bohrer, Thomas S Chaffee, Pavlina Chuntova, Nicholas J Brady, Patrice M Witschen, Sarah E Kemp, Andrew C Nelson, Bruce Walcheck, Kathryn L Schwertfeger
The presence of inflammatory cells within the tumor microenvironment has been tightly linked to mammary tumor formation and progression. Specifically, interactions between tumor cells and infiltrating macrophages can contribute to the generation of a pro-tumorigenic microenvironment. Understanding the complex mechanisms that drive tumor cell-macrophage cross-talk will ultimately lead to the development of approaches to prevent or treat early stage breast cancers. As described here, we demonstrate that the cell surface protease a disintegrin and metalloproteinase 17 (ADAM17) is expressed by macrophages in mammary tumors and contributes to regulating the expression of pro-inflammatory mediators, including inflammatory cytokines and the inflammatory mediator cyclooxygenase-2 (Cox-2)...
July 2016: Genes & Cancer
Marion K Gordon, Andrea DeSantis-Rodrigues, Rita Hahn, Peihong Zhou, Yokechen Chang, Kathy K H Svoboda, Donald R Gerecke
Mustard exposures result in epithelial-stromal separations in the cornea and epidermal-dermal separations in the skin. Large blisters often manifest in skin, while the cornea develops microblisters, and, when enough form, the epithelium sloughs. If the exposure is severe, healing can be imperfect and can result in long-term adverse consequences. For the cornea, this could manifest as recurrent corneal erosions. Since the corneal epithelial-stromal separations are in the region identified by electron microscopy as the lamina lucida, the same region affected by the blistering disease junctional epidermolysis bullosa (JEB), we postulated that the molecules that are defective in JEB would be the same ones cleaved by mustard compounds...
August 2016: Annals of the New York Academy of Sciences
Inken Lorenzen, Juliane Lokau, Yvonne Korpys, Mirja Oldefest, Charlotte M Flynn, Ulrike Künzel, Christoph Garbers, Matthew Freeman, Joachim Grötzinger, Stefan Düsterhöft
An important, irreversible step in many signalling pathways is the shedding of membrane-anchored proteins. A Disintegrin And Metalloproteinase (ADAM) 17 is one of the major sheddases involved in a variety of physiological and pathophysiological processes including regeneration, differentiation, and cancer progression. This central role in signalling implies that ADAM17 activity has to be tightly regulated, including at the level of localisation. Most mature ADAM17 is localised intracellularly, with only a small amount at the cell surface...
October 12, 2016: Scientific Reports
Martin R Goodier, Chiara Lusa, Sam Sherratt, Ana Rodriguez-Galan, Ron Behrens, Eleanor M Riley
Cross-linking of FcγRIII (CD16) by immune complexes induces antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells, contributing to control of intracellular pathogens; this pathway can also be targeted for immunotherapy of cancerous or otherwise diseased cells. However, downregulation of CD16 expression on activated NK cells may limit or regulate this response. Here, we report sustained downregulation of CD16 expression on NK cells in vivo after intramuscular (but not intranasal) influenza vaccination...
2016: Frontiers in Immunology
Pallab Kumar Borah, Sourav Chakraborty, Anupam N Jha, Sanchaita Rajkhowa, Raj Kumar Duary
ADAM metallopeptidase domain 17 (ADAM17) is an attractive target for the development of new anti-inflammatory drugs. We aimed to identify selective inhibitors of ADAM17 against matrix metalloproteinase enzymes (MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-13, and MMP-16) which have substantial structural similarity. Target proteins were docked with 29 anti-inflammatory natural molecule ligands and a known selective inhibitor IK682. The ligands were screened based on Lipinski rules, interaction with the ADAM17 active site cavity, and then ranked using the proportional odds model multinomial logistic regression...
October 5, 2016: Journal of Molecular Graphics & Modelling
Shinji Hirata, Takahiko Murata, Daisuke Suzuki, Sou Nakamura, Ryoko Jono-Ohnishi, Hidenori Hirose, Akira Sawaguchi, Satoshi Nishimura, Naoshi Sugimoto, Koji Eto
: : Donor-independent platelet concentrates for transfusion can be produced in vitro from induced pluripotent stem cells (iPSCs). However, culture at 37°C induces ectodomain shedding on platelets of glycoprotein Ibα (GPIbα), the von Willebrand factor receptor critical for adhesive function and platelet lifetime in vivo, through temperature-dependent activation of a disintegrin and metalloproteinase 17 (ADAM17). The shedding can be suppressed by using inhibitors of panmetalloproteinases and possibly of the upstream regulator p38 mitogen-activated protein kinase (p38 MAPK), but residues of these inhibitors in the final platelet products may be accompanied by harmful risks that prevent clinical application...
October 5, 2016: Stem Cells Translational Medicine
S Ai, Y Y Lin, J Zheng, C X Qiu, Y J Liu, X Lin
Shenkangling plays a role of Yishenhuoxue effect for the treatment of children with nephrotic syndrome. The aim of this study was to investigate the effects of Shenkangling intervention on the mitogen-activated protein kinase (MAPK) pathway in rats with Adriamycin-induced nephropathy (AN) and its underlying mechanism of action. Nephrosis was induced in healthy Sprague-Dawley rats by doxorubicin and the rats were untreated or treated with prednisone, simvastatin, Shenkangling, or a combination thereof. Using real-time PCR, the mRNA expression levels of Chemokine (C-X-C motif) ligand 16 (CXCL16), A Disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), and ADAM17 in the renal tissues of these rats were found to be decreased by the various treatments compared to those in the untreated doxorubicin-induced nephrosis rats...
August 19, 2016: Genetics and Molecular Research: GMR
Neele Schumacher, Stefanie Schmidt, Jeanette Schwarz, Dana Dohr, Juliane Lokau, Jürgen Scheller, Christoph Garbers, Athena Chalaris, Stefan Rose-John, Björn Rabe
Neutrophil and mononuclear cell infiltration during inflammatory processes is highly regulated. The first cells at the site of infection or inflammation are neutrophils, followed by mononuclear cells. IL-6 plays an important role during inflammatory states. It has been shown in several models that the soluble form of IL-6R (sIL-6R) is involved in the recruitment of mononuclear cells by a mechanism called IL-6 trans-signaling. It had been speculated that sIL-6R was generated at the site of inflammation by shedding from neutrophils via activation of the metalloprotease ADAM17...
October 3, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Nuray Erin, Tümay İpekçi, Bahar Akkaya, İrem Hicran Özbudak, Mehmet Baykara
BACKGROUND: ADAM9, 10, and 17 are a class of disintegrins and metallproteinases with α-secretase activity. There are conflicting results regarding the role(s) of ADAM9, 10, and 17 in carcinogenesis, and only a few studies have examined their levels and cellular localization in renal cell carcinoma (RCC). Studies examining changes in α-secretase activity in RCC compared to enzymatic activity of the uninvolved kidney are lacking. METHOD: A cross-sectional study was conducted in 56 patients undergoing radical nephrectomy after the diagnosis of RCC...
September 28, 2016: Urologic Oncology
Hongyu Shen, Liangpeng Li, Siying Zhou, Dandan Yu, Sujin Yang, Xiu Chen, Dandan Wang, Shanliang Zhong, Jianhua Zhao, Jinhai Tang
A disintegrin and metalloproteinase (ADAM) family members are known to process the target membrane-bound molecules through the quick induction of their protease activities under interaction with other molecules, which have diverse roles in tissue morphogenesis and pathophysiological remodeling. Among these, ADAM17 is a membrane-bound protease that sheds the extracellular domain of various receptors or its ligands from the cell membrane and subsequently activates downstream signaling transduction pathways. Importantly, breast cancer remains a mainspring of cancer-induced death in women, and numerous regulatory pathways have been implicated in the formation of breast cancer...
September 22, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Eirini Kefaloyianni, Muthu Lakshmi Muthu, Jakob Kaeppler, Xiaoming Sun, Venkata Sabbisetti, Athena Chalaris, Stefan Rose-John, Eitan Wong, Irit Sagi, Sushrut S Waikar, Helmut Rennke, Benjamin D Humphreys, Joseph V Bonventre, Andreas Herrlich
Kidney fibrosis following kidney injury is an unresolved health problem and causes significant morbidity and mortality worldwide. In a study into its molecular mechanism, we identified essential causative features. Acute or chronic kidney injury causes sustained elevation of a disintegrin and metalloprotease 17 (ADAM17); of its cleavage-activated proligand substrates, in particular of pro-TNFα and the EGFR ligand amphiregulin (pro-AREG); and of the substrates' receptors. As a consequence, EGFR is persistently activated and triggers the synthesis and release of proinflammatory and profibrotic factors, resulting in macrophage/neutrophil ingress and fibrosis...
August 18, 2016: JCI Insight
Xiaoming Ju, Xuanmao Jiao, Adam Ertel, Mathew C Casimiro, Gabriele Di Sante, Shengqiong Deng, Zhiping Li, Agnese Di Rocco, Tingting Zhan, Adam Hawkins, Tanya Stoyanova, Sebastiano Ando, Alessandro Fatatis, Michael P Lisanti, Leonard G Gomella, Lucia R Languino, Richard G Pestell
Proteomic analysis of castration-resistant prostate cancer demonstrated the enrichment of SRC tyrosine kinase activity in approximately ninety percent of patients. Src is known to induce cyclin D1, and a cyclin D1-regulated gene expression module predict poor outcome in human prostate cancer. The tumor-associated calcium signal transducer 2 [TACSTD2/Trop2/M1S1] is enriched in the prostate, promoting prostate stem cell self-renewal upon proteolytic activation via a γ-secretase cleavage complex (PS1, PS2) and TACE (ADAM17), which releases the Trop2 intracellular domain (Trop2 ICD)...
September 15, 2016: Cancer Research
Christian Hundhausen, Alena Roth, Elizabeth Whalen, Janice Chen, Anya Schneider, S Alice Long, Shan Wei, Rebecca Rawlings, MacKenzie Kinsman, Stephen P Evanko, Thomas N Wight, Carla J Greenbaum, Karen Cerosaletti, Jane H Buckner
Interleukin-6 (IL-6) is a key pathogenic cytokine in multiple autoimmune diseases including rheumatoid arthritis and multiple sclerosis, suggesting that dysregulation of the IL-6 pathway may be a common feature of autoimmunity. The role of IL-6 in type 1 diabetes (T1D) is not well understood. We show that signal transducer and activator of transcription 3 (STAT3) and STAT1 responses to IL-6 are significantly enhanced in CD4 and CD8 T cells from individuals with T1D compared to healthy controls. The effect is IL-6-specific because it is not seen with IL-10 or IL-27 stimulation, two cytokines that signal via STAT3...
September 14, 2016: Science Translational Medicine
Karsten Mahnke, Jurgina Useliene, Sabine Ring, Paula Kage, Verena Jendrossek, Simon C Robson, Matilda Bylaite-Bucinskiene, Kerstin Steinbrink, Alexander H Enk
Injection of regulatory T cells (Treg) followed by sensitization with TNCB induced a transient increase in size and cellularity of skin draining lymph nodes (LN) in mice. This led us to hypothesize that Treg may affect the trafficking of T cells from - and to peripheral LN. Two to three hours after sensitization we found fewer CD8(+) T cells expressing CD62L in LN as compared to untreated controls. Injection of wildtype Treg prevented this down-regulation of CD62L. In contrast, Treg devoid of the ATP-degrading ecto-enzyme CD39 were unable to do so...
September 10, 2016: Journal of Investigative Dermatology
Katsuaki Ieguchi, Yoshiro Maru
No abstract text is available yet for this article.
August 2016: Journal of Thoracic Disease
Yiming Shao, Junbing He, Feng Chen, Yujie Cai, Jianghao Zhao, Yao Lin, Zihan Yin, Hua Tao, Xin Shao, Pengru Huang, Mingkang Yin, Wenying Zhang, Zhou Liu, Lili Cui
BACKGROUND: A disintegrin and metalloproteinase 17 (ADAM17) has been confirmed to play a significant role in the pathogenesis of sepsis. However, little is known about the clinical relevance of ADAM17 polymorphisms to sepsis onset and development. METHODS: This study analyzed the associations of five ADAM17 promoter polymorphisms (rs55790676, rs12692386, rs11684747, rs1524668 and rs11689958) with sepsis (370 sepsis cases and 400 controls). Genotyping was performed using pyrosequencing and polymerase chain reaction-length polymorphism method...
2016: Cellular Physiology and Biochemistry
Xiaoping Qing, Lindsay Rogers, Arthur Mortha, Yonit Lavin, Patricia Redecha, Priya D Issuree, Thorsten Maretzky, Miriam Merad, David McIlwain, Tak W Mak, Christopher M Overall, Carl P Blobel, Jane E Salmon
CSF1R (colony stimulating factor 1 receptor) is the main receptor for CSF1 and has crucial roles in regulating myelopoeisis. CSF1R can be proteolytically released from the cell surface by ADAM17 (A disintegrin and metalloprotease 17). Here, we identified CSF1R as a major substrate of ADAM17 in an unbiased degradomics screen. We explored the impact of CSF1R shedding by ADAM17 and its upstream regulator, inactive rhomboid protein 2 (iRhom2, gene name Rhbdf2), on homeostatic development of mouse myeloid cells...
September 7, 2016: European Journal of Immunology
Esther Groth, Jessica Pruessmeyer, Aaron Babendreyer, Julian Schumacher, Tobias Pasqualon, Daniela Dreymueller, Shigeki Higashiyama, Inken Lorenzen, Joachim Grötzinger, Didier Cataldo, Andreas Ludwig
By mediating proteolytic shedding on the cell surface the disintegrin and metalloproteinases ADAM10 and ADAM17 function as critical regulators of growth factors, cytokines and adhesion molecules. We here report that stimulation of lung epithelial A549 tumor cells with phorbol-12-myristate-13-acetate (PMA) leads to the downregulation of the surface expressed mature form of ADAM17 without affecting ADAM10 expression. This reduction could not be sufficiently explained by metalloproteinase-mediated degradation, dynamin-mediated internalization or microdomain redistribution of ADAM17...
September 3, 2016: Biochimica et Biophysica Acta
Shanli Tsui, Jie Wang, Ling Wang, Wei Dai, Luo Lu
BACKGROUND: The purpose of the study is to elicit the epigenetic mechanism involving CCCTC binding factor (CTCF)-mediated chromatin remodeling that regulates PAX6 gene interaction with differentiation-associated genes to control corneal epithelial differentiation. METHODS: Cell cycle progression and specific keratin expressions were measured to monitor changes of differentiation-induced primary human limbal stem/progenitor (HLS/P), human corneal epithelial (HCE) and human telomerase-immortalized corneal epithelial (HTCE) cells...
2016: PloS One
Alma Delia Campos-Parra, Alejandra Padua-Bracho, Abraham Pedroza-Torres, Gabriela Figueroa-González, Jorge Fernández-Retana, Oliver Millan-Catalan, Oscar Peralta-Zaragoza, David Cantú de León, Luis A Herrera, Carlos Pérez-Plasencia
OBJECTIVE: The objective of the present study was to provide genomic and transcriptomic information that may improve clinical outcomes for locally advanced cervical cancer (LACC) patients by searching for therapeutic targets or potential biomarkers through the analysis of significantly altered signaling pathways in LACC. METHODS: Microarray-based transcriptome profiling of 89 tumor samples from women with LACC was performed. Through Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, significantly over-expressed genes in LACC were identified; these genes were validated by quantitative reverse transcription-polymerase chain reaction in an independent cohort, and the protein expression data were obtained from the Human Protein Atlas...
August 28, 2016: Gynecologic Oncology
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