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Tomoyuki Sasaki, Toshiaki Shirai, Nagaharu Tsukiji, Shimon Otake, Shogo Tamura, Jiro Ichikawa, Makoto Osada, Kaneo Satoh, Yukio Ozaki, Katsue Suzuki-Inoue
BACKGROUND: Rhodocytin, a disulfide-linked heterodimeric C-type lectin consisting of α- and β-subunits from Calloselasma rhodostoma, induces platelet aggregation through C-type lectin-like receptor 2 (CLEC-2). CLEC-2 is a physiological binding partner of podoplanin (PDPN) expressed on some tumor cell types and is involved in tumor cell-induced platelet aggregation and tumor metastasis. Thus, modified rhodocytin may be a possible source for anti-CLEC-2 medicine in both anti-platelet and anti-metastasis therapy...
February 28, 2018: Journal of Thrombosis and Haemostasis: JTH
Lozan Sheriff, Asma Alanazi, Lewis S C Ward, Carl Ward, Hafsa Munir, Julie Rayes, Mohammed Alassiri, Steve P Watson, Phil N Newsome, G Ed Rainger, Neena Kalia, Jon Frampton, Helen M McGettrick, Gerard B Nash
We investigated the adhesive behaviour of mesenchymal stem cells (MSC) in blood, which might influence their fate when infused as therapy. Isolated human bone marrow (BM) or umbilical cord (UC) MSC adhered efficiently from flow to the matrix proteins, collagen or fibronectin, but did not adhere to endothelial selectins. However, when suspended in blood, BMMSC no longer adhered to collagen, while UCMSC adhered along with many aggregated platelets. Neither MSC adhered to fibronectin from flowing blood, although the fibronectin surface did become coated with a platelet monolayer...
February 28, 2018: Stem Cells
Carsten Deppermann
Platelets patrol the vasculature and adhere at sites of vascular damage after trauma to limit blood loss. In recent years, however, it has become clear that platelets also contribute to pathophysiologic processes such as thrombosis, atherosclerosis, stroke, sepsis and many more. An exciting new role for them is in non-classical hemostasis to prevent bleeding in the inflamed vasculature. Recent studies suggest that GPVI, CLEC-2, integrin αIIbβ3 (GPIIb/IIIa), and the content of platelet α- and dense granules are important players in this process...
February 15, 2018: Platelets
Yao-Wen Chang, Mika K Kaneko, Shinji Yamada, Yukinari Kato
The mucin-type membrane glycoprotein podoplanin (PDPN) is frequently overexpressed in numerous malignant cancers, including squamous cell carcinoma, germinal neoplasia, mesothelioma, lung cancer, oral cancer, and brain tumor. PDPN expression is strongly associated with cancer progression and poor prognosis. Furthermore, PDPN binds to C-type lectin-like receptor 2 (CLEC-2) on platelets, followed by PDPN-mediated platelet aggregation to facilitate tumor metastasis. We have previously reported a novel anti-cat PDPN (cPDPN) monoclonal antibody (mAb), PMab-52, which specifically detects cPDPN using flow cytometry analysis and successfully identifies cPDPN in feline squamous cell carcinomas...
February 2, 2018: Monoclonal Antibodies in Immunodiagnosis and Immunotherapy
Jun Mori, Zoltan Nagy, Giada Di Nunzio, Christopher W Smith, Mitchell J Geer, Rashid Al Ghaithi, Johanna P van Geffen, Silke Heising, Luke Boothman, Bibian M E Tullemans, Joao N Correia, Louise Tee, Marijke J E Kuijpers, Paul Harrison, Johan W M Heemskerk, Gavin E Jarvis, Alexander Tarakhovsky, Arthur Weiss, Alexandra Mazharian, Yotis A Senis
Src family kinases (SFKs) coordinate the initiating and propagating activation signals in platelets, however it remains unclear how they are regulated. Here we show that ablation of C-terminal Src kinase (Csk) and receptor-like protein tyrosine-phosphatase CD148 in mice results in a dramatic increase in platelet SFK activity, demonstrating that these proteins are essential regulators of platelet reactivity. Paradoxically, Csk/CD148-deficient mice exhibit reduced in vivo and ex vivo thrombus formation and increased bleeding following injury, rather than a prothrombotic phenotype...
January 4, 2018: Blood
Shuchi Gupta, Deya Cherpokova, Markus Spindler, Martina Morowski, Markus Bender, Bernhard Nieswandt
At sites of vascular injury, exposed subendothelial collagens trigger platelet activation and thrombus formation by interacting with the immunoreceptor tyrosine-based activation motif (ITAM)-coupled glycoprotein (GP) VI on the platelet surface. Platelets are derived from the cytoplasm of megakaryocytes (MKs), which extend large proplatelets into bone marrow (BM) sinusoids that are then released into the blood stream where the final platelet sizing and maturation occurs. The mechanisms that prevent activation of MKs and forming proplatelets in the collagen-rich BM environment remain largely elusive...
January 2, 2018: Blood
Björn Bauer, Alexander Steinle
Innate immune cells sense danger through a plethora of germline-encoded receptors that recognize pathogen-associated molecular patterns (PAMPs) or cellular molecules that are exposed only by stressed, infected, malignant, or dead cells. Many of these danger-sensing receptors belong to the C-type lectin-like superfamily (CLSF) and therefore are called C-type lectin-like receptors (CTLRs). Certain activating CTLRs, namely, CLEC-2, Dectin-1, DNGR-1, NKp80, and NKp65, which are encoded by genes that are clustered together in a subregion of the mammalian natural killer gene complex (NKC), use a single copy tyrosine signaling module termed the hemi-immunoreceptor tyrosine-based activation motif (hemITAM)...
December 5, 2017: Science Signaling
Theodora A M Claushuis, Alex F de Vos, Bernard Nieswandt, Louis Boon, Joris J T H Roelofs, Onno J de Boer, Cornelis van 't Veer, Tom van der Poll
Platelet collagen receptor glycoprotein VI (GPVI) and podoplanin receptor C-type lectin-like receptor 2 (CLEC2) are receptors implicated in platelet activation that both signal via an immunoreceptor tyrosine-based activation motif. Platelets are necessary for host defense and prevention of hemorrhage during sepsis, but the role of platelet GPVI and CLEC2 herein is unknown. To investigate this, we infected mice depleted of platelet GPVI or CLEC2 by antibody treatment or GPVI-/- mice with the common human sepsis pathogen Klebsiella pneumoniae via the airways to induce pneumonia-derived sepsis...
February 22, 2018: Blood
Lijun Xia
No abstract text is available yet for this article.
November 16, 2017: Blood
Sanjeev K Gotru, Wenchun Chen, Peter Kraft, Isabelle C Becker, Karen Wolf, Simon Stritt, Susanna Zierler, Heike M Hermanns, Deviyani Rao, Anne-Laure Perraud, Carsten Schmitz, René P Zahedi, Peter J Noy, Michael G Tomlinson, Thomas Dandekar, Masayuki Matsushita, Vladimir Chubanov, Thomas Gudermann, Guido Stoll, Bernhard Nieswandt, Attila Braun
OBJECTIVE: TRPM7 (transient receptor potential melastatin-like 7 channel) is a ubiquitously expressed bifunctional protein comprising a transient receptor potential channel segment linked to a cytosolic α-type serine/threonine protein kinase domain. TRPM7 forms a constitutively active Mg(2+) and Ca(2+) permeable channel, which regulates diverse cellular processes in both healthy and diseased conditions, but the physiological role of TRPM7 kinase remains largely unknown. APPROACH AND RESULTS: Here we show that point mutation in TRPM7 kinase domain deleting the kinase activity in mice (Trpm7(R/R) ) causes a marked signaling defect in platelets...
November 16, 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
Shunsuke Itai, Shinji Yamada, Mika K Kaneko, Hiroyuki Harada, Yumiko Kagawa, Satoru Konnai, Yukinari Kato
Oral squamous cell carcinoma is an aggressive tumor in cats; however, molecular-targeted therapies against this tumor, including antibody therapy, have not been developed. Sensitive and specific monoclonal antibodies (mAbs) against highly expressed membrane proteins are needed to develop antibody therapies. Podoplanin, a type I transmembrane glycoprotein, is expressed in many human malignant tumors, including brain tumor, esophageal cancer, lung cancer, mesothelioma, and oral cancer. Podoplanin binds to C-type lectin-like receptor-2 (CLEC-2) and activates platelet aggregation, which is involved in cancer metastasis...
November 1, 2017: Monoclonal Antibodies in Immunodiagnosis and Immunotherapy
Stephanie E Lombard, Alice Y Pollitt, Craig E Hughes, Ying Di, Tom Mckinnon, Chris A O'callaghan, Steve P Watson
The podoplanin-CLEC-2 axis is critical in mice for prevention of hemorrhage in the cerebral vasculature during mid-gestation. This raises the question as to how platelets are captured by podoplanin on neuroepithelial cells in a high shear environment. In this study, we demonstrate that mouse platelets form stable aggregates on mouse podoplanin at arterial shear through a CLEC-2 and Src kinase-dependent pathway. Adhesion and aggregation are also dependent on the platelet glycoprotein (GP) receptors, integrin αIIbβ3 and GPIb, and the feedback agonists ADP and thromboxane A2 (TxA2)...
November 1, 2017: Platelets
C Delierneux, N Donis, L Servais, O Wéra, P Lancellotti, C Oury
In a recent issue of the Journal of Thrombosis and Haemostasis, we published a study demonstrating that phosphorothioate (PS)-modified CpG oligodeoxynucleotides (PS-CpG ODN) types A, B, and C activate platelets via CLEC-2 [1]. This study followed an initial article by Flierl et al. showing that PS-CpG ODN type C exerts platelet activating effect through GPVI [2]. In a Letter to the Editor, Flierl et al. now present new computational modeling data confirming that PS-CpG ODN type C can bind to CLEC-2 monomers or homodimers, or even to two homodimers, and would therefore be able to cause receptor clustering on platelet surface...
October 20, 2017: Journal of Thrombosis and Haemostasis: JTH
U Flierl, T L Nero, B Lim, R K Andrews, M W Parker, E E Gardiner, K Peter
We read with great interest the article by Delierneux et al. [1] in the Journal of Thrombosis and Haemostasis. The authors elegantly describe a mechanism of platelet activation by CpG oligodeoxynucleotides (ODNs) through CLEC-2 mediated binding and uptake. This is the second platelet activation mechanism to be attributed to CpG ODNs, the first being the one described by our group involving platelet-specific collagen receptor glycoprotein VI (GPVI) [2]. CpG ODNs are short single-stranded DNA molecules resembling bacterial DNA and they were developed as potential drug candidates, largely due to their immunostimulatory properties via activation of toll-like receptor 9 (TLR9) [3]...
October 20, 2017: Journal of Thrombosis and Haemostasis: JTH
Katsue Suzuki-Inoue, Nagaharu Tsukiji, Toshiaki Shirai, Makoto Osada, Osamu Inoue, Yukio Ozaki
No abstract text is available yet for this article.
October 9, 2017: Seminars in Thrombosis and Hemostasis
Alyssa N Nylander, Gerald D Ponath, Pierre-Paul Axisa, Mayyan Mubarak, Mary Tomayko, Vijay K Kuchroo, David Pitt, David A Hafler
Recent data indicate that there are different subpopulations of Th17 cells that can express a regulatory as opposed to an inflammatory gene signature. The transmembrane glycoprotein PDPN is critical in the development of multiple organs including the lymphatic system and has been described on T cells in mouse models of autoimmune Th17 inflammation. Here, we demonstrate that unlike in mice, PDPN+ T cells induced under classic Th17-polarizing conditions express transcription factors associated with Th17 cells but do not produce IL-17...
September 7, 2017: JCI Insight
Siân Lax, Julie Rayes, Surasak Wichaiyo, Elizabeth J Haining, Kate Lowe, Beata Grygielska, Ryan Laloo, Per Flodby, Zea Borok, Edward D Crandall, David R Thickett, Steve P Watson
There is no therapeutic intervention proven to prevent acute respiratory distress syndrome (ARDS). Novel mechanistic insights into the pathophysiology of ARDS are therefore required. Platelets are implicated in regulating many of the pathogenic processes that occur during ARDS; however, the mechanisms remain elusive. The platelet receptor CLEC-2 has been shown to regulate vascular integrity at sites of acute inflammation. Therefore the purpose of this study was to establish the role of CLEC-2 and its ligand podoplanin in a mouse model of ARDS...
December 1, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
Elizabeth J Haining, Deya Cherpokova, Karen Wolf, Isabelle C Becker, Sarah Beck, Johannes A Eble, David Stegner, Steve P Watson, Bernhard Nieswandt
C-type lectin-like receptor 2 (CLEC-2) is a platelet receptor that is critical during development in blood-lymph separation and implicated in thrombus stability in thrombosis and hemostasis. It is the only known platelet activatory receptor that participates in both of these aspects of platelet function, and it is the only one to signal through a hemi-immunoreceptor tyrosine-based activation motif (hemITAM). Current investigations into the function of CLEC-2 in vivo have focused on knockout (KO) studies in which both the receptor and its signaling are deleted, making it impossible to explore the possible signaling-independent functions of the receptor, which are indicated by its only known physiological ligand, podoplanin, being an integral membrane protein...
November 16, 2017: Blood
Shinji Yamada, Shunsuke Itai, Takuro Nakamura, Miyuki Yanaka, Noriko Saidoh, Yao-Wen Chang, Saori Handa, Hiroyuki Harada, Yumiko Kagawa, Osamu Ichii, Satoru Konnai, Mika K Kaneko, Yukinari Kato
Podoplanin (PDPN) is expressed in several normal tissues, such as lymphatic endothelial cells, podocytes of renal glomerulus, and type I alveolar cells of lung. PDPN activates platelet aggregation by binding to C-type lectin-like receptor-2 (CLEC-2) on platelet. Although monoclonal antibodies (mAbs) against human PDPN, mouse PDPN, rat PDPN, rabbit PDPN, dog PDPN, and bovine PDPN have been established, anticat PDPN (cPDPN) mAbs have not been developed. In this study, we immunized mice with Chinese hamster ovary (CHO)-K1 cell lines expressing cPDPN, and developed anti-cPDPN mAbs...
October 2017: Monoclonal Antibodies in Immunodiagnosis and Immunotherapy
Stacey A Langan, Leyre Navarro-Núñez, Steve P Watson, Gerard B Nash
Lymphatic endothelial cells (LEC) express the transmembrane receptor podoplanin whose only known endogenous ligand CLEC-2 is found on platelets. Both podoplanin and CLEC-2 are required for normal lymphangiogenesis as mice lacking either protein develop a blood-lymphatic mixing phenotype. We investigated the roles of podoplanin and its interaction with platelets in migration and tube formation by LEC. Addition of platelets or antibody-mediated crosslinking of podoplanin inhibited LEC migration induced by vascular endothelial growth factors (VEGF-A or VEGF-C), but did not modify basal migration or the response to basic fibroblast growth factor or epidermal growth factor...
July 20, 2017: Platelets
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