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Floriane S Tissot, Soline Estrach, Etienne Boulter, Laurence Cailleteau, Lionel Tosello, Laetitia Seguin, Sabrina Pisano, Stéphane Audebert, Olivier Croce, Chloé C Féral
Skin homeostasis relies on fine tuning of epidermis/dermis interactions and is affected by aging. While extracellular matrix (ECM) proteins, such as integrins, are involved in aging, the molecular basis of the skin changes need to be further investigated. Here, we showed that integrin co-receptor, SLC3A2, required for cell proliferation, is expressed at the surface of resting dermal fibroblasts (DF) in young patients, and drastically reduced with aging. In vivo SLC3A2 DF deletion induced major skin phenotypes resembling premature aging...
June 12, 2018: Journal of Investigative Dermatology
Colin D Weekes, Lee S Rosen, Anna Capasso, Kit Man Wong, Weilan Ye, Maria Anderson, Bruce McCall, Jill Fredrickson, Eric Wakshull, Steve Eppler, Quyen Shon-Nguyen, Rupal Desai, Mahrukh Huseni, Priti S Hegde, Tony Pourmohamad, Ina Rhee, Alberto Bessudo
PURPOSE: MINT1526A is a monoclonal antibody that blocks the interaction of integrin alpha 5 beta 1 (α5β1) with its extracellular matrix ligands. This phase I study evaluated the safety and pharmacokinetics of MINT1526A with or without bevacizumab in patients with advanced solid tumors. METHODS: MINT1526A was administered every 3 weeks (Q3W) as monotherapy (arm 1) or in combination with bevacizumab 15 mg/kg, Q3W (arm 2). Each arm included a 3 + 3 dose-escalation stage and a dose-expansion stage...
June 15, 2018: Cancer Chemotherapy and Pharmacology
Sibel Isal, Julien Pierson, Laetitia Imbert, Alexandra Clement, Charlotte Collet, Sophie Pinel, Nicolas Veran, Aurélie Reinhard, Sylvain Poussier, Guillaume Gauchotte, Steeven Frezier, Gilles Karcher, Pierre-Yves Marie, Fatiha Maskali
BACKGROUND: Tracers triggering αvβ3 integrins, such as certain RGD-containing peptides, were found promising in previous pilot studies characterizing high-grade gliomas. However, only limited comparisons have been performed with current PET tracers. This study aimed at comparing the biodistribution of 18 F-fluorodeoxyglucose (18 F-FDG) with that of 68 Ga-NODAGA-RGD, an easily synthesized monomeric RGD compound with rapid kinetics, in two different rodent models of engrafted human glioblastoma...
June 15, 2018: EJNMMI Research
Alba Manresa-Arraut, Flemming Fryd Johansen, Cord Brakebusch, Shohreh Issazadeh-Navikas, Henrik Hasseldam
T-cells are known to be intimately involved in the pathogenesis of multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). T-cell activation is controlled by a range of intracellular signaling pathways regulating cellular responses such as proliferation, cytokine production, integrin expression, and migration. These processes are crucial for the T-cells' ability to mediate inflammatory processes in autoimmune diseases such as MS. RhoA is a ubiquitously expressed small GTPase well described as a regulator of the actin cytoskeleton...
2018: Frontiers in Immunology
Gabriel Espinosa-Carrasco, Cécile Le Saout, Pierre Fontanaud, Aurélien Michau, Patrice Mollard, Javier Hernandez, Marie Schaeffer
T cell search behavior is dictated by their need to encounter their specific antigen to eliminate target cells. However, mechanisms controlling effector T cell motility are highly tissue-dependent. Specifically, how diabetogenic T cells encounter their target beta cells in dispersed islets throughout the pancreas (PA) during autoimmune diabetes remains unclear. Using intra-vital 2-photon microscopy in a mouse model of diabetes, we found that CXCR3 chemokine downregulated CD8+ T cell motility specifically within islets, promoting effector cell confinement to their target sites...
2018: Frontiers in Immunology
Tingting Li, Jin'e Liu, Hao Cai, Baomei Wang, Yunfeng Feng, Jun Liu
Cell-matrix interactions play critical roles in cell adhesion, tissue remodeling and cancer metastasis. Discoidin domain receptor 2 (DDR2) is a collagen receptor belonging to receptor tyrosine kinase (RTK) family. It is a powerful regulator of collagen deposition in the extracellular matrix (ECM). Although the oligomerization of DDR extracellular domain (ECD) proteins can affect matrix remodeling by inhibiting fibrillogenesis, it is still unknown how cellular DDR2 is incorporated into collagen matrix. Using 3-dimentional (3D) imaging for migrating cells, we identified a novel mechanism that explains how DDR2 incorporating into collagen matrix, which we named as posterior remnant tethering...
2018: International Journal of Biological Sciences
Sidsel Støy, Thomas Damgaard Sandahl, Anne Louise Hansen, Bent Deleuran, Thomas Vorup-Jensen, Hendrik Vilstrup, Tue Wenzel Kragstrup
OBJECTIVES: During alcoholic hepatitis (AH) monocytes traverse the vascular boundaries and massively invade the liver. In principle, tissue extravasation can be limited through shedding of CD18 integrins from leukocytes, including monocytes. The soluble (s) product sCD18 conceals adhesion receptors on the endothelium, which reduces monocyte extravasation. In AH, monocytes are dysfunctional, but whether this involves their self-generated anti-migration is unknown. Our aim was, therefore, to investigate monocyte CD18 dynamics in AH...
June 15, 2018: Clinical and Translational Gastroenterology
Farhana Jahan, Sudarrshan Madhavan, Taisia Rolova, Larisa Viazmina, Mikaela Grönholm, Carl G Gahmberg
The integrin leukocyte function-associated antigen-1 (LFA-1) plays a pivotal role in leukocyte adhesion and migration, but the mechanism(s) by which this integrin is regulated has remained incompletely understood. LFA-1 integrin activity requires phosphorylation of its β2-chain and interactions of its cytoplasmic tail with various cellular proteins. The α-chain is constitutively phosphorylated and necessary for cellular adhesion, but how the α-chain regulates adhesion has remained enigmatic. We now show that substitution of the α-chain phosphorylation site (S1140A) in T cells inhibits the phosphorylation of the functionally important Thr-758 in the β2-chain, binding of α-actinin and 14-3-3 protein, and expression of an integrin-activating epitope after treatment with the stromal cell-derived factor-1α...
June 14, 2018: Journal of Biological Chemistry
Abdullah Mahmood Ali, Yumin Huang, Ronald Feitosa Pinheiro, Fumin Xue, Jingping Hu, Nicholas Iverson, Daniela Hoehn, Diego Coutinho, Jehanzeb Kayani, Brian Chernak, Joseph Lane, Christopher Hillyer, Naomi Galili, Joseph Jurcic, Narla Mohandas, Xiuli An, Azra Raza
Anemia is the defining feature in most patients with myelodysplastic syndromes (MDS), yet defects in erythropoiesis have not been well characterized. We examined freshly obtained bone marrow (BM) samples for stage-specific abnormalities during terminal erythroid differentiation (TED) from 221 samples (MDS, n = 205 from 113 unique patients; normal, n = 16) by measuring the surface expression of glycophorin A, band 3, and integrin α-4. Clinical and biologic associations were sought with presence or absence of TED and the specific stage of erythroid arrest...
June 26, 2018: Blood Advances
Mohammed Alasseiri, Afsar U Ahmed, Bryan R G Williams
Integrin-linked kinase (ILK) has emerged as a critical adaptor and mediator protein in cell signaling pathways that is commonly deregulated in acute myeloid leukemia (AML). This has led to the expectation that therapeutic targeting of ILK may be a useful option in treating leukemia. Although ILK can regulate many cellular processes, including cell differentiation, survival, migration, apoptosis and production of pro-inflammatory cytokines, its role in promoting AML is still unclear. However, its ability to mediate phosphorylation and regulate the important hematopoietic stem cell regulators protein kinase B (AKT) and glycogen synthase kinase-3β supports ILK as an attractive target for the development of novel anticancer therapeutics...
June 7, 2018: Cytokine & Growth Factor Reviews
Caiyun Liu, Like Qu, Chuanke Zhao, Chengchao Shou
BACKGROUND: Increasing evidence reveals a significant correlation between gamma-synuclein (SNCG) level and tumor invasion and metastasis in various human cancers. Our previous investigation showed that SNCG could secrete into extracellular environment and promoted tumor cell motility, but the mechanism is unknown. METHODS: The membrane binding ability of SNCG was characterized by immunohistochemical staining, immunofluorescence staining and fractionation of colorectal cancer (CRC) cell membrane...
June 15, 2018: Journal of Experimental & Clinical Cancer Research: CR
Alicia M Salvi, Kris A DeMali
Throughout their lifetimes, all cells experience force. These forces are sensed by cell surface adhesion receptors, such as the cadherins and integrins. Much attention has focused on identifying how these adhesion receptors transmit force. In contrast, less is known regarding how these force-activated pathways are integrated with other cellular processes. In this review, we describe how cadherins and integrins transmit force, and discuss how these adhesion receptors are linked to cell metabolism. We focus on understanding this connection by highlighting how the cadherins and integrins interact with a master regulator of energy homeostasis, AMP-activated protein kinase (AMPK) and its upstream activator, Liver Kinase B1 (LKB1)...
June 11, 2018: Current Opinion in Cell Biology
Xiaojia Xu, Yulian Li, Yaping Liang, Mingjuan Yin, Yan Zhang, Lingfeng Huang, Zuwei Yu, Jindong Ni
It is known that multiple genetic variants can affect immune responses to the hepatitis B virus (HBV) vaccine. A case-control study was undertaken to examine the possible association of low responsiveness to the HBV vaccine in a Chinese population with genetic polymorphisms in integrin subunit alpha L, CD58, tumor necrosis factor superfamily member 15, C-C motif chemokine ligand 15, transforming growth factor beta 3, and B-cell lymphoma 6 protein. The copy numbers of these six genes were detected in 129 low responders, 129 middle responders and 129 high responders to HBV vaccination...
June 11, 2018: Infection, Genetics and Evolution
Yi Guo, Benhong Xu, Zhenxing Sun, Youtu Wu, Wei Shi, Jin Wang, Xianbin Meng, Wei Ge, Guihuai Wang
Spinal arteriovenous malformations (sAVM) are a rare and heterogeneous group of blood vessel disorders that affect spinal cord function directly or indirectly; however, the pathogenesis of sAVM is still unclear. In this study, we compared four sAVM specimens obtained during surgery and donated control samples in a Tandem Mass Tag (TMT)-labeled proteomic analysis. We identified 3101 proteins, 654 of which were differentially expressed in sAVM samples compared with the controls. Of these, 96 proteins were upregulated and 358 proteins were downregulated...
June 11, 2018: Microvascular Research
Koji Maruta, Chikako Watanabe, Hideaki Hozumi, Chie Kurihara, Hirotaka Furuhashi, Takeshi Takajo, Yoshikiyo Okada, Kazuhiko Shirakabe, Masaaki Higashiyama, Shunsuke Komoto, Kengo Tomita, Shigeaki Nagao, Toshiaki Ishizuka, Soichiro Miura, Ryota Hokari
The enhanced recruitment of leukocytes to the inflamed colon is a key feature of ulcerative colitis (UC). The gut-specific adhesion molecules involved in leukocyte recruitment have emerged as recent therapeutic targets. Nicotine absorbed from smoking has been reported to work protectively in UC patients. Our hypothesis is that nicotine may suppress the aberrant leukocyte recruitment and colonic inflammation via the suppression of the overexpressed gut-specific adhesion molecules in the inflamed colon. To test this hypothesis, the severity of colitis and the degree of leukocyte recruitment induced by gut-specific adhesion molecules were assessed in dextran sulfate sodium (DSS) colitis mice (C57BL/6J mice treated with 3% DSS) with or without nicotine treatment...
June 14, 2018: Journal of Leukocyte Biology
Vinay Shukla, Pooja Popli, Jyoti Bala Kaushal, Kanchan Gupta, Anila Dwivedi
Tubulin polymerization promoting protein 3 (TPPP3) is known to be expressed in the endometrium in a cyclic manner, its functional role in the physiology of implantation remains unknown. Here we demonstrate a novel function of TPPP3 during the window of implantation and in the establishment of pregnancy using a mouse model. The increased protein expression of TPPP3 and β-catenin during peri-implantation period i.e. D5 (receptive phase, 0800 h) was observed as compared to that on D1 (non-receptive phase, 0800 h)...
June 12, 2018: Biology of Reproduction
Qi Wang, Tae Hee Han, Peter Nguyen, Michal Jarnik, Mihaela Serpe
Assembly, maintenance and function of synaptic junctions depend on extracellular matrix (ECM) proteins and their receptors. Here we report that Tenectin (Tnc), a Mucin-type protein with RGD motifs, is an ECM component required for the structural and functional integrity of synaptic specializations at the neuromuscular junction (NMJ) in Drosophila. Using genetics, biochemistry, electrophysiology, histology and electron microscopy, we show that Tnc is secreted from motor neurons and striated muscles and accumulates in the synaptic cleft...
June 14, 2018: ELife
Suisui Hao, Yu Zhang, Jie Meng, Jian Liu, Tao Wen, Ning Gu, Haiyan Xu
Most of the existing scaffolds for guiding tissue regeneration do not provide direct mechanical stimulation to the cells grown on them. In this work, we used nanofibrous superparamagnetic scaffolds with applied magnetic fields to build a "dynamic" scaffold platform and investigated the modulating effects of this platform on the phenotypes of fibroblasts. The results of enzyme-linked immunosorbent and transwell assays indicated that fibroblasts cultivated in this platform secreted significantly higher type I collagen, vascular endothelial growth factor A, and transforming growth factor-β1 and did so in a time-dependent manner...
June 14, 2018: ACS Applied Materials & Interfaces
Ryota Kawahara, Yuki Niwa, Siro Simizu
Vasculogenic mimicry (VM) formation by cancer cells is known to play a crucial role in tumor progression, whereas the detailed mechanism of which has been unclear. In this study, we focused on integrin β1 (ITGB1) and assessed the role of ITGB1 on VM formation. We used in vitro methods to seed cancer cells on Matrigel to evaluate the capability of VM formation. We performed ITGB1 gene deletion by using the CRISPR/Cas9 system and these ITGB1-knockout cells did not exhibit the VM-like network formation. Further, re-introduction of ITGB1 rescued VM-like network formation in ITGB1-knockout cells...
June 14, 2018: Cancer Science
Timothy N Perkins, Elizabeth A Oczypok, Pavle S Milutinovic, Regina E Dutz, Tim D Oury
BACKGROUND: The receptor for advanced glycation endproducts (RAGE) has been implicated as a critical molecule in the pathogenesis of experimental asthma/allergic airway inflammation (AAI). It has been previously shown that RAGE acts both upstream of interleukin-33 (IL-33) release and downstream of IL-33 release via RAGE-dependent IL-33 induced accumulation of type 2 innate lymphoid cells (ILC2s) in the lungs, which perpetuate type 2 inflammation and mucus metaplasia. However, the mechanism by which RAGE mediates downstream IL-33 induced type 2 inflammatory responses is unknown...
June 14, 2018: Allergy
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