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https://www.readbyqxmd.com/read/28332555/loxl2-drives-epithelial-mesenchymal-transition-via-activation-of-ire1-xbp1-signalling-pathway
#1
Eva P Cuevas, Pilar Eraso, María J Mazón, Vanesa Santos, Gema Moreno-Bueno, Amparo Cano, Francisco Portillo
Epithelial-to-Mesenchymal Transition (EMT) is a key process contributing to the aggressiveness of cancer cells. EMT is triggered by activation of different transcription factors collectively known as EMT-TFs. Different cellular cues and cell signalling networks activate EMT at transcriptional and posttranscriptional level in different biological and pathological situations. Among them, overexpression of LOXL2 (lysyl oxidase-like 2) induces EMT independent of its catalytic activity. Remarkably, perinuclear/cytoplasmic accumulation of LOXL2 is a poor prognosis marker of squamous cell carcinomas and is associated to basal breast cancer metastasis by mechanisms no yet fully understood...
March 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28330808/germline-genetic-biomarkers-of-sunitinib-efficacy-in-advanced-renal-cell-carcinoma-results-from-the-renal-effect-trial
#2
Robert J Motzer, Robert A Figlin, Jean-François Martini, Subramanian Hariharan, Neeraj Agarwal, Chun Xiao Li, J Andrew Williams, Thomas E Hutson
BACKGROUND: Sunitinib, the vascular endothelial growth factor pathway inhibitor, is an established standard-of-care for advanced renal cell carcinoma (RCC). This study aimed to assess correlations between candidate germline single nucleotide polymorphisms (SNPs) and sunitinib efficacy in patients from the RENAL EFFECT trial (NCT00267748), a randomized phase II study in patients with metastatic RCC comparing the 4-weeks-on/2-weeks-off schedule and a continuous daily dosing schedule. PATIENTS AND METHODS: Informed consent for pharmacogenetics research was obtained from 202 out of 289 treated patients in the trial...
February 27, 2017: Clinical Genitourinary Cancer
https://www.readbyqxmd.com/read/28325283/silencing-of-carbohydrate-sulfotransferase-15-hinders-murine-pulmonary-fibrosis-development
#3
Yoshiro Kai, Koichi Tomoda, Hiroyuki Yoneyama, Masahiro Kitabatake, Atsuhiro Nakamura, Toshihiro Ito, Masanori Yoshikawa, Hiroshi Kimura
Pulmonary fibrosis is a progressive lung disorder characterized by interstitial fibrosis, for which no effective treatments are available. Chondroitin sulfate proteoglycan (CSPG) has been shown to be a mediator, but the specific component of glycosaminoglycan chains of CSPG has not been explored. We show that chondroitin sulfate E-type (CS-E) is involved in fibrogenesis. Small interfering RNA (siRNA) targeting carbohydrate sulfotransferase 15 (CHST15) was designed to inhibit CHST15 mRNA and its product, CS-E...
March 17, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28273952/comparative-analysis-of-lysyl-oxidase-like-family-members-in-pulmonary-fibrosis
#4
Verena Aumiller, Benjamin Strobel, Merrit Romeike, Michael Schuler, Birgit E Stierstorfer, Sebastian Kreuz
Extracellular matrix (ECM) composition and stiffness are major driving forces for the development and persistence of fibrotic diseases. Lysyl oxidase (LOX) and LOX-like (LOXL) proteins play crucial roles in ECM remodeling due to their collagen crosslinking and intracellular functions. Here, we systematically investigated LOX/L expression in primary fibroblasts and epithelial cells under fibrotic conditions, Bleomycin (BLM) induced lung fibrosis and in human IPF tissue. Basal expression of all LOX/L family members was detected in epithelial cells and at higher levels in fibroblasts...
December 2017: Scientific Reports
https://www.readbyqxmd.com/read/28257048/vanillin-suppresses-cell-motility-by-inhibiting-stat3-mediated-hif-1%C3%AE-mrna-expression-in-malignant-melanoma-cells
#5
Eun-Ji Park, Yoon-Mi Lee, Taek-In Oh, Byeong Mo Kim, Beong-Ou Lim, Ji-Hong Lim
Recent studies have shown that vanillin has anti-cancer, anti-mutagenic, and anti-metastatic activity; however, the precise molecular mechanism whereby vanillin inhibits metastasis and cancer progression is not fully elucidated. In this study, we examined whether vanillin has anti-cancer and anti-metastatic activities via inhibition of hypoxia-inducible factor-1α (HIF-1α) in A2058 and A375 human malignant melanoma cells. Immunoblotting and quantitative real time (RT)-PCR analysis revealed that vanillin down-regulates HIF-1α protein accumulation and the transcripts of HIF-1α target genes related to cancer metastasis including fibronectin 1 (FN1), lysyl oxidase-like 2 (LOXL2), and urokinase plasminogen activator receptor (uPAR)...
March 1, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28246311/selective-loxl2-inhibition-potent-antifibrotic-effects-in-ongoing-fibrosis-and-fibrosis-regression
#6
Fernando Magdaleno, Jonel Trebicka
No abstract text is available yet for this article.
February 28, 2017: Gut
https://www.readbyqxmd.com/read/28246207/a-phase-ii-randomized-double-blind-placebo-controlled-study-of-simtuzumab-in-combination-with-folfiri-for-the-second-line-treatment-of-metastatic-kras-mutant-colorectal-adenocarcinoma
#7
J Randolph Hecht, Al B Benson, Dmitry Vyushkov, Yingsi Yang, Johanna Bendell, Udit Verma
LESSONS LEARNED: The safety profile in the patient groups who received FOLFIRI and simtuzumab did not differ from that in the FOLFIRI and placebo group.The addition of simtuzumab to chemotherapy with FOLFIRI does not improve clinical outcomes in patients with metastatic KRAS mutant colorectal carcinoma. BACKGROUND: Simtuzumab, a humanized IgG4 monoclonal antibody to lysyl oxidase-like 2 (LOXL2), blocks desmoplastic reaction in colorectal carcinoma (CRC) cells in vitro...
February 28, 2017: Oncologist
https://www.readbyqxmd.com/read/28199967/pre-clinical-evaluation-of-small-molecule-loxl2-inhibitors-in-breast-cancer
#8
Joan Chang, Morghan C Lucas, Lidia E Leonte, Marc Garcia-Montolio, Lukram Babloo Singh, Alison D Findlay, Mandar Deodhar, Jonathan S Foot, Wolfgang Jarolimek, Paul Timpson, Janine T Erler, Thomas R Cox
Lysyl Oxidase-like 2 (LOXL2), a member of the lysyl oxidase family of amine oxidases is known to be important in normal tissue development and homeostasis, as well as the onset and progression of solid tumors. Here we tested the anti-tumor properties of two generations of novel small molecule LOXL2 inhibitor in the MDA-MB-231 human model of breast cancer. We confirmed a functional role for LOXL2 activity in the progression of primary breast cancer. Inhibition of LOXL2 activity inhibited the growth of primary tumors and reduced primary tumor angiogenesis...
February 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28196225/blood-vessel-basement-membrane-alterations-in-human-retinal-microaneurysms-during-aging
#9
Mariana López-Luppo, Victor Nacher, David Ramos, Joana Catita, Marc Navarro, Ana Carretero, Alfonso Rodriguez-Baeza, Luísa Mendes-Jorge, Jesús Ruberte
Purpose: Microaneurysms, considered a hallmark of retinal vascular disease, are present in aged retinas. Here, the basement membrane of human retinal microaneurysms has been analyzed during aging. Methods: Retinas were obtained from 17 nondiabetic donors. Whole mount retinas and paraffin sections were marked immunohistochemically with antibodies against the main components of the blood basement membrane. Trypsin digestion and transmission electron microscopy also were performed...
February 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28096061/connexin37-deficiency-alters-organic-bone-matrix-cortical-bone-geometry-and-increases-wnt-%C3%AE-catenin-signaling
#10
Rafael Pacheco-Costa, Jay R Kadakia, Emily G Atkinson, Joseph M Wallace, Lilian I Plotkin, Rejane D Reginato
Deletion of connexin (Cx) 37 in mice leads to increased cancellous bone mass due to defective osteoclast differentiation. Paradoxically; however, Cx37-deficient mice exhibit reduced cortical thickness accompanied by higher bone strength, suggesting a contribution of Cx37 to bone matrix composition. Thus, we investigated whether global deletion of Cx37 alters the composition of organic bone extracellular matrix. Five-month-old Cx37(-/-) mice exhibited increased marrow cavity area, and periosteal and endocortical bone surface resulting in higher total area in tibia compared to Cx37(+/+) control mice...
January 16, 2017: Bone
https://www.readbyqxmd.com/read/28087451/in-depth-comparative-analysis-of-the-chicken-eggshell-membrane-proteome
#11
Tamer A E Ahmed, Henri-Pierre Suso, Maxwell T Hincke
The avian eggshell membrane (ESM) is stabilized by extensive cross-linkages, making the identification of its protein constituents technically challenging. Herein, we applied various extraction/solubilization conditions followed by proteomic analysis to characterize the protein constituents of ESM derived from the unfertilized chicken eggs. The egg white and eggshell proteomes (including previous published work) were determined and compared to ESM to identify proteins that are relatively or highly specific to ESM...
January 10, 2017: Journal of Proteomics
https://www.readbyqxmd.com/read/28073888/selective-targeting-of-lysyl-oxidase-like-2-loxl2-suppresses-hepatic-fibrosis-progression-and-accelerates-its-reversal
#12
Naoki Ikenaga, Zhen-Wei Peng, Kahini A Vaid, Susan B Liu, Shuhei Yoshida, Deanna Y Sverdlov, Amanda Mikels-Vigdal, Victoria Smith, Detlef Schuppan, Yury V Popov
BACKGROUND/AIMS: We studied the role of lysyl oxidase-like 2 (LOXL2) in collagen crosslinking and hepatic progenitor cell (HPC) differentiation, and the therapeutic efficacy of a LOXL2-blocking monoclonal antibody on liver fibrosis progression/reversal in mice. METHODS: Anti-LOXL2 antibody, control antilysyl oxidase antibody or placebo was administered during thioacetamide (TAA)-induced fibrosis progression or during recovery. Therapeutic efficacy in biliary fibrosis was tested in BALB/c...
January 10, 2017: Gut
https://www.readbyqxmd.com/read/28056989/induction-of-altered-gene-expression-profiles-in-cultured-bovine-granulosa-cells-at-high-cell-density
#13
Anja Baufeld, Dirk Koczan, Jens Vanselow
BACKGROUND: In previous studies it has been shown that bovine granulosa cells (GC) cultured at a high plating density dramatically change their physiological and molecular characteristics, thus resembling an early stage of luteinization. During the present study, these specific effects on the GC transcriptome were comprehensively analysed to clarify the underlying mechanisms. METHODS: GC were cultured in serum free medium with FSH and IGF-1 stimulation at different initial plating density...
January 5, 2017: Reproductive Biology and Endocrinology: RB&E
https://www.readbyqxmd.com/read/27966531/targeting-loxl2-for-cardiac-interstitial-fibrosis-and-heart-failure-treatment
#14
Jin Yang, Konstantinos Savvatis, Jong Seok Kang, Peidong Fan, Hongyan Zhong, Karen Schwartz, Vivian Barry, Amanda Mikels-Vigdal, Serge Karpinski, Dmytro Kornyeyev, Joanne Adamkewicz, Xuhui Feng, Qiong Zhou, Ching Shang, Praveen Kumar, Dillon Phan, Mario Kasner, Begoña López, Javier Diez, Keith C Wright, Roxanne L Kovacs, Peng-Sheng Chen, Thomas Quertermous, Victoria Smith, Lina Yao, Carsten Tschöpe, Ching-Pin Chang
Interstitial fibrosis plays a key role in the development and progression of heart failure. Here, we show that an enzyme that crosslinks collagen-Lysyl oxidase-like 2 (Loxl2)-is essential for interstitial fibrosis and mechanical dysfunction of pathologically stressed hearts. In mice, cardiac stress activates fibroblasts to express and secrete Loxl2 into the interstitium, triggering fibrosis, systolic and diastolic dysfunction of stressed hearts. Antibody-mediated inhibition or genetic disruption of Loxl2 greatly reduces stress-induced cardiac fibrosis and chamber dilatation, improving systolic and diastolic functions...
December 14, 2016: Nature Communications
https://www.readbyqxmd.com/read/27939076/efficacy-of-simtuzumab-versus-placebo-in-patients-with-idiopathic-pulmonary-fibrosis-a-randomised-double-blind-controlled-phase-2-trial
#15
Ganesh Raghu, Kevin K Brown, Harold R Collard, Vincent Cottin, Kevin F Gibson, Robert J Kaner, David J Lederer, Fernando J Martinez, Paul W Noble, Jin Woo Song, Athol U Wells, Timothy P M Whelan, Wim Wuyts, Emmanuel Moreau, Scott D Patterson, Victoria Smith, Selina Bayly, Jason W Chien, Qi Gong, Jenny J Zhang, Thomas G O'Riordan
BACKGROUND: Lysyl oxidase-like 2 (LOXL2) catalyses collagen cross-linking and is implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). The aim of this study was to investigate the efficacy and safety of simtuzumab, a monoclonal antibody against LOXL2, in patients with IPF. METHODS: In this randomised, double-blind, phase 2 trial, we recruited patients aged 45-85 years with definite IPF diagnosed prior to 3 years of screening from 183 hospitals and respiratory clinics in 14 countries...
January 2017: Lancet Respiratory Medicine
https://www.readbyqxmd.com/read/27869162/the-histone-demethylase-kdm4b-regulates-peritoneal-seeding-of-ovarian-cancer
#16
C Wilson, L Qiu, Y Hong, T Karnik, G Tadros, B Mau, T Ma, Y Mu, J New, R J Louie, S Gunewardena, A K Godwin, O W Tawfik, J Chien, K F Roby, A J Krieg
Epithelial ovarian cancer (EOC) has poor prognosis and rapid recurrence because of widespread dissemination of peritoneal metastases at diagnosis. Multiple pathways contribute to the aggressiveness of ovarian cancer, including hypoxic signaling mechanisms. In this study, we have determined that the hypoxia-inducible histone demethylase KDM4B is expressed in ∼60% of EOC tumors assayed, including primary and matched metastatic tumors. Expression of KDM4B in tumors is positively correlated with expression of the tumor hypoxia marker CA-IX, and is robustly induced in EOC cell lines exposed to hypoxia...
November 21, 2016: Oncogene
https://www.readbyqxmd.com/read/27860390/increased-lysyl-oxidase-like-2-associates-with-a-poor-prognosis-in-non-small-cell-lung-cancer
#17
Ping Zhan, Xiao-Jing Lv, Ya-Nan Ji, Haiyan Xie, Li-Ke Yu
BACKGROUND: Lysyl oxidase-like 2 (LOXL2) is a member of the lysyl oxidase family and is associated with invasiveness and metastasis in breast cancer. However, its relevance in non-small cell lung cancer (NSCLC) remained largely unknown. METHODS: LOXL2 protein levels in a cohort of NSCLC and adjacent normal lung tissues were evaluated and analyzed their clinicopathologic and prognostic significance. RESULTS: It was found that cytoplasmic and nuclear LOXL2 levels were higher in lung adenocarcinoma (AD) and squamous cell carcinoma (SCC) tissues than in paired adjacent normal tissues...
November 18, 2016: Clinical Respiratory Journal
https://www.readbyqxmd.com/read/27784228/a-perspective-on-stem-cells-as-biological-systems-that-produce-differentiated-osteoblasts-and-odontoblasts
#18
REVIEW
Shahrul Hisham Zainal Ariffin, Thanaletchumi Manogaran, Intan Zarina Zainol Abidin, Rohaya Megat Abdul Wahab, Sahidan Senafi
Stem cells (SCs) are capable of self-renewal and multilineage differentiation. Human mesenchymal stem cells (MSCs) and haematopoietic stem cells (HSCs) which can be obtained from multiple sources, are suitable for application in regenerative medicine and transplant therapy. The aim of this review is to evaluate the potential of genomic and proteomic profiling analysis to identify the differentiation of MSCs and HSCs towards osteoblast and odontoblast lineages. In vitro differentiation towards both of these lineages can be induced using similar differentiation factors...
2017: Current Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/27770022/lysyl-oxidase-like-2-cross-links-collagen-iv-of-glomerular-basement-membrane
#19
Carolina Añazco, Alberto J López-Jiménez, Mohamed Rafi, Lorenzo Vega-Montoto, Ming-Zhi Zhang, Billy G Hudson, Roberto M Vanacore
The 7S dodecamer is recognized as an important structural cross-linking domain of collagen IV networks that provide mechanical stability to basement membranes, a specialized form of extracellular matrix essential for the development and maintenance of tissue architecture. Although the 7S dodecamer is stabilized by covalent cross-linking, the molecular mechanism by which such cross-links are formed has not been revealed. Here, we aimed to identify the enzyme(s) that cross-links the 7S dodecamer and characterize its expression in the kidney glomerulus...
December 9, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27769988/influencing-the-tumor-microenvironment-a-phase-ii-study-of-copper-depletion-using-tetrathiomolybdate-in-patients-with-breast-cancer-at-high-risk-for-recurrence-and-in-preclinical-models-of-lung-metastases
#20
Nancy Chan, Amy Willis, Naomi Kornhauser, Maureen M Ward, Sharrell B Lee, Eleni Nackos, Bo Ri Seo, Ellen Chuang, Tessa Cigler, Anne Moore, Diana Donovan, Marta Vallee Cobham, Veronica Fitzpatrick, Sarah Schneider, Alysia Wiener, Jessica Guillaume-Abraham, Elnaz Aljom, Richard Zelkowitz, J David Warren, Maureen E Lane, Claudia Fischbach, Vivek Mittal, Linda Vahdat
PURPOSE: Bone marrow-derived progenitor cells, including VEGFR2(+) endothelial progenitor cells (EPCs) and copper-dependent pathways, model the tumor microenvironment. We hypothesized that copper depletion using tetrathiomolybdate would reduce EPCs in high risk for patients with breast cancer who have relapsed. We investigated the effect of tetrathiomolybdate on the tumor microenvironment in preclinical models. EXPERIMENTAL DESIGN: Patients with stage II triple-negative breast cancer (TNBC), stage III and stage IV without any evidence of disease (NED), received oral tetrathiomolybdate to maintain ceruloplasmin (Cp) between 8 and 17 mg/dL for 2 years or until relapse...
October 21, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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