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https://www.readbyqxmd.com/read/28097239/metastasis-regulation-by-ppard-expression-in-cancer-cells
#1
Xiangsheng Zuo, Weiguo Xu, Min Xu, Rui Tian, Micheline J Moussalli, Fei Mao, Xiaofeng Zheng, Jing Wang, Jeffrey S Morris, Mihai Gagea, Cathy Eng, Scott Kopetz, Dipen M Maru, Asif Rashid, Russell Broaddus, Daoyan Wei, Mien-Chie Hung, Anil K Sood, Imad Shureiqi
Peroxisome proliferator-activated receptor-δ (PPARD) is upregulated in many major human cancers, but the role that its expression in cancer cells has in metastasis remains poorly understood. Here, we show that specific PPARD downregulation or genetic deletion of PPARD in cancer cells significantly repressed metastasis in various cancer models in vivo. Mechanistically, PPARD promoted angiogenesis via interleukin 8 in vivo and in vitro. Analysis of transcriptome profiling of HCT116 colon cancer cells with or without genetic deletion of PPARD and gene expression patterns in The Cancer Genome Atlas colorectal adenocarcinoma database identified novel pro-metastatic genes (GJA1, VIM, SPARC, STC1, SNCG) as PPARD targets...
January 12, 2017: JCI Insight
https://www.readbyqxmd.com/read/28097238/quantitative-measurement-of-lymphatic-function-in-mice-by-noninvasive-near-infrared-imaging-of-a-peripheral-vein
#2
Steven T Proulx, Qiaoli Ma, Diana Andina, Jean-Christophe Leroux, Michael Detmar
Optical imaging methods have been developed to measure lymphatic function in skin; however, the lymphatic system of many organs is not accessible to this technology. Since lymphatic transport of macromolecules from any organ proceeds to the blood circulation, we aimed to develop a method that can measure lymphatic function by monitoring the fluorescence in a superficial vein of an interstitially injected tracer. We selected a 40-kDa PEGylated near-infrared dye conjugate, as it showed lymphatic system-specific uptake and extended circulation in blood...
January 12, 2017: JCI Insight
https://www.readbyqxmd.com/read/28097237/oxidized-camkii-promotes-asthma-through-the-activation-of-mast-cells
#3
Jingjing Qu, Danh C Do, Yufeng Zhou, Elizabeth Luczak, Wayne Mitzner, Mark E Anderson, Peisong Gao
Oxidation of calmodulin-dependent protein kinase II (ox-CaMKII) by ROS has been associated with asthma. However, the contribution of ox-CaMKII to the development of asthma remains to be fully characterized. Here, we tested the effect of ox-CaMKII on IgE-mediated mast cell activation in an allergen-induced mouse model of asthma using oxidant-resistant CaMKII MMVVδ knockin (MMVVδ) mice. Compared with WT mice, the allergen-challenged MMVVδ mice displayed less airway hyperresponsiveness (AHR) and inflammation...
January 12, 2017: JCI Insight
https://www.readbyqxmd.com/read/28097236/lung-vaso-occlusion-in-sickle-cell-disease-mediated-by-arteriolar-neutrophil-platelet-microemboli
#4
Margaret F Bennewitz, Maritza A Jimenez, Ravi Vats, Egemen Tutuncuoglu, Jude Jonassaint, Gregory J Kato, Mark T Gladwin, Prithu Sundd
In patients with sickle cell disease (SCD), the polymerization of intraerythrocytic hemoglobin S promotes downstream vaso-occlusive events in the microvasculature. While vaso-occlusion is known to occur in the lung, often in the context of systemic vaso-occlusive crisis and the acute chest syndrome, the pathophysiological mechanisms that incite lung injury are unknown. We used intravital microscopy of the lung in transgenic humanized SCD mice to monitor acute vaso-occlusive events following an acute dose of systemic lipopolysaccharide sufficient to trigger events in SCD but not control mice...
January 12, 2017: JCI Insight
https://www.readbyqxmd.com/read/28097235/a-patient-derived-xenograft-platform-to-study-brca-deficient-ovarian-cancers
#5
Erin George, Hyoung Kim, Clemens Krepler, Brandon Wenz, Mehran Makvandi, Janos L Tanyi, Eric Brown, Rugang Zhang, Patricia Brafford, Stephanie Jean, Robert H Mach, Yiling Lu, Gordon B Mills, Meenhard Herlyn, Mark Morgan, Xiaochen Zhang, Robert Soslow, Ronny Drapkin, Neil Johnson, Ying Zheng, George Cotsarelis, Katherine L Nathanson, Fiona Simpkins
Approximately 50% of high-grade serous ovarian cancers (HGSOCs) have defects in genes involved in homologous recombination (HR) (i.e., BRCA1/2). Preclinical models to optimize therapeutic strategies for HR-deficient (HRD) HGSOC are lacking. We developed a preclinical platform for HRD HGSOCs that includes primary tumor cultures, patient-derived xenografts (PDXs), and molecular imaging. Models were characterized by immunohistochemistry, targeted sequencing, and reverse-phase protein array analysis. We also tested PDX tumor response to PARP, CHK1, and ATR inhibitors...
January 12, 2017: JCI Insight
https://www.readbyqxmd.com/read/28097234/kruppel-like-factor4-regulates-prdm1-expression-through-binding-to-an-autoimmune-risk-allele
#6
Su Hwa Jang, Helen Chen, Peter K Gregersen, Betty Diamond, Sun Jung Kim
A SNP identified as rs548234, which is found in PRDM1, the gene that encodes BLIMP1, is a risk allele associated with systemic lupus erythematosus (SLE). BLIMP1 expression was reported to be decreased in women with the PRDM1 rs548234 risk allele compared with women with the nonrisk allele in monocyte-derived DCs (MO-DCs). In this study, we demonstrate that BLIMP1 expression is regulated by the binding of Kruppel-like factor 4 (KLF4) to the risk SNP. KLF4 is highly expressed in MO-DCs but undetectable in B cells, consistent with the lack of altered expression of BLIMP1 in B cells from risk SNP carriers...
January 12, 2017: JCI Insight
https://www.readbyqxmd.com/read/28097233/ectonucleotidase-cd39-driven-control-of-postinfarction-myocardial-repair-and-rupture
#7
Nadia R Sutton, Takanori Hayasaki, Matthew C Hyman, Anuli C Anyanwu, Hui Liao, Danica Petrovic-Djergovic, Linda Badri, Amy E Baek, Natalie Walker, Keigo Fukase, Yogendra Kanthi, Scott H Visovatti, Ellen L Horste, Jessica J Ray, Sascha N Goonewardena, David J Pinsky
Mechanical complications of myocardial infarction (MI) are often fatal. Little is known about endogenous factors that predispose to myocardial rupture after MI. Ectonucleoside triphosphate diphosphohydrolase (CD39) could be a critical mediator of propensity to myocardial rupture after MI due to its role in modulating inflammation and thrombosis. Using a model of permanent coronary artery ligation, rupture was virtually abrogated in cd39(-/-) mice versus cd39(+/+) controls, with elevated fibrin and collagen deposition and marked neutrophil and macrophage influx...
January 12, 2017: JCI Insight
https://www.readbyqxmd.com/read/28097232/vps34-regulates-myofibril-proteostasis-to-prevent-hypertrophic-cardiomyopathy
#8
Hirotaka Kimura, Satoshi Eguchi, Junko Sasaki, Keiji Kuba, Hiroki Nakanishi, Shunsuke Takasuga, Masakazu Yamazaki, Akiteru Goto, Hiroyuki Watanabe, Hiroshi Itoh, Yumiko Imai, Akira Suzuki, Noboru Mizushima, Takehiko Sasaki
Hypertrophic cardiomyopathy (HCM) is a common heart disease with a prevalence of 1 in 500 in the general population. Several mutations in genes encoding cardiac proteins have been found in HCM patients, but these changes do not predict occurrence or prognosis and the molecular mechanisms underlying HCM remain largely elusive. Here we show that cardiac expression of vacuolar protein sorting 34 (Vps34) is reduced in a subset of HCM patients. In a mouse model, muscle-specific loss of Vps34 led to HCM-like manifestations and sudden death...
January 12, 2017: JCI Insight
https://www.readbyqxmd.com/read/28097231/protein-disulfide-isomerase-inhibition-blocks-thrombin-generation-in-humans-by-interfering-with-platelet-factor-v-activation
#9
Jack D Stopa, Donna Neuberg, Maneka Puligandla, Bruce Furie, Robert Flaumenhaft, Jeffrey I Zwicker
BACKGROUND: Protein disulfide isomerase (PDI) is required for thrombus formation. We previously demonstrated that glycosylated quercetin flavonoids such as isoquercetin inhibit PDI activity and thrombus formation in animal models, but whether extracellular PDI represents a viable anticoagulant target in humans and how its inhibition affects blood coagulation remain unknown. METHODS: We evaluated effects of oral administration of isoquercetin on platelet-dependent thrombin generation in healthy subjects and patients with persistently elevated anti-phospholipid antibodies...
January 12, 2017: JCI Insight
https://www.readbyqxmd.com/read/28097230/protection-against-plasmodium-falciparum-malaria-by-pfspz-vaccine
#10
Judith E Epstein, Kristopher M Paolino, Thomas L Richie, Martha Sedegah, Alexandra Singer, Adam J Ruben, Sumana Chakravarty, April Stafford, Richard C Ruck, Abraham G Eappen, Tao Li, Peter F Billingsley, Anita Manoj, Joana C Silva, Kara Moser, Robin Nielsen, Donna Tosh, Susan Cicatelli, Harini Ganeshan, Jessica Case, Debbie Padilla, Silas Davidson, Lindsey Garver, Elizabeth Saverino, Tooba Murshedkar, Anusha Gunasekera, Patrick S Twomey, Sharina Reyes, James E Moon, Eric R James, Natasha Kc, Minglin Li, Esteban Abot, Arnel Belmonte, Kevin Hauns, Maria Belmonte, Jun Huang, Carlos Vasquez, Shon Remich, Mary Carrington, Yonas Abebe, Amy Tillman, Bradley Hickey, Jason Regules, Eileen Villasante, B Kim Lee Sim, Stephen L Hoffman
BACKGROUND: A radiation-attenuated Plasmodium falciparum (Pf) sporozoite (SPZ) malaria vaccine, PfSPZ Vaccine, protected 6 of 6 subjects (100%) against homologous Pf (same strain as in the vaccine) controlled human malaria infection (CHMI) 3 weeks after 5 doses administered intravenously. The next step was to assess protective efficacy against heterologous Pf (different from Pf in the vaccine), after fewer doses, and at 24 weeks. METHODS: The trial assessed tolerability, safety, immunogenicity, and protective efficacy of direct venous inoculation (DVI) of 3 or 5 doses of PfSPZ Vaccine in non-immune subjects...
January 12, 2017: JCI Insight
https://www.readbyqxmd.com/read/28097229/anti-sirp%C3%AE-antibodies-as-a-potential-new-tool-for-cancer-immunotherapy
#11
Tadahiko Yanagita, Yoji Murata, Daisuke Tanaka, Sei-Ichiro Motegi, Eri Arai, Edwin Widyanto Daniwijaya, Daisuke Hazama, Ken Washio, Yasuyuki Saito, Takenori Kotani, Hiroshi Ohnishi, Per-Arne Oldenborg, Noel Verjan Garcia, Masayuki Miyasaka, Osamu Ishikawa, Yae Kanai, Takahide Komori, Takashi Matozaki
Tumor cells are thought to evade immune surveillance through interaction with immune cells. Much recent attention has focused on the modification of immune responses as a basis for new cancer treatments. SIRPα is an Ig superfamily protein that inhibits phagocytosis in macrophages upon interaction with its ligand CD47 expressed on the surface of target cells. Here, we show that SIRPα is highly expressed in human renal cell carcinoma and melanoma. Furthermore, an anti-SIRPα Ab that blocks the interaction with CD47 markedly suppressed tumor formation by renal cell carcinoma or melanoma cells in immunocompetent syngeneic mice...
January 12, 2017: JCI Insight
https://www.readbyqxmd.com/read/28097228/kappa-opioid-receptor-signaling-protects-cartilage-tissue-against-posttraumatic-degeneration
#12
Ling Wu, Shu Zhang, Ruzanna Shkhyan, Siyoung Lee, Francesca Gullo, Claire D Eliasberg, Frank A Petrigliano, Kai Ba, Jing Wang, Yunfeng Lin, Denis Evseenko
Osteoarthritis is the most common form of arthritis, and pain relief with opioid-like drugs is a commonly used therapeutic for osteoarthritic patients. Recent studies published by our group showed that the kappa opioid receptor (KOR) is highly expressed during human development in joint-forming cells. However, the precise role of this receptor in the skeletal system remains elusive. The main aim of the current study was to investigate the role of KOR signaling in synovial and cartilaginous tissues in pathological conditions...
January 12, 2017: JCI Insight
https://www.readbyqxmd.com/read/28097227/a-xenogeneic-free-system-generating-functional-human-gut-organoids-from-pluripotent-stem-cells
#13
Hajime Uchida, Masakazu Machida, Takumi Miura, Tomoyuki Kawasaki, Takuya Okazaki, Kengo Sasaki, Seisuke Sakamoto, Noriaki Ohuchi, Mureo Kasahara, Akihiro Umezawa, Hidenori Akutsu
Functional intestines are composed of cell types from all 3 primary germ layers and are generated through a highly orchestrated and serial developmental process. Directed differentiation of human pluripotent stem cells (hPSCs) has been shown to yield gut-specific cell types; however, these structures do not reproduce critical functional interactions between cell types of different germ layers. Here, we developed a simple protocol for the generation of mature functional intestinal organoids from hPSCs under xenogeneic-free conditions...
January 12, 2017: JCI Insight
https://www.readbyqxmd.com/read/28097226/ifitm1-targets-hiv-1-latently-infected-cells-for-antibody-dependent-cytolysis
#14
Rui André Saraiva Raposo, Miguel de Mulder Rougvie, Dominic Paquin-Proulx, Phillip M Brailey, Vinicius D Cabido, Paul M Zdinak, Allison S Thomas, Szu-Han Huang, Greta A Beckerle, Richard B Jones, Douglas F Nixon
HIV-1 persistence in latent reservoirs during antiretroviral therapy (ART) is the main obstacle to virus eradication. To date, there is no marker that adequately identifies latently infected CD4(+) T cells in vivo. Using a well-established ex vivo model, we generated latently infected CD4(+) T cells and identified interferon-induced transmembrane protein 1 (IFITM1), a transmembrane antiviral factor, as being overexpressed in latently infected cells. By targeting IFITM1, we showed the efficient and specific killing of a latently infected cell line and CD4(+) T cells from ART-suppressed patients through antibody-dependent cytolysis...
January 12, 2017: JCI Insight
https://www.readbyqxmd.com/read/28018977/heterogeneous-perivascular-cell-coverage-affects-breast-cancer-metastasis-and-response-to-chemotherapy
#15
Jiha Kim, Pedro Correa de Sampaio, Donna Marie Lundy, Qian Peng, Kurt W Evans, Hikaru Sugimoto, Mihai Gagea, Yvonne Kienast, Nayra Soares do Amaral, Rafael Malagoli Rocha, Hans Petter Eikesdal, Per Eystein Lønning, Funda Meric-Bernstam, Valerie S LeBleu
Angiogenesis and co-optive vascular remodeling are prerequisites of solid tumor growth. Vascular heterogeneity, notably perivascular composition, may play a critical role in determining the rate of cancer progression. The contribution of vascular pericyte heterogeneity to cancer progression and therapy response is unknown. Here, we show that angiopoietin-2 (Ang2) orchestrates pericyte heterogeneity in breast cancer with an effect on metastatic disease and response to chemotherapy. Using multispectral imaging of human breast tumor specimens, we report that perivascular composition, as defined by the ratio of PDGFRβ(-) and desmin(+) pericytes, provides information about the response to epirubicin but not paclitaxel...
December 22, 2016: JCI Insight
https://www.readbyqxmd.com/read/28018976/identifying-the-third-dimension-in-2d-fluoroscopy-to-create-3d-cardiac-maps
#16
Jasbir Sra, David Krum, Indrajit Choudhuri, Barry Belanger, Mark Palma, Donald Brodnick, Daniel B Rowe
Three-dimensional cardiac mapping is important for optimal visualization of the heart during cardiac ablation for the treatment of certain arrhythmias. However, many hospitals and clinics worldwide cannot afford the high cost of the current mapping systems. We set out to determine if, using predefined algorithms, comparable 3D cardiac maps could be created by a new device that relies on data generated from single-plane fluoroscopy and patient recording and monitoring systems, without the need for costly equipment, infrastructure changes, or specialized catheters...
December 22, 2016: JCI Insight
https://www.readbyqxmd.com/read/28018975/disease-modifying-effects-of-orally-bioavailable-nf-%C3%AE%C2%BAb-inhibitors-in-dystrophin-deficient-muscle
#17
David W Hammers, Margaret M Sleeper, Sean C Forbes, Cora C Coker, Michael R Jirousek, Michael Zimmer, Glenn A Walter, H Lee Sweeney
Duchenne muscular dystrophy (DMD) is a devastating muscle disease characterized by progressive muscle deterioration and replacement with an aberrant fatty, fibrous matrix. Chronic upregulation of nuclear factor κB (NF-κB) is implicated as a driver of the dystrophic pathogenesis. Herein, 2 members of a novel class of NF-κB inhibitors, edasalonexent (formerly CAT-1004) and CAT-1041, were evaluated in both mdx mouse and golden retriever muscular dystrophy (GRMD) dog models of DMD. These orally bioavailable compounds consist of a polyunsaturated fatty acid conjugated to salicylic acid and potently suppress the pathogenic NF-κB subunit p65/RelA in vitro...
December 22, 2016: JCI Insight
https://www.readbyqxmd.com/read/28018974/hypoxia-sensing-through-%C3%AE-adrenergic-receptors
#18
Hoi I Cheong, Kewal Asosingh, Olivia R Stephens, Kimberly A Queisser, Weiling Xu, Belinda Willard, Bo Hu, Josephine Kam Tai Dermawan, George R Stark, Sathyamangla V Naga Prasad, Serpil C Erzurum
Life-sustaining responses to low oxygen, or hypoxia, depend on signal transduction by HIFs, but the underlying mechanisms by which cells sense hypoxia are not completely understood. Based on prior studies suggesting a link between the β-adrenergic receptor (β-AR) and hypoxia responses, we hypothesized that the β-AR mediates hypoxia sensing and is necessary for HIF-1α accumulation. Beta blocker treatment of mice suppressed hypoxia induction of renal HIF-1α accumulation, erythropoietin production, and erythropoiesis in vivo...
December 22, 2016: JCI Insight
https://www.readbyqxmd.com/read/28018973/inactivation-of-abl-kinases-suppresses-non-small-cell-lung-cancer-metastasis
#19
Jing Jin Gu, Clay Rouse, Xia Xu, Jun Wang, Mark W Onaitis, Ann Marie Pendergast
Current therapies to treat non-small cell lung carcinoma (NSCLC) have proven ineffective owing to transient, variable, and incomplete responses. Here we show that ABL kinases, ABL1 and ABL2, promote metastasis of lung cancer cells harboring EGFR or KRAS mutations. Inactivation of ABL kinases suppresses NSCLC metastasis to brain and bone, and other organs. ABL kinases are required for expression of prometastasis genes. Notably, ABL1 and ABL2 depletion impairs extravasation of lung adenocarcinoma cells into the lung parenchyma...
December 22, 2016: JCI Insight
https://www.readbyqxmd.com/read/28018972/metabolic-profiling-indicates-impaired-pyruvate-dehydrogenase-function-in-myalgic-encephalopathy-chronic-fatigue-syndrome
#20
Øystein Fluge, Olav Mella, Ove Bruland, Kristin Risa, Sissel E Dyrstad, Kine Alme, Ingrid G Rekeland, Dipak Sapkota, Gro V Røsland, Alexander Fosså, Irini Ktoridou-Valen, Sigrid Lunde, Kari Sørland, Katarina Lien, Ingrid Herder, Hanne Thürmer, Merete E Gotaas, Katarzyna A Baranowska, Louis M L J Bohnen, Christoph Schäfer, Adrian McCann, Kristian Sommerfelt, Lars Helgeland, Per M Ueland, Olav Dahl, Karl J Tronstad
Myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) is a debilitating disease of unknown etiology, with hallmark symptoms including postexertional malaise and poor recovery. Metabolic dysfunction is a plausible contributing factor. We hypothesized that changes in serum amino acids may disclose specific defects in energy metabolism in ME/CFS. Analysis in 200 ME/CFS patients and 102 healthy individuals showed a specific reduction of amino acids that fuel oxidative metabolism via the TCA cycle, mainly in female ME/CFS patients...
December 22, 2016: JCI Insight
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