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https://www.readbyqxmd.com/read/28651365/cathepsin-k-inhibitors-for-osteoporosis-biology-potential-clinical-utility-and-lessons-learned
#1
Matthew T Drake, Bart L Clarke, Merry Jo Oursler, Sundeep Khosla
Cathepsin K is a cysteine protease member of the cathepsin lysosomal protease family. While cathepsin K is highly expressed in osteoclasts, lower levels of cathepsin K are also found in a variety of other tissues. Secretion of cathepsin K from the osteoclast into the sealed osteoclast-bone cell interface results in efficient degradation of type I collagen. The absence of cathepsin K activity in humans results in pycnodysostosis, characterized by increased bone mineral density and fractures. Pharmacological cathepsin K inhibition leads to continuous increases in BMD for up to five years of treatment and improves bone strength at the spine and hip...
June 23, 2017: Endocrine Reviews
https://www.readbyqxmd.com/read/28651122/activation-of-irf3-contributes-to-ifn-%C3%AE-and-isg54-expression-during-the-immune-responses-to-b16f10-tumor-growth
#2
Zachary Guinn, Deborah M Brown, Thomas M Petro
Interferon Regulatory Factor (IRF-3) has been shown to contribute to immune control of B16 melanoma tumor growth. We have shown previously that IRF-3 has a role in IFN-γ-induced expression of pro-apoptotic interferon stimulated gene 54 (ISG54) in macrophages and IFN-γ in T cells. To investigate the IRF3-IFN-γ-ISG54 nexus, we injected C57Bl/6 (B6) and IRF3KO mice s.c. with luciferase-producing B16-F10 tumor cells. Tumor growth as measured by luciferase levels was similar between B6 and IRF3KO mice at days 2 and 6, but was significantly greater at day 9 in IRF3KO mice compared with B6 mice...
June 23, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28651073/hemophilia-a-inhibitor-treatment-the-promise-of-engineered-t-cell-therapy
#3
REVIEW
Kalpana Parvathaneni, Maha Abdeladhim, Kathleen P Pratt, David W Scott
Hemophilia A is a bleeding disorder caused by mutations in the gene encoding factor VIII (FVIII), a cofactor protein that is essential for normal blood clotting. Approximately, 1 in 3 patients with severe hemophilia A produce neutralizing antibodies (inhibitors) that block its biologic function in the clotting cascade. Current efforts to eliminate inhibitors consist of repeated FVIII injections under what is termed an "ITI" protocol (Immune Tolerance Induction). However, this method is extremely costly and approximately 30% of patients undergoing ITI do not achieve peripheral tolerance...
June 9, 2017: Translational Research: the Journal of Laboratory and Clinical Medicine
https://www.readbyqxmd.com/read/28650992/galectin-8-as-an-immunosuppressor-in-experimental-autoimmune-encephalomyelitis-and-a-target-of-human-early-prognostic-antibodies-in-multiple-sclerosis
#4
Evelyn Pardo, Claudia Cárcamo, Reinaldo Uribe-San Martín, Ethel Ciampi, Fabián Segovia-Miranda, Cristobal Curkovic-Peña, Fabián Montecino, Christopher Holmes, Juan Enrique Tichauer, Eric Acuña, Francisco Osorio-Barrios, Marjorie Castro, Priscilla Cortes, Claudia Oyanadel, David M Valenzuela, Rodrigo Pacheco, Rodrigo Naves, Andrea Soza, Alfonso González
Galectin-8 (Gal-8) is a member of a glycan-binding protein family that regulates the immune system, among other functions, and is a target of antibodies in autoimmune disorders. However, its role in multiple sclerosis (MS), an autoimmune inflammatory disease of the central nervous system (CNS), remains unknown. We study the consequences of Gal-8 silencing on lymphocyte subpopulations and the development of experimental autoimmune encephalitis (EAE), to then assess the presence and clinical meaning of anti-Gal-8 antibodies in MS patients...
2017: PloS One
https://www.readbyqxmd.com/read/28650473/testes-specific-protease-50-promotes-cell-proliferation-via-inhibiting-activin-signaling
#5
Z-B Song, P Wu, J-S Ni, T Liu, C Fan, Y-L Bao, Y Wu, L-G Sun, C-L Yu, Y-X Huang, Y-X Li
Testes-specific protease 50 (TSP50), a novelly identified oncogene, has the capacity to induce cell proliferation, cell invasion and tumor growth. Further studies indicated that CAGA-luc (an activin-responsive reporter construct) reporter activity could be significantly suppressed by TSP50 overexpression, implying that the activin signaling may participate in TSP50-mediated cell proliferation. Here, we reported that TSP50 had an inhibitory effect on activin signaling. Mechanistic studies revealed that TSP50 could interact with ActRIIA, inhibit activin typeIreceptor (ActRIB) phosphorylation, repress Smad2/3 nuclear accumulation and finally promote cell proliferation by reducing the expression of activin signal target gene p27...
June 26, 2017: Oncogene
https://www.readbyqxmd.com/read/28650470/signaling-coupled-epigenomic-regulation-of-gene-expression
#6
REVIEW
R Kumar, S Deivendran, T R Santhoshkumar, M R Pillai
Inheritance of genomic information independent of the DNA sequence, the epigenetics, as well as gene transcription are profoundly shaped by serine/threonine and tyrosine signaling kinases and components of the chromatin remodeling complexes. To precisely respond to a changing external milieu, human cells efficiently translate upstream signals into post-translational modifications (PTMs) on histones and coregulators such as corepressors, coactivators, DNA-binding factors and PTM modifying enzymes. Because a protein with multiple residues for putative PTMs is expected to undergo more than one PTM in cells stimulated with growth factors, the outcome of combinational PTM codes on histones and coregulators is profoundly shaped by regulatory interplays between PTMs...
June 26, 2017: Oncogene
https://www.readbyqxmd.com/read/28650445/a-distinct-function-of-the-retinoblastoma-protein-in-the-control-of-lipid-composition-identified-by-lipidomic-profiling
#7
H Muranaka, A Hayashi, K Minami, S Kitajima, S Kohno, Y Nishimoto, N Nagatani, M Suzuki, L A N Kulathunga, N Sasaki, N Okada, T Matsuzaka, H Shimano, H Tada, C Takahashi
Here, by combining lipidomics with transcriptome analysis, we demonstrate that Rb depletion in mouse embryonic fibroblastss induces significant alterations in their lipid composition. We discovered that Rb depletion induced increase in lysophosphatidylserine, diacylglycerol (DAG), fatty acid (FA), acylcarnitine, phosphatidylcholine (PC), arachidonoyl ethanolamine, and decrease in phosphatidylglycerol, monoacylglycerol, without change in total lipid per protein levels. Analysis of the acyl chain composition of DAG, PC and phosphatidylserine revealed increase of saturated and mono-unsaturated acyl chains with specific carbon chain length...
June 26, 2017: Oncogenesis
https://www.readbyqxmd.com/read/28650437/antigen-capturing-nanoparticles-improve-the-abscopal-effect-and-cancer-immunotherapy
#8
Yuanzeng Min, Kyle C Roche, Shaomin Tian, Michael J Eblan, Karen P McKinnon, Joseph M Caster, Shengjie Chai, Laura E Herring, Longzhen Zhang, Tian Zhang, Joseph M DeSimone, Joel E Tepper, Benjamin G Vincent, Jonathan S Serody, Andrew Z Wang
Immunotherapy holds tremendous promise for improving cancer treatment. To administer radiotherapy with immunotherapy has been shown to improve immune responses and can elicit the 'abscopal effect'. Unfortunately, response rates for this strategy remain low. Herein we report an improved cancer immunotherapy approach that utilizes antigen-capturing nanoparticles (AC-NPs). We engineered several AC-NP formulations and demonstrated that the set of protein antigens captured by each AC-NP formulation is dependent on the NP surface properties...
June 26, 2017: Nature Nanotechnology
https://www.readbyqxmd.com/read/28650331/expression-of-th17-and-cd4-cd25-t-regulatory-cells-in-peripheral-blood-of-acute-leukemia-patients-and-their-prognostic-significance
#9
Mingli Xiang, Li Guo, Yan Ma, Yi Li
To discuss the expression of T helper cell 17 (Th17) cells and CD4+ CD25+ Foxp3+ regulatory T cells (Treg) in peripheral blood (PB) of patients with acute leukemia (AL), and to explore the relationship between them and disease prognosis. 40 patients diagnosed with acute leukemia in The First Affiliated Hospital of Zhengzhou University from July 2012 to August 2014 were selected as the observation group. Meanwhile, 40 healthy people were taken as the control group. Flow Cytometry Method (FCM) was used to detect the level of Th17 cells and CD4(+) CD25(+) Foxp3(+) cells in peripheral blood of the two groups, and enzyme-linked immuno sorbent assay (ELISA) method was used to test the level of IL17 and TGF-β in peripheral blood of two groups; reverse transcription-polymerase chain reaction (RT-PCR) was adopted to analyze the mRNA levels of RORγT and Foxp3 in peripheral blood...
March 2017: Pakistan Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28649611/lrrk2-levels-in-immune-cells-are-increased-in-parkinson-s-disease
#10
D A Cook, G T Kannarkat, A F Cintron, Laura M Butkovich, Kyle B Fraser, J Chang, N Grigoryan, S A Factor, Andrew B West, J M Boss, M G Tansey
Mutations associated with leucine-rich repeat kinase 2 are the most common known cause of Parkinson's disease. The known expression of leucine-rich repeat kinase 2 in immune cells and its negative regulatory function of nuclear factor of activated T cells implicates leucine-rich repeat kinase 2 in the development of the inflammatory environment characteristic of Parkinson's disease. The aim of this study was to determine the expression pattern of leucine-rich repeat kinase 2 in immune cell subsets and correlate it with the immunophenotype of cells from Parkinson's disease and healthy subjects...
2017: NPJ Parkinson's Disease
https://www.readbyqxmd.com/read/28649610/evaluation-of-the-safety-and-immunomodulatory-effects-of-sargramostim-in-a-randomized-double-blind-phase-1-clinical-parkinson-s-disease-trial
#11
Howard E Gendelman, Yuning Zhang, Pamela Santamaria, Katherine E Olson, Charles R Schutt, Danish Bhatti, Bhagya Laxmi Dyavar Shetty, Yaman Lu, Katherine A Estes, David G Standaert, Elizabeth Heinrichs-Graham, LuAnn Larson, Jane L Meza, Matthew Follett, Erica Forsberg, Gary Siuzdak, Tony W Wilson, Carolyn Peterson, R Lee Mosley
A potential therapeutic role for immune transformation in Parkinson's disease evolves from more than a decade of animal investigations demonstrating regulatory T cell (Treg) nigrostriatal neuroprotection. To bridge these results to human disease, we conducted a randomized, placebo-controlled double-blind phase 1 trial with a well-studied immune modulator, sargramostim (granulocyte-macrophage colony-stimulating factor). We enrolled 17 age-matched non-Parkinsonian subjects as non-treated controls and 20 Parkinson's disease patients...
2017: NPJ Parkinson's Disease
https://www.readbyqxmd.com/read/28649380/gitr-ligand-fusion-protein-agonist-enhances-the-tumor-antigen-specific-cd8-t-cell-response-and-leads-to-long-lasting-memory
#12
Nick M Durham, Nick Holoweckyj, Randall S MacGill, Kelly McGlinchey, Ching Ching Leow, Scott H Robbins
BACKGROUND: The expansion of antigen-specific CD8 T cells is important in generating an effective and long-lasting immune response to tumors and viruses. Glucocorticoid-induced tumor necrosis factor receptor family-related receptor (GITR) is a co-stimulatory receptor that binds the GITR ligand (GITRL). Agonism of GITR can produce important signals that drive expansion of effector T cell populations. METHODS: We explored two separate murine tumor models, CT26 and TC-1, for responsiveness to GITR Ligand Fusion Protein(GITRL-FP) monotherapy...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28649243/distinct-blood-and-visceral-adipose-tissue-regulatory-t-cell-and-innate-lymphocyte-profiles-characterize-obesity-and-colorectal-cancer
#13
Gloria Donninelli, Manuela Del Cornò, Marina Pierdominici, Beatrice Scazzocchio, Rosaria Varì, Barbara Varano, Ilenia Pacella, Silvia Piconese, Vincenzo Barnaba, Massimo D'Archivio, Roberta Masella, Lucia Conti, Sandra Gessani
Visceral adipose tissue (VAT) is a main site where metabolic and immunologic processes interplay to regulate, at local and systemic level, the inflammatory status and immune response. Obesity-associated inflammation and immune dysfunctions are inextricably linked to tumor but, in spite of intense efforts, the mechanisms underpinning this association remain elusive. In this report, we characterized the profile of VAT-associated and circulating innate lymphocyte and regulatory T (Treg) cell subsets underlying inflammatory conditions, such as obesity and colorectal cancer (CRC)...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28649127/the-novel-%C3%AE-glucan-ycp-improves-the-survival-rates-and-symptoms-in-septic-mice-by-regulating-myeloid-derived-suppressor-cells
#14
Dan Liu, Ming You, Guang-Feng Zhao, Xiu-Jun Li, Yu-Xian Song, Huan Dou, Wen-Bing Yao, Xiang-Dong Gao, Ya-Yi Hou
Sepsis is a life-threatening health condition that is initially characterized by uncontrolled inflammation, followed by the development of persistent immunosuppression. YCP is a novel α-glucan purified from the mycelium of the marine fungus Phoma herbarum YS4108, which has displayed strong antitumor activity via enhancing host immune responses. In this study, we investigated whether YCP could influence the development of sepsis in a mouse model. Caecal ligation and puncture (CLP)-induced sepsis was established in mice that were treated with YCP (20 mg/kg, ip or iv) 2 h before, 4 and 24 h after the CLP procedure, and then every other day...
June 26, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28649004/macc1-regulates-fas-mediated-apoptosis-through-stat1-3-mcl-1-signaling-in-solid-cancers
#15
Harikrishnan Radhakrishnan, Katharina Ilm, Wolfgang Walther, Senji Shirasawa, Takehiko Sasazuki, Peter T Daniel, Bernhard Gillissen, Ulrike Stein
MACC1 was identified as a novel player in cancer progression and metastasis, but its role in death receptor-mediated apoptosis is still unexplored. We show that MACC1 knockdown sensitizes cancer cells to death receptor-mediated apoptosis. For the first time, we provide evidence for STAT signaling as a MACC1 target. MACC1 knockdown drastically reduced STAT1/3 activating phosphorylation, thereby regulating the expression of its apoptosis targets Mcl-1 and Fas. STAT signaling inhibition by the JAK1/2 inhibitor ruxolitinib mimicked MACC1 knockdown-mediated molecular signatures and apoptosis sensitization to Fas activation...
June 22, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28648941/low-grade-fibromyxoid-sarcoma-clinical-morphologic-and-genetic-features
#16
REVIEW
Mustafa Mohamed, Cyril Fisher, Khin Thway
Low-grade fibromyxoid sarcoma (LGFMS) is a bland spindle cell neoplasm that typically arises in the deep soft tissues of the proximal extremities or trunk of young adults. The majority of LGFMS are characterized by a recurrent (7;16)(q34;p11) translocation, resulting in the FUS-CREB3L2 fusion gene, which generates a chimeric protein with transcriptional regulatory activity. Small numbers harbor a FUS-CREB3L1 fusion resulting from t(11;16)(p11;p11), whilst rare cases harbor the EWSR1-CREB3L1 fusion. LGFMS is of low to moderate cellularity and consists of bland spindle cells with small, angulated nuclei and scant, wispy cytoplasm, arranged in a whorled growth pattern and typically showing abrupt transition from myxoid to fibrous areas...
June 2017: Annals of Diagnostic Pathology
https://www.readbyqxmd.com/read/28648940/upregulation-of-inhibitory-signaling-receptor-programmed-death-marker-1-pd-1-in-disease-evolution-from-cutaneous-lymphoid-dyscrasias-to-mycosis-fungoides-and-sezary-s-syndrome
#17
Giang Huong Nguyen, Luke C Olson, Cynthia M Magro
BACKGROUND: Negative immunoregulatory checkpoints impede effective immune responses to tumor and reduce the action of anticancer agents. One such example is programmed death marker-1 (PD-1), an inhibitory signaling receptor expressed on activated and regulatory T-cells. PD-1 expression was reported in a few reports, but the expression profile of PD-1 and mycosis fungoides (MF) remains largely to be characterized. DESIGN: In this study, skin biopsies from 42 prelymphomatous T-cell dyscrasias (CLD), 9 Sezary's syndrome (SS), 103 MF, and 20 CD30+ lymphoproliferative diseases (LPD) were examined for PD-1 expression using immunohistochemistry...
June 2017: Annals of Diagnostic Pathology
https://www.readbyqxmd.com/read/28648519/an-upregulation-of-cd8-cd25-foxp3-t-cells-with-suppressive-function-through-interleukin-2-pathway-in-pulmonary-arterial-hypertension
#18
Rong Zhu, Liang Chen, Yaqiong Xiong, Nana Wang, Xiaochen Xie, Yongqing Hong, Zili Meng
Accumulating evidence suggests that abnormal inflammation plays a critical role in the pathogenesis of pulmonary arterial hypertension (PAH). CD8(+)CD25(+)Foxp3(+) T cell is a novel cell subtype, and its role in PAH is not yet investigated. Here, we observed that PAH patients presented a significant upregulation of CD8(+)CD25(+)Foxp3(+) T cells and a downregulation of CD4(+)CD25(+)Foxp3(+) T cells compared to healthy controls. Regardless, the total number of CD25(+)Foxp3(+) T cells in PAH patients was still smaller than that in healthy controls...
June 22, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28648384/a-novel-and-rapid-method-to-quantify-treg-mediated-suppression-of-cd4-t-cells
#19
Anna E Long, Megan Tatum, Carmen Mikacenic, Jane H Buckner
Measuring regulatory T cell suppression provides important insight into T cell dysfunction in autoimmune disease. However, to date, suppression assays are limited by the requirement for freshly isolated cells, and significant cell numbers. Here, we present a novel and rapid in vitro assay using effector T cell surface expression of both CD25 and CD134 as a surrogate marker of regulatory T cell-mediated suppression. This surface marker-based suppression assay works for frozen samples and for samples with limited cell numbers...
June 22, 2017: Journal of Immunological Methods
https://www.readbyqxmd.com/read/28648331/il-35-as-a-newly-proposed-homeostasis-associated-molecular-pattern-plays-three-major-functions-including-anti-inflammatory-initiator-effector-and-blocker-in-cardiovascular-diseases
#20
Xinyuan Li, Pu Fang, William Y Yang, Hong Wang, Xiaofeng Yang
IL-35 is a new anti-inflammatory cytokine identified in 2007, which inhibits inflammation and immune responses by inducing regulatory T cells and regulatory B cells and suppressing effector T cells and macrophages. The unique initiator and effector anti-inflammatory properties of IL-35 bring tremendous interest in investigating its role during cardiovascular disease (CVD) development, in which inflammatory processes are firmly established as central to its development and complications. In this review, we update recent understanding of how IL-35 is produced and regulated in the cells...
June 22, 2017: Cytokine
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