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https://www.readbyqxmd.com/read/28916522/viral-infection-sensitizes-human-fetal-membranes-to-bacterial-lipopolysaccharide-by-mertk-inhibition-and-inflammasome-activation
#1
Sarah N Cross, Julie A Potter, Paulomi Aldo, Ja Young Kwon, Mary Pitruzzello, Mancy Tong, Seth Guller, Carla V Rothlin, Gil Mor, Vikki M Abrahams
Chorioamnionitis, premature rupture of fetal membranes (FMs), and subsequent preterm birth are associated with local infection and inflammation, particularly IL-1β production. Although bacterial infections are commonly identified, other microorganisms may play a role in the pathogenesis. Because viral pandemics, such as influenza, Ebola, and Zika, are becoming more common, and pregnant women are at increased risk for associated complications, this study evaluated the impact that viral infection had on human FM innate immune responses...
September 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28904208/genome-wide-screen-of-gamma-secretase-mediated-intramembrane-cleavage-of-receptor-tyrosine-kinases
#2
Johannes A M Merilahti, Veera K Ojala, Anna M Knittle, Arto T Pulliainen, Klaus Elenius
Receptor tyrosine kinases (RTK) have been demonstrated to signal via regulated intramembrane proteolysis (RIP), in which ectodomain shedding and subsequent intramembrane cleavage by gamma-secretase leads to release of a soluble intracellular receptor fragment with functional activity. For most RTKs, however, it is not known whether they can exploit this new signaling mechanism or not. Here we used a system-wide screen to address the frequency of susceptibility to gamma-secretase cleavage among human RTKs. The screen covering 45 of the 55 human RTKs identified 12 new as well as all 9 previously published gamma-secretase substrates...
September 13, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28903394/melittin-suppresses-tumor-progression-by-regulating-tumor-associated-macrophages-in-a-lewis-lung-carcinoma-mouse-model
#3
Chanju Lee, Sung-Joo S Bae, Hwansoo Joo, Hyunsu Bae
Tumor-associated macrophages (TAM) are a major component of tumor stroma. It has been reported that TAMs have M2-like phenotype and facilitate tumor progression by promoting angiogenesis and immunosuppression. Melittin, a major polypeptide of bee venom, has been widely studied as an anti-cancer drug due to its cytotoxicity to malignant cells. However, very little is known regarding the effect of melittin on immune cells in the tumor microenvironment. This study focuses on the effect of melittin on TAMs in a Lewis lung carcinoma mouse model...
August 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28901507/%C3%AE-7-nicotinic-acetylcholine-receptor-in-tumor-associated-macrophages-inhibits-colorectal-cancer-metastasis-through-the-jak2-stat3-signaling-pathway
#4
Rushan Fei, Yuanwei Zhang, Saisai Wang, Tao Xiang, Wenbin Chen
Considerable evidence has implied that α7 nicotinic receptor subtypes play an important role in chronic inflammatory and neuropathic pain signaling. The aim of the present study was to determine the role of endogenous α7nAChR signaling in tumor-associated macrophages (TAMs) in human colorectal cancer (CRC) metastasis and prognosis. α7nAChR expression in primary tumor cells and adjacent stroma cells especially in TAMs in 51 CRC patients was observed. Using a human monocyte THP-derived macrophages (TMs) with α7nAChR-siRNA knockdown (TMα7-/-) and a CRC cell Transwell co-culture model, the migration and invasion of two CRC cells, LoVo and SW620, were determined...
September 4, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28881721/lower-beclin-1-downregulates-her2-expression-to-enhance-tamoxifen-sensitivity-and-predicts-a-favorable-outcome-for-er-positive-breast-cancer
#5
Yu Gu, Tianxiang Chen, Guangliang Li, Cong Xu, Zhenzhen Xu, Jing Zhang, Kuifeng He, Linyan Zheng, Zhonghai Guan, Xinyun Su, Jiang Cao, Lisong Teng
Tamoxifen(TAM) is one of the most effective endocrine treatment for estrogen receptor(ER)-positive breast cancer, however drug resistance greatly limits benefit of it. Our purpose is to uncover the role of Beclin 1 in tamoxifen resistance and prognosis of ER positive breast cancer. We established a tamoxifen resistant ER-positive breast cancer cell subline MCF-7R presenting with higher Beclin 1 and human epidermal growth factor receptor 2(HER2) levels than MCF-7. Silencing Beclin 1 decreased levels of HER2 and significantly promoted TAM sensitivity of MCF-7 and MCF-7R in vitro...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28881682/inhibition-of-fak-kinase-activity-preferentially-targets-cancer-stem-cells
#6
Vihren N Kolev, Winnie F Tam, Quentin G Wright, Sean P McDermott, Christian M Vidal, Irina M Shapiro, Qunli Xu, Max S Wicha, Jonathan A Pachter, David T Weaver
Because cancer stem cells (CSCs) have been implicated in chemo-resistance, metastasis and tumor recurrence, therapeutic targeting of CSCs holds promise to address these clinical challenges to cancer treatment. VS-4718 and VS-6063 are potent inhibitors of focal adhesion kinase (FAK), a non-receptor tyrosine kinase that mediates cell signals transmitted by integrins and growth factor receptors. We report here that inhibition of FAK kinase activity by VS-4718 or VS-6063 preferentially targets CSCs, as demonstrated by a panel of orthogonal CSC assays in cell line models and surgically resected primary breast tumor specimens cultured ex vivo...
August 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28878029/interleukin-4-receptor-targeted-pro-apoptotic-peptide-blocks-tumor-growth-and-metastasis-by-enhancing-anti-tumor-immunity
#7
Sri Murugan Poongkavithai Vadevoo, Jung-Eun Kim, Gowri Rangaswamy Gunassekaran, Hyun-Kyung Jung, Lianhua Chi, Dong Eon Kim, Seung-Hyo Lee, Sin-Hyeog Im, Byungheon Lee
Cellular crosstalk between tumors and M2-polarized tumor-associated macrophages (TAMs) favors tumor progression. Upregulation of interleukin 4 receptor (IL4R) is observed in diverse tumors and TAMs. We tested whether an IL4R-targeted pro-apoptotic peptide could inhibit tumor progression. The IL4R-binding peptide (IL4RPep-1) preferentially bound to IL4R-expressing tumor cells and M2-polarized macrophages both in vitro and in 4T1 breast tumors in vivo. To selectively kill IL4R-expressing cells, we designed an IL4R-targeted pro-apoptotic peptide, IL4RPep-1-K, by adding the pro-apoptotic peptide (KLAKLAK)2 to the end of IL4RPep-1...
September 6, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28874532/schwann-cells-use-tam-receptor-mediated-phagocytosis-in-addition-to-autophagy-to-clear-myelin-in-a-mouse-model-of-nerve-injury
#8
Amanda Brosius Lutz, Won-Suk Chung, Steven A Sloan, Glenn A Carson, Lu Zhou, Emilie Lovelett, Sean Posada, J Bradley Zuchero, Ben A Barres
Ineffective myelin debris clearance is a major factor contributing to the poor regenerative ability of the central nervous system. In stark contrast, rapid clearance of myelin debris from the injured peripheral nervous system (PNS) is one of the keys to this system's remarkable regenerative capacity, but the molecular mechanisms driving PNS myelin clearance are incompletely understood. We set out to discover new pathways of PNS myelin clearance to identify novel strategies for activating myelin clearance in the injured central nervous system, where myelin debris is not cleared efficiently...
September 5, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28860163/proximal-tubular-cannabinoid-1-receptor-regulates-obesity-induced-ckd
#9
Shiran Udi, Liad Hinden, Brian Earley, Adi Drori, Noa Reuveni, Rivka Hadar, Resat Cinar, Alina Nemirovski, Joseph Tam
Obesity-related structural and functional changes in the kidney develop early in the course of obesity and occur independently of hypertension, diabetes, and dyslipidemia. Activating the renal cannabinoid-1 receptor (CB1R) induces nephropathy, whereas CB1R blockade improves kidney function. Whether these effects are mediated via a specific cell type within the kidney remains unknown. Here, we show that specific deletion of CB1R in the renal proximal tubule cells did not protect the mice from obesity, but markedly attenuated the obesity-induced lipid accumulation in the kidney and renal dysfunction, injury, inflammation, and fibrosis...
August 31, 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/28858473/molecular-targeted-immunotherapeutic-strategy-for-melanoma-via-dual-targeting-nanoparticles-delivering-small-interfering-rna-to-tumor-associated-macrophages
#10
Yuan Qian, Sha Qiao, Yanfeng Dai, Guoqiang Xu, Bolei Dai, Lisen Lu, Xiang Yu, Qingming Luo, Zhihong Zhang
Tumor-associated macrophages (TAMs) are a promising therapeutic target for cancer immunotherapy. Targeted delivery of therapeutic drugs to the tumor-promoting M2-like TAMs is challenging. Here, we developed M2-like TAM dual-targeting nanoparticles (M2NPs), whose structure and function were controlled by α-peptide (a scavenger receptor B type 1 (SR-B1) targeting peptide) linked with M2pep (an M2 macrophage binding peptide). By loading anti-colony stimulating factor-1 receptor (anti-CSF-1R) small interfering RNA (siRNA) on the M2NPs, we developed a molecular-targeted immunotherapeutic approach to specifically block the survival signal of M2-like TAMs and deplete them from melanoma tumors...
September 6, 2017: ACS Nano
https://www.readbyqxmd.com/read/28842504/functional-defects-in-clostridium-difficile-tcdb-toxin-uptake-identify-cspg4-receptor-binding-determinants
#11
Pulkit Gupta, Zhifen Zhang, Seiji N Sugiman-Marangos, John Tam, Swetha Raman, Jean-Philippe Julien, Heather K Kroh, D Borden Lacy, Nicholas Murgolo, Kavitha Bekkari, Alex G Therien, Lorraine D Hernandez, Roman A Melnyk
Clostridium difficile is a major nosocomial pathogen that produces two exotoxins, TcdA and TcdB, with TcdB thought to be the primary determinant in human disease. TcdA and TcdB are large, multi-domain proteins, each harboring a cytotoxic glucosyltransferase domain that is delivered into the cytosol from endosomes via a translocation domain following receptor-mediated endocytosis of toxins from the cell surface. While there are currently no known host cell receptors for TcdA, three cell-surface receptors for TcdB have been identified: CSPG4, NECTIN3 and FZD1/2/7...
August 23, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28839265/combinatorial-bioactive-botanicals-re-sensitize-tamoxifen-treatment-in-er-negative-breast-cancer-via-epigenetic-reactivation-of-er%C3%AE-expression
#12
Yuanyuan Li, Syed M Meeran, Trygve O Tollefsbol
Conventional cancer prevention has primarily focused on single chemopreventive compounds that may not be sufficiently efficacious. We sought to investigate potential combinatorial effects of epigenetic bioactive botanicals including epigallocatechin-3-gallate (EGCG) in green tea polyphenols (GTPs) and sulforaphane (SFN) in broccoli sprouts (BSp) on neutralizing epigenetic aberrations in estrogen receptor-α (ERα) leading to enhanced anti-hormone therapeutic efficacy in ERα-negative breast cancer. Our results showed that this combinatorial treatment re-sensitized ERα-dependent cellular inhibitory responses to an estrogen antagonist, tamoxifen (TAM), via at least in part, epigenetic reactivation of ERα expression in ERα-negative breast cancer cells...
August 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28834216/beyond-the-m-csf-receptor-novel-therapeutic-targets-in-tumor-associated-macrophages
#13
REVIEW
Stefano Bonelli, Xenia Geeraerts, Evangelia Bolli, Jiri Keirsse, Maté Kiss, Ana Rita Pombo Antunes, Helena Van Damme, Karen De Vlaminck, Kiavash Movahedi, Damya Laoui, Geert Raes, Jo A Van Ginderachter
Tumor-associated macrophages (TAM) are by now established as important regulators of tumor progression by impacting on tumor immunity, angiogenesis and metastasis. Hence, a multitude of approaches are currently pursued to intervene with TAM's protumor activities, the most advanced of which being a blockade of M-CSF/M-CSFR signaling. M-CSFR signaling largely impacts on the differentiation of macrophages, including TAM, and hence strongly influences the numbers of these cells in tumors. However, a repolarization of TAM towards a more antitumor phenotype may be more elegant and may yield stronger effects on tumor growth...
August 20, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28833396/a-mir-7-gas6-tyro3-axis-regulates-the-growth-and-invasiveness-of-sorafenib-resistant-cells-in-human-hepatocellular-carcinoma
#14
T D Kabir, C Ganda, R M Brown, D J Beveridge, K L Richardson, V Chaturvedi, P Candy, M Epis, L Wintle, F Kalinowski, C Kopp, L M Stuart, G C Yeoh, J George, P J Leedman
Sorafenib remains the only approved drug for treating patients with advanced hepatocellular carcinoma (HCC). However, the therapeutic effect of sorafenib is transient and patients invariably develop sorafenib resistance (SR). Recently, TYRO3, a member of the TAM family of receptor tyrosine kinases, was identified as being aberrantly expressed in a significant proportion of HCC, however its role in SR is unknown. In this study, we generated two functionally distinct sorafenib resistant human Huh-7 HCC cell lines, in order to identify new mechanisms to abrogate acquired SR, as well as new potential therapeutic targets in HCC...
August 18, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28830860/human%C3%A2-pluripotent-stem-cell-derived-tsc2-haploinsufficient-smooth-muscle-cells-recapitulate%C3%A2-features-of-lymphangioleiomyomatosis
#15
Lisa M Julian, Sean P Delaney, Ying Wang, Alexander A Goldberg, Carole Doré, Julien Yockell-Lelièvre, Roger Y Tam, Krinio Giannikou, Fiona McMurray, Molly S Shoichet, Mary-Ellen Harper, Elizabeth P Henske, David J Kwiatkowski, Thomas N Darling, Joel Moss, Arnold S Kristof, William L Stanford
Lymphangioleiomyomatosis (LAM) is a progressive destructive neoplasm of the lung associated with inactivating mutations in the TSC1 or TSC2 tumor suppressor genes. Cell or animal models that accurately reflect the pathology of LAM have been challenging to develop. Here we generated a robust human cell model of LAM by reprogramming TSC2 mutation-bearing fibroblasts from a patient with both Tuberous Sclerosis Complex (TSC) and LAM (TSC-LAM) into induced pluripotent stem cells (iPSCs), followed by selection of cells that resemble those found in LAM tumors by unbiased in vivo differentiation...
August 22, 2017: Cancer Research
https://www.readbyqxmd.com/read/28828403/stress-increases-peripheral-axon-growth-and-regeneration-through-glucocorticoid-receptor-dependent-transcriptional-programs
#16
Jessica K Lerch, Jessica K Alexander, Kathryn M Madalena, Dario Motti, Tam Quach, Akhil Dhamija, Alicia Zha, John C Gensel, Jeanette Webster Marketon, Vance P Lemmon, John L Bixby, Phillip G Popovich
Stress and glucocorticoid (GC) release are common behavioral and hormonal responses to injury or disease. In the brain, stress/GCs can alter neuron structure and function leading to cognitive impairment. Stress and GCs also exacerbate pain, but whether a corresponding change occurs in structural plasticity of sensory neurons is unknown. Here, we show that in female mice (Mus musculus) basal GC receptor (Nr3c1, also known as GR) expression in dorsal root ganglion (DRG) sensory neurons is 15-fold higher than in neurons in canonical stress-responsive brain regions (M...
July 2017: ENeuro
https://www.readbyqxmd.com/read/28804691/combination-of-celecoxib-celebrex-%C3%A2-and-cd19-car-redirected-ctl-immunotherapy-for-the-treatment-of-b-cell-non-hodgkin-s-lymphomas
#17
REVIEW
Tam Nm Dinh, Alexandra S Onea, Ali R Jazirehi
The nonsteroidal anti-inflammatory drug (NSAID) Celecoxib (Celebrex(®)) received Food and Drug Administration (FDA) approval in 1998 for treatment of osteoarthritis and rheumatoid arthritis, and in recent years, its use has been extended to various types of malignancies, such as breast, colon, and urinary cancers. To maintain the survival of malignant B cells, non-Hodgkin's Lymphoma (NHL) is highly dependent on inflammatory microenvironment, and is inhibited by celecoxib. Celecoxib hinders tumor growth interacting with various apoptotic genes, such as cyclooxygenase-2 (Cox-2), B-cell lymphoma 2 (Bcl-2) family, phosphor-inositide-3 kinase/serine-threonine-specific protein kinase (PI3K/Akt), and inhibitors of apoptosis proteins (IAP) family...
2017: American Journal of Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/28802563/metabolic-circuit-involving-free-fatty-acids-microrna-122-and-triglyceride-synthesis-in-liver-and-muscle-tissues
#18
Chofit Chai, Mila Rivkin, Liav Berkovits, Alina Simerzin, Elina Zorde-Khvalevsky, Nofar Rosenberg, Shiri Klein, Dayana Yaish, Ronen Durst, Shoshana Shpitzen, Shiran Udi, Joseph Tam, Joerg Heeren, Anna Worthmann, Christoph Schramm, Johannes Kluwe, Revital Ravid, Eran Hornstein, Hilla Giladi, Eithan Galun
BACKGROUND & AIMS: Effective treatments are needed for hepatic steatosis characterized by accumulation of triglycerides in hepatocytes, which leads to hepatocellular carcinoma. MicroRNA 122 (MIR122) is expressed only in the liver, where it regulates lipid metabolism. We investigated the mechanism by which free fatty acids (FFAs) regulate MIR122 expression and the effect of MIR122 on triglyceride synthesis. METHODS: We analyzed MIR122 promoter activity and validated its target mRNAs by transfection of luciferase reporter plasmids into Huh7, BNL-1ME, and HEK293 cultured cell lines...
August 9, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28795252/ipet-study-an-flt-pet-window-study-to-assess-the-activity-of-the-steroid-sulfatase-inhibitor-irosustat-in-early-breast-cancer
#19
Carlo Palmieri, Richard Szydlo, Marie Miller, Laura Barker, Neva H Patel, Hironobu Sasano, Tara Barwick, Henry Tam, Dimitri Hadjiminas, Jasmin Lee, Abeer Shaaban, Hanna Nicholas, R Charles Coombes, Laura M Kenny
BACKGROUND: Steroid sulfatase (STS) is involved in oestrogen biosynthesis and irosustat is a first generation, irreversible steroid sulfatase inhibitor. A pre-surgical window-of-opportunity study with irosustat was undertaken in estrogen receptor-positive (ER+) breast cancer to assess the effect of irosustat on tumour cell proliferation as measured by 3'-deoxy-3'-[18F] fluorothymidine uptake measured by PET scanning (FLT-PET) and Ki67. METHODS: Postmenopausal women with untreated ER+ early breast cancer were recruited, and imaged with FLT-PET at baseline and after at least 2 weeks treatment with irosustat, 40 mg once daily orally...
August 9, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/28783667/tumor-location-determines-tissue-specific-recruitment-of-tumor-associated-macrophages-and-antibody-dependent-immunotherapy-response
#20
Birgit Lehmann, Markus Biburger, Christin Brückner, Andrea Ipsen-Escobedo, Sina Gordan, Christian Lehmann, David Voehringer, Thomas Winkler, Niels Schaft, Diana Dudziak, Horia Sirbu, Georg F Weber, Falk Nimmerjahn
Despite recent advances in activating immune cells to target tumors, the presence of some immune cells, such as tumor-associated macrophages (TAMs) or tumor-associated neutrophils (TANs), may promote rather than inhibit tumor growth. However, it remains unclear how antibody-dependent tumor immunotherapies, such as cytotoxic or checkpoint control antibodies, affect different TAM or TAN populations, which abundantly express activating Fcγ receptors. In this study, we show that the tissue environment determines which cellular effector pathways are responsible for antibody-dependent tumor immunotherapy...
January 6, 2017: Science Immunology
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