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https://www.readbyqxmd.com/read/28637014/a-combination-of-valproic-acid-sodium-salt-chir99021-e-616452-tranylcypromine-and-3-deazaneplanocin-a-causes-stem-cell-like-characteristics-in-cancer-cells
#1
Shuang Sha, Yuanfen Zhai, Chengzhao Lin, Heyong Wang, Qing Chang, Shuang Song, Mingqiang Ren, Gentao Liu
Many studies are based on the hypothesis that recurrence and drug resistance in lung carcinoma are due to a subpopulation of cancer stem-like cells (CSLCs) in solid tumors. Therefore it is crucial to screen for and recognize lung CSLCs. In this study, we stimulated non-small cell lung cancer (NSCLC) A549 cells to display stem cell-like characteristics using a combination of five small molecule compounds. The putative A549 stem cells activated an important CSLC marker, CD133 protein, as well multiple CSLC-related genes including ATP-binding cassette transporter G2 (ABCG2), C-X-C chemokine receptor type 4 (CXCR4), NESTIN, and BMI1...
June 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28631441/genetic-landscape-and-deregulated-pathways-in-b-cell-lymphoid-malignancies
#2
R Rosenquist, S Beà, M-Q Du, B Nadel, Q Pan-Hammarström
With the introduction of next-generation sequencing, the genetic landscape of the complex group of B-cell lymphoid malignancies has rapidly been unravelled in recent years. This has provided important information about recurrent genetic events and identified key pathways deregulated in each lymphoma subtype. In parallel, there has been intense search and development of novel types of targeted therapy that 'hit' central mechanisms in lymphoma pathobiology, such as BTK, PI3K or BCL2 inhibitors. In this review, we will outline the current view of the genetic landscape of selected entities: follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, chronic lymphocytic leukaemia and marginal zone lymphoma...
June 20, 2017: Journal of Internal Medicine
https://www.readbyqxmd.com/read/28624262/dibenzazepine-loaded-nanoparticles-induce-local-browning-of-white-adipose-tissue-to-counteract-obesity
#3
Chunhui Jiang, Mario Alberto Cano-Vega, Feng Yue, Liangju Kuang, Naagarajan Narayanan, Gozde Uzunalli, Madeline P Merkel, Shihuan Kuang, Meng Deng
Inhibition of Notch signaling via systemic drug administration triggers conversion of white adipocytes into beige adipocytes (browning) and reduces adiposity. However, translation of this discovery into clinical practice is challenged by potential off-target side effects and lack of control over the location and temporal extent of beige adipocyte biogenesis. Here, we demonstrate an alternative approach to stimulate browning using nanoparticles (NPs) composed of FDA-approved poly(lactide-co-glycolide) that enable sustained local release of a Notch inhibitor (dibenzazepine, DBZ)...
June 15, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28621429/the-sumo-targeted-ubiquitin-ligase-dgrn-is-essential-for-drosophila-innate-immunity
#4
Bella Koltun, Eliza Shackelford, François Bonnay, Nicolas Matt, Jean Marc Reichhart, Amir Orian
The ability of metazoans to combat pathogenic infection involves both systemic and local responses to the invading pathogens. Ubiquitin and SUMO pathways molecularly regulate the response to infection, immune signaling and gene expression. Here, we report that Degringolade (Dgrn, CG10981), a SUMO-targeted ubiquitin ligase connecting the two pathways, is essential for the innate immunity response in Drosophila. dgrn(DK) null and heterozygous mutant adult flies are severely immune-compromised and succumb rapidly to both pathogenic bacteria and fungi infections...
2017: International Journal of Developmental Biology
https://www.readbyqxmd.com/read/28617078/interplay-between-notch-and-p53-promotes-neuronal-cell-death-in-ischemic-stroke
#5
Priyanka Balaganapathy, Sang-Ha Baik, Karthik Mallilankaraman, Christopher G Sobey, Dong-Gyu Jo, Thiruma V Arumugam
Stroke is the world's second leading cause of mortality, with a high incidence of morbidity. Numerous neuronal membrane receptors are activated by endogenous ligands and may contribute to infarct development. Notch is a well-characterized membrane receptor involved in cell differentiation and proliferation, and now shown to play a pivotal role in cell death during ischemic stroke. Blockade of Notch signaling by inhibition of γ-secretase, an enzyme that generates the active form of Notch, is neuroprotective following stroke...
January 1, 2017: Journal of Cerebral Blood Flow and Metabolism
https://www.readbyqxmd.com/read/28615417/t-cell-restricted-notch-signaling-contributes-to-pulmonary-th1-and-th2-immunity-during-cryptococcus-neoformans-infection
#6
Lori M Neal, Yafeng Qiu, Jooho Chung, Enze Xing, Woosung Cho, Antoni N Malachowski, Ashley R Sandy-Sloat, John J Osterholzer, Ivan Maillard, Michal A Olszewski
Cryptococcus neoformans is a ubiquitous, opportunistic fungal pathogen but the cell signaling pathways that drive T cell responses regulating antifungal immunity are incompletely understood. Notch is a key signaling pathway regulating T cell development, and differentiation and functional responses of mature T cells in the periphery. The targeting of Notch signaling within T cells has been proposed as a potential treatment for alloimmune and autoimmune disorders, but it is unknown whether disturbances to T cell immunity may render these patients vulnerable to fungal infections...
June 14, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28607007/synergistic-activity-with-notch-inhibition-and-androgen-ablation-in-erg-positive-prostate-cancer-cells
#7
Ahmed A Mohamed, Shyh-Han Tan, Charles P Xavier, Shilpa Katta, Wei Huang, Lakshmi Ravindranath, Muhammad Jamal, Hua Li, Meera Srivastava, Eri S Srivatsan, Taduru L Sreenath, David G McLeod, Alagarsamy Srinivasan, Gyorgy Petrovics, Albert Dobi, Shiv Srivastava
The oncogenic activation of the ETS related gene (ERG) due to gene fusions is present in over half of prostate cancer (CaP) in Western countries. Due to its high incidence and oncogenic role, ERG and components of ERG network have emerged as potential drug targets for CaP. Utilizing gene expression datasets, from matched normal and prostate tumor epithelial cells, an association of NOTCH transcription factors with ERG expression status was identified; confirming that NOTCH factors are direct transcriptional targets of ERG...
June 12, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28601732/intermittent-compressive-stress-regulates-notch-target-gene-expression-via-transforming-growth-factor-%C3%AE-signaling-in-murine-pre-osteoblast-cell-line
#8
Jeeranan Manokawinchoke, Prasit Pavasant, Thanaphum Osathanon
OBJECTIVE: Different mechanical stimuli regulate behaviors of various cell types, including osteoblasts, osteocytes, and periodontal ligament fibroblasts. Notch signaling participates in the mechanical stress-regulated cell responses. The present study investigated the regulation of Notch target gene and sclerostin (Sost) expression in murine pre-osteoblast cell line (MC3T3-E1) under intermittent compressive stress. METHODS: MC3T3-E1 were subjected to the intermittent compressive force under the computerized controlled machine...
June 1, 2017: Archives of Oral Biology
https://www.readbyqxmd.com/read/28600728/the-critical-role-of-notch1-tlr-4-signaling-in-the-inflammatory-and-fungicidal-activity-of-macrophages-against-paracoccidioides-brasiliensis-strain-pb18
#9
Lavínia Maria Dal'Mas Romera, Gilberto Hideo Kaihami, Grasielle Pereira Jannuzzi, José Roberto Fogaça de Almeida, Sandro Rogério de Almeida
Paracoccidioidomycosis is a systemic mycosis of deep nature that primarily affects the lung and can spread via lymphatic and hematogenous to other organs and tissues. It is mainly caused by Paracoccidioides brasiliensis fungus which exhibits thermal dimorphism. The innate immune system mediated by macrophages is extremely important for the control of infection and is involved in the induction and regulation of immune/inflammatory response. These cells are able to recognize pathogens through pattern recognition receptors (PRRs) such as Toll-like receptors (TLR)...
June 9, 2017: Mycopathologia
https://www.readbyqxmd.com/read/28600474/use-of-angiotensin-system-inhibitors-is-associated-with-immune-activation-and-longer-survival-in-non-metastatic-pancreatic-ductal-adenocarcinoma
#10
Hao Liu, Kamila Naxerova, Matthias Pinter, Joao Incio, Hang Lee, Kohei Shigeta, William W Ho, Jonathan A Crain, Alex Jacobson, Theodoros Michelakos, Daniella Dias-Santos, Andrea Zanconato, Theodore S Hong, Jeffrey W Clark, Janet E Murphy, David P Ryan, Vikram Deshpande, Keith D Lillemoe, Carlos Fernandez-Del Castillo, Michael Downes, Ronald M Evans, James Michaelson, Cristina R Ferrone, Yves Boucher, Rakesh K Jain
Angiotensin system inhibitors (ASIs) can improve prognosis in multiple cancer types, including pancreatic ductal adenocarcinoma (PDAC). However, no study has examined the effect of ASIs alone or combined with adjuvant chemotherapy in resected PDAC patients.<br /><br />Experimental Design: We performed an analysis of the records of ASI users and non-user patients with PDAC seen at Massachusetts General Hospital between January 2006 and December 2010. To identify mechanisms of ASIs in PDAC, we performed RNA-Seq of resected primary lesions...
June 9, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28599454/differential-expression-of-the-notch1-receptor-and-its-ligands-dll1-dll3-and-dll4-in-distinct-human-pituitary-adenoma-subtypes
#11
Jianfu Zhang, Hua Gao, Yazhuo Zhang
Pituitary adenoma (PA) is a common type of benign tumor of the pituitary gland that is characterized by specific signs and symptoms, primarily associated with hypersecretion of pituitary glycoprotein hormones (thyroid-stimulating, growth and adrenocorticotrophic hormones, and prolactin). Surgery is the first-line treatment, although postoperative residual tissues/cells and subsequent recurrence remain notable complications. Gene therapy is an effective approach for treatment, as previous studies have demonstrated that the Notch signaling pathway participates in the pathogenesis of PA...
June 2017: Oncology Letters
https://www.readbyqxmd.com/read/28591987/-notch-signaling-pathway-participates-in-the-differentiation-of-hepatic-progenitor-cells-into-bile-duct-epithelial-cells-and-progression-of-hepatic-fibrosis-in-cholestatic-liver-fibrosis-rat
#12
Y P Mu, X Zhang, Y Xu, W W Fan, X W Li, J M Chen, G F Chen, P Liu
Objective: To investigate differentiation direction of hepatic progenitor cells (HPCs) in cholestatic liver fibrosis (CLF), and the role of Notch signaling pathway in the differentiation of HPCs. Methods: A CLF rat model was established by bile duct ligation (BDL) followed by monitoring changes of Notch signal pathway and the cellular origin of proliferating cholangiocytes. After intraperitoneal injection of DAPT (a Notch signaling inhibitor) after bile duct ligation, the progress of liver fibrosis and the proliferation of cholangiocytes after inhibition of the Notch pathway were analyzed...
June 8, 2017: Zhonghua Bing Li Xue za Zhi Chinese Journal of Pathology
https://www.readbyqxmd.com/read/28589698/wnt-and-shh-signals-regulate-neural-stem-cell-proliferation-and-differentiation-in-the-optic-tectum-of-adult-zebrafish
#13
Shiori Shitasako, Yoko Ito, Ryoichi Ito, Yuto Ueda, Yuki Shimizu, Toshio Ohshima
Adult neurogenesis occurs more commonly in teleosts, represented by zebrafish, than in mammals. Zebrafish is therefore considered a suitable model to study adult neurogenesis, for which the regulatory molecular mechanisms remain little known. Our previous study revealed that neuroepithelial-like neural stem cells (NSCs) are located at the edge of the dorsomedial region. We also showed that Notch signaling inhibits NSC proliferation in this region. In the present study, we reported the expression of Wnt and Shh signaling components in this region of the optic tectum...
June 7, 2017: Developmental Neurobiology
https://www.readbyqxmd.com/read/28583585/effects-of-the-notch-signalling-pathway-on-hyperoxia-induced-immature-brain-damage-in-newborn-mice
#14
Min Du, Yuting Tan, Guangjian Liu, Lan Liu, Fei Cao, Jianxia Liu, Pu Jiang, Ying Xu
Hyperoxia exposure can cause dramatic release of proinflammatory cytokines, leading to neuronal apoptosis and inducing white matter damage in newborn mouse brains. Some studies indicated that the Notch activation was provoked during inflammation and might regulate adaptive and innate immune responses. Moreover, the pathway also regulated oligodendrocyte maturation which was disrupted in neonatal mice after hyperoxia exposure. This study sought to investigate whether the Notch signalling activation contributed to immature brain damage after hyperoxia exposure...
June 3, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28583499/the-effect-of-blocking-notch-signaling-by-%C3%AE-secretase-inhibitor-on-allergic-rhinitis
#15
Le Shi, Yue Ma, Chunquan Zheng, Qingzhao Zhang
OBJECTIVE: This study aimed to investigate the effect of blocking Notch signaling by γ-secretase inhibitor (GSI) on allergic rhinitis. METHOD: GSI, N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butylester (DAPT) was administered to ovalbumin-induced AR mice models intranasally. We observed symptoms of sneezing and nose rubbing. To detect the inflammatory state, the serum OVA-specific-IgE, IFN-γ, IL-4, and IL-5 were analyzed by ELISA, and Th cell cytokines in nasal mucosa were analyzed by RT-PCR, including T-bet, IFN-γ, GATA-3, IL-4, and IL-5...
July 2017: International Journal of Pediatric Otorhinolaryngology
https://www.readbyqxmd.com/read/28574612/basal-cell-carcinoma-pathogenesis-and-therapy-involving-hedgehog-signaling-and-beyond
#16
Anshika Bakshi, Sandeep C Chaudhary, Mehtab Rana, Craig A Elmets, Mohammad Athar
Basal cell carcinoma (BCC) of the skin is driven by aberrant hedgehog signaling. Thus blocking this signaling pathway by small molecules such as vismodegib inhibits tumor growth. Primary cilium in the epidermal cells plays an integral role in the processing of hedgehog signaling related proteins. Recent genomic studies point to the involvement of additional genetic mutations that might be associated with the development of BCCs, suggesting significance of other signaling pathways, such as WNT, NOTCH, mTOR, and Hippo, aside from hedgehog in the pathogenesis of this human neoplasm...
June 2, 2017: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/28570994/targeting-adam17-inhibits-human-colorectal-adenocarcinoma-progression-and-tumor-initiating-cell-frequency
#17
Joseph Dosch, Elizabeth Ziemke, Shanshan Wan, Kathryn Luker, Theodore Welling, Karin Hardiman, Eric Fearon, Suneetha Thomas, Matthew Flynn, Jonathan Rios-Doria, Robert Hollingsworth, Ronald Herbst, Elaine Hurt, Judith Sebolt-Leopold
ADAM17 (a disintegrin and metalloproteinase 17)/TACE (TNFα converting enzyme) has emerged as a potential therapeutic target in colorectal cancer (CRC) and other cancers, due in part to its role in regulating various tumor cell surface proteins and growth factors and cytokines in the tumor microenvironment. The emergence of MEDI3622, a highly potent and specific antibody-based ADAM17 inhibitor, has allowed testing of the concept that targeting ADAM17 may be an important new therapeutic approach for CRC patients...
May 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28539479/%C3%AE-secretase-inhibitors-in-cancer-clinical-trials-are-pharmacologically-and-functionally-distinct
#18
Yong Ran, Fokhrul Hossain, Antonio Pannuti, Christian B Lessard, Gabriela Z Ladd, Joo In Jung, Lisa M Minter, Barbara A Osborne, Lucio Miele, Todd E Golde
γ-Secretase inhibitors (GSIs) are being actively repurposed as cancer therapeutics based on the premise that inhibition of NOTCH1 signaling in select cancers is therapeutic. Using novel assays to probe effects of GSIs against a broader panel of substrates, we demonstrate that clinical GSIs are pharmacologically distinct. GSIs show differential profiles of inhibition of the various NOTCH substrates, with some enhancing cleavage of other NOTCH substrates at concentrations where NOTCH1 cleavage is inhibited. Several GSIs are also potent inhibitors of select signal peptide peptidase (SPP/SPPL) family members...
May 24, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28534531/unravelling-the-biology-of-sclc-implications-for-therapy
#19
REVIEW
Joshua K Sabari, Benjamin H Lok, James H Laird, John T Poirier, Charles M Rudin
Small-cell lung cancer (SCLC) is an aggressive malignancy associated with a poor prognosis. First-line treatment has remained unchanged for decades, and a paucity of effective treatment options exists for recurrent disease. Nonetheless, advances in our understanding of SCLC biology have led to the development of novel experimental therapies. Poly [ADP-ribose] polymerase (PARP) inhibitors have shown promise in preclinical models, and are under clinical investigation in combination with cytotoxic therapies and inhibitors of cell-cycle checkpoints...
May 23, 2017: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/28526832/identification-of-a-novel-chalcone-derivative-that-inhibits-notch-signaling-in-t-cell-acute-lymphoblastic-leukemia
#20
Mattia Mori, Luca Tottone, Deborah Quaglio, Nadezda Zhdanovskaya, Cinzia Ingallina, Marisa Fusto, Francesca Ghirga, Giovanna Peruzzi, Maria Elisa Crestoni, Fabrizio Simeoni, Francesca Giulimondi, Claudio Talora, Bruno Botta, Isabella Screpanti, Rocco Palermo
Notch signaling is considered a rational target in the therapy of several cancers, particularly those harbouring Notch gain of function mutations, including T-cell acute lymphoblastic leukemia (T-ALL). Although currently available Notch-blocking agents are showing anti-tumor activity in preclinical studies, they are not effective in all the patients and often cause severe side-effects, limiting their widespread therapeutic use. Here, by functional and biological analysis of the most representative molecules of an in house library of natural products, we have designed and synthetized the chalcone-derivative 8 possessing Notch inhibitory activity at low micro molar concentration in T-ALL cell lines...
May 19, 2017: Scientific Reports
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