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https://www.readbyqxmd.com/read/27908880/an-anti-cd3-anti-cll-1-bispecific-antibody-for-the-treatment-of-acute-myeloid-leukemia
#1
Steven R Leong, Siddharth Sukumaran, Maria Hristopoulos, Klara Totpal, Shannon Stainton, Elizabeth Lu, Alfred Wong, Lucinda Tam, Robert Newman, Brian R Vuillemenot, Diego Ellerman, Chen Gu, Mary Mathieu, Mark S Dennis, Allen Nguyen, Bing Zheng, Crystal Zhang, Genee Lee, Yu-Waye Chu, Rodney A Prell, Kedan Lin, Steven T Laing, Andrew G Polson
Acute myeloid leukemia (AML) is major unmet medical need. Most patients have poor long-term survival and treatment has not significantly changed in 40 years. Recently, bispecific antibodies that redirect the cytotoxic activity of effector T-cells by binding to CD3, the signaling component of the T-cell receptor, and a tumor target have shown clinical activity. Notably, blinatumomab is approved to treat relapsed/refractory acute lymphoid leukemia. Here we describe the design, discovery, pharmacological activity, pharmacokinetics, and safety of a CD3 T-cell-dependent bispecific (TDB) full-length human IgG1 therapeutic antibody targeting CLL-1 that could potentially be used in humans to treat AML...
December 1, 2016: Blood
https://www.readbyqxmd.com/read/27900261/targeting-the-endocannabinoid-cb1-receptor-system-for-treating-obesity-in-prader-willi-syndrome
#2
Ibrahim Knani, Brian J Earley, Shiran Udi, Alina Nemirovski, Rivka Hadar, Asaad Gammal, Resat Cinar, Harry J Hirsch, Yehuda Pollak, Itai Gross, Talia Eldar-Geva, Daniela P Reyes-Capo, Joan C Han, Andrea M Haqq, Varda Gross-Tsur, Rachel Wevrick, Joseph Tam
OBJECTIVE: Extreme obesity is a core phenotypic feature of Prader-Willi syndrome (PWS). Among numerous metabolic regulators, the endocannabinoid (eCB) system is critically involved in controlling feeding, body weight, and energy metabolism, and a globally acting cannabinoid-1 receptor (CB1R) blockade reverses obesity both in animals and humans. The first-in-class CB1R antagonist rimonabant proved effective in inducing weight loss in adults with PWS. However, it is no longer available for clinical use because of its centrally mediated, neuropsychiatric, adverse effects...
December 2016: Molecular Metabolism
https://www.readbyqxmd.com/read/27895032/molecular-pathways-receptor-ectodomain-shedding-in-treatment-resistance-and-monitoring-of-cancer
#3
Miles A Miller, Ryan J Sullivan, Douglas A Lauffenburger
Proteases known as sheddases cleave the extracellular domains of their substrates from the cell surface. The A Disintegrin and Metalloproteinases ADAM10 and ADAM17 are among the most prominent sheddases, being widely expressed in many tissues, frequently over-expressed in cancer, and promiscuously cleaving diverse substrates. It is increasingly clear that the proteolytic shedding of transmembrane receptors impacts pathophysiology and drug response. Receptor substrates of sheddases include the cytokine receptors TNFR1 and IL-6R; the Notch receptors; type-I and -III TGF-β receptors; receptor tyrosine kinases (RTKs) such as HER2, HER4, and VEGFR2; and in particular, MET and TAM-family RTKs AXL and Mer (MerTK)...
November 28, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27889048/the-use-of-high-dose-estrogens-for-the-treatment-of-breast-cancer
#4
REVIEW
Herjan J T Coelingh Bennink, Carole Verhoeven, Alice E Dutman, Jos Thijssen
Estrogens are known to stimulate the growth of breast cancer but they are also an effective treatment for this disease (this has been termed the 'estrogen paradox'). The fact that estrogens can be an effective treatment for breast cancer is something that has almost been forgotten, whereas the fear for estrogens remains. This paper reviews the use of estrogens for the treatment of breast cancer and identifies possible applications. The data summarised in this review demonstrate that high-dose estrogens are effective for the treatment of advanced breast cancer, both as first-line treatment as well as for treatment after occurrence of endocrine resistance to TAM and AIs...
January 2017: Maturitas
https://www.readbyqxmd.com/read/27883134/non-fluorescent-quantification-of-single-mrna-with-transient-absorption-microscopy
#5
Jing Liu, Joseph M K Irudayaraj
Single molecule detection is confounded by the background signals from the biological environment, such as autofluorescence, Rayleigh scattering, or turbidity in cells and tissues. In this article, we report on the utilization of gold nanoparticles (AuNPs) as an orthogonal probe for non-fluorescence detection of single molecules with a transient absorption microscopy (TAM). The developed system and concepts were validated by quantitative evaluation of human epidermal receptor 2 (Her2) mRNA in cancer cells and tissues at single copy sensitivity...
November 24, 2016: Nanoscale
https://www.readbyqxmd.com/read/27881334/-over-expression-of-receptor-interacting-protein-140-in-tumor-associated-macrophages-suppresses-invasion-and-proliferation-of-hepatoma-cells-in-vitro
#6
Zhu-Jun Yi, Yun Zhou, Wen-Feng Zhang, Hao Chen, Wei Zhao, Zuo-Jin Liu, Jian-Ping Gong
OBJECTIVE: To investigate the role of receptor-interacting protein 140 (RIP140) in tumor-associated macrophages (TAMs) in the invasion and proliferation of hepatoma cells in vitro. METHODS: Western blotting, qRT-PCR and flow cytometry were performed to examine the effects of lentivirus-mediated RIP140 over-expression in mouse peritoneal macrophages (PMs). Western blotting, qRT-PCR and immunofluorescence staining were used to detect the expression of RIP140 in TAMs following stimulation of the PMs with hepatocellular carcinoma conditioned medium (HCM) for 24 h...
November 20, 2016: Nan Fang Yi Ke da Xue Xue Bao, Journal of Southern Medical University
https://www.readbyqxmd.com/read/27846280/development-and-application-of-a-microfluidics-based-panel-in-the-basal-luminal-transcriptional-characterization-of-archival-bladder-cancers
#7
Doris Kim, YounJeong Choi, James Ireland, Oded Foreman, Rachel N Tam, Rajesh Patel, Erica B Schleifman, Maipelo Motlhabi, Dorothy French, Cheryl V Wong, Eric Peters, Luciana Molinero, Rajiv Raja, Lukas C Amler, Garret M Hampton, Mark R Lackner, Omar Kabbarah
In the age of personalized medicine stratifying tumors into molecularly defined subtypes associated with distinctive clinical behaviors and predictable responses to therapies holds tremendous value. Towards this end, we developed a custom microfluidics-based bladder cancer gene expression panel for characterization of archival clinical samples. In silico analysis indicated that the content of our panel was capable of accurately segregating bladder cancers from several public datasets into the clinically relevant basal and luminal subtypes...
2016: PloS One
https://www.readbyqxmd.com/read/27837347/tamoxifen-resistance-and-metastasis-of-human-breast-cancer-cells-were-mediated-by-the-membrane-associated-estrogen-receptor-er-%C3%AE-36-signaling-in-vitro
#8
Wenwen Gu, Nian Dong, Peng Wang, Changgen Shi, Jun Yang, Jian Wang
The drug resistance and tumor metastasis have been the main obstacles for the longer-term therapeutic effects of tamoxifen (TAM) on estrogen receptor-positive (ER(+)) breast cancer, but the mechanisms underlying the TAM resistance are still unclear. Here, we demonstrated that the membrane-associated estrogen receptor ER-α36 signaling, but not the G protein-coupled estrogen receptor 1 (GPER1) signaling, might be involved in the TAM resistance and metastasis of breast cancer cells. In this study, a model of ER(+) breast cancer cell MCF-7 that involves the up-regulated expression of ER-α36 and unchanged expression of ER-α66 and GPER1 was established via the removal of insulin from the cell culture medium...
November 11, 2016: Cell Biology and Toxicology
https://www.readbyqxmd.com/read/27834816/targeting-the-tam-receptors-in-leukemia
#9
REVIEW
Madeline G Huey, Katherine A Minson, H Shelton Earp, Deborah DeRyckere, Douglas K Graham
Targeted inhibition of members of the TAM (TYRO-3, AXL, MERTK) family of receptor tyrosine kinases has recently been investigated as a novel strategy for treatment of hematologic malignancies. The physiologic functions of the TAM receptors in innate immune control, natural killer (NK) cell differentiation, efferocytosis, clearance of apoptotic debris, and hemostasis have previously been described and more recent data implicate TAM kinases as important regulators of erythropoiesis and megakaryopoiesis. The TAM receptors are aberrantly or ectopically expressed in many hematologic malignancies including acute myeloid leukemia, B- and T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and multiple myeloma...
November 8, 2016: Cancers
https://www.readbyqxmd.com/read/27822406/pd-1-inhibition-and-treatment-of-advanced-melanoma-role-of-pembrolizumab
#10
REVIEW
Ali R Jazirehi, Alexandra Lim, Tam Dinh
Remarkable clinical responses have been seen in patients with metastatic melanoma with targeted therapy (BRAFi vemurafenib, MEKi) and with modern immune cell-based approaches such as TCR engineered adoptive cell transfer (ACT) and earlier experiences with high-dose IL-2. The proximal mediators of these immune therapies are tumor-reactive CTL. Various mechanisms of resistance to immune-mediated apoptotic signals have been described, including phenotypic changes, effector cell exhaustion, functional tolerance, deficiencies in Ag processing and presentation, and mutation or down-regulation of antigenic epitopes...
2016: American Journal of Cancer Research
https://www.readbyqxmd.com/read/27815995/impairment-of-the-executive-attention-network-in-premenopausal-women-with-hormone-receptor-positive-breast-cancer-treated-with-tamoxifen
#11
Xingui Chen, Jingjing Li, Jingjie Zhang, Xiaoxuan He, Chunyan Zhu, Lei Zhang, Xinglong Hu, Kai Wang
Tamoxifen (TAM) is most commonly prescribed for patients with hormone-sensitive breast cancer and exerts agonistic/antagonistic effects on estrogen receptors throughout the body. Accumulating evidence has revealed that breast cancer patients receiving TAM manifest cognitive dysfunction. However, whether these patients have a global attention deficit or a more selective impairment of specific attention networks remains unknown. In the present study, we sought to explore the attention function of premenopausal women with hormone receptor-positive breast cancer treated with TAM using the attention network test (ANT)...
January 2017: Psychoneuroendocrinology
https://www.readbyqxmd.com/read/27807228/tim-1-promotes-hepatitis-c-virus-cell-attachment-and-infection
#12
Jing Wang, Luhua Qiao, Zhouhua Hou, Guangxiang Luo
: Human TIM and TAM family proteins were recently found to serve as phosphatidylserine receptors which promote infection of many different viruses including dengue virus, West Nile virus, Ebola virus, Marburg virus, and Zika virus. In the present study, we provide substantial evidence demonstrating that TIM-1 is important for efficient infection of hepatitis C virus (HCV). The knockdown of TIM-1 expression significantly reduced HCV infection but not HCV RNA replication. Likewise, TIM-1 knockout in Huh-7...
November 2, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27801848/the-gas6-tam-system-and-multiple-sclerosis
#13
REVIEW
Mattia Bellan, Mario Pirisi, Pier Paolo Sainaghi
Growth arrest specific 6 (Gas6) is a multimodular circulating protein, the biological actions of which are mediated by the interaction with three transmembrane tyrosine kinase receptors: Tyro3, Axl, and MerTK, collectively named TAM. Over the last few decades, many progresses have been done in the understanding of the biological activities of this highly pleiotropic system, which plays a role in the regulation of immune response, inflammation, coagulation, cell growth, and clearance of apoptotic bodies. Recent findings have further related Gas6 and TAM receptors to neuroinflammation in general and, specifically, to multiple sclerosis (MS)...
October 28, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27797715/tumor-associated-macrophage-derived-ccl20-enhances-the-growth-and-metastasis-of-pancreatic-cancer
#14
Bingyan Liu, Yiping Jia, Jun Ma, Shaoqiu Wu, Haosheng Jiang, Yan Cao, Xianjun Sun, Xiang Yin, Shuo Yan, Mingyi Shang, Aiwu Mao
Pancreatic cancer is an aggressive malignancy with a high metastatic potential that results in a high mortality rate worldwide. Although macrophages have the potential to kill tumor cells and elicit immune responses against tumors, there is evidence that tumor-associated macrophages (TAMs) promote tumor progression and suppress T-cell responses. CC-chemokine ligand 20 (CCL20) and its unique receptor CC-chemokine receptor 6 (CCR6) are exploited by cancer cells for migration and metastasis and play important roles in the development and progression of cancer...
October 19, 2016: Acta Biochimica et Biophysica Sinica
https://www.readbyqxmd.com/read/27791185/control-of-embryonic-stem-cell-self-renewal-and-differentiation-via-coordinated-alternative-splicing-and-translation-of-yy2
#15
Soroush Tahmasebi, Seyed Mehdi Jafarnejad, Ingrid S Tam, Thomas Gonatopoulos-Pournatzis, Edna Matta-Camacho, Yoshinori Tsukumo, Akiko Yanagiya, Wencheng Li, Yaser Atlasi, Maxime Caron, Ulrich Braunschweig, Dana Pearl, Arkady Khoutorsky, Christos G Gkogkas, Robert Nadon, Guillaume Bourque, Xiang-Jiao Yang, Bin Tian, Hendrik G Stunnenberg, Yojiro Yamanaka, Benjamin J Blencowe, Vincent Giguère, Nahum Sonenberg
Translational control of gene expression plays a key role during the early phases of embryonic development. Here we describe a transcriptional regulator of mouse embryonic stem cells (mESCs), Yin-yang 2 (YY2), that is controlled by the translation inhibitors, Eukaryotic initiation factor 4E-binding proteins (4E-BPs). YY2 plays a critical role in regulating mESC functions through control of key pluripotency factors, including Octamer-binding protein 4 (Oct4) and Estrogen-related receptor-β (Esrrb). Importantly, overexpression of YY2 directs the differentiation of mESCs into cardiovascular lineages...
November 1, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27788141/study-of-early-elevated-gas6-plasma-level-as-a-predictor-of-mortality-in-a-prospective-cohort-of-patients-with-sepsis
#16
Grégoire Stalder, Yok Ai Que, Sara Calzavarini, Laurent Burnier, Christophe Kosinski, Pierluigi Ballabeni, Thierry Roger, Thierry Calandra, Michel A Duchosal, Lucas Liaudet, Philippe Eggimann, Anne Angelillo-Scherrer
BACKGROUND: Growth arrest-specific gene 6 (Gas6), a vitamin K-dependent protein interacting with anionic phospholipids and TAM tyrosine kinase receptors, is elevated in plasma of septic patients. Previous studies did not find different levels between survivors and non-survivors at admission because either they included a low number of patients (<50) or a low number of non-survivors (5%). OBJECTIVES: To determine, in a larger cohort of septic patients comprising an expected number of non-survivors, the performance of the plasma level of Gas6 and its soluble receptor Axl (sAxl) within 24 hours of admission to predict in-ICU mortality...
2016: PloS One
https://www.readbyqxmd.com/read/27783989/mfhas1-promotes-colorectal-cancer-progress-by-regulating-polarization-of-tumor-associated-macrophages-via-stat6-signaling-pathway
#17
Wankun Chen, Yajun Xu, Jing Zhong, Huihui Wang, Meilin Weng, Qian Cheng, Qichao Wu, Zhirong Sun, Hui Jiang, Minmin Zhu, Yu Ren, Pingbo Xu, Jiawei Chen, Changhong Miao
Malignant fibrous histiocytoma amplified sequence 1 (MFHAS1) is a predicted oncoprotein that demonstrates tumorigenic activity in vivo; however, the mechanisms involved are unknown. Macrophages are divided into the pro-inflammatory M1 and anti-inflammatory/protumoral M2 subtypes. Tumor cells can induce M2 polarization of tumor-associated macrophages (TAMs) to promote metastasis; but the underlying pathways require to be elucidated. In this study, we detected a positive association between MFHAS1 expression in TAMs and human colorectal cancer (CRC) TNM stage...
October 21, 2016: Oncotarget
https://www.readbyqxmd.com/read/27783662/mertk-inhibition-induces-polyploidy-and-promotes-cell-death-and-cellular-senescence-in-glioblastoma-multiforme
#18
Alexandra Sufit, Alisa B Lee-Sherick, Deborah DeRyckere, Manali Rupji, Bhakti Dwivedi, Marileila Varella-Garcia, Angela M Pierce, Jeanne Kowalski, Xiaodong Wang, Stephen V Frye, H Shelton Earp, Amy K Keating, Douglas K Graham
BACKGROUND: MER receptor tyrosine kinase (MERTK) is expressed in a variety of malignancies, including glioblastoma multiforme (GBM). Our previous work demonstrated that inhibition of MERTK using RNA interference induced cell death and chemosensitivity in GBM cells, implicating MERTK as a potential therapeutic target. Here we investigate whether a novel MERTK-selective small molecule tyrosine kinase inhibitor, UNC2025, has similar anti-tumor effects in GBM cell lines. METHODS: Correlations between expression of GAS6, a MERTK ligand, and prognosis were determined using data from the TCGA database...
2016: PloS One
https://www.readbyqxmd.com/read/27780585/purinergic-signaling-in-kidney-disease
#19
REVIEW
Robert I Menzies, Frederick W Tam, Robert J Unwin, Matthew A Bailey
Nucleotides are key subunits for nucleic acids and provide energy for intracellular metabolism. They can also be released from cells to act physiologically as extracellular messengers or pathologically as danger signals. Extracellular nucleotides stimulate membrane receptors in the P2 and P1 family. P2X are ATP-activated cation channels; P2Y and P1 are G-protein coupled receptors activated by ATP, ADP, UTP, and UDP in the case of P2 or adenosine for P1. Renal P2 receptors influence both vascular contractility and tubular function...
October 22, 2016: Kidney International
https://www.readbyqxmd.com/read/27780404/autophagy-induced-by-axl-receptor-tyrosine-kinase-alleviates-acute-liver-injury-via-inhibition-of-nlrp3-inflammasome-activation-in-mice
#20
Jihye Han, Joonbeom Bae, Chang-Yong Choi, Sang-Pil Choi, Hyung-Sik Kang, Eun-Kyeong Jo, Jongsun Park, Young Sik Lee, Hyun-Seuk Moon, Chung-Gyu Park, Myung-Shik Lee, Taehoon Chun
Severe hepatic inflammation is a common cause of acute or chronic liver disease. Macrophages are one of the key mediators which regulate the progress of hepatic inflammation. Increasing evidence shows that the TAM (TYRO3, AXL and MERTK) family of RTKs (receptor tyrosine kinases), which is expressed in macrophages, alleviates inflammatory responses through a negative feedback loop. However, the functional contribution of each TAM family member to the progression of hepatic inflammation remains elusive. In this study, we explore the role of individual TAM family proteins during autophagy induction and evaluate their contribution to hepatic inflammation...
October 26, 2016: Autophagy
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