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https://www.readbyqxmd.com/read/28350865/multi-drug-loaded-micelles-delivering-chemotherapy-and-targeted-therapies-directed-against-hsp90-and-the-pi3k-akt-mtor-pathway-in-prostate-cancer
#1
Bao Le, Ginny L Powers, Yu Tong Tam, Nicholas Schumacher, Rita L Malinowski, Laura Steinke, Glen Kwon, Paul C Marker
BACKGROUND: Advanced prostate cancers that are resistant to all current therapies create a need for new therapeutic strategies. One recent innovative approach to cancer therapy is the simultaneous use of multiple FDA-approved drugs to target multiple pathways. A challenge for this approach is caused by the different solubility requirements of each individual drug, resulting in the need for a drug vehicle that is non-toxic and capable of carrying multiple water-insoluble antitumor drugs...
2017: PloS One
https://www.readbyqxmd.com/read/28341790/tumor-associated-macrophages-can-contribute-to-antitumor-activity-through-fc%C3%AE-rmediated-processing-of-antibody-drug-conjugates
#2
Fu Li, Michelle Ulrich, Mechthild Jonas, Ivan J Stone, Germein Linares, Xinqun Zhang, Lori Westendorf, Dennis R Benjamin, Che-Leung Law
The primary mechanism of antibody-drug conjugates (ADCs) is targeted delivery of a cytotoxic payload to tumor cells via cancer-associated membrane receptors. However, the tumor microenvironment likely plays a role in ADC penetration, distribution, and processing and thus impacts the overall antitumor activity. Here, we report on the potential contribution of Fc-FcγR interactions between ADCs and tumor-associated macrophages (TAMs) to the preclinical antitumor activities of ADCs. In the CD30+ L-428 Hodgkin lymphoma model, anti-CD30-vcMMAE and a non-binding control (hIgG-vcMMAE) demonstrated similar antitumor activity as well as similar payload release in the tumors...
March 24, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28336455/targeted-delivery-of-epirubicin-to-tumor-associated-macrophages-by-sialic-acid-cholesterol-conjugate-modified-liposomes-with-improved-antitumor-activity
#3
Songlei Zhou, Ting Zhang, Bo Peng, Xiang Luo, Xinrong Liu, Ling Hu, Yang Liu, Donghua Di, Yanzhi Song, Yihui Deng
With the knowledge that the receptors of sialic acid are overexpressed on the surface of tumor-associated macrophages (TAMs), which play a crucial role in the tumor's progression and metastasis, a sialic acid-cholesterol conjugate (SA-CH) was synthesized and modified on the surface of epirubicin (EPI)-loaded liposomes (EPI-SAL) to improve the delivery of EPI to the TAMs. The liposomes were developed using remote loading technology via a pH gradient. The liposomes were evaluated for particle size, encapsulation efficiency, in vitro release, stability, in vitro cytotoxicity and pharmacokinetics...
March 20, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/28333143/molecular-insights-of-gas6-tam-in-cancer-development-and-therapy
#4
REVIEW
Guiling Wu, Zhiqiang Ma, Wei Hu, Dongjin Wang, Bing Gong, Chongxi Fan, Shuai Jiang, Tian Li, Jianyuan Gao, Yang Yang
Since growth arrest-specific gene 6 (Gas6) was discovered in 1988, numerous studies have highlighted the role of the Gas6 protein and its receptors Tyro3, Axl and Mer (collectively referred to as TAM), in proliferation, apoptosis, efferocytosis, leukocyte migration, sequestration and platelet aggregation. Gas6 has a critical role in the development of multiple types of cancers, including pancreatic, prostate, oral, ovarian and renal cancers. Acute myelocytic leukaemia (AML) is a Gas6-dependent cancer, and Gas6 expression predicts poor prognosis in AML...
March 23, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28332980/a-receptor-and-neuron-that-activate-a-circuit-limiting-sucrose-consumption
#5
Ryan M Joseph, Jennifer S Sun, Edric Tam, John R Carlson
The neural control of sugar consumption is critical for normal metabolism. In contrast to sugar-sensing taste neurons that promote consumption, we identify a taste neuron that limits sucrose consumption in Drosophila. Silencing of the neuron increases sucrose feeding; optogenetic activation decreases it. The feeding inhibition depends on the IR60b receptor, as shown by behavioral analysis and Ca2+ imaging of an IR60b mutant. The IR60b phenotype shows a high degree of chemical specificity when tested with a broad panel of tastants...
March 23, 2017: ELife
https://www.readbyqxmd.com/read/28327095/interferon-signaling-in-ascites-associated-macrophages-is-linked-to-a-favorable-clinical-outcome-in-a-subgroup-of-ovarian-carcinoma-patients
#6
Till Adhikary, Annika Wortmann, Florian Finkernagel, Sonja Lieber, Andrea Nist, Thorsten Stiewe, Uwe Wagner, Sabine Müller-Brüsselbach, Silke Reinartz, Rolf Müller
BACKGROUND: Although tumor-associated macrophages (TAMs) are essential for cancer progression, connections between different clinical outcomes and transcriptional networks have not been reported. We have addressed this issue by analyzing global expression patterns of TAMs isolated from the ascites of ovarian cancer patients. RESULTS: TAMs isolated from different ovarian cancer patients can be stratified by coexpression or principal component analysis into subgroups with specific biological features and associated with distinct clinical outcomes...
March 21, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28324044/inverse-regulation-of-dht-synthesis-enzymes-5%C3%AE-reductase-types-1-and-2-by-the-androgen-receptor-in-prostate-cancer
#7
Étienne Audet-Walsh, Tracey Yee, Ingrid S Tam, Vincent Giguère
5α-reductase types 1 and 2, encoded by SRD5A1 and SRD5A2, are the two enzymes that can catalyze the conversion of testosterone to dihydrotestosterone, the most potent androgen receptor (AR) agonist in prostate cells. 5α-reductase type 2 is the predominant isoform expressed in the normal prostate. However, its expression decreases during prostate cancer (PCa) progression, while SRD5A1 increases and the mechanism underlying this transcriptional regulatory switch is still unknown. Interrogation of SRD5A mRNA expression in three publicly available datasets confirmed that SRD5A1 is increased in primary and metastatic PCa compared to non-tumoral prostate tissues, while SRD5A2 is decreased...
January 23, 2017: Endocrinology
https://www.readbyqxmd.com/read/28319612/colony-stimulating-factor-1-receptor-is-a-central-component-of-the-foreign-body-response-to-biomaterial-implants-in-rodents-and-non-human%C3%A2-primates
#8
Joshua C Doloff, Omid Veiseh, Arturo J Vegas, Hok Hei Tam, Shady Farah, Minglin Ma, Jie Li, Andrew Bader, Alan Chiu, Atieh Sadraei, Stephanie Aresta-Dasilva, Marissa Griffin, Siddharth Jhunjhunwala, Matthew Webber, Sean Siebert, Katherine Tang, Michael Chen, Erin Langan, Nimit Dholokia, Raj Thakrar, Meirigeng Qi, Jose Oberholzer, Dale L Greiner, Robert Langer, Daniel G Anderson
Host recognition and immune-mediated foreign body response to biomaterials can compromise the performance of implanted medical devices. To identify key cell and cytokine targets, here we perform in-depth systems analysis of innate and adaptive immune system responses to implanted biomaterials in rodents and non-human primates. While macrophages are indispensable to the fibrotic cascade, surprisingly neutrophils and complement are not. Macrophages, via CXCL13, lead to downstream B cell recruitment, which further potentiated fibrosis, as confirmed by B cell knockout and CXCL13 neutralization...
March 20, 2017: Nature Materials
https://www.readbyqxmd.com/read/28315462/implications-of-cerebrovascular-atp-binding-cassette-transporter-g1-abcg1-and-apolipoprotein-m-in-cholesterol-transport-at-the-blood-brain-barrier
#9
Alexandra Carmen Kober, Anil Paul Chirackal Manavalan, Carmen Tam-Amersdorfer, Andreas Holmér, Ahmed Saeed, Elham Fanaee-Danesh, Martina Zandl, Nicole Maria Albrecher, Ingemar Björkhem, Gerhard M Kostner, Björn Dahlbäck, Ute Panzenboeck
Impaired cholesterol/lipoprotein metabolism is linked to neurodegenerative diseases such as Alzheimer's disease (AD). Cerebral cholesterol homeostasis is maintained by the highly efficient blood-brain barrier (BBB) and flux of the oxysterols 24(S)-hydroxycholesterol and 27-hydroxycholesterol, potent liver-X-receptor (LXR) activators. HDL and their apolipoproteins are crucial for cerebral lipid transfer, and loss of ATP binding cassette transporters (ABC)G1 and G4 results in toxic accumulation of oxysterols in the brain...
March 14, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28285690/the-cell-cell-interaction-between-tumor-associated-macrophages-and-small-cell-lung-cancer-cells-is-involved-in-tumor-progression-via-stat3-activation
#10
Toyohisa Iriki, Koji Ohnishi, Yukio Fujiwara, Hasita Horlad, Yoichi Saito, Cheng Pan, Koei Ikeda, Takeshi Mori, Makoto Suzuki, Hidenori Ichiyasu, Hirotsugu Kohrogi, Motohiro Takeya, Yoshihiro Komohara
OBJECTIVES: Small cell lung cancer (SCLC) is an aggressive tumor with a poor prognosis. It is well known that various stromal cells, including macrophages, play a role in tumor progression in several types of malignant tumors; however, the significance of tumor-associated macrophages (TAMs) in SCLC has not been fully elucidated. Signal transducer and activator of transcription 3 (STAT3) is a molecule well-known to be related to tumor progression. In the present study, we investigated the relationship of TAMs and SCLC cells to test the hypothesis that TAMs induce tumor progression in SCLC via STAT3 activation...
April 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28273456/circulating-nod1-activators-and-hematopoietic-nod1-contribute-to-metabolic-inflammation-and-insulin-resistance
#11
Kenny L Chan, Theresa H Tam, Parastoo Boroumand, David Prescott, Sheila R Costford, Nichole K Escalante, Noah Fine, YuShan Tu, Susan J Robertson, Dilshaayee Prabaharan, Zhi Liu, Philip J Bilan, Michael W Salter, Michael Glogauer, Stephen E Girardin, Dana J Philpott, Amira Klip
Insulin resistance is a chronic inflammatory condition accompanying obesity or high fat diets that leads to type 2 diabetes. It is hypothesized that lipids and gut bacterial compounds in particular contribute to metabolic inflammation by activating the immune system; however, the receptors detecting these "instigators" of inflammation remain largely undefined. Here, we show that circulating activators of NOD1, a receptor for bacterial peptidoglycan, increase with high fat feeding in mice, suggesting that NOD1 could be a critical sensor leading to metabolic inflammation...
March 7, 2017: Cell Reports
https://www.readbyqxmd.com/read/28272423/small-molecule-inhibitors-block-gas6-inducible-tam-activation-and-tumorigenicity
#12
Stanley G Kimani, Sushil Kumar, Nitu Bansal, Kamalendra Singh, Vladyslav Kholodovych, Thomas Comollo, Youyi Peng, Sergei V Kotenko, Stefan G Sarafianos, Joseph R Bertino, William J Welsh, Raymond B Birge
TAM receptors (Tyro-3, Axl, and Mertk) are a family of three homologous type I receptor tyrosine kinases that are implicated in several human malignancies. Overexpression of TAMs and their major ligand Growth arrest-specific factor 6 (Gas6) is associated with more aggressive staging of cancers, poorer predicted patient survival, acquired drug resistance and metastasis. Here we describe small molecule inhibitors (RU-301 and RU-302) that target the extracellular domain of Axl at the interface of the Ig-1 ectodomain of Axl and the Lg-1 of Gas6...
March 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28270700/growth-arrest-specific-6-enhances-the-suppressive-function-of-cd4-cd25-regulatory-t-cells-mainly-through-axl-receptor
#13
Guang-Ju Zhao, Jia-Yi Zheng, Jia-Lan Bian, Long-Wang Chen, Ning Dong, Yan Yu, Guang-Liang Hong, Arvine Chandoo, Yong-Ming Yao, Zhong-Qiu Lu
Background. Growth arrest-specific (Gas) 6 is one of the endogenous ligands of TAM receptors (Tyro3, Axl, and Mertk), and its role as an immune modulator has been recently emphasized. Naturally occurring CD4(+)CD25(+) regulatory T cells (Tregs) are essential for the active suppression of autoimmunity. The present study was designed to investigate whether Tregs express TAM receptors and the potential role of Gas6-TAM signal in regulating the suppressive function of Tregs. Methods. The protein and mRNA levels of TAM receptors were determined by using Western blot, immunofluorescence, flow cytometry, and RT-PCR...
2017: Mediators of Inflammation
https://www.readbyqxmd.com/read/28270510/down-regulation-of-forkhead-box-protein-a1-foxa1-leads-to-cancer-stem-cell-like-properties-in-tamoxifen-resistant-breast-cancer-cells-through-induction-of-interleukin-6
#14
Noritaka Yamaguchi, Yuji Nakayama, Naoto Yamaguchi
The selective estrogen receptor (ER) modulator tamoxifen inhibits ER signaling in breast cancer cells, and it is used for the treatment of ER-positive breast cancer. However, this type of cancer often acquires resistance to tamoxifen, and a better understanding of the molecular mechanisms underlying tamoxifen-resistance is required. In this study, we established tamoxifen-resistant (TAM-R) breast cancer cells by long-term tamoxifen treatment of ER-positive breast cancer MCF7 cells. In TAM-R cells, expression of not only ERα, a major form of ER in breast cancer, but also its transcriptional partner forkhead box protein A1 (FOXA1) was found to be reduced...
March 7, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28258690/tam-receptor-tyrosine-kinases-as-emerging-targets-of-innate-immune-checkpoint-blockade-for-cancer-therapy
#15
REVIEW
Yemsratch T Akalu, Carla V Rothlin, Sourav Ghosh
Cancer immunotherapy utilizing T-cell checkpoint inhibitors has shown tremendous clinical success. Yet, this mode of treatment is effective in only a subset of patients. Unresponsive patients tend to have non-T-cell-inflamed tumors that lack markers associated with the activation of adaptive anti-tumor immune responses. Notably, elimination of cancer cells by T cells is critically dependent on the optimal activity of innate immune cells. Therefore, identifying new targets that regulate innate immune cell function and promote the engagement of adaptive tumoricidal responses is likely to lead to the development of improved therapies against cancer...
March 2017: Immunological Reviews
https://www.readbyqxmd.com/read/28251492/key-roles-of-axl-and-mer-receptor-tyrosine-kinases-in-resistance-to-multiple-anticancer-therapies
#16
REVIEW
Marie Schoumacher, Mike Burbridge
A major challenge in anticancer treatment is the pre-existence or emergence of resistance to therapy. AXL and MER are two members of the TAM (TYRO3-AXL-MER) family of receptor tyrosine kinases, which, when activated, can regulate tumor cell survival, proliferation, migration and invasion, angiogenesis, and tumor-host interactions. An increasing body of evidence strongly suggests that these receptors play major roles in resistance to targeted therapies and conventional cytotoxic agents. Multiple resistance mechanisms exist, including the direct and indirect crosstalk of AXL and MER with other receptors and the activation of feedback loops regulating AXL and MER expression and activity...
March 2017: Current Oncology Reports
https://www.readbyqxmd.com/read/28246332/metabolic-origins-of-spatial-organization-in-the-tumor-microenvironment
#17
Carlos Carmona-Fontaine, Maxime Deforet, Leila Akkari, Craig B Thompson, Johanna A Joyce, Joao B Xavier
The genetic and phenotypic diversity of cells within tumors is a major obstacle for cancer treatment. Because of the stochastic nature of genetic alterations, this intratumoral heterogeneity is often viewed as chaotic. Here we show that the altered metabolism of cancer cells creates predictable gradients of extracellular metabolites that orchestrate the phenotypic diversity of cells in the tumor microenvironment. Combining experiments and mathematical modeling, we show that metabolites consumed and secreted within the tumor microenvironment induce tumor-associated macrophages (TAMs) to differentiate into distinct subpopulations according to local levels of ischemia and their position relative to the vasculature...
February 28, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28245343/eplerenone-for-hypertension
#18
REVIEW
Tina Sc Tam, May Hy Wu, Sarah C Masson, Matthew P Tsang, Sarah N Stabler, Angus Kinkade, Anthony Tung, Aaron M Tejani
BACKGROUND: Eplerenone is an aldosterone receptor blocker that is chemically derived from spironolactone. In Canada, it is indicated for use as adjunctive therapy to reduce mortality for heart failure patients with New York Heart Association (NYHA) class II systolic chronic heart failure and left ventricular systolic dysfunction. It is also used as adjunctive therapy for patients with heart failure following myocardial infarction. Additionally, it is indicated for the treatment of mild and moderate essential hypertension for patients who cannot be treated adequately with other agents...
February 28, 2017: Cochrane Database of Systematic Reviews
https://www.readbyqxmd.com/read/28222641/genotyping-guided-approach-versus-the-conventional-approach-in-selection-of-oral-p2y12-receptor-blockers-in-chinese-patients-suffering-from-acute-coronary-syndrome
#19
Chor Cheung Tam, Janette Kwok, Anthony Wong, Arthur Yung, Catherine Shea, Shun Ling Kong, Wing Hong Tang, David Siu, Raymond Chan, Stephen Lee
Objective The CYP2C19 loss-of-function (LoF) allele is present in half of the East Asian population and is associated with high on-treatment platelet reactivity (HTPR). This study aimed to investigate whether a rapid genotyping-guided approach is feasible and efficacious for selecting P2Y12 receptor blockers in Chinese patients suffering from acute coronary syndrome (ACS). Methods This was a single-centre, prospective, randomized, open-label study. A total of 132 patients with ACS were randomized to the rapid genotyping-guided treatment group (GG, N = 65) or the standard treatment group (SG, N = 67)...
February 2017: Journal of International Medical Research
https://www.readbyqxmd.com/read/28213819/conditional-knockout-of-activin-like-kinase-1-alk-1-leads-to-heart-failure-without-maladaptive-remodeling
#20
Kevin J Morine, Xiaoying Qiao, Vikram Paruchuri, Mark J Aronovitz, Emily E Mackey, Lyanne Buiten, Jonathan Levine, Keshan Ughreja, Prerna Nepali, Robert M Blanton, Richard H Karas, S Paul Oh, Navin K Kapur
Activin like kinase-1 (AlK-1) mediates signaling via the transforming growth factor beta (TGFβ) family of ligands. AlK-1 activity promotes endothelial proliferation and migration. Reduced AlK-1 activity is associated with arteriovenous malformations. No studies have examined the effect of global AlK-1 deletion on indices of cardiac remodeling. We hypothesized that reduced levels of AlK-1 promote maladaptive cardiac remodeling. To test this hypothesis, we employed AlK-1 conditional knockout mice (cKO) harboring the ROSA26-CreER knock-in allele, whereby a single dose of intraperitoneal tamoxifen triggered ubiquitous Cre recombinase-mediated excision of floxed AlK-1 alleles...
February 17, 2017: Heart and Vessels
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