The TIM and TAM families of phosphatidylserine receptors mediate dengue virus entry.

PubMed

Meertens, Laurent; Carnec, Xavier; Lecoin, Manuel Perera; Ramdasi, Rasika; Guivel-Benhassine, Florence; Lew, Erin; Lemke, Greg; Schwartz, Olivier; Amara, Ali

2012-10-18

Dengue viruses (DVs) are responsible for the most medically relevant arboviral diseases. However, the molecular interactions mediating DV entry are poorly understood. We determined that TIM and TAM proteins, two receptor families that mediate the phosphatidylserine (PtdSer)-dependent phagocytic removal of apoptotic cells, serve as DV entry factors. Cells poorly susceptible to DV are robustly infected after ectopic expression of TIM or TAM receptors. Conversely, DV infection of susceptible cells is inhibited by anti-TIM or anti-TAM antibodies or knockdown of TIM and TAM expression. TIM receptors facilitate DV entry by directly interacting with virion-associated PtdSer. TAM-mediated infection relies on indirect DV recognition, in which the TAM ligand Gas6 acts as a bridging molecule by binding to PtdSer within the virion. This dual mode of virus recognition by TIM and TAM receptors reveals how DVs usurp the apoptotic cell clearance pathway for infectious entry. Copyright © 2012 Elsevier Inc. All rights reserved.

Biology and management of transient abnormal myelopoiesis (TAM) in children with Down syndrome.

PubMed

Roy, Anindita; Roberts, Irene; Vyas, Paresh

2012-08-01

Children with Down syndrome (DS) have an increased risk of Acute Myeloid Leukaemia (ML-DS), particularly megakaryoblastic leukaemia, which is clonally -related to the neonatal myeloproliferative syndrome, Transient Abnormal Myelopoiesis (TAM) unique to infants with DS. Molecular, biological, and clinical data indicate that TAM is initiated before birth when fetal liver haematopoietic cells trisomic for chromosome 21 acquire mutations in GATA1. TAM usually resolves spontaneously by 6 months; however 20-30% subsequently develop ML-DS harbouring the same GATA1 mutation(s). This review focuses on recent studies describing haematological, clinical and biological features of TAM and discusses approaches to diagnose, treat and monitor minimal residual disease in TAM. An important unanswered question is whether ML-DS is always preceded by TAM as it may be clinically and possibly haematologically 'silent'. We have briefly discussed the role of population-based screening for TAM and development of treatment strategies to eliminate the preleukaemic TAM clone, thereby preventing ML-DS. Copyright © 2012 Elsevier Ltd. All rights reserved.

GAS6/TAM Pathway Signaling in Hemostasis and Thrombosis.

PubMed

Law, Luke A; Graham, Douglas K; Di Paola, Jorge; Branchford, Brian R

2018-01-01

The GAS6/TYRO3-AXL-MERTK (TAM) signaling pathway is essential for full and sustained platelet activation, as well as thrombus stabilization. Inhibition of this pathway decreases platelet aggregation, shape change, clot retraction, aggregate formation under flow conditions, and surface expression of activation markers. Transgenic mice deficient in GAS6, or any of the TAM family of receptors that engage this ligand, exhibit in vivo protection against arterial and venous thrombosis but do not demonstrate either spontaneous or prolonged bleeding compared to their wild-type counterparts. Comparable results are observed in wild-type mice treated with pharmacological inhibitors of the GAS6-TAM pathway. Thus, GAS6/TAM inhibition offers an attractive novel therapeutic option that may allow for a moderate reduction in platelet activation and decreased thrombosis while still permitting the primary hemostatic function of platelet plug formation.

The Structure of a Conserved Domain of TamB Reveals a Hydrophobic β Taco Fold.

PubMed

Josts, Inokentijs; Stubenrauch, Christopher James; Vadlamani, Grishma; Mosbahi, Khedidja; Walker, Daniel; Lithgow, Trevor; Grinter, Rhys

2017-12-05

The translocation and assembly module (TAM) plays a role in the transport and insertion of proteins into the bacterial outer membrane. TamB, a component of this system spans the periplasmic space to engage with its partner protein TamA. Despite efforts to characterize the TAM, the structure and mechanism of action of TamB remained enigmatic. Here we present the crystal structure of TamB amino acids 963-1,138. This region represents half of the conserved DUF490 domain, the defining feature of TamB. TamB 963-1138 consists of a concave, taco-shaped β sheet with a hydrophobic interior. This β taco structure is of dimensions capable of accommodating and shielding the hydrophobic side of an amphipathic β strand, potentially allowing TamB to chaperone nascent membrane proteins from the aqueous environment. In addition, sequence analysis suggests that the structure of TamB 963-1138 is shared by a large portion of TamB. This architecture could allow TamB to act as a conduit for membrane proteins. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

The Gas6/TAM System and Multiple Sclerosis.

PubMed

Bellan, Mattia; Pirisi, Mario; Sainaghi, Pier Paolo

2016-10-28

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). In this paper, we review the biology of the Gas6/TAM system and the current evidence supporting its potential role in the pathogenesis of MS.

Small molecule inhibitors block Gas6-inducible TAM activation and tumorigenicity.

PubMed

Kimani, Stanley G; Kumar, Sushil; Bansal, Nitu; Singh, Kamalendra; Kholodovych, Vladyslav; Comollo, Thomas; Peng, Youyi; Kotenko, Sergei V; Sarafianos, Stefan G; Bertino, Joseph R; Welsh, William J; Birge, Raymond B

2017-03-08

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. These inhibitors effectively block Gas6-inducible Axl receptor activation with low micromolar IC 50s in cell-based reporter assays, inhibit Gas6-inducible motility in Axl-expressing cell lines, and suppress H1299 lung cancer tumor growth in a mouse xenograft NOD-SCIDγ model. Furthermore, using homology models and biochemical verifications, we show that RU301 and 302 also inhibit Gas6 inducible activation of Mertk and Tyro3 suggesting they can act as pan-TAM inhibitors that block the interface between the TAM Ig1 ectodomain and the Gas6 Lg domain. Together, these observations establish that small molecules that bind to the interface between TAM Ig1 domain and Gas6 Lg1 domain can inhibit TAM activation, and support the further development of small molecule Gas6-TAM interaction inhibitors as a novel class of cancer therapeutics.

TAM receptors, Gas6, and protein S: roles in inflammation and hemostasis.

PubMed

van der Meer, Jonathan H M; van der Poll, Tom; van 't Veer, Cornelis

2014-04-17

TAM receptors (Tyro3, Axl, and Mer) belong to a family of receptor tyrosine kinases that have important effects on hemostasis and inflammation. Also, they affect cell proliferation, survival, adhesion, and migration. TAM receptors can be activated by the vitamin K-dependent proteins Gas6 and protein S. Protein S is more commonly known as an important cofactor for protein C as well as a direct inhibitor of multiple coagulation factors. To our knowledge, the functions of Gas6 are limited to TAM receptor activation. When activated, the TAM receptors have effects on primary hemostasis and coagulation and display an anti-inflammatory or a proinflammatory effect, depending on cell type. To comprehend the effects that the TAM receptors and their ligands have on hemostasis and inflammation, we compare studies that report the different phenotypes displayed by mice with deficiencies in the genes of this receptor family and its ligands (protein S(+/-), Gas6(-/-), TAM(-/-), and variations of these). In this manner, we aim to display which features are attributable to the different ligands. Because of the effects TAM receptors have on hemostasis, inflammation, and cancer growth, their modulation could make interesting therapeutic targets in thromboembolic disease, atherosclerosis, sepsis, autoimmune disease, and cancer.

Ligand Activation of TAM Family Receptors-Implications for Tumor Biology and Therapeutic Response.

PubMed

Davra, Viralkumar; Kimani, Stanley G; Calianese, David; Birge, Raymond B

2016-11-29

The TAM family of receptors (i.e., Tyro3, Axl, and Mertk), and their ligands Growth arrest specific factor 6 (Gas6) and Protein S (Pros1) contribute to several oncogenic processes, such as cell survival, invasion, migration, chemo-resistance, and metastasis, whereby expression often correlates with poor clinical outcomes. In recent years, there has been great interest in the study of TAM receptors in cancer, stemming both from their roles as oncogenic signaling receptors, as well as their roles in tumor immunology. As a result, several classes of TAM inhibitors that include small molecule tyrosine kinase inhibitors, monoclonal antibodies, decoy receptors, as well as novel strategies to target TAM ligands are being developed. This paper will review the biology of TAM receptors and their ligands with a focus on cancer, as well as evidence-based data for the continued pursuit of TAM/Gas6 inhibitors in clinical practice.

TAM receptor knockout mice are susceptible to retinal autoimmune induction.

PubMed

Ye, Fei; Li, Qiutang; Ke, Yan; Lu, Qingjun; Han, Lixia; Kaplan, Henry J; Shao, Hui; Lu, Qingxian

2011-06-16

TAM receptors are expressed mainly by dendritic cells and macrophages in the immune system, and mice lacking TAM receptors develop systemic autoimmune diseases because of inefficient negative control of the cytokine signaling in those cells. This study aims to test the susceptibility of the TAM triple knockout (tko) mice to the retina-specific autoantigen to develop experimental autoimmune uveoretinitis (EAU). TAM tko mice that were or were not immunized with interphotoreceptor retinoid-binding protein (IRBP) peptides were evaluated for retinal infiltration of the macrophages and CD3(+) T cells by immunohistochemistry, spontaneous activation of CD4(+) T cells, and memory T cells by flow cytometry and proliferation of IRBP-specific CD4(+) T cells by [(3)H]thymidine incorporation assay. Ocular inflammation induced by IRBP peptide immunization and specific T cell transfer were observed clinically by funduscopy and confirmed by histology. Tko mice were found to have less naive, but more activated, memory T cells, among which were exhibited high sensitivity to ocular IRBP autoantigens. Immunization with a low dose of IRBP and adoptive transfer of small numbers of IRBP-specific T cells from immunized tko mice caused the infiltration of lymphocytes, including CD3(+) T cells, into the tko retina. Mice without TAM receptor spontaneously develop IRBP-specific CD4(+) T cells and are more susceptible to retinal autoantigen immunization. This TAM knockout mouse line provides an animal model with which to study the role of antigen-presenting cells in the development of T cell-mediated uveitis.

The roles of TAM receptor tyrosine kinases in the mammalian testis and immunoprivileged sites.

PubMed

Deng, Tingting; Chen, Qiaoyuan; Han, Daishu

2016-01-01

Three members of a receptor tyrosine kinase family, including Tyro3, Axl, and Mer, are collectively called as TAM receptors. TAM receptors have two common ligands, namely, growth arrest specific gene 6 (Gas6) and protein S (ProS). The TAM-Gas6/ProS system is essential for phagocytic removal of apoptotic cells, and plays critical roles in regulating immune response. Genetic studies have shown that TAM receptors are essential regulators of the tissue homeostasis in immunoprivileged sites, including the testis, retina and brain. The mechanisms by which the TAM-Gas6/ProS system regulates the tissue homeostasis in immunoprivileged sites are emerging. The roles of the TAM-Gas6/ProS system in regulating the immune privilege were intensively investigated in the mouse testis, and several studies were performed in the eye and brain. This review summarizes our current understanding of TAM signaling in the testis and other immunoprivileged tissues, as well as highlights topics that are worthy of further investigation.

TAM Receptors Are Not Required for Zika Virus Infection in Mice.

PubMed

Hastings, Andrew K; Yockey, Laura J; Jagger, Brett W; Hwang, Jesse; Uraki, Ryuta; Gaitsch, Hallie F; Parnell, Lindsay A; Cao, Bin; Mysorekar, Indira U; Rothlin, Carla V; Fikrig, Erol; Diamond, Michael S; Iwasaki, Akiko

2017-04-18

Tyro3, Axl, and Mertk (TAM) receptors are candidate entry receptors for infection with the Zika virus (ZIKV), an emerging flavivirus of global public health concern. To investigate the requirement of TAM receptors for ZIKV infection, we used several routes of viral inoculation and compared viral replication in wild-type versus Axl -/- , Mertk -/- , Axl -/- Mertk -/- , and Axl -/- Tyro3 -/- mice in various organs. Pregnant and non-pregnant mice treated with interferon-α-receptor (IFNAR)-blocking (MAR1-5A3) antibody and infected subcutaneously with ZIKV showed no reliance on TAMs for infection. In the absence of IFNAR-blocking antibody, adult female mice challenged intravaginally with ZIKV showed no difference in mucosal viral titers. Similarly, in young mice that were infected with ZIKV intracranially or intraperitoneally, ZIKV replication occurred in the absence of TAM receptors, and no differences in cell tropism were observed. These findings indicate that, in mice, TAM receptors are not required for ZIKV entry and infection. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Esterified dendritic TAM radicals with very high stability and enhanced oxygen sensitivity.

PubMed

Song, Yuguang; Liu, Yangping; Hemann, Craig; Villamena, Frederick A; Zweier, Jay L

2013-02-15

In this work, we have developed a new class of dendritic TAM radicals (TG, TdG, and dTdG) through a convergent method based on the TAM core CT-03 or its deuterated analogue dCT-03 and trifurcated Newkome-type monomer. Among these radicals, dTdG exhibits the best EPR properties with sharpest EPR singlet and highest O(2) sensitivity due to deuteration of both the ester linker groups and the TAM core CT-03. Like the previous dendritic TAM radicals, these new compounds also show extremely high stability toward various reactive species owing to the dendritic encapsulation. The highly charged nature of these molecules resulting from nine carboxylate groups prevents concentration-dependent EPR line broadening at physiological pH. Furthermore, we demonstrate that these TAM radicals can be easily derivatized (e.g., PEGylation) at the nine carboxylate groups and the resulting PEGylated analogue dTdG-PEG completely inhibits the albumin binding, thereby enhancing suitability for in vivo applications. These new dendritic TAM radicals show great potential for in vivo EPR oximetric applications and provide insights on approaches to develop improved and targeted EPR oximetric probes for biomedical applications.

Functional analysis of TamA, a coactivator of nitrogen-regulated gene expression in Aspergillus nidulans.

PubMed

Small, A J; Todd, R B; Zanker, M C; Delimitrou, S; Hynes, M J; Davis, M A

2001-06-01

The tam A gene of Aspergillus nidulans encodes a 739-amino acid protein with similarity to Uga35p/Dal81p/DurLp of Saccharomyces cerevisiae. It has been proposed that TamA functions as a co-activator of AreA, the major nitrogen regulatory protein in A. nidulans. Because AreA functions as a transcriptional activator under nitrogen-limiting conditions, we investigated whether TamA was also present in the nucleus. We found that a GFP-TamA fusion protein was predominantly localised to the nucleus in the presence and absence of ammonium, and that AreA was not required for this distribution. As the predicted DNA-binding domain of TamA is not essential for function, we have used a number of approaches to further define functionally important regions. We have cloned the tamA gene of A. oryzae and compared its functional and sequence characteristics with those of A. nidulans tamA and S. cerevisiae UGA35/DAL81/DURL. The Aspergillus homologues are highly conserved and functionally interchangeable, whereas the S. cerevisiae gene does not complement a tamA mutant when expressed in A. nidulans. Uga35p/Dal81p/DurLp was also found to be unable to recruit AreA. The sequence changes in a number of tamA mutant alleles were determined, and altered versions of TamA were tested for tamA complementation and interaction with AreA. Changes in most regions of TamA appeared to destroy its function, suggesting that the overall conformation of the protein may be critical for its activity.

Cytoplasmic PELP1 and ERRgamma Protect Human Mammary Epithelial Cells from Tam-Induced Cell Death

PubMed Central

Girard, Brian J.; Regan Anderson, Tarah M.; Welch, Siya Lem; Nicely, Julie; Seewaldt, Victoria L.; Ostrander, Julie H.

2015-01-01

Tamoxifen (Tam) is the only FDA-approved chemoprevention agent for pre-menopausal women at high risk for developing breast cancer. While Tam reduces a woman's risk of developing estrogen receptor positive (ER+) breast cancer, the molecular mechanisms associated with risk reduction are poorly understood. Prior studies have shown that cytoplasmic proline, glutamic acid and leucine rich protein 1 (PELP1) promotes Tam resistance in breast cancer cell lines. Herein, we tested for PELP1 localization in breast epithelial cells from women at high risk for developing breast cancer and found that PELP1 was localized to the cytoplasm in 36% of samples. In vitro, immortalized HMECs expressing a nuclear localization signal (NLS) mutant of PELP1 (PELP1-cyto) were resistant to Tam-induced death. Furthermore, PELP1-cyto signaling through estrogen-related receptor gamma (ERRγ) promoted cell survival in the presence of Tam. Overexpression of ERRγ in immortalized HMECs protected cells from Tam-induced death, while knockdown of ERRγ sensitized PELP1-cyto expressing HMECs to Tam. Moreover, Tam-induced HMEC cell death was independent of apoptosis and involved accumulation of the autophagy marker LC3-II. Expression of PELP1-cyto and ERRγ reduced Tam-induced LC3-II accumulation, and knockdown of ERRγ increased LC3-II levels in response to Tam. Additionally, PELP1-cyto expression led to the upregulation of MMP-3 and MAOB, known PELP1 and ERRγ target genes, respectively. Our data indicate that cytoplasmic PELP1 induces signaling pathways that converge on ERRγ to promote cell survival in the presence of Tam. These data suggest that PELP1 localization and/or ERRγ activation could be developed as tissue biomarkers for Tam responsiveness. PMID:25789479

Cytoplasmic PELP1 and ERRgamma protect human mammary epithelial cells from Tam-induced cell death.

PubMed

Girard, Brian J; Regan Anderson, Tarah M; Welch, Siya Lem; Nicely, Julie; Seewaldt, Victoria L; Ostrander, Julie H

2015-01-01

Tamoxifen (Tam) is the only FDA-approved chemoprevention agent for pre-menopausal women at high risk for developing breast cancer. While Tam reduces a woman's risk of developing estrogen receptor positive (ER+) breast cancer, the molecular mechanisms associated with risk reduction are poorly understood. Prior studies have shown that cytoplasmic proline, glutamic acid and leucine rich protein 1 (PELP1) promotes Tam resistance in breast cancer cell lines. Herein, we tested for PELP1 localization in breast epithelial cells from women at high risk for developing breast cancer and found that PELP1 was localized to the cytoplasm in 36% of samples. In vitro, immortalized HMECs expressing a nuclear localization signal (NLS) mutant of PELP1 (PELP1-cyto) were resistant to Tam-induced death. Furthermore, PELP1-cyto signaling through estrogen-related receptor gamma (ERRγ) promoted cell survival in the presence of Tam. Overexpression of ERRγ in immortalized HMECs protected cells from Tam-induced death, while knockdown of ERRγ sensitized PELP1-cyto expressing HMECs to Tam. Moreover, Tam-induced HMEC cell death was independent of apoptosis and involved accumulation of the autophagy marker LC3-II. Expression of PELP1-cyto and ERRγ reduced Tam-induced LC3-II accumulation, and knockdown of ERRγ increased LC3-II levels in response to Tam. Additionally, PELP1-cyto expression led to the upregulation of MMP-3 and MAOB, known PELP1 and ERRγ target genes, respectively. Our data indicate that cytoplasmic PELP1 induces signaling pathways that converge on ERRγ to promote cell survival in the presence of Tam. These data suggest that PELP1 localization and/or ERRγ activation could be developed as tissue biomarkers for Tam responsiveness.

Normalization of TAM post-receptor signaling reveals a cell invasive signature for Axl tyrosine kinase.

PubMed

Kimani, Stanley G; Kumar, Sushil; Davra, Viralkumar; Chang, Yun-Juan; Kasikara, Canan; Geng, Ke; Tsou, Wen-I; Wang, Shenyan; Hoque, Mainul; Boháč, Andrej; Lewis-Antes, Anita; De Lorenzo, Mariana S; Kotenko, Sergei V; Birge, Raymond B

2016-09-06

Tyro3, Axl, and Mertk (TAMs) are a family of three conserved receptor tyrosine kinases that have pleiotropic roles in innate immunity and homeostasis and when overexpressed in cancer cells can drive tumorigenesis. In the present study, we engineered EGFR/TAM chimeric receptors (EGFR/Tyro3, EGFR/Axl, and EGF/Mertk) with the goals to interrogate post-receptor functions of TAMs, and query whether TAMs have unique or overlapping post-receptor activation profiles. Stable expression of EGFR/TAMs in EGFR-deficient CHO cells afforded robust EGF inducible TAM receptor phosphorylation and activation of downstream signaling. Using a series of unbiased screening approaches, that include kinome-view analysis, phosphor-arrays, RNAseq/GSEA analysis, as well as cell biological and in vivo readouts, we provide evidence that each TAM has unique post-receptor signaling platforms and identify an intrinsic role for Axl that impinges on cell motility and invasion compared to Tyro3 and Mertk. These studies demonstrate that TAM show unique post-receptor signatures that impinge on distinct gene expression profiles and tumorigenic outcomes.

Targeting Gas6/TAM in cancer cells and tumor microenvironment.

PubMed

Wu, Guiling; Ma, Zhiqiang; Cheng, Yicheng; Hu, Wei; Deng, Chao; Jiang, Shuai; Li, Tian; Chen, Fulin; Yang, Yang

2018-01-31

Growth arrest-specific 6, also known as Gas6, is a human gene encoding the Gas6 protein, which was originally found to be upregulated in growth-arrested fibroblasts. Gas6 is a member of the vitamin K-dependent family of proteins expressed in many human tissues and regulates several biological processes in cells, including proliferation, survival and migration, by binding to its receptors Tyro3, Axl and Mer (TAM). In recent years, the roles of Gas6/TAM signalling in cancer cells and the tumour microenvironment have been studied, and some progress has made in targeted therapy, providing new potential directions for future investigations of cancer treatment. In this review, we introduce the Gas6 and TAM receptors and describe their involvement in different cancers and discuss the roles of Gas6 in cancer cells, the tumour microenvironment and metastasis. Finally, we introduce recent studies on Gas6/TAM targeting in cancer therapy, which will assist in the experimental design of future analyses and increase the potential use of Gas6 as a therapeutic target for cancer.

Clinical application and prognostic assessment of serum Tumor Associated Material (TAM) from esophageal cancer patients.

PubMed

Zhou, K; Yan, Y; Zhao, S; Li, B

2014-01-01

To explore the correlation between serum levels of Tumor Associated Materials (TAM) and clinicopathological parameters and prognosis in patients with esophageal cancer (EC). The levels of TAM were determined by chemical colorimetry in 100 EC patients and 100 healthy controls. Serum TAM levels were significantly higher in patients with esophageal carcinoma than in the control group (p < 0.001). High levels of TAM were associated with tumor size (p = 0.004), tumor depth (p < 0.001), stage (p < 0.001), lymph node metastases (p < 0.001), tumor differentiation (p = 0.001), tumor respectability (p = 0.002) and disease progression (p < 0.001). The poor prognostic outcomes were correlated with an elevated level of TAM (p = 0.001). Kaplan-Meier analysis showed patients with increased levels of TAM after operation had an lower overall survival (p < 0.001) and disease-free survival (p < 0.001). In addition, multivariate Cox proportional hazard analyses revealed that TAM may be an independent factor affecting the overall survival and disease-free survival (p < 0.001). The detection of TAM could be used to screen for tumor and assess unfavorable prognosis in patients with EC.

Regulation of phagocytosis by TAM receptors and their ligands

PubMed Central

Lu, Qingxian; Li, Qiutang; Lu, Qingjun

2010-01-01

The TAM family of receptors is preferentially expressed by professional and non-professional phagocytes, including macrophages, dendritic cells and natural killer cells in the immune system, osteoclasts in bone, Sertoli cells in testis, and retinal pigmental epithelium cells in the retina. Mutations in the Mertk single gene or in different combinations of the double or triple gene mutations in the same cell cause complete or partial impairment in phagocytosis of their preys; and as a result, either the normal apoptotic cells cannot be efficiently removed or the tissue neighbor cells die by apoptosis. This scenario of TAM regulation represents a widely adapted model system used by phagocytes in all different tissues. The present review will summarize current known functional roles of TAM receptors and their ligands, Gas 6 and protein S, in the regulation of phagocytosis. PMID:21057587

TAM receptors support neural stem cell survival, proliferation and neuronal differentiation.

PubMed

Ji, Rui; Meng, Lingbin; Jiang, Xin; Cvm, Naresh Kumar; Ding, Jixiang; Li, Qiutang; Lu, Qingxian

2014-01-01

Tyro3, Axl and Mertk (TAM) receptor tyrosine kinases play multiple functional roles by either providing intrinsic trophic support for cell growth or regulating the expression of target genes that are important in the homeostatic regulation of immune responses. TAM receptors have been shown to regulate adult hippocampal neurogenesis by negatively regulation of glial cell activation in central nervous system (CNS). In the present study, we further demonstrated that all three TAM receptors were expressed by cultured primary neural stem cells (NSCs) and played a direct growth trophic role in NSCs proliferation, neuronal differentiation and survival. The cultured primary NSCs lacking TAM receptors exhibited slower growth, reduced proliferation and increased apoptosis as shown by decreased BrdU incorporation and increased TUNEL labeling, than those from the WT NSCs. In addition, the neuronal differentiation and maturation of the mutant NSCs were impeded, as characterized by less neuronal differentiation (β-tubulin III+) and neurite outgrowth than their WT counterparts. To elucidate the underlying mechanism that the TAM receptors play on the differentiating NSCs, we examined the expression profile of neurotrophins and their receptors by real-time qPCR on the total RNAs from hippocampus and primary NSCs; and found that the TKO NSC showed a significant reduction in the expression of both nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), but accompanied by compensational increases in the expression of the TrkA, TrkB, TrkC and p75 receptors. These results suggest that TAM receptors support NSCs survival, proliferation and differentiation by regulating expression of neurotrophins, especially the NGF.

Increased Circulating and Urinary Levels of Soluble TAM Receptors in Diabetic Nephropathy.

PubMed

Ochodnicky, Peter; Lattenist, Lionel; Ahdi, Mohamed; Kers, Jesper; Uil, Melissa; Claessen, Nike; Leemans, Jaklien C; Florquin, Sandrine; Meijers, Joost C M; Gerdes, Victor E A; Roelofs, Joris J T H

2017-09-01

TAM receptors (Tyro3, Axl, and Mer) have been implicated in innate immunity. Circulating TAM receptor soluble forms (sTyro3, sAxl, sMer) are related to autoimmune disorders. We investigated TAM and their ligand protein S in patients with diabetes. Urinary and plasma levels of protein S, sTyro3, sAxl, and sMer were determined in 126 patients with diabetes assigned to a normoalbuminuric or macroalbuminuric (urinary albumin excretion <30 mg/24 hours and >300 mg/24 hours, respectively) study group and 18 healthy volunteers. TAM and protein S immunostaining was performed on kidney biopsy specimens from patients with diabetic nephropathy (n = 9) and controls (n = 6). TAM expression and shedding by tubular epithelial cells were investigated by PCR and enzyme-linked immunosorbent assay in an in vitro diabetes model. Patients with macroalbuminuria diabetes had higher circulating levels of sMer and more urinary sTyro3 and sMer than normoalbuminuric diabetics. Increased clearance of sTyro3 and sMer was associated with loss of tubular Tyro3 and Mer expression in diabetic nephropathy tissue and glomerular depositions of protein S. During in vitro diabetes, human kidney cells had down-regulation of Tyro3 and Mer mRNA and increased shedding of sTyro3 and sMer. Renal injury in diabetes is associated with elevated systemic and urine levels of sMer and sTyro3. This is the first study reporting excretion of sTAM receptors in urine, identifying the kidney as a source of sTAM. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Enveloped viruses disable innate immune responses in dendritic cells by direct activation of TAM receptors.

PubMed

Bhattacharyya, Suchita; Zagórska, Anna; Lew, Erin D; Shrestha, Bimmi; Rothlin, Carla V; Naughton, John; Diamond, Michael S; Lemke, Greg; Young, John A T

2013-08-14

Upon activation by the ligands Gas6 and Protein S, Tyro3/Axl/Mer (TAM) receptor tyrosine kinases promote phagocytic clearance of apoptotic cells and downregulate immune responses initiated by Toll-like receptors and type I interferons (IFNs). Many enveloped viruses display the phospholipid phosphatidylserine on their membranes, through which they bind Gas6 and Protein S and engage TAM receptors. We find that ligand-coated viruses activate TAM receptors on dendritic cells (DCs), dampen type I IFN signaling, and thereby evade host immunity and promote infection. Upon virus challenge, TAM-deficient DCs display type I IFN responses that are elevated in comparison to wild-type cells. As a consequence, TAM-deficient DCs are relatively resistant to infection by flaviviruses and pseudotyped retroviruses, but infection can be restored with neutralizing type I IFN antibodies. Correspondingly, a TAM kinase inhibitor antagonizes the infection of wild-type DCs. Thus, TAM receptors are engaged by viruses in order to attenuate type I IFN signaling and represent potential therapeutic targets. Copyright © 2013 Elsevier Inc. All rights reserved.

Phosphatidylserine Sensing by TAM Receptors Regulates AKT-Dependent Chemoresistance and PD-L1 Expression.

PubMed

Kasikara, Canan; Kumar, Sushil; Kimani, Stanley; Tsou, Wen-I; Geng, Ke; Davra, Viralkumar; Sriram, Ganapathy; Devoe, Connor; Nguyen, Khanh-Quynh N; Antes, Anita; Krantz, Allen; Rymarczyk, Grzegorz; Wilczynski, Andrzej; Empig, Cyril; Freimark, Bruce; Gray, Michael; Schlunegger, Kyle; Hutchins, Jeff; Kotenko, Sergei V; Birge, Raymond B

2017-06-01

Tyro3, Axl, and Mertk (collectively TAM receptors) are three homologous receptor tyrosine kinases that bind vitamin K-dependent endogenous ligands, Protein S (ProS), and growth arrest-specific factor 6 (Gas6), and act as bridging molecules to promote phosphatidylserine (PS)-mediated clearance of apoptotic cells (efferocytosis). TAM receptors are overexpressed in a vast array of tumor types, whereby the level of expression correlates with the tumor grade and the emergence of chemo- and radioresistance to targeted therapeutics, but also have been implicated as inhibitory receptors on infiltrating myeloid-derived cells in the tumor microenvironment that can suppress host antitumor immunity. In the present study, we utilized TAM-IFNγR1 reporter lines and expressed TAM receptors in a variety of epithelial cell model systems to show that each TAM receptor has a unique pattern of activation by Gas6 or ProS, as well as unique dependency for PS on apoptotic cells and PS liposomes for activity. In addition, we leveraged this system to engineer epithelial cells that express wild-type TAM receptors and show that although each receptor can promote PS-mediated efferocytosis, AKT-mediated chemoresistance, as well as upregulate the immune checkpoint molecule PD-L1 on tumor cells, Mertk is most dominant in the aforementioned pathways. Functionally, TAM receptor-mediated efferocytosis could be partially blocked by PS-targeting antibody 11.31 and Annexin V, demonstrating the existence of a PS/PS receptor (i.e., TAM receptor)/PD-L1 axis that operates in epithelial cells to foster immune escape. These data provide a rationale that PS-targeting, anti-TAM receptor, and anti-PD-L1-based therapeutics will have merit as combinatorial checkpoint inhibitors. Implications: Many tumor cells are known to upregulate the immune checkpoint inhibitor PD-L1. This study demonstrates a role for PS and TAM receptors in the regulation of PD-L1 on cancer cells. Mol Cancer Res; 15(6); 753-64. ©2017 AACR

The role of TAM family receptors and ligands in the nervous system: From development to pathobiology.

PubMed

Shafit-Zagardo, Bridget; Gruber, Ross C; DuBois, Juwen C

2018-03-04

Tyro3, Axl, and Mertk, referred to as the TAM family of receptor tyrosine kinases, are instrumental in maintaining cell survival and homeostasis in mammals. TAM receptors interact with multiple signaling molecules to regulate cell migration, survival, phagocytosis and clearance of metabolic products and cell debris called efferocytosis. The TAMs also function as rheostats to reduce the expression of proinflammatory molecules and prevent autoimmunity. All three TAM receptors are activated in a concentration-dependent manner by the vitamin K-dependent growth arrest-specific protein 6 (Gas6). Gas6 and the TAMs are abundantly expressed in the nervous system. Gas6, secreted by neurons and endothelial cells, is the sole ligand for Axl. ProteinS1 (ProS1), another vitamin K-dependent protein functions mainly as an anti-coagulant, and independent of this function can activate Tyro3 and Mertk, but not Axl. This review will focus on the role of the TAM receptors and their ligands in the nervous system. We highlight studies that explore the function of TAM signaling in myelination, the visual cortex, neural cancers, and multiple sclerosis (MS) using Gas6 -/- and TAM mutant mice models. Copyright © 2018. Published by Elsevier Inc.

Subcellular compartmentalization of Cd and Zn in two bivalves. II. Significance of trophically available metal (TAM)

USGS Publications Warehouse

Wallace, W.G.; Luoma, S.N.

2003-01-01

This paper examines how the subcellular partitioning of Cd and Zn in the bivalves Macoma balthica and Potamocorbula amurensis may affect the trophic transfer of metal to predators. Results show that the partitioning of metals to organelles, 'enzymes' and metallothioneins (MT) comprise a subcellular compartment containing trophically available metal (TAM; i.e. metal trophically available to predators), and that because this partitioning varies with species, animal size and metal, TAM is similarly influenced. Clams from San Francisco Bay, California, were exposed for 14 d to 3.5 ??g 1-1 Cd and 20.5 ??g 1-1 Zn, including 109Cd and 65Zn as radiotracers, and were used in feeding experiments with grass shrimp Palaemon macrodatylus, or used to investigate the subcellular partitioning of metal. Grass shrimp fed Cd-contaminated P. amurensis absorbed ???60% of ingested Cd, which was in accordance with the partitioning of Cd to the bivalve's TAM compartment (i.e. Cd associated with organelles, 'enzymes' and MT); a similar relationship was found in previous studies with grass shrimp fed Cd-contaminated oligochaetes. Thus, TAM may be used as a tool to predict the trophic transfer of at least Cd. Subcellular fractionation revealed that ???34% of both the Cd and Zn accumulated by M. balthica was associated with TAM, while partitioning to TAM in P. amurensis was metal-dependent (???60% for TAM-Cd%, ???73% for TAM-Zn%). The greater TAM-Cd% of P. amurensis than M. balthica is due to preferential binding of Cd to MT and 'enzymes', while enhanced TAM-Zn% of P. amurensis results from a greater binding of Zn to organelles. TAM for most species-metal combinations was size-dependent, decreasing with increased clam size. Based on field data, it is estimated that of the 2 bivalves, P. amurensis poses the greater threat of Cd exposure to predators because of higher tissue concentrations and greater partitioning as TAM; exposure of Zn to predators would be similar between these species.

The Role of TAM Family Receptors in Immune Cell Function: Implications for Cancer Therapy.

PubMed

Paolino, Magdalena; Penninger, Josef M

2016-10-21

The TAM receptor protein tyrosine kinases-Tyro3, Axl, and Mer-are essential regulators of immune homeostasis. Guided by their cognate ligands Growth arrest-specific gene 6 (Gas6) and Protein S (Pros1), these receptors ensure the resolution of inflammation by dampening the activation of innate cells as well as by restoring tissue function through promotion of tissue repair and clearance of apoptotic cells. Their central role as negative immune regulators is highlighted by the fact that deregulation of TAM signaling has been linked to the pathogenesis of autoimmune, inflammatory, and infectious diseases. Importantly, TAM receptors have also been associated with cancer development and progression. In a cancer setting, TAM receptors have a dual regulatory role, controlling the initiation and progression of tumor development and, at the same time, the associated anti-tumor responses of diverse immune cells. Thus, modulation of TAM receptors has emerged as a potential novel strategy for cancer treatment. In this review, we discuss our current understanding of how TAM receptors control immunity, with a particular focus on the regulation of anti-tumor responses and its implications for cancer immunotherapy.

The Role of TAM Family Receptors in Immune Cell Function: Implications for Cancer Therapy

PubMed Central

Paolino, Magdalena; Penninger, Josef M.

2016-01-01

The TAM receptor protein tyrosine kinases—Tyro3, Axl, and Mer—are essential regulators of immune homeostasis. Guided by their cognate ligands Growth arrest-specific gene 6 (Gas6) and Protein S (Pros1), these receptors ensure the resolution of inflammation by dampening the activation of innate cells as well as by restoring tissue function through promotion of tissue repair and clearance of apoptotic cells. Their central role as negative immune regulators is highlighted by the fact that deregulation of TAM signaling has been linked to the pathogenesis of autoimmune, inflammatory, and infectious diseases. Importantly, TAM receptors have also been associated with cancer development and progression. In a cancer setting, TAM receptors have a dual regulatory role, controlling the initiation and progression of tumor development and, at the same time, the associated anti-tumor responses of diverse immune cells. Thus, modulation of TAM receptors has emerged as a potential novel strategy for cancer treatment. In this review, we discuss our current understanding of how TAM receptors control immunity, with a particular focus on the regulation of anti-tumor responses and its implications for cancer immunotherapy. PMID:27775650

IL6 induces TAM resistance via kinase-specific phosphorylation of ERα in OVCA cells.

PubMed

Wang, Yue; Niu, Xiu Long; Guo, Xiao Qin; Yang, Jing; Li, Ling; Qu, Ye; Xiu Hu, Cun; Mao, Li Qun; Wang, Dan

2015-06-01

About 40-60% of ovarian cancer (OVCA) cases express ERα, but only a small proportion of patients respond clinically to anti-estrogen treatment with estrogen receptor (ER) antagonist tamoxifen (TAM). The mechanism of TAM resistance in the course of OVCA progression remains unclear. However, IL6 plays a critical role in the development and progression of OVCA. Our recent results indicated that IL6 secreted by OVCA cells may promote the resistance of these cells to TAM via ER isoforms and steroid hormone receptor coactivator-1. Here we demonstrate that both exogenous (a relatively short period of treatment with recombinant IL6) and endogenous IL6 (generated as a result of transfection with a plasmid encoding sense IL6) increases expression of pERα-Ser118 and pERα-Ser167 in non-IL6-expressing A2780 cells, while deleting endogenous IL6 expression in IL6-overexpressing CAOV-3 cells (by transfection with a plasmid encoding antisense IL6) reduces expression of pERα-Ser118 and pERα-Ser167, indicating that IL6-induced TAM resistance may also be associated with increased expression of pERα-Ser118 and pERα-Ser167 in OVCA cells. Results of further investigation indicate that IL6 phosphorylates ERα at Ser118 and Ser167 by triggering activation of MEK/ERK and phosphotidylinositol 3 kinase/Akt signaling, respectively, to activate the ER pathway and thereby induce OVCA cells resistance to TAM. These results indicate that IL6 secreted by OVCA cells may also contribute to the refractoriness of these cells to TAM via the crosstalk between ER and IL6-mediated intracellular signal transduction cascades. Overexpression of IL6 not only plays an important role in OVCA progression but also promotes TAM resistance. Our results indicate that TAM-IL6-targeted adjunctive therapy may lead to a more effective intervention than TAM alone. © 2015 Society for Endocrinology.

Molecular insights of Gas6/TAM in cancer development and therapy.

PubMed

Wu, Guiling; Ma, Zhiqiang; Hu, Wei; Wang, Dongjin; Gong, Bing; Fan, Chongxi; Jiang, Shuai; Li, Tian; Gao, Jianyuan; Yang, Yang

2017-03-23

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. Interestingly, Gas6 also has a role in establishing tumour dormancy in the bone marrow microenvironment and in suppressing intestinal tumorigenesis. Numerous studies regarding cancer therapy have targeted Gas6 and TAM receptors with good results. However, some findings have suggested that Gas6 is associated with the development of resistance to cancer therapies. Concerning these significant effects of Gas6 in numerous cancers, we discuss the roles of Gas6 in cancer development in this review. First, we introduce basic knowledge on Gas6 and TAM receptors. Next, we describe and discuss the involvement of Gas6 and TAM receptors in cancers from different organ systems. Finally, we highlight the progress in therapies targeting Gas6 and TAM receptors. This review presents the significant roles of Gas6 in cancers from different systems and may contribute to the continued promotion of Gas6 as a therapeutic target.

Modeling the acceptance of clinical information systems among hospital medical staff: an extended TAM model.

PubMed

Melas, Christos D; Zampetakis, Leonidas A; Dimopoulou, Anastasia; Moustakis, Vassilis

2011-08-01

Recent empirical research has utilized the Technology Acceptance Model (TAM) to advance the understanding of doctors' and nurses' technology acceptance in the workplace. However, the majority of the reported studies are either qualitative in nature or use small convenience samples of medical staff. Additionally, in very few studies moderators are either used or assessed despite their importance in TAM based research. The present study focuses on the application of TAM in order to explain the intention to use clinical information systems, in a random sample of 604 medical staff (534 physicians) working in 14 hospitals in Greece. We introduce physicians' specialty as a moderator in TAM and test medical staff's information and communication technology (ICT) knowledge and ICT feature demands, as external variables. The results show that TAM predicts a substantial proportion of the intention to use clinical information systems. Findings make a contribution to the literature by replicating, explaining and advancing the TAM, whereas theory is benefited by the addition of external variables and medical specialty as a moderator. Recommendations for further research are discussed. Copyright © 2011 Elsevier Inc. All rights reserved.

TAM Receptor Tyrosine Kinases: Biologic Functions, Signaling, and Potential Therapeutic Targeting in Human Cancer

PubMed Central

Linger, Rachel M. A.; Keating, Amy K.; Earp, H. Shelton; Graham, Douglas K.

2011-01-01

Tyro-3, Axl, and Mer constitute the TAM family of receptor tyrosine kinases (RTKs) characterized by a conserved sequence within the kinase domain and adhesion molecule-like extracellular domains. This small family of RTKs regulates an intriguing mix of processes, including cell proliferation/survival, cell adhesion and migration, blood clot stabilization, and regulation of inflammatory cytokine release. Genetic or experimental alteration of TAM receptor function can contribute to a number of disease states, including coagulopathy, autoimmune disease, retinitis pigmentosa, and cancer. In this chapter, we first provide a comprehensive review of the structure, regulation, biologic functions, and down-stream signaling pathways of these receptors. In addition, we discuss recent evidence which suggests a role for TAM receptors in oncogenic mechanisms as family members are over-expressed in a spectrum of human cancers and have prognostic significance in some. Possible strategies for targeted inhibition of the TAM family in the treatment of human cancer are described. Further research will be necessary to evaluate the full clinical implications of TAM family expression and activation in cancer. PMID:18620092

Development of Test-Analysis Models (TAM) for correlation of dynamic test and analysis results

NASA Technical Reports Server (NTRS)

Angelucci, Filippo; Javeed, Mehzad; Mcgowan, Paul

1992-01-01

The primary objective of structural analysis of aerospace applications is to obtain a verified finite element model (FEM). The verified FEM can be used for loads analysis, evaluate structural modifications, or design control systems. Verification of the FEM is generally obtained as the result of correlating test and FEM models. A test analysis model (TAM) is very useful in the correlation process. A TAM is essentially a FEM reduced to the size of the test model, which attempts to preserve the dynamic characteristics of the original FEM in the analysis range of interest. Numerous methods for generating TAMs have been developed in the literature. The major emphasis of this paper is a description of the procedures necessary for creation of the TAM and the correlation of the reduced models with the FEM or the test results. Herein, three methods are discussed, namely Guyan, Improved Reduced System (IRS), and Hybrid. Also included are the procedures for performing these analyses using MSC/NASTRAN. Finally, application of the TAM process is demonstrated with an experimental test configuration of a ten bay cantilevered truss structure.

Explaining the Discrepancy in the Mediating Role of Attitude in the TAM

ERIC Educational Resources Information Center

López-Bonilla, Luis Miguel; López-Bonilla, Jesús Manuel

2017-01-01

The debate about the role of attitude in the technology acceptance model (TAM) seems to have re-emerged in two prestigious journals in the field of educational technology. Among the publications on this debate, there are authors in favour of excluding the attitude of TAM, whereas others are in favour of including it. These opinions are derived…

TAM receptors affect adult brain neurogenesis by negative regulation of microglial cell activation.

PubMed

Ji, Rui; Tian, Shifu; Lu, Helen J; Lu, Qingjun; Zheng, Yan; Wang, Xiaomin; Ding, Jixiang; Li, Qiutang; Lu, Qingxian

2013-12-15

TAM tyrosine kinases play multiple functional roles, including regulation of the target genes important in homeostatic regulation of cytokine receptors or TLR-mediated signal transduction pathways. In this study, we show that TAM receptors affect adult hippocampal neurogenesis and loss of TAM receptors impairs hippocampal neurogenesis, largely attributed to exaggerated inflammatory responses by microglia characterized by increased MAPK and NF-κB activation and elevated production of proinflammatory cytokines that are detrimental to neuron stem cell proliferation and neuronal differentiation. Injection of LPS causes even more severe inhibition of BrdU incorporation in the Tyro3(-/-)Axl(-/-)Mertk(-/-) triple-knockout (TKO) brains, consistent with the LPS-elicited enhanced expression of proinflammatory mediators, for example, IL-1β, IL-6, TNF-α, and inducible NO synthase, and this effect is antagonized by coinjection of the anti-inflammatory drug indomethacin in wild-type but not TKO brains. Conditioned medium from TKO microglia cultures inhibits neuron stem cell proliferation and neuronal differentiation. IL-6 knockout in Axl(-/-)Mertk(-/-) double-knockout mice overcomes the inflammatory inhibition of neurogenesis, suggesting that IL-6 is a major downstream neurotoxic mediator under homeostatic regulation by TAM receptors in microglia. Additionally, autonomous trophic function of the TAM receptors on the proliferating neuronal progenitors may also promote progenitor differentiation into immature neurons.

The TAM receptor Mertk protects against neuroinvasive viral infection by maintaining blood-brain barrier integrity.

PubMed

Miner, Jonathan J; Daniels, Brian P; Shrestha, Bimmi; Proenca-Modena, Jose L; Lew, Erin D; Lazear, Helen M; Gorman, Matthew J; Lemke, Greg; Klein, Robyn S; Diamond, Michael S

2015-12-01

The TAM receptors Tyro3, Axl and Mertk are receptor tyrosine kinases that dampen host innate immune responses following engagement with their ligands Gas6 and Protein S, which recognize phosphatidylserine on apoptotic cells. In a form of apoptotic mimicry, many enveloped viruses display phosphatidylserine on the outer leaflet of their membranes, enabling TAM receptor activation and downregulation of antiviral responses. Accordingly, we hypothesized that a deficiency of TAM receptors would enhance antiviral responses and protect against viral infection. Unexpectedly, mice lacking Mertk and/or Axl, but not Tyro3, exhibited greater vulnerability to infection with neuroinvasive West Nile and La Crosse encephalitis viruses. This phenotype was associated with increased blood-brain barrier permeability, which enhanced virus entry into and infection of the brain. Activation of Mertk synergized with interferon-β to tighten cell junctions and prevent virus transit across brain microvascular endothelial cells. Because TAM receptors restrict pathogenesis of neuroinvasive viruses, these findings have implications for TAM antagonists that are currently in clinical development.

Utilization of Multimedia Laboratory: An Acceptance Analysis using TAM

NASA Astrophysics Data System (ADS)

Modeong, M.; Palilingan, V. R.

2018-02-01

Multimedia is often utilized by teachers to present a learning materials. Learning that delivered by multimedia enables people to understand the information of up to 60% of the learning in general. To applying the creative learning to the classroom, multimedia presentation needs a laboratory as a space that provides multimedia needs. This study aims to reveal the level of student acceptance on the multimedia laboratories, by explaining the direct and indirect effect of internal support and technology infrastructure. Technology Acceptance Model (TAM) is used as the basis of measurement on this research, through the perception of usefulness, ease of use, and the intention, it’s recognized capable of predicting user acceptance about technology. This study used the quantitative method. The data analysis using path analysis that focuses on trimming models, it’s performed to improve the model of path analysis structure by removing exogenous variables that have insignificant path coefficients. The result stated that Internal Support and Technology Infrastructure are well mediated by TAM variables to measure the level of technology acceptance. The implications suggest that TAM can measure the success of multimedia laboratory utilization in Faculty of Engineering UNIMA.

Clonal selection in xenografted TAM recapitulates the evolutionary process of myeloid leukemia in Down syndrome.

PubMed

Saida, Satoshi; Watanabe, Ken-ichiro; Sato-Otsubo, Aiko; Terui, Kiminori; Yoshida, Kenichi; Okuno, Yusuke; Toki, Tsutomu; Wang, RuNan; Shiraishi, Yuichi; Miyano, Satoru; Kato, Itaru; Morishima, Tatsuya; Fujino, Hisanori; Umeda, Katsutsugu; Hiramatsu, Hidefumi; Adachi, Souichi; Ito, Etsuro; Ogawa, Seishi; Ito, Mamoru; Nakahata, Tatsutoshi; Heike, Toshio

2013-05-23

Transient abnormal myelopoiesis (TAM) is a clonal preleukemic disorder that progresses to myeloid leukemia of Down syndrome (ML-DS) through the accumulation of genetic alterations. To investigate the mechanism of leukemogenesis in this disorder, a xenograft model of TAM was established using NOD/Shi-scid, interleukin (IL)-2Rγ(null) mice. Serial engraftment after transplantation of cells from a TAM patient who developed ML-DS a year later demonstrated their self-renewal capacity. A GATA1 mutation and no copy number alterations (CNAs) were detected in the primary patient sample by conventional genomic sequencing and CNA profiling. However, in serial transplantations, engrafted TAM-derived cells showed the emergence of divergent subclones with another GATA1 mutation and various CNAs, including a 16q deletion and 1q gain, which are clinically associated with ML-DS. Detailed genomic analysis identified minor subclones with a 16q deletion or this distinct GATA1 mutation in the primary patient sample. These results suggest that genetically heterogeneous subclones with varying leukemia-initiating potential already exist in the neonatal TAM phase, and ML-DS may develop from a pool of such minor clones through clonal selection. Our xenograft model of TAM may provide unique insight into the evolutionary process of leukemia.

Targeting of TAM Receptors Ameliorates Fibrotic Mechanisms in Idiopathic Pulmonary Fibrosis.

PubMed

Espindola, Milena S; Habiel, David M; Narayanan, Rohan; Jones, Isabelle; Coelho, Ana L; Murray, Lynne A; Jiang, Dianhua; Noble, Paul W; Hogaboam, Cory M

2018-06-01

Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant lung remodeling, which progressively abolishes lung function in an RTK (receptor tyrosine kinase)-dependent manner. Gas6 (growth arrest-specific 6) ligand, Tyro3 (TYRO3 protein tyrosine kinase 3), and Axl (anexelekto) RTK expression and activity are increased in IPF. To determine if targeting these RTK pathways would inhibit fibroblast activation and the development of pulmonary fibrosis. Quantitative genomic, proteomic, and functional analyses were used to determine Gas6/TAM (Tyro3, Axl, and Mertk [MER proto-oncogene, tyrosine kinase]) RTK expression and activation in tissues and fibroblasts from normal and IPF lungs. The profibrotic impact of these RTK pathways were also examined in bleomycin-induced pulmonary fibrosis and in SCID/Bg mice that developed pulmonary fibrosis after the intravenous administration of primary IPF fibroblasts. Gas6, Axl, and Tyro3 were increased in both rapidly and slowly progressive IPF compared with normal lung samples and fibroblasts. Targeting these pathways with either specific antibodies directed at Gas6 or Axl, or with small-molecule TAM inhibitors indicated that the small molecule-mediated targeting approach was more efficacious in both in vitro and in vivo studies. Specifically, the TAM receptor inhibitor R428 (also known as BGB324) significantly inhibited the synthetic, migratory, and proliferative properties of IPF fibroblasts compared with the other Gas6/TAM receptor targeting agents. Finally, loss of Gas6 expression decreased lung fibrotic responses to bleomycin and treatment with R428 inhibited pulmonary fibrosis in humanized SCID/Bg mice. Gas6/TAM receptor activity contributes to the activation of pulmonary fibroblasts in IPF, suggesting that targeting this RTK pathway might be an effective antifibrotic strategy in this disease.

The bromodomain protein LEX-1 acts with TAM-1 to modulate gene expression in C. elegans.

PubMed

Tseng, Rong-Jeng; Armstrong, Kristin R; Wang, Xiaodong; Chamberlin, Helen M

2007-11-01

In many organisms, repetitive DNA serves as a trigger for gene silencing. However, some gene expression is observed from repetitive genomic regions such as heterochromatin, suggesting mechanisms exist to modulate the silencing effects. From a genetic screen in C. elegans, we have identified mutations in two genes important for expression of repetitive sequences: lex-1 and tam-1. Here we show that lex-1 encodes a protein containing an ATPase domain and a bromodomain. LEX-1 is similar to the yeast Yta7 protein, which maintains boundaries between silenced and active chromatin. tam-1 has previously been shown to encode a RING finger/B-box protein that modulates gene expression from repetitive DNA. We find that lex-1, like tam-1, acts as a class B synthetic multivulva (synMuv) gene. However, since lex-1 and tam-1 mutants have normal P granule localization, it suggests they act through a mechanism distinct from other class B synMuvs. We observe intragenic (interallelic) complementation with lex-1 and a genetic interaction between lex-1 and tam-1, data consistent with the idea that the gene products function in the same biological process, perhaps as part of a protein complex. We propose that LEX-1 and TAM-1 function together to influence chromatin structure and to promote expression from repetitive sequences.

The carbon chain-selective adenylation enzyme TamA: the missing link between fatty acid and pyrrole natural product biosynthesis.

PubMed

Marchetti, Piera M; Kelly, Van; Simpson, Joanna P; Ward, Mairi; Campopiano, Dominic J

2018-04-18

The marine bacterium Pseudoalteromonas tunicata produces the bipyrrole antibiotic tambjamine YP1. This natural product is built from common amino acid and fatty acid building blocks in a biosynthetic pathway that is encoded in the tam operon which contains 19 genes. The exact role that each of these Tam proteins plays in tambjamine biosynthesis is not known. Here, we provide evidence that TamA initiates the synthesis and controls the chain length of the essential tambjamine fatty amine tail. Sequence analysis suggests the unusual TamA is comprised of an N-terminal adenylation (ANL) domain fused to a C-terminal acyl carrier protein (ACP). Mass spectrometry analysis of recombinant TamA revealed the surprising presence of bound C11 and C12 acyl-adenylate intermediates. Acylation of the ACP domain was observed upon attachment of the phosphopantetheine (4'-PP) arm to the ACP. We also show that TamA can transfer fatty acids ranging in chain length from C6-C13 to an isolated ACP domain. Thus TamA bridges the gap between primary and secondary metabolism by linking fatty acid and pyrrole biosynthetic pathways.

TAM: a method for enrichment and depletion analysis of a microRNA category in a list of microRNAs.

PubMed

Lu, Ming; Shi, Bing; Wang, Juan; Cao, Qun; Cui, Qinghua

2010-08-09

MicroRNAs (miRNAs) are a class of important gene regulators. The number of identified miRNAs has been increasing dramatically in recent years. An emerging major challenge is the interpretation of the genome-scale miRNA datasets, including those derived from microarray and deep-sequencing. It is interesting and important to know the common rules or patterns behind a list of miRNAs, (i.e. the deregulated miRNAs resulted from an experiment of miRNA microarray or deep-sequencing). For the above purpose, this study presents a method and develops a tool (TAM) for annotations of meaningful human miRNAs categories. We first integrated miRNAs into various meaningful categories according to prior knowledge, such as miRNA family, miRNA cluster, miRNA function, miRNA associated diseases, and tissue specificity. Using TAM, given lists of miRNAs can be rapidly annotated and summarized according to the integrated miRNA categorical data. Moreover, given a list of miRNAs, TAM can be used to predict novel related miRNAs. Finally, we confirmed the usefulness and reliability of TAM by applying it to deregulated miRNAs in acute myocardial infarction (AMI) from two independent experiments. TAM can efficiently identify meaningful categories for given miRNAs. In addition, TAM can be used to identify novel miRNA biomarkers. TAM tool, source codes, and miRNA category data are freely available at http://cmbi.bjmu.edu.cn/tam.

An interview with Patrick Tam by Kathryn Senior.

PubMed

Tam, Patrick

2010-12-01

Patrick Tam's research is focused on the cellular and molecular mechanisms of body patterning during mouse development. He agreed to be interviewed by Development to talk about his interest in mouse development, new concepts in gastrulation, X-linked diseases and his dream of an African safari.

Understanding Student Teachers' Behavioural Intention to Use Technology: Technology Acceptance Model (TAM) Validation and Testing

ERIC Educational Resources Information Center

Wong, Kung-Teck; Osman, Rosma bt; Goh, Pauline Swee Choo; Rahmat, Mohd Khairezan

2013-01-01

This study sets out to validate and test the Technology Acceptance Model (TAM) in the context of Malaysian student teachers' integration of their technology in teaching and learning. To establish factorial validity, data collected from 302 respondents were tested against the TAM using confirmatory factor analysis (CFA), and structural equation…

Evaluation of Brāhmī ghṛtam in children suffering from Attention Deficit Hyperactivity Disorder

PubMed Central

Bhalerao, Supriya; Munshi, Renuka; Nesari, Tanuja; Shah, Heenal

2013-01-01

Introduction: Attention Deficit Hyperactivity Disorder (ADHD) is characterized by a persistent pattern of inattention and/or hyperactivity-impulsivity. In view of the adverse effects associated with psycho-stimulants used for the treatment of this disorder, efficacy of Brāhmī ghṛtam was evaluated in this condition. Materials and Methods: After following due ethical considerations, children of either sex between the age group of 6 and 12 years diagnosed to be suffering from mixed variety of ADHD as per The Diagnostic and Statistical Manual of Mental Disorders (DSM) IV criteria irrespective of other co-morbid psychiatric illnesses were recruited in the study. Initially a pilot study (n = 10) was carried out to confirm the efficacy of the identified dose of Brāhmī ghṛtam. Using this dose, further therapeutic confirmatory study (n = 27) was carried out, wherein Brāhmī ghṛtam was compared with methylphenidate. Effect on ADHD symptoms was assessed using the Dupaul ADHD rating scale and this was the main efficacy parameter. Results: In the pilot exploratory study, Brāhmī ghṛtam showed 66% decrease in total ADHD score. In the therapeutic confirmatory study, only 16% improvement was seen with Brāhmī ghṛtam, which was similar to methylphenidate, standard treatment for ADHD that was used as a comparator in the present study. No side-effects were reported in both studies. Conclusion: Our study thus has adequately demonstrated efficacy and safety of Brāhmī ghṛtam in ADHD. PMID:25284947

TAM 304 wheat – Adapted to the adequate rainfall or high-input irrigation production system in the Southern Great Plains

USDA-ARS?s Scientific Manuscript database

TAM 304 wheat is a medium-early hard red winter wheat. It is a great dryland or semi-irrigated wheat. TAM 304 performs best under adequate rainfall, limited irrigation, or irrigation, but does not perform as well under extended drought. TAM 304 performs exceptionally well under foliar disease pressu...

Growth Arrest-Specific 6 (Gas6) and TAM Receptors in Mouse Platelets.

PubMed

Uras, Fikriye; Küçük, Burhanettin; Bingöl Özakpınar, Özlem; Demir, Ahmet Muzaffer

2015-03-05

Growth arrest-specific 6 (Gas6) is a newly discovered vitamin K-dependent protein, which is a ligand for TAM receptors [Tyro3 (Sky), Axl, and Mer] from the tyrosine kinase family. Gas6 knockout mice were resistant to venous and arterial thrombosis. There are contradictory reports on the presence of Gas6 and its receptors in mouse platelets. The objective of this study was to investigate whether Gas6 and its receptors were present in mouse platelets or not. Specific pathogen-free BALB/c male and female mice of 8-10 weeks old and 25-30 g in weight were anesthetized under light ether anesthesia and blood samples were taken from their hearts. RNAs were isolated from isolated platelets, and then mRNAs encoding Gas6 and TAM receptors were detected by reverse transcription-polymerase chain reaction (RT-PCR). Protein concentrations of Gas6 and TAM receptors in platelets were measured by ELISA, but not those of Mer, because of the absence of any commercial ELISA kit for mouse specimens. RT-PCR results indicated the presence of mRNAs encoding Gas6 and Mer in mouse platelets. However, although RT-PCR reactions were performed at various temperatures and cycles, we could not detect the presence of mRNAs encoding Axl and Tyro3 (Sky). Receptor protein levels of Axl and Tyro3 were below the detection limits of the ELISA method. We found the presence of mRNAs encoding Gas6 and the receptor Mer in mouse platelets, but not Axl and Tyro3. Gas6, Axl, and Tyro3 protein levels were below the detection limits of the ELISA. The presence of mRNA is not obvious evidence of protein expression in platelets that have no nucleus or DNA. Further studies are required to clarify the presence of Gas6/TAM receptors in platelets using real-time PCR and more sensitive immunological methods, and future studies on mechanisms will indicate whether the Gas6/TAM pathway is a strategy for treatment of disorders.

TAM receptor tyrosine kinase function and the immunopathology of liver disease.

PubMed

Mukherjee, S K; Wilhelm, A; Antoniades, C G

2016-06-01

Tyro3, Axl, MERTK (TAM) receptor tyrosine kinases are implicated in the regulation of the innate immune response through clearance of apoptotic cellular debris and control of cytokine signaling cascades. As a result they are pivotal in regulating the inflammatory response to tissue injury. Within the liver, immune regulatory signaling is employed to prevent the overactivation of innate immunity in response to continual antigenic challenge from the gastrointestinal tract. In this review we appraise current understanding of the role of TAM receptor function in the regulation of both innate and adaptive immunity, with a focus on its impact upon hepatic inflammatory pathology. Copyright © 2016 the American Physiological Society.

The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells.

PubMed

Paolino, Magdalena; Choidas, Axel; Wallner, Stephanie; Pranjic, Blanka; Uribesalgo, Iris; Loeser, Stefanie; Jamieson, Amanda M; Langdon, Wallace Y; Ikeda, Fumiyo; Fededa, Juan Pablo; Cronin, Shane J; Nitsch, Roberto; Schultz-Fademrecht, Carsten; Eickhoff, Jan; Menninger, Sascha; Unger, Anke; Torka, Robert; Gruber, Thomas; Hinterleitner, Reinhard; Baier, Gottfried; Wolf, Dominik; Ullrich, Axel; Klebl, Bert M; Penninger, Josef M

2014-03-27

Tumour metastasis is the primary cause of mortality in cancer patients and remains the key challenge for cancer therapy. New therapeutic approaches to block inhibitory pathways of the immune system have renewed hopes for the utility of such therapies. Here we show that genetic deletion of the E3 ubiquitin ligase Cbl-b (casitas B-lineage lymphoma-b) or targeted inactivation of its E3 ligase activity licenses natural killer (NK) cells to spontaneously reject metastatic tumours. The TAM tyrosine kinase receptors Tyro3, Axl and Mer (also known as Mertk) were identified as ubiquitylation substrates for Cbl-b. Treatment of wild-type NK cells with a newly developed small molecule TAM kinase inhibitor conferred therapeutic potential, efficiently enhancing anti-metastatic NK cell activity in vivo. Oral or intraperitoneal administration using this TAM inhibitor markedly reduced murine mammary cancer and melanoma metastases dependent on NK cells. We further report that the anticoagulant warfarin exerts anti-metastatic activity in mice via Cbl-b/TAM receptors in NK cells, providing a molecular explanation for a 50-year-old puzzle in cancer biology. This novel TAM/Cbl-b inhibitory pathway shows that it might be possible to develop a 'pill' that awakens the innate immune system to kill cancer metastases.

MicroRNA‑663b mediates TAM resistance in breast cancer by modulating TP73 expression.

PubMed

Jiang, Hua; Cheng, Lin; Hu, Pan; Liu, Renbin

2018-05-23

Breast cancer is the second leading cause of cancer‑associated mortalities in women. Tamoxifen (TAM) is an endocrine therapy commonly used in the treatment of patients with breast cancer expressing estrogen receptor α. However, treatment often ends in failure due to the emergence of drug resistance. MicroRNAs (miRNAs), a family of small non‑coding RNAs, serve critical roles in the regulation of gene expression and cell events. To date, whether miRNA‑663b could mediate TAM resistance in breast cancer remains unknown. Therefore, the aim of the present study was to investigate the role of miRNA‑663b in TAM resistance in breast cancer. The results demonstrated that miRNA‑663b was upregulated in breast cancer with TAM resistance. Tumor protein 73 (TP73) was a direct target of miRNA‑663b, and was negatively regulated by miRNA‑663b in MCF‑7 cells. Furthermore, it was identified that downregulation of miRNA‑663b inhibited cell proliferation ability and promoted cell apoptosis, resulting in enhanced TAM sensitivity. In addition, these findings suggested that TP73 silencing may have eliminated the effects of miRNA‑663b inhibitor on breast cancer cells. In conclusion, the present study verified a novel molecular link between miRNA‑663b and TP73, and indicated that miRNA‑663b may be a critical therapeutic target in breast cancer.

Genetic diversity and phylogenetic analysis of Tams1 of Theileria annulata isolates from three continents between 2000 and 2012.

PubMed

Wang, Jiay; Yang, Xianyong; Wang, Yuge; Jing, Zhihong; Meng, Kai; Liu, Jianzhu; Guo, Huijun; Xu, Ruixue; Cheng, Ziqiang

2014-01-01

Theileria annulata, which is part of the Theileria sergenti/Theileria buffeli/Theileria orientalis group, preferentially infects cattle and results in high mortality and morbidity in the Mediterranean, Middle East, and Central Asia. The polypeptide Tams1 is an immunodominant major merozoite piroplasm surface antigen of T. annulata that could be used as a marker for epidemiological studies and phylogenetic analysis. In the present study, a total of 155 Tams1 sequences were investigated for genetic diversity and phylogenetic relationships through phylogenetic analysis. Results showed that the Tams1 sequences were divided into two major groups and that distribution for some isolates also exhibited geographic specificity. As targeting polymorphic genes for parasite detection may result in underestimation of infection, polymerase chain reaction (PCR) assay using two different probes targeting tams-1 genes of these two groups can be more credible. In addition, the direction of the spread of the disease was discovered to be from the Mediterranean or the tropical zone to the Eurasian peninsula, Middle East, Southern Asia, and Africa, particularly for Group 2. A similar occurrence was also found between the Ms1 gene of Theileria lestoquardi and the Tams1 gene of T. annulata, which explains cross-immunogenicity to a certain extent. However, no potential glycosylation site in the Tams1 of T. annulata was found in this study, which illustrated that instead of N-glycosylation, other modifications have more significant effects on the immunogenicity of the Tams1 protein.

Et Tu, Counselor: may an in-house attorney file a qui tam action against the attorney's employer?

PubMed

Brown, L C; Anwar, H R

1999-01-01

Most corporations probably do not consider their in-house counsel to be potential qui tam threats. That may be a naive assumption. Case law provides an illustrative view of the legal ramifications involved when an attorney brings a qui tam suit. In general, there is no prohibition on attorneys who wish to bring these actions. Nevertheless, a corporation can take preventive steps to eliminate the likelihood of attorney qui tam actions. In addition, the corporation can take advantage of state professional ethics laws to mount a defensive action against the attorney who files any such action.

TAM Receptor Tyrosine Kinases in Cancer Drug Resistance.

PubMed

Vouri, Mikaella; Hafizi, Sassan

2017-06-01

Receptor tyrosine kinases (RTK) are major regulators of key biological processes, including cell growth, survival, and differentiation, and were established early on as proto-oncogenes, with aberrant expression linked to tumor progression in many cancers. Therefore, RTKs have emerged as major targets for selective therapy with small-molecule inhibitors. However, despite improvements in survival rates, it is now apparent that the targeting of RTKs with selective inhibitors is only transiently effective, as the majority of patients eventually become resistant to therapy. As chemoresistance is the leading cause of cancer spread, progression, and mortality, there is an increasing need for understanding the mechanisms by which cancer cells can evade therapy-induced cell death. The TAM (Tyro3, Axl, Mer) subfamily of RTKs in particular feature in a variety of cancer types that have developed resistance to a broad range of therapeutic agents, including both targeted as well as conventional chemotherapeutics. This article reviews the roles of TAMs as tumor drivers and as mediators of chemoresistance, and the potential effectiveness of targeting them as part of therapeutic strategies to delay or combat resistance. Cancer Res; 77(11); 2775-8. ©2017 AACR . ©2017 American Association for Cancer Research.

TAM receptor-dependent regulation of SOCS3 and MAPKs contributes to proinflammatory cytokine downregulation following chronic NOD2 stimulation of human macrophages.

PubMed

Zheng, Shasha; Hedl, Matija; Abraham, Clara

2015-02-15

Microbial-induced cytokine regulation is critical to intestinal immune homeostasis. Acute stimulation of nucleotide-binding oligomerization domain 2 (NOD2), the Crohn's disease-associated sensor of bacterial peptidoglycan, induces cytokines. However, cytokines are attenuated after chronic NOD2 and pattern recognition receptor stimulation of macrophages; similar attenuation is observed in intestinal macrophages. The role of Tyro3, Axl, and Mer (TAM) receptors in regulating chronic pattern recognition receptor stimulation and NOD2-induced outcomes has not been examined. Moreover, TAM receptors have been relatively less investigated in human macrophages. Whereas TAM receptors did not downregulate acute NOD2-induced cytokines in primary human macrophages, they were essential for downregulating signaling and proinflammatory cytokine secretion after chronic NOD2 and TLR4 stimulation. Axl and Mer were similarly required in mice for cytokine downregulation after chronic NOD2 stimulation in vivo and in intestinal tissues. Consistently, TAM expression was increased in human intestinal myeloid-derived cells. Chronic NOD2 stimulation led to IL-10- and TGF-β-dependent TAM upregulation in human macrophages, which, in turn, upregulated suppressor of cytokine signaling 3 expression. Restoring suppressor of cytokine signaling 3 expression under TAM knockdown conditions restored chronic NOD2-mediated proinflammatory cytokine downregulation. In contrast to the upregulated proinflammatory cytokines, attenuated IL-10 secretion was maintained in TAM-deficient macrophages upon chronic NOD2 stimulation. The level of MAPK activation in TAM-deficient macrophages after chronic NOD2 stimulation was insufficient to upregulate IL-10 secretion; however, full restoration of MAPK activation under these conditions restored c-Fos, c-Jun, musculoaponeurotic fibrosarcoma oncogene homolog K, and PU.1 binding to the IL-10 promoter and IL-10 secretion. Therefore, TAM receptors are critical for

[Effect of Evn-50 on cell growth and apoptosis in tamoxifen-resistance human breast cancer cell line MCF-7/TAM-R].

PubMed

Hu, Hui-yong; Zhou, Jun; Wan, Fang; Dong, Li-feng; Zhang, Feng; Wang, Yi-ke; Chen, Fang-fang; Chen, Yi-ding

2012-09-01

To investigate the effect of Evn-50 extracted from Vitex negundo on human breast cancer cell line MCF-7 and MCF-7/TAM-R cells in vitro. MCF-7 and tamoxifen-resistant MCF-7/TAM-R cells were treated with Evn-50,tamoxifen or combination of Evn-50 and tamoxifen. Cell proliferation inhibition rates were determined by MTT assay. The apoptosis rate and the change of cell cycle were detected by PI staining flow cytometry. Protein expression of phospho-MAPK 44/42 (Thr202/Tyr204),MAPK P44/42, phospho-AKT (Ser473) and AKT were detected with Western blotting. The viability of MCF-7 cells was decreased in combination group [(28.65 ±11.43)%] and Evn-50 group [(53.02 ±15.14)%] compared with TAM group (P<0.01). The cell viability of MCF-7/TAM-R in combination group [(42.11 ±14.30)%] was significantly lower than that in TAM group [(92.18 ±13.16)%] (P<0.01). The cell apoptosis rate was dependent on the time of treatment in all groups,the effects on apoptosis and G2/M phase cells were most prominent at 72 h (P<0.01). Western blotting revealed that protein levels of phosphorylated AKT and p-MAPK44/42 decreased,while the expression of total AKT and MAPK44/42 was stable. In MCF-7/TAM-R cells,the expression of phosphorylation of AKT and MAPK44/42 protein was not changed in Evn-50 or TAM alone group,but significantly inhibited in the combination group at 72 h. Evn-50 can inhibit cell growth and induce apoptosis in MCF-7 and MCF-7/TAM-R cells,it can reverse tamoxifen-resistance of MCF-7/TAM-R cells.The mechanisms may be related to the down-regulation of phosphorylated ERK1/2 in MAPK signal pathway and phosphorylated AKT in AKT signal pathway.

Monocyte and plasma expression of TAM ligand and receptor in renal failure: Links to unregulated immunity and chronic inflammation.

PubMed

Lee, Iris J; Hilliard, Brendan A; Ulas, Mehriban; Yu, Daohai; Vangala, Chandan; Rao, Swati; Lee, Jean; Gadegbeku, Crystal A; Cohen, Philip L

2015-06-01

Chronic inflammation is increased in patients with chronic kidney disease (CKD) and contributes to cardiovascular morbidity and mortality. Specific immune mechanisms and pathways that drive and maintain chronic inflammation in CKD are not well described. The TAM ligands (Gas6 and protein S) and receptors (Axl and Mer) have been recently recognized as playing a prominent role in immune regulation. The receptors exist in both soluble and cell-bound forms; the soluble receptors (sAxl and sMer) are believed to compete with the bound receptors and thus inhibit their function. In this study, we determined the expression of cell-bound and soluble TAM proteins in patients with CKD. CKD patients had significantly lower expression of Mer in monocytes, yet increased expression of soluble TAM receptors sAxl and sMer in plasma compared to controls. The metalloproteinase ADAM 17, responsible for cleavage of Mer to its soluble form, was increased in patient monocytes. Elevated levels of soluble TAM receptors were more evident in patients with progressive renal failure. These observations suggest that functional deficiency of TAM receptor-mediated regulation of inflammation may contribute to chronic inflammation in patients with CKD. Copyright © 2015 Elsevier Inc. All rights reserved.

Tyura Tam Space Launch Facility, Kazakhstan, CIS

NASA Technical Reports Server (NTRS)

1992-01-01

Located in Kazakhstan on the Syr Darya River, the Tyura Tam Cosmodrome has been the launch site for 72 cosmonaut crews. The landing runway of the Buran space shuttle can be seen in the left center. Further to the right, near the center is the launch site for the Soyuz. The mission control center is located 1,300 miles away near Moscow. In the lower right, is the city of Leninsk, seen as a dark region next to the river.

Investigating Students' Acceptance and Self-Efficacy of E-Learning at Al-Aqsa University Based on TAM Model

ERIC Educational Resources Information Center

Mahdi, Hasan Rebhi

2014-01-01

The study aimed at investigating the influence of E-learning Self-Efficacy (ELSE) on the acceptance of e-learning by using the Technology Acceptance Model (TAM). According to the TAM which used as the theoretical basis, both of the Perceived Usefulness (PU) and the Perceived Ease of Use (PEOU) influence directly the end user's Behavioral Intention…

Dynamic Simulation of 1D Cellular Automata in the Active aTAM.

PubMed

Jonoska, Nataša; Karpenko, Daria; Seki, Shinnosuke

2015-07-01

The Active aTAM is a tile based model for self-assembly where tiles are able to transfer signals and change identities according to the signals received. We extend Active aTAM to include deactivation signals and thereby allow detachment of tiles. We show that the model allows a dynamic simulation of cellular automata with assemblies that do not record the entire computational history but only the current updates of the states, and thus provide a way for (a) algorithmic dynamical structural changes in the assembly and (b) reusable space in self-assembly. The simulation is such that at a given location the sequence of tiles that attach and detach corresponds precisely to the sequence of states the synchronous cellular automaton generates at that location.

Dynamic Simulation of 1D Cellular Automata in the Active aTAM

PubMed Central

Jonoska, Nataša; Karpenko, Daria; Seki, Shinnosuke

2016-01-01

The Active aTAM is a tile based model for self-assembly where tiles are able to transfer signals and change identities according to the signals received. We extend Active aTAM to include deactivation signals and thereby allow detachment of tiles. We show that the model allows a dynamic simulation of cellular automata with assemblies that do not record the entire computational history but only the current updates of the states, and thus provide a way for (a) algorithmic dynamical structural changes in the assembly and (b) reusable space in self-assembly. The simulation is such that at a given location the sequence of tiles that attach and detach corresponds precisely to the sequence of states the synchronous cellular automaton generates at that location. PMID:27789918

The relationship between the expression of TAM, survivin and the degree of necrosis of the tumor after cisplatin treatment in osteosarcoma.

PubMed

Chen, G

2017-02-01

To explore the relationship between the expression of TAM, survivin and the degree of necrosis of the tumor after cisplatin treatment in osteosarcoma. The mice model of osteosarcoma S180 were injected with 6 mg/kg/day of cisplatin (observation group) or the same amount of normal saline (control group) for 4 weeks. Mice were sacrificed at days 1, 4, 9, 14, 18, 22 and 28, respectively, 24 h before administration of the drug or saline, and tumor tissues were collected. The size of the tumor samples was measured and the correlation of TAM, survivin expression in osteosarcoma and necrosis degree of tumor tissue after cisplatin treatment was studied using various methods including fluorescence quantitative PCR, enzyme linked immunosorbent assay (ELISA), Western blotting and immunohistochemistry. Fluorescence quantitative PCR showed that the expression of TAM, survivin mRNA in the control group was significantly higher than that in the observation group. Also, the ELISA monitoring showed that the expression of mice TAM, survivin protein in vivo was significantly lower than TAM, survivin protein expression of mice in vivo in the observation group (2.3 µg/l, 1.6 µg/l) relatively to the control group (9.7 mg/l, 10.3 µg/l). Consistent with the Western blot data, ELISA results showed that the expression of survivin and TAM protein decreased gradually with the prolongation of drug treatment along the time in the observation group. The volume and weight of the tumor in the observation group were significantly less than that of the control group. Additionally, the tumor necrosis of mice in the observation group was more significant, suggesting that the meant of the size of tumor tissue decreased significantly with the extension of the time of drug treatment. Immunohistochemical results showed that the rate of the positive cell of TAM and survivin in the observation group (82.3%) was significantly higher (p<0.05) than that in the control group (19.5%). However, the rate of the

The Axl kinase domain in complex with a macrocyclic inhibitor offers first structural insights into an active TAM receptor kinase.

PubMed

Gajiwala, Ketan S; Grodsky, Neil; Bolaños, Ben; Feng, Junli; Ferre, RoseAnn; Timofeevski, Sergei; Xu, Meirong; Murray, Brion W; Johnson, Ted W; Stewart, Al

2017-09-22

The receptor tyrosine kinase family consisting of Tyro3, Axl, and Mer (TAM) is one of the most recently identified receptor tyrosine kinase families. TAM receptors are up-regulated postnatally and maintained at high levels in adults. They all play an important role in immunity, but Axl has also been implicated in cancer and therefore is a target in the discovery and development of novel therapeutics. However, of the three members of the TAM family, the Axl kinase domain is the only one that has so far eluded structure determination. To this end, using differential scanning fluorimetry and hydrogen-deuterium exchange mass spectrometry, we show here that a lower stability and greater dynamic nature of the Axl kinase domain may account for its poor crystallizability. We present the first structural characterization of the Axl kinase domain in complex with a small-molecule macrocyclic inhibitor. The Axl crystal structure revealed two distinct conformational states of the enzyme, providing a first glimpse of what an active TAM receptor kinase may look like and suggesting a potential role for the juxtamembrane region in enzyme activity. We noted that the ATP/inhibitor-binding sites of the TAM members closely resemble each other, posing a challenge for the design of a selective inhibitor. We propose that the differences in the conformational dynamics among the TAM family members could potentially be exploited to achieve inhibitor selectivity for targeted receptors. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

The RING finger/B-box factor TAM-1 and a retinoblastoma-like protein LIN-35 modulate context-dependent gene silencing in Caenorhabditis elegans.

PubMed

Hsieh, J; Liu, J; Kostas, S A; Chang, C; Sternberg, P W; Fire, A

1999-11-15

Context-dependent gene silencing is used by many organisms to stably modulate gene activity for large chromosomal regions. We have used tandem array transgenes as a model substrate in a screen for Caenorhabditis elegans mutants that affect context-dependent gene silencing in somatic tissues. This screen yielded multiple alleles of a previously uncharacterized gene, designated tam-1 (for tandem-array-modifier). Loss-of-function mutations in tam-1 led to a dramatic reduction in the activity of numerous highly repeated transgenes. These effects were apparently context dependent, as nonrepetitive transgenes retained activity in a tam-1 mutant background. In addition to the dramatic alterations in transgene activity, tam-1 mutants showed modest alterations in expression of a subset of endogenous cellular genes. These effects include genetic interactions that place tam-1 into a group called the class B synMuv genes (for a Synthetic Multivulva phenotype); this family plays a negative role in the regulation of RAS pathway activity in C. elegans. Loss-of-function mutants in other members of the class-B synMuv family, including lin-35, which encodes a protein similar to the tumor suppressor Rb, exhibit a hypersilencing in somatic transgenes similar to that of tam-1 mutants. Molecular analysis reveals that tam-1 encodes a broadly expressed nuclear protein with RING finger and B-box motifs.

TAM receptor-dependent regulation of SOCS3 and MAPKs contributes to pro-inflammatory cytokine downregulation following chronic NOD2 stimulation of human macrophages1

PubMed Central

Zheng, Shasha; Hedl, Matija; Abraham, Clara

2014-01-01

Microbial-induced cytokine regulation is critical to intestinal immune homeostasis. Acute stimulation of NOD2, the Crohn’s disease-associated sensor of bacterial peptidoglycan, induces cytokines. However, cytokines are attenuated after chronic NOD2 and pattern recognition receptor (PRR) stimulation of macrophages; similar attenuation is observed in intestinal macrophages. The role of Tyro3, Axl and Mer (TAM) receptors in regulating chronic PRR stimulation and NOD2-induced outcomes has not been examined. Moreover, TAM receptors have been relatively less investigated in human macrophages. Whereas TAM receptors did not downregulate acute NOD2-induced cytokines in primary human macrophages, they were essential for downregulating signaling and pro-inflammatory cytokine secretion after chronic NOD2 and TLR4 stimulation. Axl and Mer were similarly required in mice for cytokine downregulation after chronic NOD2 stimulation in vivo and in intestinal tissues. Consistently, TAM expression was increased in human intestinal myeloid-derived cells. Chronic NOD2 stimulation led to IL-10- and TGFβ-dependent TAM upregulation in human macrophages, which in turn, upregulated SOCS3 expression. Restoring SOCS3 expression under TAM knockdown conditions restored chronic NOD2-mediated pro-inflammatory cytokine downregulation. In contrast to the upregulated pro-inflammatory cytokines, attenuated IL-10 secretion was maintained in TAM-deficient macrophages upon chronic NOD2 stimulation. The level of MAPK activation in TAM-deficient macrophages after chronic NOD2 stimulation was insufficient to upregulate IL-10 secretion; however, full restoration of MAPK activation under these conditions restored c-Fos, c-Jun, MAFK and PU.1 binding to the IL-10 promoter and IL-10 secretion. Therefore, TAM receptors are critical for downregulating pro-inflammatory cytokines under the chronic NOD2 stimulation conditions observed in the intestinal environment. PMID:25567680

The Tyrosine Aminomutase TAM1 Is Required for β-Tyrosine Biosynthesis in Rice

PubMed Central

Yan, Jian; Aboshi, Takako; Teraishi, Masayoshi; Strickler, Susan R.; Spindel, Jennifer E.; Tung, Chih-Wei; Takata, Ryo; Matsumoto, Fuka; Maesaka, Yoshihiro; McCouch, Susan R.; Okumoto, Yutaka; Mori, Naoki; Jander, Georg

2015-01-01

Non-protein amino acids, often isomers of the standard 20 protein amino acids, have defense-related functions in many plant species. A targeted search for jasmonate-induced metabolites in cultivated rice (Oryza sativa) identified (R)-β-tyrosine, an isomer of the common amino acid (S)-α-tyrosine in the seeds, leaves, roots, and root exudates of the Nipponbare cultivar. Assays with 119 diverse cultivars showed a distinct presence/absence polymorphism, with β-tyrosine being most prevalent in temperate japonica cultivars. Genetic mapping identified a candidate gene on chromosome 12, which was confirmed to encode a tyrosine aminomutase (TAM1) by transient expression in Nicotiana benthamiana and in vitro enzyme assays. A point mutation in TAM1 eliminated β-tyrosine production in Nipponbare. Rice cultivars that do not produce β-tyrosine have a chromosome 12 deletion that encompasses TAM1. Although β-tyrosine accumulation was induced by the plant defense signaling molecule jasmonic acid, bioassays with hemipteran and lepidopteran herbivores showed no negative effects at physiologically relevant β-tyrosine concentrations. In contrast, root growth of Arabidopsis thaliana and other tested dicot plants was inhibited by concentrations as low as 1 μM. As β-tyrosine is exuded into hydroponic medium at higher concentrations, it may contribute to the allelopathic potential of rice. PMID:25901084

TAM receptor tyrosine kinases as emerging targets of innate immune checkpoint blockade for cancer therapy.

PubMed

Akalu, Yemsratch T; Rothlin, Carla V; Ghosh, Sourav

2017-03-01

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. Here, we review the TAM receptor tyrosine kinases-TYRO3, AXL, and MERTK-as an emerging class of innate immune checkpoints that participate in key steps of anti-tumoral immunity. Namely, TAM-mediated efferocytosis, negative regulation of dendritic cell activity, and dysregulated production of chemokines collectively favor the escape of malignant cells. Hence, disabling TAM signaling may promote engagement of adaptive immunity and complement T-cell checkpoint blockade. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

State-of-the-art of small molecule inhibitors of the TAM family: the point of view of the chemist.

PubMed

Baladi, Tom; Abet, Valentina; Piguel, Sandrine

2015-11-13

The TAM family of tyrosine kinases receptors (Tyro3, Axl and Mer) is implicated in cancer development, autoimmune reactions and viral infection and is therefore emerging as an effective and attractive therapeutic target. To date, only a few small molecules have been intentionally designed to block the TAM kinases, while most of the inhibitors were developed for blocking different protein kinases and then identified through selectivity profile studies. This minireview will examine in terms of chemical structure the different compounds able to act on either one, two or three TAM kinases with details about structure-activity relationships, drug-metabolism and pharmacokinetics properties where they exist. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

?`Es necesario calcular detalladamente funciones de partición atómicas?

NASA Astrophysics Data System (ADS)

Milone, L. A.; Merlo, D. C.

Basándonos en extensos y precisos cómputos de funciones de partición realizados por nosotros para distintos átomos, se muestra que en el cálculo u obtención de ciertas magnitudes (notablemente la presión electrónica, la abundancia de un elemento deducida a partir de un estado fuertemente ionizado, etc.) el error porcentual que se comete es pequeño (inferior a 1 %) si se adopta, como valor de la función de partición, el peso estadístico del término correspondiente al estado fundamental del átomo. Esta notable simplificación acelera el cálculo, por ejemplo, de un modelo de atmósfera estelar, sin disminuir la precisión de los resultados.

Age-related changes in expression and signaling of TAM receptor inflammatory regulators in monocytes.

PubMed

Wang, Xiaomei; Malawista, Anna; Qian, Feng; Ramsey, Christine; Allore, Heather G; Montgomery, Ruth R

2018-02-09

The multifactorial immune deterioration in aging--termed "inflamm-aging"--is comprised of a state of low-grade, chronic inflammation and complex dysregulation of responses to immune stimulation. The TAM family (Tyro 3, Axl, and Mer) of receptor tyrosine kinases are negative regulators of Toll like receptor-mediated immune responses that broadly inhibit cytokine receptor cascades to inhibit inflammation. Here we demonstrate elevated expression of TAM receptors in monocytes of older adults, and an age-dependent difference in signaling mediator AKT resulting in dysregulated responses to signaling though Mer. Our results may be especially significant in tissue, where levels of Mer are highest, and may present avenues for modulation of chronic tissue inflammation noted in aging.

Nanoparticle formulation enhanced protective immunity provoked by PYGPI8p-transamidase related protein (PyTAM) DNA vaccine in Plasmodium yoelii malaria model.

PubMed

Cherif, Mahamoud Sama; Shuaibu, Mohammed Nasir; Kodama, Yukinobu; Kurosaki, Tomoaki; Helegbe, Gideon Kofi; Kikuchi, Mihoko; Ichinose, Akitoyo; Yanagi, Tetsuo; Sasaki, Hitoshi; Yui, Katsuyuki; Tien, Nguyen Huy; Karbwang, Juntra; Hirayama, Kenji

2014-04-07

We have previously reported the new formulation of polyethylimine (PEI) with gamma polyglutamic acid (γ-PGA) nanoparticle (NP) to have provided Plasmodium yoelii merozoite surface protein-1 (PyMSP-1) plasmid DNA vaccine with enhanced protective cellular and humoral immunity in the lethal mouse malaria model. PyGPI8p-transamidase-related protein (PyTAM) was selected as a possible candidate vaccine antigen by using DNA vaccination screening from 29 GPI anchor and signal sequence motif positive genes picked up using web-based bioinformatics tools; though the observed protection was not complete. Here, we observed augmented protective effect of PyTAM DNA vaccine by using PEI and γ-PGA complex as delivery system. NP-coated PyTAM plasmid DNA immunized mice showed a significant survival rate from lethal P. yoelii challenge infection compared with naked PyTAM plasmid or with NP-coated empty plasmid DNA group. Antigen-specific IgG1 and IgG2b subclass antibody levels, proportion of CD4 and CD8T cells producing IFN-γ in the splenocytes and IL-4, IFN-γ, IL-12 and TNF-α levels in the sera and in the supernatants from ex vivo splenocytes culture were all enhanced by the NP-coated PyTAM DNA vaccine. These data indicates that NP augments PyTAM protective immune response, and this enhancement was associated with increased DC activation and concomitant IL-12 production. Copyright © 2014 Elsevier Ltd. All rights reserved.

Impaired CXCL4 expression in tumor-associated macrophages (TAMs) of ovarian cancers arising in endometriosis.

PubMed

Furuya, Mitsuko; Tanaka, Reiko; Miyagi, Etsuko; Kami, Daisuke; Nagahama, Kiyotaka; Miyagi, Yohei; Nagashima, Yoji; Hirahara, Fumiki; Inayama, Yoshiaki; Aoki, Ichiro

2012-06-01

Inflammatory cells play important roles in progression of solid neoplasms including ovarian cancers. Tumor-associated macrophages (TAMs) contribute to angiogenesis and immune suppression by modulating microenvironment. Ovarian cancer develops occasionally on the bases of endometriosis, a chronic inflammatory disease. We have recently demonstrated differential expressions of CXCR3 variants in endometriosis and ovarian cancers. In this study, we showed impaired CXCL4 expression in TAMs of ovarian cancers arising in endometriosis. The expressions of CXCL4 and its variant CXCL4L1 were investigated among normal ovaries (n = 26), endometriosis (n = 18) and endometriosis-associated ovarian cancers (EAOCs) composed of clear cell (n = 13) and endometrioid (n = 11) types. In addition, four cases of EAOCs that contained both benign and cancer lesions contiguously in single cysts were investigated in the study. Western blot and quantitative RT-PCR analyses revealed significant downregulation of CXCL4 and CXCL4L1 in EAOCs compared with those in endometriosis. In all EAOCs coexisting with endometriosis in the single cyst, the expression levels of CXCL4 and CXCL4L1 were significantly lower in cancer lesions than in corresponding endometriosis. Histopathological study revealed that CXCL4 was strongly expressed in CD68 (+) infiltrating macrophages of endometriosis. In microscopically transitional zone between endometriosis and EAOC, CD68 (+) macrophages often demonstrated CXCL4 (-) pattern. The majority of CD68 (+) TAMs in overt cancer lesions were negative for CXCL4. Collective data indicate that that CXCL4 insufficiency may be involved in specific inflammatory microenvironment of ovarian cancers arising in endometriosis. Suppression of CXCL4 in cancer lesions is likely to be attributable to TAMs in part.

Impaired CXCL4 expression in tumor-associated macrophages (TAMs) of ovarian cancers arising in endometriosis

PubMed Central

Furuya, Mitsuko; Tanaka, Reiko; Miyagi, Etsuko; Kami, Daisuke; Nagahama, Kiyotaka; Miyagi, Yohei; Nagashima, Yoji; Hirahara, Fumiki; Inayama, Yoshiaki; Aoki, Ichiro

2012-01-01

Inflammatory cells play important roles in progression of solid neoplasms including ovarian cancers. Tumor-associated macrophages (TAMs) contribute to angiogenesis and immune suppression by modulating microenvironment. Ovarian cancer develops occasionally on the bases of endometriosis, a chronic inflammatory disease. We have recently demonstrated differential expressions of CXCR3 variants in endometriosis and ovarian cancers. In this study, we showed impaired CXCL4 expression in TAMs of ovarian cancers arising in endometriosis. The expressions of CXCL4 and its variant CXCL4L1 were investigated among normal ovaries (n = 26), endometriosis (n = 18) and endometriosis-associated ovarian cancers (EAOCs) composed of clear cell (n = 13) and endometrioid (n = 11) types. In addition, four cases of EAOCs that contained both benign and cancer lesions contiguously in single cysts were investigated in the study. Western blot and quantitative RT-PCR analyses revealed significant downregulation of CXCL4 and CXCL4L1 in EAOCs compared with those in endometriosis. In all EAOCs coexisting with endometriosis in the single cyst, the expression levels of CXCL4 and CXCL4L1 were significantly lower in cancer lesions than in corresponding endometriosis. Histopathological study revealed that CXCL4 was strongly expressed in CD68+ infiltrating macrophages of endometriosis. In microscopically transitional zone between endometriosis and EAOC, CD68+ macrophages often demonstrated CXCL4− pattern. The majority of CD68+ TAMs in overt cancer lesions were negative for CXCL4. Collective data indicate that that CXCL4 insufficiency may be involved in specific inflammatory microenvironment of ovarian cancers arising in endometriosis. Suppression of CXCL4 in cancer lesions is likely to be attributable to TAMs in part. PMID:22555803

Porphyromonas gingivalis Promotes Unrestrained Type I Interferon Production by Dysregulating TAM Signaling via MYD88 Degradation.

PubMed

Mizraji, Gabriel; Nassar, Maria; Segev, Hadas; Sharawi, Hafiz; Eli-Berchoer, Luba; Capucha, Tal; Nir, Tsipora; Tabib, Yaara; Maimon, Avraham; Dishon, Shira; Shapira, Lior; Nussbaum, Gabriel; Wilensky, Asaf; Hovav, Avi-Hai

2017-01-10

Whereas type I interferons (IFNs-I) were proposed to be elevated in human periodontitis, their role in the disease remains elusive. Using a bacterial-induced model of murine periodontitis, we revealed a prolonged elevation in IFN-I expression. This was due to the downregulation of TAM signaling, a major negative regulator of IFN-I. Further examination revealed that the expression of certain TAM components was reduced as a result of prolonged degradation of MYD88 by the infection. As a result of such prolonged IFN-I production, innate immunological functions of the gingiva were disrupted, and CD4 + T cells were constitutively primed by dendritic cells, leading to elevated RANKL expression and, subsequently, alveolar bone loss (ABL). Blocking IFN-I signaling restored proper immunological function and prevented ABL. Importantly, a loss of negative regulation on IFN-I expression by TAM signaling was also evident in periodontitis patients. These findings thus suggest a role for IFN-I in the pathogenesis of periodontitis. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Structural elucidation of the DFG-Asp in and DFG-Asp out states of TAM kinases and insight into the selectivity of their inhibitors.

PubMed

Messoussi, Abdellah; Peyronnet, Lucile; Feneyrolles, Clémence; Chevé, Gwénaël; Bougrin, Khalid; Yasri, Aziz

2014-10-10

Structural elucidation of the active (DFG-Asp in) and inactive (DFG-Asp out) states of the TAM family of receptor tyrosine kinases is required for future development of TAM inhibitors as drugs. Herein we report a computational study on each of the three TAM members Tyro-3, Axl and Mer. DFG-Asp in and DFG-Asp out homology models of each one were built based on the X-ray structure of c-Met kinase, an enzyme with a closely related sequence. Structural validation and in silico screening enabled identification of critical amino acids for ligand binding within the active site of each DFG-Asp in and DFG-Asp out model. The position and nature of amino acids that differ among Tyro-3, Axl and Mer, and the potential role of these residues in the design of selective TAM ligands, are discussed.

Extended TAM Model: Impacts of Convenience on Acceptance and Use of Moodle

ERIC Educational Resources Information Center

Hsu, Hsiao-hui; Chang, Yu-ying

2013-01-01

The increasing online access to courses, programs, and information has shifted the control and responsibility of learning process from instructors to learners. Learners' perceptions of and attitudes toward e-learning constitute a critical factor to the success of such system. The purpose of this study is to take TAM (technology acceptance model)…

A novel RNA binding surface of the TAM domain of TIP5/BAZ2A mediates epigenetic regulation of rRNA genes.

PubMed

Anosova, Irina; Melnik, Svitlana; Tripsianes, Konstantinos; Kateb, Fatiha; Grummt, Ingrid; Sattler, Michael

2015-05-26

The chromatin remodeling complex NoRC, comprising the subunits SNF2h and TIP5/BAZ2A, mediates heterochromatin formation at major clusters of repetitive elements, including rRNA genes, centromeres and telomeres. Association with chromatin requires the interaction of the TAM (TIP5/ARBP/MBD) domain of TIP5 with noncoding RNA, which targets NoRC to specific genomic loci. Here, we show that the NMR structure of the TAM domain of TIP5 resembles the fold of the MBD domain, found in methyl-CpG binding proteins. However, the TAM domain exhibits an extended MBD fold with unique C-terminal extensions that constitute a novel surface for RNA binding. Mutation of critical amino acids within this surface abolishes RNA binding in vitro and in vivo. Our results explain the distinct binding specificities of TAM and MBD domains to RNA and methylated DNA, respectively, and reveal structural features for the interaction of NoRC with non-coding RNA. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

DOE Project 353: TAMS Prototype and production coupling alignment units

DOE Office of Scientific and Technical Information (OSTI.GOV)

Field, K.V.

1996-02-01

TAMS is an electronic measurement system used to determine the alignment of turbine-generator shafts at the coupling interface. The displacement transducer is a strain gage based sensor mounted in a portable probe. The measurement system was experiencing zero input drift and temperature induced drift. This project endeavored to determine the source of these problems and to revise a unit to be returned to a customer, Baltimore Gas and Electric (BGE), within a period of five weeks.

OSD1 promotes meiotic progression via APC/C inhibition and forms a regulatory network with TDM and CYCA1;2/TAM.

PubMed

Cromer, Laurence; Heyman, Jefri; Touati, Sandra; Harashima, Hirofumi; Araou, Emilie; Girard, Chloe; Horlow, Christine; Wassmann, Katja; Schnittger, Arp; De Veylder, Lieven; Mercier, Raphael

2012-01-01

Cell cycle control is modified at meiosis compared to mitosis, because two divisions follow a single DNA replication event. Cyclin-dependent kinases (CDKs) promote progression through both meiosis and mitosis, and a central regulator of their activity is the APC/C (Anaphase Promoting Complex/Cyclosome) that is especially required for exit from mitosis. We have shown previously that OSD1 is involved in entry into both meiosis I and meiosis II in Arabidopsis thaliana; however, the molecular mechanism by which OSD1 controls these transitions has remained unclear. Here we show that OSD1 promotes meiotic progression through APC/C inhibition. Next, we explored the functional relationships between OSD1 and the genes known to control meiotic cell cycle transitions in Arabidopsis. Like osd1, cyca1;2/tam mutation leads to a premature exit from meiosis after the first division, while tdm mutants perform an aberrant third meiotic division after normal meiosis I and II. Remarkably, while tdm is epistatic to tam, osd1 is epistatic to tdm. We further show that the expression of a non-destructible CYCA1;2/TAM provokes, like tdm, the entry into a third meiotic division. Finally, we show that CYCA1;2/TAM forms an active complex with CDKA;1 that can phosphorylate OSD1 in vitro. We thus propose that a functional network composed of OSD1, CYCA1;2/TAM, and TDM controls three key steps of meiotic progression, in which OSD1 is a meiotic APC/C inhibitor.

Purification and Bicelle Crystallization for Structure Determination of the E. coli Outer Membrane Protein TamA.

PubMed

Gruss, Fabian; Hiller, Sebastian; Maier, Timm

2015-01-01

TamA is an Omp85 protein involved in autotransporter assembly in the outer membrane of Escherichia coli. It comprises a C-terminal 16-stranded transmembrane β-barrel as well as three periplasmic POTRA domains, and is a challenging target for structure determination. Here, we present a method for crystal structure determination of TamA, including recombinant expression in E. coli, detergent extraction, chromatographic purification, and bicelle crystallization in combination with seeding. As a result, crystals in space group P21212 are obtained, which diffract to 2.3 Å resolution. This protocol also serves as a template for structure determination of other outer membrane proteins, in particular of the Omp85 family.

Development of CANDLES low background HPGe detector and half-life measurement of 180Tam

NASA Astrophysics Data System (ADS)

Chan, W. M.; Kishimoto, T.; Umehara, S.; Matsuoka, K.; Suzuki, K.; Yoshida, S.; Nakajima, K.; Iida, T.; Fushimi, K.; Nomachi, M.; Ogawa, I.; Tamagawa, Y.; Hazama, R.; Takemoto, Y.; Nakatani, N.; Takihira, Y.; Tozawa, M.; Kakubata, H.; Trang, V. T. T.; Ohata, T.; Tetsuno, K.; Maeda, T.; Khai, B. T.; Li, X. L.; Batpurev, T.

2018-01-01

A low background HPGe detector system was developed at CANDLES Experimental Hall for multipurpose use. Various low background techniques were employed, including hermatic shield design, radon gas suppression, and background reduction analysis. A new pulse shape discrimination (PSD) method was specially created for coaxial Ge detector. Using this PSD method, microphonics noise and background event at low energy region less than 200 keV can be rejected effectively. Monte Carlo simulation by GEANT4 was performed to acquire the detection efficiency and study the interaction of gamma-rays with detector system. For rare decay measurement, the detector was utilized to detect the nature's most stable isomer tantalum-180m (180Tam) decay. Two phases of tantalum physics run were completed with total livetime of 358.2 days, which Phase II has upgraded shield configuration. The world most stringent half-life limit of 180Tam has been successfully achieved.

Somatostatin Derivate (smsDX) Attenuates the TAM-Stimulated Proliferation, Migration and Invasion of Prostate Cancer via NF-κB Regulation.

PubMed

Guo, Zhaoxin; Xing, Zhaoquan; Cheng, Xiangyu; Fang, Zhiqing; Jiang, Chao; Su, Jing; Zhou, Zunlin; Xu, Zhonghua; Holmberg, Anders; Nilsson, Sten; Liu, Zhaoxu

2015-01-01

Tumor development and progression are influenced by macrophages of the surrounding microenvironment. To investigate the influences of an inflammatory tumor microenvironment on the growth and metastasis of prostate cancer, the present study used a co-culture model of prostate cancer (PCa) cells with tumor-associated macrophage (TAM)-conditioned medium (MCM). MCM promoted PCa cell (LNCaP, DU145 and PC-3) growth, and a xenograft model in nude mice consistently demonstrated that MCM could promote tumor growth. MCM also stimulated migration and invasion in vitro. Somatostatin derivate (smsDX) significantly attenuated the TAM-stimulated proliferation, migration and invasion of prostate cancer. Immunohistochemistry revealed that NF-κB was over-expressed in PCa and BPH with chronic inflammatory tissue specimens and was positively correlated with macrophage infiltration. Further investigation into the underlying mechanism revealed that NF-κB played an important role in macrophage infiltration. SmsDX inhibited the paracrine loop between TAM and PCa cells and may represent a potential therapeutic agent for PCa.

Assessing the utility of TAM, TPB, and UTAUT for advanced driver assistance systems.

PubMed

Rahman, Md Mahmudur; Lesch, Mary F; Horrey, William J; Strawderman, Lesley

2017-11-01

Advanced Driver Assistance Systems (ADAS) are intended to enhance driver performance and improve transportation safety. The potential benefits of these technologies, such as reduction in number of crashes, enhancing driver comfort or convenience, decreasing environmental impact, etc., have been acknowledged by transportation safety researchers and federal transportation agencies. Although these systems afford safety advantages, they may also challenge the traditional role of drivers in operating vehicles. Driver acceptance, therefore, is essential for the implementation of these systems into the transportation system. Recognizing the need for research into the factors affecting driver acceptance, this study assessed the utility of the Technology Acceptance Model (TAM), the Theory of Planned Behavior (TPB), and the Unified Theory of Acceptance and Use of Technology (UTAUT) for modelling driver acceptance in terms of Behavioral Intention to use an ADAS. Each of these models propose a set of factors that influence acceptance of a technology. Data collection was done using two approaches: a driving simulator approach and an online survey approach. In both approaches, participants interacted with either a fatigue monitoring system or an adaptive cruise control system combined with a lane-keeping system. Based on their experience, participants responded to several survey questions to indicate their attitude toward using the ADAS and their perception of its usefulness, usability, etc. A sample of 430 surveys were collected for this study. Results found that all the models (TAM, TPB, and UTAUT) can explain driver acceptance with their proposed sets of factors, each explaining 71% or more of the variability in Behavioral Intention. Among the models, TAM was found to perform the best in modelling driver acceptance followed by TPB. The findings of this study confirm that these models can be applied to ADAS technologies and that they provide a basis for understanding driver

The TAM-family receptor Mer mediates production of HGF through the RhoA-dependent pathway in response to apoptotic cells.

PubMed

Park, Hyun-Jung; Baen, Ji-Yeon; Lee, Ye-Ji; Choi, Youn-Hee; Kang, Jihee Lee

2012-08-01

The TAM receptor protein tyrosine kinases Tyro3, Axl, and Mer play important roles in macrophage function. We investigated the roles of the TAM receptors in mediating the induction of hepatocyte growth factor (HGF) during the interaction of macrophages with apoptotic cells. Mer-specific neutralizing antibody, small interfering RNA (siRNA), and a recombinant Mer protein (Mer/Fc) inhibited HGF mRNA and protein expression, as well as activation of RhoA, Akt, and specific mitogen-activated protein (MAP) kinases in response to apoptotic cells. Inhibition of Axl or Tyro3 with specific antibodies, siRNA, or Fc-fusion proteins did not prevent apoptotic cell-induced HGF mRNA and protein expression and did not inhibit activation of the postreceptor signaling molecules RhoA and certain MAP kinases, including extracellular signal-regulated protein kinase and c-Jun NH(2)-terminal kinase. However, Axl- and Tyro3-specific blockers did inhibit the activation of Akt and p38 MAP kinase in response to apoptotic cells. In addition, none of the TAM receptors mediated the effects of apoptotic cells on transforming growth factor-β or epidermal growth factor mRNA expression. However, they were involved in the induction of vascular endothelial growth factor mRNA expression. Our data provide evidence that when macrophages interact with apoptotic cells, only Mer of the TAM-family receptors is responsible for mediating transcriptional HGF production through a RhoA-dependent pathway.

Actividad funcional cerebral en estado de reposo: REDES EN CONEXIÓN

PubMed Central

Proal, Erika; Alvarez-Segura, Mar; de la Iglesia-Vayá, Maria; Martí-Bonmatí, Luis; Castellanos, F. Xavier

2015-01-01

Resumen El análisis de la conectividad funcional mediante resonancia magnética funcional (RMf) puede llevarse a cabo durante la realización de una tarea, la percepción de un estímulo o en estado de reposo. Estos análisis han demostrado su fiabilidad y reproducibilidad con diferentes enfoques (matemáticos, estadísticos, físicos) para seleccionar los vóxeles activados. El estudio de la señal de baja frecuencia en la actividad cerebral a través del contraste BOLD en estado de reposo ha revelado patrones de actividad cortical sincronizados, permitiendo describir la arquitectura funcional intrínseca del cerebro humano. La comunidad científica internacional dispone de recursos compartidos que contribuirán mediante este análisis de RMf en estado de reposo a la obtención de diagnósticos y tratamientos más precisos y avanzados en el campo de las neurociencias. PMID:21365601

Understanding Intention to Use Electronic Information Resources: A Theoretical Extension of the Technology Acceptance Model (TAM)

PubMed Central

Tao, Donghua

2008-01-01

This study extended the Technology Acceptance Model (TAM) by examining the roles of two aspects of e-resource characteristics, namely, information quality and system quality, in predicting public health students’ intention to use e-resources for completing research paper assignments. Both focus groups and a questionnaire were used to collect data. Descriptive analysis, data screening, and Structural Equation Modeling (SEM) techniques were used for data analysis. The study found that perceived usefulness played a major role in determining students’ intention to use e-resources. Perceived usefulness and perceived ease of use fully mediated the impact that information quality and system quality had on behavior intention. The research model enriches the existing technology acceptance literature by extending TAM. Representing two aspects of e-resource characteristics provides greater explanatory information for diagnosing problems of system design, development, and implementation. PMID:18999300

Understanding intention to use electronic information resources: A theoretical extension of the technology acceptance model (TAM).

PubMed

Tao, Donghua

2008-11-06

This study extended the Technology Acceptance Model (TAM) by examining the roles of two aspects of e-resource characteristics, namely, information quality and system quality, in predicting public health students' intention to use e-resources for completing research paper assignments. Both focus groups and a questionnaire were used to collect data. Descriptive analysis, data screening, and Structural Equation Modeling (SEM) techniques were used for data analysis. The study found that perceived usefulness played a major role in determining students' intention to use e-resources. Perceived usefulness and perceived ease of use fully mediated the impact that information quality and system quality had on behavior intention. The research model enriches the existing technology acceptance literature by extending TAM. Representing two aspects of e-resource characteristics provides greater explanatory information for diagnosing problems of system design, development, and implementation.

‘TAM 112’ Wheat, resistant to greenbug and wheat curl mite and adapted to the dryland production system in the Southern High Plains

USDA-ARS?s Scientific Manuscript database

‘TAM 112’ (PI 643143), a hard red winter wheat (Triticum aestivum L.) is an F4 derived line from the cross U1254-7-9-2-1/TXGH10440. U1254-7-9-2 is a USDA-ARS germplasm line from the Plant Science and Entomology Research unit, Manhattan, Kansas. It was developed from the cross TAM 200/TA2460. TA24...

Examining the Antecedents of ICT Adoption in Education Using an Extended Technology Acceptance Model (TAM)

ERIC Educational Resources Information Center

Teeroovengadum, Viraiyan; Heeraman, Nabeel; Jugurnath, Bhavish

2017-01-01

This study assesses the determinants of ICT adoption by educators in the teaching and learning process in the context of a developing country, Mauritius. A hierarchical regression analysis is used, to firstly determine the incremental effects of factors from the technology acceptance model (TAM) while controlling for demographic variables such as…

Fragilidad y su asociación con mortalidad, hospitalizaciones y dependencia funcional en mexicanos de 60 años o más

PubMed Central

de León González, Enrique Díaz; Pérez, Héctor Eloy Tamez; Hermosillo, Hugo Gutiérrez; Rodríguez, Javier Armando Cedillo; Torres, Gabriela

2016-01-01

Fundamento y objetivo Determinar la asociación entre fragilidad y mortalidad, dependencia funcional, caídas y hospitalizaciones en el Estudio Nacional de Salud y Envejecimiento en México (ENASEM). Sujetos y métodos Estudio prospectivo poblacional en México en el que se seleccionaron sujetos de 60 años o más, que fueron evaluados en las variables de fragilidad durante la primera vuelta del estudio en el año 2001 y que incluyó: dificultad para levantarse de una silla después de haber estado sentado(a) durante largo tiempo, pérdida de peso de 5 kilogramos o más en los últimos dos años y falta de energía. Los sujetos fueron catalogados como robustos, prefrágiles y frágiles cuando tenían cero, una o dos de las características anteriores, respectivamente. La mortalidad, hospitalizaciones, caídas y dependencia funcional fueron evaluadas en la segunda vuelta del estudio en el año 2003. Se calculó el riesgo relativo para cada una de las complicaciones, así como análisis multivariado con regresión de Cox para el caso de mortalidad y regresión logística para el resto. Resultados Los estados de prefragilidad y fragilidad se asociaron independientemente con mortalidad, con índices de riesgo ajustados de 1,61 (intervalo de confianza del 95% [IC 95%] 1,01-2,55) y 1,94 (IC 95% 1,20-3,13), respectivamente. Sólo el estado de fragilidad se asoció independientemente con hospitalización y dependencia funcional, con una razón de momios ajustada de 1,53 (IC 95% 1,13-2,07) y 3,07 (IC 95% 1,76-5,34), respectivamente. No hubo asociación entre los estados de prefragilidad y fragilidad con caídas. Conclusión El estado de fragilidad se asocia independientemente con mortalidad, hospitalizaciones y disfuncionalidad en actividades básicas de la vida diaria en los siguientes dos años en población mexicana. PMID:21612803

Recombinant expression, purification, crystallization and preliminary X-ray diffraction analysis of the C-terminal DUF490(963-1138) domain of TamB from Escherichia coli.

PubMed

Josts, Inokentijs; Grinter, Rhys; Kelly, Sharon M; Mosbahi, Khedidja; Roszak, Aleksander; Cogdell, Richard; Smith, Brian O; Byron, Olwyn; Walker, Daniel

2014-09-01

TamB is a recently described inner membrane protein that, together with its partner protein TamA, is required for the efficient secretion of a subset of autotransporter proteins in Gram-negative bacteria. In this study, the C-terminal DUF490963-1138 domain of TamB was overexpressed in Escherichia coli K-12, purified and crystallized using the sitting-drop vapour-diffusion method. The crystals belonged to the primitive trigonal space group P3121, with unit-cell parameters a = b = 57.34, c = 220.74 Å, and diffracted to 2.1 Å resolution. Preliminary secondary-structure and X-ray diffraction analyses are reported. Two molecules are predicted to be present in the asymmetric unit. Experimental phasing using selenomethionine-labelled protein will be undertaken in the future.

Soluble TAM receptor tyrosine kinases in rheumatoid arthritis: correlation with disease activity and bone destruction.

PubMed

Xu, L; Hu, F; Zhu, H; Liu, X; Shi, L; Li, Y; Zhong, H; Su, Y

2018-04-01

The TAM receptor tyrosine kinases (TAM RTK) are a subfamily of receptor tyrosine kinases, the role of which in autoimmune diseases such as systemic lupus erythematosus has been well explored, while their functions in rheumatoid arthritis (RA) remain largely unknown. In this study, we investigated the role of soluble TAM receptor tyrosine kinases (sAxl/sMer/sTyro3) in patients with RA. A total of 306 RA patients, 100 osteoarthritis (OA) patients and 120 healthy controls (HCs) were enrolled into this study. The serum concentrations of sAxl/sMer/sTyro3 were measured by enzyme-linked immunosorbent assay (ELISA), then the associations between sAxl/sMer/sTyro3 levels and clinical features of RA patients were analysed. We also investigated whether sTyro3 could promote osteoclast differentiation in vitro in RA patients. The results showed that compared with healthy controls (HCs), sTyro3 levels in the serum of RA patients were elevated remarkably and sMer levels were decreased significantly, whereas there was no difference between HCs and RA patients on sAxl levels. The sTyro3 levels were correlated weakly but positively with white blood cells (WBC), immunoglobulin (Ig)M, rheumatoid factor (RF), swollen joint counts, tender joint counts, total sharp scores and joint erosion scores. Conversely, there were no significant correlations between sMer levels and the above indices. Moreover, RA patients with high disease activity also showed higher sTyro3 levels. In-vitro osteoclast differentiation assay showed further that tartrate-resistant acid phosphatase (TRAP) + osteoclasts were increased significantly in the presence of sTyro3. Collectively, our study indicated that serum sTyro3 levels were elevated in RA patients and correlated positively with disease activity and bone destruction, which may serve as an important participant in RA pathogenesis. © 2017 British Society for Immunology.

Activation of TrkB with TAM-163 Results in Opposite Effects on Body Weight in Rodents and Non-Human Primates

PubMed Central

Perreault, Mylène; Feng, Guo; Will, Sarah; Gareski, Tiffany; Kubasiak, David; Marquette, Kimberly; Vugmeyster, Yulia; Unger, Thaddeus J.; Jones, Juli; Qadri, Ariful; Hahm, Seung; Sun, Ying; Rohde, Cynthia M.; Zwijnenberg, Raphael; Paulsen, Janet; Gimeno, Ruth E.

2013-01-01

Strong genetic data link the Tyrosine kinase receptor B (TrkB) and its major endogenous ligand brain-derived neurotrophic factor (BDNF) to the regulation of energy homeostasis, with loss-of-function mutations in either gene causing severe obesity in both mice and humans. It has previously been reported that peripheral administration of the endogenous TrkB agonist ligand neurotrophin-4 (NT-4) profoundly decreases food intake and body weight in rodents, while paradoxically increasing these same parameters in monkeys. We generated a humanized TrkB agonist antibody, TAM-163, and characterized its therapeutic potential in several models of type 2 diabetes and obesity. In vitro, TAM-163 bound to human and rodent TrkB with high affinity, activated all aspects of the TrkB signaling cascade and induced TrkB internalization and degradation in a manner similar to BDNF. In vivo, peripheral administration of TAM-163 decreased food intake and/or body weight in mice, rats, hamsters, and dogs, but increased food intake and body weight in monkeys. The magnitude of weight change was similar in rodents and non-human primates, occurred at doses where there was no appreciable penetration into deep structures of the brain, and could not be explained by differences in exposures between species. Rather, peripherally administered TAM-163 localized to areas in the hypothalamus and the brain stem located outside the blood-brain barrier in a similar manner between rodents and non-human primates, suggesting differences in neuroanatomy across species. Our data demonstrate that a TrkB agonist antibody, administered peripherally, causes species-dependent effects on body weight similar to the endogenous TrkB ligand NT-4. The possible clinical utility of TrkB agonism in treating weight regulatory disorder, such as obesity or cachexia, will require evaluation in man. PMID:23700410

TAM receptors Tyro3 and Mer as novel targets in colorectal cancer.

PubMed

Schmitz, Robin; Valls, Aida Freire; Yerbes, Rosario; von Richter, Sophie; Kahlert, Christoph; Loges, Sonja; Weitz, Jürgen; Schneider, Martin; Ruiz de Almodovar, Carmen; Ulrich, Alexis; Schmidt, Thomas

2016-08-30

CRC remains the third most common cancer worldwide with a high 5-year mortality rate in advanced cases. Combined with chemotherapy, targeted therapy is an additional treatment option. However as CRC still escapes targeted therapy the vigorous search for new targets is warranted to increase patients´ overall survival. In this study we describe a new role for Gas6/protein S-TAM receptor interaction in CRC. Gas6, expressed by tumor-infiltrating M2-like macrophages, enhances malignant properties of tumor cells including proliferation, invasion and colony formation. Upon chemotherapy macrophages increase Gas6 synthesis, which significantly attenuates the cytotoxic effect of 5-FU chemotherapy on tumor cells. The anti-coagulant protein S has similar effects as Gas6.In CRC patient samples Tyro3 was overexpressed within the tumor. In-vitro inhibition of Tyro3 and Mer reduces tumor cell proliferation and sensitizes tumor cells to chemotherapy. Moreover high expression of Tyro3 and Mer in tumor tissue significantly shortens CRC patients´ survival. Various in vitro models were used to investigate the role of Gas6 and its TAM receptors in human CRC cells, by stimulation (rhGas6) and knockdown (siRNA) of Axl, Tyro3 and Mer. In terms of a translational research, we additionally performed an expression analysis in human CRC tissue and analyzed the medical record of these patients. Tyro3 and Mer represent novel therapeutic targets in CRC and warrant further preclinical and clinical investigation in the future.

Qualitative and quantitative trait loci conditioning resistance to Puccinia coronata pathotypes NQMG and LGCG in the oat (Avena sativa L.) cultivars Ogle and TAM O-301.

PubMed

Jackson, E W; Obert, D E; Menz, M; Hu, G; Bonman, J M

2008-02-01

Mapping disease resistance loci relies on the type and precision of phenotypic measurements. For crown rust of oat, disease severity is commonly assessed based on visual ratings of infection types (IT) and/or diseased leaf area (DLA) of infected plants in the greenhouse or field. These data can be affected by several variables including; (i) non-uniform disease development in the field; (ii) atypical symptom development in the greenhouse; (iii) the presence of multiple pathogenic races or pathotypes in the field, and (iv) rating bias. To overcome these limitations, we mapped crown rust resistance to single isolates in the Ogle/TAM O-301 (OT) recombinant inbred line (RIL) population using detailed measurements of IT, uredinia length (UL) and relative fungal DNA (FDNA) estimates determined by q-PCR. Measurements were taken on OT parents and recombinant inbred lines (RIL) inoculated with Puccinia coronata pathotypes NQMG and LGCG in separate greenhouse and field tests. Qualitative mapping identified an allele conferred by TAM O-301 on linkage group (LG) OT-11, which produced a bleached fleck phenotype to both NQMG and LGCG. Quantitative mapping identified two major quantitative trait loci (QTL) originating from TAM O-301 on LGs OT-11 and OT-32 which reduced UL and FDNA of both isolates in all experiments. Additionally, minor QTLs that reduced UL and FDNA were detected on LGs OT-15 and OT-8, originating from TAM O-301, and on LG OT-27, originating from Ogle. Detailed assessments of the OT population using two pathotypes in both the greenhouse and field provided comprehensive information to effectively map the genes responsible for crown rust resistance in Ogle and TAM O-301 to NQMG and LGCG.

Validating the Satisfaction and Continuance Intention of E-Learning Systems: Combining TAM and IS Success Models

ERIC Educational Resources Information Center

Lin, Tung-Cheng; Chen, Ching-Jen

2012-01-01

Many e-learning studies have evaluated learning attitudes and behaviors, based on TAM. However, a successful e-learning system (ELS) should take both system and information quality into account by applying ISM developed by Delone and McLean. In addition, the acceptance for information system depends on the perceived usefulness and ease of use…

Anticancer effect of luteolin is mediated by downregulation of TAM receptor tyrosine kinases, but not interleukin-8, in non-small cell lung cancer cells.

PubMed

Lee, Youn Ju; Lim, Taeho; Han, Min Su; Lee, Sun-Hwa; Baek, Suk-Hwan; Nan, Hong-Yan; Lee, Chuhee

2017-02-01

TAM receptor tyrosine kinases (RTKs), Tyro3, Axl and MerTK, transduce diverse signals responsible for cell survival, growth, proliferation and anti-apoptosis. In the present study, we demonstrated the effect of luteolin, a flavonoid with antioxidant, anti-inflammatory and anticancer activities, on the expression and activation of TAM RTKs and the association with its cytotoxicity in non-small cell lung cancer (NSCLC) cells. We observed the cytotoxic effect of luteolin in parental A549 and H460 cells as well as in cisplatin-resistant A549/CisR and H460/CisR cells. Exposure of these cells to luteolin also resulted in a dose‑dependent decrease in clonogenic ability. Next, luteolin was found to decrease the protein levels of all three TAM RTKs in the A549 and A549/CisR cells in a dose‑dependent manner. In a similar manner, in H460 and H460/CisR cells, the protein levels of Axl and Tyro3 were decreased following luteolin treatment. In addition, Axl promoter activity was decreased by luteolin, indicating that luteolin suppresses Axl expression at the transcriptional level. We next found that luteolin abrogated Axl phosphorylation in response to growth arrest-specific 6 (Gas6), its ligand, implying the inhibitory effect of luteolin on Gas6-induced Axl activation. Ectopic expression of Axl was observed to attenuate the antiproliferative effect of luteolin, while knockdown of the Axl protein level using a gold nanoparticle-assisted gene delivery system increased its cytotoxicity. In contrast to the inhibitory effect of luteolin on the expression of TAM RTKs, interleukin-8 (IL-8) production was not decreased by luteolin in H460 and H460/CisR cells, while IL-8 production/cell was increased. Collectively, our data suggest that TAM RTKs, but not IL-8, are promising therapeutic targets of luteolin to abrogate cell proliferation and to overcome chemoresistance in NSCLC cells.

Vitamin K-dependent proteins GAS6 and Protein S and TAM receptors in patients of systemic lupus erythematosus: correlation with common genetic variants and disease activity.

PubMed

Recarte-Pelz, Pedro; Tàssies, Dolors; Espinosa, Gerard; Hurtado, Begoña; Sala, Núria; Cervera, Ricard; Reverter, Joan Carles; de Frutos, Pablo García

2013-03-12

Growth arrest-specific gene 6 protein (GAS6) and protein S (ProS) are vitamin K-dependent proteins present in plasma with important regulatory functions in systems of response and repair to damage. They interact with receptor tyrosine kinases of the Tyro3, Axl and MerTK receptor tyrosine kinase (TAM) family, involved in apoptotic cell clearance (efferocytosis) and regulation of the innate immunity. TAM-deficient mice show spontaneous lupus-like symptoms. Here we tested the genetic profile and plasma levels of components of the system in patients with systemic lupus erythematosus (SLE), and compare them with a control healthy population. Fifty SLE patients and 50 healthy controls with matched age, gender and from the same geographic area were compared. Genetic analysis was performed in GAS6 and the TAM receptor genes on SNPs previously identified. The concentrations of GAS6, total and free ProS, and the soluble forms of the three TAM receptors (sAxl, sMerTK and sTyro3) were measured in plasma from these samples. Plasma concentrations of GAS6 were higher and, total and free ProS were lower in the SLE patients compared to controls, even when patients on oral anticoagulant treatment were discarded. Those parameters correlated with SLE disease activity index (SLEDAI) score, GAS6 being higher in the most severe cases, while free and total ProS were lower. All 3 soluble receptors increased its concentration in plasma of lupus patients. The present study highlights that the GAS6/ProS-TAM system correlates in several ways with disease activity in SLE. We show here that this correlation is affected by common polymorphisms in the genes of the system. These findings underscore the importance of mechanism of regulatory control of innate immunity in the pathology of SLE.

Vitamin K-dependent proteins GAS6 and Protein S and TAM receptors in patients of systemic lupus erythematosus: correlation with common genetic variants and disease activity

PubMed Central

2013-01-01

Introduction Growth arrest-specific gene 6 protein (GAS6) and protein S (ProS) are vitamin K-dependent proteins present in plasma with important regulatory functions in systems of response and repair to damage. They interact with receptor tyrosine kinases of the Tyro3, Axl and MerTK receptor tyrosine kinase (TAM) family, involved in apoptotic cell clearance (efferocytosis) and regulation of the innate immunity. TAM-deficient mice show spontaneous lupus-like symptoms. Here we tested the genetic profile and plasma levels of components of the system in patients with systemic lupus erythematosus (SLE), and compare them with a control healthy population. Methods Fifty SLE patients and 50 healthy controls with matched age, gender and from the same geographic area were compared. Genetic analysis was performed in GAS6 and the TAM receptor genes on SNPs previously identified. The concentrations of GAS6, total and free ProS, and the soluble forms of the three TAM receptors (sAxl, sMerTK and sTyro3) were measured in plasma from these samples. Results Plasma concentrations of GAS6 were higher and, total and free ProS were lower in the SLE patients compared to controls, even when patients on oral anticoagulant treatment were discarded. Those parameters correlated with SLE disease activity index (SLEDAI) score, GAS6 being higher in the most severe cases, while free and total ProS were lower. All 3 soluble receptors increased its concentration in plasma of lupus patients. Conclusions The present study highlights that the GAS6/ProS-TAM system correlates in several ways with disease activity in SLE. We show here that this correlation is affected by common polymorphisms in the genes of the system. These findings underscore the importance of mechanism of regulatory control of innate immunity in the pathology of SLE. PMID:23497733

EPR Oximetry Sensor-Developing a TAM Derivative for In Vivo Studies.

PubMed

Boś-Liedke, Agnieszka; Walawender, Magdalena; Woźniak, Anna; Flak, Dorota; Gapiński, Jacek; Jurga, Stefan; Kucińska, Małgorzata; Plewiński, Adam; Murias, Marek; Elewa, Marwa; Lampp, Lisa; Imming, Peter; Tadyszak, Krzysztof

2018-06-01

Oxygenation is one of the most important physiological parameters of biological systems. Low oxygen concentration (hypoxia) is associated with various pathophysiological processes in different organs. Hypoxia is of special importance in tumor therapy, causing poor response to treatment. Triaryl methyl (TAM) derivative radicals are commonly used in electron paramagnetic resonance (EPR) as sensors for quantitative spatial tissue oxygen mapping. They are also known as magnetic resonance imaging (MRI) contrast agents and fluorescence imaging compounds. We report the properties of the TAM radical tris(2,3,5,6-tetrachloro-4-carboxy-phenyl)methyl, (PTMTC), a potential multimodal (EPR/fluorescence) marker. PTMTC was spectrally analyzed using EPR and characterized by estimation of its sensitivity to the oxygen in liquid environment suitable for intravenous injection (1 mM PBS, pH = 7.4). Further, fluorescent emission of the radical was measured using the same solvent and its quantum yield was estimated. An in vitro cytotoxicity examination was conducted in two cancer cell lines, HT-29 (colorectal adenocarcinoma) and FaDu (squamous cell carcinoma) and followed by uptake studies. The stability of the radical in different solutions (PBS pH = 7.4, cell media used for HT-29 and FaDu cells culturing and cytotoxicity procedure, full rat blood and blood plasma) was determined. Finally, a primary toxicity test of PTMTC was carried out in mice. Results of spectral studies confirmed the multimodal properties of PTMTC. PTMTC was demonstrated to be not absorbed by cancer cells and did not interfere with luciferin-luciferase based assays. Also in vitro and in vivo tests showed that it was non-toxic and can be freely administrated till doses of 250 mg/kg BW via both i.v. and i.p. injections. This work illustrated that PTMTC is a perfect candidate for multimodal (EPR/fluorescence) contrast agent in preclinical studies.

S100A9+ MDSC and TAM-mediated EGFR-TKI resistance in lung adenocarcinoma: the role of RELB.

PubMed

Feng, Po-Hao; Yu, Chih-Teng; Chen, Kuan-Yuan; Luo, Ching-Shan; Wu, Shen Ming; Liu, Chien-Ying; Kuo, Lu Wei; Chan, Yao-Fei; Chen, Tzu-Tao; Chang, Chih-Cheng; Lee, Chun-Nin; Chuang, Hsiao-Chi; Lin, Chiou-Feng; Han, Chia-Li; Lee, Wei-Hwa; Lee, Kang-Yun

2018-01-26

Monocytic myeloid-derived suppressor cells (MDSCs), particularly the S100A9+ subset, has been shown initial clinical relevance. However, its role in EGFR-mutated lung adenocarcinoma, especially to EGFR-tyrosine kinase inhibitor (EGFR-TKI) is not clear. In a clinical setting of EGFR mutated lung adenocarcinoma, a role of the MDSC apart from T cell suppression was also investigated. Blood monocytic S100A9 + MDSC counts were higher in lung cancer patients than healthy donors, and were associated with poor treatment response and shorter progression-free survival (PFS). S100A9 + MDSCs in PBMC were well correlated to tumor infiltrating CD68 + and S100A9 + cells, suggesting an origin of TAMs. Patient's MDMs, mostly from S100A9 + MDSC, similar to primary alveolar macrophages from patients, both expressed S100A9 and CD206, attenuated EGFR-TKI cytotoxicity. Microarray analysis identified up-regulation of the RELB signaling genes, confirmed by Western blotting and functionally by RELB knockdown. In conclusion, blood S100A9 + MDSC is a predictor of poor treatment response to EGFR-TKI, possibly via its derived TAMs through activation of the non-canonical NF-κB RELB pathway. Patients with activating EGFR mutation lung adenocarcinoma receiving first line EGFR TKIs were prospectively enrolled. Peripheral blood mononuclear cells (PBMCs) were collected for MDSCs analysis and for monocyte-derived macrophages (MDMs) and stored tissue for TAM analysis by IHC. A transwell co-culture system of MDMs/macrophages and H827 cells was used to detect the effect of macrophages on H827 and microarray analysis to explore the underlying molecular mechanisms, functionally confirmed by RNA interference.

Phosphatidylserine Is the Signal for TAM Receptors and Their Ligands.

PubMed

Lemke, Greg

2017-09-01

Nature repeatedly repurposes, in that molecules that serve as metabolites, energy depots, or polymer subunits are at the same time used to deliver signals within and between cells. The preeminent example of this repurposing is ATP, which functions as a building block for nucleic acids, an energy source for enzymatic reactions, a phosphate donor to regulate intracellular signaling, and a neurotransmitter to control the activity of neurons. A series of recent studies now consolidates the view that phosphatidylserine (PtdSer), a common phospholipid constituent of membrane bilayers, is similarly repurposed for use as a signal between cells and that the ligands and receptors of the Tyro3/Axl/Mer (TAM) family of receptor tyrosine kinases (RTKs) are prominent transducers of this signal. Copyright © 2017 Elsevier Ltd. All rights reserved.

Consumer acceptance of a quick response (QR) code for the food traceability system: Application of an extended technology acceptance model (TAM).

PubMed

Kim, Yeong Gug; Woo, Eunju

2016-07-01

The objectives of this study are to apply the TAM using the addition of perceived information to individuals' behavioral intention to use the QR code for the food traceability system; and to determine the moderating effects of food involvement on the relationship between perceived information and perceived usefulness. Results from a survey of 420 respondents are analyzed using structural equation modeling. The study findings reveal that the extended TAM has a satisfactory fit to the data and that the underlying dimensions have a significant effect on consumers' intention to use the QR code for the food traceability system. In addition, food involvement plays a significant moderating function in the relationship between perceived information and perceived usefulness. The implications of this study for future research are discussed. Copyright © 2016 Elsevier Ltd. All rights reserved.

Investigating the Effect of Learning Styles in a Blended E-Learning System: An Extension of the Technology Acceptance Model (TAM)

ERIC Educational Resources Information Center

Al-Azawei, Ahmed; Parslow, Patrick; Lundqvist, Karsten

2017-01-01

This study assesses learner perceptions of a blended e-learning system (BELS) and the feasibility of accommodating educational hypermedia systems (EHSs) according to learning styles using a modified version of the technology acceptance model (TAM). Recently, Moodle has been adopted by an Iraqi university alongside face-to-face (F2F) classrooms to…

Exploring the Intrinsic Motivation of Hedonic Information Systems Acceptance: Integrating Hedonic Theory and Flow with TAM

NASA Astrophysics Data System (ADS)

Wang, Zhihuan

Research on Information Systems (IS) acceptance is substantially focused on extrinsic motivation in workplaces, little is known about the underlying intrinsic motivations of Hedonic IS (HIS) acceptance. This paper proposes a hybrid HIS acceptance model which takes the unique characteristics of HIS and multiple identities of a HIS user into consideration by interacting Hedonic theory, Flow theory with Technology Acceptance Model (TAM). The model was empirically tested by a field survey. The result indicates that emotional responses, imaginal responses, and flow experience are three main contributions of HIS acceptance.

Berberine enhances the anti‑tumor activity of tamoxifen in drug‑sensitive MCF‑7 and drug‑resistant MCF‑7/TAM cells.

PubMed

Wen, Chunjie; Wu, Lanxiang; Fu, Lijuan; Zhang, Xue; Zhou, Honghao

2016-09-01

Berberine, an isoquinoline alkaloid, has been previously demonstrated to possess anti‑breast cancer properties. Tamoxifen is widely used in the prevention and treatment of estrogen receptor-positive breast cancer. Thus, the aim of the present study was to assess whether berberine enhanced the anticancer effect of tamoxifen, and the underlying mechanism involved in this combined effect in tamoxifen-sensitive (MCF-7) and tamoxifen-resistant (MCF-7/TAM) cells using MTS, flow cytometry and western blot assays. The results indicated that berberine demonstrated dose‑ and time‑dependent anti‑proliferative activity in MCF‑7 and MCF‑7/TAM cells. Furthermore, the combination of berberine and tamoxifen induced cell growth inhibition more effectively than tamoxifen alone. The present study also demonstrated that combinational treatment is more effective in inducing G1 phase arrest and activating apoptosis compared tamoxifen alone, which may be due to upregulation of P21 expression and downregulation of the B‑cell CLL/lymphoma 2(Bcl‑2)/Bcl‑2 associated X protein ratio. The results of the present study suggested that berberine may potentially be useful as an adjuvant agent in cancer chemotherapy to enhance the effect of tamoxifen, which will be useful for anti‑tumor therapy and further research.

A Qualitative Case Study to Investigate the Technology Acceptance Experience Outlined in the TAM Using the Kubler-Ross Stages of Grieving and Acceptance

ERIC Educational Resources Information Center

Sotelo, Benjamin Eladio

2015-01-01

The Technology Acceptance Model (TAM) has been an important model for the understanding of end user acceptance regarding technology and a framework used in thousands of researched scenarios since publication in 1986. Similarly, the Kubler-Ross model of death and dying has also been used as a model for the study of acceptance within the medical…

Assessing the Intention to Use Technology among Pre-Service Teachers in Singapore and Malaysia: A Multigroup Invariance Analysis of the Technology Acceptance Model (TAM)

ERIC Educational Resources Information Center

Teo, Timothy; Lee, Chwee Beng; Chai, Ching Sing; Wong, Su Luan

2009-01-01

This study assesses the pre-service teachers' self-reported future intentions to use technology in Singapore and Malaysia. A survey was employed to validate items from past research. Using the Technology Acceptance Model (TAM) as a research framework, 495 pre-service teachers from Singapore and Malaysia responded to an 11-item questionnaires…

The Technology Acceptance Model for Resource-Limited Settings (TAM-RLS): A Novel Framework for Mobile Health Interventions Targeted to Low-Literacy End-Users in Resource-Limited Settings.

PubMed

Campbell, Jeffrey I; Aturinda, Isaac; Mwesigwa, Evans; Burns, Bridget; Santorino, Data; Haberer, Jessica E; Bangsberg, David R; Holden, Richard J; Ware, Norma C; Siedner, Mark J

2017-11-01

Although mobile health (mHealth) technologies have shown promise in improving clinical care in resource-limited settings (RLS), they are infrequently brought to scale. One limitation to the success of many mHealth interventions is inattention to end-user acceptability, which is an important predictor of technology adoption. We conducted in-depth interviews with 43 people living with HIV in rural Uganda who had participated in a clinical trial of a short messaging system (SMS)-based intervention designed to prompt return to clinic after an abnormal laboratory test. Interviews focused on established features of technology acceptance models, including perceived ease of use and perceived usefulness, and included open-ended questions to gain insight into unexplored issues related to the intervention's acceptability. We used conventional (inductive) and direct content analysis to derive categories describing use behaviors and acceptability. Interviews guided development of a proposed conceptual framework, the technology acceptance model for resource-limited settings (TAM-RLS). This framework incorporates both classic technology acceptance model categories as well as novel factors affecting use in this setting. Participants described how SMS message language, phone characteristics, and experience with similar technologies contributed to the system's ease of use. Perceived usefulness was shaped by the perception that the system led to augmented HIV care services and improved access to social support from family and colleagues. Emergent themes specifically related to mHealth acceptance among PLWH in Uganda included (1) the importance of confidentiality, disclosure, and stigma, and (2) the barriers and facilitators downstream from the intervention that impacted achievement of the system's target outcome. The TAM-RLS is a proposed model of mHealth technology acceptance based upon end-user experiences in rural Uganda. Although the proposed model requires validation, the TAM

Schwann cells use TAM receptor-mediated phagocytosis in addition to autophagy to clear myelin in a mouse model of nerve injury.

PubMed

Brosius Lutz, Amanda; Chung, Won-Suk; Sloan, Steven A; Carson, Glenn A; Zhou, Lu; Lovelett, Emilie; Posada, Sean; Zuchero, J Bradley; Barres, Ben A

2017-09-19

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. Here we show that Schwann cells, the myelinating glia of the PNS, collaborate with hematogenous macrophages to clear myelin debris using TAM (Tyro3, Axl, Mer) receptor-mediated phagocytosis as well as autophagy. In a mouse model of PNS nerve crush injury, Schwann cells up-regulate TAM phagocytic receptors Axl and Mertk following PNS injury, and Schwann cells lacking both of these phagocytic receptors exhibit significantly impaired myelin phagocytosis both in vitro and in vivo. Autophagy-deficient Schwann cells also display reductions in myelin clearance after mouse nerve crush injury, as has been recently shown following nerve transection. These findings add a mechanism, Axl/Mertk-mediated myelin clearance, to the repertoire of cellular machinery used to clear myelin in the injured PNS. Given recent evidence that astrocytes express Axl and Mertk and have previously unrecognized phagocytic potential, this pathway may be a promising avenue for activating myelin clearance after CNS injury.

The expression of inflammatory cytokines, TAM tyrosine kinase receptors and their ligands is upregulated in venous leg ulcer patients: a novel insight into chronic wound immunity.

PubMed

Filkor, Kata; Németh, Tibor; Nagy, István; Kondorosi, Éva; Urbán, Edit; Kemény, Lajos; Szolnoky, Győző

2016-08-01

The systemic host defence mechanisms, especially innate immunity, in venous leg ulcer patients are poorly investigated. The aim of the current study was to measure Candida albicans killing activity and gene expressions of pro- and anti-inflammatory cytokines and innate immune response regulators, TAM receptors and ligands of peripheral blood mononuclear cells separated from 69 venous leg ulcer patients and 42 control probands. Leg ulcer patients were stratified into responder and non-responder groups on the basis of wound healing properties. No statistical differences were found in Candida killing among controls, responders and non-responders. Circulating blood mononuclear cells of patients overexpress pro-inflammatory (IL-1α, TNFα, CXCL-8) and anti-inflammatory (IL-10) cytokines as well as TAM receptors (Tyro, Axl, MerTK) and their ligands Gas6 and Protein S compared with those of control individuals. IL-1α is notably overexpressed in venous leg ulcer treatment non-responders; in contrast, Axl gene expression is robustly stronger among responders. These markers may be considered as candidates for the prediction of treatment response among venous leg ulcer patients. © 2015 Medicalhelplines.com Inc and John Wiley & Sons Ltd.

Estimación de pequeñas perturbaciones en satélites geocéntricos como un problema inverso

NASA Astrophysics Data System (ADS)

Zadunaisky, P. E.

El movimiento geocéntrico de un satélite artificial es simulado automáticamente por un sistema de ecuaciones diferenciales de segundo orden que incluyen dos funciones perturbadoras. La primera representa el segundo término del potencial gravitatorio de la Tierra y la segunda corresponde al frenado atmosférico. Asumiendo como conocidas, por hipótesis o por mediciones, la posición y velocidad del satélite en instantes sucesivos se estiman las perturbaciones a intervalos sucesivos por un método determinístico. Para ilustrar el método y comprobar la precisión de nuestros resultados hemos simulado dos ejemplos incluyendo valores conocidos de las perturbaciones que luego comparamos con los resultados de nuestro método. El método puede aplicarse por ejemplo para el intervalo de una revolución satelital lo cual permitiría el diseño inmediato de una maniobra correctiva de la órbita satelital.

Early Modern Humans and Morphological Variation in Southeast Asia: Fossil Evidence from Tam Pa Ling, Laos

PubMed Central

Demeter, Fabrice; Shackelford, Laura; Westaway, Kira; Duringer, Philippe; Bacon, Anne-Marie; Ponche, Jean-Luc; Wu, Xiujie; Sayavongkhamdy, Thongsa; Zhao, Jian-Xin; Barnes, Lani; Boyon, Marc; Sichanthongtip, Phonephanh; Sénégas, Frank; Karpoff, Anne-Marie; Patole-Edoumba, Elise; Coppens, Yves; Braga, José

2015-01-01

Little is known about the timing of modern human emergence and occupation in Eastern Eurasia. However a rapid migration out of Africa into Southeast Asia by at least 60 ka is supported by archaeological, paleogenetic and paleoanthropological data. Recent discoveries in Laos, a modern human cranium (TPL1) from Tam Pa Ling‘s cave, provided the first evidence for the presence of early modern humans in mainland Southeast Asia by 63-46 ka. In the current study, a complete human mandible representing a second individual, TPL 2, is described using discrete traits and geometric morphometrics with an emphasis on determining its population affinity. The TPL2 mandible has a chin and other discrete traits consistent with early modern humans, but it retains a robust lateral corpus and internal corporal morphology typical of archaic humans across the Old World. The mosaic morphology of TPL2 and the fully modern human morphology of TPL1 suggest that a large range of morphological variation was present in early modern human populations residing in the eastern Eurasia by MIS 3. PMID:25849125

Agonistic TAM-163 antibody targeting tyrosine kinase receptor-B: applying mechanistic modeling to enable preclinical to clinical translation and guide clinical trial design.

PubMed

Vugmeyster, Yulia; Rohde, Cynthia; Perreault, Mylene; Gimeno, Ruth E; Singh, Pratap

2013-01-01

TAM-163, an agonist monoclonal antibody targeting tyrosine receptor kinase-B (TrkB), is currently being investigated as a potential body weight modulatory agent in humans. To support the selection of the dose range for the first-in-human (FIH) trial of TAM-163, we conducted a mechanistic analysis of the pharmacokinetic (PK) and pharmacodynamic (PD) data (e.g., body weight gain) obtained in lean cynomolgus and obese rhesus monkeys following single doses ranging from 0.3 to 60 mg/kg. A target-mediated drug disposition (TMDD) model was used to describe the observed nonlinear PK and Emax approach was used to describe the observed dose-dependent PD effect. The TMDD model development was supported by the experimental determination of the binding affinity constant (9.4 nM) and internalization rate of the drug-target complex (2.08 h(-1)). These mechanistic analyses enabled linking of exposure, target (TrkB) coverage, and pharmacological activity (e.g., PD) in monkeys, and indicated that ≥ 38% target coverage (time-average) was required to achieve significant body weight gain in monkeys. Based on the scaling of the TMDD model from monkeys to humans and assuming similar relationship between the target coverage and pharmacological activity between monkey and humans, subcutaneous (SC) doses of 1 and 15 mg/kg in humans were projected to be the minimally and the fully pharmacologically active doses, respectively. Based on the minimal anticipated biological effect level (MABEL) approach for starting dose selection, the dose of 0.05 mg/kg (3 mg for a 60 kg human) SC was recommended as the starting dose for FIH trials, because at this dose level<10% target coverage was projected at Cmax (and all other time points). This study illustrates a rational mechanistic approach for the selection of FIH dose range for a therapeutic protein with a complex model of action.

Promiscuity and selectivity of small-molecule inhibitors across TAM receptor tyrosine kinases in pediatric leukemia.

PubMed

Liu, Mao-Hua; Chen, Shi-Bing; Yu, Juan; Liu, Cheng-Jun; Zhang, Xiao-Jing

2017-08-01

The TAM receptor tyrosine kinase family member Mer has been recognized as an attractive therapeutic target for pediatric leukemia. Beside Mer the family contains other two kinases, namely, Tyro3 and Axl, which are highly homologues with Mer and thus most existing small-molecule inhibitors show moderate or high promiscuity across the three kinases. Here, the structural basis and energetic property of selective binding of small-molecule inhibitors to the three kinases were investigated at molecular level. It is found that the selectivity is primarily determined by the size, shape and configuration of kinase's ATP-binding site; the Mer and Axl possess a small, closed active pocket as compared to the bulky, open pocket of Tyro3. The location and conformation of active-site residues of Mer and Axl are highly consistent, suggesting that small-molecule inhibitors generally have a low Mer-over-Axl selectivity and a high Mer-over-Tyro3 selectivity. We demonstrated that the difference in ATP binding potency to the three kinases is also responsible for inhibitor selectivity. We also found that the long-range interactions and allosteric effect arising from rest of the kinase's active site can indirectly influence inhibitor binding and selectivity. Copyright © 2017 Elsevier Inc. All rights reserved.

Exacerbation of innate immune response in mouse primary cultured sertoli cells caused by nanoparticulate TiO2 involves the TAM/TLR3 signal pathway.

PubMed

Wu, Nan; Hong, Fashui; Zhou, Yingjun; Wang, Yajing

2017-01-01

Sertoli cells provide appropriate mitogens, differentiation factors and sources of energy for developing germ cells throughout the lifetime of males, and protect these germ cells from harmful agents and from the host's own immune system. Therefore, reductions in the rate and quality of spermatogenesis caused by nanoparticulate titanium dioxide (nano-TiO 2 ) may be closely involved in the immunoregulation of Sertoli cells. However, the underlying mechanism of this response is still unclear. To address this issue, we used mouse primary cultured Sertoli cells to examine the toxic effects of nano-TiO 2 via alterations in morphology, cell viability, and activation of the TAM/TLR3 signal pathway. The results demonstrated that nano-TiO 2 could cross the cytomembrane into the cytoplasm or nucleus, decrease Sertoli cell viability, damage morphology (such as elongated fusiform, cellular and nuclear shrinkage) and induce the expression of various immune mediators and inflammatory cytokines, including TLR3(+0.31-fold to +0.81-fold), IL-lβ(+0.33-fold to +5.0-fold), NF-κB(+0.22-fold to +3.65-fold), IL-6(+0.47-fold to +3.53-fold), TNF-α(+0.14-fold to +2.44-fold), IFN-α(+0.17-fold to +2.27-fold), and IFN-β(+0.09-fold to +2.29-fold), and suppress the expression of Tyro3(-9.33% to -61.93%), Axl(-19.03% to -60.67%), Mer(-8.04% to -59.16%), and IκB(-34.35% to -86.59%) in primary cultured Sertoli cells. These results suggest that testicular innate immune responses to pathogens caused by nano-TiO 2 may be involved in the regulatory mechanisms of TAM/TLR3 signaling in testicular Sertoli cells. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 198-208, 2017. © 2016 Wiley Periodicals, Inc.

TUBERCULOSIS COMO ENFERMEDAD OCUPACIONAL

PubMed Central

Mendoza-Ticona, Alberto

2014-01-01

Existe evidencia suficiente para declarar a la tuberculosis como enfermedad ocupacional en diversos profesionales especialmente entre los trabajadores de salud. En el Perú están normados y reglamentados los derechos laborales inherentes a la tuberculosis como enfermedad ocupacional, como la cobertura por discapacidad temporal o permanente. Sin embargo, estos derechos aún no han sido suficientemente socializados. En este trabajo se presenta información sobre el riesgo de adquirir tuberculosis en el lugar de trabajo, se revisan las evidencias para declarar a la tuberculosis como enfermedad ocupacional en trabajadores de salud y se presenta la legislación peruana vigente al respecto. PMID:22858771

Funciones de partición atómicas: Fuentes confiables de datos

NASA Astrophysics Data System (ADS)

Merlo, D. C.; Milone, L. A.

Se llevó a cabo una revisión minuciosa del cálculo de funciones de partición atómicas de átomos livianos, en estados neutro y una vez ionizados, partiendo del Hidrógeno y llegando al Sodio, incluyendo también al K I y el Ca II. Al respecto, se realizó una investigación exhaustiva de referencias bibliográficas existentes hasta el presente, las cuales fueron cotejadas con cálculos propios llevados a cabo mediante el procedimiento de depresión del contínuo (0.001 a 0.5 eV). Nuestros resultados muestran un muy buen acuerdo con las expresiones interpolatorias de Traving et al (1966), al presente, la referencia más completa en cuanto a especies atómicas consideradas. Puntualizamos, además, ciertas deficiencias de estas relaciones de ajuste para decrementos del potencial de ionización altos (Δ χ >= 0.5) eV).

Exploring the role of ethnic media and the community readiness to combat stigma attached to mental illness among Vietnamese immigrants: the pilot project Tam An (Inner Peace in Vietnamese).

PubMed

Han, Meekyung; Cao, Lien; Anton, Karen

2015-01-01

Vietnamese Americans are at high risk for developing mental health disorders due to multiple risk factors such as trauma and acculturative stress. However, the utilization of mental health services has been low. The pilot project Tam An was implemented to raise mental health awareness by engaging community resources in the Vietnamese population. Informed by the Community Readiness Model and through local ethnic media sources, messages to destigmatize mental health and promote the willingness to initiate mental health treatment were presented. Using an exploratory perspective, findings from focus group data suggest that the project improved the community's stage of readiness.

Development of a trans-admittance mammography (TAM) using 60×60 electrode array

NASA Astrophysics Data System (ADS)

Zhao, Mingkang; Liu, Qin; In Oh, Tong; Woo, Eung Je; Seo, Jin Keun

2010-04-01

We have developed a trans-admittance mammography (TAM) system as a supplementary or alternative method of the X-ray mammography to diagnose the breast cancer. Mechanical structure of the system is similar to the X-ray mammography with the breast placed between two plates. The pair of plates is movable to accommodate breasts with different sizes and rotatable to provide multiple images with different projection angles. Without using ionizing radiation, it acquires a projection image of tissue admittivity values. One plate is a flat solid electrode where we apply a constant sinusoidal voltage with a variable frequency. The other is equipped with 60×60 array of current-sensing electrodes, of which potentials are kept at the signal reference level. The electrode array is connected to six switching modules and each module routes current signals from 600 electrodes to two ammeter modules. Each ammeter module includes six channels of ammeters and each one of them comprises an independent current-to-voltage converter, voltage amplifier, ADC and digital phase-sensitive demodulator. Each ammeter sequentially measures exit currents from 50 electrodes chosen by the corresponding switching module. An FPGA controls six ammeters to collect real- and imaginary-parts of trans-admittance data from 300 electrodes. A separate FPGA arbitrates data and command exchanges between a DSP-based main controller and ammeter modules. It also generates a sinusoidal voltage signal to be applied to the breast. All the 3600 complex current data from 12 ammeter modules are transferred to the main controller, which is interfaced to a PC through an isolated USB. The system is provided with a program to display real- and imaginary-parts of measured trans-admittance maps. The measured maps at multiple frequencies are incorporated into a frequency-difference anomaly detection algorithm. In this paper, we describe the design and construction of the system.

Consumers' acceptance of medicinal herbs: An application of the technology acceptance model (TAM).

PubMed

Jokar, Nargesh Khatun; Noorhosseini, Seyyed Ali; Allahyari, Mohammad Sadegh; Damalas, Christos A

2017-07-31

The shift in consumers' preferences from synthetic to 'natural' products has led to a resurgence of interest in medicinal plants, particularly in developing countries. However, research data about consumers' preferences for particular products is hard to find. The main objective of this study was to contribute to the general understanding of consumers' intention for selecting medicinal herbs for consumption. Factors underpinning consumers' acceptance of medicinal herbs were studied with the technology acceptance model (TAM) in Rasht City of Iran using a structured questionnaire. Most respondents had low to moderate familiarity with consumption of medicinal herbs. However, about half of the respondents (47.5%) showed a high level of acceptance of medicinal herbs. Herbs like spearmint (Mentha spicata L.), spinach (Spinacia oleracea L.), basil (Ocimum basilicum L.), Damask rose (Rosa × damascena Herrm.), saffron (Crocus sativus L.), cinnamon (Cinnamomum verum J.Presl), flixweed [Descurainia sophia (L.) Webb ex Prantl], red feathers (Echium amoenum Fisch. & C.A.Mey.), and green tea [Camellia sinensis (L.) Kuntze] had the highest consumption rate among the majority (over 75%) of citizens of Rasht. The highest rate of perceived usefulness of medicinal herbs was related to their perceived role in healing diseases. The variable of importance of use of medicinal herbs had the strongest direct effect and the variables of perceived usefulness and attitude towards use had the second and third strongest direct effect on the acceptance of medicinal herbs' use at p < 0.01. Findings provide a useful evaluation of the acceptance of medicinal herbs and may serve as a benchmark for future research and evaluation concerning the use of medicinal herbs over time. For plant producers, more effective and targeted crop development should be encouraged, whereas for retailers better marketing and delivery strategies should be sought. Copyright © 2017 Elsevier Ireland Ltd. All rights

Regulación del flujo sanguíneo uterino. II. Funciones de estrógeno y receptores estrogénicos α/β en acciones genómicas y no-genómicas del endotelio uterino *

PubMed Central

Mayra, Pastore R.; Rosalina, Villalón L.; López, Gladys; Iruretagoyena, Jesús; Magness, Ronald

2015-01-01

Resumen El embarazo está marcado por cambios y adaptaciones cardiovasculares que son importantes para el crecimiento y mantenimiento de la placenta y el feto. Durante este periodo, las adaptaciones vasculares uterinas manifiestan cambios clasificados como de corto o largo plazo los cuales están relacionados con adaptaciones vasodilatadoras, angiogénicas o de remodelación. El estrógeno y los receptores estrogénicos clásicos (REs), RE-α y RE-β, han demostrado ser parcialmente responsables por facilitar el incremento dramático en el fluido sanguíneo uterino necesario durante el embarazo. En ésta revisión bibliográfica se discuten la base estructural para la diversidad y selectividad funcional de los REs por el estrógeno, el papel de los REs sobre los efectos genómicos y no-genómicos en células endoteliales de arterias uterinas (CEAU). Estos temas integran el conocimiento científico sobre la regulación molecular de CEAU para mantener el incremento fisiológico en la perfusión útero-placentaria observada durante un embarazo normal. PMID:26113751

Formation of tamoxifen-DNA adducts in multiple organs of adult female cynomolgus monkeys dosed with tamoxifen for 30 days.

PubMed

Schild, Laura J; Divi, Rao L; Beland, Frederick A; Churchwell, Mona I; Doerge, Daniel R; Gamboa da Costa, Gonçalo; Marques, M Matilde; Poirier, Miriam C

2003-09-15

The use of the antiestrogen tamoxifen (TAM) is associated with an increase in endometrial cancer. TAM-induced endometrial carcinogenesis may proceed through a genotoxin-mediated pathway, although the detection of endometrial TAM-DNA adducts in exposed women is still controversial. In this study, a monkey model has been used to investigate the question of TAM-DNA adduct formation in primates. Two methods have been used to determine TAM-DNA adducts: a TAM-DNA chemiluminescence immunoassay (TAM-DNA CIA), using an antiserum that has specificity for (E)-alpha-(deoxyguanosin-N(2)-yl)-tamoxifen (dG-TAM) and (E)-alpha-(deoxyguanosin-N(2)-yl)-N-desmethyltamoxifen (dG-desmethyl-TAM) and electrospray ionization tandem mass spectrometry (ES-MS/MS) coupled with on-line sample preparation and high-performance liquid chromatography (HPLC). Mature (19 year old) cynomolgus monkeys were given either vehicle control (n = 1) or TAM (n = 3) twice daily for a total dose of 2 mg of TAM/kg body weight (bw)/day for 30 days by naso-gastric intubation. Tissues were harvested, and DNA was isolated from uterus, ovary, liver, brain cortex, and kidney. By TAM-DNA CIA, values for uterine TAM-DNA adducts in two monkeys were 0.9 and 1.7 adducts/10(8) nucleotides, whereas values for ovarian TAM-DNA adducts in the same animals were 0.4 and 0.5 adducts/10(8) nucleotides. Liver, brain cortex, and kidney DNA samples from the three exposed monkeys had TAM-DNA levels of 2.1-4.2 adducts/10(8) nucleotides, 0.4-5.0 adducts/10(8) nucleotides, and 0.7-2.1 adducts/10(8) nucleotides, respectively. By HPLC-ES-MS/MS, the levels of TAM-DNA adducts detected in all tissues were comparable with those observed by TAM-DNA CIA. Thus, values for uterine TAM-DNA adducts ranged from 0.5 to 1.4 adducts/10(8) nucleotides, whereas values for ovarian TAM-DNA adducts, measurable in two monkeys, were 0.2 and 0.3 adducts/10(8) nucleotides. Liver DNA contained the highest TAM-DNA adduct levels (7.0-11.1 adducts/10(8) nucleotides

Tamoxifen-DNA adduct formation in monkey and human reproductive organs.

PubMed

Hernandez-Ramon, Elena E; Sandoval, Nicole A; John, Kaarthik; Cline, J Mark; Wood, Charles E; Woodward, Ruth A; Poirier, Miriam C

2014-05-01

The estrogen analog tamoxifen (TAM), used for adjuvant therapy of breast cancer, induces endometrial and uterine tumors in breast cancer patients. Proliferation stimulus of the uterine endometrium is likely involved in tumor induction, but genotoxicity may also play a role. Formation of TAM-DNA adducts in human tissues has been reported but remains controversial. To address this issue, we examined TAM-DNA adducts in uteri from two species of monkeys, Erythrocebus patas (patas) and Macaca fascicularis (macaque), and in human endometrium and myometrium. Monkeys were given 3-4 months of chronic TAM dosing scaled to be equivalent to the daily human dose. In the uteri, livers and brains from the patas (n = 3), and endometrium from the macaques (n = 4), TAM-DNA adducts were measurable by TAM-DNA chemiluminescence immunoassay. Average TAM-DNA adduct values for the patas uteri (23 adducts/10(8) nucleotides) were similar to those found in endometrium of the macaques (19 adducts/10(8) nucleotides). Endometrium of macaques exposed to both TAM and low-dose estradiol (n = 5) averaged 34 adducts/10(8) nucleotides. To examine TAM-DNA persistence in the patas, females (n = 3) were exposed to TAM for 3 months and to no drug for an additional month, resulting in low or non-detectable TAM-DNA in livers and uteri. Human endometrial and myometrial samples from women receiving (n = 8) and not receiving (n = 8) TAM therapy were also evaluated. Women receiving TAM therapy averaged 10.3 TAM-DNA adducts/10(8) nucleotides, whereas unexposed women showed no detectable TAM-DNA. The data indicate that genotoxicity, in addition to estrogen agonist effects, may contribute to TAM-induced human endometrial cancer.

Hepatic DNA adduct dosimetry in rats fed tamoxifen: a comparison of methods.

PubMed

Schild, Laura J; Phillips, David H; Osborne, Martin R; Hewer, Alan; Beland, Frederick A; Churchwell, Mona I; Brown, Karen; Gaskell, Margaret; Wright, Elizabeth; Poirier, Miriam C

2005-03-01

Liver homogenates from rats fed tamoxifen (TAM) in the diet were shared among four different laboratories. TAM-DNA adducts were assayed by high pressure liquid chromatography-electrospray tandem mass spectrometry (HPLC-ES-MS/MS), TAM-DNA chemiluminescence immunoassay (TAM-DNA CIA), and (32)P-postlabeling with either thin layer ((32)P-P-TLC) or liquid chromatography ((32)P-P-HPLC) separation. In the first study, rats were fed a diet containing 500 p.p.m. TAM for 2 months, and the values for measurements of the (E)-alpha-(deoxyguanosin-N(2)-yl)-tamoxifen (dG-N(2)-TAM) adduct in replicate rat livers varied by 3.5-fold when quantified using 'in house' TAM-DNA standards, or other approaches where appropriate. In the second study, rats were fed 0, 50, 250 or 500 p.p.m. TAM for 2 months, and TAM-DNA values were quantified using both 'in house' approaches as well as a newly synthesized [N-methyl-(3)H]TAM-DNA standard that was shared among all the participating groups. In the second study, the total TAM-DNA adduct values varied by 2-fold, while values for the dG-N(2)-TAM varied by 2.5-fold. Ratios of dG-N(2)-TAM:(E)-alpha-(deoxyguanosin-N(2)-yl)-N-desmethyltamoxifen (dG-N(2)-N-desmethyl-TAM) in the second study were approximately 1:1 over the range of doses examined. The study demonstrated a remarkably good agreement for TAM-DNA adduct measurements among the diverse methods employed.

Physicochemical, Antioxidant, and Cytotoxic Properties of Xao Tam Phan (Paramignya trimera) Root Extract and Its Fractions.

PubMed

Nguyen, Van Tang; Sakoff, Jennette A; Scarlett, Christopher J

2017-04-01

Xao tam phan (Paramignya trimera (Oliv.) Guillaum) has been used as a medicinal plant for cancer prevention and treatment in recent years. The objective of this study was to determine the physicochemical, antioxidant, and cytotoxic properties of crude P. trimera root (PTR) extract and its fractions using MeOH as a solvent and microwave-assisted extraction as an advanced technique for preparation of the PTR extract. The results showed that the PTR extract had high contents of saponins, phenolics, flavonoids, and proanthocyanidins (7731.05 mg escin equiv. (EE), 238.13 mg gallic acid equiv. (GAE), 81.49 mg rutin equiv., and 58.08 mg catechin equiv. (CE)/g dried extract, resp.). Antioxidant activity of PTR extract was significantly higher (P < 0.05) than those of four its fractions and ostruthin, a key bioactive compound in the P. trimera, while potent cytotoxic capacity of PTR extract on various cancer cell lines in terms of MiaPaCa-2 (pancreas), HT29 (colon), A2780 (ovarian), H460 (lung), A431 (skin), Du145 (prostate), BE2-C (neuroblastoma), MCF-7 (breast), MCF-10A (normal breast), and U87, SJ-G2, SMA (glioblastoma) was observed with GI 50 values ranging from 15 to 32 μg/ml. Cytotoxic potential on pancreatic cancer cells of PTR extract (100 - 200 μg/ml) was significantly higher (P < 0.05) than those of its four fractions (50 μg/ml), ostruthin (20 μg/ml) and gemcitabine (50 nm), and being comparable to a saponin-enriched extract from quillajia bark, a commercial product. Based on the results achieved, we can conclude that the PTR extract is a potential source for application of in the nutraceutical, medical, and pharmaceutical industries. © 2017 Wiley-VHCA AG, Zurich, Switzerland.

Differential effect of EGFR inhibitors on tamoxifen-resistant breast cancer cells.

PubMed

Kim, Sangmin; Lee, Jeongmin; Oh, Soo Jin; Nam, Seok Jin; Lee, Jeong Eon

2015-09-01

Although tamoxifen is the most common and effective therapy for treatment of estrogen receptor-α (ER-α) breast cancer patients, resistance of endocrine therapy occurs, either de novo or acquired during therapy. Here, we investigated the clinical value of epidermal growth factor receptor (EGFR) in tamoxifen-resistant (TamR) patients and the differential effect of EGFR inhibitors, neratinib and gefitinib, on TamR breast cancer cell model. The morphology of TamR MCF7 cells showed mesenchymal phenotypes and did not induce cell death by tamoxifen treatment compared with tamoxifen‑sensitive (TamS) MCF7 cells. In addition, mesenchymal marker proteins, including N-cadherin (N-cad), fibronectin (FN), and Slug, significantly increased in TamR cells. In contrast, ER-α and E-cadherin (E-cad) were greatly decreased. We also found that the levels of EGFR and HER2 expression were increased in TamR cells. Furthermore, we observed that EGFR expression was directly involved with poor prognosis of tamoxifen-treated breast cancer patients using the GSE1378 date set. Thus, we treated TamR and TamS cells with EGFR inhibitors, neratinib and gefitinib, respectively. Interestingly, neratinib induced apoptotic cell death of TamR but not gefitinib. Cleaved PARP-1 expression was also increased by neratinib treatment in TamR cells. Therefore, we suggest that neratinib may be a potential therapeutic drug for treating TamR breast cancer.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Prather, Paul L.; FrancisDevaraj, FeAna; Dates, Centdrika R.

Highlights: •Tamoxifen produces cytotoxicity via estrogen-receptor (ER) independent mechanisms. •Tamoxifen binds to CB1 and CB2 cannabinoid receptors and acts as an inverse agonist. •CB1 and CB2 receptors are novel molecular targets for Tamoxifen. •ER-independent effects for Tamoxifen may be mediated via CB1 and/or CB2 receptors. -- Abstract: Tamoxifen (Tam) is classified as a selective estrogen receptor modulator (SERM) and is used for treatment of patients with ER-positive breast cancer. However, it has been shown that Tam and its cytochrome P450-generated metabolite 4-hydroxy-Tam (4OH-Tam) also exhibit cytotoxic effects in ER-negative breast cancer cells. These observations suggest that Tam and 4OH-Tam canmore » produce cytotoxicity via estrogen receptor (ER)-independent mechanism(s) of action. The molecular targets responsible for the ER-independent effects of Tam and its derivatives are poorly understood. Interestingly, similar to Tam and 4OH-Tam, cannabinoids have also been shown to exhibit anti-proliferative and apoptotic effects in ER-negative breast cancer cells, and estrogen can regulate expression levels of cannabinoid receptors (CBRs). Therefore, this study investigated whether CBRs might serve as novel molecular targets for Tam and 4OH-Tam. We report that both compounds bind to CB1 and CB2Rs with moderate affinity (0.9–3 μM). Furthermore, Tam and 4OH-Tam exhibit inverse activity at CB1 and CB2Rs in membrane preparations, reducing basal G-protein activity. Tam and 4OH-Tam also act as CB1/CB2R-inverse agonists to regulate the downstream intracellular effector adenylyl cyclase in intact cells, producing concentration-dependent increases in intracellular cAMP. These results suggest that CBRs are molecular targets for Tam and 4OH-Tam and may contribute to the ER-independent cytotoxic effects reported for these drugs. Importantly, these findings also indicate that Tam and 4OH-Tam might be used as structural scaffolds for development of novel

Effects of flaxseed lignan and oil on bone health of breast-tumor-bearing mice treated with or without tamoxifen.

PubMed

Chen, Jianmin; Saggar, Jasdeep K; Ward, Wendy E; Thompson, Lilian U

2011-01-01

Previous studies showed that flaxseed lignan (secoisolariciresinol diglucoside, SDG) and oil (FO) inhibit established breast tumor growth in athymic mice with or without tamoxifen (TAM) treatment. TAM was found to increase bone mineral content (BMC) and density (BMD) in breast cancer patients. It is not known whether SDG or FO alone or combined with TAM affects bone health. Hence, the effects of SDG and FO, alone or in combination, on BMC, BMD, and biomechanical bone strength in ovariectomized athymic mice with established human breast tumors (MCF-7) treated with or without TAM were studied. In a factorial design, mice were divided into four non-TAM and four TAM groups. Each group consisted of mice fed a basal diet (BD), SDG (1 g/kg), FO (38.5 g/kg) or SDG + FO (combination) diets. The TAM group had TAM implants that provide a 5-mg TAM dose released over 60 d. TAM exerted an overall significant effect in increasing BMC, BMD, and biomechanical strength in femurs and lumbar vertebra. Without TAM treatment, SDG produced significant lower femur BMD (6%) while FO produced lower vertebrae BMC (8%) and BMD (6%). With TAM treatment, SDG and FO did not exert an effect on BMC and BMD at the femur or vertebra. SDG and FO produced no marked effect on biomechanical bone strength with or without TAM treatment. In conclusion, FS components did not significantly attenuate the positive effects on bone induced by TAM in this model system, indicating no apparent adverse effects on bone health.

Anti-tumour strategies aiming to target tumour-associated macrophages

PubMed Central

Tang, Xiaoqiang; Mo, Chunfen; Wang, Yongsheng; Wei, Dandan; Xiao, Hengyi

2013-01-01

Tumour-associated macrophages (TAMs) represent a predominant population of inflammatory cells that present in solid tumours. TAMs are mostly characterized as alternatively activated M2-like macrophages and are known to orchestrate nearly all stages of tumour progression. Experimental investigations indicate that TAMs contribute to drug-resistance and radio-protective effects, and clinical evidence shows that an elevated number of TAMs and their M2 profile are correlated with therapy failure and poor prognosis in cancer patients. Recently, many studies on TAM-targeted strategies have made significant progress and some pilot works have achieved encouraging results. Among these, connections between some anti-tumour drugs and their influence on TAMs have been suggested. In this review, we will summarize recent advances in TAM-targeted strategies for tumour therapy. Based on the proposed mechanisms, those strategies are grouped into four categories: (i) inhibiting macrophage recruitment; (ii) suppressing TAM survival; (iii) enhancing M1-like tumoricidal activity of TAMs; (iv) blocking M2-like tumour-promoting activity of TAMs. It is desired that further attention be drawn to this research field and more effort be made to promote TAM-targeted tumour therapy. PMID:23113570

Tumor-Associated Macrophages Associate with Cerebrospinal Fluid Interleukin-10 and Survival in Primary Central Nervous System Lymphoma (PCNSL).

PubMed

Sasayama, Takashi; Tanaka, Kazuhiro; Mizowaki, Takashi; Nagashima, Hiroaki; Nakamizo, Satoshi; Tanaka, Hirotomo; Nishihara, Masamitsu; Mizukawa, Katsu; Hirose, Takanori; Itoh, Tomoo; Kohmura, Eiji

2016-07-01

Increased tumor-associated macrophages (TAMs) have been reported to be associated with poor prognosis in various tumors; however, the importance of TAMs in primary central nervous system lymphoma (PCNSL) has not been clarified. In 47 patients with PCNSL who were treated with high-dose methotrexate (MTX) and radiotherapy, the relationships between the infiltration levels of TAMs and the clinicopathological parameters were analyzed. Univariate analysis of the Cox proportional hazards model using continuous scales revealed that increased CD68 positive (+) TAMs was significantly associated with inferior progression-free survival (PFS) (P = 0.04), and trends were observed for the increased CD163(+)  TAMs and having shorter PFS (P = 0.05). However, increased TAMs were not associated with overall survival. Because TAMs are known to produce various cytokines, we examined the relationships between cerebrospinal fluid (CSF) cytokines and TAMs. CSF interleukin-6 (IL-6) and soluble IL-2 receptor were not correlated with the infiltration rate of TAMs; however, CSF IL-10 level was correlated with infiltration levels of CD68 and CD163(+)  TAMs. We also confirmed the expression of IL-10 in CD68(+)  and CD163(+)  TAMs by double immunostaining analysis. Our results indicate that a high level of IL-10 in CSF may be positively associated with the infiltration level of TAMs in PCNSLs. © 2015 International Society of Neuropathology.

Novel Shape-Stabilized Phase Change Materials Composed of Polyethylene Glycol/Nonsurfactant-Templated Mesoporous Silica: Preparation and Thermal Properties

NASA Astrophysics Data System (ADS)

Chen, Yan; Zhu, Yingying; Wang, Jinbao; Lv, Mengjiao; Zhang, Xiongjie; Gao, Junkai; Zhang, Zijun; Lei, Hao

2017-12-01

A novel shape-stabilized phase change material (PEG/TAMS), fabricated using tannic acid-templated mesoporous silica (TAMS) as a support for polyethylene glycol, was developed for thermal energy storage. The method used to synthesize TAMS was simple, cost effective, environmentally friendly, and free of surfactant. The characterization results indicated that PEG was physically absorbed to TAMS and that TAMS had no influence on the crystal structure of PEG. According to the TGA thermograms, PEG/TAMS has excellent thermal stability and can be applied over a wide temperature range. Additionally, the differential scanning calorimetry results suggested that PEG/TAMS has good thermal properties and that its fusion and solidification enthalpies reached 114.7 J/g and 102.4 J/g, respectively. The results indicated that PEG/TAMS has great potential for practical applications.

Direct, Differential Effects of Tamoxifen, 4-Hydroxytamoxifen, and Raloxifene on Cardiac Myocyte Contractility and Calcium Handling

PubMed Central

Asp, Michelle L.; Martindale, Joshua J.; Metzger, Joseph M.

2013-01-01

Tamoxifen (Tam), a selective estrogen receptor modulator, is in wide clinical use for the treatment and prevention of breast cancer. High Tam doses have been used for treatment of gliomas and cancers with multiple drug resistance, but long QT Syndrome is a side effect. Tam is also used experimentally in mice for inducible gene knockout in numerous tissues, including heart; however, the potential direct effects of Tam on cardiac myocyte mechanical function are not known. The goal of this study was to determine the direct, acute effects of Tam, its active metabolite 4-hydroxytamoxifen (4OHT), and related drug raloxifene (Ral) on isolated rat cardiac myocyte mechanical function and calcium handling. Tam decreased contraction amplitude, slowed relaxation, and decreased Ca2+ transient amplitude. Effects were primarily observed at 5 and 10 μM Tam, which is relevant for high dose Tam treatment in cancer patients as well as Tam-mediated gene excision in mice. Myocytes treated with 4OHT responded similarly to Tam-treated cells with regard to both contractility and calcium handling, suggesting an estrogen-receptor independent mechanism is responsible for the effects. In contrast, Ral increased contraction and Ca2+ transient amplitudes. At 10 μM, all drugs had a time-dependent effect to abolish cellular contraction. In conclusion, Tam, 4OHT, and Ral adversely and differentially alter cardiac myocyte contractility and Ca2+ handling. These findings have important implications for understanding the Tam-induced cardiomyopathy in gene excision studies and may be important for understanding effects on cardiac performance in patients undergoing high-dose Tam therapy. PMID:24205315

Tumor-associated macrophages induce the expression of FOXQ1 to promote epithelial-mesenchymal transition and metastasis in gastric cancer cells.

PubMed

Guo, Jian; Yan, Yan; Yan, Yu; Guo, Qinyue; Zhang, Mingxin; Zhang, Jia; Goltzman, David

2017-10-01

Gastric cancer (GC) is one of the most common malignancies, and is the second leading cause of cancer-related deaths worldwide. Macrophages infiltrated in the tumor microenvironment (TME) called tumor-associated macrophages (TAMs) are key orchestrators in TME. In GC, it has been reported that infiltration of TAMs is associated with epithelial-mesenchymal transition (EMT)-related proteins in human GC tissues, but the exactly mechanism has not been clarified. In the present study, we aimed to elucidate the underlying mechanism of TAMs on GC cells. THP-1 cells were used to investigate the effects of TAMs on GC cells. The effects of invasion and migration induced by coculture with TAMs were investigated by Transwell invasion and wound healing assays. The expression of EMT-related genes and forkhead box Q1 (FOXQ1) were examined in MKN45 and MKN74 cells after being co-cultured with TAMs. The density of TAMs and the expression of FOXQ1 were analyzed by immunohistochemistry in GC tissues. Our results revealed that, co-culture with TAMs promoted the invasion and migration of GC cells. Co-culture with TAMs induced EMT in GC cells. FOXQ1 is essential for TAM-induced EMT and metastasis in GC cells. Furthermore, silencing of FOXQ1 blocked the effect of TAM-enhanced EMT and metastasis of GC cells. High expression of CD68 was correlated with positive FOXQ1 expression (r=0.613; P<0.001) in clinical GC samples. Our data provided evidence that TAMs promote EMT, invasion and migration of GC cells via FOXQ1. Therefore, the TAM/FOXQ1 axis may represent a novel target for GC cells.

Up-regulation of HOXB cluster genes are epigenetically regulated in tamoxifen-resistant MCF7 breast cancer cells.

PubMed

Yang, Seoyeon; Lee, Ji-Yeon; Hur, Ho; Oh, Ji Hoon; Kim, Myoung Hee

2018-05-28

Tamoxifen (TAM) is commonly used to treat estrogen receptor (ER)-positive breast cancer. Despite the remarkable benefits, resistance to TAM presents a serious therapeutic challenge. Since several HOX transcription factors have been proposed as strong candidates in the development of resistance to TAM therapy in breast cancer, we generated an in vitro model of acquired TAM resistance using ER-positive MCF7 breast cancer cells (MCF7-TAMR), and analyzed the expression pattern and epigenetic states of HOX genes. HOXB cluster genes were uniquely up-regulated in MCF7-TAMR cells. Survival analysis of in slico data showed the correlation of high expression of HOXB genes with poor response to TAM in ER-positive breast cancer patients treated with TAM. Gain- and loss-of-function experiments showed that the overexpression of multi HOXB genes in MCF7 renders cancer cells more resistant to TAM, whereas the knockdown restores TAM sensitivity. Furthermore, activation of HOXB genes in MCF7-TAMR was associated with histone modifications, particularly the gain of H3K9ac. These findings imply that the activation of HOXB genes mediate the development of TAM resistance, and represent a target for development of new strategies to prevent or reverse TAM resistance.

Tamoxifen metabolite isomer separation and quantification by liquid chromatography-tandem mass spectrometry.

PubMed

Jaremko, Malgorzata; Kasai, Yumi; Barginear, Myra F; Raptis, George; Desnick, Robert J; Yu, Chunli

2010-12-15

Tamoxifen (Tam), the antiestrogen used to treat estrogen receptor-positive breast cancer is a pro-drug that is converted to its major active metabolites, endoxifen and 4-hydroxy-tamoxifen (4-OH-Tam) by various biotransformation enzymes of which cytochrome P450-2D6 (CYP2D6) is key. The usual Tam dose is 20 mg daily; however, the plasma active metabolite concentrations vary due to common genetic variants encoding the biotransformation enzymes and environmental factors (e.g., concomitant drugs) that inhibit these enzymes. Effective treatment depends on adequate Tam conversion to its active isomers. To monitor metabolite plasma levels, a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to separate and quantitate Tam, N-desmethyl-tamoxifen (ND-Tam), and tamoxifen-N-oxide (Tam-N-oxide), and the E, Z, and Z' isomers of endoxifen and 4-OH-Tam. Known standards were used to identify each metabolite/isomer. Quantitation of these metabolites in plasma was linear from 0.6 to 2000 nM. Intra- and inter-assay reproducibilities were 0.2-8.4% and 0.6-6.3%, respectively. Accuracy determined by spike experiments with known standards was 86-103%. Endoxifen, 4-OH-Tam, and their isomers were stable in fresh frozen plasma for ≥6 months. This method provides the first sensitive, specific, accurate, and reproducible quantitation of Tam and its metabolite isomers for monitoring Tam-treated breast cancer patients.

Measurement of the $Z$ transverse momentum distribution in $$\\bar{p} p \\to Z \\to e^+ e-$$ events with the D0 detector

DOE Office of Scientific and Technical Information (OSTI.GOV)

Magana-Mendoza, Leonel

1997-10-01

La medicion de la distribucion de momento longitudinal en eventos pmore » $$\\bar{p}$$ → Z → e +e -constituye una prueba para las parametrizaciones de las funciones de distribucion partonica, al mismo tiempo que proporciona un nuevo conjunto de datos que pueden ser empleados como parametros de entrada en los ajustes globales encaminados a mejorar dichas parametrizaciones.« less

Infiltration of tumour-associated macrophages in prostate biopsy specimens is predictive of disease progression after hormonal therapy for prostate cancer.

PubMed

Nonomura, Norio; Takayama, Hitoshi; Nakayama, Masashi; Nakai, Yasutomo; Kawashima, Atsunari; Mukai, Masatoshi; Nagahara, Akira; Aozasa, Katsuyuki; Tsujimura, Akira

2011-06-01

• To evaluate tumour-associated macrophage (TAM) infiltration in prostate biopsy specimens as a possible prognostic factor for prostate cancer (PCa) after hormonal therapy. • Immunostaining of TAMs in prostate biopsy specimens was performed using a monoclonal antibody CD68 for 71 patients having PCa treated with hormonal therapy. • Six microscopic (×400) fields around the cancer foci were selected for TAM counting. • The median value of serum prostate-specific antigen (PSA) was 50.1 ng/mL, and the median TAM count was 22. • Recurrence-free survival was significantly better in patients with fewer TAMs (<22) than in those with higher numbers of TAMs (≥22) (P < 0.001). • TAM count was higher in those with higher serum PSA (PSA), higher Gleason score, clinical T stage or those with PSA failure. Cox multivariate analysis showed that TAM count is one of the prognostic factors for PCa treated by hormonal therapy (P < 0.0001). • TAM infiltration in prostate needle biopsy specimens is a useful predictive factor for PSA failure or progression of PCa after hormonal therapy. © 2010 THE AUTHORS. BJU INTERNATIONAL © 2010 BJU INTERNATIONAL.

Optimizing tamoxifen-inducible Cre/loxp system to reduce tamoxifen effect on bone turnover in long bones of young mice.

PubMed

Zhong, Zhendong A; Sun, Weihua; Chen, Haiyan; Zhang, Hongliang; Lay, Yu-An E; Lane, Nancy E; Yao, Wei

2015-12-01

For tamoxifen-dependent Cre recombinase, also known as CreER recombinase, tamoxifen (TAM) is used to activate the Cre to generate time- and tissue-specific mouse mutants. TAM is a potent CreER system inducer; however, TAM is also an active selective estrogen receptor modulator (SERM) that can influence bone homeostasis. The purpose of this study was to optimize the TAM dose for Cre recombinase activation while minimizing the effects of TAM on bone turnover in young growing mice. To evaluate the effects of TAM on bone turnover and bone mass, 1-month-old wild-type male and female mice were intraperitoneally injected with TAM at 0, 1, 10 or 100mg/kg/day for four consecutive days, or 100, 300 mg/kg/day for one day. The distal femurs were analyzed one month after the last TAM injection by microCT, mechanical test, and surface-based bone histomorphometry. Similar doses of TAM were used in Col1 (2.3 kb)-CreERT2; mT/mG reporter male mice to evaluate the dose-dependent efficacy of Cre-ER activation in bone tissue. A TAM dose of 100 mg/kg × 4 days significantly increased trabecular bone volume/total volume (BV/TV) of the distal femur, femur length, bone strength, and serum bone turnover markers compared to the 0mg control group. In contrast, TAM doses ≤ 10 mg/kg did not significantly change any of these parameters compared to the 0mg group, although a higher bone strength was observed in the 10mg group. Surface-based histomorphometry revealed that the 100mg/kg dose of TAM dose significantly increased trabecular bone formation and decreased periosteal bone formation at 1-week post-TAM treatment. Using the reporter mouse model Col1-CreERT2; mT/mG, we found that 10mg/kg TAM induced Col1-CreERT2 activity in bone at a comparable level to the 100mg/kg dose. TAM treatment at 100mg/kg/day × 4 days significantly affects bone homeostasis, resulting in an anabolic bone effect on trabecular bone in 1-month-old male mice. However, a lower dose of TAM at 10 mg/kg/day × 4 days can

Tumor-associated macrophages drive spheroid formation during early transcoelomic metastasis of ovarian cancer

PubMed Central

Yin, Mingzhu; Li, Xia; Tan, Shu; Zhou, Huanjiao Jenny; Ji, Weidong; Bellone, Stefania; Xu, Xiaocao; Zhang, Haifeng; Santin, Alessandro D.; Lou, Ge

2016-01-01

Tumor-associated macrophages (TAMs) can influence ovarian cancer growth, migration, and metastasis, but the detailed mechanisms underlying ovarian cancer metastasis remain unclear. Here, we have shown a strong correlation between TAM-associated spheroids and the clinical pathology of ovarian cancer. Further, we have determined that TAMs promote spheroid formation and tumor growth at early stages of transcoelomic metastasis in an established mouse model for epithelial ovarian cancer. M2 macrophage–like TAMs were localized in the center of spheroids and secreted EGF, which upregulated αMβ2 integrin on TAMs and ICAM-1 on tumor cells to promote association between tumor cells and TAM. Moreover, EGF secreted by TAMs activated EGFR on tumor cells, which in turn upregulated VEGF/VEGFR signaling in surrounding tumor cells to support tumor cell proliferation and migration. Pharmacological blockade of EGFR or antibody neutralization of ICAM-1 in TAMs blunted spheroid formation and ovarian cancer progression in mouse models. These findings suggest that EGF secreted from TAMs plays a critical role in promoting early transcoelomic metastasis of ovarian cancer. As transcoelomic metastasis is also associated with many other cancers, such as pancreatic and colon cancers, our findings uncover a mechanism for TAM-mediated spheroid formation and provide a potential target for the treatment of ovarian cancer and other transcoelomic metastatic cancers. PMID:27721235

Pharmacokinetics of endoxifen and tamoxifen in female mice: implications for comparative in vivo activity studies.

PubMed

Reid, Joel M; Goetz, Matthew P; Buhrow, Sarah A; Walden, Chad; Safgren, Stephanie L; Kuffel, Mary J; Reinicke, Kathryn E; Suman, Vera; Haluska, Paul; Hou, Xiaonan; Ames, Matthew M

2014-12-01

Reduced CYP2D6 metabolism and low Z-endoxifen (ENDX) concentrations may increase the risk of breast cancer recurrence in tamoxifen (TAM)-treated women. Little is known regarding the differences between TAM and ENDX murine pharmacokinetics or the effect of administration route on plasma concentrations of each drug. The pharmacokinetics of TAM and ENDX were characterized in female mice. For subcutaneous [s.c.] and oral TAM (4, 10 and 20 mg/kg), TAM AUC increased in a linear manner, but concentrations of the active metabolites [ENDX and 4-hydroxytamoxifen (4HT)] remained low. For oral TAM (20 mg), 4HT concentrations were tenfold greater (>25 ng/ml) than achievable in TAM-treated humans. Both oral (10-200 mg/kg) and s.c. (2.5-25 mg/kg) ENDX·HCl resulted in a greater than dose-proportional increase in AUC, with eightfold greater ENDX concentrations than an equivalent TAM dose. ENDX accumulated in plasma after 5-day dosing of 25 or 100 mg/kg ENDX·HCl and exceeded target concentrations of 0.1 and 1.0 μM, respectively, by twofold to fourfold. In murine models, oral ENDX yields substantially higher ENDX concentrations, compared to TAM. The low 4HT and ENDX concentrations observed in mice receiving s.c. TAM mirror the TAM pharmacokinetics in humans with impaired CYP2D6 metabolism. These data support the ongoing development of ENDX as a novel agent for the endocrine treatment of ER-positive breast cancer.

Assessment of Nanobiotechnology-Targeted siRNA Designed to Inhibit NF-kappaB Classical And Alternative Signaling in Breast Tumor Macrophages

DTIC Science & Technology

2012-07-01

tumor microenvironment we intend to deliver siRNA specifically to tumor- associated-macrophages ( TAMs ). Therefore, the proposed work seeks to synthesize...characterize and assess multifunctional nanoparticles for siRNA delivery specifically to tumor-associated-macrophages ( TAMs ). The nanoparticles...knockdown protein expression of NF-κB modulators with exceptional specificity for TAMs . TAM -specific nanoparticle targeting offers an innovative approach

Arrested development of the myxozoan parasite, Myxobolus cerebralis, in certain populations of mitochondrial 16S lineage III Tubifex tubifex.

PubMed

Baxa, D V; Kelley, G O; Mukkatira, K S; Beauchamp, K A; Rasmussen, C; Hedrick, R P

2008-01-01

Laboratory populations of Tubifex tubifex from mitochondrial (mt)16S ribosomal DNA (rDNA) lineage III were generated from single cocoons of adult worms releasing the triactinomyxon stages (TAMs) of the myxozoan parasite, Myxobolus cerebralis. Subsequent worm populations from these cocoons, referred to as clonal lines, were tested for susceptibility to infection with the myxospore stages of M. cerebralis. Development and release of TAMs occurred in five clonal lines, while four clonal lines showed immature parasitic forms that were not expelled from the worm (non-TAM producers). Oligochaetes from TAM- and non-TAM-producing clonal lines were confirmed as lineage III based on mt16S rDNA and internal transcribed spacer region 1 (ITS1) sequences, but these genes did not differentiate these phenotypes. In contrast, random amplified polymorphic DNA analyses of genomic DNA demonstrated unique banding patterns that distinguished the phenotypes. Cohabitation of parasite-exposed TAM- and non-TAM-producing phenotypes showed an overall decrease in expected TAM production compared to the same exposure dose of the TAM-producing phenotype without cohabitation. These studies suggest that differences in susceptibility to parasite infection can occur in genetically similar T. tubifex populations, and their coexistence may affect overall M. cerebralis production, a factor that may influence the severity of whirling disease in wild trout populations.

Enhancement of anticancer effect of interferon-γ gene transfer against interferon-γ-resistant tumor by depletion of tumor-associated macrophages.

PubMed

Kiyota, Tsuyoshi; Takahashi, Yuki; Watcharanurak, Kanitta; Nishikawa, Makiya; Ohara, Saori; Ando, Mitsuru; Watanabe, Yoshihiko; Takakura, Yoshinobu

2014-05-05

Tumor-associated macrophages (TAMs) negatively affect the therapeutic effects of anticancer agents. To examine the role of TAMs in interferon (IFN)-γ gene therapy, we selected two types of solid tumors, which varied in the number of TAMs, and investigated the effects of IFN-γ gene transfer on tumor growth. Many TAMs were detected in the solid tumors of murine adenocarcinoma colon-26 cells, whereas few TAMs were detected in murine melanoma B16-BL6 cells. IFN-γ gene transfer hardly suppressed the growth of colon-26 tumors, whereas it was effective in suppressing the growth of B16-BL6 tumors. The antiproliferative effects of IFN-γ on cultured colon-26 cells were similar to those on cultured B16-BL6 cells. To evaluate the role of TAMs, we injected clodronate liposomes (CLs) modified with poly(ethylene glycol) (PEG) to functionally deplete TAMs in tumor-bearing mice. Repeated injections of PEG-CLs significantly retarded the growth of colon-26 tumors and combination with IFN-γ gene transfer further inhibited the growth. In contrast, PEG-CLs hardly retarded the growth of B16-BL6 tumors. These results clearly indicate that TAM depletion is effective in enhancing the therapeutic effect of IFN-γ in TAM-repleted and IFN-γ-resistant tumors.

Autophagy-induced RelB/p52 activation mediates tumour-associated macrophage repolarisation and suppression of hepatocellular carcinoma by natural compound baicalin

PubMed Central

Tan, H-Y; Wang, N; Man, K; Tsao, S-W; Che, C-M; Feng, Y

2015-01-01

The plasticity of tumour-associated macrophages (TAMs) has implicated an influential role in hepatocellular carcinoma (HCC). Repolarisation of TAM towards M1 phenotype characterises an immune-competent microenvironment that favours tumour regression. To investigate the role and mechanism of TAM repolarisation in suppression of HCC by a natural compound baicalin, Orthotopic HCC implantation model was used to investigate the effect of baicalin on HCC; liposome-clodronate was introduced to suppress macrophage populations in mice; bone marrow-derived monocytes (BMDMs) were induced to unpolarised, M1-like, M2-like macrophages and TAM using different conditioned medium. We observed that oral administration of baicalin (50 mg/kg) completely blocked orthotopic growth of implanted HCC. Suppression of HCC by baicalin was diminished when mice macrophage was removed by clodronate treatment. Baicalin induced repolarisation of TAM to M1-like phenotype without specific toxicity to either phenotype of macrophages. Baicalin initiated TAM reprogramming to M1-like macrophage, and promoted pro-inflammatory cytokines production. Co-culturing of HCC cells with baicalin-treated TAMs resulted in reduced proliferation and motility in HCC. Baicalin had minimal effect on derivation of macrophage polarisation factors by HCC cells, while directly induced repolarisation of TAM and M2-like macrophage. This effect was associated with elevated autophagy, and transcriptional activation of RelB/p52 pathway. Suppression of autophagy or RelB abolished skewing of baicalin-treated TAM. Autophagic degradation of TRAF2 in baicalin-treated TAM might be responsible for RelB/p52 activation. Our findings unveil the essential role of TAM repolarisation in suppressive effect of baicalin on HCC, which requires autophagy-associated activation of RelB/p52. PMID:26492375

Arrested development of the myxozoan parasite, Myxobolus cerebralis, in certain populations of mitochondrial 16S lineage III Tubifex tubifex

USGS Publications Warehouse

Baxa, D.V.; Kelley, G.O.; Mukkatira, K.S.; Beauchamp, K.A.; Rasmussen, C.; Hedrick, R.P.

2008-01-01

Laboratory populations of Tubifex tubifex from mitochondrial (mt)16S ribosomal DNA (rDNA) lineage III were generated from single cocoons of adult worms releasing the triactinomyxon stages (TAMs) of the myxozoan parasite, Myxobolus cerebralis. Subsequent worm populations from these cocoons, referred to as clonal lines, were tested for susceptibility to infection with the myxospore stages of M. cerebralis. Development and release of TAMs occurred in five clonal lines, while four clonal lines showed immature parasitic forms that were not expelled from the worm (non-TAM producers). Oligochaetes from TAM- and non-TAM-producing clonal lines were confirmed as lineage III based on mt16S rDNA and internal transcribed spacer region 1 (ITS1) sequences, but these genes did not differentiate these phenotypes. In contrast, random amplified polymorphic DNA analyses of genomic DNA demonstrated unique banding patterns that distinguished the phenotypes. Cohabitation of parasite-exposed TAM- and non-TAM-producing phenotypes showed an overall decrease in expected TAM production compared to the same exposure dose of the TAM-producing phenotype without cohabitation. These studies suggest that differences in susceptibility to parasite infection can occur in genetically similar T. tubifex populations, and their coexistence may affect overall M. cerebralis production, a factor that may influence the severity of whirling disease in wild trout populations. ?? 2007 Springer-Verlag.

Proteomic identification of E6AP as a molecular target of tamoxifen in MCF7 cells.

PubMed

Lochab, Savita; Pal, Pooja; Kanaujiya, Jitendra K; Tripathi, Shashi B; Kapoor, Isha; Bhatt, Madan L B; Sanyal, Sabyasachi; Behre, Gerhard; Trivedi, Arun K

2012-05-01

Tamoxifen (Tam) is most widely used selective estrogen receptor modulator (SERM) for treatment of hormone-responsive breast cancer. Despite being regularly used in clinical therapy for breast cancer since 1971, the mechanism of Tam action remains largely unclear. In order to gain insights into Tam-mediated antibreast cancer actions, we applied 2DE and MS based proteomics approach to identify target proteins of Tam. We identified E6-associated protein, i.e. E6AP (UBE3A) among others to be regulated by Tam that otherwise is upregulated in breast tumors. We confirmed our 2DE finding by immunoblotting and further show that Tam leads to inhibition of E6AP expression presumably by promoting its autoubiquitination, which is coupled with nuclear export and subsequent proteasome-mediated degradation. Furthermore, we show that Tam- and siE6AP-mediated inhibition of E6AP leads to enhanced G0-G1 growth arrest and apoptosis, which is also evident from significant upregulation of cytochrome-c, Bax, p21, and PARP cleavage. Taken together, our data suggest that, Tam-targeted E6AP inhibition is in fact required for Tam-mediated antibreast cancer actions. Thus, E6AP may be a therapeutic target in breast cancer. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

GPER promotes tamoxifen-resistance in ER+ breast cancer cells by reduced Bim proteins through MAPK/Erk-TRIM2 signaling axis.

PubMed

Yin, Heng; Zhu, Qing; Liu, Manran; Tu, Gang; Li, Qing; Yuan, Jie; Wen, Siyang; Yang, Guanglun

2017-10-01

Tamoxifen resistance is a major clinical challenge in breast cancer treatment. Our previous studies find that GPER and its down-stream signaling play a pivotal role in the development of tamoxifen (TAM) resistance. cDNA array analysis indicated a set of genes associated with cell apoptosis are aberrant in GPER activated and TAM-resistant MCF-7R cells compared with TAM-sensitive MCF-7 cells. Among these genes, Bim (also named BCL2-L11), a member of the BH3-only pro-apoptotic protein family is significantly decreased, and TRIM RING finger protein TRIM2 (a ubiquitin ligase) is highly expressed in MCF-7R. To understand the mechanism of TAM-resistance in GPER activated ER+ breast cancer, the function of TRIM2 and Bim inducing cell apoptosis was studied. By using immunohistochemical and western blot analysis, there is an adverse correlation between TRIM2 and Bim in TAM-resistant breast tumor tissues and MCF-7R cells. Knockdown Bim in TAM-sensitive MCF-7 cells or overexpression of Bim in TAM-resistant MCF-7 cells significantly changed its sensibility to TAM through altering the levels of cleaved PARP and caspase-3. Activation of GPER and its downstream signaling MAPK/ERK, not PI3K/AKT, led to enhanced TRIM2 protein levels and affected the binding between TRIM2 and Bim which resulted in a reduced Bim in TAM-resistant breast cancer cells. Thus, the present study provides a novel insight to TAM-resistance in ER-positive breast cancer cells.

Application of TAM III to study sensitivity of soil organic matter degradation to temperature

NASA Astrophysics Data System (ADS)

Vikegard, Peter; Barros, Nieves; Piñeiro, Verónica

2014-05-01

Traditionally, studies of soil biodegradation are based on CO2 dissipation rates. CO2 is a product of aerobic degradation of labile organic substrates like carbohydrates. That limits the biodegradation concept to just one of the soil organic matter fractions. This feature is responsible for some problems to settle the concept of soil organic matter (SOM) recalcitrance and for controversial results defining sensitivity of SOM to temperature. SOM consists of highly complex macromolecules constituted by fractions with different chemical nature and redox state affecting the chemical nature of biodegradation processes. Biodegradation of fractions more reduced than carbohydrates take place through metabolic pathways that dissipate less CO2 than carbohydrate respiration, that may not dissipate CO2, or that even may uptake CO2. These compounds can be considered more recalcitrant and with lower turnover times than labile SOM just because they are degraded at lower CO2 rates that may be just a consequence of the metabolic path. Nevertheless, decomposition of every kind of organic substrate always releases heat. For this reason, the measurement of the heat rate by calorimetry yields a more realistic measurement of the biodegradation of the SOM continuum. TAM III is one of the most recent calorimeters designed for directly measuring in real time the heat rate associated with any degradation process. It is designed as a multichannel system allowing the concomitant measurement of to up 24 samples at isothermal conditions or through a temperature scanning mode from 18 to 100ºC, allowing the continous measure of any sample at controlled non-isothermal conditions. The temperature scanning mode was tested in several soil samples collected at different depths to study their sensitivity to temperature changes from 18 to 35 ºC calculating the Q10 and the activation energy (EA) by the Arrhenius equation. It was attempted to associate the obtained EA values with the soil thermal

Recent DDT and PCB contamination in the sediment and biota of the Como Bay (Lake Como, Italy).

PubMed

Bettinetti, R; Quadroni, S; Boggio, E; Galassi, S

2016-01-15

Due to its peculiar geographical and morphological characteristics, Lake Como (Northern Italy) represents an interesting study-case for investigating the sub-basin scale circulation of persistent organic pollutants (POPs) that, despite being banned since the 1970s, have reached surprisingly high concentrations in some southern alpine lakes as a consequence of their release from melting glaciers in recent years. In particular, the Como Bay, which is located in the city of Como, seems noteworthy because its waters have a longer residence time than the other areas of the lake. The analyses of the historical concentration of PCBs, pp′DDT and its metabolites in a sediment core sampled from the Como Bay covering a time-period from their ban to recent times, showed that the DDTs have never experienced a significant (p < 0.05) decrease over time, with concentrations of the most abundant homologue, pp′DDE, ranging from 27 to 75 ng g(-1) d.w. Conversely PCBs significantly (p < 0.05) decreased towards recent times, reaching concentrations around 80 ng g(-1) d.w. The contribution of high altitude and local sources was recorded also in the food web: both zooplankton and the zooplanktivorous fish agone were mainly contaminated by pp′DDE (81.4 ng g(-1) w.w. and 534.6 ng g(-1) w.w. respectively) and by the PCB metabolite hexa-CB (449.7 ng g(-1) w.w. and 1672.1 ng g(-1) w.w. respectively). The DDT concentrations in the agone (sampled during the years 2006–2009) never exceeded the limits for human consumption in Italy, while concentrations of six selected PCBs exceeded human health advisory recommendations in one of the fish samples analysed, when it was approximately two times higher than the recommended value of 125 ng g(-1) w.w.

Effects of water temperature and substrate type on spore production and release in eastern Tubifex tubifex worms infected with Myxobolus cerebralis

USGS Publications Warehouse

Blazer, V.S.; Waldrop, T.B.; Schill, W.B.; Densmore, Christine L.; Smith, D.

2003-01-01

Eastern Tubifex tubifex worms were exposed to Myxobolus cerebralis spores at 9, 13, 17, and 20 C in 1-L jars that contained sand, mud, or leaf litter as substrata. Beginning 60 days after exposure, water from each jar was filtered daily and examined for the presence of waterborne triactinomyxon spores (TAMs). On discovering a single TAM from an experimental jar, 48 T. tubifex worms from that jar were placed individually into 24-well plates. Spores released from individual infected T. tubifex worms were quantified to determine the first day of TAM release from infected worms, the infection rate, the total number of TAMs released per worm, and the duration of release. No TAMs were found in any of the jars incubated at 20 C or in uninfected, control worms at any temperature. The total number of TAMs released by infected worms in mud and sand was highest at 13 C compared with other temperatures. Infection rates among individual worms increased with temperature between 9 and 17 C. Higher temperatures (up to 17 C) induced earlier TAM releases among infected worms, and substratum did not influence this production parameter. The average duration of TAM release decreased as the temperature increased from 9 to 17 C, and there was a significant effect of substratum in the groups maintained at 13 and 17 C. In all temperature treatments between 9 and 17 C, the duration of release was least in the worms maintained in leaf litter, as was the total number of TAMs released during the experimental period and the median number of TAMs per production day.

Biocompatible mannosylated endosomal-escape nanoparticles enhance selective delivery of short nucleotide sequences to tumor associated macrophages

NASA Astrophysics Data System (ADS)

Ortega, Ryan A.; Barham, Whitney J.; Kumar, Bharat; Tikhomirov, Oleg; McFadden, Ian D.; Yull, Fiona E.; Giorgio, Todd D.

2014-12-01

Tumor associated macrophages (TAMs) can modify the tumor microenvironment to create a pro-tumor niche. Manipulation of the TAM phenotype is a novel, potential therapeutic approach to engage anti-cancer immunity. siRNA is a molecular tool for knockdown of specific mRNAs that is tunable in both strength and duration. The use of siRNA to reprogram TAMs to adopt an immunogenic, anti-tumor phenotype is an attractive alternative to ablation of this cell population. One current difficulty with this approach is that TAMs are difficult to specifically target and transfect. We report here successful utilization of novel mannosylated polymer nanoparticles (MnNP) that are capable of escaping the endosomal compartment to deliver siRNA to TAMs in vitro and in vivo. Transfection with MnNP-siRNA complexes did not significantly decrease TAM cell membrane integrity in culture, nor did it create adverse kidney or liver function in mice, even at repeated doses of 5 mg kg-1. Furthermore, MnNP effectively delivers labeled nucleotides to TAMs in mice with primary mammary tumors. We also confirmed TAM targeting in the solid tumors disseminated throughout the peritoneum of ovarian tumor bearing mice following injection of fluorescently labeled MnNP-nucleotide complexes into the peritoneum. Finally, we show enhanced uptake of MnNP in lung metastasis associated macrophages compared to untargeted particles when using an intubation delivery method. In summary, we have shown that MnNP specifically and effectively deliver siRNA to TAMs in vivo.

NF-κB RelA renders tumor-associated macrophages resistant to and capable of directly suppressing CD8+ T cells for tumor promotion.

PubMed

Li, Liwen; Han, Lei; Sun, Fan; Zhou, Jingjiao; Ohaegbulam, Kim C; Tang, Xudong; Zang, Xingxing; Steinbrecher, Kris A; Qu, Zhaoxia; Xiao, Gutian

2018-01-01

Activation of the inflammatory transcription factor NF-κB in tumor-associated macrophages (TAMs) is assumed to contribute to tumor promotion. However, whether and how NF-κB drives the antitumor macrophages to become pro-tumorigenic have not been determined in any cancer type yet. Similarly, how TAMs repress CD8 + cytotoxic T lymphocytes (CTLs) remains largely unknown, although their importance in regulatory T (Treg) cell regulation and tumor promotion has been well appreciated. Here, using an endogenous lung cancer model we uncover a direct crosstalk between TAMs and CTLs. TAMs suppress CTLs through the T-cell inhibitory molecule B7x (B7-H4/B7S1) in a cell-cell contact manner, whereas CTLs kill TAMs in a tumor antigen-specific manner. Remarkably, TAMs secrete the known T-cell suppressive cytokine interleukin-10 (IL-10) to activate, but not to repress, CTLs. Notably, one major role of cell-intrinsic NF-κB RelA is to drive TAMs to suppress CTLs for tumor promotion. It induces B7x expression in TAMs directly, and restricts IL-10 expression indirectly by repressing expression of the NF-κB cofactor Bcl3 and subsequent Bcl3/NF-κB1-mediated transcription of IL-10. It also renders TAMs resistant to CTLs by up-regulating anti-apoptotic genes. These studies help understand how immunity is shaped in lung tumorigenesis, and suggest a RelA-targeted immunotherapy for this deadliest cancer.

A Comprehensive Proteomics Analysis Reveals a Secretory Path- and Status-Dependent Signature of Exosomes Released from Tumor-Associated Macrophages.

PubMed

Zhu, Yinghui; Chen, Xianwei; Pan, Qingfei; Wang, Yang; Su, Siyuan; Jiang, Cuicui; Li, Yang; Xu, Ningzhi; Wu, Lin; Lou, Xiaomin; Liu, Siqi

2015-10-02

Exosomes are 30-120 nm-sized membrane vesicles of endocytic origin that are released into the extracellular environment and play roles in cell-cell communication. Tumor-associated macrophages (TAMs) are important constituents of the tumor microenvironment; thus, it is critical to study the features and complex biological functions of TAM-derived exosomes. Here, we constructed a TAM cell model from a mouse macrophage cell line, Ana-1, and performed comparative proteomics on exosomes, exosome-free media, and cells between TAMs and Ana-1. Proteomic analysis between exosome and exosome-free fractions indicated that the functions of exosome dominant proteins were mainly enriched in RNA processing and proteolysis. TAM status dramatically affected the abundances of 20S proteasome subunits and ribosomal proteins in their exosomes. The 20S proteasome activity assay strongly indicated that TAM exosomes possessed higher proteolytic activity. In addition, Ana-1- and TAM-derived exosomes have different RNA profiles, which may result from differential RNA processing proteins. Taken together, our comprehensive proteomics study provides novel views for understanding the complicated roles of macrophage-derived exosomes in the tumor microenvironment.

Interactions of the anticancer drug tamoxifen with lipid membranes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Khadka, Nawal K.; Cheng, Xiaolin; Ho, Chian Sing

Interactions of the hydrophobic anticancer drug tamoxifen (TAM) with lipid model membranes were studied using calcein-encapsulated vesicle leakage, attenuated total reflection Fourier transform infrared (FTIR) spectroscopy, small-angle neutron scattering (SANS), atomic force microscopy (AFM) based force spectroscopy, and all-atom molecular dynamics (MD) simulations. The addition of TAM enhances membrane permeability, inducing calcein to translocate from the interior to the exterior of lipid vesicles. A large decrease in the FTIR absorption band’s magnitude was observed in the hydrocarbon chain region, suggesting suppressed bond vibrational dynamics. Bilayer thickening was determined from SANS data. Force spectroscopy measurements indicate that the lipid bilayer areamore » compressibility modulus KA is increased by a large amount after the incorporation of TAM. MD simulations show that TAM decreases the lipid area and increases chain order parameters. Moreover, orientational and positional analyses show that TAM exhibits a highly dynamic conformation within the lipid bilayer. Lastly, our detailed experimental and computational studies of TAM interacting with model lipid membranes shed new light on membrane modulation by TAM.« less

Interactions of the anticancer drug tamoxifen with lipid membranes

DOE PAGES

Khadka, Nawal K.; Cheng, Xiaolin; Ho, Chian Sing; ...

2015-05-19

Interactions of the hydrophobic anticancer drug tamoxifen (TAM) with lipid model membranes were studied using calcein-encapsulated vesicle leakage, attenuated total reflection Fourier transform infrared (FTIR) spectroscopy, small-angle neutron scattering (SANS), atomic force microscopy (AFM) based force spectroscopy, and all-atom molecular dynamics (MD) simulations. The addition of TAM enhances membrane permeability, inducing calcein to translocate from the interior to the exterior of lipid vesicles. A large decrease in the FTIR absorption band’s magnitude was observed in the hydrocarbon chain region, suggesting suppressed bond vibrational dynamics. Bilayer thickening was determined from SANS data. Force spectroscopy measurements indicate that the lipid bilayer areamore » compressibility modulus KA is increased by a large amount after the incorporation of TAM. MD simulations show that TAM decreases the lipid area and increases chain order parameters. Moreover, orientational and positional analyses show that TAM exhibits a highly dynamic conformation within the lipid bilayer. Lastly, our detailed experimental and computational studies of TAM interacting with model lipid membranes shed new light on membrane modulation by TAM.« less

Circumventing Therapeutic Resistance and the Emergence of Disseminated Breast Cancer Cells Through Non-Invasive Optical Imaging

DTIC Science & Technology

2014-07-01

vesicle degradation in vivo. Lastly, we have established four pairs of parental and isogenic matched tamoxifen ( tam )-resistant cell lines (MCF7, T47D...members of the HER receptor family (EGFR/HER1; HER2; HER3) are upregulated with the development of tam -resistance; furthermore, differences in receptor...Figure 4 Increased HER receptor expression in response to tam -treated MDA-MB-361 cells and tam -resistant 361 cells. Steady-state levels of the

The effect of tamoxifen and raloxifene on estrogen metabolism and endometrial cancer risk.

PubMed

Williams-Brown, Marian Y; Salih, Sana M; Xu, Xia; Veenstra, Timothy D; Saeed, Muhammad; Theiler, Shaleen K; Diaz-Arrastia, Concepcion R; Salama, Salama A

2011-09-01

Selective estrogen receptor modulators (SERMs) demonstrate differential endometrial cancer (EC) risk. While tamoxifen (TAM) use increases the risk of endometrial hyperplasia and malignancy, raloxifene (RAL) has neutral effects on the uterus. How TAM increases the risk of EC and why TAM and RAL differentially modulate the risk for EC, however, remain elusive. Here, we tested the hypothesis that TAM increases the risk for EC, at least in part, by enhancing the local estrogen biosynthesis and directing estrogen metabolism towards the formation of genotoxic and hormonally active estrogen metabolites. In addition, the differential effects of TAM and RAL in EC risk are attributed to their differential effect on estrogen metabolism/metabolites. The endometrial cancer cell line (Ishikawa cells) and the nonmalignant immortalized human endometrial glandular cell line (EM1) were used for the study. The profile of estrogen/estrogen metabolites (EM), depurinating estrogen-DNA adducts, and the expression of estrogen-metabolizing enzymes in cells treated with 17β-estradiol (E2) alone or in combination with TAM or RAL were investigated using high performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS(2)), ultraperformance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS), and Western blot analysis, respectively. TAM significantly increased the total EM and enhanced the formation of hormonally active and carcinogenic estrogen metabolites, 4-hydroxestrone (4-OHE1) and 16α-hydroxyestrone, with concomitant reduction in the formation of antiestrogenic and anticarcinogenic 2-hydroxyestradiol and 2-methoxyestradiol. Furthermore, TAM increased the formation of depurinating estrogen-DNA adducts 4-OHE1 [2]-1-N7Guanine and 4-OHE1 [2]-1-N3 Adenine. TAM-induced alteration in EM and depurinating DNA adduct formation is associated with altered expression of estrogen metabolizing enzymes CYP1A1, CYP1B1, COMT, NQO1, and SF-1 as revealed by

Circumventing Therapeutic Resistance and the Emergence of Disseminated Breast Cancer Cells Through Non-Invasive Optical Imaging

DTIC Science & Technology

2014-07-01

vivo. Lastly, we have established four pairs of parental and isogenic matched tamoxifen ( tam )-resistant cell lines (MCF7, T47D, MDA-MB-361 and HCC1428...receptor family (EGFR/HER1; HER2; HER3) are upregulated with the development of tam -resistance; furthermore, differences in receptor expression between ER...Increased HER receptor expression in response to tam -treated MDA-MB-361 cells and tam -resistant 361 cells. Steady-state levels of the indicated proteins

Índice de vulnerabilidad de adultos mayores en Medellín, Barranquilla y Pasto.

PubMed

Cardona, Doris; Segura, Ángela; Segura, Alejandra; Muñoz, Diana; Jaramillo, Daniel; Lizcano, Douglas; Agudelo, Maite Catalina; Arango, Catalina; Morales, Santiago

2018-05-01

Introducción. La vulnerabilidad puede entenderse como la carencia de recursos materiales e inmateriales que impide el aprovechamiento de oportunidades en distintos aspectos de la vida. Estos recursos de bienestar evitan el deterioro de la calidad de vida.Objetivo. Construir un índice de vulnerabilidad con las características de los capitales físico, humano, social y funcional de los adultos mayores de tres ciudades de Colombia en el 2016, y determinar los factores asociados con esta condición.Materiales y métodos. Se hizo un estudio transversal con información primaria mediante 1.514 encuestas a personas de 60 años o más de Medellín, Barranquilla y Pasto. En la construcción del índice se usó el análisis factorial con los métodos de componentes principales y de rotación ortogonal varimax.Resultados. Las condiciones que generaban vulnerabilidad se relacionaron principalmente con el capital humano (calidad de vida, salud mental y hábitos); los demás capitales aportaron un solo componente, así: capital físico (ocupación), capital social (acompañamiento) y capital funcional (independencia funcional). La vulnerabilidad fue mayor en los residentes de Pasto. Los factores asociados con la vulnerabilidad fueron la ciudad de residencia, el sexo, el nivel educativo y el rol en el hogar.Conclusión. En el 58,55 % de las personas mayores, la vulnerabilidad se explicó por el uso del tiempo, la independencia funcional y el bienestar subjetivo. Estos hallazgos aportan elementos para el mejoramiento de la calidad de vida, principalmente en cuanto a la capacidad funcional para mantener la independencia, estar ocupados y fortalecer la salud mental.

Acceptance of Internet Banking Systems among Young Managers

NASA Astrophysics Data System (ADS)

Ariff, Mohd Shoki Md; M, Yeow S.; Zakuan, Norhayati; Zaidi Bahari, Ahamad

2013-06-01

The aim of this paper is to determine acceptance of internet banking system among potential young users, specifically future young managers. The relationships and the effects of computer self-efficacy (CSE) and extended technology acceptance model (TAM) on the behavioural intention (BI) to use internet banking system were examined. Measurement of CSE, TAM and BI were adapted from previous studies. However construct for TAM has been extended by adding a new variable which is perceived credibility (PC). A survey through questionnaire was conducted to determine the acceptance level of CSE, TAM and BI. Data were obtained from 275 Technology Management students, who are pursuing their undergraduate studies in a Malaysia's public university. The confirmatory factor analysis performed has identified four variables as determinant factors of internet banking acceptance. The first variable is computer self-efficacy (CSE), and another three variables from TAM constructs which are perceived usefulness (PU), perceived ease of use (PE) and perceived credibility (PC). The finding of this study indicated that CSE has a positive effect on PU and PE of the Internet banking systems. Respondents' CSE was positively affecting their PC of the systems, indicating that the higher the ability of one in computer skills, the higher the security and privacy issues of PC will be concerned. The multiple regression analysis indicated that only two construct of TAM; PU and PC were significantly associated with BI. It was found that the future managers' CSE indirectly affects their BI to use the internet banking systems through PU and PC of TAM. TAM was found to have direct effects on respondents' BI to use the systems. Both CSE and the PU and PC of TAM were good predictors in understanding individual responses to information technology. The role of PE of the original TAM to predict the attitude of users towards the use of information technology systems was surprisingly insignificant.

Investigation of discriminant metabolites in tamoxifen-resistant and choline kinase-alpha-downregulated breast cancer cells using 1H-nuclear magnetic resonance spectroscopy.

PubMed

Kim, Hoe Suk; Tian, Lianji; Kim, Hyeonjin; Moon, Woo Kyung

2017-01-01

Metabolites linked to changes in choline kinase-α (CK-α) expression and drug resistance, which contribute to survival and autophagy mechanisms, are attractive targets for breast cancer therapies. We previously reported that autophagy played a causative role in driving tamoxifen (TAM) resistance of breast cancer cells (BCCs) and was also promoted by CK-α knockdown, resulting in the survival of TAM-resistant BCCs. There is no comparative study yet about the metabolites resulting from BCCs with TAM-resistance and CK-α knockdown. Therefore, the aim of this study was to explore the discriminant metabolic biomarkers responsible for TAM resistance as well as CK-α expression, which might be linked with autophagy through a protective role. A total of 33 intracellular metabolites, including a range of amino acids, energy metabolism-related molecules and others from cell extracts of the parental cells (MCF-7), TAM-resistant cells (MCF-7/TAM) and CK-α knockdown cells (MCF-7/shCK-α, MCF-7/TAM/shCK-α) were analyzed by proton nuclear magnetic resonance spectroscopy (1H-NMRS). Principal component analysis (PCA) and partial least square discriminant analysis (PLS-DA) revealed the existence of differences in the intracellular metabolites to separate the 4 groups: MCF-7 cells, MCF-7/TAM cells, MCF-7-shCK-α cells, and MCF-7/TAM/shCK-α cells. The metabolites with VIP>1 contributed most to the differentiation of the cell groups, and they included fumarate, UA (unknown A), lactate, myo-inositol, glycine, phosphocholine, UE (unknown E), glutamine, formate, and AXP (AMP/ADP/ATP). Our results suggest that these altered metabolites would be promising metabolic biomarkers for a targeted therapeutic strategy in BCCs that exhibit TAM-resistance and aberrant CK-α expression, which triggers a survival and drug resistance mechanism.

Antitumor effect of nuclear factor-κB decoy transfer by mannose-modified bubble lipoplex into macrophages in mouse malignant ascites

PubMed Central

Kono, Yusuke; Kawakami, Shigeru; Higuchi, Yuriko; Maruyama, Kazuo; Yamashita, Fumiyoshi; Hashida, Mitsuru

2014-01-01

Patients with malignant ascites (MAs) display several symptoms, such as dyspnea, nausea, pain, and abdominal tenderness, resulting in a significant reduction in their quality of life. Tumor-associated macrophages (TAMs) play a crucial role in MA progression. Because TAMs have a tumor-promoting M2 phenotype, conversion of the M2 phenotypic function of TAMs would be promising for MA treatment. Nuclear factor-κB (NF-κB) is a master regulator of macrophage polarization. Here, we developed targeted transfer of a NF-κB decoy into TAMs by ultrasound (US)-responsive, mannose-modified liposome/NF-κB decoy complexes (Man-PEG bubble lipoplexes) in a mouse peritoneal dissemination model of Ehrlich ascites carcinoma. In addition, we investigated the effects of NF-κB decoy transfection into TAMs on MA progression and mouse survival rates. Intraperitoneal injection of Man-PEG bubble lipoplexes and US exposure transferred the NF-κB decoy into TAMs effectively. When the NF-κB decoy was delivered into TAMs by this method in the mouse peritoneal dissemination model, mRNA expression of the Th2 cytokine interleukin (IL)-10 in TAMs was decreased significantly. In contrast, mRNA levels of Th1 cytokines (IL-12, tumor necrosis factor-α, and IL-6) were increased significantly. Moreover, the expression level of vascular endothelial growth factor in ascites was suppressed significantly, and peritoneal angiogenesis showed a reduction. Furthermore, NF-κB decoy transfer into TAMs significantly decreased the ascitic volume and number of Ehrlich ascites carcinoma cells in ascites, and prolonged mouse survival. In conclusion, we transferred a NF-κB decoy efficiently by Man-PEG bubble lipoplexes with US exposure into TAMs, which may be a novel approach for MA treatment. PMID:24850474

Triple negative breast cancer: Key role of Tumor-Associated Macrophages in regulating the activity of anti-PD-1/PD-L1 agents.

PubMed

Santoni, Matteo; Romagnoli, Emanuela; Saladino, Tiziana; Foghini, Laura; Guarino, Stefania; Capponi, Marco; Giannini, Massimo; Cognigni, Paolo Decembrini; Ferrara, Gerardo; Battelli, Nicola

2018-01-01

Triple-negative breast cancer (TNBC) is associated with a poor prognosis, due to its aggressive behaviour and lack of effective targeted therapies. Immunocheckpoint inhibitors, such as anti-programmed cell death 1 (PD-1) and anti-PD-ligand(L)1 agents, are in course of investigation in TNBC, used alone or in combination with other systemic or local approaches. However, the high cost of these drugs and the lack of validated predictive biomarkers support the development of strategies aimed to overcome resistance and optimize the efficacy of these approaches. Tumor-Associated Macrophages (TAMs) derive from peripheral blood monocytes recruited into the TNBC microenvironment and, in response to several stimuli, undergo M1 (classical) or M2 (alternative) activation. In TNBC, TAMs promote tumor growth and progression by several mechanisms that include the secretion of inhibitory cytokines, the reduction of effector functions of Tumor Infiltrating Lymphocytes (TILs) and the promotion of Regulatory T cell (Treg). Interestingly, TAMs have been shown to directly and indirectly modulate PD-1/PD-L1 expression in tumor environment. On this scenario, several TAM-centered strategies have been proposed, such as the suppression of TAM recruitment, the depletion of their number, the switch of M2 TAMs into antitumor M1 phenotype and the inhibition of TAM-associated molecules. In this review, we will illustrate the activity of TAMs and associated molecules in TNBC, focusing on their role in modulating the expression of PD-1/PD-L1 and on the emerging TAM-tailored strategies for TNBC patients. Copyright © 2017 Elsevier B.V. All rights reserved.

Liposomal formulation of {alpha}-tocopheryl maleamide: In vitro and in vivo toxicological profile and anticancer effect against spontaneous breast carcinomas in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Turanek, Jaroslav; Wang Xiufang; Knoetigova, Pavlina

2009-06-15

The vitamin E analogue {alpha}-tocopheryl succinate ({alpha}-TOS) is an efficient anti-cancer drug. Improved efficacy was achieved through the synthesis of {alpha}-tocopheryl maleamide ({alpha}-TAM), an esterase-resistant analogue of {alpha}-tocopheryl maleate. In vitro tests demonstrated significantly higher cytotoxicity of {alpha}-TAM towards cancer cells (MCF-7, B16F10) compared to {alpha}-TOS and other analogues prone to esterase-catalyzed hydrolysis. However, in vitro models demonstrated that {alpha}-TAM was cytotoxic to non-malignant cells (e.g. lymphocytes and bone marrow progenitors). Thus we developed lyophilized liposomal formulations of both {alpha}-TOS and {alpha}-TAM to solve the problem with cytotoxicity of free {alpha}-TAM (neurotoxicity and anaphylaxis), as well as the low solubilitymore » of both drugs. Remarkably, neither acute toxicity nor immunotoxicity implicated by in vitro tests was detected in vivo after application of liposomal {alpha}-TAM, which significantly reduced the growth of cancer cells in hollow fiber implants. Moreover, liposomal formulation of {alpha}-TAM and {alpha}-TOS each prevented the growth of tumours in transgenic FVB/N c-neu mice bearing spontaneous breast carcinomas. Liposomal formulation of {alpha}-TAM demonstrated anti-cancer activity at levels 10-fold lower than those of {alpha}-TOS. Thus, the liposomal formulation of {alpha}-TAM preserved its strong anti-cancer efficacy while eliminating the in vivo toxicity found of the free drug applied in DMSO. Liposome-based targeted delivery systems for analogues of vitamin E are of interest for further development of efficient and safe drug formulations for clinical trials.« less

The Structure of L-Tyrosine 2,3-Aminomutase frmo the C-1027 Enediyne Antitumor Antibiotic Biosynthetic Pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Christianson,C.; Montavon, T.; Van Lanen, S.

2007-01-01

The SgcC4 L-tyrosine 2,3-aminomutase (SgTAM) catalyzes the formation of (S)-{beta}-tyrosine in the biosynthetic pathway of the enediyne antitumor antibiotic C-1027. SgTAM is homologous to the histidine ammonia lyase family of enzymes whose activity is dependent on the methylideneimidazole-5-one (MIO) cofactor. Unlike the lyase enzymes, SgTAM catalyzes additional chemical transformations resulting in an overall stereospecific 1,2-amino shift in the substrate L-tyrosine to generate (S)-{beta}-tyrosine. Previously, we provided kinetic, spectroscopic, and mutagenesis data supporting the presence of MIO in the active site of SgTAM [Christenson, S. D.; Wu, W.; Spies, A.; Shen, B.; and Toney, M. D. (2003) Biochemistry 42, 12708-12718]. Heremore » we report the first X-ray crystal structure of an MIO-containing aminomutase, SgTAM, and confirm the structural homology of SgTAM to ammonia lyases. Comparison of the structure of SgTAM to the L-tyrosine ammonia lyase from Rhodobacter sphaeroides provides insight into the structural basis for aminomutase activity. The results show that SgTAM has a closed active site well suited to retain ammonia and minimize the formation of lyase elimination products. The amino acid determinants for substrate recognition and catalysis can be predicted from the structure, setting the framework for detailed mechanistic investigations.« less

8-bromo-7-methoxychrysin Reversed M2 Polarization of Tumor-associated Macrophages Induced by Liver Cancer Stem-like Cells.

PubMed

Sun, Shuwen; Cui, Yinghong; Ren, Kaiqun; Quan, Meifang; Song, Zhenwei; Zou, Hui; Li, Duo; Zheng, Yu; Cao, Jianguo

2017-01-01

Hepatocellular carcinoma (HCC) is related to chronic liver inflammation. M2 polarization of tumor-associated macrophages (TAMs) in the tumor microenvironment promotes liver cancer stem-like cell (LCSLC) self-renewal capability and carcinogenicity. Therefore, reversing M2 polarization of TAMs could be an effective approach to cure HCC. To evaluate whether 8-bromo-7-methoxychrysin (BrMC) has an effect on M2 polarization of TAMs. LCSLC and conditional medium were obtained by sphere forming assay. Identification of LCSLC were analyzed by sphere forming, wound-healing and invasion assay. TAM and effects of BrMC on it were validated by immunofluorescence staining, ELISA and griess assay. Expressions of cancer stem cell and macrophage marker were analyzed by western blotting. Our results showed that BrMC significantly suppressed the expression of the M2 macrophage marker CD163. Furthermore, BrMC influenced the secretion profile of cytokines of TAMs. Mechanistically, BrMC reversed M2 polarization of TAMs due to inhibition of NF-κB activation. BrMC may be a potentially novel flavonoid agent that can be applied for disrupting the interaction of LCSLCs and TAMs.

Amelioration of tamoxifen-induced liver injury in rats by grape seed extract, black seed extract and curcumin.

PubMed

El-Beshbishy, Hesham A; Mohamadin, Ahmed M; Nagy, Ayman A; Abdel-Naim, Ashraf B

2010-03-01

Liver injury was induced in female rats using tamoxifen (TAM). Grape seeds (Vitis vinifera) extract (GSE), black seed (Nigella sativa) extract (NSE), curcumin (CUR) or silymarin (SYL) were orally administered to TAM-intoxicated rats. Liver histopathology of TAM-intoxicated:rats showed pathological changes. TAM-intoxication elicited declines in liver antioxidant enzymes levels (glutathione peroxidase, glutathione reductase, superoxide dismutase and catalase), reduced glutathione (GSH) and GSH/GSSG ratio plus the hepatic elevations in lipid peroxides, oxidized glutathione (GSSG), tumor necrosis factor-alpha (TNF-alpha) and serum liver enzymes; alanine transaminase, aspartate transaminase, alkaline phosphatase, lactate dehydrogenase and gamma glutamyl transferase levels. Oral intake of NSE, GSE, CUR or SYL to TAM-intoxicated rats, attenuated histopathological changes and corrected all parameters mentioned above. Improvements were prominent in case of NSE (similarly SYL) > CUR > GSE. Data indicated that NSE, GSE or CUR act as free radicals scavengers and protect TAM-induced liver injury in rats.

Targeting tumor-associated macrophages by anti-tumor Chinese materia medica.

PubMed

Pu, Wei-Ling; Sun, Li-Kang; Gao, Xiu-Mei; Rüegg, Curzio; Cuendet, Muriel; Hottiger, Micheal O; Zhou, Kun; Miao, Lin; Zhang, Yun-Sha; Gebauer, Margaret

2017-10-01

Tumor-associated macrophages (TAMs) play a key role in all stages of tumorigenesis and tumor progression. TAMs secrete different kinds of cytokines, chemokines, and enzymes to affect the progression, metastasis, and resistance to therapy depending on their state of reprogramming. Therapeutic benefit in targeting TAMs suggests that macrophages are attractive targets for cancer treatment. Chinese materia medica (CMM) is an important approach for treating cancer in China and in the Asian region. According to the theory of Chinese medicine (CM) and its practice, some prescriptions of CM regulate the body's internal environment possibly including the remodeling the tumor microenvironment (TME). Here we briefly summarize the pivotal effects of TAMs in shaping the TME and promoting tumorigenesis, invasion, metastasis and immunosuppression. Furthermore, we illustrate the effects and mechanisms of CMM targeting TAMs in antitumor therapy. Finally, we reveal the CMM's dual-regulatory and multi-targeting functions on regulating TAMs, and hopefully, provide the theoretical basis for CMM clinical practice related to cancer therapy.

Tumor-associated macrophages: implications in cancer immunotherapy.

PubMed

Petty, Amy J; Yang, Yiping

2017-03-01

Tumor-associated macrophages (TAMs), representing most of the leukocyte population in solid tumors, demonstrate great phenotypic heterogeneity and diverse functional capabilities under the influence of the local tumor microenvironment. These anti-inflammatory and protumorigenic macrophages modulate the local microenvironment to facilitate tumor growth and metastasis. In this review, we examine the origin of TAMs and the complex regulatory networks within the tumor microenvironment that facilitate the polarization of TAMs toward a protumoral phenotype. More extensively, we evaluate the mechanisms by which TAMs mediate angiogenesis, metastasis, chemotherapeutic resistance and immune evasion. Lastly, we will highlight novel interventional strategies targeting TAMs in preclinical studies and in early clinical trials that have significant potential in improving efficacy of current chemotherapeutic and/or immunotherapeutic approaches.

Magnetic Resonance Imaging of Tumor Associated Macrophages: Clinical Translation.

PubMed

Aghighi, Maryam; Theruvath, Ashok Joseph; Pareek, Anuj; Pisani, Laura; Alford, Raphael; Muehe, Anne Monika; Sethi, Tarsheen K; Holdsworth, Samantha J; Hazard, Florette K; Gratzinger, Dita; Luna-Fineman, Sandra; Advani, Ranjana H; Spunt, Sheri L; Daldrup-Link, Heike E

2018-05-15

Tumor associated macrophages (TAM) in malignant tumors have been linked to tumor aggressiveness and represent a new target for cancer immunotherapy. As new TAM-targeted immunotherapies are entering clinical trials, it is important to detect and quantify TAM with non-invasive imaging techniques. The purpose of this study was to determine if ferumoxytol-enhanced MRI can detect TAM in lymphomas and bone sarcomas of pediatric patients and young adults. In a first-in-patient , IRB-approved prospective clinical trial, 25 pediatric and young adult patients with lymphoma or bone sarcoma underwent ferumoxytol-enhanced MRI. To confirm ferumoxytol enhancement, five pilot patients (2 lymphoma, 3 bone sarcoma) underwent pre- and post-contrast MRI. Subsequently, 20 patients (10 lymphoma, 10 bone sarcoma) underwent ferumoxytol-enhanced MRI 24-48 hours after intravenous injection, followed by tumor biopsy/resection and macrophage staining. To determine if ferumoxytol-MRI can differentiate tumors with different TAM content, we compared T2* relaxation times of lymphomas and bone sarcomas. Tumor T2* values of 20 patients were correlated with CD68+ and CD163+ TAM quantities on histopathology. Significant ferumoxytol tumor enhancement was noted on post-contrast scans compared to pre-contrast scans ( P = 0.036). Bone sarcomas and lymphomas demonstrated significantly different MRI enhancement and TAM density ( P < 0.05). Within each tumor group, T2* signal enhancement on MR images correlated significantly with the density of CD68+ and CD163+ TAM ( P < 0.05). Ferumoxytol-enhanced MRI is immediately clinically applicable and could be used to stratify patients with TAM-rich tumors to immune-targeted therapies and to monitor tumor response to these therapies. Copyright ©2018, American Association for Cancer Research.

In Vitro and In Vivo Effects of Jia-Wei-Xiao-Yao-San in Human Breast Cancer MCF-7 Cells Treated With Tamoxifen.

PubMed

Chen, Jiun-Liang; Chang, Chun-Ju; Wang, Jir-You; Wen, Che-Sheng; Tseng, Ling-Ming; Chang, Wen-Chi; Noomhorm, Nattanant; Liu, Hui-Ju; Chen, Wei-Shone; Chiu, Jen-Hwey; Shyr, Yi-Ming

2014-05-01

There is epidemiological evidence that Jia-Wei-Xiao-Yao-San (JWXYS) is the most common Chinese medicine decoction coprescribed with tamoxifen (Tam) when breast cancer is treated by hormonal therapy. However, whether there is interaction between JWXYS and Tam remains to be clarified. The aim of this study was to investigate the in vitro and in vivo effects of JWXYS on human breast cancer MCF-7 cells treated with Tam. In vitro cultured MCF-7 cells were cotreated with JWXYS and Tam. This was followed by MTT ([4,5-cimethylthiazol-2-yl]- 2,5-diphenyl tetrazolium bromide) assays and cell cycle analysis to assess cell proliferation; Western blot analysis was used to analyze the expression of various proteins involved in growth-related signal pathways. In addition, immunohistochemistry was used to detect autophagy among the cancer cells. In vivo analysis used female athymic nude mice implanted with MCF-7 cells; these mice were randomly assigned to 6 groups. All mice were killed humanely after 21 days of treatment; body weight, tumor volume, and tumor weight were then measured. JWXYS was not cytotoxic to MCF-7 cells, based on the fact that there were no statistically significant changes between the JWXYS + Tam groups and the Tam-alone group in cell numbers, cell cycle progression, and cell proliferation signals, the latter including the expression levels of AKT, ERK, P38, p27(Kip1), and light chain (LC3)-I, II. Furthermore, using the MCF-7 xenograft mouse model, there were no significant changes between the JWXYS (1.3-3.9 gm/kg) + Tam groups and the Tam-alone group in terms of tumor weight and the protein expression levels of AKT, ERK, P38, and p27 (Kip1). However, there was a significant decrease in LC3-II protein expression with the low-dose JWXYS + Tam group but not with the middle- or high-dose JWXYS + Tam groups compared with the Tam-alone group. Based on in vitro studies and in vivo functional studies, there is no obvious interaction between JWXYS and Tam. However

48 CFR 1201.301 - Policy.

Code of Federal Regulations, 2011 CFR

2011-10-01

... the Transportation Acquisition Manual (TAM). OA procedures necessary to implement or supplement the (FAR) 48 CFR chapter 1, (TAR) 48 CFR chapter 12, or TAM may be issued by the Head of the Contracting... procedures may be more restrictive or require higher approval levels than those permitted by the TAM unless...

Tumor-associated macrophages promote neuroblastoma via STAT3 phosphorylation and up-regulation of c-MYC

PubMed Central

Hadjidaniel, Michael D.; Muthugounder, Sakunthala; Hung, Long T.; Sheard, Michael A.; Shirinbak, Soheila; Chan, Randall Y.; Nakata, Rie; Borriello, Lucia; Malvar, Jemily; Kennedy, Rebekah J.; Iwakura, Hiroshi; Akamizu, Takashi; Sposto, Richard; Shimada, Hiroyuki; DeClerck, Yves A.; Asgharzadeh, Shahab

2017-01-01

Tumor-associated macrophages (TAMs) are strongly associated with poor survival in neuroblastomas that lack MYCN amplification. To study TAM action in neuroblastomas, we used a novel murine model of spontaneous neuroblastoma lacking MYCN amplification, and observed recruitment and polarization of TAMs, which in turn enhanced neuroblastoma proliferation and growth. In both murine and human neuroblastoma cells, we found that TAMs increased STAT3 activation in neuroblastoma cells and transcriptionally up-regulated the MYC oncogene. Analysis of human neuroblastoma tumor specimens revealed that MYC up-regulation correlates with markers of TAM infiltration. In an IL6ko neuroblastoma model, the absence of IL-6 protein had no effect on tumor development and prevented neither STAT3 activation nor MYC up-regulation. In contrast, inhibition of JAK-STAT activation using AZD1480 or the clinically admissible inhibitor ruxolitinib significantly reduced TAM-mediated growth of neuroblastomas implanted subcutaneously in NOD scid gamma mice. Our results point to a unique mechanism in which TAMs promote tumor cells that lack amplification of an oncogene common to the malignancy by up-regulating transcriptional expression of a distinct oncogene from the same gene family, and underscore the role of IL-6-independent activation of STAT3 in this mechanism. Amplification of MYCN or constitutive up-regulation of MYC protein is observed in approximately half of high-risk tumors; our findings indicate a novel role of TAMs as inducers of MYC expression in neuroblastomas lacking independent oncogene activation. PMID:29207662

Hypomethylation associated enhanced transcription of trefoil factor-3 mediates tamoxifen-stimulated oncogenicity of ER+ endometrial carcinoma cells.

PubMed

Pandey, Vijay; Zhang, Min; Chong, Qing-Yun; You, Mingliang; Raquib, Ainiah Rushdiana; Pandey, Amit K; Liu, Dong-Xu; Liu, Liang; Ma, Lan; Jha, Sudhakar; Wu, Zheng-Sheng; Zhu, Tao; Lobie, Peter E

2017-09-29

Tamoxifen (TAM) is widely used as an adjuvant therapy for women with breast cancer (BC). However, TAM possesses partial oestrogenic activity in the uterus and its use has been associated with an increased incidence of endometrial carcinoma (EC). The molecular mechanism for these observations is not well understood. Herein, we demonstrated that forced expression of Trefoil factor 3 ( TFF3) , in oestrogen receptor-positive (ER+) EC cells significantly increased cell cycle progression, cell survival, anchorage-independent growth, invasiveness and tumour growth in xenograft models. Clinically, elevated TFF3 protein expression was observed in EC compared with normal endometrial tissue, and its increased expression in EC was significantly associated with myometrial invasion. TAM exposure increased expression of TFF3 in ER+ EC cells and its elevated expression resulted in increased oncogenicity and invasiveness. TAM-stimulated expression of TFF3 in EC cells was associated with hypomethylation of the TFF3 promoter sequence and c-JUN/SP1-dependent transcriptional activation. In addition, small interfering ( si) RNA -mediated depletion or polyclonal antibody inhibition of TFF3 significantly abrogated oncogenicity and invasiveness in EC cells consequent to TAM induction or forced expression of TFF3. Hence, TAM-stimulated upregulation of TFF3 in EC cells was critical in promoting EC progression associated with TAM treatment. Importantly, inhibition of TFF3 function might be an attractive molecular modality to abrogate the stimulatory effects of TAM on endometrial tissue and to limit the progression of EC.

The Prognostic and Clinicopathological Significance of Tumor-Associated Macrophages in Patients with Gastric Cancer: A Meta-Analysis.

PubMed

Yin, Songcheng; Huang, Jinyu; Li, Zhan; Zhang, Junyan; Luo, Jiazi; Lu, Chunyang; Xu, Hao; Xu, Huimian

2017-01-01

Comprehensive studies have investigated the prognostic and clinicopathological value of tumor-associated macrophages (TAMs) in gastric cancer patients, yet results remain controversial. Therefore, we performed a meta-analysis to clarify this issue. PubMed, Embase, and the Cochrane Library databases were searched to identify eligible studies. We extracted hazard ratios (HRs) and odds ratios (ORs) with their corresponding 95% confidence intervals (95% CIs) to estimate the effect sizes. In addition, subgroup analysis and sensitivity analysis were also conducted. A total of 19 studies involving 2242 patients were included. High generalised TAMs density was significantly associated with poor overall survival (OS) (HR 1.49, 95% CI 1.15-1.95). Subgroup analysis revealed that CD68+ TAMs had no significant effect on OS (HR 1.38, 95% CI 1.00-1.91). High M1 TAMs density was correlated with better OS (HR 0.45, 95% CI 0.32-0.65). By contrast, high density of M2 TAMs was correlated with a poor prognosis for OS (HR 1.48, 95% CI 1.25-1.75). Furthermore, high M2 TAMs density was correlated with larger tumor size, diffuse Lauren type, poor histologic differentiation, deeper tumor invasion, lymph node metastasis, and advanced TNM stage. Overall, this meta-analysis reveal that although CD68+ TAMs infiltration has the neutral prognostic effects on OS, the M1/M2 polarization of TAMs are predicative factor of prognosis in gastric cancer patients.

Tamoxifen resistance and metastasis of human breast cancer cells were mediated by the membrane-associated estrogen receptor ER-α36 signaling in vitro.

PubMed

Gu, Wenwen; Dong, Nian; Wang, Peng; Shi, Changgen; Yang, Jun; Wang, Jian

2017-04-01

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. The mechanism of TAM resistance in the ER + breast cancer cell line MCF-7 was investigated, and the results showed that the stimulating effect of insulin on susceptibility of MCF-7 to TAM was mediated by ER-α36 and that the expression level of ER-α36 in TAM-resistant MCF-7 cells was also significantly increased. Both TAM and estradiol (E2) could promote the migration of triple negative (ER-α66 - /PR - /HER2 - ) and ER-α36 + /GPER1 + breast cancer cells MDA-MB-231. The migration of MDA-MB-231 cells was inhibited by the down-regulated intracellular expression of ER-α36 by transient transfection of specific small interfering RNA, whereas no effect of GPER1 down-regulation was observed. Meanwhile, the effect of TAM on the migration of ER-α36-down-regulated MDA-MB-231 cells was also reduced. Furthermore, it was found that TAM enhanced the distribution of integrin β1 on the cell surface but did not affect the expression of integrin β1 in MDA-MB-231 cells. Collectively, these data suggested that ER-α36 signaling might play critical roles in acquired and de novo TAM resistance and metastasis of breast cancer, and ER-α36 might present a potential biomarker of TAM resistance in the clinical diagnosis and treatment of ER + breast cancer.

Peroxidase-mediated dealkylation of tamoxifen, detected by electrospray ionization-mass spectrometry, and activation to form DNA adducts.

PubMed

Gaikwad, Nilesh W; Bodell, William J

2012-01-15

Tamoxifen (TAM) is extensively used for the treatment and prevention of breast cancer. Associated with TAM treatment is a two- to eightfold increase in risk of endometrial cancer. To understand the mechanisms associated with this increased risk several pathways for TAM metabolism and DNA adduct formation have been studied. The purpose of this study was to investigate the role of peroxidase enzymes in the metabolism of TAM and its activation to form DNA adducts. Using advanced tandem mass spectrometry we have investigated the peroxidase-mediated metabolism of TAM. Incubation of TAM with horseradish peroxidase (HRP) and H(2)O(2) produced multiple metabolites. Electrospray ionization-MS/MS analysis of the metabolites demonstrated a peak at 301.3m/z with daughter ions at 183.0, 166.9, 128.9, and 120.9m/z, which identified the metabolite as metabolite E (ME). The levels of ME were significantly inhibited by the addition of ascorbic acid to the incubation mixture. Co-incubation of either TAM or ME and DNA with HRP and H(2)O(2) produced three DNA adducts with a RAL of 1.97±0.01×10(-7) and 8.45±2.7×10(-7). Oxidation of ME with MnO(2) produced metabolite E quinone methide (MEQM). Furthermore, incubation of either TAM or ME with HRP and H(2)O(2) resulted in formation of MEQM. Reaction of calf thymus DNA with MEQM produced three DNA adducts with a RAL of 9.8±1.0×10(-7). Rechromatography analyses indicated that DNA adducts 1, 2, and 3 formed in the HRP activation of either TAM or ME were the same as those formed by the chemical reaction of DNA with MEQM. The results of these studies demonstrate that peroxidase enzymes can both metabolize TAM to form the primary metabolite ME and activate ME to a quinone methide intermediate, which reacts with DNA to form adducts. It is possible that peroxidase enzymes or peroxidase-like activity in endometrium could contribute to the formation of DNA damage and genotoxic effects in endometrium after TAM administration. Published by

Harnessing the cross-talk between tumor cells and tumor-associated macrophages with a nano-drug for modulation of glioblastoma immune microenvironment.

PubMed

Li, Tong-Fei; Li, Ke; Wang, Chao; Liu, Xin; Wen, Yu; Xu, Yong-Hong; Zhang, Quan; Zhao, Qiu-Ya; Shao, Ming; Li, Yan-Ze; Han, Min; Komatsu, Naoki; Zhao, Li; Chen, Xiao

2017-12-28

Glioblastoma (GBM) is the most frequent and malignant brain tumor with a high mortality rate. The presence of a large population of macrophages (Mφ) in the tumor microenvironment is a prominent feature of GBM and these so-called tumor-associated Mφ (TAM) closely interact with the GBM cells to promote the survival, progression and therapy resistance of the GBM. Various therapeutic strategies have been devised either targeting the GBM cells or the TAM but few have addressed the cross-talks between the two cell populations. The present study was carried out to explore the possibility of exploiting the cross-talks between the GBM cells (GC) and TAM for modulation of the GBM microenvironment through using Nano-DOX, a drug composite based on nanodiamonds bearing doxorubicin. In the in vitro work on human cell models, Nano-DOX-loaded TAM were first shown to be viable and able to infiltrate three-dimensional GC spheroids and release cargo drug therein. GC were then demonstrated to encourage Nano-DOX-loaded TAM to unload Nano-DOX back into GC which consequently emitted damage-associated molecular patterns (DAMPs) that are powerful immunostimulatory agents as well as indicators of cell damage. Nano-DOX was next proven to be a more potent inducer of GC DAMPs emission than doxorubicin. As a result, Nano-DOX-damaged GC exhibited an enhanced ability to attract both TAM and Nano-DOX-loaded TAM. Most remarkably, Nano-DOX-damaged GC reprogrammed the TAM from a pro-GBM phenotype to an anti-GBM phenotype that suppressed GC growth. Finally, the in vivo relevance of the in vitro findings was tested in animal study. Mice bearing orthotopic human GBM xenografts were intravenously injected with Nano-DOX-loaded mouse TAM which were found releasing drug in the GBM xenografts 24h after injection. GC damage was evidenced by the induction of DAMPs emission within the xenografts and a shift of TAM phenotype was detected as well. Taken together, our results demonstrate a novel way with

Cancer-promoting tumor-associated macrophages: new vistas and open questions.

PubMed

Mantovani, Alberto; Germano, Giovanni; Marchesi, Federica; Locatelli, Marco; Biswas, Subhra K

2011-09-01

Tumor-associated macrophages (TAMs) are key components of the tumor macroenvironment. Cancer- and host cell-derived signals generally drive the functions of TAMs towards an M2-like polarized, tumor-propelling mode; however, when appropriately re-educated. TAMs also have the potential to elicit tumor destructive reactions. Here, we discuss recent advances regarding the immunobiology of TAMs and highlight open questions including the mechanisms of their accumulation (recruitment versus proliferation), their diversity and how to best therapeutically target these cells. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Dectin-1 Activation by a Natural Product β-Glucan Converts Immunosuppressive Macrophages into an M1-like Phenotype

PubMed Central

Liu, Min; Luo, Fengling; Ding, Chuanlin; Albeituni, Sabrin; Hu, Xiaoling; Ma, Yunfeng; Cai, Yihua; McNally, Lacey; Sanders, Mary Ann; Jain, Dharamvir; Kloecker, Goetz; Bousamra, Michael; Zhang, Huang-ge; Higashi, Richard M.; Lane, Andrew N.; Fan, Teresa W-M.; Yan, Jun

2015-01-01

Tumor-associated macrophages (TAM) with an M2-like phenotype have been linked to tumor-elicited inflammation, immunosuppression, and resistance to chemotherapies in cancer, thus representing an attractive target for an effective cancer immunotherapy. Here, we demonstrate that particulate yeast-derived β-glucan, a natural polysaccharide compound, converts polarized M2 macrophages or immunosuppressive TAM into an M1-like phenotype with potent immuno-stimulating activity. This process is associated with macrophage metabolic reprograming with enhanced glycolysis, krebs cycle and glutamine utilization. In addition, particulate β-glucan converts immunosuppressive TAM via the C-type lectin receptor dectin-1-induced Syk-Card9-Erk pathway. Further in vivo studies show that oral particulate β-glucan treatment significantly delays tumor growth, which is associated with in vivo TAM phenotype conversion and enhanced effector T cell activation. Mice injected with particulate β-glucan-treated TAM mixed with tumor cells have significantly reduced tumor burden with less blood vascular vessels compared to those with TAM plus tumor cell injection. In addition, macrophage depletion significantly reduced the therapeutic efficacy of particulate β-glucan in tumor-bearing mice. These findings have established a new paradigm for macrophage polarization and immunosuppressive TAM conversion and shed the light on the action mode of β-glucan treatment in cancer. PMID:26453753

CDDO-Me Redirects Activation of Breast Tumor Associated Macrophages.

PubMed

Ball, Michael S; Shipman, Emilie P; Kim, Hyunjung; Liby, Karen T; Pioli, Patricia A

2016-01-01

Tumor-associated macrophages can account for up to 50% of the tumor mass in breast cancer patients and high TAM density is associated with poor clinical prognosis. Because TAMs enhance tumor growth, development, and metastatic potential, redirection of TAM activation may have significant therapeutic benefit. Our studies in primary human macrophages and murine breast TAMs suggest that the synthetic oleanane triterpenoid CDDO-methyl ester (CDDO-Me) reprograms the activation profile of TAMs from tumor-promoting to tumor-inhibiting. We show that CDDO-Me treatment inhibits expression of IL-10 and VEGF in stimulated human M2 macrophages and TAMs but increases expression of TNF-α and IL-6. Surface expression of CD206 and CD163, which are characteristic of M2 activation, is significantly attenuated by CDDO-Me. In contrast, CDDO-Me up-regulates surface expression of HLA-DR and CD80, which are markers of M1 activation, and importantly potentiates macrophage activation of autologous T cells but inhibits endothelial cell vascularization. These results show for the first time that CDDO-Me redirects activation of M2 macrophages and TAMs from immune-suppressive to immune-stimulatory, and implicate a role for CDDO-Me as an immunotherapeutic in the treatment of breast and potentially other types of cancer.

CDDO-Me Redirects Activation of Breast Tumor Associated Macrophages

PubMed Central

Ball, Michael S.; Shipman, Emilie P.; Kim, Hyunjung; Liby, Karen T.; Pioli, Patricia A.

2016-01-01

Tumor-associated macrophages can account for up to 50% of the tumor mass in breast cancer patients and high TAM density is associated with poor clinical prognosis. Because TAMs enhance tumor growth, development, and metastatic potential, redirection of TAM activation may have significant therapeutic benefit. Our studies in primary human macrophages and murine breast TAMs suggest that the synthetic oleanane triterpenoid CDDO-methyl ester (CDDO-Me) reprograms the activation profile of TAMs from tumor-promoting to tumor-inhibiting. We show that CDDO-Me treatment inhibits expression of IL-10 and VEGF in stimulated human M2 macrophages and TAMs but increases expression of TNF-α and IL-6. Surface expression of CD206 and CD163, which are characteristic of M2 activation, is significantly attenuated by CDDO-Me. In contrast, CDDO-Me up-regulates surface expression of HLA-DR and CD80, which are markers of M1 activation, and importantly potentiates macrophage activation of autologous T cells but inhibits endothelial cell vascularization. These results show for the first time that CDDO-Me redirects activation of M2 macrophages and TAMs from immune-suppressive to immune-stimulatory, and implicate a role for CDDO-Me as an immunotherapeutic in the treatment of breast and potentially other types of cancer. PMID:26918785

Nanomedicine Strategies to Target Tumor-Associated Macrophages

PubMed Central

Binnemars-Postma, Karin; Storm, Gert; Prakash, Jai

2017-01-01

In recent years, the influence of the tumor microenvironment (TME) on cancer progression has been better understood. Macrophages, one of the most important cell types in the TME, exist in different subtypes, each of which has a different function. While classically activated M1 macrophages are involved in inflammatory and malignant processes, activated M2 macrophages are more involved in the wound-healing processes occurring in tumors. Tumor-associated macrophages (TAM) display M2 macrophage characteristics and support tumor growth and metastasis by matrix remodeling, neo-angiogenesis, and suppressing local immunity. Due to their detrimental role in tumor growth and metastasis, selective targeting of TAM for the treatment of cancer may prove to be beneficial in the treatment of cancer. Due to the plastic nature of macrophages, their activities may be altered to inhibit tumor growth. In this review, we will discuss the therapeutic options for the modulation and targeting of TAM. Different therapeutic strategies to deplete, inhibit recruitment of, or re-educate TAM will be discussed. Current strategies for the targeting of TAM using nanomedicine are reviewed. Passive targeting using different nanoparticle systems is described. Since TAM display a number of upregulated surface proteins compared to non-TAM, specific targeting using targeting ligands coupled to nanoparticles is discussed in detail. PMID:28471401

48 CFR 1201.104 - Applicability.

Code of Federal Regulations, 2010 CFR

2010-10-01

... Transportation Acquisition Manual (TAM): (1) Statute; (2) (FAR) 48 CFR chapter 1 or other applicable regulation; (3) (TAR) 48 CFR chapter 12; (4) DOT Orders; and (5) TAM. (c) The Maritime Administration may depart... CFR chapter 1, (TAR) 48 CFR chapter 12 and TAM do not apply to the Federal Aviation Administration as...

Validating the Technology Acceptance Model in the Context of the Laboratory Information System-Electronic Health Record Interface System

ERIC Educational Resources Information Center

Aquino, Cesar A.

2014-01-01

This study represents a research validating the efficacy of Davis' Technology Acceptance Model (TAM) by pairing it with the Organizational Change Readiness Theory (OCRT) to develop another extension to the TAM, using the medical Laboratory Information Systems (LIS)--Electronic Health Records (EHR) interface as the medium. The TAM posits that it is…

48 CFR 1201.104 - Applicability.

Code of Federal Regulations, 2011 CFR

2011-10-01

... Transportation Acquisition Manual (TAM): (1) Statute; (2) (FAR) 48 CFR chapter 1 or other applicable regulation; (3) (TAR) 48 CFR chapter 12; (4) DOT Orders; and (5) TAM. (c) The Maritime Administration may depart... CFR chapter 1, (TAR) 48 CFR chapter 12 and TAM do not apply to the Federal Aviation Administration as...

Characterization of dynamics in complex lyophilized formulations: I. Comparison of relaxation times measured by isothermal calorimetry with data estimated from the width of the glass transition temperature region.

PubMed

Chieng, Norman; Mizuno, Masayasu; Pikal, Michael

2013-10-01

The purposes of this study are to characterize the relaxation dynamics in complex freeze dried formulations and to investigate the quantitative relationship between the structural relaxation time as measured by thermal activity monitor (TAM) and that estimated from the width of the glass transition temperature (ΔT(g)). The latter method has advantages over TAM because it is simple and quick. As part of this objective, we evaluate the accuracy in estimating relaxation time data at higher temperatures (50 °C and 60 °C) from TAM data at lower temperature (40 °C) and glass transition region width (ΔT(g)) data obtained by differential scanning calorimetry. Formulations studied here were hydroxyethyl starch (HES)-disaccharide, HES-polyol, and HES-disaccharide-polyol at various ratios. We also re-examine, using TAM derived relaxation times, the correlation between protein stability (human growth hormone, hGH) and relaxation times explored in a previous report, which employed relaxation time data obtained from ΔT(g). Results show that most of the freeze dried formulations exist in single amorphous phase, and structural relaxation times were successfully measured for these systems. We find a reasonably good correlation between TAM measured relaxation times and corresponding data obtained from estimates based on ΔT(g), but the agreement is only qualitative. The comparison plot showed that TAM data are directly proportional to the 1/3 power of ΔT(g) data, after correcting for an offset. Nevertheless, the correlation between hGH stability and relaxation time remained qualitatively the same as found with using ΔT(g) derived relaxation data, and it was found that the modest extrapolation of TAM data to higher temperatures using ΔT(g) method and TAM data at 40 °C resulted in quantitative agreement with TAM measurements made at 50 °C and 60 °C, provided the TAM experiment temperature, is well below the Tg of the sample. Copyright © 2013 Elsevier B.V. All rights

Characterization of Dynamics in Complex Lyophilized Formulations: I. Comparison of Relaxation Times Measured by Isothermal Calorimetry with Data Estimated from the Width of the Glass Transition Temperature Region

PubMed Central

Chieng, Norman; Mizuno, Masayasu; Pikal, Michael

2013-01-01

The purposes of this study are to characterize the relaxation dynamics in complex freeze dried formulations and to investigate the quantitative relationship between the structural relaxation time as measured by thermal activity monitor (TAM) and that estimated from the width of the glass transition temperature (ΔTg). The latter method has advantages over TAM because it is simple and quick. As part of this objective, we evaluate the accuracy in estimating relaxation time data at higher temperatures (50°C and 60°C) from TAM data at lower temperature (40°C) and glass transition region width (ΔTg) data obtained by differential scanning calorimetry. Formulations studied here were hydroxyethyl starch (HES)-disaccharide, HES-polyol and HES-disaccharide-polyol at various ratios. We also re-examine, using TAM derived relaxation times, the correlation between protein stability (human growth hormone, hGH) and relaxation times explored in a previous report, which employed relaxation time data obtained from ΔTg. Results show that most of the freeze dried formulations exist in single amorphous phase, and structural relaxation times were successfully measured for these systems. We find a reasonably good correlation between TAM measured relaxation times and corresponding data obtained from estimates based on ΔTg, but the agreement is only qualitative. The comparison plot showed that TAM data is directly proportional to the 1/3 power of ΔTg data, after correcting for an offset. Nevertheless, the correlation between hGH stability and relaxation time remained qualitatively the same as found with using ΔTg derived relaxation data, and it was found that the modest extrapolation of TAM data to higher temperatures using ΔTg method and TAM data at 40°C resulted in quantitative agreement with TAM measurements made at 50 °C and 60 °C, provided the TAM experiment temperature is well below the Tg of the sample. PMID:23608636

Tamoxifen induces the expression of maspin through estrogen receptor-alpha.

PubMed

Liu, Zesheng; Shi, Heidi Y; Nawaz, Zafar; Zhang, Ming

2004-06-08

Maspin (mammary serine protease inhibitor) is a tumor suppressor gene that plays an important role in inhibiting tumor growth, invasion and metastasis. Maspin expression is down regulated at transcription level in primary and metastatic breast tumor cells. Previous studies on hormonal regulation of maspin prompt us to test whether an estrogen antagonist tamoxifen (TAM) can exert its anti-tumor function by up regulating maspin gene expression. For this purpose, we first tested whether maspin promoter could be activated in normal and several breast tumor cells. We then carried out a series of promoter analysis in which estrogen receptors and TAM were reconstituted in an in vitro cell culture system. Here we report our new finding that tumor suppresser gene maspin is one of the TAM target genes. TAM induces a maspin/luciferase reporter in cell culture and this induction requires the presence of (estrogen receptor alpha) ERalpha but not estrogen receptor-beta (ERbeta). Maspin promoter deletion and mutation analysis showed that the cis element(s) within a region between -90and+87 bp but not the HRE site (-272 bp) was involved in TAM induction of maspin expression. TAM bound ERalpha may directly control maspin gene expression through the interaction with cofactor (s). Analysis using several ERalpha mutants showed that the N-terminal A/B motif (AF-1) was critical for maspin basal level transcription activation. An ERalpha mutant with point mutations at DNA binding domain abolished estrogen induction of an ERE-luciferase reporter but was still active in activating maspin promoter by TAM. LBD-AF2 domain was required for ERalpha-dependent TAM induction. Deletion of LBD-AF2 or a point mutation in the ERalpha LBD-AF2 region (LBDmtL539A) completely abolished the activation of maspin promoter, suggesting that TAM induction of maspin involves the recruitment of cofactor(s) by ERalpha to the maspin promoter region. This finding indicates that one of the pathways for cancer

Infiltration of diametrically polarized macrophages predicts overall survival of patients with gastric cancer after surgical resection.

PubMed

Zhang, Heng; Wang, Xuefei; Shen, Zhenbin; Xu, Jiejie; Qin, Jing; Sun, Yihong

2015-10-01

Tumor-associated macrophages (TAMs), the most predominant tumor-infiltrating immune cells, are emerging prognostic factors and therapeutic targets for personalized therapy against malignant neoplasms. We aimed to evaluate the prognostic significance of diametrically polarized TAMs in gastric cancer and generate a predictive nomogram to refine a risk stratification system. We evaluated polarized functional status of infiltrated TAMs by immunohistochemical staining of CD68, CD11c, and CD206 in 180 consecutive gastric cancer patients from Zhongshan Hospital, Shanghai, China. Prognostic values were assessed in these patients. We created a predictive nomogram by integrating polarized TAMs with the TNM staging system for overall survival of gastric cancer patients. CD68(+) TAMs display polarized programs comprising CD11c(+) proinflammatory macrophages (M1) and CD206(+) immunosuppressive macrophages (M2) that configure versatile infiltration files in gastric cancer. CD11c(+) TAMs negatively correlated with lymph node metastasis (p = 0.012), whereas CD206(+) TAMs correlated with the Lauren classification (p = 0.031). No prognostic difference was observed for overall survival for CD68 density (high vs low, p = 0.1031), whereas high versus low CD11c density (p < 0.0001) and low vs high CD206 density (p = 0.0105) indicate better overall survival. Multivariate Cox regression analysis identified CD11c and CD206 as independent prognostic factors (p < 0.001 and p = 0.030, respectively), which could be integrated with the TNM staging system to generate a predictive nomogram for patient outcomes. Infiltration of polarized TAMs, a novel identified independent prognostic factor, could be combined with the TNM stage to refine a risk stratification system and better stratify patients with different prognosis. Tipping TAMs to an antitumoral phenotype might be a promising therapeutic target for postoperative treatment.

Involvement of multiple cellular pathways in regulating resistance to tamoxifen in BIK-suppressed MCF-7 cells.

PubMed

Viedma-Rodríguez, Rubí; Ruiz Esparza-Garrido, Ruth; Baiza-Gutman, Luis Arturo; Velázquez-Flores, Miguel Ángel; García-Carrancá, Alejandro; Salamanca-Gómez, Fabio; Arenas-Aranda, Diego

2015-09-01

Majority of women with estrogen receptor (ER)-positive breast cancers initially respond to hormone therapies such as tamoxifen (TAM; antagonist of estrogen). However, many tumors eventually become resistant to TAM. Therefore, understanding the various cellular components involved in causing resistance to TAM is of paramount importance in designing novel entities for efficacious hormone therapy. Previously, we found that suppression of BIK gene expression induced TAM resistance in MCF-7 breast cancer cells. In order to understand the response of these cells to TAM and its association with resistance, a microarray analysis of gene expression was performed in the BIK-suppressed MCF-7 cells and compared it to the TAM-only-treated cells (controls). Several genes participating in various cellular pathways were identified. Molecules identified in the drug resistance pathway were 14-3-3z or YWHAZ, WEE1, PRKACA, NADK, and HSP90AA 1. Further, genes involved in cell cycle control, apoptosis, and cell proliferation were also found differentially expressed in these cells. Transcriptional and translational analysis of key molecules such as STAT2, AKT 3, and 14-3-3z revealed similar changes at the messenger RNA (mRNA) as well as at the protein level. Importantly, there was no cytotoxic effect of TAM on BIK-suppressed MCF-7 cells. Further, these cells were not arrested at the G0-G1 phase of the cell cycle although 30 % of BIK-suppressed cells were arrested at the G2 phase of the cycle on TAM treatment. Furthermore, we found a relevant interaction between 14-3-3z and WEE1, suggesting that the cytotoxic effect of TAM was prevented in BIK-suppressed cells because this interaction leads to transitory arrest in the G2 phase leading to the repair of damaged DNA and allowing the cells to proliferate.

Quantitative monitoring of tamoxifen in human plasma extended to 40 metabolites using liquid-chromatography high-resolution mass spectrometry: new investigation capabilities for clinical pharmacology.

PubMed

Dahmane, Elyes; Boccard, Julien; Csajka, Chantal; Rudaz, Serge; Décosterd, Laurent; Genin, Eric; Duretz, Bénédicte; Bromirski, Maciej; Zaman, Khalil; Testa, Bernard; Rochat, Bertrand

2014-04-01

Liquid-chromatography (LC) high-resolution (HR) mass spectrometry (MS) analysis can record HR full scans, a technique of detection that shows comparable selectivity and sensitivity to ion transitions (SRM) performed with triple-quadrupole (TQ)-MS but that allows de facto determination of "all" ions including drug metabolites. This could be of potential utility in in vivo drug metabolism and pharmacovigilance studies in order to have a more comprehensive insight in drug biotransformation profile differences in patients. This simultaneous quantitative and qualitative (Quan/Qual) approach has been tested with 20 patients chronically treated with tamoxifen (TAM). The absolute quantification of TAM and three metabolites in plasma was realized using HR- and TQ-MS and compared. The same LC-HR-MS analysis allowed the identification and relative quantification of 37 additional TAM metabolites. A number of new metabolites were detected in patients' plasma including metabolites identified as didemethyl-trihydroxy-TAM-glucoside and didemethyl-tetrahydroxy-TAM-glucoside conjugates corresponding to TAM with six and seven biotransformation steps, respectively. Multivariate analysis allowed relevant patterns of metabolites and ratios to be associated with TAM administration and CYP2D6 genotype. Two hydroxylated metabolites, α-OH-TAM and 4'-OH-TAM, were newly identified as putative CYP2D6 substrates. The relative quantification was precise (<20 %), and the semiquantitative estimation suggests that metabolite levels are non-negligible. Metabolites could play an important role in drug toxicity, but their impact on drug-related side effects has been partially neglected due to the tremendous effort needed with previous MS technologies. Using present HR-MS, this situation should evolve with the straightforward determination of drug metabolites, enlarging the possibilities in studying inter- and intra-patients drug metabolism variability and related effects.

Effect of tamoxifen, methoxyprogesterone acetate and combined treatment on cellular proliferation and apoptosis in SKOV3/DDP cells via the regulation of vascular endothelial growth factor.

PubMed

Wen, Lv; Hong, Ding; Yanyin, Wu; Mingyue, Zhang; Baohua, Li

2013-05-01

The aim of this study was to investigate the effect of tamoxifen (TAM), methoxyprogesterone acetate (MPA) and their combined treatment on cisplatin-resistant ovarian cancer SKOV3/DDP cells, as well as the potential mechanisms. MTT assay was used to investigate the effect of different concentrations (0.01, 0.1, 1, 10 and 100 μM) of TAM, MPA and their combined treatment on the proliferation of cisplatin-resistant ovarian cancer SKOV3/DDP cells. Flow cytometry was employed to analyze the cell cycle and apoptosis rate of SKOV3/DDP cells treated with medium concentration (10 μM) of TAM, MPA and their combined treatment. Change in the protein level of vascular endothelial growth factor (VEGF) in response to drug treatments was measured using Western-blot. The proliferation of SKOV3/DDP cells was inhibited by 1, 10 and 100 μM of TAM or MPA in a dose-dependent manner. Compared to the control group, 10 μM TAM could significantly arrest SKOV3/DDP cells in the G0/G1 stage and induce apoptosis (p < 0.01). However, 10 μM MPA only promoted cell apoptosis, while exhibited little effect on the cell cycle. We further found that 10 μM TAM could remarkably reduce the protein expression of VEGF, while 10 μM MPA only induce a slight reduction. Strikingly, the combined treatment of TAM and MPA exhibited additive effect on the proliferation, cell cycle, apoptosis rate and VEGF expression of SKOV3/DDP cells. We found that TAM, MPA and their combined treatment exhibited significant inhibitory effect on the cisplatin-resistant ovarian cancer SKOV3/DDP cells. Hence, TAM and MPA could be potential cytotoxic drugs to treat cisplatin-resistant patients with advanced ovarian cancer.

Examining the Moderating Effect of Individual-Level Cultural Values on Users' Acceptance of E-Learning in Developing Countries: A Structural Equation Modeling of an Extended Technology Acceptance Model

ERIC Educational Resources Information Center

Tarhini, Ali; Hone, Kate; Liu, Xiaohui; Tarhini, Takwa

2017-01-01

In this study, we examine the effects of individual-level culture on the adoption and acceptance of e-learning tools by students in Lebanon using a theoretical framework based on the Technology Acceptance Model (TAM). To overcome possible limitations of using TAM in developing countries, we extend TAM to include "subjective norms" (SN)…

Tirandamycin biosynthesis is mediated by co-dependent oxidative enzymes

NASA Astrophysics Data System (ADS)

Carlson, Jacob C.; Li, Shengying; Gunatilleke, Shamila S.; Anzai, Yojiro; Burr, Douglas A.; Podust, Larissa M.; Sherman, David H.

2011-08-01

Elucidation of natural product biosynthetic pathways provides important insights into the assembly of potent bioactive molecules, and expands access to unique enzymes able to selectively modify complex substrates. Here, we show full reconstitution, in vitro, of an unusual multi-step oxidative cascade for post-assembly-line tailoring of tirandamycin antibiotics. This pathway involves a remarkably versatile and iterative cytochrome P450 monooxygenase (TamI) and a flavin adenine dinucleotide-dependent oxidase (TamL), which act co-dependently through the repeated exchange of substrates. TamI hydroxylates tirandamycin C (TirC) to generate tirandamycin E (TirE), a previously unidentified tirandamycin intermediate. TirE is subsequently oxidized by TamL, giving rise to the ketone of tirandamycin D (TirD), after which a unique exchange back to TamI enables successive epoxidation and hydroxylation to afford, respectively, the final products tirandamycin A (TirA) and tirandamycin B (TirB). Ligand-free, substrate- and product-bound crystal structures of bicovalently flavinylated TamL oxidase reveal a likely mechanism for the C10 oxidation of TirE.

Rejecting Admission Offers to a Selective Math and Science School

ERIC Educational Resources Information Center

Jones, Brent M.

2014-01-01

An exploratory study of applicants who rejected admission to the Texas Academy of Mathematics and Science (TAMS) is described in this article. TAMS is a residential early college entry program at the University of North Texas in Denton. Up to 600 mathematically talented sophomores apply to TAMS each year and among the 200 selectees, a predictable…

Effect of alpha(1)-acid glycoprotein on the pharmacokinetics of tamsulosin in rats treated with turpentine oil.

PubMed

Matsushima, H; Watanabe, T; Higuchi, S

2000-04-01

The pharmacokinetics of tamsulosin (TAM) was investigated using male Sprague-Dawley rats in which plasma alpha(1)-acid glycoprotein (alpha(1)-AGP) levels were elevated by the subcutaneous injection of 0.2 mL/kg of turpentine oil. alpha(1)-AGP levels increased about eight times after turpentine oil treatment, causing a threefold decrease in plasma unbound fraction (f(u)) of TAM. When 0.3 mg/kg of TAM was dosed intravenously, total and nonrenal clearances (CL(tot) and CL(nr)) in turpentine-treated rats were 47% and 44% lower than those in nontreated controls, respectively. The area under the concentration-time curve of plasma unbound TAM (AUC(inf,u)) was lower than that in the control. When 1 mg/kg of TAM was dosed orally, oral clearance (CL(oral)) in alpha1-AGP-induced rats was 65% lower than in the control. The AUC(inf,u) and unbound oral clearance (CL(oral,u)) were nearly equal in both groups. Moreover, a positive correlation was observed between fu and CL(oral) of TAM (r(2) = 0.603, P < 0.01), whereas no correlation was observed between f(u) and CL(oral,u). The absolute bioavailability (BA) increased from 19.2% to 46.9% by induction of alpha(1)-AGP. These results suggest that decreased f(u) caused by the elevation of plasma alpha(1)-AGP level affects the pharmacokinetics of TAM, but does not affect the CL(oral,u,) which represents the hepatic metabolism of TAM. Copyright 2000 Wiley-Liss, Inc.

Developing analytical approaches to explore the connection between endocrine-active pharmaceuticals in water to effects in fish

USGS Publications Warehouse

Jones-Lepp, Tammy L.; Taniguchi-Fu, Randi L.; Morgan, Jade; Nance Jr., Trevor; Ward, Matthew; Alvarez, David A.; Mills, Lesley

2015-01-01

The emphasis of this research project was to develop and optimize a solid-phase extraction method and highperformance liquid chromatography-electrospray ionizationmass spectrometry method, such that a linkage between the detection of endocrine-active pharmaceuticals (EAPs) in the aquatic environment and subsequent effects on fish populations could eventually be studied. Four EAPs were studied: tamoxifen (TAM), exemestane (EXE), letrozole (LET), anastrozole (ANA); and three TAM metabolites: 4- hydroxytamoxifen, e/z endoxifen, and n-desmethyl tamoxifen. In aqueous matrices, the use of isotopically labeled standards for the EAPs allowed for the generation of good recoveries, greater than 80 %, and low relative standard deviations (% RSDs) (3 to 27 %). TAM metabolites had lower recoveries in the spiked water matrices: 35 to 93 % in waste/source water compared to 58 to 110 % in DI water. The precision in DI water was acceptable ranging from 8 to 38 % RSD. However, the precision in real environmental wastewaters could be poor, ranging from 15 to 120 % RSD, dependent upon unique matrix effects. In plasma, the overall recoveries of the EAPs were acceptable: 88 to 110 %, with %RSDs of 6 to 18 % (Table 3). The spiked recoveries of the TAM metabolites from plasma were good, ranging from 77 to 120 %, with %RSDs ranging from 27 to 32 %. Two of the TAM metabolites, 4- hydroxytamoxifen and n-desmethyl tamoxifen, were confirmed in most of the environmental aqueous samples. The discovery of TAM metabolites demonstrates that the source of the TAM metabolites, TAM, is constant, introducing a pseudo-persistence of this chemical into the environment.

M1-like macrophages change tumor blood vessels and microenvironment in murine melanoma

PubMed Central

Kamińska, Natalia; Matuszczak, Sybilla; Cichoń, Tomasz; Pamuła-Piłat, Jolanta; Czapla, Justyna; Smolarczyk, Ryszard; Skwarzyńska, Daria; Kulik, Klaudia; Szala, Stanisław

2018-01-01

Tumor-associated macrophages (TAMs) play a significant role in at least two key processes underlying neoplastic progression: angiogenesis and immune surveillance. TAMs phenotypic changes play important role in tumor vessel abnormalization/ normalization. M2-like TAMs stimulate immunosuppression and formation of defective tumor blood vessels leading to tumor progression. In contrast M1-like TAMs trigger immune response and normalize irregular tumor vascular network which should sensitize cancer cells to chemo- and radiotherapy and lead to tumor growth regression. Here, we demonstrated that combination of endoglin-based DNA vaccine with interleukin 12 repolarizes TAMs from tumor growth-promoting M2-like phenotype to tumor growth-inhibiting M1-like phenotype. Combined therapy enhances tumor infiltration by CD4+, CD8+ lymphocytes and NK cells. Depletion of TAMs as well as CD8+ lymphocytes and NK cells, but not CD4+ lymphocytes, reduces the effect of combined therapy. Furthermore, combined therapy improves tumor vessel maturation, perfusion and reduces hypoxia. It caused that suboptimal doses of doxorubicin reduced the growth of tumors in mice treated with combined therapy. To summarize, combination of antiangiogenic drug and immunostimulatory agent repolarizes TAMs phenotype from M2-like (pro-tumor) into M1-like (anti-tumor) which affects the structure of tumor blood vessels, improves the effect of chemotherapy and leads to tumor growth regression. PMID:29320562

A triarylmethyl spin label for long-range distance measurement at physiological temperatures using T1 relaxation enhancement

NASA Astrophysics Data System (ADS)

Yang, Zhongyu; Bridges, Michael D.; López, Carlos J.; Rogozhnikova, Olga Yu.; Trukhin, Dmitry V.; Brooks, Evan K.; Tormyshev, Victor; Halpern, Howard J.; Hubbell, Wayne L.

2016-08-01

Site-directed spin labeling (SDSL) in combination with electron paramagnetic resonance (EPR) spectroscopy has become an important tool for measuring distances in proteins on the order of a few nm. For this purpose pairs of spin labels, most commonly nitroxides, are site-selectively introduced into the protein. Recent efforts to develop new spin labels are focused on tailoring the intrinsic properties of the label to either extend the upper limit of measurable distances at physiological temperature, or to provide a unique spectral lineshape so that selective pairwise distances can be measured in a protein or complex containing multiple spin label species. Triarylmethyl (TAM) radicals are the foundation for a new class of spin labels that promise to provide both capabilities. Here we report a new methanethiosulfonate derivative of a TAM radical that reacts rapidly and selectively with an engineered cysteine residue to generate a TAM containing side chain (TAM1) in high yield. With a TAM1 residue and Cu2+ bound to an engineered Cu2+ binding site, enhanced T1 relaxation of TAM should enable measurement of interspin distances up to 50 Å at physiological temperature. To achieve favorable TAM1-labeled protein concentrations without aggregation, proteins are tethered to a solid support either site-selectively using an unnatural amino acid or via native lysine residues. The methodology is general and readily extendable to complex systems, including membrane proteins.

Tumor-Associated Macrophages and Mast Cells Positive to Tryptase Are Correlated with Angiogenesis in Surgically-Treated Gastric Cancer Patients.

PubMed

Sammarco, Giuseppe; Gadaleta, Cosmo Damiano; Zuccalà, Valeria; Albayrak, Emre; Patruno, Rosa; Milella, Pietro; Sacco, Rosario; Ammendola, Michele; Ranieri, Girolamo

2018-04-12

Mast cells and macrophages can play a role in tumor angiogenesis by stimulating microvascular density (MVD). The density of mast cells positive to tryptase (MCDPT), tumor-associated macrophages (TAMs), and MVD were evaluated in a series of 86 gastric cancer (GC) tissue samples from patients who had undergone potential curative surgery. MCDPT, TAMs, and MVD were assessed in tumor tissue (TT) and in adjacent normal tissue (ANT) by immunohistochemistry and image analysis. Each of the above parameters was correlated with the others and, in particular for TT, with important clinico-pathological features. In TT, a significant correlation between MCDPT, TAMs, and MVD was found by Pearson t -test analysis ( p ranged from 0.01 to 0.02). No correlation to the clinico-pathological features was found. A significant difference in terms of mean MCDPT, TAMs, and MVD between TT and ANT was found ( p ranged from 0.001 to 0.002). Obtained data suggest MCDPT, TAMs, and MVD increased from ANT to TT. Interestingly, MCDPT and TAMs are linked in the tumor microenvironment and they play a role in GC angiogenesis in a synergistic manner. The assessment of the combination of MCDPT and TAMs could represent a surrogate marker of angiogenesis and could be evaluated as a target of novel anti-angiogenic therapies in GC patients.

Oncoprotein HBXIP enhances HOXB13 acetylation and co-activates HOXB13 to confer tamoxifen resistance in breast cancer.

PubMed

Liu, Bowen; Wang, Tianjiao; Wang, Huawei; Zhang, Lu; Xu, Feifei; Fang, Runping; Li, Leilei; Cai, Xiaoli; Wu, Yue; Zhang, Weiying; Ye, Lihong

2018-02-23

Resistance to tamoxifen (TAM) frequently occurs in the treatment of estrogen receptor positive (ER+) breast cancer. Accumulating evidences indicate that transcription factor HOXB13 is of great significance in TAM resistance. However, the regulation of HOXB13 in TAM-resistant breast cancer remains largely unexplored. Here, we were interested in the potential effect of HBXIP, an oncoprotein involved in the acceleration of cancer progression, on the modulation of HOXB13 in TAM resistance of breast cancer. The Kaplan-Meier plotter cancer database and GEO dataset were used to analyze the association between HBXIP expression and relapse-free survival. The correlation of HBXIP and HOXB13 in ER+ breast cancer was assessed by human tissue microarray. Immunoblotting analysis, qRT-PCR assay, immunofluorescence staining, Co-IP assay, ChIP assay, luciferase reporter gene assay, cell viability assay, and colony formation assay were performed to explore the possible molecular mechanism by which HBXIP modulates HOXB13. Cell viability assay, xenograft assay, and immunohistochemistry staining analysis were utilized to evaluate the effect of the HBXIP/HOXB13 axis on the facilitation of TAM resistance in vitro and in vivo. The analysis of the Kaplan-Meier plotter and the GEO dataset showed that mono-TAM-treated breast cancer patients with higher HBXIP expression levels had shorter relapse-free survivals than patients with lower HBXIP expression levels. Overexpression of HBXIP induced TAM resistance in ER+ breast cancer cells. The tissue microarray analysis revealed a positive association between the expression levels of HBXIP and HOXB13 in ER+ breast cancer patients. HBXIP elevated HOXB13 protein level in breast cancer cells. Mechanistically, HBXIP prevented chaperone-mediated autophagy (CMA)-dependent degradation of HOXB13 via enhancement of HOXB13 acetylation at the lysine 277 residue, causing the accumulation of HOXB13. Moreover, HBXIP was able to act as a co-activator of HOXB13 to

Acyl chain length and charge effect on Tamoxifen-lipid model membrane interactions

NASA Astrophysics Data System (ADS)

Bilge, Duygu; Kazanci, Nadide; Severcan, Feride

2013-05-01

Tamoxifen (TAM), which is an antiestrogenic agent, is widely used during chemotherapy of breast, pancreas, brain and liver cancers. In this study, TAM and model membrane interactions in the form of multilamellar vesicles (MLVs) were studied for lipids containing different acyl chain length and different charge status as a function of different TAM (1, 6, 9 and 15 mol%) concentrations. Zwitterionic lipids namely dipalmitoyl phosphatidylcholine (DPPC), and dimyristoylphosphatidylcholine (DMPC) lipids were used to see the acyl chain length effect and anionic dipalmitoyl phosphtidylglycerol (DPPG) lipid was used to see the charge effect. For this purpose Fourier transform-infrared (FTIR) spectroscopic and differential scanning calorimetric (DSC) techniques have been conducted. For zwitterionic lipid, concentration dependent different action of TAM was observed both in the gel and liquid crystalline phases by significantly increasing the lipid order and decreasing the dynamics for 1 mol% TAM, while decreasing the lipid order and increasing the dynamics of the lipids for higher concentrations (6, 9 and 15 mol%). However, different than neutral lipids, the dynamics and disorder of DPPG liposome increased for all TAM concentrations. The interactions between TAM and head group of multilamellar liposomes was monitored by analyzing the Cdbnd O stretching and PO2- antisymmetric double bond stretching bands. Increasing Tamoxifen concentrations led to a dehydration around these functional groups in the polar part of the lipids. DSC studies showed that for all types of lipids, TAM eliminates the pre-transition, shifts the main phase transition to lower temperatures and broadened the phase transition curve. The results indicate that not the acyl chain length but the charge status of the polar head group induces different effects on lipid membranes order and dynamics.

Hydroxychloroquine inhibits autophagy to potentiate antiestrogen responsiveness in ER+ breast cancer

PubMed Central

Cook, Katherine L.; Wärri, Anni; Soto-Pantoja, David R.; Clarke, Pamela A.G.; Cruz, M. Idalia; Zwart, Alan; Clarke, Robert

2014-01-01

Purpose Estrogen receptor-α (ERα) targeted therapies including tamoxifen (TAM) or Faslodex (ICI) are used to treat ER+ breast cancers. Up to 50% of tumors will acquire resistance to these interventions. Autophagy has been implicated as a major driver of antiestrogen resistance. We have explored the ability of hydroxychloroquine (HCQ), which inhibits autophagy, to affect antiestrogen responsiveness. Experimental Design TAM-resistant MCF7-RR and ICI-resistant/TAM cross-resistant LCC9 ER+ breast cancer cells were injected into mammary fat pads of female athymic mice and treated with TAM and/or ICI in combination with oral low-dose HCQ. Results We show HCQ can increase antiestrogen responsiveness in MCF7-RR and LCC9 cells and tumors, likely through the inhibition of autophagy. However, the combination of ICI+HCQ was less effective than HCQ alone in vivo, unlike the TAM+HCQ combination. Antiestrogen treatment stimulated angiogenesis in tumors but did not prevent HCQ effectiveness. The lower efficacy of ICI+HCQ was associated with ICI effects on cell-mediated immunity within the tumor microenvironment. The mouse chemokine KC (CXCL1) and IFNγ were differentially regulated by both TAM and ICI treatments, suggesting a possible effect on macrophage development/activity. Consistent with these observations, TAM+HCQ treatment increased tumor CD68+ cells infiltration, whereas ICI and ICI+HCQ reduced peripheral tumor macrophage content. Moreover, macrophage elimination of breast cancer target cells in vitro was reduced following exposure to ICI. Conclusion HCQ restores antiestrogen sensitivity to resistant tumors. Moreover, the beneficial combination of TAM+HCQ suggests a positive outcome for ongoing neoadjuvant clinical trials using this combination for the treatment of ER+ ductal carcinoma in situ lesions. PMID:24928945

Interactions of tamoxifen with distearoyl phosphatidylcholine multilamellar vesicles: FTIR and DSC studies

NASA Astrophysics Data System (ADS)

Bilge, Duygu; Sahin, Ipek; Kazanci, Nadide; Severcan, Feride

2014-09-01

Interactions of a non-steroidal antiestrogen drug, tamoxifen (TAM), with distearoyl-sn-glycero-3-phosphatidylcholine (DSPC) multilamellar liposomes (MLVs) were investigated as a function of drug concentration (1-15 mol%) by using two noninvasive techniques, namely Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). FTIR spectroscopy results show that increasing TAM concentrations (except 1 mol%) increased the wavenumbers of the CH2 stretching modes, implying an disordering effect for DSPC MLVs both in the gel and liquid crystalline phases. The bandwidth values of the CH2 stretchings except for 1 mol% increased when TAM concentrations increased for DSPC liposomes, indicating an increase in the dynamics of liposomes. The Cdbnd O stretching and PO2- antisymmetric double bond stretching bands were analyzed to study interactions of TAM with head groups of lipids. As the concentrations of TAM increased, dehydration occurred around these functional groups in the polar part of the lipids. The DSC studies on thermal properties of DSPC lipids indicate that TAM eliminated the pre transition, shifted the main phase transition to lower temperatures and broadened the phase transition curve of the liposomes.

Deciphering the Tectonic History of the Northern Transantarctic Mountains

NASA Astrophysics Data System (ADS)

Hansen, Samantha; Graw, Jordan; Brenn, Gregory; Kenyon, Lindsey; Park, Yongcheol; DuBay, Brian

2016-04-01

The Transantarctic Mountains (TAMs) are the largest non-compressional mountain range in the world, and their structure plays a key role in the climatic and tectonic development of Antarctica. While numerous uplift mechanisms for the TAMs have been proposed, there is little consensus on their origin. Over the past three years, we have operated a network of 15 broadband seismic stations within a previously unexplored portion of the northern TAMs. Using data collected by this array, we have undertaken numerous studies to further assess the crustal and lithospheric structure beneath the mountain range and to differentiate between competing origin models. Receiver functions indicate crustal thickening inland from the Ross Sea coast but comparable crustal thickness beneath the TAMs and the East Antarctic plateau, indicating little evidence for a substantial crustal root beneath the mountain range. Body and surface wave analyses show a pronounced low-velocity anomaly beneath Terror Rift, adjacent to the TAMs, and extending beneath Victoria Land in the upper mantle. Together, these findings support a thermally-buoyant source of uplift for the northern TAMs and broad flexure of the East Antarctic lithosphere.

Radiosensitization of human glioma cells by tamoxifen is associated with the inhibition of PKC-ι activity in vitro.

PubMed

Yang, Lei; Yuan, Xiaopeng; Wang, Jie; Gu, Cheng; Zhang, Haowen; Yu, Jiahua; Liu, Fenju

2015-07-01

The present study aimed to investigate the radiosensitizing effects of tamoxifen (TAM), a non-steroidal anti-estrogen drug, in human glioma A172 and U251 cells in vitro . A colony-forming assay revealed that TAM enhances radiosensitivity in A172 and U251 cells. Treatment with TAM also increased the percentage of apoptotic cells subsequent to ionizing radiation, and increased the expression of apoptotic markers, including cleaved caspase-3 and poly(ADP-ribose) polymerase. Ionizing radiation induced G2/M phase arrest, which was alleviated within 24 h when the radiation-induced DNA damage was repaired. However, flow cytometry analysis revealed that TAM treatment delayed the recovery of cell cycle progression. Additional examination demonstrated that TAM-mediated protein kinase C-ι (PKC-ι) inhibition may lead to the activation of pro-apoptotic B-cell lymphoma 2-associated death promoter, and the dephosphorylation of cyclin-dependent kinase 7, resulting in increased cell apoptosis and sustained G2/M phase arrest following exposure to radiation. The present data indicate that the radiosensitizing effects of TAM on glioma cells are partly due to the inhibition of PKC-ι activity in vitro .

LA BIOÉTICA COMO QUEHACER FILOSÓFICO

PubMed Central

Ferrer, Jorge José

2009-01-01

El artículo examina el estatuto epistemológico de la bioética como disciplina académica. El autor sostiene que el estatuto epistemológico de un discurso lo determina la pregunta fundamental que se plantea y la respuesta que se busca, focos integradores del discurso. En el caso de la bioética, la pregunta fundamental es de índole moral. La bioética es pues una disciplina ética que tiene su hogar epistemológico en la filosofía. El autor también defiende el concepto de “éticas aplicadas”. Sugiere finalmente que el método de la bioética, sobre todo la que se hace desde nuestras latitudes, debería adoptar el círculo hermenéutico como metodología para su filosofar. PMID:20463860

[PK/PD breakpoints and clinical/bacteriological effects of cefcapene pivoxil fine granules for children at free drug concentrations in pediatric patients with respiratory infection].

PubMed

Toyonaga, Yoshikiyo; Iwai, Naoichi; Motohiro, Takashi; Sunakawa, Keisuke; Fujii, Ryochi

2008-06-01

A post-marketing clinical study was previously conducted in pediatric patients with respiratory infection to evaluate the pharmacokinetics, efficacy and safety of cefcapene pivoxil (CFPN-PI) fine granules for children. Based on the results from this study, we evaluated PK/PD breakpoints and clinical/bacteriological effects of CFPN-PI at free drug concentrations in pediatric patients with respiratory infection to determine an effective and safe dosage regimen of CFPN-PI. The following results were obtained from 61 pediatric patients evaluated in our research. 1) The response rate of pediatric respiratory infection to CFPN-PI was 100% for laryngopharyngitis, 84.6% for acute bronchitis, 100% for tonsillitis, 100% for pneumonia and 95.8% for all. 2) The bacteriological response (eradication rate of Haemophilus influenzae, Streptococcus pyogenes, Moraxella catarrhalis, Streptococcus pneumoniae, etc.) of pediatric respiratory infection to CFPN-PI was 87.5% for laryngopharyngitis, 66.7% for acute bronchitis, 75.0% for tonsillitis, 63.6% for pneumonia and 73.8% for all. 3) The blood concentration simulation demonstrated that the PK/PD breakpoint exceeding the time above MIC (TAM) of 40% after administration of CFPN-PI 3 mg/kg three times daily was 0.27 microg/mL. 4) The pediatric patients with respiratory infection were stratified by the TAM (%) of CFPN-PI into 40% to 100% (TAM > or = 40% group) and 0% to 40% (TAM < 40% group) to compare the clinical and bacteriological effects of CFPN-PI. The clinical and bacteriological response rates, respectively, were 97.4% and 77.8% in the TAM > or = 40% group, and 88.9% and 62.5% in the TAM < 40% group. There was no difference in the clinical effect between the two TAM-stratified groups. On the other hand, the bacteriological effect, i.e., eradication rate, tended to be higher in the TAM > or = 40% group than in the TAM < 40% group, although the between-group difference was not statistically significant.

Tamoxifen mutagenesis and carcinogenesis in livers of lambda/lacI transgenic rats: selective influence of phenobarbital promotion.

PubMed

Styles, J A; Davies, R; Fenwick, S; Walker, J; White, I N; Smith, L L

2001-01-10

Administration of tamoxifen (TAM) (20 mg/kg per day p.o.) for 6 weeks to female lambda/lacI transgenic rats caused a 4-fold increase in mutation frequency (MF) at the lacI gene locus in the livers of dosed animals compared with controls. After cessation of dosing, the MF showed a further increase with time at 2, 12 and 24 weeks, respectively. Phenobarbital promotion of similarly treated animals resulted in no increase in mutation frequency compared with TAM alone. Treatment with phenobarbital or TAM+phenobarbital resulted in time-dependent increases in liver weight compared with the corresponding controls. There was an increase in cell proliferation in the phenobarbital and TAM+phenobarbital groups, and at 24 weeks in the TAM dosed animals compared with controls. There was also a progressive increase in the number of GST-P expressing foci in the livers of TAM and TAM + phenobarbital rats compared with controls. The induction of cell proliferation and GSTP foci in the rat liver by phenobarbital is consistent with its ability to promote tamoxifen-initiated liver tumours in the rat. If the lacI gene is regarded as being representative of the rat genome in general (albeit that the gene is bacterial) the above observations suggest that promotion by tamoxifen confers selective advantage on mutated genes at loci that contribute to the tumour phenotype and that promotion of rat liver tumours by tamoxifen is not dependent simply upon the enhancement of cellular proliferation.

Hypoxia promotes glioma-associated macrophage infiltration via periostin and subsequent M2 polarization by upregulating TGF-beta and M-CSFR

PubMed Central

Guo, Xiaofan; Xue, Hao; Shao, Qianqian; Wang, Jian; Guo, Xing; Chen, Xi; Zhang, Jinsen; Xu, Shugang; Li, Tong; Zhang, Ping; Gao, Xiao; Qiu, Wei

2016-01-01

Tumor-associated macrophages (TAMs) are enriched in gliomas and help create a tumor-immunosuppressive microenvironment. A distinct M2-skewed type of macrophages makes up the majority of glioma TAMs, and these cells exhibit pro-tumor functions. Gliomas contain large hypoxic areas, and the presence of a correlation between the density of M2-polarized TAMs and hypoxic areas suggests that hypoxia plays a supportive role during TAM recruitment and induction. Here, we investigated the effects of hypoxia on human macrophage recruitment and M2 polarization. We also investigated the influence of the HIF inhibitor acriflavine (ACF) on M2 TAM infiltration and tumor progression in vivo. We found that hypoxia increased periostin (POSTN) expression in glioma cells and promoted the recruitment of macrophages. Hypoxia-inducible POSTN expression was increased by TGF-α via the RTK/PI3K pathway, and this effect was blocked by treating hypoxic cells with ACF. We also demonstrated that both a hypoxic environment and hypoxia-treated glioma cell supernatants were capable of polarizing macrophages toward a M2 phenotype. ACF partially reversed the M2 polarization of macrophages by inhibiting the upregulation of M-CSFR in macrophages and TGF-β in glioma cells under hypoxic conditions. Administering ACF also ablated tumor progression in vivo. Our findings reveal a mechanism that underlies hypoxia-induced TAM enrichment and M2 polarization and suggest that pharmacologically inhibiting HIFs may reduce M2-polarized TAM infiltration and glioma progression. PMID:27602954

In situ proliferation contributes to accumulation of tumor-associated macrophages in spontaneous mammary tumors.

PubMed

Tymoszuk, Piotr; Evens, Hanneke; Marzola, Vanessa; Wachowicz, Katarzyna; Wasmer, Marie-Helene; Datta, Sebak; Müller-Holzner, Elisabeth; Fiegl, Heidi; Böck, Günther; van Rooijen, Nico; Theurl, Igor; Doppler, Wolfgang

2014-08-01

Infiltration of a neoplasm with tumor-associated macrophages (TAMs) is considered an important negative prognostic factor and is functionally associated with tumor vascularization, accelerated growth, and dissemination. However, the ontogeny and differentiation pathways of TAMs are only incompletely characterized. Here, we report that intense local proliferation of fully differentiated macrophages rather than low-pace recruitment of blood-borne precursors drives TAM accumulation in a mouse model of spontaneous mammary carcinogenesis, the MMTVneu strain. TAM differentiation and expansion is regulated by CSF1, whose expression is directly controlled by STAT1 at the gene promoter level. These findings appear to be also relevant for human breast cancer, in which an interrelationship between STAT1, CSF1, and macrophage marker expression was identified. We propose that, akin to various MU subtypes in nonmalignant tissues, local proliferation and CSF1 play a vital role in the homeostasis of TAMs. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Physicochemical Properties, Antioxidant and Anti-proliferative Capacities of Dried Leaf and Its Extract from Xao tam phan (Paramignya trimera).

PubMed

Nguyen, Van Tang; Sakoff, Jennette A; Scarlett, Christopher J

2017-06-01

Xao tam phan (Paramignya trimera) has been used for the treatment of cancer and cancer-like aliments. Among different parts of the P. trimera plant, leaf is considered as a residual part after harvesting of the root. This study aimed to determine the physiochemical properties and the antioxidant and anti-proliferative capacities of P. trimera leaf (PTL) using microwave drying for the preparation of dry sample; MeOH and microwave-assisted extraction for the preparation of crude extract; and freeze-drying for the preparation of powdered extract. The results showed that total phenolic, total flavonoid, proanthocyanidin, and saponin contents of PTL prepared by microwave drying at 450 W were 25.4 mg gallic acid equiv. (GAE), 86.3 mg rutin equiv. (RE), 5.6 mg catechin equiv. (CE), and 702.1 mg escin equiv. (EE) per gram dried sample, respectively. Gallic acid, protocatechuic acid, ellagic acid, rutin, and quercetin were identified in the PTL MeOH extract. Dried PTL displayed potent antioxidant activity, while the powdered PTL extract exhibited great anti-proliferative capacity on various cancer cell lines including MiaPaCa-2 (pancreas), HT29 (colon), A2780 (ovarian), H460 (lung), A431 (skin), Du145 (prostate), BE2-C (neuroblastoma), MCF-7 (breast), MCF-10A (normal breast), and U87, SJ-G2, and SMA (glioblastoma). Anti-proliferative capacity on pancreatic cancer cells (MiaCaPa2, BxPc3, and CFPAC1) of PTL extract (200 μg/ml) was significantly higher (P < 0.05) than those of ostruthin (20 μg/ml) and gemcitabine (50 nm), and to be comparable to the powdered P. trimera root extract and a saponin-enriched extract from quillajia bark (a commercial product). The findings from this study allow us to conclude that the PTL is a rich source of phytochemicals that possess promising antioxidant and anti-proliferative activities, therefore it shows potential as lead compounds for application in the nutraceutical, medicinal and pharmaceutical industries. © 2017 Wiley

Combination of low-concentration of novel phytoestrogen (8,9)-furanyl-pterocarpan-3-ol from Pachyrhizus erosus attenuated tamoxifen-associated growth inhibition on breast cancer T47D cells

PubMed Central

Nurrochmad, Arief; Lukitaningsih, Endang; Monikawati, Ameilinda; Septhea, Dita Brenna; Meiyanto, Edy

2013-01-01

Objective To investigate the estrogenic effect of (8,9)-furanyl-pterocarpan-3-ol (FPC) on growth of human breast cancer T47D cells and the interactions between the FPC and tamoxifen (TAM), on the growth of estrogen receptor-dependent breast cancer T47D cells. Methods The proliferation effect of FPC were conducted on T47D cells in vitro by MTT test. T47D cells were treated with FPC alone (0.01-200 µmol/L) or in combination with TAM 20 nmol/L. Furthermore, the expression of ERα or c-Myc were also determined by immunohistochemistry. Results The results indicated that administration of an anti-estrogen TAM showed growth inhibitory effect on T47D cells, wheraes co-administered with low concentration (less than 1 µmol/L) of FPC attenuated to promote cell proliferation. In contrast, the combination of TAM with higher doses (more than 20 µmol/L) of FPC showed growth inhibitory. This result was supported by immunocytochemistry studies that the administration of 20 nmol/L TAM down-regulated ER-α and c-Myc, but the combination of 20 nmol/L TAM and 1 µmol/L FPC robustly up-regulated expression of ER-α. Thus, the reduced growth inhibition of TAM 20 nmol/L by FPC 1 µmol/L on T47D cells may act via the modulation of ER-α. Conclusions The findings indicate and suggest that FPC had estrogenic activity at low concentrations and anti-estrogenic effect that are likely to be regulated by c-Myc and estrogen receptors. We also confirm that low concentration of FPC attenuated the growth-inhibitory effects of TAM on mammary tumor prevention. Therefore, the present study suggests that caution is warranted regarding the consumption of dietary FPC by breast cancer patients while on TMA therapy.

Whirling disease among snake river cutthroat trout in two spring streams in Wyoming

USGS Publications Warehouse

Hubert, W.A.; Joyce, M.P.; Gipson, R.; Zafft, D.; Money, D.; Hawk, D.; Taro, B.

2002-01-01

We assessed endemic age-0 cutthroat trout Oncorhynchus clarki for evidence of pathology associated with Myxobolus cerebralis in two streams formed by springs in western Wyoming. We hypothesized that the location of spawning sites in spring streams would affect the extent of exposure of cutthroat trout fry to M. cerebralis triactinomyxons (tams), occurrence of the parasite in their bodies, and clinical signs of whirling disease. The spring streams were warm relative to nearby streams flowing from the mountains or spawning and emergence of fry was early compared with fish in mountain streams. Tams were abundant early in the summer and clinical signs of whirling disease among age-0 fish were seen as early as mid-June in one stream. There were high densities of tams in one stream, and densities declined with upstream progression from May through July, whereas in the other stream, low densities of tams were observed in the downstream portion early in the summer, and they were not detected in July and August. Age-0 cutthroat trout were abundant; clinical signs of whirling disease were evident, and histological evidence of whirling disease was common in the stream where tams were abundant. Low densities of age-0 cutthroat trout and no clinical signs of whirling disease were observed in the stream where tams were not abundant. Among sentinel fish in the stream with abundant tams, we found extensive occurrence of M. cerebralis, with many fish showing clinical signs and histological evidence of pathology associated with M. cerebralis. The proportion of sentinel fish with clinical and histological signs of whirling disease decreased with upstream progression. In the stream with low tam, densities sentinel fish became infected with M. cerebralis, but there were essentially no clinical signs or histological indications of whirling disease. ?? 2002 by the American Fisheries Society.

[Advances in nanoparticle-targeting tumor associated macrophages for cancer imaging and therapy].

PubMed

Fengliang, Guo; Guping, Tang; Qinglian, H U

2017-03-25

Tumor tissues are composed of tumor cells and complicate microenvironment. Tumor associated macrophages (TAMs) as an important component in tumor microenvironment, play fundamental roles in tumor progression, metastasis and microenvironment regulation. Recently, studies have found that nanotechnology, as an emerging platform, provides unique potential for cancer imaging and therapy. With the nanotechnology, TAMs imaging presents direct evidence for cancer development, progression, and the effectiveness of cancer treatments; it also can regulate the immunosuppression of tumor microenvironment and improve therapeutic efficiency through TAMs targeted killing or phenotypic transformation. In this article, we illustrate the function of TAMs and review the latest development in nano-carriers and their applications in tumor associated macrophage targeting cancer imaging and therapy.

Reactivity Control of Rhodium Cluster Ions by Alloying with Tantalum Atoms.

PubMed

Mafuné, Fumitaka; Tawaraya, Yuki; Kudoh, Satoshi

2016-02-18

Gas phase, bielement rhodium and tantalum clusters, RhnTam(+) (n + m = 6), were prepared by the double laser ablation of Rh and Ta rods in He carrier gas. The clusters were introduced into a reaction gas cell filled with nitric oxide (NO) diluted with He and were subjected to collisions with NO and He at room temperature. The product species were observed by mass spectrometry, demonstrating that the NO molecules were sequentially adsorbed on the RhnTam(+) clusters to form RhnTam(+)NxOx (x = 1, 2, 3, ...) species. In addition, oxide clusters, RhnTam(+)O2, were also observed, suggesting that the NO molecules were dissociatively adsorbed on the cluster, the N atoms migrated on the surface to form N2, and the N2 molecules were released from RhnTam(+)N2O2. The reactivity, leading to oxide formation, was composition dependent: oxide clusters were dominantly formed for the bielement clusters containing both Rh and Ta atoms, whereas such clusters were hardly formed for the single-element Rhn(+) and Tam(+) clusters. DFT calculations indicated that the Ta atoms induce dissociation of NO on the clusters by lowering the dissociation energy, whereas the Rh atoms enable release of N2 by lowering the binding energy of the N atoms on the clusters.

Tamoxifen reduces P-gp-mediated multidrug resistance via inhibiting the PI3K/Akt signaling pathway in ER-negative human gastric cancer cells.

PubMed

Mao, Zonglei; Zhou, Jin; Luan, Junwei; Sheng, Weihua; Shen, Xiaochun; Dong, Xiaoqiang

2014-03-01

Multidrug resistance (MDR), mediated by overexpression of drug efflux transporters such as P-glycoprotein (P-gp), is a major problem limiting successful chemotherapy of gastric cancer. Tamoxifen (TAM), a triphenylethylene nonsteroidal antiestrogen agent, shows broad-spectrum antitumor properties. Emerging studies demonstrated that TAM could significantly reduce the MDR in a variety of human cancers. Here we investigated the effects and possible underlying mechanisms of action of TAM on the reversion of MDR in ER-negative human gastric cancer cells. Our results demonstrated that in MDR phenotype SGC7901/CDDP gastric cancer cells TAM dramatically lowered the IC50 of CDDP, 5-FU and ADM, increased the intracellular Rhodamine123 accumulation and induced G0/G1 phase arrest, while G2/M phase decreased accordingly. Furthermore, at the molecular level, TAM substantially decreased the expression of P-gp, p-Akt and the Akt-regulated downstream effectors such as p-GSK-3β, p-BAD, Bcl-XL and cyclinD1 proteins without affecting the expression of t-Akt, t-GSK-3β, t-BAD proteins in SGC7901/CDDP cells. Thus, our findings demonstrate that TAM reverses P-gp-mediated gastric cancer cell MDR via inhibiting the PI3K/Akt signaling pathway. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

The Role of Tumor Associated Macrophage in Recurrent Growth of Tumor Stem Cell

DTIC Science & Technology

2012-09-01

According to the recent cancer stem cell (CSC) theory, recurrent tumor must arise from a dormant tumor stem cell whose re- growth is triggered by...shifting of microenvironment. This project aims at clarifying the roles of TAM in recurrent growth of dormant stem cell in breast cancer. We hypothesize...the stem cell . We have established necessary mouse colonies and also developed the method to generate TAM. We have also shown that TAM indeed

The Comparison of Thyroarytenoid Muscle Myectomy and Type II Thyroplasty for Spasmodic Dysphonia.

PubMed

Nomoto, Masaki; Tokashiki, Ryoji; Hiramatsu, Hiroyuki; Konomi, Ujimoto; Motohashi, Rei; Sakurai, Eriko; Toyomura, Fumimasa; Ueda, Yuri; Inoue, Shun; Tsukahara, Kiyoaki; Suzuki, Mamoru

2015-07-01

Surgical treatments for adductor spasmodic dysphonia include bilateral thyroarytenoid muscle myectomy (TAM) and type II thyroplasty (TPII), both of which are commonly performed. The present study aimed to compare the effects of TAM and TPII. Retrospective study. Subjects were 30 and 35 patients who underwent TAM and TPII, between March 2008 and November 2012. Voice quality was evaluated based on "voice handicap index 10 (VHI10)" and auditory impressions before and 6 months after surgery using five parameters: "strangulation," "interruption," "tremor," "grade," and "breathiness." Comparison of the two procedures revealed significant improvements in VHI10, strangulation, interruption, and tremor, and a significant decline in breathiness after surgery. In particular, VHI10 was improved by more than six points in 90% of patients with TAM, and 96% with TPII. No significant difference was observed between the severities of two procedures preoperatively. Comparison of each postoperative score between the two procedures revealed that TAM significantly improved strangulation, interruption, and tremor, and significantly worsened breathiness, with no significant difference in VHI10. Scatter plots (x: preoperative scores; y: postoperative scores) and regression lines of evaluation items demonstrated that TAM is more effective than TPII in severe cases. Compared with TPII, TAM tends to improve strangulation, interruption, and tremor; however, it tends to worsen breathiness postoperatively. Postoperative VHI10 scores did not differ significantly between the two procedures. Given favorable improvement rates, both surgical procedures were considered effective. Copyright © 2015 The Voice Foundation. Published by Elsevier Inc. All rights reserved.

Tamoxifen and ICI 182, 780 activate hypothalamic G protein-coupled estrogen receptor 1 to rapidly facilitate lordosis in female rats

PubMed Central

Long, Nathan; Long, Bertha; Mana, Asma; Le, Dream; Nguyen, Lam; Chokr, Sima; Sinchak, Kevin

2017-01-01

In the female rat, sexual receptivity (lordosis) can be facilitated by sequential activation of estrogen receptor (ER) α and G protein-coupled estrogen receptor 1 (GPER) by estradiol. In the estradiol benzoate (EB) primed ovariectomized (OVX) rat, EB initially binds to ERα in the plasma membrane that complexes with and transactivates metabotropic glutamate receptor 1a to activate β-endorphin neurons in the arcuate nucleus of the hypothalamus (ARH) that project to the medial preoptic nucleus (MPN). This activates MPN μ-opioid receptors (MOP), inhibiting lordosis. Infusion of non-esterified 17β-estradiol into the ARH rapidly reduces MPN MOP activation and facilitates lordosis via GPER. Tamoxifen (TAM) and ICI 182,780 (ICI) are selective estrogen receptor modulators that activate GPER. Therefore, we tested the hypothesis that TAM and ICI rapidly facilitate lordosis via activation of GPER in the ARH. Our first experiment demonstrated that injection of TAM intraperitoneal, or ICI into the lateral ventricle, deactivated MPN MOP and facilitated lordosis in EB-primed rats. We then tested whether TAM and ICI were acting rapidly through a GPER dependent pathway in the ARH. In EB-primed rats, ARH infusion of either TAM or ICI facilitated lordosis and reduced MPN MOP activation within 30 minutes compared to controls. These effects were blocked by pretreatment with the GPER antagonist, G15. Our findings demonstrate that TAM and ICI deactivate MPN MOP and facilitate lordosis in a GPER dependent manner. Thus, TAM and ICI may activate GPER in the CNS to produce estrogenic actions in neural circuits that modulate physiology and behavior. PMID:28063803

Tamoxifen and ICI 182,780 activate hypothalamic G protein-coupled estrogen receptor 1 to rapidly facilitate lordosis in female rats.

PubMed

Long, Nathan; Long, Bertha; Mana, Asma; Le, Dream; Nguyen, Lam; Chokr, Sima; Sinchak, Kevin

2017-03-01

In the female rat, sexual receptivity (lordosis) can be facilitated by sequential activation of estrogen receptor (ER) α and G protein-coupled estrogen receptor 1 (GPER) by estradiol. In the estradiol benzoate (EB) primed ovariectomized (OVX) rat, EB initially binds to ERα in the plasma membrane that complexes with and transactivates metabotropic glutamate receptor 1a to activate β-endorphin neurons in the arcuate nucleus of the hypothalamus (ARH) that project to the medial preoptic nucleus (MPN). This activates MPN μ-opioid receptors (MOP), inhibiting lordosis. Infusion of non-esterified 17β-estradiol into the ARH rapidly reduces MPN MOP activation and facilitates lordosis via GPER. Tamoxifen (TAM) and ICI 182,780 (ICI) are selective estrogen receptor modulators that activate GPER. Therefore, we tested the hypothesis that TAM and ICI rapidly facilitate lordosis via activation of GPER in the ARH. Our first experiment demonstrated that injection of TAM intraperitoneal, or ICI into the lateral ventricle, deactivated MPN MOP and facilitated lordosis in EB-primed rats. We then tested whether TAM and ICI were acting rapidly through a GPER dependent pathway in the ARH. In EB-primed rats, ARH infusion of either TAM or ICI facilitated lordosis and reduced MPN MOP activation within 30min compared to controls. These effects were blocked by pretreatment with the GPER antagonist, G15. Our findings demonstrate that TAM and ICI deactivate MPN MOP and facilitate lordosis in a GPER dependent manner. Thus, TAM and ICI may activate GPER in the CNS to produce estrogenic actions in neural circuits that modulate physiology and behavior. Published by Elsevier Inc.

Effects of tamoxifen on neuronal morphology, connectivity and biochemistry of hypothalamic ventromedial neurons: Impact on the modulators of sexual behavior.

PubMed

Sá, Susana I; Teixeira, Natércia; Fonseca, Bruno M

2018-01-01

Tamoxifen (TAM) is a selective estrogen receptor modulator, widely used in the treatment and prevention of estrogen-dependent breast cancer. Although with great clinical results, women on TAM therapy still report several side effects, such as sexual dysfunction, which impairs quality of life. The anatomo-functional substrates of the human sexual behavior are still unknown; however, these same substrates are very well characterized in the rodent female sexual behavior, which has advantage of being a very simple reflexive response, dependent on the activation of estrogen receptors (ERs) in the ventrolateral division of the hypothalamic ventromedial nucleus (VMNvl). In fact, in the female rodent, the sexual behavior is triggered by increasing circulation levels of estradiol that changes the nucleus neurochemistry and modulates its intricate neuronal network. Therefore, we considered of notice the examination of the possible neurochemical alterations and the synaptic plasticity impairment in VMNvl neurons of estradiol-primed female rats treated with TAM that may be in the basis of this neurological disorder. Accordingly, we used stereological and biochemical methods to study the action of TAM in axospinous and axodendritic synaptic plasticity and on ER expression. The administration of TAM changed the VMNvl neurochemistry by reducing ERα mRNA and increasing ERβ mRNA expression. Furthermore, present results show that TAM induced neuronal atrophy and reduced synaptic connectivity, favoring electrical inactivity. These data suggest that these cellular and molecular changes may be a possible neuronal mechanism of TAM action in the disruption of the VMNvl network, leading to the development of behavioral disorders. Copyright © 2017 Elsevier Inc. All rights reserved.

Transient Abnormal Myelopoiesis and AML in Down Syndrome: an Update.

PubMed

Bhatnagar, Neha; Nizery, Laure; Tunstall, Oliver; Vyas, Paresh; Roberts, Irene

2016-10-01

Children with constitutional trisomy 21 (Down syndrome (DS)) have a unique predisposition to develop myeloid leukaemia of Down syndrome (ML-DS). This disorder is preceded by a transient neonatal preleukaemic syndrome, transient abnormal myelopoiesis (TAM). TAM and ML-DS are caused by co-operation between trisomy 21, which itself perturbs fetal haematopoiesis and acquired mutations in the key haematopoietic transcription factor gene GATA1. These mutations are found in almost one third of DS neonates and are frequently clinically and haematologcially 'silent'. While the majority of cases of TAM undergo spontaneous remission, ∼10 % will progress to ML-DS by acquiring transforming mutations in additional oncogenes. Recent advances in the unique biological, cytogenetic and molecular characteristics of TAM and ML-DS are reviewed here.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hatkevich, Talia; Ramos, Joseph; Santos-Sanchez, Idalys

Since over 60% of breast cancers are estrogen receptor positive (ER+), many therapies have targeted the ER. The ER is activated by both estrogen binding and phosphorylation. While anti-estrogen therapies, such as tamoxifen (Tam) have been successful they do not target the growth factor promoting phosphorylation of the ER. Other proliferation pathways such as the phosphatidylinositol-3 kinase, (PI3K) and the mitogen-activated protein kinase (MAPK) pathways are activated in breast cancer cells and are associated with poor prognosis. Thus targeting multiple cellular proliferation and survival pathways at the onset of treatment is critical for the development of more effective therapies. Themore » grapefruit flavanone naringenin (Nar) is an inhibitor of both the PI3K and MAPK pathways. Previous studies examining either Nar or Tam used charcoal-stripped serum which removed estrogen as well as other factors. We wanted to use serum containing medium in order to retain all the potential inducers of cell proliferation so as not to exclude any targets of Nar. Here we show that a Nar–Tam combination is more effective than either Tam alone or Nar alone in MCF-7 breast cancer cells. We demonstrate that a Nar–Tam combination impaired cellular proliferation and viability to a greater extent than either component alone in MCF-7 cells. Furthermore, the use of a Nar–Tam combination requires lower concentrations of both compounds to achieve the same effects on proliferation and viability. Nar may function by inhibiting both PI3K and MAPK pathways as well as localizing ERα to the cytoplasm in MCF-7 cells. Our results demonstrate that a Nar–Tam combination induces apoptosis and impairs proliferation signaling to a greater extent than either compound alone. These studies provide critical information for understanding the molecular mechanisms involved in cell proliferation and apoptosis in breast cancer cells. - Highlights: • Nar–Tam impairs cell viability more effectively

Chemoresistance in Pancreatic Cancer Is Driven by Stroma-Derived Insulin-Like Growth Factors

PubMed Central

Ahmed, Muhammad S.; Rainer, Carolyn; Nielsen, Sebastian R.; Quaranta, Valeria; Weyer-Czernilofsky, Ulrike; Engle, Danielle D.; Perez-Mancera, Pedro A.; Coupland, Sarah E.; Taktak, Azzam; Bogenrieder, Thomas; Tuveson, David A.; Campbell, Fiona; Schmid, Michael C.; Mielgo, Ainhoa

2017-01-01

Tumor-associated macrophages (TAM) and myofibroblasts are key drivers in cancer that are associated with drug resistance in many cancers, including pancreatic ductal adenocarcinoma (PDAC). However, our understanding of the molecular mechanisms by which TAM and fibroblasts contribute to chemoresistance is unclear. In this study, we found that TAM and myofibroblasts directly support chemoresistance of pancreatic cancer cells by secreting insulin-like growth factors (IGF) 1 and 2, which activate insulin/IGF receptors on pancreatic cancer cells. Immunohistochemical analysis of biopsies from patients with pancreatic cancer revealed that 72% of the patients expressed activated insulin/IGF receptors on tumor cells, and this positively correlates with increased CD163+ TAM infiltration. In vivo, we found that TAM and myofibroblasts were the main sources of IGF production, and pharmacologic blockade of IGF sensitized pancreatic tumors to gemcitabine. These findings suggest that inhibition of IGF in combination with chemotherapy could benefit patients with PDAC, and that insulin/IGF1R activation may be used as a biomarker to identify patients for such therapeutic intervention. PMID:27742686

Implementation of Total Asset Management at the University of Tasmania.

ERIC Educational Resources Information Center

Smith, Matt

2002-01-01

Describes the implementation of total asset management (TAM) at the University of Tasmania to better link physical resources management with the university's strategic planning. Discusses TAM's principles, objectives, and future direction. (EV)

Variability in triactinomyxon production from Tubifex tubifex populations from the same mitochondrial DNA lineage infected with Myxobolus cerebralis, the causative agent of whirling disease in salmonids

USGS Publications Warehouse

Rasmussen, C.; Zickovich, J.; Winton, J.R.; Kerans, B.L.

2008-01-01

Myxobolus cerebralis, the causative agent of whirling disease, infects both salmonid fish and an aquatic oligochaete, Tubifex tubifex. Although M. cerebralis has been detected in river drainages throughout the United States, disease severity among wild fish populations has been highly variable. Tubifex tubifex populations have been genetically characterized using sequences from the 16S mitochondrial DNA (mtDNA) gene, the 18S ribosomal RNA gene, the internal transcribed spacer region 1 (ITS1), and randomly amplified polymorphic DNA (RAPD). Our earlier work indicated that large differences in compatibility between the parasite and populations of T. tubifex may play a substantial role in the distribution of whirling disease and resulting mortality in different watersheds. In the present study, we examined 4 laboratory populations of T. tubifex belonging to 16S mtDNA lineage III and 1 population belonging to 16S mtDNA lineage I for triactinomyxon (TAM) production after infection with M. cerebralis myxospores. All 4 16S mtDNA lineage III populations produced TAMs, but statistically significant differences in TAM production were observed. Most individuals in the 16S mtDNA lineage III-infected populations produced TAMs. The 16S mtDNA lineage I population produced few TAMs. Further genetic characterization of the 16S mtDNA lineage III populations with RAPD markers indicated that populations producing similar levels of TAMs had more genetic similarity. ?? American Society of Parasitologists 2008.

Targeted delivery of epirubicin to tumor-associated macrophages by sialic acid-cholesterol conjugate modified liposomes with improved antitumor activity.

PubMed

Zhou, Songlei; Zhang, Ting; Peng, Bo; Luo, Xiang; Liu, Xinrong; Hu, Ling; Liu, Yang; Di, Donghua; Song, Yanzhi; Deng, Yihui

2017-05-15

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. And the in vitro and in vivo cellular uptake studies demonstrated EPI-SAL achieved enhanced accumulation of EPI into TAMs. The antitumor studies indicated that EPI-SAL provided the strongest antitumor activity compared with the other formulations (EPI-S, EPI-CL and EPI-PL represent EPI solution, conventional liposomal EPI, PEGylated liposomal EPI, respectively), and the survival percent of tumor-bearing mice was 83.3%. The superior antitumor efficacy was probably attributed to the killing of TAMs by EPI-SAL, and modulating the tumor microenvironment with the depletion of TAMs. These findings suggested that SA-CH decorated EPI-loaded liposomes may present an effective strategy to eradicate TAMs, which may be a promising approach for cancer therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

Inhibition of TGF-β signaling in combination with TLR7 ligation re-programs a tumoricidal phenotype in tumor-associated macrophages.

PubMed

Peng, Jiao; Tsang, Julia Yuen Shan; Li, Daxu; Niu, Na; Ho, Derek Hoi Hang; Lau, Kwok Fai; Lui, Vincent Chi Hang; Lamb, Jonathan Robert; Chen, Yan; Tam, Paul Kwong Hang

2013-05-01

Inadequate immunity that occurs in a tumor environment is in part due to the presence of M2-type tumor-associated macrophages (TAMs). TGF-β has a multi-functional role in tumor development including modulating the biological activity of both the tumor and TAMs. In this study, using an in vitro TAM/tumor cell co-culture system ligation of TLR7, which is expressed on TAMs but not the tumor cells, in the presence of TGF-β receptor I inhibitor re-programmed the phenotype of the TAMs. In part they adopted the phenotype characteristic of M1-type macrophages, namely they had increased tumoricidal activity and elevated expression of iNOS, CD80 and MHC class II, while TGF-β secretion was reduced. The reprogrammed phenotype was accompanied by enhanced NF-κB nuclear translocation. The pro-angiogenesis factor VEGF was down-regulated and in vivo the number of CD31-positive tumor capillaries was also reduced. Furthermore, in vivo we observed that TLR7 ligation/TGF-β receptor I inhibition increased tumor apoptosis and elevated the number of CD4+, CD8+, and CD19+ cells as well as neutrophils infiltrating the tumor. Our data demonstrate that selective TLR stimulation with TGF-β inhibition can reprogram TAMs towards an M1-like phenotype and thereby provides new perspectives in cancer therapy. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Consolidated asset management for Minnesota local agencies.

DOT National Transportation Integrated Search

2016-06-01

Transportation agencies are increasingly turning their attention to transportation asset management (TAM), a systematic process for tracking the conditions of physical infrastructure to make better decisions about its maintenance. TAM is mandated by ...

Continuous tamoxifen delivery improves locomotor recovery 6h after spinal cord injury by neuronal and glial mechanisms in male rats.

PubMed

Colón, Jennifer M; González, Pablo A; Cajigas, Ámbar; Maldonado, Wanda I; Torrado, Aranza I; Santiago, José M; Salgado, Iris K; Miranda, Jorge D

2018-01-01

No treatment is available for patients with spinal cord injury (SCI). Patients often arrive to the hospital hours after SCI suggesting the need of a therapy that can be used on a clinically relevant window. Previous studies showed that Tamoxifen (TAM) treatment 24h after SCI benefits locomotor recovery in female rats. Tamoxifen exerts beneficial effects in male and female rodents but a gap of knowledge exists on: the therapeutic window of TAM, the spatio-temporal mechanisms activated and if this response is sexually dimorphic. We hypothesized that TAM will favor locomotor recovery when administered up-to 24h after SCI in male Sprague-Dawley rats. Rats received a thoracic (T10) contusion using the MACSIS impactor followed by placebo or TAM (15mg/21days) pellets in a therapeutic window of 0, 6, 12, or 24h. Animals were sacrificed at 2, 7, 14, 28 or 35days post injury (DPI) to study the molecular and cellular changes in the acute and chronic stages. Immediate or delayed therapy (t=6h) improved locomotor function, increased white matter spared tissue, and neuronal survival. TAM reduced reactive gliosis during chronic stages and increased the expression of Olig-2. A significant difference was observed in estrogen receptor alpha between male and female rodents from 2 to 28 DPI suggesting a sexually dimorphic characteristic that could be related to the behavioral differences observed in the therapeutic window of TAM. This study supports the use of TAM in the SCI setting due to its neuroprotective effects but with a significant sexually dimorphic therapeutic window. Copyright © 2017 Elsevier Inc. All rights reserved.

The anti-oestrogen ICI 182,780, but not tamoxifen, inhibits the growth of MCF-7 breast cancer cells refractory to long-term oestrogen deprivation through down-regulation of oestrogen receptor and IGF signalling.

PubMed

Martin, L-A; Pancholi, S; Chan, C M W; Farmer, I; Kimberley, C; Dowsett, M; Johnston, S R D

2005-12-01

Long-term culture of MCF-7 wild-type (wt) cells in steroid-depleted medium (LTED) results in hypersensitivity to oestradiol (E2) coinciding with elevated levels of ERalpha and enhanced growth factor signalling. In this study, we aimed to compare the effects of the pure anti-oestrogen ICI 182,780 (ICI) with the competitive anti-oestrogen tamoxifen (TAM) on oestrogen and IGF signalling in these cells. Wt MCF-7 and LTED cells were treated with a log 7 concentration range of E2, TAM or ICI. Effects on cell growth, ERalpha transactivation, expression of ERalpha, ERbeta and components of the IGF pathway were measured with and without insulin. In the presence of insulin, growth of LTED cells was refractory to TAM but inhibited by ICI and E2. In the absence of insulin, LTED cells showed persistent hypersensitivity to E2, and remained inhibited by ICI but were largely unaffected by TAM. ICI but not TAM inhibited ER-mediated gene transcription and treatment with ICI resulted in a dose-dependent reduction in ERalpha levels whilst having no effect on ERbeta expression. IGF-I receptor and insulin receptor substrate 2 levels were increased in LTED versus the Wt MCF-7 cells, and ICI but not TAM reduced their expression in a dose-dependent fashion. Thus IGF signalling as well as ERalpha expression and function are enhanced during LTED. While the resultant cells are resistant to TAM, ICI down-regulates ERalpha, reducing IGF signalling and cell growth. These results support the use of ICI in women with ER-positive breast cancer who have relapsed on an aromatase inhibitor.

Electrospray ionization-tandem mass spectrometry and 32P-postlabeling analyses of tamoxifen-DNA adducts in humans.

PubMed

Beland, Frederick A; Churchwell, Mona I; Doerge, Daniel R; Parkin, Daniel R; Malejka-Giganti, Danuta; Hewer, Alan; Phillips, David H; Carmichael, Paul L; Gamboa da Costa, Gonçalo; Marques, M Matilde

2004-07-21

Although the nonsteroidal antiestrogen tamoxifen is used as an adjuvant chemotherapeutic agent to treat hormone-dependent breast cancer and as a chemopreventive agent in women with elevated risk of breast cancer, it has also been reported to increase the risk of endometrial cancer. Reports of low levels of tamoxifen-DNA adducts in human endometrial tissue have suggested that tamoxifen induces endometrial cancer by a genotoxic mechanism. However, these findings have been controversial. We used electrospray ionization-tandem mass spectrometry (ES-MS/MS) and 32P-postlabeling analyses to investigate the presence of tamoxifen-DNA adducts in human endometrial tissue. Endometrial DNA from eight tamoxifen-treated women and eight untreated women was hydrolyzed to nucleosides and assayed for (E)-alpha-(deoxyguanosin-N2-yl)-tamoxifen (dG-Tam) and (E)-alpha-(deoxyguanosin-N2-yl)-N-desmethyltamoxifen (dG-desMeTam), the two major tamoxifen-DNA adducts that have been reported to be present in humans and/or experimental animals treated with tamoxifen, using on-line sample preparation coupled with high-performance liquid chromatography (HPLC) and ES-MS/MS. The same DNA samples were assayed for the presence of dG-Tam and dG-desMeTam by (32)P-postlabeling methodology, using two different DNA digestion and labeling protocols, followed by both thin-layer chromatography and HPLC. We did not detect either tamoxifen-DNA adduct by HPLC-ES-MS/MS analyses (limits of detection for dG-Tam and dG-desMeTam were two adducts per 10(9) nucleotides and two adducts per 10(8) nucleotides, respectively) or by 32P-postlabeling analyses (limit of detection for both adducts was one adduct per 10(9) nucleotides) in any of the endometrial DNA samples. The initiation of endometrial cancer by tamoxifen is probably not due to a genotoxic mechanism involving the formation of dG-Tam or dG-desMeTam.

CYP4A in tumor-associated macrophages promotes pre-metastatic niche formation and metastasis.

PubMed

Chen, X W; Yu, T J; Zhang, J; Li, Y; Chen, H L; Yang, G F; Yu, W; Liu, Y Z; Liu, X X; Duan, C F; Tang, H L; Qiu, M; Wang, C L; Zheng, H; Yue, J; Guo, A M; Yang, J

2017-08-31

Tumor-associated macrophages (TAMs) play an essential role in metastasis. However, what enables TAMs to have a superior capacity to establish pre-metastatic microenvironment in distant organs is unclear. Here we have begun to uncover the effects of cytochrome P450 (CYP) 4A in TAMs on lung pre-metastatic niche formation and metastasis. CYP4A + TAM infiltration was positively associated with metastasis, pre-metastatic niche formation and poor prognosis in breast cancer patients. The pharmacological inhibition of CYP4A reduced lung pre-metastatic niche formation (evidenced by a decrease in vascular endothelial growth factor receptor 1 positive (VEGFR1 + ) myeloid cell recruitment and pro-metastatic protein expression) and metastatic burden, accompanied with TAM polarization away from the M2 phenotype in spontaneous metastasis models of 4T1 breast cancer and B16F10 melanoma. Co-implantation of 4T1 cells with CYP4A10 high macrophages promoted lung pre-metastatic niche formation and metastasis. Depletion of TAMs disrupted lung pre-metastatic niches and thereby prevented metastasis. Treatment with the CM from CYP4A10 high M2 macrophages (M2) increased pre-metastatic niche formation and metastatic burden in the lungs, whereas CYP4A inhibition attenuated these effects. In vitro TAM polarization away from the M2 phenotype induced by CYP4A inhibition decreased VEGFR1 + myeloid cell migration and fibronectin expression, accompanied with downregulation of STAT3 signaling. Conversely, overexpression of CYP4A or exogenous addition of 20-hydroxyeicosatetraenoic acid promoted M2 polarization and cytokine production of macrophages and thereby enhanced migration of VEGFR1 + myeloid cells, which were reversed by siRNA or pharmacological inhibition of STAT3. Importantly, a combined blocking M2 macrophage-derived factors TGF-β, VEGF and SDF-1 abolished VEGFR1 + myeloid cell migration and fibroblast activation induced by CYP4A. In summary, CYP4A in TAMs is crucial for lung pre

Prevention of Breast Cancer Cell Transformation by Blockade of the AP-1 Transcription Factor

DTIC Science & Technology

1998-10-01

184 M . Stampfer Immortal HMECs: 184B5 M . Stampfer Immortal, anchorage dependent MCF10A A. Russo Breast Cancer cell lines: MCF7 WT K. Cowan Cancer cells...34 []-DOX [] +DOX Sr-- 2.0 T -,ri-i-rTI•r-1.1.1 H S1ɘ.5 -0.5 0.0- - -- --" "r 0.0 " - " -- m #1#2 #31~ #1#2 #3 , •#1 #2~ , #1 #2 Vector TAM-67 Vector TAM...6F 0 2 4 6 8 02460.0 ... 1.50. ( ’ M 2’ #3 65 ’ 9 91234567 1234567 1.25 L. TAM-67 TAM-67 o-2.0-(.~1.00. 0.75. ~ 1.5’ d0.50 1.I1.07 0.25 10. .) 0 .0 1

Implementation of transportation asset management in Grandview, Missouri : final report.

DOT National Transportation Integrated Search

2017-02-01

The successful implementation of transportation asset management (TAM) by local governments facilitates the optimization of limited resources. The use of a data-driven TAM program helps to identify and prioritize needs, identify and dedicate resource...

Transportation asset management : a vehicle for mainstreaming ITS?

DOT National Transportation Integrated Search

2001-06-01

This paper examines the use of transportation asset management (TAM) as a mechanism for mainstreaming" intelligent transportation systems (ITS) into the transportation decision-making process. TAM is an emerging set of tools and techniques that compr...

Noise of High-Performance Aircraft at Afterburner

DTIC Science & Technology

2015-10-07

Naval Research Project Title : Noise of High-Performance Aircraft at Afterburner Principal Investigator Dr. Christopher Tam Department...to 08/14/2015 Noise of High-Performance Aircraft at Afterburner Tam, Christopher Sponsored Research Administratiion Florida State University

Como Podar Arboles (Spanish Version), How to Prune Trees

Treesearch

Maureen McDonough; Russell; Lisa Burban; Lee Nancarrow; United States Department of Agriculture, Forest Service, Northeastern Area, State and Private Forestry

2004-01-01

Introduccion, El proposito de la poda es tener plantas fuertes, sanas y atractivas. Esta meta se puede alcanzar sabiendo como, cuando y por que podar, y siguiendo unos cuantos principios muy sencillos.

Gender differences associated with enrollment in the Texas Academy of Mathematics and Science

NASA Astrophysics Data System (ADS)

Burns, Robert Thomas

This study sought to determine if different factors had influenced females and males to select engineering/science-related studies at the Texas Academy of Mathematics and Science (TAMS). The data were collected in the fall semester in 1997 at TAMS located on the University of North Texas campus from a survey of factors reported in the literature that had influenced students to enroll in engineering/science-related curriculum. Of the 380 TAMS students enrolled fall semester, 303 or 85% participated in the study. Those who participated included 135 or 45% females and 168 or 55% males. A dichotomous discriminant function analysis to identify relationships between the criterion variable (gender) and the predictor variable (factors) was used. The analysis of variance (ANOVA) was used to identify any significant predictor (factor) when the criterion was gender. Analysis of the data indicated no difference between females and males concerning factors that influenced them to enroll in TAMS. Neither discriminant function analysis nor the regression analysis using weighted least squares could significantly establish any relationship that could predict a student to be female or male with respect to factors that influenced them to enroll in TAMS. The factors were ranked utilizing the Thurstone equal appearing intervals scale for both females and males. Both females and males in TAMS ranked extrinsic interest including job opportunity, salary, and promotion, as the most important factor. The least important factor for both females and males was family encouragement. The findings indicate that TAMS students based their enrollment decision on factors independent of those suggested in the literature as applying to males and females. This may have resulted from the fact that these students are a unique population biased toward valuing a math/science curriculum.

Macrophages From Irradiated Tumors Express Higher Levels of iNOS, Arginase-I and COX-2, and Promote Tumor Growth

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tsai, C.-S.; Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taiwan; Chen, F.-H.

2007-06-01

Purpose: To investigate the effects of single and fractionated doses of radiation on tumors and tumor-associated macrophages (TAMs), and to elucidate the potential of TAMs to influence tumor growth. Methods and Materials: A murine prostate cell line, TRAMP-C1, was grown in C57Bl/6J mice to 4-mm tumor diameter and irradiated with either 25 Gy in a single dose, or 60 Gy in 15 fractions. The tumors were removed at the indicated times and assessed for a variety of markers related to TAM content, activation status, and function. Results: In tumors receiving a single radiation dose, arginase (Arg-I), and cycloxygenase-2 (COX-2) mRNAmore » expression increased as a small transient wave within 24 h and a larger persistent wave starting after 3 days. Inducible nitric oxide synthase (iNOS) mRNA was elevated only after 3 days and continued to increase up to 3 weeks. After fractionated irradiation, Arg-1 and COX-2 mRNA levels increased within 5 days, whereas iNOS was increased only after 10 fractions of irradiation had been given. Increased levels of Arg-I, COX-2, and, to a lesser extent, iNOS protein were found to associate with TAMs 1-2 weeks after tumor irradiation. Function of TAMs were compared by mixing them with TRAMP-C1 cells and injecting them into mice; TRAMP-C1 cells mixed with TAMs from irradiated tumors appeared earlier and grew significantly faster than those mixed with TAMs from unirradiated tumors or TRAMP-C1 alone. Conclusions: Tumor-associated macrophages in the postirradiated tumor microenvironment express higher levels of Arg-1, COX-2, and iNOS, and promote early tumor growth in vivo.« less

Biopolymer mediated nanoparticles synthesized from Adenia hondala for enhanced tamoxifen drug delivery in breast cancer cell line

NASA Astrophysics Data System (ADS)

Varadharajaperumal, Pradeepa; Subramanian, Balakumar; Santhanam, Amutha

2017-09-01

Silver nanoparticles (AgNPs) are an important class of nanomaterials, which have used as antimicrobial and disinfectant agents due to their detrimental effect on target cells. In the present study it was explored to deliver a novel tamoxifen drug system that can be used in breast cancer treatment, based on chitosan coated silver nanoparticles on MCF-7 human breast cancer cells. AgNPs synthesized from Adenia hondala tuber extract were used to make the chitosan coated AgNPs (Ch-AgNPs), in which the drug tamoxifen was loaded on chitosan coated silver nanoparticles (Tam-Ch-AgNPs) to construct drug loaded nanoparticles as drug delivery system. The morphology and characteristics of the Ch-AgNPs were investigated by UV, FTIR, zeta potential and FESEM. Furthermore, the toxicity of AgNPs, Ch-AgNPs, Tam-Ch-AgNPs was evaluated through cell viability, lactate dehydrogenase leakage, reactive oxygen species generation, caspase-3, DNA laddering, and TUNEL assay in human breast cancer cells (MCF-7) and HBL-100 continuous cell line as a control. Treatment of cancer cells with various concentrations of AgNPs, Ch-AgNPs, Tam-Ch-AgNPs for 24 h revealed that Tam-Ch-AgNPs could inhibit cell viability and induce significant membrane leakage in a dose-dependent manner. Cells exposed to Tam-Ch-AgNPs showed increased reactive oxygen species and hydroxyl radical production when compared to AgNPs, Ch-AgNPs. Furthermore, the apoptotic effects of AgNPs, Ch-AgNPs, Tam-Ch-AgNPs were confirmed by activation of caspase-3 and DNA nuclear fragmentation. The present findings suggest that Tam-Ch-AgNPs could contribute to the development of a suitable anticancer drug delivery.

Fast method for simultaneous quantification of tamoxifen and metabolites in dried blood spots using an entry level LC-MS/MS system.

PubMed

Tré-Hardy, Marie; Capron, Arnaud; Antunes, Marina Venzon; Linden, Rafael; Wallemacq, Pierre

2016-11-01

The purpose of this study was to develop and validate a new liquid chromatography-tandem mass spectrometric (LC-MSMS) assay for the simultaneous quantification of tamoxifen (TAM) and its main therapeutically active metabolites, N-desmethyltamoxifen (NDT), 4-hydroxytamoxifen (4HT) and endoxifen (END) in dried blood spots. Ultrasound assisted methanolic extraction was used for TAM and metabolites extraction from dried blood spot. After evaporation and methanol reconstitution, the extract was injected into a LC-MSMS system. Reversed phase chromatography was performed on a C18 grafted column in gradient mode. TAM, metabolites, and internal standard (diazepam-d 5 ; IS) were identified in positive electrospray ionization mode using m/z transition of 372.5>72.1 (TAM); 374.23>58.10 (END); 358.27>58.10 (NDT); 388.23>44.80 (4HT) and 290.00>198.00 (IS). Total analytical run time was 6.5min. Assay was linear from 1 to 500ng/mL for all substances and presented intra and inter-assay precision and accuracy <15%. TAM, NDT, 4HT and END limits of quantification and detection were of 1 and 0.5ng/mL; 1 and 3ng/mL; 1.7 and 3ng/mL; 0.6 and 2ng/mL, respectively. Recovery ranged from 83.8 to 96.3% with matrix effect ranged from 4.3 to 29.8% for TAM and its metabolites. Hematocrit value ≤40% appeared to negatively influence accuracy of the method. In conclusion, the method described here is somewhat accessible, relatively fast, sensitive and selective with no interference. This assay might be used to investigate the level of TAM and its metabolites in DBS for therapeutic drug monitoring purposes. Copyright © 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Lecithin/chitosan controlled release nanopreparations of tamoxifen citrate: loading, enzyme-trigger release and cell uptake.

PubMed

Barbieri, Stefano; Sonvico, Fabio; Como, Caterina; Colombo, Gaia; Zani, Franca; Buttini, Francesca; Bettini, Ruggero; Rossi, Alessandra; Colombo, Paolo

2013-05-10

Tamoxifen citrate (TAM), an anticancer drug with amphiphilic properties, was loaded in lecithin/chitosan nanoparticles (LCN) with a view to oral administration. The influence of tamoxifen loading on the physico-chemical properties of nanoparticles was studied. Size, surface charge and morphological properties of tamoxifen-loaded nanoparticles (LCN-TAM) were assessed. The increase in the tamoxifen amount in the LCN-TAM preparation up to 60 mg/100 ml maintained the positive zeta potential value of about +45 mV. A statistically significant decrease in particle size was observed for TAM amounts between 5 and 20mg. A strong influence of loaded tamoxifen on the structure of lecithin/chitosan nanoparticles was observed, supported by the quantification of free chitosan and morphological analysis. A loading of tamoxifen in nanoparticles of around 19% was obtained. The release of the drug from the LCN-TAM colloidal dispersion was measured, showing that tamoxifen citrate was released very slowly in simulated gastro-intestinal fluids without enzymes. When enzymes able to dismantle the nanoparticle structure were added to the dissolution medium, drug release was triggered and continued in a prolonged manner. Tamoxifen-loaded nanoparticles showed cytotoxicity towards MCF-7 cells comparable to that obtained with tamoxifen citrate solution, but the rate of this toxic effect was dependent on drug release. Caco-2 cells, used as a model of the intestinal epithelium, were shown to take up the TAM loaded nanoparticles extensively. Copyright © 2013 Elsevier B.V. All rights reserved.

Expression of the Homeobox Gene HOXA9 in Ovarian Cancer Induces Peritoneal Macrophages to Acquire an M2 Tumor-Promoting Phenotype

PubMed Central

Ko, Song Yi; Ladanyi, Andras; Lengyel, Ernst; Naora, Honami

2015-01-01

Tumor-associated macrophages (TAMs) exhibit an M2 macrophage phenotype that suppresses anti-tumor immune responses and often correlates with poor outcomes in patients with cancer. Patients with ovarian cancer frequently present with peritoneal carcinomatosis, but the mechanisms that induce naïve peritoneal macrophages into TAMs are poorly understood. In this study, we found an increased abundance of TAMs in mouse i.p. xenograft models of ovarian cancer that expressed HOXA9, a homeobox gene that is associated with poor prognosis in patients with ovarian cancer. HOXA9 expression in ovarian cancer cells stimulated chemotaxis of peritoneal macrophages and induced macrophages to acquire TAM-like features. These features included induction of the M2 markers, CD163 and CD206, and the immunosuppressive cytokines, IL-10 and chemokine ligand 17, and down-regulation of the immunostimulatory cytokine, IL-12. HOXA9-mediated induction of TAMs was primarily due to the combinatorial effects of HOXA9-induced, tumor-derived transforming growth factor-β2 and chemokine ligand 2 levels. High HOXA9 expression in clinical specimens of ovarian cancer was strongly associated with increased abundance of TAMs and intratumoral T-regulatory cells and decreased abundance of CD8+ tumor-infiltrating lymphocytes. Levels of immunosuppressive cytokines were also elevated in ascites fluid of patients with tumors that highly expressed HOXA9. HOXA9 may, therefore, stimulate ovarian cancer progression by promoting an immunosuppressive microenvironment via paracrine effects on peritoneal macrophages. PMID:24332016

Chitosan-palmitic acid based polymeric micelles as promising carrier for circumventing pharmacokinetic and drug delivery concerns of tamoxifen.

PubMed

Thotakura, Nagarani; Dadarwal, Mukesh; Kumar, Rajendra; Singh, Bhupinder; Sharma, Gajanand; Kumar, Pramod; Katare, Om Prakash; Raza, Kaisar

2017-09-01

Being a BCS class II drug and a good substrate for microsomal enzymes, tamoxifen (TAM) offers a scope for research owing to poor aqueous solubility and compromised bioavailability. The present study designs a novel copolymer derived from palmitic acid and chitosan, and evaluate the derived TAM-loaded micelles for various delivery attributes. The nanometric micellar carriers not only substantially loaded the drug, but also controlled the rate of release of TAM. The designed nanocarrier significantly enhanced the cytotoxicity of TAM on MCF-7 cancer cells. The developed system was designed for intravenous route and was observed to be substantially haemo-compatible with an enhancement of approx. 5 times in AUC vis-a-vis plain drug. The findings employing new polymer-based carrier are promising in nature for the better delivery of similar drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

Evidence-based decision making : developing a knowledge base for successful program outcomes in transportation asset management.

DOT National Transportation Integrated Search

2015-12-01

MAP-21 and AASHTOs framework for transportation asset management (TAM) offer opportunities to use more : rigorous approaches to collect and apply evidence within a TAM context. This report documents the results of a study : funded by the Georgia D...

Effects of H sub 2 S addition on the performance of fresh vs. used CoMo catalysts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rankel, L.A.

1991-01-01

When a Co/Mo catalyst is used for processing vanadium-containing heavy oils, vanadium deposits on the catalyst. As the amount of vanadium on the CoMo catalyst increases, the catalytic effects of CoMo decline and the presence of vanadium starts to influence the hydroprocessing products. Model feeds have been used to explore the changes in the catalytic activity of CoMo, aged CoMo, and VS{sub x} on alumina. Desulfurization, denitrogenation, deoxygenation, aromatics hydrogenation, and metals removal were monitored. This paper reports that, upon the addition of hydrogen sulfide to hydrogen, improvements in the catalysts for aromatics hydrogenation, denitrogenation and metals removal were observed.

48 CFR 1201.105-2 - Arrangement of regulations.

Code of Federal Regulations, 2010 CFR

2010-10-01

... chapter 12 will be cited by “FAR” followed by the FAR numbered cite, and cross reference to the TAM in (TAR) 48 CFR chapter 12 will be cited by “TAM” followed by the TAM numbered cite. References to...

76 FR 5410 - STP Nuclear Operating Company; Notice of Intent To Prepare an Environmental Impact Statement and...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-31

... scope of the NEPA review by contacting the NRC Project Manager, Mr. Tam Tran, by telephone at 800-368-5642, extension 3617, or by e-mail at Tam[email protected] no later than February 23, 2011. Members of the...

An object-based image analysis approach for aquaculture ponds precise mapping and monitoring: a case study of Tam Giang-Cau Hai Lagoon, Vietnam.

PubMed

Virdis, Salvatore Gonario Pasquale

2014-01-01

Monitoring and mapping shrimp farms, including their impact on land cover and land use, is critical to the sustainable management and planning of coastal zones. In this work, a methodology was proposed to set up a cost-effective and reproducible procedure that made use of satellite remote sensing, object-based classification approach, and open-source software for mapping aquaculture areas with high planimetric and thematic accuracy between 2005 and 2008. The analysis focused on two characteristic areas of interest of the Tam Giang-Cau Hai Lagoon (in central Vietnam), which have similar farming systems to other coastal aquaculture worldwide: the first was primarily characterised by locally referred "low tide" shrimp ponds, which are partially submerged areas; the second by earthed shrimp ponds, locally referred to as "high tide" ponds, which are non-submerged areas on the lagoon coast. The approach was based on the region-growing segmentation of high- and very high-resolution panchromatic images, SPOT5 and Worldview-1, and the unsupervised clustering classifier ISOSEG embedded on SPRING non-commercial software. The results, the accuracy of which was tested with a field-based aquaculture inventory, showed that in favourable situations (high tide shrimp ponds), the classification results provided high rates of accuracy (>95 %) through a fully automatic object-based classification. In unfavourable situations (low tide shrimp ponds), the performance degraded due to the low contrast between the water and the pond embankments. In these situations, the automatic results were improved by manual delineation of the embankments. Worldview-1 necessarily showed better thematic accuracy, and precise maps have been realised at a scale of up to 1:2,000. However, SPOT5 provided comparable results in terms of number of correctly classified ponds, but less accurate results in terms of the precision of mapped features. The procedure also demonstrated high degrees of reproducibility

An investigation of abdominal muscle recruitment for sustained phonation in 25 healthy singers.

PubMed

Macdonald, Ian; Rubin, John S; Blake, Ed; Hirani, Shashi; Epstein, Ruth

2012-11-01

The purpose of this study was to investigate the baseline muscle thickness and recruitment patterns of the transversus abdominis muscle (TAM) and the internal oblique muscle (IOM) during semisupine phonation in a group of healthy performers. This was a 2 × 3×2 within-group, repeated-measure study in which 25 professional vocalists--12 male and 13 female performed a series of sustained pitches in differing vocal qualities. Measurements were taken with ultrasound (Sonosite Micromaxx Ultrasound System) of the baseline thickness and % recruitment during voicing, of two deep abdominal muscles--TAM and the IOM. Correlations between TAM and IOM absolute change scores, TAM and IOM percentage change scores, and changes in muscle thickness (absolute and percentage) and age were examined using Spearman's correlations. Gender differences in the four types of change scores within each combination of pitch and quality were conducted with one-way analysis of variances. Differences in muscle thickness change 1) absolute scores and 2) percentage change in TAM and IOM, by pitch and quality (and their interactions) were analyzed using linear mixed models, using restricted maximum likelihood estimations, employing a Toeplitz variance-covariance matrix structure in SPSS (IBM, 2011). Post hoc analyses for independent variable group differences used Sidak's correction for multiple comparisons. Alpha level was set to 0.05. In terms of absolute contractions (changes in the actual millimeter thickness of the muscle), the IOM was greater than the TAM. However in terms of percentage changes in muscles during phonation, the TAM was always greater than the IOM. The TAM as a percentage change was recruited preferentially and significantly in most vocal qualities tested. Although there were differences in muscle mass and recruitment patterns between genders, and males had thicker muscle mass at rest, differences due to muscle mass were not conclusive. Overall this study supports the argument

Mimicking the tumor microenvironment to regulate macrophage phenotype and assessing chemotherapeutic efficacy in embedded cancer cell/macrophage spheroid models.

PubMed

Tevis, Kristie M; Cecchi, Ryan J; Colson, Yolonda L; Grinstaff, Mark W

2017-03-01

Tumor associated macrophages (TAMs) are critical stromal components intimately involved with the progression, invasion, and metastasis of cancer cells. To address the need for an in vitro system that mimics the clinical observations of TAM localizations and subsequent functional performance, a cancer cell/macrophage spheroid model is described. The central component of the model is a triple negative breast cancer spheroid embedded in a three-dimensional collagen gel. Macrophages are incorporated in two different ways. The first is a heterospheroid, a spheroid containing both tumor cells and macrophages. The heterospheroid mimics the population of TAMs infiltrated into the tumor mass, thus being exposed to hypoxia and metabolic gradients. In the second model, macrophages are diffusely seeded in the collagen surrounding the spheroid, thus modeling TAMs in the cancer stroma. The inclusion of macrophages as a heterospheroid changes the metabolic profile, indicative of synergistic growth. In contrast, macrophages diffusely seeded in the collagen bear the same profile regardless of the presence of a tumor cell spheroid. The macrophages in the heterospheroid secrete EGF, a cytokine critical to tumor/macrophage co-migration, and an EGF inhibitor decreases the metabolic activity of the heterospheroid, which is not observed in the other systems. The increased secretion of IL-10 indicates that the heterospheroid macrophages follow an M2/TAM differentiation pathway. Lastly, the heterospheroid exhibits resistance to paclitaxel. In summary, the collagen embedded heterospheroid model promotes TAM-like characteristics, and will be of utility in cancer biology and drug discovery. Two in vitro collagen-embedded multicellular spheroid models are described that mimic the clinical observations of macrophage localization within a tumor. Incorporation of macrophages within a breast cancer spheroid emphasizes cell-cell interactions with subsequent differentiation toward a tumor

Determination of Tamoxifen and its Major Metabolites in Exposed Fish

EPA Science Inventory

Tamoxifen (TAM), (Z)-1-(p-dimethylaminoethoxyphenyl)-1, 2-diphenyl-1-butene, is a nonsteroidal agent that has been used in breast cancer treatment for decades. Its major metabolites are 4-hydroxytamoxifen (4-OHT), N-desmethyltamoxifen (DMT), and endoxifen. While TAM and metabolit...

Dynamic test/analysis correlation using reduced analytical models

NASA Technical Reports Server (NTRS)

Mcgowan, Paul E.; Angelucci, A. Filippo; Javeed, Mehzad

1992-01-01

Test/analysis correlation is an important aspect of the verification of analysis models which are used to predict on-orbit response characteristics of large space structures. This paper presents results of a study using reduced analysis models for performing dynamic test/analysis correlation. The reduced test-analysis model (TAM) has the same number and orientation of DOF as the test measurements. Two reduction methods, static (Guyan) reduction and the Improved Reduced System (IRS) reduction, are applied to the test/analysis correlation of a laboratory truss structure. Simulated test results and modal test data are used to examine the performance of each method. It is shown that selection of DOF to be retained in the TAM is critical when large structural masses are involved. In addition, the use of modal test results may provide difficulties in TAM accuracy even if a large number of DOF are retained in the TAM.

Tumour-associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(IV) pro-drug

PubMed Central

Miller, Miles A.; Zheng, Yao-Rong; Gadde, Suresh; Pfirschke, Christina; Zope, Harshal; Engblom, Camilla; Kohler, Rainer H.; Iwamoto, Yoshiko; Yang, Katherine S.; Askevold, Bjorn; Kolishetti, Nagesh; Pittet, Mikael; Lippard, Stephen J.; Farokhzad, Omid C.; Weissleder, Ralph

2015-01-01

Therapeutic nanoparticles (TNPs) aim to deliver drugs more safely and effectively to cancers, yet clinical results have been unpredictable owing to limited in vivo understanding. Here we use single-cell imaging of intratumoral TNP pharmacokinetics and pharmacodynamics to better comprehend their heterogeneous behaviour. Model TNPs comprising a fluorescent platinum(IV) pro-drug and a clinically tested polymer platform (PLGA-b-PEG) promote long drug circulation and alter accumulation by directing cellular uptake toward tumour-associated macrophages (TAMs). Simultaneous imaging of TNP vehicle, its drug payload and single-cell DNA damage response reveals that TAMs serve as a local drug depot that accumulates significant vehicle from which DNA-damaging Pt payload gradually releases to neighbouring tumour cells. Correspondingly, TAM depletion reduces intratumoral TNP accumulation and efficacy. Thus, nanotherapeutics co-opt TAMs for drug delivery, which has implications for TNP design and for selecting patients into trials. PMID:26503691

Tamoxifen is a potent antioxidant modulator for sperm quality in patients with idiopathic oligoasthenospermia.

PubMed

Guo, Li; Jing, Jun; Feng, Yu-Ming; Yao, Bing

2015-09-01

To explore the new mechanisms of tamoxifen (TAM) in the treatment for patients with idiopathic oligoasthenospermia-antioxidation. In a prospective, randomized, controlled clinical trial, 120 cases of idiopathic oligoasthenospermia were enrolled and randomly assigned to the indomethacin group (n = 60) treated with indomethacin (25 mg, bid) and TAM group (n = 60) treated with TAM (10 mg, bid) for 3 months. Before and after treatment, we evaluated semen parameters, serum malondialdehyde (MDA) and total antioxidant capacity (TAC), seminal plasma MDA and TAC, spermatozoa intracellular reactive oxygen species (ROS), sperm succinate dehydrogenase (SDH) activity, sperm mitochondrial membrane potential (MMP), and sperm adenosine triphosphate (ATP) content. The independent t test and one-way repeated measures analysis of variance were used to compare the variables between and within two groups. In the indomethacin group, the percentage of progressive motile sperms, total motility, sperm MMP, and ATP content were increased significantly after 3-month treatment (P < 0.05). In the TAM group, total sperm count, sperm concentration, the percentage of progressive motile sperms, total motility, serum and seminal plasma TAC, sperm MMP, and ATP content were significantly improved or increased (P < 0.05), while spermatozoa intracellular ROS was significantly decreased (P < 0.05). Compared to the indomethacin group, TAM treatment showed better improvement in total sperm count, sperm concentration, serum TAC, seminal plasma TAC, spermatozoa intracellular ROS, and sperm SDH activity. TAM treatment can significantly improve sperm quality, which is achieved through alleviating oxidative stress, improving sperm mitochondrial functionality, and subsequently increasing sperm motility.

Breast cancers from black women exhibit higher numbers of immunosuppressive macrophages with proliferative activity and of crown-like structures associated with lower survival compared to non-black Latinas and Caucasians.

PubMed

Koru-Sengul, Tulay; Santander, Ana M; Miao, Feng; Sanchez, Lidia G; Jorda, Merce; Glück, Stefan; Ince, Tan A; Nadji, Mehrad; Chen, Zhibin; Penichet, Manuel L; Cleary, Margot P; Torroella-Kouri, Marta

2016-07-01

Racial disparities in breast cancer incidence and outcome are a major health care challenge. Patients in the black race group more likely present with an early onset and more aggressive disease. The occurrence of high numbers of macrophages is associated with tumor progression and poor prognosis in solid malignancies. Macrophages are observed in adipose tissues surrounding dead adipocytes in "crown-like structures" (CLS). Here we investigated whether the numbers of CD163+ tumor-associated macrophages (TAMs) and/or CD163+ CLS are associated with patient survival and whether there are significant differences across blacks, non-black Latinas, and Caucasians. Our findings confirm that race is statistically significantly associated with the numbers of TAMs and CLS in breast cancer, and demonstrate that the highest numbers of CD163+ TAM/CLS are found in black breast cancer patients. Our results reveal that the density of CD206 (M2) macrophages is a significant predictor of progression-free survival univariately and is also significant after adjusting for race and for HER2, respectively. We examined whether the high numbers of TAMs detected in tumors from black women were associated with macrophage proliferation, using the Ki-67 nuclear proliferation marker. Our results reveal that TAMs actively divide when in contact with tumor cells. There is a higher ratio of proliferating macrophages in tumors from black patients. These findings suggest that interventions based on targeting TAMs may not only benefit breast cancer patients in general but also serve as an approach to remedy racial disparity resulting in better prognosis patients from minority racial groups.

Microwave effects on NiMoS and CoMoS single-sheet catalysts.

PubMed

Borges, I; Silva, Alexander M; Modesto-Costa, Lucas

2018-05-04

Single-sheet nanoclusters of MoS 2 , NiMoS or CoMoS are widely used in hydrodesulfurization (HDS) catalysis in the petroleum industry. In HDS reactions under microwave irradiation, experiments indirectly pointed out that for pristine MoS 2 reaction rates are accelerated because hot spots are generated on the catalyst bed. In this work, we investigated NiMoS and CoMoS isolated single-sheet substituted catalysts before and after thiophene adsorption focusing on quantifying the effect of microwave irradiation. For that purpose, density functional theory (DFT) molecular charge densities of each system were decomposed according to the distributed multipole analysis (DMA) of Stone. Site dipole values of each system were directly associated with a larger or smaller interaction with the microwave field according to a proposed general approach. We showed that microwave enhancement of HDS reaction rates can occur more efficiently in the CoMoS and NiMoS promoted clusters compared to pristine MoS 2 in the following order: CoMoS > NiMoS > MoS 2 . The atomic origin of the catalyst hot spots induced by microwaves was clearly established in the promoted clusters.

Identification of the Mechanisms Underlying Antiestrogen Resistance: Breast Cancer Research Partnership Between FIU-UM Braman Family Breast Cancer Institute

DTIC Science & Technology

2011-06-01

sulforaphane contributes to tam sensitivity in tam resistant LCC2 cells by increasing expression of p27. In: Proceedings of the Annual Meeting of...Slingerland, J., and Roy, D. (2010) Modulation of thioredoxin reductase by sulforaphane may restore tamoxifen sensitivity in resistant LCC2 cells

The Influence of Teachers' Conceptions of Teaching and Learning on Their Technology Acceptance

ERIC Educational Resources Information Center

Teo, Timothy; Zhou, Mingming

2017-01-01

Prior research has attempted to incorporate different personal variables within extant theories of technology acceptance models (TAMs). This study further extends TAM by incorporating teachers' conceptions of teaching and learning (CoTL) in two forms: constructivist and traditional conceptions. The moderating effects of teachers' demographic…

48 CFR 1202.1 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-10-01

... “procuring activity.” Contracting officer (CO) means an individual authorized by virtue of their position or... Transportation Acquisition Regulation (TAR) and Transportation Acquisition Manual (TAM). Department of... Administration (FAA); (FAA is exempt from FAR, TAR and TAM pursuant to the Department of Transportation and...

48 CFR 1202.1 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-10-01

... “procuring activity.” Contracting officer (CO) means an individual authorized by virtue of their position or... Transportation Acquisition Regulation (TAR) and Transportation Acquisition Manual (TAM). Department of... Administration (FAA); (FAA is exempt from FAR, TAR and TAM pursuant to the Department of Transportation and...

48 CFR 1202.1 - Definitions.

Code of Federal Regulations, 2014 CFR

2014-10-01

... “procuring activity.” Contracting officer (CO) means an individual authorized by virtue of their position or... Transportation Acquisition Regulation (TAR) and Transportation Acquisition Manual (TAM). Department of... Administration (FAA); (FAA is exempt from FAR, TAR and TAM pursuant to the Department of Transportation and...

48 CFR 1202.1 - Definitions.

Code of Federal Regulations, 2013 CFR

2013-10-01

... “procuring activity.” Contracting officer (CO) means an individual authorized by virtue of their position or... Transportation Acquisition Regulation (TAR) and Transportation Acquisition Manual (TAM). Department of... Administration (FAA); (FAA is exempt from FAR, TAR and TAM pursuant to the Department of Transportation and...

48 CFR 1202.1 - Definitions.

Code of Federal Regulations, 2012 CFR

2012-10-01

... “procuring activity.” Contracting officer (CO) means an individual authorized by virtue of their position or... Transportation Acquisition Regulation (TAR) and Transportation Acquisition Manual (TAM). Department of... Administration (FAA); (FAA is exempt from FAR, TAR and TAM pursuant to the Department of Transportation and...

High-capacity quantum key distribution via hyperentangled degrees of freedom

NASA Astrophysics Data System (ADS)

Simon, David S.; Sergienko, Alexander V.

2014-06-01

Quantum key distribution (QKD) has long been a promising area for the application of quantum effects in solving real-world problems. However, two major obstacles have stood in the way of its widespread application: low secure key generation rates and short achievable operating distances. In this paper, a new physical mechanism for dealing with the first of these problems is proposed: the interplay between different degrees of freedom in a hyperentangled system (parametric down-conversion) is used to increase the Hilbert space dimension available for key generation while maintaining security. Polarization-based Bell tests provide security checking, while orbital angular momentum (OAM) and total angular momentum (TAM) provide a higher key generation rate. Whether to measure TAM or OAM is decided randomly in each trial. The concurrent noncommutativity of TAM with OAM and polarization provides the physical basis for quantum security. TAM measurements link polarization to OAM, so that if the legitimate participants measure OAM while the eavesdropper measures TAM (or vice-versa), then polarization entanglement is lost, revealing the eavesdropper. In contrast to other OAM-based QKD methods, complex active switching between OAM bases is not required; instead, passive switching by beam splitters combined with much simpler active switching between polarization bases makes implementation at high OAM more practical.

Tamoxifen-loaded liposomal topical formulation arrests hair growth in mice.

PubMed

Bhatia, A; Singh, B; Amarji, B; Katare, O P

2010-08-01

For several decades, androgens have dominated endocrine research in the domain of hair growth control. However, it has long been known that oestrogens also tend to alter hair follicle (HF) growth and cycling significantly by binding to locally expressed high-affinity oestrogen receptors (ORs). Tamoxifen (TAM) is a selective OR modulator. The current work aims to investigate the effect of topically applied TAM on the hair growth of mice. Test formulations were applied once daily on the shaved back area of the mice for a period of 5 weeks. The effect of these formulations was studied by visual and histological examinations. Animals treated with saline and placebo gel formulation showed significant hair growth on the 20th day. The number and length of follicles were also found to be normal. In contrast, no hair growth was observed in the animals treated with TAM gel, even after the termination of treatment. The HFs were found to be arrested in telogen phase with clear signs of follicle dystrophy. The hair growth-retarding effect of TAM observed in the current study clearly demonstrates its OR agonistic effect on hair growth. This work also provides a distinct lead towards the possible potential of TAM liposomal gel in the treatment of hirsutism.

Tamoxifen impairs prepubertal mammary development and alters expression of estrogen receptor α (ESR1) and progesterone receptors (PGR).

PubMed

Tucker, H L M; Parsons, C L M; Ellis, S; Rhoads, M L; Akers, R M

2016-01-01

Research has shown that prepubertal heifers experience allometric mammary growth that is influenced by the ovaries. Our purpose was to determine the role of estrogen in prepubertal mammary gland development. Sixteen Holstein calves were randomly assigned to 1 of 2 treatment groups: tamoxifen-injected (TAM) or control (CON). Calves were administered the antiestrogen tamoxifen (0.3 mg kg(1) d(1)) or placebo from 28 to 120 d of age. At 120 d, calves were euthanized and udders removed. Weight and DNA content of trimmed parenchymal tissue were halved (P ≤ 0.0001) in TAM compared with CON calves. Parenchymal samples from 3 zones of the left rear mammary gland (lower, middle, and outer regions) were processed for immunohistochemical staining for estrogen receptor α (ESR1) and progesterone receptor (PGR), Ki67-positive cells, and 5-bromo-2'-deoxyuridine label retaining cells (LRCs). Overall, neither the percentage nor location within the epithelial tissue layer of either ESR1- or PGR-positive cells was impacted by TAM treatment. However, image analysis indicated a 6.2-fold lower (P = 0.0001) level of ESR1 protein expression in TAM calves. Similarly, messenger RNA expression of ESR1 was also reduced (P = 0.0001) in TAM heifers. In contrast, expression of PGR protein was greater by 43% (P = 0.03) in TAM calves, but messenger RNA expression did not differ between treatments. Overall, TAM calves had a higher (P ≤ 0.03) percentage and density (cells per tissue area) of Ki67-positive cells. Irrespective of treatment, there were also more Ki67-labeled cells in the outer zones of the mammary gland (P ≤ 0.001). We were able to effectively use multispectral imaging to identify positive cells and quantify the expression of ESR1 and PGR protein. We also identified and counted the proportion of label retaining cells (LCR) (putative epithelial stem cells). We noted an overall 2.9-fold greater number of LRCs in TAM heifers and more LRCs in the outer sampling zones. This suggests

A sup 57 Co Moessbauer emission spectrometric study of some supported CoMo hydrodesulfurization catalysts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Veen, J.A.R. van; Hendriks, P.A.J.M.; Beens, H.

1992-01-01

A suite of 11 CoMo/Al{sub 2}O{sub 4} (and one CoMo/SiO{sub 2}) catalysts has been prepared employing four preparation routes, viz. one sequential-impregnation route and three different coimpregnation routes. Speciation of the Co present in the oxidic precursors (octahedral vs tetrahedral Co) and in the activated, sulfided catalysts (CoMoS, Co{sub 9}S{sub 8}, and unsulfided Co) was effected with the aid of {sup 57}Co Moessbauer emission spectroscopy (MES). A linear relation between the thiophene-hydrodesulfurization (HDS) activity and wt% Co-in-CoMoS was observed for each preparation route, but no unique correlation was found to exist. This was traced to the fact that the preparationmore » routes differ in the amount of CoMoS I and CoMoS II they produce in the activated catalyst. Although these two phases differ in specific activity, CoMoS II being twice as active in thiophene HDS as CoMoS I, they cannot be distinguished on the basis of their Moessbauer parameters. It appears that octahedral Co is easier to sulfide than tetrahedral Co, but a substantial fraction of the latter is also found to be capable of entering CoMoS upon sulfidation. The reduced effectiveness of high-loading catalysts is traced to their being prone to CoMoO{sub 4} formation in the calcination step. A rationalization of this behavior is offered.« less

Como Lo Hago Yo: Myelomeningocele

PubMed Central

Lazareff, Jorge

2014-01-01

Fortificación con ádico fólico es efectiva, pero aún falta conciencia en los jóvenes. La legalidad del aborto aumenta la importancia de la consulta prenatal. Realizo la cirugía bajo microcoscopio por razones didácticas. Irrigación continua para reducir la temperatura del tejido. Trato a la plaqueta como tejido viable. No suturo la plaqueta. No cierro músculo. ATB por una semana después de cirugía. Hidrocefalia: Válvula en todos los casos de ventriculomegalia. Médula anclada: Desanclar una sola vez. Chiari II: Revisar la válvula. Incluir en el seguimiento rendimiento escolar, puede indicar obstrucción de la válvula o médula anclada. PMID:24791217

Identification of the Mechanisms Underlying Antiestrogen Resistance: Breast Cancer Research Partnership between FIU-UM Braman Family Breast Cancer Institute

DTIC Science & Technology

2012-06-01

D. Increase in TrxR by sulforaphane contributes to tam sensitivity in tam resistant LCC2 cells by increasing expression of p27. In: Proceedings of...9. Penney R., Felty, Q., Slingerland, J., and Roy, D. (2010) Modulation of thioredoxin reductase by sulforaphane may restore tamoxifen sensitivity

Cross-National Comparisons of College Students' Attitudes toward Diet/Fitness Apps on Smartphones

ERIC Educational Resources Information Center

Cho, Jaehee; Lee, H. Erin; Quinlan, Margaret

2017-01-01

Objective: Based on the technology acceptance model (TAM), we explored the nationally-bounded roles of four predictors (subjective norms, entertainment, recordability, and networkability) in determining the TAM variables of perceived usefulness (PU), perceived ease of use (PEOU), and behavioral intention (BI) to use diet/fitness apps on…

A Path Analysis of Pre-Service Teachers' Attitudes to Computer Use: Applying and Extending the Technology Acceptance Model in an Educational Context

ERIC Educational Resources Information Center

Teo, Timothy

2010-01-01

The purpose of this study is to examine pre-service teachers' attitudes to computers. This study extends the technology acceptance model (TAM) framework by adding subjective norm, facilitating conditions, and technological complexity as external variables. Results show that the TAM and subjective norm, facilitating conditions, and technological…

An Exploration of the Factors Influencing the Adoption of an IS Governance Framework

ERIC Educational Resources Information Center

Parker, Sharon L.

2013-01-01

This research explored IT governance framework adoption, leveraging established IS theories. It applied both the technology acceptance model (TAM) and the technology, organization, environment (TOE) models. The study consisted of developing a model utilizing TOE and TAM, deriving relevant hypotheses. Interviews with a group of practitioners…

E-Book Acceptance among Undergraduate Students: A Look at the Moderating Role of Technology Innovativeness

ERIC Educational Resources Information Center

Ngafeeson, Madison N.; Sun, Jun

2015-01-01

This paper utilizes the technology acceptance model (TAM) to uncover the moderating roles of technology innovativeness. A study of 158 undergraduate students revealed that the original TAM constructs and relationships were reliable, supported, and applicable in the measurement of e-book acceptance. Interestingly, personal technology innovativeness…

miRNA let-7b modulates macrophage polarization and enhances tumor-associated macrophages to promote angiogenesis and mobility in prostate cancer.

PubMed

Wang, Zhigang; Xu, Lu; Hu, Yinying; Huang, Yanqin; Zhang, Yujuan; Zheng, Xiufen; Wang, Shanshan; Wang, Yifan; Yu, Yanrong; Zhang, Meng; Yuan, Keng; Min, Weiping

2016-05-09

Macrophage polarization is a highly plastic physiological process that responds to a variety of environmental factors by changing macrophage phenotype and function. Tumor-associated macrophages (TAMs) are generally recognized as promoting tumor progression. As universal regulators, microRNAs (miRNAs) are functionally involved in numerous critical cellular processes including macrophage polarization. Let-7b, a miRNA, has differential expression patterns in inflamed tissues compared with healthy controls. However, whether and how miRNA let-7b regulates macrophage phenotype and function is unclear. In this report, we find that up-regulation of let-7b is characteristic of prostatic TAMs, and down-regulation of let-7b in TAMs leads to changes in expression profiles of inflammatory cytokines, such as IL-12, IL-23, IL-10 and TNF-α. As a result, TAMs treated with let-7b inhibitors reduce angiogenesis and prostate carcinoma (PCa) cell mobility. Let-7b may play a vital role in regulating macrophage polarization, thus modulating the prognosis of prostate cancer.

In vivo triarylmethyl radical stabilization through encapsulation in Pluronic F-127 hydrogel

NASA Astrophysics Data System (ADS)

Abbas, Kahina; Boutier-Pischon, Audrey; Auger, Florian; Françon, Dominique; Almario, Antonio; Frapart, Yves-Michel

2016-09-01

In vivo electron paramagnetic resonance (EPR) imaging and spectroscopy are non-invasive technologies used to specifically detect and quantify paramagnetic species. However, the relative instability of spin probes such as triarylmethyl radicals limits their application to conduct oxygen quantification and mapping. In this study we encapsulated tetrathiatriarylmethyl radical (TAM; known as "Finland" probe) in Pluronic F-127 hydrogel (PF-127) in order to limit its degradation and evaluate its in vitro and in vivo EPR properties as a function of oxygen. Our results show that the EPR signal of encapsulated TAM in PF-127 hydrogel is similar to the one in solution. Although it is less sensitive to oxygen, it is suitable for oximetry. We also demonstrated that the incorporation of TAM in PF-127 hydrogel leads to an improved in vivo EPR stability of the radical under anesthesia. This new formulation enables high quality EPR imaging and oximetry and paves the way for the application of TAM radical-based probes in various biomedical fields.

Reconstitution of a nanomachine driving the assembly of proteins into bacterial outer membranes

NASA Astrophysics Data System (ADS)

Shen, Hsin-Hui; Leyton, Denisse L.; Shiota, Takuya; Belousoff, Matthew J.; Noinaj, Nicholas; Lu, Jingxiong; Holt, Stephen A.; Tan, Khershing; Selkrig, Joel; Webb, Chaille T.; Buchanan, Susan K.; Martin, Lisandra L.; Lithgow, Trevor

2014-10-01

In biological membranes, various protein secretion devices function as nanomachines, and measuring the internal movements of their component parts is a major technological challenge. The translocation and assembly module (TAM) is a nanomachine required for virulence of bacterial pathogens. We have reconstituted a membrane containing the TAM onto a gold surface for characterization by quartz crystal microbalance with dissipation (QCM-D) and magnetic contrast neutron reflectrometry (MCNR). The MCNR studies provided structural resolution down to 1 Å, enabling accurate measurement of protein domains projecting from the membrane layer. Here we show that dynamic movements within the TamA component of the TAM are initiated in the presence of a substrate protein, Ag43, and that these movements recapitulate an initial stage in membrane protein assembly. The reconstituted system provides a powerful new means to study molecular movements in biological membranes, and the technology is widely applicable to studying the dynamics of diverse cellular nanomachines.

Adoptively transferred immune T cells eradicate established tumors in spite of cancer-induced immune suppression

PubMed Central

Arina, Ainhoa; Schreiber, Karin; Binder, David C.; Karrison, Theodore; Liu, Rebecca B.; Schreiber, Hans

2014-01-01

Myeloid-derived CD11b+Gr1+ suppressor cells (MDSC) and tumor-associated macrophages (TAM) are considered a major obstacle for effective adoptive T cell therapy. Myeloid cells suppress naive T cell proliferation ex vivo and can prevent the generation of T cell responses in vivo. We find, however, that immune T cells adoptively transferred eradicate well-established tumors in the presence of MDSC and TAM which are strongly immunosuppressive ex vivo. These MDSC and TAM were comparable in levels and immunosuppression among different tumor models. Longitudinal microscopy of tumors in vivo revealed that after T cell transfer tumor vasculature and cancer cells disappeared simultaneously. During T-cell mediated tumor destruction, the tumor stroma contained abundant myeloid cells (mainly TAM) that retained their suppressive properties. Preimmunized but not naive mice resisted immune suppression caused by an unrelated tumor-burden supporting the idea that in vivo, myeloid immunosuppressive cells can suppress naive but not memory T cell responses. PMID:24367029

The technology acceptance model: its past and its future in health care.

PubMed

Holden, Richard J; Karsh, Ben-Tzion

2010-02-01

Increasing interest in end users' reactions to health information technology (IT) has elevated the importance of theories that predict and explain health IT acceptance and use. This paper reviews the application of one such theory, the Technology Acceptance Model (TAM), to health care. We reviewed 16 data sets analyzed in over 20 studies of clinicians using health IT for patient care. Studies differed greatly in samples and settings, health ITs studied, research models, relationships tested, and construct operationalization. Certain TAM relationships were consistently found to be significant, whereas others were inconsistent. Several key relationships were infrequently assessed. Findings show that TAM predicts a substantial portion of the use or acceptance of health IT, but that the theory may benefit from several additions and modifications. Aside from improved study quality, standardization, and theoretically motivated additions to the model, an important future direction for TAM is to adapt the model specifically to the health care context, using beliefs elicitation methods.

THE TECHNOLOGY ACCEPTANCE MODEL: ITS PAST AND ITS FUTURE IN HEALTH CARE

PubMed Central

HOLDEN, RICHARD J.; KARSH, BEN-TZION

2009-01-01

Increasing interest in end users’ reactions to health information technology (IT) has elevated the importance of theories that predict and explain health IT acceptance and use. This paper reviews the application of one such theory, the Technology Acceptance Model (TAM), to health care. We reviewed 16 data sets analyzed in over 20 studies of clinicians using health IT for patient care. Studies differed greatly in samples and settings, health ITs studied, research models, relationships tested, and construct operationalization. Certain TAM relationships were consistently found to be significant, whereas others were inconsistent. Several key relationships were infrequently assessed. Findings show that TAM predicts a substantial portion of the use or acceptance of health IT, but that the theory may benefit from several additions and modifications. Aside from improved study quality, standardization, and theoretically motivated additions to the model, an important future direction for TAM is to adapt the model specifically to the health care context, using beliefs elicitation methods. PMID:19615467

Immobilized copper(II) macrocyclic complex on MWCNTs with antibacterial activity

NASA Astrophysics Data System (ADS)

Tarlani, Aliakbar; Narimani, Khashayar; Mohammadipanah, Fatemeh; Hamedi, Javad; Tahermansouri, Hasan; Amini, Mostafa M.

2015-06-01

In a new approach, a copper(II) tetraaza macrocyclic complex (CuTAM) was covalently bonded on modified multi-walled carbon nanotubes (MWCNTs). To achieve this purpose, MWCNTs were converted to MWCNT-COCl and then reacted to NH groups of TAM ligand. The prepared material was characterized by Fourier Transform Infrared (FT-IR), X-ray diffraction (XRD), Raman spectroscopy, thermal gravimetric analysis (TGA), and FESEM (field emission scanning electron microscopy). FT-IR and TGA demonstrated the presence of the organic moieties, and XRD proved that the structure of MWCNTs remained intact during the three modification steps. An increase in the ID/IG ratio in Raman spectra confirmed the surface modifications. Finally, the samples were subjected to an antibacterial assessment to compare their biological activity. The antibacterial test showed that the grafted complex on the surface of the nanotube (MWCNT-CO-CuTAM) has higher antibacterial activity against Bacillus subtilis ATCC 6633 than the MWCNT-COOH and CuTAM with 1000 and 2000 μg/mL.

Molecular-Targeted Immunotherapeutic Strategy for Melanoma via Dual-Targeting Nanoparticles Delivering Small Interfering RNA to Tumor-Associated Macrophages.

PubMed

Qian, Yuan; Qiao, Sha; Dai, Yanfeng; Xu, Guoqiang; Dai, Bolei; Lu, Lisen; Yu, Xiang; Luo, Qingming; Zhang, Zhihong

2017-09-26

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. We confirmed the validity of SR-B1 for M2-like TAM targeting and demonstrated the synergistic effect of the two targeting units (α-peptide and M2pep) in the fusion peptide (α-M2pep). After being administered to tumor-bearing mice, M2NPs had higher affinity to M2-like TAMs than to tissue-resident macrophages in liver, spleen, and lung. Compared with control treatment groups, M2NP-based siRNA delivery resulted in a dramatic elimination of M2-like TAMs (52%), decreased tumor size (87%), and prolonged survival. Additionally, this molecular-targeted strategy inhibited immunosuppressive IL-10 and TGF-β production and increased immunostimulatory cytokines (IL-12 and IFN-γ) expression and CD8 + T cell infiltration (2.9-fold) in the tumor microenvironment. Moreover, the siRNA-carrying M2NPs down-regulated expression of the exhaustion markers (PD-1 and Tim-3) on the infiltrating CD8 + T cells and stimulated their IFN-γ secretion (6.2-fold), indicating the restoration of T cell immune function. Thus, the dual-targeting property of M2NPs combined with RNA interference provides a potential strategy of molecular-targeted cancer immunotherapy for clinical application.

Macrophages Modulate Migration and Invasion of Human Tongue Squamous Cell Carcinoma

PubMed Central

Pirilä, Emma; Väyrynen, Otto; Sundquist, Elias; Päkkilä, Kaisa; Nyberg, Pia; Nurmenniemi, Sini; Pääkkönen, Virve; Pesonen, Paula; Dayan, Dan; Vered, Marilena; Uhlin-Hansen, Lars; Salo, Tuula

2015-01-01

Oral tongue squamous cell carcinoma (OTSCC) has a high mortality rate and the incidence is rising worldwide. Despite advances in treatment, the disease lacks specific prognostic markers and treatment modality. The spreading of OTSCC is dependent on the tumor microenvironment and involves tumor-associated macrophages (TAMs). Although the presence of TAMs is associated with poor prognosis in OTSCC, the specific mechanisms underlying this are still unknown. The aim here was to investigate the effect of macrophages (Mfs) on HSC-3 tongue carcinoma cells and NF-kappaB activity. We polarized THP-1 cells to M1 (inflammatory), M2 (TAM-like) and R848 (imidazoquinoline-treated) type Mfs. We then investigated the effect of Mfs on HSC-3 cell migration and NF-kappaB activity, cytokine production and invasion using several different in vitro migration models, a human 3D tissue invasion model, antibody arrays, confocal microscopy, immunohistochemistry and a mouse invasion model. We found that in co-culture studies all types of Mfs fused with HSC-3 cells, a process which was partially due to efferocytosis. HSC-3 cells induced expression of epidermal growth factor and transforming growth factor-beta in co-cultures with M2 Mfs. Direct cell-cell contact between M2 Mfs and HSC-3 cells induced migration and invasion of HSC-3 cells while M1 Mfs reduced HSC-3 cell invasion. M2 Mfs had an excess of NF-kappaB p50 subunit and a lack of p65 subunits both in the presence and absence of HSC-3 cells, indicating dysregulation and pro-tumorigenic NF-kappaB activation. TAM-like cells were abundantly present in close vicinity to carcinoma cells in OTSCC patient samples. We conclude that M2 Mfs/TAMs have an important role in OTSCC regulating adhesion, migration, invasion and cytokine production of carcinoma cells favouring tumor growth. These results demonstrate that OTSCC patients could benefit from therapies targeting TAMs, polarizing TAM-like M2 Mfs to inflammatory macrophages and modulating NF

GPR30 as an initiator of tamoxifen resistance in hormone-dependent breast cancer.

PubMed

Mo, Zhiqiang; Liu, Manran; Yang, Fangfang; Luo, Haojun; Li, Zhenhua; Tu, Gang; Yang, Guanglun

2013-11-29

Tamoxifen is widely used to treat hormone-dependent breast cancer, but its therapeutic benefit is limited by the development of drug resistance. Here, we investigated the role of estrogen G-protein coupled receptor 30 (GPR30) on Tamoxifen resistance in breast cancer. Primary tumors (PTs) of breast cancer and corresponding metastases (MTs) were used to evaluate the expression of GPR30 and epidermal growth factor receptor (EGFR) immunohistochemically. Tamoxifen-resistant (TAM-R) subclones derived from parent MCF-7 cells were used to investigate the role of GPR30 in the development of tamoxifen resistance, using MTT assay, western blot, RT-PCR, immunofluorescence, ELISA and flow cytometry. TAM-R xenografts were established to assess anti-tumor effects of combination therapy with GPR30 antagonist G15 plus 4-hydroxytamoxifen (Tam), using tumor volume measurement and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). In 53 human breast cancer specimens, GPR30 expression in MTs increased compared to matched PTs; in MTs, the expression patterns of GPR30 and EGFR were closely related. Compared to parent MCF-7 cells, TAM-R cells had greater growth responses to 17β-estradiol (E2), GPR30 agonist G1 and Tam, and significantly higher activation of Mitogen-activated protein (MAP) kinases; but this increased activity was abolished by G15 or AG1478. In TAM-R cells, GPR30 cell-surface translocation facilitated crosstalk with EGFR, and reduced cAMP generation, attenuating inhibition of EGFR signaling. Combination therapy both promoted apoptosis in TAM-R cells and decreased drug-resistant tumor progression. Long-term endocrine treatment facilitates the translocation of GPR30 to cell surfaces, which interferes with the EGFR signaling pathway; GPR30 also attenuates the inhibition of MAP kinases. These factors contribute to tamoxifen resistance development in breast cancer. Combination therapy with GPR30 inhibitors and tamoxifen may provide a new therapeutic option

Thermochronologic constraints on post-Paleozoic tectonic evolution of the central Transantarctic Mountains, Antarctica

NASA Astrophysics Data System (ADS)

Fitzgerald, Paul G.

1994-08-01

Built upon the roots of a compressive orogenic belt of late Proterozoic-early Paleozoic age and once adjacent to North America, the present-day Transantarctic Mountains (TAM) represent a rift flank, resulting from episodic uplift in the Cretaceous and Cenozoic. Fault blocks are discernible in present-day topography and subglacial morphology. Fission track results give information on differential block movement (uplift and denudation) and are important in constraining models for the uplift of the range. Apatite fission track thermochronology on samples collected from the central TAM record a complex thermotectonic history for this region over the past 350 m.y. Apatite ages in the Miller Range vary from ˜250 to ˜350 Ma and are from an exhumed apatite partial annealing zone formed following cooling of Cambro-Ordovician granitoids. A period of Cretaceous denudation (≲2 km), beginning at ˜115 Ma, is recorded at Moody Nunatak on the inland side of the TAM. Near the coast, samples along the Beardmore Glacier record rapid cooling indicative of denudation initiated in the early Cenozoic (˜50 Ma). The amount of uplift ˜70 km inland of the coast in the Queen Alexandra Range since the early Cenozoic is ˜7 km, with the likelihood of an additional ˜3 km at the coast. Eastward facing topographic escarpments in the Queen Alexandra Range mark the likely position of steeply dipping normal faults, which offset the apatite ages. Apatite ages on the east side of the Beardmore Glacier mouth are generally younger (average 27 Ma) than on the west side (average 33 Ma), reflecting greater denudation. Assumptions made regarding the use of an assumed paleogeothermal gradient are tested with available geologic evidence. The fission track data neither conflict with nor confirm paleobotanical evidence from the Sirius Group in the central TAM which suggests significant surface uplift (2-3 km) of the TAM since the Pliocene. Results build upon the available fission track database along the

Anti-cancer Effect of Xao Tam Phan Paramignya trimera Methanol Root Extract on Human Breast Cancer Cell Line MCF-7 in 3D Model.

PubMed

Nguyen-Thi, Lam-Huyen; Nguyen, Sinh Truong; Tran, Thao Phuong; Phan-Lu, Chinh-Nhan; The Van, Trung; Van Pham, Phuc

2018-04-24

Cancer is one of the leading causes of death in the world. A great deal of effort has been made to discover new agents for cancer treatment. Xao tam phan (Paramignya trimera) is a traditional medicine of Vietnam used in cancer treatment for a long time, yet there is not much scientific evidence proving its anticancer potency. The study aimed to evaluate the toxicity of Paramignya trimera extract (PTE) on multicellular tumor spheres (MCTS) of MCF-7 cells using hanging drop technique. Firstly, MCF-7 cells were seeded on hanging drop plates, spheroid size was tracked, and growth curve was measured by MTT assay and AlamarBlue ® assay. The necrotic core of MCTS was evaluated by propidium iodide (PI) staining. Toxicity of doxorubicin (DOX) and tirapazamine (TPZ) was then tested on 3D model compared to 2D culture condition. The results showed that the IC50 of DOX on 3D MCF-7 cells was nearly 50 times greater than monolayer MCF-7 cells. In contrast, TPZ (an agent which is specifically toxic under hypoxic conditions) had significantly lower IC50 in 3D condition than in 2D. The toxicity tests for PTE showed that PTE strongly inhibited MCF-7 cells in both 2D and 3D conditions. Interestingly, the IC50 of PTE in 3D model was remarkably lower than in 2D (IC50 value was 168.9 ± 11.65 μg/ml compared to 260.8 ± 16.54 μg/ml, respectively). The invasion assay showed that PTE completely inhibited invasion of MCF-7 cells at 250 μg/mL concentration. Also, flow cytometry results indicated that PTE effectively induced apoptosis in MCF-7 spheroids in 3D condition at 250 μg/mL concentration. The results from this study emphasize the promise of PTE in cancer therapy.

Pre-Service Teachers' Attitude towards Information and Communication Technology Usage: A Ghanaian Survey

ERIC Educational Resources Information Center

Gyamfi, Stephen Adu

2017-01-01

This study employed the Technology Acceptance Model (TAM) to empirically investigate factors that influence Ghanaian pre-service teachers' attitudes towards Information and Communication Technology (ICT) usage. To achieve this aim, the study extended the TAM framework by adding leadership support and job relevance as exogenous variables. Data were…

The Role of Peer Influence and Perceived Quality of Teaching in Faculty Acceptance of Web-Based Learning Management Systems

ERIC Educational Resources Information Center

Salajan, Florin D.; Welch, Anita G.; Ray, Chris M.; Peterson, Claudette

2015-01-01

This study's primary investigation is the impact of "peer influence" and "perceived quality of teaching" on faculty members' usage of web-based learning management systems within the Technology Acceptance Model (TAM) framework. These factors are entered into an extended TAM as external variables impacting on the core constructs…

Transcriptomics of induced defense responses to greenbug aphid feeding in near isogenic wheat lines

USDA-ARS?s Scientific Manuscript database

The greenbug is an important cereal pest periodically threatening wheat yields in the United States and around the world. Although the greenbug resistance gene Gb3 has been widely deployed in wheat cultivars in the southern High Plains (for example, TAM 110 and TAM 112), the molecular mechanisms of ...

Integrating Electronic Reverse Auctions into Defense Procurement: Exploratory Research on Opportunities, Issues, Processes, Risks, and Cultural Implications

DTIC Science & Technology

2009-12-18

TAM ) ...............................................21 F. Relational Exchange...SAF/AQC Secretary of the Air Force for Acquisition TAM Technology Adoption Model UA Uncertainty Avoidance USAAVE United States Army...of policy, thereby (1) easing the learning curve for individual COs, (2) maximizing e-RA use where it is appropriate and (3) saving substantial

Survival benefit of tamoxifen and aromatase inhibitor in male and female breast cancer.

PubMed

Eggemann, Holm; Altmann, Udo; Costa, Serban-Dan; Ignatov, Atanas

2018-02-01

Our goal was to compare the survival advantage of tamoxifen (TAM) and aromatase inhibitor (AI) in female (FBC) and male breast cancer (MBC). We performed a retrospective study of 2785 FBC and 257 MBC patients treated with hormonal therapy. The median follow-up was 106 months (range 3-151 months) and 42 months (range 2-115 months) for FBC and MBC, respectively. The patients were divided into two groups according to the hormonal therapy used: TAM-treated and AI-treated. MBC was characterized by older age, advanced tumor stage, and higher rate of lymph node metastases, in comparison with FBC. Matching analysis was performed using six prognostic criteria: patient age, tumor stage, tumor grade, lymph node status, human epidermal growth factor receptor (HER2) status, and administration of chemotherapy. The female and male patients were matched 2:1. In this analysis, 316 women and 158 men treated with TAM, and 60 women and 30 men treated with AI, were included. The overall survival (OS) was estimated by the Kaplan-Meier method and was compared between FBC and MBC. TAM-treated FBC and MBC patients had similar 5-year OS, 85.1 and 89.2%, respectively (p = 0.972). Notably, FBC patients treated with AI had significantly greater 5-year OS (85.0%) in comparison with AI-treated MBC patients (5-year OS of 73.3%; p = 0.028). The OS of TAM-treated patients with MBC was similar to the OS of TAM-treated FBC patients, whereas AI treatment is associated with poorer survival of MBC patients.

Treatment Adherence and Its Impact on Disease-Free Survival in the Breast International Group 1-98 Trial of Tamoxifen and Letrozole, Alone and in Sequence.

PubMed

Chirgwin, Jacquie H; Giobbie-Hurder, Anita; Coates, Alan S; Price, Karen N; Ejlertsen, Bent; Debled, Marc; Gelber, Richard D; Goldhirsch, Aron; Smith, Ian; Rabaglio, Manuela; Forbes, John F; Neven, Patrick; Láng, István; Colleoni, Marco; Thürlimann, Beat

2016-07-20

To investigate adherence to endocrine treatment and its relationship with disease-free survival (DFS) in the Breast International Group (BIG) 1-98 clinical trial. The BIG 1-98 trial is a double-blind trial that randomly assigned 6,193 postmenopausal women with hormone receptor-positive early breast cancer in the four-arm option to 5 years of tamoxifen (Tam), letrozole (Let), or the agents in sequence (Let-Tam, Tam-Let). This analysis included 6,144 women who received at least one dose of study treatment. Conditional landmark analyses and marginal structural Cox proportional hazards models were used to evaluate the relationship between DFS and treatment adherence (persistence [duration] and compliance with dosage). Competing risks regression was used to assess demographic, disease, and treatment characteristics of the women who stopped treatment early because of adverse events. Both aspects of low adherence (early cessation of letrozole and a compliance score of < 90%) were associated with reduced DFS (multivariable model hazard ratio, 1.45; 95% CI, 1.09 to 1.93; P = .01; and multivariable model hazard ratio, 1.61; 95% CI, 1.08 to 2.38; P = .02, respectively). Sequential treatments were associated with higher rates of nonpersistence (Tam-Let, 20.8%; Let-Tam, 20.3%; Tam 16.9%; Let 17.6%). Adverse events were the reason for most trial treatment early discontinuations (82.7%). Apart from sequential treatment assignment, reduced adherence was associated with older age, smoking, node negativity, or prior thromboembolic event. Both persistence and compliance are associated with DFS. Toxicity management and, for sequential treatments, patient and physician awareness, may improve adherence. © 2016 by American Society of Clinical Oncology.

Relative susceptibility and effects on performance of Rio Grande cutthroat trout and rainbow trout challenged with Myxobolus cerebralis

USGS Publications Warehouse

DuBey, R.J.; Caldwell, C.A.; Gould, W.R.

2007-01-01

We evaluated the susceptibility of Rio Grande cutthroat trout (RGCT) Oncorhynchus clarkii virginalis to infection by Myxobolus cerebralis in a laboratory experiment. In the same experiment, rainbow trout (RBT) O. mykiss were similarly exposed to M. cerebralis as a reference of known sensitivity to the parasite. Treatments consisting of six parasite concentrations (0, 50, 100, 250, 500, and 1,000 triactinomyxons [TAMS] per fish) were randomized within a complete block design using RGCT and RBT fry beginning at 60 d posthatch (600 degree-days at 10??C). The laboratory experiment was terminated at 130 d postexposure (1,900 degree-days at 10??C). Diagnostic metrics included clinical signs (behavioral and black tail), survival, myxospore counts, histology, and a swimming performance challenge. Clinical signs of whirling disease were observed within both species at 500 and 1,000 TAMs/fish by 66 d postexposure to the disease. Rio Grande cutthroat trout exhibited significantly lower survival (50% cumulative mortality at 1,000 TAMs/fish) and a significant concentration response compared with RBT (8% cumulative mortality at 1,000 TAMs/fish). Histological scoring of cranial sections using a 0-5 scale of increasing pathogenic effect revealed greater disease severity in RGCT (3.20) than in RBT (2.43) at 100 TAMs/fish but no difference at 1,000 TAMs/fish (4.15 and 4.12, respectively). Swimming performance revealed detectably lower critical swimming speed in both RGCT and RBT in relation to increased parasite concentrations, the RGCT exhibiting detectably lower critical swimming speeds than the RBT at increased parasite concentration. If M. cerebralis were to spread to areas supporting RGCT, population-level effects may occur. ?? Copyright by the American Fisheries Society 2007.

Development of Y-shaped peptide for constructing nanoparticle systems targeting tumor-associated macrophages in vitro and in vivo

NASA Astrophysics Data System (ADS)

Yan, Lu; Gao, Yunxiang; Pierce, Ryan; Dai, Liming; Kim, Julian; Zhang, Mei

2014-04-01

Tumor-associated macrophage (TAM) is increasingly being viewed as a target of great interest in tumor microenvironment due to its important role in the progression and metastasis of cancers. It has been shown that TAM indeed overexpresses unique surface marker legumain. In this study, we designed and synthesized a Y-shaped legumain-targeting peptide (Y-Leg) with functional groups allowing for further conjugation with imaging and therapeutic moieties (vide infra). The in vitro cell experiments using FITC-conjugated Y-Leg revealed its specific and selective interaction with M2-polarized macrophages (i.e., TAMs) with preference to M1 macrophages, and that the interaction was not interfered with by conjugating FITC to its functional group. Further, we constructed a nanotube system by grafting Y-Leg onto oxidized carbon nanotubes (OCNTs) loaded with paramagnetic Fe3O4 nanoparticles. The intravenous injection of the resultant Y-Leg-OCNT/Fe3O4 nanotubes to 4T1 mammary tumor-bearing mouse led to the magnetic resonance imaging (MRI) of TAM-infiltrated tumor microenvironment, revealing the targeting specificity of Y-Leg-conjugated nanotubes in vivo. The Y shape of peptide and its functional groups containing amines and imidazole can protonate at different pHs, contributing to the in vitro and in vivo targeting specificity. This study represents the first development of novel peptide and peptide-grafted nanotube system targeting M2-polarized TAMs in vivo. The methodology developed in this study is applicable to the construction of various multifunctional nanoparticle systems for selectively targeting, imaging and manipulating of TAMs for the diagnosis and treatment of cancers and inflammatory diseases identified with macrophage-infiltrated disease tissue.

Treatment Adherence and Its Impact on Disease-Free Survival in the Breast International Group 1-98 Trial of Tamoxifen and Letrozole, Alone and in Sequence

PubMed Central

Giobbie-Hurder, Anita; Coates, Alan S.; Price, Karen N.; Ejlertsen, Bent; Debled, Marc; Gelber, Richard D.; Goldhirsch, Aron; Smith, Ian; Rabaglio, Manuela; Forbes, John F.; Neven, Patrick; Láng, István; Colleoni, Marco; Thürlimann, Beat

2016-01-01

Purpose To investigate adherence to endocrine treatment and its relationship with disease-free survival (DFS) in the Breast International Group (BIG) 1-98 clinical trial. Methods The BIG 1-98 trial is a double-blind trial that randomly assigned 6,193 postmenopausal women with hormone receptor–positive early breast cancer in the four-arm option to 5 years of tamoxifen (Tam), letrozole (Let), or the agents in sequence (Let-Tam, Tam-Let). This analysis included 6,144 women who received at least one dose of study treatment. Conditional landmark analyses and marginal structural Cox proportional hazards models were used to evaluate the relationship between DFS and treatment adherence (persistence [duration] and compliance with dosage). Competing risks regression was used to assess demographic, disease, and treatment characteristics of the women who stopped treatment early because of adverse events. Results Both aspects of low adherence (early cessation of letrozole and a compliance score of < 90%) were associated with reduced DFS (multivariable model hazard ratio, 1.45; 95% CI, 1.09 to 1.93; P = .01; and multivariable model hazard ratio, 1.61; 95% CI, 1.08 to 2.38; P = .02, respectively). Sequential treatments were associated with higher rates of nonpersistence (Tam-Let, 20.8%; Let-Tam, 20.3%; Tam 16.9%; Let 17.6%). Adverse events were the reason for most trial treatment early discontinuations (82.7%). Apart from sequential treatment assignment, reduced adherence was associated with older age, smoking, node negativity, or prior thromboembolic event. Conclusion Both persistence and compliance are associated with DFS. Toxicity management and, for sequential treatments, patient and physician awareness, may improve adherence. PMID:27217455

Factors influencing the distribution of Myxobolus cerebralis, the causative agent of whirling disease, in the Cache la Poudre River, Colorado

USGS Publications Warehouse

Allen, M. Brady; Bergersen, Eric P.

2002-01-01

Oligochaetes, triactinomyxons (TAMs), and age-0 trout were sampled in the upper Cache la Poudre River, Colorado, to determine the distribution of Myxobolus cerebralis during 1997 and 1998. Densities of the intermediate host, the oligochaete Tubifex tubifex, were 3.5 orders of magnitude higher in the M. cerebralis-infected Poudre Rearing Unit (PRU) trout rearing ponds than at any of the river sampling reaches. Oligochaetes, including T. tubifex, were rare in the river (1 oligochaete m-2), except in a few stream side alcoves and eddies (50 oligochaete m-2). Species composition of oligochaetes in the river reaches was more diverse than in the PRU. Tubifex tubifex constituted 50% or less of the oligochaete community in the river and 98% in the PRU. Infection rates of T. tubifex were 1% in the area above the PRU, 2% in the PRU, and 6% below the PRU. An increased M. cerebralis intensity of infection in age-0 trout below the PRU could not be attributed entirely to the high numbers of TAMs in its effluent (3.7 TAMs l-1). Low densities of TAMs ranging from 0 to 0.2 TAMs l-1 were found in the river reaches, yet nearly all of the age-0 trout were infected soon after emergence. This suggests that very few TAMs, as measured by filtration, need be present in the water column to bring about infection in the majority of trout present. This also indicates that the parasite can persist and potentially cause reduced juvenile trout recruitment in cold, oligotrophic, sediment poor, high-gradient streams.

Geophysical investigations of the tectonic boundary between East and West Antarctica

USGS Publications Warehouse

ten Brink, Uri S.; Bannister, S.; Beaudoin, B.C.; Stern, T.A.

1993-01-01

The Transantarctic Mountains (TAM), which separate the West Antarctic rift system from the stable shield of East Antarctica, are the largest mountains developed adjacent to a rift. The cause of uplift of mountains bordering rifts is poorly understood. One notion based on observations of troughs next to many uplifted blocks is that isostatic rebound produces a coeval uplift and subsidence. The results of an over-snow seismic experiment in Antarctica do not show evidence for a trough next to the TAM but indicate the extension of rifted mantle lithosphere under the TAM. Furthermore, stretching preceded the initiation of uplift, which suggests thermal buoyancy as the cause for uplift.

Determining the Upper Mantle Seismic Structure beneath the Northern Transantarctic Mountains from Regional P- and S-wave Tomography

NASA Astrophysics Data System (ADS)

Brenn, G.; Hansen, S. E.; Park, Y.

2016-12-01

Stretching 3500 km across Antarctica, the Transantarctic Mountains (TAMs) are the largest non-compressional mountain range on Earth. It has been suggested that the TAMs may have served as a nucleation point for the large-scale glaciation of Antarctica, and understanding their tectonic history has important implications for ice sheet modeling. However, the origin and uplift mechanism associated with the TAMs is controversial, and multiple models have been proposed. Seismic investigations of the TAM's subsurface structure can provide key constraints to help evaluate these models, but previous studies have been primarily focused on the central TAMs near Ross Island. Using data from the new 15-station Transantarctic Mountain Northern Network as well as data from several smaller networks, this study investigates the upper mantle velocity structure beneath a previously unexplored portion of the northern TAMs through regional body wave tomography. Relative travel-times were calculated for 11,182 P-wave and 8,285 S-wave arrivals from 790 and 581 Mw ≥ 5.5 events, respectively, using multi-channel cross correlation, and these data were then inverted for models of the upper mantle seismic structure. Resulting P- and S-wave tomography images reveal two focused low velocity anomalies beneath Ross Island (RI; δVP= -2.0%; δVS=-1.5% to -4.0%) and Terra Nova Bay (TNB; δVP=-1.5% to -2.0%; δVS= -1.0% to -4.0%) that extend to depths of 200 and 150 km, respectively. The RI and TNB slow anomalies also extend 50-100 km laterally beneath the TAMs front and sharply abut fast velocities beneath the EA craton (δVP=0.5% to 2%; δVS=1.5% to 4.0%). A low velocity region (δVP= -1.5%), centered at 150 km depth beneath the Terror Rift (TR) and primarily constrained within the Victoria Land Basin, connects the RI and TNB anomalies. The focused low velocities are interpreted as regions of partial melt and buoyancy-driven upwelling, connected by a broad region of slow (presumably warm) upper

Modelling the Intention to Use Technology for Teaching Mathematics among Pre-Service Teachers in Serbia

ERIC Educational Resources Information Center

Teo, Timothy; Milutinovic, Verica

2015-01-01

This study aims to examine the variables that influence Serbian pre-service teachers' intention to use technology to teach mathematics. Using the technology acceptance model (TAM) as the framework, we developed a research model to include subjective norm, knowledge of mathematics, and facilitating conditions as external variables to the TAM. In…

Learning Computerese: The Role of Second Language Learning Aptitude in Technology Acceptance

ERIC Educational Resources Information Center

Warner, Janis A.; Koufteros, Xenophon; Verghese, Anto

2014-01-01

This article introduces a new construct coined as Computer User Learning Aptitude (CULA). To establish construct validity, CULA is embedded in a nomological network that extends the technology acceptance model (TAM). Specifically, CULA is posited to affect perceived usefulness and perceived ease of use, the two underlying TAM constructs.…

Utilization of Online Educational Resources in Teaching: A Moderated Mediation Perspective

ERIC Educational Resources Information Center

Kio, Su Iong; Lau, Meng Chan Virgina

2017-01-01

The study builds on a newly modified Technology Acceptance Model (TAM) to substantiate the motivation and operation of teachers' utilization of online learning resources. A "Comprehensiveness" construct is proposed in the modified TAM to reflect the breadth and depth of rich online knowledge. This new construct serves as the mediator…

The Effects of Cognitive Style on Edmodo Users' Behaviour: A Structural Equation Modeling-Based Multi-Group Analysis

ERIC Educational Resources Information Center

Ursavas, Omer Faruk; Reisoglu, Ilknur

2017-01-01

Purpose: The purpose of this paper is to explore the validity of extended technology acceptance model (TAM) in explaining pre-service teachers' Edmodo acceptance and the variation of variables related to TAM among pre-service teachers having different cognitive styles. Design/methodology/approach: Structural equation modeling approach was used to…

Applying the Extended Technology Acceptance Model to the Use of Clickers in Student Learning: Some Evidence from Macroeconomics Classes

ERIC Educational Resources Information Center

Wu, Xiaoyu; Gao, Yuan

2011-01-01

This paper applies the extended technology acceptance model (exTAM) in information systems research to the use of clickers in student learning. The technology acceptance model (TAM) posits that perceived ease of use and perceived usefulness of technology influence users' attitudes toward using and intention to use technology. Research subsequent…

Deregulation of PPARβ/δ target genes in tumor-associated macrophages by fatty acid ligands in the ovarian cancer microenvironment.

PubMed

Schumann, Tim; Adhikary, Till; Wortmann, Annika; Finkernagel, Florian; Lieber, Sonja; Schnitzer, Evelyn; Legrand, Nathalie; Schober, Yvonne; Nockher, W Andreas; Toth, Philipp M; Diederich, Wibke E; Nist, Andrea; Stiewe, Thorsten; Wagner, Uwe; Reinartz, Silke; Müller-Brüsselbach, Sabine; Müller, Rolf

2015-05-30

The nuclear receptor peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is a lipid ligand-inducible transcription factor associated with macrophage polarization. However, its function in tumor-associated macrophages (TAMs) has not been investigated to date. Here, we report the PPARβ/δ-regulated transcriptome and cistrome for TAMs from ovarian carcinoma patients. Comparison with monocyte-derived macrophages shows that the vast majority of direct PPARβ/δ target genes are upregulated in TAMs and largely refractory to synthetic agonists, but repressible by inverse agonists. Besides genes with metabolic functions, these include cell type-selective genes associated with immune regulation and tumor progression, e.g., LRP5, CD300A, MAP3K8 and ANGPTL4. This deregulation is not due to increased expression of PPARβ/δ or its enhanced recruitment to target genes. Instead, lipidomic analysis of malignancy-associated ascites revealed high concentrations of polyunsaturated fatty acids, in particular linoleic acid, acting as potent PPARβ/δ agonists in macrophages. These fatty acid ligands accumulate in lipid droplets in TAMs, thereby providing a reservoir of PPARβ/δ ligands. These observations suggest that the deregulation of PPARβ/δ target genes by ligands of the tumor microenvironment contributes to the pro-tumorigenic polarization of ovarian carcinoma TAMs. This conclusion is supported by the association of high ANGPTL4 expression with a shorter relapse-free survival in serous ovarian carcinoma.

Deregulation of PPARβ/δ target genes in tumor-associated macrophages by fatty acid ligands in the ovarian cancer microenvironment

PubMed Central

Finkernagel, Florian; Lieber, Sonja; Schnitzer, Evelyn; Legrand, Nathalie; Schober, Yvonne; Nockher, W. Andreas; Toth, Philipp M.; Diederich, Wibke E.; Nist, Andrea; Stiewe, Thorsten; Wagner, Uwe; Reinartz, Silke; Müller-Brüsselbach, Sabine; Müller, Rolf

2015-01-01

The nuclear receptor peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is a lipid ligand-inducible transcription factor associated with macrophage polarization. However, its function in tumor-associated macrophages (TAMs) has not been investigated to date. Here, we report the PPARβ/δ-regulated transcriptome and cistrome for TAMs from ovarian carcinoma patients. Comparison with monocyte-derived macrophages shows that the vast majority of direct PPARβ/δ target genes are upregulated in TAMs and largely refractory to synthetic agonists, but repressible by inverse agonists. Besides genes with metabolic functions, these include cell type-selective genes associated with immune regulation and tumor progression, e.g., LRP5, CD300A, MAP3K8 and ANGPTL4. This deregulation is not due to increased expression of PPARβ/δ or its enhanced recruitment to target genes. Instead, lipidomic analysis of malignancy-associated ascites revealed high concentrations of polyunsaturated fatty acids, in particular linoleic acid, acting as potent PPARβ/δ agonists in macrophages. These fatty acid ligands accumulate in lipid droplets in TAMs, thereby providing a reservoir of PPARβ/δ ligands. These observations suggest that the deregulation of PPARβ/δ target genes by ligands of the tumor microenvironment contributes to the pro-tumorigenic polarization of ovarian carcinoma TAMs. This conclusion is supported by the association of high ANGPTL4 expression with a shorter relapse-free survival in serous ovarian carcinoma. PMID:25968567

In Vitro and In Vivo Effects of Tamoxifen against Larval Stage Echinococcus granulosus

PubMed Central

Nicolao, María Celeste; Elissondo, María Celina; Denegri, Guillermo M.; Goya, Alejandra B.

2014-01-01

Cystic echinococcosis is a zoonotic infection caused by the larval stage of the cestode Echinococcus granulosus. Chemotherapy currently employs benzimidazoles; however, 40% of cases do not respond favorably. With regard to these difficulties, novel therapeutic tools are needed to optimize treatment in humans. The aim of this work was to explore the in vitro and in vivo effects of tamoxifen (TAM) against E. granulosus. In addition, possible mechanisms for the susceptibility of TAM are discussed in relation to calcium homeostasis, P-glycoprotein inhibition, and antagonist effects on a putative steroid receptor. After 24 h of treatment, TAM, at a low micromolar concentration range (10 to 50 μM), inhibited the survival of E. granulosus protoscoleces and metacestodes. Moreover, we demonstrated the chemotherapeutic and chemopreventive pharmacological effects of the drug. At a dose rate of 20 mg/kg of body weight, TAM induced protection against the infection in mice. In the clinical efficacy studies, a reduction in cyst weight was observed after the administration of 20 mg/kg in mice with cysts developed during 3 or 6 months, compared to that of those collected from control mice. Since the collateral effects of high TAM doses have been largely documented in clinical trials, the use of low doses of this drug as a short-term therapy may be a novel alternative approach for human cystic echinococcosis treatment. PMID:24936598

The Role of Voluntariness in Distance Education Students' Usage of a Course Website

ERIC Educational Resources Information Center

Ramayah, T.

2010-01-01

This study looks at the usage of a course website among distance learning business management students in a public institution of higher learning in Malaysia. The Technology Acceptance Model (TAM) was used as the basis of the research framework but voluntariness was added as a possible moderating factor. TAM postulates that perceived usefulness…

Perceived Convenience in an Extended Technology Acceptance Model: Mobile Technology and English Learning for College Students

ERIC Educational Resources Information Center

Chang, Chi-Cheng; Yan, Chi-Fang; Tseng, Ju-Shih

2012-01-01

Since convenience is one of the features for mobile learning, does it affect attitude and intention of using mobile technology? The technology acceptance model (TAM), proposed by David (1989), was extended with perceived convenience in the present study. With regard to English language mobile learning, the variables in the extended TAM and its…

Cúmulos globulares como trazadores de bimodalidad estelar en galaxias cD

NASA Astrophysics Data System (ADS)

Forte, J. C.

Se muestra que tanto la forma de los perfiles de brillo como de color observados en dos galaxias arquetípicas de tipo cD (NGC 1399 y NGC 4486) son compatibles con la presencia de poblaciones estelares bi-modales que comparten la misma distribución espacial y composición química de las familias dominantes de cúmulos globulares asociadas con ellas. El modelo resultante también predice una variación de la frecuencia específica de los cúmulos como función del radio galactocéntrico. Se discute este resultado en el contexto de una variedad de escenarios astrofísicos que intentan describir la formación de galaxias cD.

Seasonal and Circadian Variation in Salivary Testosterone in Rural Bolivian Men

PubMed Central

Vitzthum, Virginia J.; Worthman, Carol M.; Beall, Cynthia M.; Thornburg, Jonathan; Vargas, Enrique; Villena, Mercedes; Soria, Rudy; Caceres, Esperanza; Spielvogel, Hilde

2013-01-01

Testosterone (T) plays a key role in the increase and maintenance of muscle mass and bone density in adult men. Life history theory predicts that environmental stress may prompt a reallocation of such investments to those functions critical to survival. We tested this hypothesis in two studies of rural Bolivian adult men by comparing free T levels and circadian rhythms during late winter, which is especially severe, to those in less arduous seasons. For each pair of salivary TAM/TPM samples (collected in a ~12-hour period), circadian rhythm was considered classic (CCLASSIC) if TAM>110%TPM, reverse (CREVERSE) if TPM>110%TAM, and flat (CFLAT) otherwise. We tested the hypotheses that mean TAM>mean TPM and that mean TLWTAM pairs, 51%=CCLASSIC, 39%=CREVERSE, 10%=CFLAT; in Study B, of 184 TAM-TPM pairs, 55%=CCLASSIC, 33%=CREVERSE, 12%=CFLAT. Based on fitting linear mixed models, in both studies TOTHER-AM>TOTHER-PM (A: p=0.035, B: p=0.0005) and TOTHER-AM>TLW-AM (A: p=0.054, B: p=0.007); TPM did not vary seasonally, and T diurnality was not significant during late winter. T diurnality varied substantially between days within an individual, between individuals and between seasons, but neither T levels nor diurnality varied with age. These patterns may reflect the seasonally varying but unscheduled, life-long, strenuous physical labor that typifies many non-industrialized economies. These results also suggest that single morning samples may substantially underestimate peak circulating T for an individual and, most importantly, that exogenous signals may moderate diurnality and the trajectory of age-related change in the male gonadal axis. PMID:19367574

Understanding Which Residues of the Active Site and Loop Structure of a Tyrosine Aminomutase Define Its Mutase and Lyase Activities.

PubMed

Attanayake, Gayanthi; Walter, Tyler; Walker, Kevin D

2018-05-30

Site-directed mutations and substrate analogues were used to gain insights into the branch-point reaction of the 3,5-dihydro-5-methylidene-4 H-imidazol-4-one (MIO)-tyrosine aminomutase from Oryza sativa ( OsTAM). Exchanging the active residues of OsTAM (Y125C/N446K) for those in a phenylalanine aminomutase TcPAM altered its substrate specificity from tyrosine to phenylalanine. The aminomutase mechanism of OsTAM surprisingly changed almost exclusively to that of an ammonia lyase making cinnamic acid (>95%) over β-phenylalanine [Walter, T., et al. (2016) Biochemistry 55, 3497-3503]. We hypothesized that the missing electronics or sterics on the aryl ring of the phenylalanine substrate, compared with the sizable electron-donating hydroxyl of the natural tyrosine substrate, influenced the unexpected lyase reactivity of the OsTAM mutant. The double mutant was incubated with 16 α-phenylalanine substituent analogues of varying electronic strengths and sterics. The mutant converted each analogue principally to its acrylate with ∼50% conversion of the p-Br substrate, making only a small amount of the β-amino acid. The inner loop structure over the entrance to the active site was also mutated to assess how the lyase and mutase activities are affected. An OsTAM loop mutant, matching the loop residues of TcPAM, still chiefly made >95% of the acrylate from each substrate. A combined active site:loop mutant was most reactive but remained a lyase, making 10-fold more acrylates than other mutants did. While mutations within the active site changed the substrate specificity of OsTAM, continued exploration is needed to fully understand the interplay among the inner loop, the substrate, and the active site in defining the mutase and lyase activities.

Heme oxygenase-1 expression protects the heart from acute injury caused by inducible Cre recombinase

PubMed Central

Hull, Travis D.; Bolisetty, Subashini; DeAlmeida, Angela; Litovsky, Silvio H.; Prabhu, Sumanth D.; Agarwal, Anupam; George, James F.

2013-01-01

The protective effect of heme oxygenase-1 (HO-1) expression in cardiovascular disease has been previously demonstrated using transgenic animal models in which HO-1 is constitutively overexpressed in the heart. However, the temporal requirements for protection by HO-1 induction relative to injury have not been investigated, but are essential to employ HO-1 as a therapeutic strategy in human cardiovascular disease states. Therefore, we generated mice with cardiac-specific, tamoxifen (TAM)-inducible overexpression of a human HO-1 (hHO-1) transgene (MHC-HO-1 mice) by breeding mice with cardiac-specific expression of a TAM-inducible Cre recombinase (MHC-Cre mice) with mice containing an hHO-1 transgene preceded by a floxed stop signal (CBA-flox mice). MHC-HO-1 overexpress the HO-1 gene and enzymatically protein following TAM administration (40 mg/kg body weight on two consecutive days). In MHC-Cre controls, TAM administration leads to severe, acute cardiac toxicity, cardiomyocyte necrosis, and 80% mortality by day 3. This cardiac toxicity is accompanied by a significant increase in inflammatory cells in the heart that are predominantly neutrophils. In MHC-HO-1 mice, HO-1 overexpression ameliorates the depression of cardiac function and high mortality rate observed in MHC-Cre mice following TAM administration and attenuates cardiomyocyte necrosis and neutrophil infiltration. These results highlight that HO-1 induction is sufficient to prevent the depression of cardiac function observed in mice with TAM-inducible Cre recombinase expression by protecting the heart from necrosis and neutrophil infiltration. These findings are important because MHC-Cre mice are widely used in cardiovascular research despite the limitations imposed by Cre-induced cardiac toxicity and also because inflammation is an important pathological component of many human cardiovascular diseases. PMID:23732814

Heme oxygenase-1 expression protects the heart from acute injury caused by inducible Cre recombinase.

PubMed

Hull, Travis D; Bolisetty, Subhashini; DeAlmeida, Angela C; Litovsky, Silvio H; Prabhu, Sumanth D; Agarwal, Anupam; George, James F

2013-08-01

The protective effect of heme oxygenase-1 (HO-1) expression in cardiovascular disease has been previously demonstrated using transgenic animal models in which HO-1 is constitutively overexpressed in the heart. However, the temporal requirements for protection by HO-1 induction relative to injury have not been investigated, but are essential to employ HO-1 as a therapeutic strategy in human cardiovascular disease states. Therefore, we generated mice with cardiac-specific, tamoxifen (TAM)-inducible overexpression of a human HO-1 (hHO-1) transgene (myosin heavy chain (MHC)-HO-1 mice) by breeding mice with cardiac-specific expression of a TAM-inducible Cre recombinase (MHC-Cre mice), with mice containing an hHO-1 transgene preceded by a floxed-stop signal. MHC-HO-1 mice overexpress HO-1 mRNA and the enzymatically active protein following TAM administration (40 mg/kg body weight on 2 consecutive days). In MHC-Cre controls, TAM administration leads to severe, acute cardiac toxicity, cardiomyocyte necrosis, and 80% mortality by day 3. This cardiac toxicity is accompanied by a significant increase in inflammatory cells in the heart that are predominantly neutrophils. In MHC-HO-1 mice, HO-1 overexpression ameliorates the depression of cardiac function and high mortality rate observed in MHC-Cre mice following TAM administration and attenuates cardiomyocyte necrosis and neutrophil infiltration. These results highlight that HO-1 induction is sufficient to prevent the depression of cardiac function observed in mice with TAM-inducible Cre recombinase expression by protecting the heart from necrosis and neutrophil infiltration. These findings are important because MHC-Cre mice are widely used in cardiovascular research despite the limitations imposed by Cre-induced cardiac toxicity, and also because inflammation is an important pathological component of many human cardiovascular diseases.

Imaging macrophage distribution and density in mammary tumors and lung metastases using fluorine-19 MRI cell tracking.

PubMed

Makela, Ashley V; Foster, Paula J

2018-09-01

The presence of tumor-associated macrophages (TAMs) correlates with breast cancer progression and metastatic spread. Metastasis-associated macrophages (MAMs) are also recruited to distant sites, where they support metastatic growth. In this study, we demonstrate that in vivo fluorine-19 ( 19 F)-based MRI cell tracking can evaluate the density and distribution of macrophages within murine breast cancer tumors and associated metastases. Three murine breast cancer cell lines with different metastatic potentials (4T1, 168FARN, and 67NR) were implanted into the mammary fat pad in mice. In vivo whole body 19 F MRI was performed on tumor-bearing mice 24 hours post-intravenous injection of a perfluorocarbon (PFC) agent, which was taken up by macrophages in situ. TAMs were detected mainly in the periphery of primary tumors, and higher numbers of TAMs were detected in the more aggressive 4T1 tumors. Tumors had significantly greater 19 F spins/mm 3 when they were smaller, suggesting more TAM infiltration in early-stage tumors. 19 F signal was observed within lung metastases in mice with 4T1 tumors, and fluorescence microscopy confirmed the presence of PFC-positive macrophages. This study shows for the first time proof of the ability to use MRI cell tracking to visualize MAMs in the lungs. The ability to detect and monitor the number of TAMs in individual tumors with 19 F MRI would allow for identification of breast tumors with heavy infiltration of TAMs and could be used as a biomarker for decisions about how to best treat these patients as well as for monitoring responses to therapy. Magn Reson Med 80:1138-1147, 2018. © 2018 International Society for Magnetic Resonance in Medicine. © 2018 International Society for Magnetic Resonance in Medicine.

Quantitative profiling of drug-associated proteomic alterations by combined 2-nitrobenzenesulfenyl chloride (NBS) isotope labeling and 2DE/MS identification.

PubMed

Ou, Keli; Kesuma, Djohan; Ganesan, Kumaresan; Yu, Kun; Soon, Sou Yen; Lee, Suet Ying; Goh, Xin Pei; Hooi, Michelle; Chen, Wei; Jikuya, Hiroyuki; Ichikawa, Tetsuo; Kuyama, Hiroki; Matsuo, Ei-ichi; Nishimura, Osamu; Tan, Patrick

2006-09-01

The identification of drug-responsive biomarkers in complex protein mixtures is an important goal of quantitative proteomics. Here, we describe a novel approach for identifying such drug-induced protein alterations, which combines 2-nitrobenzenesulfenyl chloride (NBS) tryptophan labeling with two-dimensional gel electrophoresis (2DE)/mass spectrometry (MS). Lysates from drug-treated and control samples are labeled with light or heavy NBS moiety and separated on a common 2DE gel, and protein alterations are identified by MS through the differential intensity of paired NBS peptide peaks. Using NBS/2DE/MS, we profiled the proteomic alterations induced by tamoxifen (TAM) in the estrogen receptor (ER) positive MCF-7 breast cancer cell line. Of 88 protein spots that significantly changed upon TAM treatment, 44 spots representing 23 distinct protein species were successfully identified with NBS-paired peptides. Of these 23 TAM-altered proteins, 16 (70%) have not been previously associated with TAM or ER activity. We found the NBS labeling procedure to be both technically and biologically reproducible, and the NBS/2DE/MS alterations exhibited good concordance with conventional 2DE differential protein quantitation, with discrepancies largely due to the comigration of distinct proteins in the regular 2DE gels. To validate the NBS/2DE/MS results, we used immunoblotting to confirm GRP78, CK19, and PA2G4 as bona fide TAM-regulated proteins. Furthermore, we demonstrate that PA2G4 expression can serve as a novel prognostic factor for disease-free survival in two independent breast cancer patient cohorts. To our knowledge, this is the first report describing the proteomic changes in breast cancer cells induced by TAM, the most commonly used selective estrogen receptor modulator (SERM). Our results indicate that NBS/2DE/MS may represent a more reliable approach for cellular protein quantitation than conventional 2DE approaches.

Effect of chronic administration of mestranol, tamoxifen, and toremifene on hepatic ploidy in rats.

PubMed

Dragan, Y P; Shimel, R J; Bahnub, N; Sattler, G; Vaughan, J R; Jordan, V C; Pitot, H C

1998-06-01

The nonsteroidal antiestrogen tamoxifen increases the incidence of rat liver cancer through a variety of mechanisms. To compare the effects of tamoxifen (TAM) and a structurally similar analog toremifene (TOR) on rat liver, we determined the ploidy distribution for hepatocytes isolated from rats treated for 18 months with these antiestrogens or the estrogenic compound mestranol (MS). Female Sprague-Dawley rats were subjected to a 70% partial hepatectomy and administered the solvent, trioctanoin, or diethylnitrosamine (10 mg DEN/kg). After a 2-week recovery from the surgery, the rats were administered a basal diet or one containing TAM (250 or 500 ppm), TOR (250, 500, or 750 ppm), or MS (0.2 ppm) for 18 months. Pathologic changes in the liver were examined in the 15-22 rats per treatment group at the 18-month time point. An increased incidence of hepatocellular carcinomas (HCC) was detected in the 500 ppm TAM group, but not with the other treatments that did not include DEN. Both TOR and TAM promoted formation of DEN-initiated HCCs. At sacrifice, four to five rats per group were perfused and the hepatocytes isolated and cultured. Karyotypic analysis was performed on colcemid-blocked cells after 2 days in culture. The hepatic ploidy distribution was characterized in Giemsa-stained metaphase spreads. These studies indicated that chronic treatment with TAM alone resulted in a shift from tetraploid to diploid, as was also observed for rats treated once with DEN. TOR and MS alone did not cause this change in hepatic ploidy at the doses examined. A shift toward an increased content of diploid hepatocytes occurred in all rats treated once with DEN followed by TAM, TOR, or MS. These results indicate that tamoxifen administration results in a shift toward growth of diploid hepatocytes, thus contributing to its carcinogenic action in the rat liver.

Expression of decoy receptor 3 in diffuse sclerosing variant of papillary thyroid carcinoma: correlation with M2 macrophage differentiation and lymphatic invasion.

PubMed

Chang, Wei-Chin; Chen, Jui-Yu; Lee, Chen-Hsen; Yang, An-Hang

2013-06-01

The diffuse sclerosing variant of papillary thyroid carcinoma (DSV-PTC) is a unique variant of PTC that is characterized by extensive lymphovascular invasion of tumor cells in a background of lymphocytic thyroiditis. The lymphatic emboli contain tumor cells as well as macrophages, but the recruitment of these macrophages is not well understood. The aim of this study was to determine the relationship between the expression of Decoy receptor 3 (DcR3), the recruitment of tumor-associated macrophages (TAMs), and lymphatic invasion in DSV-PTC. We retrospectively examined 14 cases of DSV-PTC using immunohistochemistry studies. The density of TAMs, lymphatic vessel density, lymphatic invasion, tumor emboli area, and DcR3 expression were assessed. Statistical analyses were performed using Fisher's exact test, unpaired t-test, and linear regression. The lymphatic tumor emboli contained a relatively higher density of TAMs than stroma and classical PTC (CPTC) areas. In addition, the number of lymphatic invasions and the size of the tumor emboli area were positively correlated with the number of M2 TAMs. A higher density of M2 TAMs was associated with older patients and larger tumor size. Moreover, DcR3 was expressed only in lymphatic tumor cells and squamous metaplastic tumor cells, but not in macrophages and CPTC. In addition, the preferential expression of DcR3 in tumors was associated with higher levels of M2 TAMs and lymphatic invasion. Despite the fact that the exact relationship between DcR3, M2 macrophages, and lymphatic invasion in DSV-PTC remains to be elucidated, our findings suggest that DcR3 expression in DSV-PTC tumor cells may promote the polarized macrophage differentiation toward the M2 phenotype. This phenomenon may further promote lymphatic invasion of DSV-PTC tumor cells.

Attitude-Independent Magnetometer Calibration for Spin-Stabilized Spacecraft

NASA Technical Reports Server (NTRS)

Natanson, Gregory

2005-01-01

The paper describes a three-step estimator to calibrate a Three-Axis Magnetometer (TAM) using TAM and slit Sun or star sensor measurements. In the first step, the Calibration Utility forms a loss function from the residuals of the magnitude of the geomagnetic field. This loss function is minimized with respect to biases, scale factors, and nonorthogonality corrections. The second step minimizes residuals of the projection of the geomagnetic field onto the spin axis under the assumption that spacecraft nutation has been suppressed by a nutation damper. Minimization is done with respect to various directions of the body spin axis in the TAM frame. The direction of the spin axis in the inertial coordinate system required for the residual computation is assumed to be unchanged with time. It is either determined independently using other sensors or included in the estimation parameters. In both cases all estimation parameters can be found using simple analytical formulas derived in the paper. The last step is to minimize a third loss function formed by residuals of the dot product between the geomagnetic field and Sun or star vector with respect to the misalignment angle about the body spin axis. The method is illustrated by calibrating TAM for the Fast Auroral Snapshot Explorer (FAST) using in-flight TAM and Sun sensor data. The estimated parameters include magnetic biases, scale factors, and misalignment angles of the spin axis in the TAM frame. Estimation of the misalignment angle about the spin axis was inconclusive since (at least for the selected time interval) the Sun vector was about 15 degrees from the direction of the spin axis; as a result residuals of the dot product between the geomagnetic field and Sun vectors were to a large extent minimized as a by-product of the second step.

Technological Diffusion within Educational Institutions: Applying the Technology Acceptance Model.

ERIC Educational Resources Information Center

Wolski, Stacy; Jackson, Sally

Expectancy models of behavior such as the Theory of Reasoned Action (TRA) and the Technology Acceptance Model (TAM) offer guidelines that aid efforts to facilitate use of new technology. These models remind us that both acceptance of and resistance to technology use are grounded in beliefs and norms regarding the technology. Although TAM is widely…

The Decision to Adopt Educational Technology in Technical Education: A Multivariate Study

ERIC Educational Resources Information Center

Beasley, Shannon Wilson Sewell

2016-01-01

Since the seminal work of Davis in 1989 produced the Technology Acceptance Model (TAM), researchers have sought to extend the framework and use the resulting models to describe the predictors of technology adoption specific to various populations. Although the TAM has been used to understand the adoption of technology in higher education, most of…

Correction to: The effects of the calcium-magnesium-bicarbonate content in thermal mineral water on chronic low back pain: a randomized, controlled follow-up study

NASA Astrophysics Data System (ADS)

Gáti, Tamás; Tefner, Ildikó Katalin; Kovács, Lajos; Hodosi, Katalin; Bender, Tamás

2018-02-01

The original article mistakenly displays each set of author names in the wrong order, i.e., first names as last names and vice versa. The author correct names are: Tamás Gáti, Ildikó Katalin Tefner, Lajos Kovács, Katalin Hodosi, Tamás Bender. The original article has been corrected.

Erratum: Correction to: The effects of the calcium-magnesium-bicarbonate content in thermal mineral water on chronic low back pain: a randomized, controlled follow-up study

NASA Astrophysics Data System (ADS)

Gáti, Tamás; Tefner, Ildikó Katalin; Kovács, Lajos; Hodosi, Katalin; Bender, Tamás

2018-05-01

The original article mistakenly displays each set of author names in the wrong order, i.e., first names as last names and vice versa. The author correct names are: Tamás Gáti, Ildikó Katalin Tefner, Lajos Kovács, Katalin Hodosi, Tamás Bender. The original article has been corrected.

The Texas Academy of Mathematics and Science: A 20-Year Perspective

ERIC Educational Resources Information Center

Jones, Brent M.

2011-01-01

The Texas Academy of Mathematics and Science (TAMS) is a publicly financed, residential early college entrance institute at the University of North Texas at Denton. Created in 1987, TAMS enables high-achieving students planning STEM careers to complete their last 2 years of high school simultaneously with their first 2 years of college. Admission…

User Acceptance of Social Learning Systems in Higher Education: An Application of the Extended Technology Acceptance Model

ERIC Educational Resources Information Center

Akman, Ibrahim; Turhan, Cigdem

2017-01-01

This study aims to explore the users' behaviour and acceptance of social media for learning in higher educational institutions with the help of the extended Technology Acceptance Model (TAM). TAM has been extended to investigate how ethical and security awareness of users affect the actual usage of social learning applications. For this purpose, a…

Concurrent use of traditional medicine and ART: Perspectives of patients, providers and traditional healers in Durban, South Africa

PubMed Central

Belisle, Hannah Appelbaum; Hennink, Monique; Ordóñez, Claudia E.; John, Sally; Ngubane-Joye, Eunephacia; Hampton, Jane; Sunpath, Henry; Preston-Whyte, Eleanor; Marconi, Vincent C.

2014-01-01

The concurrent use of traditional African medicine (TAM) and allopathic medicine is not well understood for people living with HIV (PLHIV) in the era of antiretroviral therapy (ART). This cross-sectional, qualitative study examines perceptions of the concurrent use of TAM and ART among: i) patients receiving ART at the Sinikithemba HIV Clinic of McCord Hospital, in Durban, South Africa; ii) allopathic medical providers (doctors, nurses, HIV counsellors) from Sinikithemba; and iii) local traditional healers. Data were collected through in-depth interviews and focus group discussions with 26 participants between July and October, 2011. Patients in this study did not view TAM as an alternative to ART; rather, results show that patients employ TAM and ART for distinctly different needs. More research is needed to further understand the relationship between traditional and allopathic approaches to health care in South Africa, to improve cultural relevance in the provision and delivery of care for PLHIV, and to pragmatically address the concerns of healthcare providers and public health officials managing this intersection in South Africa and elsewhere. PMID:25346069

Morphotectonic architecture of the Transantarctic Mountains rift flank between the Royal Society Range and the Churchill Mountains based on geomorphic analysis

USGS Publications Warehouse

Demyanick, Elizabeth; Wilson, Terry J.

2007-01-01

Extensional forces within the Antarctic Plate have produced the Transantarctic Mountains rift-flank uplift along the West Antarctic rift margin. Large-scale linear morphologic features within the mountains are controlled by bedrock structure and can be recognized and mapped from satellite imagery and digital elevation models (DEMs). This study employed the Antarctic Digital Database DEM to obtain slope steepness and aspect maps of the Transantarctic Mountains (TAM) between the Royal Society Range and the Churchill Mountains, allowing definition of the position and orientation of the morphological axis of the rift-flank. The TAM axis, interpreted as a fault-controlled escarpment formed by coast-parallel retreat, provides a marker for the orientation of the faulted boundary between the TAM and the rift system. Changes in position and orientation of the TAM axis suggests the rift flank is segmented into tectonic blocks bounded by relay ramps and transverse accommodation zones. The transverse boundaries coincide with major outlet glaciers, supporting interpretation of rift structures between them. The pronounced morphological change across Byrd Glacier points to control by structures inherited from the Ross orogen.

Lactate - A new frontier in the immunology and therapy of prostate cancer.

PubMed

Nenu, Iuliana; Gafencu, Grigore-Aristide; Popescu, Tiberiu; Kacso, Gabriel

2017-01-01

Prostate cancer, one of the most common male malignancies with an increasing incidence in the recent years, requires the development of new methods of treatment. One of the most debated subjects is the tumor-associated macrophages (TAM). Although, the pathophysiological mechanisms are still a subject of intense research, TAM acts as procarcinogenic factors. It was also demonstrated that hypoxia-inducible factor 1 (HIF1) induces the expression of TAM genes involved in prostate carcinogenesis. Furthermore, it should be noted that the stromal extracellular lactate, the result of tumoral glycolysis process is one of the HIF1 activators. In addition, lactate inhibits the differentiation of monocytes and dendritic cells and also induces the inactivation of the cytotoxic T-lymphocytes. Through an analysis of recent studies, we conclude that lactate is a vital component of several ways of modulating the immune response at the stromal prostatic adenocarcinoma including TAM activation and cytotoxic T lymphocytes immunosuppression. Our review focuses on the impact of lactate on prostatic adenocarcinoma progression in terms of its immunology, and how this influences the therapy of this condition and the clinical outcome.

An Improved SoC Test Scheduling Method Based on Simulated Annealing Algorithm

NASA Astrophysics Data System (ADS)

Zheng, Jingjing; Shen, Zhihang; Gao, Huaien; Chen, Bianna; Zheng, Weida; Xiong, Xiaoming

2017-02-01

In this paper, we propose an improved SoC test scheduling method based on simulated annealing algorithm (SA). It is our first to disorganize IP core assignment for each TAM to produce a new solution for SA, allocate TAM width for each TAM using greedy algorithm and calculate corresponding testing time. And accepting the core assignment according to the principle of simulated annealing algorithm and finally attain the optimum solution. Simultaneously, we run the test scheduling experiment with the international reference circuits provided by International Test Conference 2002(ITC’02) and the result shows that our algorithm is superior to the conventional integer linear programming algorithm (ILP), simulated annealing algorithm (SA) and genetic algorithm(GA). When TAM width reaches to 48,56 and 64, the testing time based on our algorithm is lesser than the classic methods and the optimization rates are 30.74%, 3.32%, 16.13% respectively. Moreover, the testing time based on our algorithm is very close to that of improved genetic algorithm (IGA), which is state-of-the-art at present.

Down syndrome-associated haematopoiesis abnormalities created by chromosome transfer and genome editing technologies.

PubMed

Kazuki, Yasuhiro; Yakura, Yuwna; Abe, Satoshi; Osaki, Mitsuhiko; Kajitani, Naoyo; Kazuki, Kanako; Takehara, Shoko; Honma, Kazuhisa; Suemori, Hirofumi; Yamazaki, Satoshi; Sakuma, Tetsushi; Toki, Tsutomu; Shimizu, Ritsuko; Nakauchi, Hiromitsu; Yamamoto, Takashi; Oshimura, Mitsuo

2014-08-27

Infants with Down syndrome (DS) are at a high risk of developing transient abnormal myelopoiesis (TAM). A GATA1 mutation leading to the production of N-terminally truncated GATA1 (GATA1s) in early megakaryocyte/erythroid progenitors is linked to the onset of TAM and cooperated with the effect of trisomy 21 (Ts21). To gain insights into the underlying mechanisms of the progression to TAM in DS patients, we generated human pluripotent stem cells harbouring Ts21 and/or GATA1s by combining microcell-mediated chromosome transfer and genome editing technologies. In vitro haematopoietic differentiation assays showed that the GATA1s mutation blocked erythropoiesis irrespective of an extra chromosome 21, while Ts21 and the GATA1s mutation independently perturbed megakaryopoiesis and the combination of Ts21 and the GATA1s mutation synergistically contributed to an aberrant accumulation of skewed megakaryocytes. Thus, the DS model cells generated by these two technologies are useful in assessing how GATA1s mutation is involved in the onset of TAM in patients with DS.

Partners in crime: VEGF and IL-4 conscript tumour-promoting macrophages.

PubMed

De Palma, Michele

2012-05-01

Tumour-associated macrophages (TAMs) foster tumour progression by several mechanisms, including the promotion of angiogenesis, tissue remodelling, and immunosuppression. Such pro-tumoural activities are thought to be executed by TAM subtypes that harbour features of alternatively activated (or M2-polarized) macrophages. However, the molecular signals in tumours that induce recruitment and differentiation of M2-like macrophages are not fully defined. In this issue of The Journal of Pathology, Linde et al investigate the role of the tumour-derived cytokines, VEGF and IL-4, in the recruitment and polarization of macrophages in a mouse model of skin cancer. The authors report that while VEGF-A recruits monocytes from the peripheral circulation, IL-4 induces their differentiation into tumour-promoting, M2-like macrophages. IL-4 signalling blockade was sufficient to reprogram TAMs away from the M2-like phenotype and inhibited tumour angiogenesis and growth. This study attests to the potential of reprogramming TAMs to abate their pro-angiogenic and pro-tumoural functions in tumours. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Melanoma-Derived Conditioned Media Efficiently Induce the Differentiation of Monocytes to Macrophages that Display a Highly Invasive Gene Signature

PubMed Central

Wang, Tao; Ge, Yingbin; Xiao, Min; Lopez-Coral, Alfonso; Azuma, Rikka; Somasundaram, Rajasekharan; Zhang, Gao; Wei, Zhi; Xu, Xiaowei; Rauscher, Frank J.; Herlyn, Meenhard; Kaufman, Russel E.

2013-01-01

Summary The presence of tumor-associated macrophages (TAMs) in melanomas is correlated with a poor clinical prognosis. However, there is limited information on the characteristics and biological activities of human TAMs in melanomas. In this study, we developed an in vitro method to differentiate human monocytes to macrophages using modified melanoma-conditioned medium (MCM). We demonstrate that factors from MCM-induced macrophages (MCMI-Mϕ) express both M1-Mϕ and M2-Mϕ markers, and inhibit melanoma-specific T cell proliferation. Furthermore, microarray analyses reveal that the majority of genes up-regulated in MCMI-Mϕ are associated with tumor invasion. The most strikingly up-regulated genes are CCL2 and MMP-9. Consistent with this, blockade of both CCL-2 and MMPs diminish MCMI-Mϕ-induced melanoma invasion. Finally, we demonstrate that both MCMI-Mϕ and in vivo TAMs express the pro-invasive, melanoma-associated gene, GPMNB. Our study provides a framework for understanding the mechanisms of crosstalk between TAMs and melanoma cells within the tumor microenvironment. PMID:22498258

Valorisation of Como Historical Cadastral Maps Through Modern Web Geoservices

NASA Astrophysics Data System (ADS)

Brovelli, M. A.; Minghini, M.; Zamboni, G.

2012-07-01

Cartographic cultural heritage preserved in worldwide archives is often stored in the original paper version only, thus restricting both the chances of utilization and the range of possible users. The Web C.A.R.T.E. system addressed this issue with regard to the precious cadastral maps preserved at the State Archive of Como. Aim of the project was to improve the visibility and accessibility of this heritage using the latest free and open source tools for processing, cataloguing and web publishing the maps. The resulting architecture should therefore assist the State Archive of Como in managing its cartographic contents. After a pre-processing consisting of digitization and georeferencing steps, maps were provided with metadata, compiled according to the current Italian standards and managed through an ad hoc version of the GeoNetwork Opensource geocatalog software. A dedicated MapFish-based webGIS client, with an optimized version also for mobile platforms, was built for maps publication and 2D navigation. A module for 3D visualization of cadastral maps was finally developed using the NASA World Wind Virtual Globe. Thanks to a temporal slidebar, time was also included in the system producing a 4D Graphical User Interface. The overall architecture was totally built with free and open source software and allows a direct and intuitive consultation of historical maps. Besides the notable advantage of keeping original paper maps intact, the system greatly simplifies the work of the State Archive of Como common users and together widens the same range of users thanks to the modernization of map consultation tools.

Simultaneous determination of erlotinib and tamoxifen in rat plasma using UPLC-MS/MS: Application to pharmacokinetic interaction studies.

PubMed

Maher, Hadir M; Alzoman, Nourah Z; Shehata, Shereen M

2016-08-15

Tamoxifen (TAM) is a non-steroidal estrogen receptor antagonist that enhances erlotinib (ERL)-induced cytotoxicity in the treatment of NSCLC. ERL and TAM are metabolized by CYP3A4 enzymes. In addition, both drugs have the potential of altering the enzymatic activity through either inhibition (ERL) or induction (TAM). Thus it was expected that pharmacokinetics (PK) drug-drug interactions (DDIs) could be encountered following their co-administration. In this respect, a bioanalytical UPLC-MS/MS method has been developed and validated for the simultaneous determination of ERL and TAM in rat plasma samples, using ondansetron (OND) as an internal standard (IS). Plasma samples were prepared using mixed mode cationic solid phase extraction (SPE) STRATA™ -X-C 33μm cartridges with good extraction recovery of both drugs from rat plasma (Er% from -13.92 to -3.32). The drugs were separated on a Waters BEH™ C18 column with an isocratic elution using a mobile phase composed of a mixture of acetonitrile and water, each with 0.15% formic acid, in the ratio of 80: 20, v/v. Quantitation was carried out using the positive ionization mode with multiple reaction monitoring (MRM) at m/z 394.20>278.04 (ERL), m/z 372.25>72.01 (TAM), and m/z 294.18>170.16 (OND). The method was fully validated as per the FDA guidelines over the concentration range of 0.2-50ng/mL with very low lower limit of quantification (LLOQ) of 0.2ng/mL for both ERL and TAM. The intra- and inter-day assay precision (in terms of relative standard deviation, RSD) and accuracy (in terms of percentage relative error, % Er) were evaluated for both drugs and the calculated values evaluated at four different concentration levels were within the acceptable limits (<15%) for concentrations other than LLOQ and 20% for LLOQ. The method was successfully applied to the study of possible PK-DDI following the oral administration of ERL and TAM in a combination, compared to their single administration. Copyright © 2016 Elsevier B

Upper mantle shear wave velocity structure beneath northern Victoria Land, Antarctica: Volcanism and uplift in the northern Transantarctic Mountains

NASA Astrophysics Data System (ADS)

Graw, Jordan H.; Adams, Aubreya N.; Hansen, Samantha E.; Wiens, Douglas A.; Hackworth, Lauren; Park, Yongcheol

2016-09-01

The Transantarctic Mountains (TAMs) are the largest non-compressional mountain range on Earth, and while a variety of uplift mechanisms have been proposed, the origin of the TAMs is still a matter of great debate. Most previous seismic investigations of the TAMs have focused on a central portion of the mountain range, near Ross Island, providing little along-strike constraint on the upper mantle structure, which is needed to better assess competing uplift models. Using data recorded by the recently deployed Transantarctic Mountains Northern Network, as well as data from the Transantarctic Mountains Seismic Experiment and from five stations operated by the Korea Polar Research Institute, we investigate the upper mantle structure beneath a previously unexplored portion of the mountain range. Rayleigh wave phase velocities are calculated using a two-plane wave approximation and are inverted for shear wave velocity structure. Our model shows a low velocity zone (LVZ; ∼4.24 km s-1) at ∼160 km depth offshore and adjacent to Mt. Melbourne. This LVZ extends inland and vertically upwards, with more lateral coverage above ∼100 km depth beneath the northern TAMs and Victoria Land. A prominent LVZ (∼4.16-4.24 km s-1) also exists at ∼150 km depth beneath Ross Island, which agrees with previous results in the TAMs near the McMurdo Dry Valleys, and relatively slow velocities (∼4.24-4.32 km s-1) along the Terror Rift connect the low velocity anomalies. We propose that the LVZs reflect rift-related decompression melting and provide thermally buoyant support for the TAMs uplift, consistent with proposed flexural models. We also suggest that heating, and hence uplift, along the mountain front is not uniform and that the shallower LVZ beneath northern Victoria Land provides greater thermal support, leading to higher bedrock topography in the northern TAMs. Young (0-15 Ma) volcanic rocks associated with the Hallett and the Erebus Volcanic Provinces are situated directly

Dutasteride plus tamsulosin fixed-dose combination first-line therapy versus tamsulosin monotherapy in the treatment of benign prostatic hyperplasia: a budget impact analysis in the Greek healthcare setting.

PubMed

Geitona, Maria; Karabela, Pinelopi; Katsoulis, Ioannis A; Kousoulakou, Hara; Lyberopoulou, Eleni; Bitros, Eleftherios; Xaplanteris, Loukas; Papanicolaou, Sotiria

2014-09-26

The purpose of this study was to explore the budget impact of dutasteride plus tamsulosin fixed-dose combination (DUT + TAM FDC) versus tamsulosin monotherapy, in the treatment of patients with benign prostatic hyperplasia (BPH) from the perspective of the Greek healthcare insurance system. A Microsoft Excel-based model was developed to estimate the financial consequences of adopting DUT + TAM FDC within the Greek healthcare setting. The model, compared six mutually exclusive health states in two alternative treatment options: current standard of care and the introduction of DUT + TAM FDC in the market. The model used clinical inputs from the CombAT study; data on resource use associated with the management of BPH in Greece were derived from expert panel, and unit cost data were derived from official reimbursement tariffs. A payer perspective was taken into account. As patient distribution data between public and private sectors are not available in Greece two scenarios were investigated, considering the whole eligible population in each scenario. A 4 year time horizon was taken into account and included treatment costs, number of transurethral resections of the prostate (TURPs) and acute urinary retention (AUR) episodes avoided. The clinical benefit from the market adoption of DUT + TAM FDC in Greece was 1,758 TURPs and 972 episodes of AUR avoided cumulatively in a four year period. The increase in total costs from the gradual introduction of DUT + TAM FDC to the Greek healthcare system ranges from €1.3 million in the first year to €5.8 million in the fourth year, for the public sector, and €1.2 million to €4.0 million, for the private sector. This represents an increase of 1.91% to 7.94% for the public sector and 1.10% 3.29% in the private sector, during the 4-year time horizon. Budget impact analysis (BIA) results indicated that the gradual introduction of DUT + TAM FDC, would increase the overall budget of the disease, however providing

A dual-targeting nanocarrier based on poly(amidoamine) dendrimers conjugated with transferrin and tamoxifen for treating brain gliomas.

PubMed

Li, Yan; He, Hai; Jia, Xinru; Lu, Wan-Liang; Lou, Jinning; Wei, Yen

2012-05-01

A pH-sensitive dual-targeting drug carrier (G4-DOX-PEG-Tf-TAM) was synthesized with transferrin (Tf) conjugated on the exterior and Tamoxifen (TAM) in the interior of the fourth generation PAMAM dendrimers for enhancing the blood-brain barrier (BBB) transportation and improving the drug accumulation in the glioma cells. It was found that, on average, 7 doxorubicine (DOX) molecules, over 30 PEG(1000) and PEG(2000) chains and one Tf group were bonded on the periphery of each G4 PAMAM dendrimer, while 29 TAM molecules were encapsulated into the interior of per dendrimer. The pH-triggered DOX release was 32% at pH 4.5 and 6% at pH 7.4, indicating a comparatively fast drug release at weak acidic condition and stable state of the carrier at physiological environment. The in vitro assay of the drug transport across the BBB model showed that G4-DOX-PEG-Tf-TAM exhibited higher BBB transportation ability with the transporting ratio of 6.06% in 3 h. The carrier was internalized into C6 glioma cells upon crossing the BBB model by the coactions of TfR-mediated endocytosis and the inhibition effect of TAM to the drug efflux transports. Moreover, it also displayed the in vitro accumulation of DOX in the avascular C6 glioma spheroids made the tumor volume effectively reduced. Copyright © 2012 Elsevier Ltd. All rights reserved.

Applying a general triclinic transpression model to highly partitioned brittle-ductile shear zones: A case study from the Torcal de Antequera massif, external Betics, southern Spain

NASA Astrophysics Data System (ADS)

Díaz-Azpiroz, M.; Barcos, L.; Balanyá, J. C.; Fernández, C.; Expósito, I.; Czeck, D. M.

2014-11-01

Oblique convergence and subsequent transpression kinematics can be considered as the general situation in most convergent and strike-slip tectonic boundaries. To better understand such settings, progressively more complex kinematic models have been proposed, which need to be tested against natural shear zones using standardized procedures that minimise subjectivism. In this work, a protocol to test a general triclinic transpression model is applied to the Torcal de Antequera massif (TAM), an essentially brittle shear zone. Our results, given as kinematic parameters of the transpressive flow (transpression obliquity, ϕ; extrusion obliquity, υ; and kinematic vorticity number, Wk), suggest that the bulk triclinic transpressive flow imposed on the TAM was partitioned into two different flow fields, following a general partitioning type. As such, one flow field produced narrow structural domains located at the limits of the TAM, where mainly dextral strike-slip simple-shear-dominated transpression took place (Outer domains, ODs). In contrast, the remaining part of the bulk flow produced pure-shear-dominated dextral triclinic transpression at the inner part of the TAM (Inner domain, ID). A graphical method relating internal (ϕ, Wk) to far-field (dip of the shear zone boundary, δ; angle of oblique convergence, α) transpression parameters is proposed to obtain the theoretical horizontal velocity vector (V→), which in the case of the TAM, ranges between 099 and 118. These results support the applicability of kinematic models of triclinic transpression to brittle-ductile shear zones and the potential utility of the proposed protocol.

In vitro and in vivo effects of tamoxifen against larval stage Echinococcus granulosus.

PubMed

Nicolao, María Celeste; Elissondo, María Celina; Denegri, Guillermo M; Goya, Alejandra B; Cumino, Andrea C

2014-09-01

Cystic echinococcosis is a zoonotic infection caused by the larval stage of the cestode Echinococcus granulosus. Chemotherapy currently employs benzimidazoles; however, 40% of cases do not respond favorably. With regard to these difficulties, novel therapeutic tools are needed to optimize treatment in humans. The aim of this work was to explore the in vitro and in vivo effects of tamoxifen (TAM) against E. granulosus. In addition, possible mechanisms for the susceptibility of TAM are discussed in relation to calcium homeostasis, P-glycoprotein inhibition, and antagonist effects on a putative steroid receptor. After 24 h of treatment, TAM, at a low micromolar concentration range (10 to 50 μM), inhibited the survival of E. granulosus protoscoleces and metacestodes. Moreover, we demonstrated the chemotherapeutic and chemopreventive pharmacological effects of the drug. At a dose rate of 20 mg/kg of body weight, TAM induced protection against the infection in mice. In the clinical efficacy studies, a reduction in cyst weight was observed after the administration of 20 mg/kg in mice with cysts developed during 3 or 6 months, compared to that of those collected from control mice. Since the collateral effects of high TAM doses have been largely documented in clinical trials, the use of low doses of this drug as a short-term therapy may be a novel alternative approach for human cystic echinococcosis treatment. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Efficacy of passive sand filtration in reducing exposure of salmonids to the actinospore of Myxobolus cerebralis.

PubMed

Nehring, R Barry; Thompson, Kevin G; Taurman, Karen; Atkinson, William

2003-12-03

The aquatic oligochaete Tubifex tubifex parasitized by Myxobolus cerebralis releases triactinomyxon (TAM) actinospores that can infect some species of salmonids and cause salmonid whirling disease. Silica sand was tested as a filtration medium for removal of TAMs from water containing the parasite. Laboratory tests indicated sand filtration removed > 99.99% of TAMs. In 2 different field tests, groups of 1 mo old rainbow trout Oncorhynchus mykiss were exposed for 2 wk to filtered and unfiltered water from a spring-fed pond enzootic for M. cerebralis. In November 2000, the exposure dose was estimated as between 3 and 5 TAMs fish(-1). During a March 2001 exposure, the estimated dose was between 286 and 404 TAMs fish(-1). Fish were held for 6 mo post exposure (p.e.) in laboratory aquaria for observation and evidence of clinical signs of whirling disease. We used 4 diagnostic techniques to assess the prevalence and severity of infection by M. cerebralis among fish exposed to filtered and unfiltered water. These included polymerase chain reaction (PCR) for genomic DNA of the parasite, histological evaluation for tissue damage, tissue digestion for quantification of cranial myxospores of the parasite, and total non-sampling mortality that occurred over 6 mo p.e. All diagnostic tests verified that the prevalence and severity of infection was significantly reduced among fish in treatment groups exposed to filtered water compared to those exposed to unfiltered water in both the low-dose and high-dose exposures.

PET Imaging of Tumor-Associated Macrophages with 89Zr-Labeled High-Density Lipoprotein Nanoparticles

PubMed Central

Pérez-Medina, Carlos; Tang, Jun; Abdel-Atti, Dalya; Hogstad, Brandon; Merad, Miriam; Fisher, Edward A.; Fayad, Zahi A.; Lewis, Jason S.; Mulder, Willem J.M.; Reiner, Thomas

2015-01-01

Tumor-associated macrophages (TAMs) are increasingly investigated in cancer immunology and are considered a promising target for better and tailored treatment of malignant growth. Although TAMs also have high diagnostic and prognostic value, TAM imaging still remains largely unexplored. Here, we describe the development of reconstituted high-density lipoprotein (rHDL)–facilitated TAM PET imaging in a breast cancer model. Methods Radiolabeled rHDL nanoparticles incorporating the long-lived positron-emitting nuclide 89Zr were developed using 2 different approaches. The nanoparticles were composed of phospholipids and apolipoprotein A-I (apoA-I) in a 2.5:1 weight ratio. 89Zr was complexed with deferoxamine (also known as desferrioxamine B, desferoxamine B), conjugated either to a phospholipid or to apoA-I to generate 89Zr-PL-HDL and 89Zr-AI-HDL, respectively. In vivo evaluation was performed in an orthotopic mouse model of breast cancer and included pharmacokinetic analysis, biodistribution studies, and PET imaging. Ex vivo histologic analysis of tumor tissues to assess regional distribution of 89Zr radioactivity was also performed. Fluorescent analogs of the radiolabeled agents were used to determine cell-targeting specificity using flow cytometry. Results The phospholipid- and apoA-I–labeled rHDL were produced at 79% ± 13% (n = 6) and 94% ± 6% (n = 6) radiochemical yield, respectively, with excellent radiochemical purity (>99%). Intravenous administration of both probes resulted in high tumor radioactivity accumulation (16.5 ± 2.8 and 8.6 ± 1.3 percentage injected dose per gram for apoA-I– and phospholipid-labeled rHDL, respectively) at 24 h after injection. Histologic analysis showed good colocalization of radioactivity with TAM-rich areas in tumor sections. Flow cytometry revealed high specificity of rHDL for TAMs, which had the highest uptake per cell (6.8-fold higher than tumor cells for both DiO@Zr-PL-HDL and DiO@Zr-AI-HDL) and accounted for 40.7% and

The Transantarctic Mountains of southern Victoria Land: The application of Apatite fission track analysis to a rift shoulder uplift

NASA Astrophysics Data System (ADS)

Fitzgerald, Paul G.

1992-06-01

A fission track study of the Transantarctic Mountains (TAM) in the Granite Harbour and Wilson Piedmont Glacier areas of southern Victoria Land reveals information on the timing of uplift, the amount of uplift and erosion, and the structure of the mountains, especially the onshore Transantarctic Mountain Front (TAM Front), which represents the boundary between East and West Antarctica. Apatite ages are < 175 Ma and represent a thermal regime established after heating accompanying Jurassic magmatism. An apatite age profile from Mount England records a break in slope indicating uplift began at ˜55 Ma. Horizontal sampling traverses, plus fieldwork, delineate the structure of the TAM Front as a zone of north-south striking, steeply dipping normal faults, with displacements, dominantly down to the east, of 40-1000 m. The overall structure of the mountains in the area studied can be envisaged as a large tilt block or flexure. Its westerly limb dips gently under the ice cap, compared to its faulted eastern edge, the TAM Front. The bounding structure to the south is the Ferrar fault and to the north is a graben through which the Mackay Glacier drains the polar plateau. The edge of the flexure, or axis of maximum uplift, lies at Mount Termination, ˜30 km west of the McMurdo Sound coast. There has been ˜6 km of uplift since the early Cenozoic and 4.5-5 km of erosion along this axis. The amount of uplift decreases to the west at the same rate as the decrease in dip of the Kukri Peneplain, but the amount of erosion decreases more quickly as indicated by the increasing height of the mountains to the west. The axis of maximum uplift is traced north to Granite Harbour. The axis does not parallel the coast but has a more northerly trend. North-south striking longitudinal faults that delineate the structure of the TAM Front lie at an acute angle to the axis, indicating a dextral component to the dominantly east-west extension in the Ross Embayment. Architecture of the TAM

High-energy asymmetric supercapacitors based on free-standing hierarchical Co-Mo-S nanosheets with enhanced cycling stability.

PubMed

Balamurugan, Jayaraman; Li, Chao; Peera, Shaik Gouse; Kim, Nam Hoon; Lee, Joong Hee

2017-09-21

Layered transition metal sulfides (TMS) are emerging as advanced materials for energy storage and conversion applications. In this work, we report a facile and cost-effective anion exchange technique to fabricate a layered, multifaceted, free standing, ultra-thin ternary cobalt molybdenum sulfide nanosheet (Co-Mo-S NS) architecture grown on a 3D porous Ni foam substrate. The unique Co-Mo layered double hydroxides are first synthesized as precursors and consequently transformed into ultra-thin Co-Mo-S NS. When employed as an electrode for supercapacitors, the Co-Mo-S NS delivered an ultra-high specific capacitance of 2343 F g -1 at a current density of 1 mA cm -2 with tremendous rate capability and extraordinary cycling performance (96.6% capacitance retention after 20 000 cycles). Furthermore, assembled Co-Mo-S/nitrogen doped graphene nanosheets (NGNS) in an asymmetric supercapacitor (ASC) device delivered an excellent energy density of 89.6 Wh kg -1 , an amazing power density of 20.07 kW kg -1 , and superior cycling performance (86.8% capacitance retention after 50 000 cycles). Such exceptional electrochemical performance of Co-Mo-S NS is ascribed to the good electrical contact with the 3D Ni foam, ultra-high contact area with the electrolyte, and enhanced architectural softening during the charging/discharging process. It is expected that the fabricated, unique, ultra-thin Co-Mo-S NS have great potential for future energy storage devices.

Catalytic functionalities of supported sulfides. I. Effect of support and additives on the CoMo catalyst

DOE Office of Scientific and Technical Information (OSTI.GOV)

Muralidhar, G.; Massoth, F.E.; Shabtai, J.

1984-01-01

C-S hydrogenolysis (HDS) of thiophene, hydrogenation (HYD) of 1-hexene, and hydrocracking (HCG) of 2,4,4-trimethyl-1-pentene, were used as separate model test reactions to differentiate and assess the catalytic functionalities of sulfided CoMo catalysts, and their dependence on the nature of the support and incorporation of additives. Rate constants and relative catalyst activities for these three reaction types were determined. HDS and HYD activities of CoMo supported on different types of Al/sub 2/O/sub 3/ were higher, while the HCG activity was lower compared with CoMo supported on SiO/sub 2/-Al/sub 2/O/sub 3/, SiO/sub 2/-MgO, or TiO/sub 2/. For SiO/sub 2/-Al/sub 2/O/sub 3/ supportsmore » both HDS and HYD activities decreased with increase in SiO/sub 2/ content from 10 to 75%, while HCG activity showed the opposite trend. Additives to a finished CoMo catalyst at 0.5% level caused variations in HDS and HCG activities, while HYD was essentially unaffected. HDS was promoted by NH/sub 4/HF/sub 2/ and NH/sub 4/Cl, but depressed by NaNO/sub 3/, Ca(NO/sub 3/)/sub 2/, and H/sub 3/BO/sub 3/. HCG was promoted by NH/sub 4/HF/sub 2/, NH/sub 4/Cl, and H/sub 3/BO/sub 3/. Additives at 5% level, prior to or after CoMo impregnation, showed a strong depressing effect on HDS and a lesser effect on HYD, while HCG was strongly promoted by NH/sub 4/HF/sub 2/, Ti isopropoxide, and H/sub 3/BO/sub 3/. The changes in catalytic functionalities are rationalized in terms of different interactions between CoMo phase, support, and additives. 3 tables, 1 figure.« less

The role of microglia and macrophages in glioma maintenance and progression

PubMed Central

Hambardzumyan, Dolores; Gutmann, David H; Kettenmann, Helmut

2016-01-01

There is a growing recognition that gliomas are complex tumors composed of neoplastic and non-neoplastic cells, which each individually contribute to cancer formation, progression and response to treatment. The majority of the non-neoplastic cells are tumor-associated macrophages (TAMs), either of peripheral origin or representing brain-intrinsic microglia, that create a supportive stroma for neoplastic cell expansion and invasion. TAMs are recruited to the glioma environment, have immune functions, and can release a wide array of growth factors and cytokines in response to those factors produced by cancer cells. In this manner, TAMs facilitate tumor proliferation, survival and migration. Through such iterative interactions, a unique tumor ecosystem is established, which offers new opportunities for therapeutic targeting. PMID:26713745

Insight into the validity of Leptobrachium guangxiense (Anura: Megophryidae): evidence from mitochondrial DNA sequences and morphological characters.

PubMed

Chen, Weicai; Zhang, Wei; Zhou, Shichu; Li, Ning; Huang, Yong; Mo, Yunming

2013-01-01

Lepobrachiun guangxiense Fei, Mo, Ye and Jiang, 2009 (Anura: Megophryidae), is presently thought to be endemic to Shangsi, Guangxi Province, China. A molecular phylogenetic analysis and morphological data were performed to gain insight into the phylogenetic position of this species. Maximum parsimony, maximum likelihood, and Bayesian inference methods were employed to reconstruct phylogenetic relationship, using 1914 bp of sequences from mtDNA genes of 12S rRNA, tRNAVal and 16S rRNA. Topologies revealed that L. guangxiense and Tam Dao (Vietnam) L. chapaense lineage (3A) formed a monophyletic group with well-supported values. The uncorrected p-distance of ~1.4k bp 16S rRNA data-sets between Tam Dao L. chapaense lineage (3A) and L. guangxiense is only 0.1%. Morphologically, L. guangxiense and Tam Dao L. chapaense lineage (3A) shared the same characters, and are distinguishable from "true" L. chapaense from the type locality in Sa Pa, Vietnam. Based on morphological characters and mitochondrial DNA, we suggested that the Tam Dao lineages of L. chapaense are conspecific with L. guangxiense. This represents a range extension for L. guangxiense, and a new country record for Vietnam.

ASK1-dependent endothelial cell activation is critical in ovarian cancer growth and metastasis

PubMed Central

Yin, Mingzhu; Zhou, Huanjiao Jenny; Zhang, Jiqin; Lin, Caixia; Li, Hongmei; Li, Xia; Li, Yonghao; Zhang, Haifeng; Breckenridge, David G.; Ji, Weidong

2017-01-01

We have recently reported that tumor-associated macrophages (TAMs) promote early transcoelomic metastasis of ovarian cancer by facilitating TAM–ovarian cancer cell spheroid formation. ASK1 is known to be important for macrophage activation and inflammation-mediated tumorigenesis. In the present study, we show that ASK1 deficiency attenuates TAM-spheroid formation and ovarian cancer progression in an orthotopic ovarian cancer model. Interestingly, ASK1 in stroma, but not in TAMs, is critical for peritoneal tumor growth of ovarian cancer. Moreover, overexpression of an ASK1 inhibitory protein (suppressor of cytokine signaling-1; SOCS1) in vascular endothelium attenuates vascular permeability, TAM infiltration, and ovarian cancer growth. Mechanistically, we show that ASK1 mediates degradation of endothelial junction protein VE-cadherin via a lysosomal pathway to promote macrophage transmigration. Importantly, a pharmacological ASK1 inhibitor prevents tumor-induced vascular leakage, macrophage infiltration, and tumor growth in two mouse models. Since transcoelomic metastasis is also associated with many other cancers, such as pancreatic and colon cancers, our study provides ASK1 as a therapeutic target for the treatment of ovarian cancer and other transcoelomic metastasis cancers. PMID:28931753

Axl as a mediator of cellular growth and survival

PubMed Central

Axelrod, Haley; Pienta, Kenneth J.

2014-01-01

The control of cellular growth and proliferation is key to the maintenance of homeostasis. Survival, proliferation, and arrest are regulated, in part, by Growth Arrest Specific 6 (Gas6) through binding to members of the TAM receptor tyrosine kinase family. Activation of the TAM receptors leads to downstream signaling through common kinases, but the exact mechanism within each cellular context varies and remains to be completely elucidated. Deregulation of the TAM family, due to its central role in mediating cellular proliferation, has been implicated in multiple diseases. Axl was cloned as the first TAM receptor in a search for genes involved in the progression of chronic to acute-phase leukemia, and has since been established as playing a critical role in the progression of cancer. The oncogenic nature of Axl is demonstrated through its activation of signaling pathways involved in proliferation, migration, inhibition of apoptosis, and therapeutic resistance. Despite its recent discovery, significant progress has been made in the development of effective clinical therapeutics targeting Axl. In order to accurately define the role of Axl in normal and diseased processes, it must be analyzed in a cell type-specific context. PMID:25344858

Indole-3-acetic acid in Fusarium graminearum: Identification of biosynthetic pathways and characterization of physiological effects.

PubMed

Luo, Kun; Rocheleau, Hélène; Qi, Peng-Fei; Zheng, You-Liang; Zhao, Hui-Yan; Ouellet, Thérèse

2016-09-01

Fusarium graminearum is a devastating pathogenic fungus causing fusarium head blight (FHB) of wheat. This fungus can produce indole-3-acetic acid (IAA) and a very large amount of IAA accumulates in wheat head tissues during the first few days of infection by F. graminearum. Using liquid culture conditions, we have determined that F. graminearum can use tryptamine (TAM) and indole-3-acetonitrile (IAN) as biosynthetic intermediates to produce IAA. It is the first time that F. graminearum is shown to use the l-tryptophan-dependent TAM and IAN pathways rather than the indole-3-acetamide or indole-3-pyruvic acid pathways to produce IAA. Our experiments also showed that exogenous IAA was metabolized by F. graminearum. Exogenous IAA, TAM, and IAN inhibited mycelial growth; IAA and IAN also affected the hyphae branching pattern and delayed macroconidium germination. IAA and TAM had a small positive effect on the production of the mycotoxin 15-ADON while IAN inhibited its production. Our results showed that IAA and biosynthetic intermediates had a significant effect on F. graminearum physiology and suggested a new area of exploration for fungicidal compounds. Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.

Metabolic changes in tumor cells and tumor-associated macrophages: A mutual relationship.

PubMed

Netea-Maier, Romana T; Smit, Johannes W A; Netea, Mihai G

2018-01-28

In order to adapt to the reduced availability of nutrients and oxygen in the tumor microenvironment and the increased requirements of energy and building blocks necessary for maintaining their high proliferation rate, malignant cells undergo metabolic changes that result in an increased production of lactate, nitric oxide, reactive oxygen species, prostaglandins and other byproducts of arachidonic acid metabolism that influence both the composition of the inflammatory microenvironment and the function of the tumor-associated macrophages (TAMs). In response to cues present in the TME, among which products of altered tumor cell metabolism, TAMs are also required to reprogram their metabolism, with activation of glycolysis, fatty acid synthesis and altered nitrogen cycle metabolism. These changes result in functional reprogramming of TAMs which includes changes in the production of cytokines and angiogenetic factors, and contribute to the tumor progression and metastasis. Understanding the metabolic changes governing the intricate relationship between the tumor cells and the TAMs represents an essential step towards developing novel therapeutic approaches targeting the metabolic reprogramming of the immune cells to potentiate their tumoricidal potential and to circumvent therapy resistance. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Axl as a mediator of cellular growth and survival.

PubMed

Axelrod, Haley; Pienta, Kenneth J

2014-10-15

The control of cellular growth and proliferation is key to the maintenance of homeostasis. Survival, proliferation, and arrest are regulated, in part, by Growth Arrest Specific 6 (Gas6) through binding to members of the TAM receptor tyrosine kinase family. Activation of the TAM receptors leads to downstream signaling through common kinases, but the exact mechanism within each cellular context varies and remains to be completely elucidated. Deregulation of the TAM family, due to its central role in mediating cellular proliferation, has been implicated in multiple diseases. Axl was cloned as the first TAM receptor in a search for genes involved in the progression of chronic to acute-phase leukemia, and has since been established as playing a critical role in the progression of cancer. The oncogenic nature of Axl is demonstrated through its activation of signaling pathways involved in proliferation, migration, inhibition of apoptosis, and therapeutic resistance. Despite its recent discovery, significant progress has been made in the development of effective clinical therapeutics targeting Axl. In order to accurately define the role of Axl in normal and diseased processes, it must be analyzed in a cell type-specific context.

The G protein-coupled receptor GPR30 mediates the proliferative and invasive effects induced by hydroxytamoxifen in endometrial cancer cells.

PubMed

Du, Gui-Qiang; Zhou, Long; Chen, Xiao-Yue; Wan, Xiao-Ping; He, Yin-Yan

2012-04-06

The selective ER modulator tamoxifen (TAM(1)) is the most widely used ER antagonist for treatment of women with hormone-dependent breast tumor. However, long-term treatment is associated with an increased risk of endometrial cancer. The aim of the present study was to demonstrate new insight into the role of G-protein coupled receptor 30 (GPR30) in the activity of TAM, which promoted endometrial cancer. In endometrial cancer cell lines ISHIKAWA and KLE, the potential of 4-hydroxytamoxifen (OHT), the active metabolite of TAM, 17β-estradiol (E2) and G1, a non-steroidal GPR30-specific agonist to promote cell proliferation and invasion was evaluated. All agents above induced high proliferative and invasive effects, while the down-regulation of GPR30 or the interruption of MAPK signal pathway partly or completely prevented the action of the regent. Moreover, the RNA and protein expression of GPR30 was up-regulated by G1, E2 or OHT in both cell lines. The present study provided a new insight into the mechanism involved in the agonistic activity exerted by TAM in the uterus. Copyright © 2012 Elsevier Inc. All rights reserved.

Thermophysical properties of undercooled liquid Co-Mo alloys

NASA Astrophysics Data System (ADS)

Han, X. J.; Wei, B.

2003-05-01

Using electromagnetic levitation in combination with the oscillating drop technique and drop calorimeter method, the surface tensions and specific heats of undercooled liquid Co-10 wt% Mo, Co-26.3 wt% Mo, and Co-37.6 wt% Mo alloys were measured. The containerless state during levitation produces substantial undercoolings up to 223 K (0.13TL), 213 K (0.13TL) and 110 K (0.07TL) respectively for these three alloys. In their respective undercooling ranges, the surface tensions were determined to be 1895 m 0.31(T m 1744), 1932 m 0.33(T m 1682), and 1989 m 0.34(T m 1607) mN mу. According to the Butler equation, the surface tensions of these three Co-Mo alloys were also calculated, and the results agree well with the experimental data. The specific heats of these three alloys are determined to be 41.85, 43.75 and 44.92 J molу Kу. Based on the determined surface tensions and specific heats, the changes in thermodynamics functions such as enthalpy, entropy and Gibbs free energy are predicted. Furthermore, the crystal nucleation, dendrite growth and Marangoni convection of undercooled Co-Mo alloys are investigated in the light of these measured thermophysical properties.