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Gregory M. Anstead

Bio: Gregory M. Anstead is an academic researcher from University of Texas Health Science Center at San Antonio. The author has contributed to research in topics: Indene & Estrogen receptor binding. The author has an hindex of 24, co-authored 80 publications receiving 6107 citations. Previous affiliations of Gregory M. Anstead include University of Kentucky & United States Department of Veterans Affairs.


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Journal ArticleDOI
Daniel D Murray1, Kazuo Suzuki1, Matthew Law1, Jonel Trebicka2  +1486 moreInstitutions (9)
14 Oct 2015-PLOS ONE
TL;DR: No associations with mortality were found with any circulating miRNAs studied and these results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection.
Abstract: Introduction The use of anti-retroviral therapy (ART) has dramatically reduced HIV-1 associated morbidity and mortality. However, HIV-1 infected individuals have increased rates of morbidity and mortality compared to the non-HIV-1 infected population and this appears to be related to end-organ diseases collectively referred to as Serious Non-AIDS Events (SNAEs). Circulating miRNAs are reported as promising biomarkers for a number of human disease conditions including those that constitute SNAEs. Our study sought to investigate the potential of selected miRNAs in predicting mortality in HIV-1 infected ART treated individuals. Materials and Methods A set of miRNAs was chosen based on published associations with human disease conditions that constitute SNAEs. This case: control study compared 126 cases (individuals who died whilst on therapy), and 247 matched controls (individuals who remained alive). Cases and controls were ART treated participants of two pivotal HIV-1 trials. The relative abundance of each miRNA in serum was measured, by RTqPCR. Associations with mortality (all-cause, cardiovascular and malignancy) were assessed by logistic regression analysis. Correlations between miRNAs and CD4+ T cell count, hs-CRP, IL-6 and D-dimer were also assessed. Results None of the selected miRNAs was associated with all-cause, cardiovascular or malignancy mortality. The levels of three miRNAs (miRs -21, -122 and -200a) correlated with IL-6 while miR-21 also correlated with D-dimer. Additionally, the abundance of miRs -31, -150 and -223, correlated with baseline CD4+ T cell count while the same three miRNAs plus miR-145 correlated with nadir CD4+ T cell count. Discussion No associations with mortality were found with any circulating miRNA studied. These results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection.

3,094 citations

Journal ArticleDOI
01 Mar 1997-Steroids
TL;DR: The various elements in this model for the binding of steroidal estrogens by the estrogen receptor are consistent with evidence emerging from the crystal structures of related nuclear hormone receptor ligand complexes.

619 citations

Journal ArticleDOI
TL;DR: Posaconazole appears promising as an oral therapy for zygomycosis in patients who receive required surgery and control their underlying illness, and was well tolerated and was discontinued in only one subject due to a drug rash.
Abstract: Zygomycosis, an infection that is associated with significant morbidity and mortality, is becoming common in immunocompromised patients. Posaconazole is a new extended-spectrum azole antifungal that has demonstrated in vitro and in vivo activity against zygomycetes. This report provides the results from the first 24 patients with active zygomycosis who were enrolled in two open-label, nonrandomized, multicentered compassionate trials that evaluated oral posaconazole as salvage therapy for invasive fungal infections. Posaconazole was usually given as an oral suspension of 200 mg four times a day or 400 mg twice a day. Eleven (46%) of the infections were rhinocerebral. Duration of posaconazole therapy ranged from 8 to 1,004 days (mean, 292 days; median, 182 days). Rates of successful treatment (complete cure and partial response) were 79% in 19 subjects with zygomycosis refractory to standard therapy and 80% in 5 subjects with intolerance to standard therapy. Overall, 19 of 24 subjects (79%) survived infection. Survival was also associated with surgical resection of affected tissue and stabilization or improvement of the subjects' underlying illnesses. Failures either had worsening of underlying illnesses or requested all therapy withdrawn; none of the failures received more than 31 days of posaconazole. Posaconazole oral solution was well tolerated and was discontinued in only one subject due to a drug rash. Posaconazole appears promising as an oral therapy for zygomycosis in patients who receive required surgery and control their underlying illness.

479 citations

Journal Article
TL;DR: Vitamin A restores the inflammatory response and promotes epithelialization and the synthesis of collagen and ground substances, however, vitamin A does not reverse the detrimental effects of glucocorticoids on wound contraction and infection.
Abstract: Glucocorticoids (corticosteroids) cause dehiscence of surgical incisions, increased risk of wound infection, and delayed healing of open wounds. They produce these effects by interfering with inflammation, fibroblast proliferation, collagen synthesis and degradation, deposition of connective tissue ground substances, angiogenesis, wound contraction, and re-epithelialization. These actions are mediated by the antagonism of various growth factors and cytokines. Vitamin A restores the inflammatory response and promotes epithelialization and the synthesis of collagen and ground substances. However, vitamin A does not reverse the detrimental effects of glucocorticoids on wound contraction and infection. In this paper, the known mechanisms of the interaction of glucocorticoids and retinoids are reviewed. The mutually inhibitory interplay between glucocorticoids and retinoids may serve to regulate the processes of inflammation, immunity, and connective tissue repair.

209 citations

Journal ArticleDOI
TL;DR: Malnutrition causes a failure of lymph node barrier function after L. donovani infection, which may be related to excessive production of PGE2and decreased levels of IL-10 and nitric oxide.
Abstract: Globally, protein-energy malnutrition is the most frequent cause of immunodeficiency (58). Epidemiologic and experimental studies have documented an increased risk for visceral leishmaniasis, caused by intracellular protozoan parasites of the Leishmania donovani complex, in the malnourished host (1, 2, 26). However, the immunologic basis for this association has not been established and standardized experimental models have not addressed this important issue. In this study, our goal was to investigate the mechanisms of the malnutrition-related susceptibility to visceral leishmaniasis. There were three components of the study. First, we needed to create a murine model of malnutrition that was relevant to human malnutrition in developing countries. Although the mouse has been extensively used in animal models of malnutrition, there is no standard murine model of protein-energy malnutrition (69). Human malnutrition is complex, typically involving deficiency of protein and energy with superimposed deficits of other nutrients. Zinc deficiency usually accompanies protein-energy malnutrition (19). Iron deficiency is highly prevalent in developing countries and may accompany zinc deficiency due to a common risk factor, cereal-based diets with little meat (61). Thus, in this model, in addition to protein and energy, zinc and iron were selected as deficient nutrients. Much of the vast body of data that has been collected on human malnutrition is based on anthropometric measures, i.e., weight-for-age (WA), height-for-age, and weight-for-height (13). However, in previous mouse models of malnutrition, there have been no efforts to relate morphometric measures of nutritional status to either human anthropometric scales or immunocompetence. Weight-for-age determination is advantageous because it can be measured unambiguously, provides a synthesis of linear growth and body proportion (13), and correlates with probability of death in children in developing countries (36). In this study, murine WA was correlated with specific measures of host defense and risk for visceral L. donovani infection. A second component of the study was to examine possible defects in the mediator network of the innate immune system produced by malnutrition, because it is the early events that are likely to determine whether the inoculated parasites are controlled locally or disseminate to visceral organs. The innate immune system provides a first line of defense against pathogens and instructs the differentiation of Th0 cells into Th1 and Th2 cells (18). It has been estimated that the innate immune system provides protection against 98% of the pathogens that are encountered (34). Malnutrition has been associated with an increased risk of many infections (3); however, there are no animal models that specifically examine the effect of malnutrition on the innate immune response to infection. The third part of the study was to investigate the mechanism of visceralization (the process whereby parasites disseminate from the site of cutaneous inoculation and the draining lymph nodes to the liver, spleen, and bone marrow). To reach this goal, we needed to develop a more natural animal model of visceral leishmaniasis, using the vector stage of the parasite (promastigote) and the intradermal route of infection. Although the immunopathogenesis of murine visceral leishmaniasis has been investigated, previous studies have used an unnatural (intravenous) route of infection and/or the mammalian host stage of the parasite (amastigote) as the infecting inoculum (35, 40, 43, 48, 65). The intravenous route of inoculation negates the immune processing that would occur in the skin and in the draining lymph node and therefore does not accurately reflect the immune response that would occur in a natural cutaneous infection. Furthermore, models of visceral leishmaniasis that utilize the intravenous route of inoculation do not facilitate an understanding of the mechanism of visceralization. Selection of either amastigote or promastigote as the infective inoculum may also have an important bearing on the course of infection, because these two stages of the parasite possess disparate virulence factors (9) and produce different immune responses (20). In this study, we establish a murine model of polynutrient deficiency that is similar to human malnutrition in developing regions of the world. We demonstrate that the malnourished mouse has an altered innate immune defense and is at increased risk of visceralization following cutaneous L. donovani infection.

170 citations


Cited by
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TL;DR: This paper reviews the major deep learning concepts pertinent to medical image analysis and summarizes over 300 contributions to the field, most of which appeared in the last year, to survey the use of deep learning for image classification, object detection, segmentation, registration, and other tasks.

8,730 citations

Journal ArticleDOI
TL;DR: In this paper, a general all-atom force field for atomistic simulation of common organic molecules, inorganic small molecules, and polymers was developed using state-of-the-art ab initio and empirical parametrization techniques.
Abstract: A general all-atom force field for atomistic simulation of common organic molecules, inorganic small molecules, and polymers was developed using state-of-the-art ab initio and empirical parametrization techniques. The valence parameters and atomic partial charges were derived by fitting to ab initio data, and the van der Waals (vdW) parameters were derived by conducting MD simulations of molecular liquids and fitting the simulated cohesive energies and equilibrium densities to experimental data. The combined parametrization procedure significantly improves the quality of a general force field. Validation studies based on large number of isolated molecules, molecular liquids and molecular crystals, representing 28 molecular classes, show that the present force field enables accurate and simultaneous prediction of structural, conformational, vibrational, and thermophysical properties for a broad range of molecules in isolation and in condensed phases. Detailed results of the parametrization and validation f...

4,722 citations

Journal ArticleDOI
TL;DR: The estrogenic activity of environmental chemicals and phytoestrogens in competition binding assays with ERα or ERβ protein, and in a transient gene expression assay using cells in which an acute estrogenic response is created by cotransfecting cultures with recombinant human ERβ complementary DNA (cDNA) in the presence of an estrogen-dependent reporter plasmid are investigated.
Abstract: The rat, mouse and human estrogen receptor (ER) exists as two subtypes, ER alpha and ER beta, which differ in the C-terminal ligand-binding domain and in the N-terminal transactivation domain. In this study, we investigated the estrogenic activity of environmental chemicals and phytoestrogens in competition binding assays with ER alpha or ER beta protein, and in a transient gene expression assay using cells in which an acute estrogenic response is created by cotransfecting cultures with recombinant human ER alpha or ER beta complementary DNA (cDNA) in the presence of an estrogen-dependent reporter plasmid. Saturation ligand-binding analysis of human ER alpha and ER beta protein revealed a single binding component for [3H]-17beta-estradiol (E2) with high affinity [dissociation constant (Kd) = 0.05 - 0.1 nM]. All environmental estrogenic chemicals [polychlorinated hydroxybiphenyls, dichlorodiphenyltrichloroethane (DDT) and derivatives, alkylphenols, bisphenol A, methoxychlor and chlordecone] compete with E2 for binding to both ER subtypes with a similar preference and degree. In most instances the relative binding affinities (RBA) are at least 1000-fold lower than that of E2. Some phytoestrogens such as coumestrol, genistein, apigenin, naringenin, and kaempferol compete stronger with E2 for binding to ER beta than to ER alpha. Estrogenic chemicals, as for instance nonylphenol, bisphenol A, o, p'-DDT and 2',4',6'-trichloro-4-biphenylol stimulate the transcriptional activity of ER alpha and ER beta at concentrations of 100-1000 nM. Phytoestrogens, including genistein, coumestrol and zearalenone stimulate the transcriptional activity of both ER subtypes at concentrations of 1-10 nM. The ranking of the estrogenic potency of phytoestrogens for both ER subtypes in the transactivation assay is different; that is, E2 >> zearalenone = coumestrol > genistein > daidzein > apigenin = phloretin > biochanin A = kaempferol = naringenin > formononetin = ipriflavone = quercetin = chrysin for ER alpha and E2 >> genistein = coumestrol > zearalenone > daidzein > biochanin A = apigenin = kaempferol = naringenin > phloretin = quercetin = ipriflavone = formononetin = chrysin for ER beta. Antiestrogenic activity of the phytoestrogens could not be detected, except for zearalenone which is a full agonist for ER alpha and a mixed agonist-antagonist for ER beta. In summary, while the estrogenic potency of industrial-derived estrogenic chemicals is very limited, the estrogenic potency of phytoestrogens is significant, especially for ER beta, and they may trigger many of the biological responses that are evoked by the physiological estrogens.

4,078 citations

Journal ArticleDOI
16 Oct 1997-Nature
TL;DR: The crystal structures of the LBD of ER in complex with the endogenous oestrogen, 17β-oestradiol, and the selective antagonist raloxifene provide a molecular basis for the distinctive pharmacophore of the ER and its catholic binding properties.
Abstract: Oestrogens are involved in the growth, development and homeostasis of a number of tissues. The physiological effects of these steroids are mediated by a ligand-inducible nuclear transcription factor, the oestrogen receptor (ER). Hormone binding to the ligand-binding domain (LBD) of the ER initiates a series of molecular events culminating in the activation or repression of target genes. Transcriptional regulation arises from the direct interaction of the ER with components of the cellular transcription machinery. Here we report the crystal structures of the LBD of ER in complex with the endogenous oestrogen, 17beta-oestradiol, and the selective antagonist raloxifene, at resolutions of 3.1 and 2.6 A, respectively. The structures provide a molecular basis for the distinctive pharmacophore of the ER and its catholic binding properties. Agonist and antagonist bind at the same site within the core of the LBD but demonstrate different binding modes. In addition, each class of ligand induces a distinct conformation in the transactivation domain of the LBD, providing structural evidence of the mechanism of antagonism.

3,255 citations