William G Parker
Petrified Forest National Park, Division of Resource Management, Department Member
Aetosauria is an early-diverging clade of pseudosuchians (crocodile-line archosaurs) that had a global distribution and high species diversity as a key component of various Late Triassic terrestrial faunas. It is one of only two Late... more
Aetosauria is an early-diverging clade of pseudosuchians (crocodile-line archosaurs) that had a global distribution and high species diversity as a key component of various Late Triassic terrestrial faunas. It is one of only two Late Triassic clades of large herbivorous archosaurs, and thus served a critical ecological role. Nonetheless, aetosaur phylogenetic relationships are still poorly understood, owing to an overreliance on osteoderm characters, which are often poorly constructed and suspected to be highly homoplastic. A new phylogenetic analysis of the Aetosauria, comprising 27 taxa and 83 characters, includes more than 40 new characters that focus on better sampling the cranial and endoskeletal regions, and represents the most comprenhensive phylogeny of the clade to date. Parsimony analysis recovered three most parsimonious trees; the strict consensus of these trees finds an Aetosauria that is divided into two main clades: Desmatosuchia, which includes the Desmatosuchinae an...
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During the last few years, many gene therapy strategies have been developed for various disease targets. The development of anticancer gene therapy strategies to selectively generate cytotoxic nucleoside or nucleotide analogs is an... more
During the last few years, many gene therapy strategies have been developed for various disease targets. The development of anticancer gene therapy strategies to selectively generate cytotoxic nucleoside or nucleotide analogs is an attractive goal. One such approach involves the delivery of herpes simplex virus thymidine kinase followed by the acyclic nucleoside analog ganciclovir. We have developed another gene therapy methodology for the treatment of cancer that has several significant attributes. Specifically, our approach involves the delivery of E. coli purine nucleoside phosphorylase, followed by treatment with a relatively non-toxic nucleoside prodrug that is cleaved by the enzyme to a toxic compound. This presentation describes the concept, details our search for suitable prodrugs, and summarizes the current biological data.
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2-Methyladenosine (methyl-ado) has demonstrated selective activity against Mycobacterium tuberculosis, which indicates that differences in the substrate preferences between mycobacterial and human purine metabolic enzymes can be exploited... more
2-Methyladenosine (methyl-ado) has demonstrated selective activity against Mycobacterium tuberculosis, which indicates that differences in the substrate preferences between mycobacterial and human purine metabolic enzymes can be exploited to develop novel drugs for the treatment of mycobacterial diseases. Therefore, in an effort to better understand the reasons for the anti-mycobacterial activity of methyl-ado, its metabolism has been characterized in Mycobacterium smegmatis. In a wild-type strain, methyl-ado was phosphorylated by adenosine kinase to methyl-AMP, which was further converted to methyl-ATP and incorporated into RNA. In contrast, a mutant strain of M. smegmatis was isolated that was resistant to methyl-ado, deficient in adenosine kinase activity and was not able to generate methyl-ado metabolites in cells treated with methyl-ado. These results indicated that phosphorylated metabolites of methyl-ado were responsible for the cytotoxic activity of this compound. Methyl-ado...
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2-Methyladenosine (methyl-Ado) has selective activity against Mycobacterium tuberculosis (M. tuberculosis). In an effort to better understand its mechanism of action, we have characterized its metabolism in M. tuberculosis cells. The... more
2-Methyladenosine (methyl-Ado) has selective activity against Mycobacterium tuberculosis (M. tuberculosis). In an effort to better understand its mechanism of action, we have characterized its metabolism in M. tuberculosis cells. The primary intracellular metabolite of methyl-Ado was 2-methyl-adenylate (methyl-AMP). Very little of the methyl-AMP was metabolized further. A M. tuberculosis strain that was resistant to methyl-Ado did not express adenosine kinase and did not convert methyl-Ado to methyl-AMP in intact cells. In contrast to these results, the primary intracellular metabolite of adenosine in M. tuberculosis cells was ATP, which was readily incorporated into RNA. The rate of metabolism of methyl-Ado to methyl-AMP was similar to the rate of metabolism of adenosine to ATP. Treatment of M. tuberculosis with methyl-Ado did not affect intracellular ATP levels. Methyl-Ado and Ado were also cleaved to 2-methyladenine and adenine, respectively, which accumulated in the medium outsi...
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The animal gut serves as a primary location for the complex host-microbe interplay that is essential for homeostasis and may also reflect the types of ancient selective pressures that spawned the emergence of immunity in metazoans. In... more
The animal gut serves as a primary location for the complex host-microbe interplay that is essential for homeostasis and may also reflect the types of ancient selective pressures that spawned the emergence of immunity in metazoans. In this review, we present a phylogenetic survey of gut host-microbe interactions and suggest that host defense systems arose not only to protect tissue directly from pathogenic attack but also to actively support growth of specific communities of mutualists. This functional dichotomy resulted in the evolution of immune systems much more tuned for harmonious existence with microbes than previously thought, existing as dynamic but primarily cooperative entities in the present day. We further present the protochordate Ciona intestinalis as a promising model for studying gut host-bacterial dialogue. The taxonomic position, gut physiology and experimental tractability of Ciona offer unique advantages in dissecting host-microbe interplay and can complement stu...
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It is thought that the primary function of secretory IgA (SIgA) is, in conjunction with the mucus lining of the gut, to prevent translocation of bacteria across the epithelial barrier. In this review, we evaluate the emerging idea that... more
It is thought that the primary function of secretory IgA (SIgA) is, in conjunction with the mucus lining of the gut, to prevent translocation of bacteria across the epithelial barrier. In this review, we evaluate the emerging idea that SIgA and the mucus of the large bowel may actually be involved in promicrobial activity. Central to this new model is the idea that growth of bacterial biofilms in the gut may be common and is likely advantageous to the microbial community. Evidence is examined that suggests the immune system is likely involved in the maintenance of biofilms in the gut. This model of immune inclusion, if correct, likely operates in conjunction with immune exclusion, preventing bacteria from transversing the epithelial barrier.
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XENOTRANSPLANTATION 1994; 1:36^t6 Printed in the United States of America - all rights reserved. Copyright © Munksgaard, 1994 XENOTRANSPLANTATION ISSN 0908-665X Characterization of porcine endothelial cell determinants recognized by human... more
XENOTRANSPLANTATION 1994; 1:36^t6 Printed in the United States of America - all rights reserved. Copyright © Munksgaard, 1994 XENOTRANSPLANTATION ISSN 0908-665X Characterization of porcine endothelial cell determinants recognized by human natural antibodies Collins ...
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The expression of colonization factors by gut bacteria, the growth rate of gut bacteria, and the rate of plasmid exchange by gut bacteria indicate that biofilms are a normal component of bacterial growth in the large bowel. Further, in... more
The expression of colonization factors by gut bacteria, the growth rate of gut bacteria, and the rate of plasmid exchange by gut bacteria indicate that biofilms are a normal component of bacterial growth in the large bowel. Further, in vitro experiments demonstrate that growth of normal enteric bacteria in biofilms can be facilitated by secretory IgA (SIgA) and by mucins, 2 major components of the gut milieu. However, biofilms have not been previously observed in the normal gut. In this study, bacterial colonies characteristic of biofilms were observed by electron microscopy in normal rat, baboon, and human gut by electron microscopy. Confirming these results, acridine orange staining of flash-frozen tissues revealed biofilms in the mucus lining along normal gut epithelium. Immunofluorescenct microscopy supported this finding and demonstrated an association between IgA and the biofilms. These findings provide direct evidence that biofilms are present and may play an important role in the commensal relationship between enteric bacteria and their hosts. Hematoxylin and eosin staining of formalin-fixed tissues resulted in dissociation of the luminal contents from the epithelium, suggesting that the association between biofilms and the gut epithelium is sensitive to some conditions used to preserve tissue for histologic evaluation.
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5&am... more
5'-methylthioadenosine (MTA) is a natural purine that is metabolized by methylthioadenosine phosphorylase (MTAP, E.C 2.4.2.28) in Eukarya and Archaea but generally not in bacteria. In this work, Rv0535, which has been annotated as a probable MTAP in Mycobacterium tuberculosis, was expressed in and purified from Escherichia coli BL21 (DE3). The purified protein displayed properties of a phosphorylase and MTA was the preferred substrate. Adenosine and S-adenosyl-l-homocysteine were poor substrates and no activity was detected with 5'-methylthioinosine, the other natural purines, or the natural pyrimidines. Kinetic analysis of M. tuberculosis MTAP showed that the K(m) value for MTA was 9 μM. Rv0535 was estimated as a 30 kDa protein on a denaturing SDS-PAGE gel, which agreed with the molecular mass predicted by its gene sequence. Using gel filtration chromatography, the native molecular mass of the enzyme was determined to be 60 ± 4 kDa, and thus indicated that M. tuberculosis MTAP is a dimer. Differences in active site between mycobacterial and human MTAPs were identified by homology modeling based on the crystal of the human enzyme. A complete structure-activity relationship analysis could identify differences in substrate specificity between the two enzymes to aid in the development of purine-based, anti-tuberculosis drugs.
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Profound coagulopathy has been proposed as a barrier to xenotransplantation. Disseminated intravascular coagulation (DIC) has been observed with the rejection of renal and bone marrow xenografts but has not yet been described in pulmonary... more
Profound coagulopathy has been proposed as a barrier to xenotransplantation. Disseminated intravascular coagulation (DIC) has been observed with the rejection of renal and bone marrow xenografts but has not yet been described in pulmonary xenografts. This study examined the coagulation parameters in five baboons that received pulmonary xenografts and one baboon that was exposed to porcine lung during an extracorporeal perfusion. Platelet counts, prothrombin times (PT), and levels of fibrinogen, D-dimers, and thrombin-antithrombin III complex (TAT) were analyzed. In addition, serum levels of plasminogen activator inhibitor-1 (PAI-1), thrombomodulin (TM), tissue plasminogen activator (tPA), and tissue factor (TF) were determined. Hyperacute pulmonary xenograft dysfunction, which occurred within 0-9 hr of graft reperfusion, was associated with clinically evident DIC. This coagulopathy was characterized by thrombocytopenia, decreased fibrinogen levels, elevations in PT, and increases in D-dimers and TAT. Furthermore, transient increases in PAI-1, increases in TM, and increases in tPA were observed in the serum of some but not all recipients. None of the baboons demonstrated measurable increases in soluble TF. Although DIC in renal or bone marrow xenotransplantation develops over a period of days, DIC associated with hyperacute pulmonary xenograft dysfunction develops within hours of graft reperfusion. Thus, the DIC in pulmonary xenotransplantation may represent a unique and/or accelerated version of the coagulopathy observed with renal and bone marrow xenotransplantation.
Research Interests: Electron Microscopy, Complement activation, Kidney transplantation, Transplantation, Fibrinogen, and 13 morePapio, Complication, Kidney, Animals, Blood Coagulation, Swine, Disseminated Intravascular Coagulation, Graft Rejection, Heart and Lung Transplantation, Fibrinolysis, Platelet Count, Mono, and Lung Transplantation
Antigen sensitization alters the use of genes encoding the variable and constant regions of immunoglobulin, changing avidity, and function. Alterations in variable region genes induced by carbohydrate antigens have been studied... more
Antigen sensitization alters the use of genes encoding the variable and constant regions of immunoglobulin, changing avidity, and function. Alterations in variable region genes induced by carbohydrate antigens have been studied extensively in animals but are incompletely characterized in humans. We asked how sensitization with the carbohydrate Galalpha1-3Gal modifies antibody heavy chain use. To overcome limited access to B cells, we analyzed anti-Galalpha1-3Gal antibodies from the serum of naïve and sensitized human subjects with anti-sera specific for VH families. We find that in preimmune subjects, heavy chains of IgM anti-Galalpha1-3Gal derived primarily from VH3 family members, whereas the heavy chains of IgG are from diverse VH families. After sensitization, heavy chains of IgM and IgG antibodies both derived from diverse VH families. The preimmune repertoire of IgM antibodies to Galalpha1-3Gal is thus more restricted than the antibody repertoire after sensitization, suggesting an antigen-induced shift in the repertoire.
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A major question in xenotransplantation is the nature of the humoral response that would occur following the transplantation of a xenogeneic organ into an immunosuppressed recipient as such a response could mediate delayed types of injury... more
A major question in xenotransplantation is the nature of the humoral response that would occur following the transplantation of a xenogeneic organ into an immunosuppressed recipient as such a response could mediate delayed types of injury to the graft. To begin to address this issue we characterized the changes in the properties of xenoreactive antibodies occurring in patients exposed to porcine organs under conditions simulating transplantation. In two patients whose blood had been cross-perfused through porcine livers as a treatment for hepatic failure, the titer of xenoreactive IgM increased by four-fold and the titer of xenoreactive IgG increased by sixty-fold within ten days after perfusion procedures. The xenoreactive IgM and IgG antibodies were specific for Gal alpha 1-3Gal based on binding to porcine endothelial cells and bovine thyroglobulin, which express this determinant, and on the decrease in binding following treatment of porcine endothelial cells or bovine thyroglobulin with alpha-galactosidase. The sequential addition to endothelial cells of amounts of serum known to saturate antibody-binding sites obtained before and ten days after perfusion of porcine organs revealed no increase in binding of IgM above the level observed with serum obtained before perfusion, suggesting that new determinants were not identified. Moreover, the functional avidity of binding to porcine endothelial cells of IgM in serum obtained before and ten days after perfusion of porcine organs was unchanged. Even at later times, the presence of newly elicited antibodies against porcine aortic endothelial cell targets was not detected. Thus, exposure to porcine antigens in a vascularized organ results in increases in the levels of xenoreactive IgM and IgG antibodies--however, these antibodies exhibit properties similar to natural antibodies.
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A large number of studies point toward chronic aspiration associated with gastroesophageal reflux disease (GERD) as an important factor involved in the development of asthma, the incidence of which has increased dramatically in... more
A large number of studies point toward chronic aspiration associated with gastroesophageal reflux disease (GERD) as an important factor involved in the development of asthma, the incidence of which has increased dramatically in industrially developed countries. Recent work suggests that medical intervention aimed at acid blockade is not sufficient to relieve the effects of chronic aspiration on asthma pathology, leaving surgical treatment of the disease as one of the few remaining options. This study examined the effect of chronic aspiration on the airway-associated immune response to allergens using a model of experimentally induced airway hypersensitivity in Balb/c mice. The mice received aspiration of gastric fluid on days 1, 8, 15, 22, 29, 36, 43, and 50 and were sensitized to ovalbumin by intraperitoneal (IP) injection on days 33 and 47, challenged with aerosolized ovalbumin on day 54, and killed on day 56. Control mice received sham gastric fluid aspirations, sham induction of airway hypersensitivity, or both. Chronic aspiration of 50 microl murine gastric fluid once per week for 8 weeks had a profound effect on the immune system in the lung, with upregulation of the macrophage/monocyte-associated cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-12 (IL-12) and profound downregulation of a broad array of T-cell-associated cytokines including interleukins 2, 4, 5, 6, 10, 13, and 23, as well as interferon-gamma. The aspiration-induced depression of IL-5 production in particular was found only in mice with airway hypersensitivity and not in control mice without airway hypersensitivity. The results indicate that chronic aspiration of gastric fluid has a profound effect on the nature of the allergic response to aerosolized allergens, suggesting that the aspiration may be an important factor affecting the pathogenesis of asthma.
Research Interests: Immune response, Asthma, Developing Country, Mice, Animals, and 15 moreMale, Follow-up studies, Lung, Clinical Sciences, T lymphocytes, Immune system, Tumor necrosis factor-alpha, Disease Progression, Surgical, Gastroesophageal Reflux, Gastroesophageal Reflux Disease, Enzyme Linked Immunosorbent Assay, Interleukin, Experimental Model, and Surgical Treatment
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Research Interests: Mass Spectrometry, Multidisciplinary, Hypothalamus, Animals, Affinity chromatography, and 11 moreHigh Pressure Liquid Chromatography, Cattle, Gas Chromatography/mass Spectrometry, Multienzyme complexes, Molecular weight, Retention Time, Hydrolysis, Molecular Structure, Ouabain, Isomerism, and Acid hydrolysis
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... metastable structures through artificial elastic boundary conditions (misfit strain) and/or rate-limited kinetics.18 However, a recent attempt to grow tin titanate films on sapphire and perovskite substrates from ceramic SnO2 and TiO2... more
... metastable structures through artificial elastic boundary conditions (misfit strain) and/or rate-limited kinetics.18 However, a recent attempt to grow tin titanate films on sapphire and perovskite substrates from ceramic SnO2 and TiO2 targets utilizing pulsed laser deposition (PLD ...
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... PHYSICAL REVIEW A 66, 053406 2002 Chaotic scattering from hydrogen atoms in a circularly polarized laser field Elias Okon, William Parker, Will Chism, and Linda E. Reichl Center for Studies in Statistical ... 10 A. Patel, M.... more
... PHYSICAL REVIEW A 66, 053406 2002 Chaotic scattering from hydrogen atoms in a circularly polarized laser field Elias Okon, William Parker, Will Chism, and Linda E. Reichl Center for Studies in Statistical ... 10 A. Patel, M. Protopapas, DG Lappas, and PL Knight, Phys. ...
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... John A. Secrist III,* William B. Parker, Kamal N. Tiwari, Lea Messini, Sue C. Shaddix, Lucy M. Rose, L. Lee Bennett, Jr., and John A ... We therefore set out to prepare a series of... more
... John A. Secrist III,* William B. Parker, Kamal N. Tiwari, Lea Messini, Sue C. Shaddix, Lucy M. Rose, L. Lee Bennett, Jr., and John A ... We therefore set out to prepare a series of 4'-thionucleosides as potential anticancer agents utilizing our current knowledge of desirable bases and ...
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A selective metalation at the 6-CH3 over C-8 of 6-methylpurine derivative 6 was observed with softer counter cation (Na+ or K+) of the base, while the harder Li+ showed no selectivity. In the presence of N-fluorobenzenesulfonamide (NFSI),... more
A selective metalation at the 6-CH3 over C-8 of 6-methylpurine derivative 6 was observed with softer counter cation (Na+ or K+) of the base, while the harder Li+ showed no selectivity. In the presence of N-fluorobenzenesulfonamide (NFSI), this property was utilized for the synthesis of 6-fluoromethylpurine derivatives 4 and 5 as potential toxins for suicide gene therapy.
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A novel series of 6-methylpurine nucleoside derivatives with substitutions at 5-position have been synthesised These compounds bear a 5'-heterocycle such as triazole or a imidazole with a two carbon chain, and an ether, thio ether... more
A novel series of 6-methylpurine nucleoside derivatives with substitutions at 5-position have been synthesised These compounds bear a 5'-heterocycle such as triazole or a imidazole with a two carbon chain, and an ether, thio ether or amine. To extend the SAR study of 2-fluoroadenine and 6-methyl purine nucleosides, their corresponding alpha-linker nucleosides with L-xylose and L-lyxose were also synthesized. All of these compounds have been evaluated for their substrate activity with E. coli PNP.
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As part of an ongoing program to develop novel antitumor agents over the years, we have synthesized and evaluated a number of... more
As part of an ongoing program to develop novel antitumor agents over the years, we have synthesized and evaluated a number of 4'-C-substituted nucleosides. A few years ago, we reported the first synthesis of 4'-C-hydroxymethyl-2'-fluoro arabino nucleosides, which did not exhibit any cytotoxicity. In our exploration of related compounds, we synthesized and evaluated the 4'-C-methyl-2'-fluoro arabino nucleosides in both the purine and pyrimidine series. In the pyrimidine series, 1-(4-C-methyl-2-fluoro-beta-D-arabinofuranosyl) cytosine (13) was found to be highly cytotoxic and had significant antitumor activity in mice implanted with human tumor xenografts. The synthesis and anticancer activity of this series of nucleosides are reported.
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Metalation of 6-methyl-9-(tetrahydro-2H-pyran-2-yl)purine (10) with lithiating agents of varying basicities such as n-BuLi and LiHMDS in THF at -78 degrees C resulted in metalation at both of the 6-CH(3) moiety and the 8-CH position,... more
Metalation of 6-methyl-9-(tetrahydro-2H-pyran-2-yl)purine (10) with lithiating agents of varying basicities such as n-BuLi and LiHMDS in THF at -78 degrees C resulted in metalation at both of the 6-CH(3) moiety and the 8-CH position, irrespective of the molar equivalence of the base. On the other hand, a regioselective metalation at the 6-CH(3) moiety of 10 was observed with NaHMDS or KHMDS, under similar conditions. Treatment of the potassium salts of 10 and of the protected riboside derivative 6-methyl-9-(beta-D-2,3,5-tri-O-tert-butyldimethylsilylribofuranosyl)purine (22) with N-fluorobenzenesulfonamide (NFSI) at -78 degrees C gave the corresponding 6-fluoromethylpurine derivatives 11 and 23, respectively, in good yields. Deprotection of 11 and 23 under standard conditions gave 6-fluoromethylpurine (6-FMeP, 3) and 6-fluoromethyl-9-(beta-D-ribofuranosyl)purine (6-FMePR, 4), respectively, in high yield. Both 3 and 4 demonstrated cytotoxic activity against CCRF-CEM cells in culture. 6-FMePR is a good substrate for E. coli purine nucleoside phosphorylase (E. coli PNP) with a comparable substrate activity to that of the parent nucleoside, 6-methyl-9-(beta-D-ribofuranosyl)purine (6-MePR, 21). The cytotoxic activity of 6-FMeP along with the substrate activity of 6-FMePR with E. coli PNP meet the fundamental requirements for using 6-FMeP as a potential toxin in PNP/prodrug based cancer gene therapy.
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Cancer gene therapy using suicide genes has shown great potential in tumor models. To improve efficacy, recent attention has focused on the use of oncolytic vectors. To date this strategy has not resulted in vectors with anti-tumor... more
Cancer gene therapy using suicide genes has shown great potential in tumor models. To improve efficacy, recent attention has focused on the use of oncolytic vectors. To date this strategy has not resulted in vectors with anti-tumor activities sufficiently potent to sustain complete ...
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Research Interests: Pharmacology, Clinical Trial, Measles Virus, Biological Sciences, Molecular, and 15 moreCercopithecus aethiops, Cell line, Prodrugs, Mice, Animals, Immunosuppression, Bystander Effect, Gene Targeting, Murine Model, Cyclophosphamide, Molecular Targeted Therapy, Neutralizing antibodies, Measles, Immunocompetence, and Purine Nucleoside Phosphorylase
Nucleoside anticancer drugs like gemcitabine... more
Nucleoside anticancer drugs like gemcitabine (2'-deoxy-2',2'-difluorocytidine) are potent inducers of p53, and ectopic expression of wild-type p53 sensitizes cells to these agents. However, it is also known that nucleosides are efficient activators of apoptosis in tumor cells that do not express a functional p53. To clarify this issue, we examined the effects of gemcitabine and 4'-thio-beta-d-arabinofuranosylcytosine (T-ara-C) on p73, a structural and functional homologue of p53, whose activation could also account for nucleoside-induced apoptosis because no functionally significant mutations of p73 have been reported in cancers. Acute treatment of HCT 116 colon carcinoma cells with gemcitabine or T-ara-C induced marked cytotoxicity and cleavage of caspase-3 and poly(ADP-ribose) polymerase. T-ara-C and gemcitabine markedly induced p53 accumulation as well as increased levels of phospho-p53 (Ser15/Ser20/Ser46) and induced its binding to a consensus p53 response element. Despite robust activation of p53 by T-ara-C and gemcitabine, we found that wild-type and p53-/- HCT 116 cells exhibited almost equivalent sensitivity towards these nucleosides. Examination of p73 revealed that T-ara-C and gemcitabine markedly increased p73 protein levels and p73 DNA-binding activities in both p53-/- and wild-type cells. Furthermore, T-ara-C- and gemcitabine-induced increases in p73 levels occur due to a decrease in p73 protein turnover. RNA interference studies show that nucleoside-induced p73 increases are independent of c-Abl, a nucleoside-activated kinase recently implicated in p73 stabilization. HCT 116 lines, wherein the downstream p53/p73 targets Bax and PUMA (p53 up-regulated modulator of apoptosis) were deleted, were less sensitive to T-ara-C and gemcitabine. Together, these studies indicate that c-Abl-independent p73 stabilization pathways could account for the p53-independent mechanisms in nucleoside-induced apoptosis.
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4&am... more
4'-Thio-beta-D-arabinofuranosylcytosine (T-araC), a new-generation deoxycytidine nucleoside analogue, showed significant efficacy against numerous solid tumors in preclinical studies and entered clinical development for cancer therapy. It is a structural analogue of cytarabine (araC), a clinically used drug in the treatment of acute myelogenous leukemia, which has no or very limited efficacy against solid tumors. In comparison with araC, the excellent in vivo activity of T-araC against solid tumors suggests that, in addition to inhibition of DNA synthesis, T-araC may target cellular signaling pathways, such as angiogenesis, in solid tumors. We studied T-araC and araC for their antiangiogenic activities in vitro and in vivo. Both compounds inhibited human endothelial cell proliferation with similar IC50s. However, only T-araC inhibited endothelial cell migration and differentiation into capillary tubules. T-araC also abrogated endothelial cell extracellular signal-regulated kinase (ERK) 1/2 phosphorylation, a key signaling molecule involved in cellular processes of angiogenesis. Results from chick chorioallantoic membrane angiogenesis assays revealed that T-araC significantly inhibited the development of new blood vessels in vivo, whereas araC showed much less effect. The findings of this study show a role of T-araC in antiangiogenesis and suggest that T-araC combines antiproliferative and antiangiogenic activity in one molecule for a dual mechanism of drug action to achieve the excellent in vivo efficacy against several solid tumors. This study also provides important information for optimizing dosage and sequence of T-araC administration in clinical investigations by considering T-araC as both an antiproliferative and an antiangiogenic agent.
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Survivorship analysis was used to extract unbiased (censorship-corrected) estimates of the species longevity distribution of the Cenozoic planktic Foraminifera. These estimated distributions provide the basis for monte carlo simulations... more
Survivorship analysis was used to extract unbiased (censorship-corrected) estimates of the species longevity distribution of the Cenozoic planktic Foraminifera. These estimated distributions provide the basis for monte carlo simulations of the post-Cretaceous recovery in the group. Using ...
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Emerging clinical evidence suggests that gastroesophageal reflux disease is associated with pulmonary allograft dysfunction. In this study, we used a model of rat lung transplantation to test the hypothesis that chronic aspiration of... more
Emerging clinical evidence suggests that gastroesophageal reflux disease is associated with pulmonary allograft dysfunction. In this study, we used a model of rat lung transplantation to test the hypothesis that chronic aspiration of gastric contents accelerates pulmonary allograft dysfunction. We evaluated the effects of chronic aspiration on pulmonary isografts (strain F344) and pulmonary allografts (strain WKY to strain F344). Chronic aspiration consisted of 0.5 mL/kg of filtered gastric contents injected weekly into the left lung for 4 to 8 weeks beginning 1 week after transplantation. Seven days after the last aspiration, animals were killed, and grafts were evaluated grossly and by histologic and immunochemical analyses, including Masson trichrome staining for collagen and immunostaining for CD68+ and CD8+ cells. Serum cytokine concentrations were determined by bead-based immunoassays or enzyme-linked immunosorbent assay. Allografts without aspiration (n = 12) demonstrated a relatively normal architecture with diffuse International Society for Heart and Lung Transplantation grade 3 acute rejection; occasional grade 4 rejection was noted. In contrast, allografts with chronic aspiration (n = 7) demonstrated severe grade 4 acute rejection with significant monocyte infiltration, fibrosis, and loss of normal alveolar anatomy. Grossly, 8 (67%) of 12 allografts without aspiration seemed to inflate and perfuse normally, whereas all allografts exposed to chronic aspiration were firm and shrunken, without the ability to ventilate (P = .013; Fisher exact test). Aspiration was associated with increases in graft-infiltrating macrophages and CD8+ T cells and higher levels of serum transforming growth factor beta. Chronic aspiration of gastric contents promotes accelerated allograft failure and may promote a profibrotic environment.
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Research Interests: Biofilms, Breast Cancer, Biological Sciences, Bioreactor, Humans, and 15 moreIntestinal Mucosa, Female, Animals, Bacteria, Comparative Analysis, Adult, Bacterial growth, Genetic Instability, Immune function, Commensal, Genetic Susceptibility, Appendix, Driving force, Immunoglobulin A, and Breast Neoplasms
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Research Interests: Papio, Animals, Lung Diseases, Clinical Sciences, Kidney Transplant, and 13 moreTime Factors, Swine, Blood Flow, Study design, Graft Rejection, Ct Image of Pulmonary Artery, Heart and Lung Transplantation, transplantation Immunology, The American, Pulmonary Artery, Lung Transplantation, Experimental Group, and immunoglobulin M
Swine contain large numbers of pulmonary intravascular macrophages (PIMs) that mediate the physiological response observed in acute lung injury (ALI). As the hyperacute dysfunction observed in pulmonary xenotransplantation is similar to... more
Swine contain large numbers of pulmonary intravascular macrophages (PIMs) that mediate the physiological response observed in acute lung injury (ALI). As the hyperacute dysfunction observed in pulmonary xenotransplantation is similar to endotoxin-induced ALI, PIMs may play a critical role in pulmonary xenograft dysfunction. We used liposomal clodronate to eliminate the PIM population in a model of acute swine lung injury. Experimental swine (n = 6) received liposomal clodronate (1.25 g/10 kg) and control swine (n = 5) received saline containing liposomes before infusion of lipopolysaccharide (450 ng/kg). Control swine demonstrated higher peak pulmonary artery pressures (41.8 +/- 2.2 versus 16.8 +/- 1.2 mm Hg; P < 0.0001) and higher peak pulmonary vascular resistances (1405 +/- 209 versus 353 +/- 81 dynes. s. cm(-5); P = 0.0016) in response to lipopolysaccharide infusion. Clodronate treated swine also had significantly lower serum levels of tumor necrosis factor-alpha, interleukin-6, and thrombin. Liposomal clodronate effectively attenuates acute swine lung injury induced by endotoxin. This method of depletion of the PIM population presents a promising new treatment of swine lungs before xenotransplantation.
Research Interests: Cytokines, Lipopolysaccharide, Thrombin, Humans, Animals, and 15 moreLung Diseases, Liposomes, Acute Lung Injury, Physiological Response, Clinical Sciences, Lipopolysaccharides, Swine, Tumor necrosis factor-alpha, Lung Injury, Surgical, Tumor Necrosis Factor–α (TNF), Heart and Lung Transplantation, Vascular Resistance, Acute Disease, and Lung Transplantation
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Four new tetragalloylquinic acids, 3,5-di-O-galloyl-4-O-digalloylquinic acid, 3,4-di-O-galloyl-5-O-digalloylquinic acid, 3-O-digalloyl-4,5-di-O-galloylquinic acid, and 1,3,4,5-tetra-O-galloylquinic acid, were isolated and characterized... more
Four new tetragalloylquinic acids, 3,5-di-O-galloyl-4-O-digalloylquinic acid, 3,4-di-O-galloyl-5-O-digalloylquinic acid, 3-O-digalloyl-4,5-di-O-galloylquinic acid, and 1,3,4,5-tetra-O-galloylquinic acid, were isolated and characterized from a commercial tannic acid as a new class of human immunodeficiency virus (HIV) reverse transcriptase (RT) inhibitor. Compounds 2, 3, and 4 inhibit HIV RT activity 90, 89, and 84% at 100 microM and 73, 70, and 63% at 30 microM, respectively. Compounds 2-5 also inhibit the HIV growth in cells in the range of 61-70% with low cytotoxicity at 25 microM. The HIV cell growth inhibitory effects of these compounds at 25 microM and 6.25 microM (44-57%) are comparable to their effects against the HIV RT at 30 microM and 10 microM, respectively. The inhibitory effect of 3 against DNA polymerases indicates that the selective antiviral action of 3 is determined by more than its action with HIV RT.
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A common reason for the lack of cytotoxicity of certain nucleosides is thought to be their inability to be initially activated to the monophosphate level by a nucleoside kinase or other activating enzyme. In a search for other nucleosides... more
A common reason for the lack of cytotoxicity of certain nucleosides is thought to be their inability to be initially activated to the monophosphate level by a nucleoside kinase or other activating enzyme. In a search for other nucleosides that might be worthwhile anticancer agents, we have begun to examine the utilization of monophosphate prodrugs in order to explore whether any enhanced cytotoxicity might be found for the prodrugs of candidate nucleosides that have little or no cytotoxicity. To that end, 5'-bis(pivaloyloxymethyl) phosphate prodrugs of two weakly cytotoxic compounds, 8-aza-2'-deoxyadenosine (5) and 8-bromo-2'-deoxyadenosine (9), have been prepared. These prodrugs (8 and 12) were examined for their cytotoxicity in CEM cells and were found to possess significantly enhanced cytotoxicity when compared with the corresponding parent nucleosides. Further cell culture experiments were conducted to gain insight into the mechanisms of cytotoxicity of these two prodrugs, and those data are reported.