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Biomedical subjects

C Carter

Publications and source records attributed to C Carter.

At least 19 recordsLinked to original sources
PubMed2007

Antitumor activity of sorafenib in FLT3-driven leukemic cells.

Activating internal tandem duplication (ITD) insertions in the juxtamembrane domain of the FLT3 tyrosine kinase are found in about one fourth of patients with acute myeloid leukemia and have been shown to be an independent negative prognostic factor for survival. We show that sorafenib (BAY 43-9006, Nexavar) potently inhibits FLT3 enzymatic and signaling activities. In HEK293 cells stably transfected with FLT3-WT or FLT3-ITD, sorafenib blocked basal and ligand dependent FLT3-mediated tyrosine autophosphorylation as well as extracellular signal-regulated kinase1/2 and Stat5 phosphorylation. In leukemia cell lines MV4-11 and EOL-1, sorafenib treatment resulted in decreased cell proliferation and inhibition of FLT3 signaling. The growth of the FLT3-independent RS4-11 cell line was only weakly inhibited by sorafenib. Cell cycle arrest and induction of apoptosis were observed upon treatment with sorafenib in MV4-11 and EOL-1 cells. The antitumor efficacy of sorafenib was evaluated against the MV4-11 leukemia grown subcutaneously in NCr nu/nu mice. Doses of 3 and 10 mg/kg administered orally for 14 days resulted in six and nine out of 10 animals with complete responses, respectively. The demonstration that sorafenib exhibits potent target inhibition and efficacy in FLT3-driven models suggests that this compound may have a therapeutic benefit for patients with FLT3-driven leukemias.

Animals↗
PubMed2004

SL25.1131 [3(S),3a(S)-3-methoxymethyl-7-[4,4,4-trifluorobutoxy]-3,3a,4,5-tetrahydro-1,3-oxazolo[3,4-a]quinolin-1-one], a new, reversible, and mixed inhibitor of monoamine oxidase-A and monoamine oxidase-B: biochemical and behavioral profile.

SL25.1131 [3(S),3a(S)-3-methoxymethyl-7-[4,4,4-trifluorobutoxy]-3,3a,4,5-tetrahydro-1,3-oxazolo[3,4-a]quinolin-1-one] is a new, nonselective, and reversible monoamine oxidase (MAO) inhibitor, belonging to a oxazoloquinolinone series. In vitro studies showed that SL25.1131 inhibits rat brain MAO-A and MAO-B with IC50 values of 6.7 and 16.8 nM and substrate-dependent Ki values of 3.3 and 4.2 nM, respectively. In ex vivo conditions, the oral administration of SL25.1131 induced a dose-dependent inhibition of MAO-A and MAO-B activities in the rat brain with ED50 values of 0.67 and 0.52 mg/kg, respectively. In the rat brain, duodenum, and liver, the inhibition of MAO-A and MAO-B by SL25.1131 (3.5 mg/kg p.o.) was reversible, and the recovery of MAO-A and MAO-B activities was complete 16 h after administration. SL25.1131 (3.5 mg/kg p.o.) increased tissue levels of dopamine (DA), norepinephrine, and 5-hydroxytryptamine and decreased levels of their deaminated metabolites 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindolacetic acid. In mice, SL25.1131 induced a dose-dependent potentiation of 5-hydroxytryptophan-induced tremors and phenylethylamine-induced stereotypies with ED50 values of 0.60 and 2.8 mg/kg p.o., respectively. SL25.1131 was able to reestablish normal striatal dopaminergic tone and locomotor activity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mice. In addition, when coadministered with L-DOPA, SL25.1131 increased the available DA in the striatum and the duration of L-DOPA-induced hyperactivity. The duration of the effect of L-DOPA on circling behavior in 6-hydroxydopamine-lesioned rats was also increased. The neurochemical profile of SL25.1131 demonstrates that this compound is a mixed, potent, and reversible MAO-A/B inhibitor in vitro, in vivo, and ex vivo. SL25.1131 has therapeutic potential as a symptomatic treatment during the early phase of Parkinson's disease and as an adjunct to L-DOPA therapy during the early and late phases of the disease.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2003

Cyclosporine is required to prevent severe acute GVHD following T-cell-depleted peripheral blood stem cell transplantation.

Reduced immunosuppression may improve immune recovery and increase the graft-versus-leukemia effect after allogeneic stem cell transplantation. Furthermore, the requirement for post-transplant immunosuppression following extensive T-cell depletion remains unclear. We therefore evaluated the role of cyclosporine (CSA) in recipients of HLA-identical T-cell-depleted peripheral blood stem cell transplants (PBSCT), followed by donor lymphocyte infusions (DLIs) scheduled on days +45 and +100. Before day+45, successive cohorts of patients received decreasing amounts of CSA: standard-dose (SD) CSA, low-dose (LD) CSA, or no CSA until day+45. LD CSA was as effective as SD CSA in preventing acute graft-versus-host disease (GVHD). However, moderate-to-severe acute GVHD was significantly more frequent before the day +45 DLI in patients receiving no CSA (33.3 vs 12.7%, P=0.036, including the only four grade III-IV cases). As a result of higher rates of early acute GVHD, more patients in the 'no CSA' group failed to receive any DLI (30.7 vs 7.1%, P=0.01). Overall, there was no difference in the incidence of acute GVHD, as patients receiving CSA developed more GVHD after DLI. Similarly, no significant differences were found in chronic GVHD, transplant-related mortality, or survival. These results define a role for CSA in preventing GVHD at low T-cell doses following PBSCT.

Acute Disease↗
PubMed2003

Cognition in pregnancy and the first year post-partum.

A longitudinal study measured the performance of a group of 15 pregnant women on tests of verbal memory, divided attention, and focused attention on four occasions (second trimester, third trimester, 6 weeks post-partum, and 1 year post-partum) while at the same time obtaining self-assessment ratings of these cognitive functions. A group of 14 non-pregnant women was studied at equivalent intervals. The two groups of women did not differ in performance on the objective tests, and there was no change in performance over time except for an improvement in the measure of focused attention from the first to the final testing occasion. However, the self-assessment ratings showed that in the second trimester, the pregnant women rated themselves as more impaired than before compared with the non-pregnant women for all three cognitive abilities. To ensure that this difference was not due to the retrospective nature of the comparison of current with previous cognitive ability, a second longitudinal study compared 25 pregnant and 10 non-pregnant women using daily ratings over a period of 1 week on four occasions during pregnancy and the first year post-partum. Women in the third trimester of pregnancy reported mild impairments in their focused and divided attention ability and their ability to remember what they had read compared with the non-pregnant women. The results show that there are perceived cognitive impairments during pregnancy. It is suggested that these may be the result of mild impairments which are not revealed in objective tests because they can be overcome by conscious effort in short periods of testing. Alternatively, the perceptions may not be based on actual impairments but may result from depressed mood or expectations concerning the effect of pregnancy on cognition.

Adult↗
PubMed2001

Proteins related to the Nedd4 family of ubiquitin protein ligases interact with the L domain of Rous sarcoma virus and are required for gag budding from cells.

The late assembly (L) domain of retrovirus Gag, required in the final steps of budding for efficient exit from the host cell, is thought to mediate its function through interaction with unknown cellular factors. Here, we report the identification of the Nedd4-like family of E3 ubiquitin protein ligases as proteins that specifically interact with the Rous sarcoma virus (RSV) L domain in vitro and in vivo. We screened a chicken embryo cDNA expression library by using a peptide derived from the RSV p2b sequence, isolating two unique partial cDNA clones. Neither clone interacted with a peptide containing mutations known to disrupt in vivo RSV L domain function or with human immunodeficiency virus type 1 (HIV-1) and equine infectious anemia virus (EIAV) L domain-derived peptides. The WW domain region of one of the clones, late domain-interacting protein 1 (LDI-1), but not the C2 domain, bound RSV Gag and inhibited RSV Gag budding from human 293 cells in a dominant-negative manner, functionally implicating LDI-1 in RSV particle budding from cells. RSV Gag can be coimmune precipitated from cell extracts with an antisera directed at an exogenously expressed hemagglutinin (HA)-tagged LDI-1 or endogenous Nedd4 proteins. These findings mechanistically link the cellular ubiquitination pathway to retrovirus budding.

Animals↗
PubMed2001

Recognition of E-cadherin by integrin alpha(E)beta(7): requirement for cadherin dimerization and implications for cadherin and integrin function.

We have investigated the importance of dimerization of E-cadherin in the heterophilic adhesive interaction between E-cadherin and integrin alpha(E)beta(7). Dimerization of cadherin molecules in parallel alignment is known to be essential for homophilic adhesion and has been attributed to Ca(2+)-dependent interactions in the domain 1-2 junction or to cross-intercalation of Trp2 from one molecule to the other. We have disrupted either or both of these proposed mechanisms by point mutations in E-cadherin-Fc and have tested the modified proteins for alpha(E)beta(7)-mediated cell adhesion. Prevention of Trp2 intercalation had no adverse effect on integrin-mediated adhesion, whereas disruption of Ca(2+) binding permitted adhesion but with reduced efficiency. Both modifications in combination abolished recognition by alpha(E)beta(7). In EGTA, alpha(E)beta(7) adhered to wild type E-cadherin but not to the Trp2 deletion mutant. Independent evidence that the mutations prevented either or both mechanisms for dimerization is presented. The data show that dimerization is required for recognition by alpha(E)beta(7) and that it can take place by either of two mechanisms. Implications for the roles of the alpha(E) and beta(7) integrin subunits in ligand binding and for Trp2 and Ca(2+) in the assembly of cadherin complexes are discussed.

Animals↗
PubMed2001

Role of the major homology region in assembly of HIV-1 Gag.

The major homology region (MHR) is a highly conserved sequence in the gag gene of all retroviruses, including HIV-1. Its role in assembly is unknown, but deletion of the motif significantly impairs membrane binding and viral particle formation. To begin characterizing this defect, we have determined the contribution of this region to the energetics of the assembly process. Intrinsic fluorescence studies were conducted to determine the change in free energy associated with membrane and RNA binding using tRNA and large unilamellar vesicles of 1-palmitoyl-2-oleoylphosphatidylserine as models. For the wild-type protein, the change in free energy was within RT [600 cal/(mol.K)] whether Gag binds first to RNA or to the membrane. Thus, the initial binding of Gag can be to either substrate, but in vivo conditions favor initial association to RNA presumably due to its higher local concentration. After establishing the pattern of assembly, we compared the binding energy of Gag(WT) versus the deletion mutant, Gag(Delta)(MHR). Gag(WT) bound to membranes with a 2-fold higher affinity than Gag(Delta)(MHR), and the binding to RNA was similar for the two proteins. Gag prebound to RNA or to membrane exhibited approximately 2-4-fold greater binding affinity than Gag(Delta)(MHR) for binding the membrane or RNA, respectively. Most importantly, the mutant was significantly impaired in its ability to self-associate on RNA or on membrane surfaces. This key role of the MHR in promoting productive protein-protein interactions was also seen in altered amounts of cleavage products and the lack of membrane-bound, RNA-containing replication intermediates in infected cells. These results suggest that Gag first binds to RNA and then assembles into a multimeric complex with a large membrane-binding face that facilitates subsequent membrane binding. Deletion of the MHR disrupts the protein-protein interactions required to complete this process.

Amino Acid Motifs↗
PubMed2001

Structural analysis of the N-terminal domain of the human T-cell leukemia virus capsid protein.

The N-terminal domain of the retroviral capsid (CA) protein is one of the least conserved regions encoded in the genome. Surprisingly, the three-dimensional structures of the CA from different genera exhibit alpha-helical structural features that are highly conserved. The N-terminal residues of the human immunodeficiency virus type 1 (HIV-1) and Rous sarcoma virus (RSV) capsid proteins form a beta-hairpin. To determine if this feature is conserved in the retroviral family, we cloned, expressed, purified, and solved the structure of a N-terminal 134 amino acid fragment (CA(134)) from the human T-cell leukemia virus type 1 (HTLV-I) using high resolution nuclear magnetic resonance (NMR) spectroscopy. The CA(134) fragment contains an N-terminal beta-hairpin and a central coiled-coil-like structure composed of six alpha-helices. The N-terminal Pro1 residue contacts Asp54 in the helical cluster through a salt bridge. Thus, the beta-hairpin is conserved and the helical cluster is structurally similar to other retroviral CA domains. However, although the same Asp residue defines the orientation of the hairpin in both the HTLV-1 and HIV-1 CA proteins, the HTLV-I hairpin is oriented away, rather than towards, the helical core. Significant differences were also detected in the spatial orientation and helical content of the long centrally located loop connecting the helices in the core. It has been proposed that the salt bridge allows the formation of a CA-CA interface that is important for the assembly of the conical cores that are characteristic of HIV-1. As HTLV-I forms spherical cores, the salt-bridge feature is apparently not conserved for this function although its role in determining the orientation of the beta-hairpin may be critical, along with the central loop. Comparison of three-dimensional structures is expected to elucidate the relationships between the retroviral capsid protein structure and its function.

Amino Acid Sequence↗
PubMed2001

Adenoviral delivery of osteoprotegerin ameliorates bone resorption in a mouse ovariectomy model of osteoporosis.

Osteoprotegerin (OPG) regulates bone resorption by inhibiting osteoclast formation, function, and survival. The current studies employed a mouse ovariectomy (OVX) model of estrogen deficiency to investigate gene therapy with OPG as a means of preventing osteoporosis. Young adult females injected with a recombinant adenoviral (Ad) vector carrying cDNA of either full-length OPG or a fusion protein combining the hOPG ligand-binding domain with the human immunoglobulin constant domain (Ad-hOPG-Fc) developed serum OPG concentrations exceeding the threshold needed for efficacy. However, elevated circulating OPG levels were sustained for up to 18 months only in mice given Ad-hOPG-Fc. Administration of Ad-hOPG-Fc titers between 10(7) and 10(9) pfu yielded dose-dependent increases in serum OPG. Mice subjected to OVX or sham surgery followed by immediate treatment with Ad-hOPG-Fc had significantly more bone volume with reduced osteoclast numbers in axial and appendicular bones after 4 weeks. In contrast, animals given OVX and either a control vector or vehicle had significantly less bone than did comparably treated sham-operated mice. This study demonstrates that a single adenoviral gene transfer can produce persistent high-level OPG expression and shows that gene therapy to provide sustained delivery of OPG may prove useful in treating osteoporosis.

Adenoviridae↗
PubMed2001

Effects of mammographic density and benign breast disease on breast cancer risk (United States).

BACKGROUND: Having either a history of benign breast disease, particularly atypical hyperplasia or extensive mammographic breast density, is associated with increased breast cancer risk. Previous studies have described an association between benign breast disease histology and breast density. However, whether these features measure the same risk, or are independent risk factors, has not been addressed. METHODS: This case-control study, nested within the prospective follow-up of the Breast Cancer Detection Demonstration Project, evaluated both benign histologic and mammographic density information from 347 women who later developed breast cancer and 410 age- and race-matched controls without breast cancer. Multivariate logistic regression analyses provided maximum-likelihood estimates of the odds ratios (OR) and 95% confidence intervals (CI) to evaluate the relative risk of breast cancer associated with each exposure. RESULTS: Adjusting for mammographic density, the OR for atypical hyperplasia was 2.1 (95% CI: 1.3-3.6), and adjusting for benign breast histology, the OR for > or = 75% density was 3.8 (95% CI: 2.0-7.2). Women with nonproliferative benign breast disease and > or = 75% density had an OR of 5.8 (95% CI: 1.8-18.6), and women with < 50% density and atypical hyperplasia had an OR of 4.1 (95% CI: 2.1-8.0). CONCLUSIONS: In this study, both benign breast disease histology and the percentage of the breast area with mammographic density were associated with breast cancer risk. However, women with both proliferative benign breast disease and > or = 75% density were not at as high a risk of breast cancer due to the combination of effects (p = 0.002) as women with only one of these factors.

Adult↗
PubMed2001

Dendritic cells signal T cells in the absence of exogenous antigen.

Interactions with self-major histocompatibility complex molecules on dendritic cells (DCs) are important for the survival of mature CD4+ T cells. We have followed the DC-mediated signal from the T cell surface to the nucleus and identified a pattern of activation that correlates with increased in vitro survival. This response is induced exclusively by DCs and is likely associated with a modulation of the T cell activation threshold. We have also found that DC-mediated activation results in antigen-independent cytokine gene expression, which points to a new role for DCs in shaping the cytokine milieu. Such antigen-independent activation of T cells may play a role in protective immunity, but may also induce and perpetuate autoimmune states such as multiple sclerosis.

Antigens↗
PubMed2001

Studies on transcriptional regulation of the mucosal T-cell integrin alphaEbeta7 (CD103).

Integrin alphaEbeta7 is expressed almost exclusively by mucosal T cells and mucosal dendritic antigen-presenting cells (APCs) and is thought to be induced locally by transforming growth factor-beta (TGF-beta). In mice, mRNA for the alphaE subunit was found to be abundant in mucosal T cells but absent from other tissues. Exposure of a T-cell line to TGF-beta strongly up-regulated alphaE mRNA levels within 30 min, and nuclear run-on experiments established that regulation occurred at the level of transcription. The organization of the human alphaE gene and a very closely linked novel gene, ELG, was determined. The alphaE promoter was tested in T cells and fibroblasts and functioned equally well in both cell types and did not confer TGF-beta responsiveness. Regions of the promoter providing enhancer activity and phorbol 12-myristate 13-acetate (PMA) responsiveness were identified by deletion studies. DNAse 1 hypersensitivity analysis of 36 kb of the alphaE gene revealed one hypersensitive site, found only in alphaE+ cells, located near the transcription start points. These results show that, unlike the situation with other integrins, lineage specificity and cytokine responsiveness of alphaE transcription are not conferred by the proximal promoter. Specificity may depend on distant control elements that have not yet been identified.

Animals↗
PubMed2001

The fascia iliaca block for postoperative pain relief after knee surgery.

The fascia iliaca nerve block provides excellent postoperative pain relief after knee surgery. It is easy to perform, needle insertion is not directly next to nerves or vessels, and it is associated with minimal side effects. Instructive case reports as well as a description and discussion of the technique are presented.

Journal Article↗
PubMed2001

Relative roles of vascular and airspace pressures in ventilator-induced lung injury.

OBJECTIVE: To determine whether elevations in pulmonary vascular pressure induced by mechanical ventilation are more injurious than elevations of pulmonary vascular pressure of similar magnitude occurring in the absence of mechanical ventilation. DESIGN: Prospective comparative laboratory investigation. SETTING: University research laboratory. SUBJECTS: Male New Zealand white rabbits. INTERVENTIONS: Three groups of isolated, perfused rabbit lungs were exposed to cyclic elevation of pulmonary artery pressures arising from either intermittent positive pressure mechanical ventilation or from pulsatile perfusion of lungs held motionless by continuous positive airway pressure. Peak, mean, and nadir pulmonary artery pressures and mean airway pressure were matched between groups (35, 27.4 +/- 0.74, and 20.8 +/- 1.5 mm Hg, and 17.7 +/- 0.22 cm H2O, respectively). MEASUREMENTS AND MAIN RESULTS: Lungs exposed to elevated pulmonary artery pressures attributable to intermittent positive pressure mechanical ventilation formed more edema (6.8 +/- 1.3 vs. 1.1 +/- 0.9 g/g of lung), displayed more perivascular (61 +/- 26 vs. 15 +/- 13 vessels) and alveolar hemorrhage (76 +/- 11% vs. 26 +/- 18% of alveoli), and underwent larger fractional declines in static compliance (88 +/- 4.4% vs. 48 +/- 25.1% decline) than lungs exposed to similar peak and mean pulmonary artery pressures in the absence of tidal positive pressure ventilation. CONCLUSIONS: Isolated phasic elevations of pulmonary artery pressure may cause less damage than those occurring during intermittent positive pressure mechanical ventilation, suggesting that cyclic changes in perivascular pressure surrounding extra-alveolar vessels may be important in the genesis of ventilator-induced lung injury.

Animals↗