Biomedical subjects

David A Jones

Publications and source records attributed to David A Jones.

At least 37 records · Page 2Linked to original sources

PubMed2005

Decreased T-cell receptor excision circles in cutaneous T-cell lymphoma.

PURPOSE: The T cell repertoire in patients with advanced cutaneous T cell lymphoma (CTCL) is significantly contracted despite the presence of relatively normal absolute numbers of T cells. We propose that many normal T cells were being lost in patients with CTCL, with the remaining normal T cells expanding clonally to fill the T cell compartment. T-cell receptor excision circles (TREC) form as a result of the initial gene rearrangement in naïve T cells. Although they are stable, they do not replicate and are subsequently diluted with the expansion of a population of T cells. Their concentration is therefore a measure of unexpanded naïve T cells relative to T cells that have undergone expansion. EXPERIMENTAL DESIGN: We analyzed TRECs from unfractionated peripheral blood T cells from 108 CTCL patients by quantitative PCR. In patients with obvious peripheral blood involvement, we also analyzed TRECs from clonal and nonclonal T cells. RESULTS: We found a decrease in the number of TRECs in peripheral blood of patients with CTCL at all stages of disease, and this decrease was proportional to the loss of complexity of the T cell repertoire as measured by complementarity-determining region 3 spectratyping. In patients with leukemic CTCL and a numerically expanded clone, we also found a significantly lower-than-expected number of TRECs in the nonclonal normal T cells. CONCLUSIONS: We hypothesize that the nonmalignant T cells have proliferated to fill the empty T cell repertoire space left by the loss of other T cells, leading to diminished TRECs and loss of T-cell receptor diversity.

Adult↗

PubMed2005

Differences in cell death induction by Phytophthora Elicitins are determined by signal components downstream of MAP kinase kinase in different species of Nicotiana and cultivars of Brassica rapa and Raphanus sativus.

Elicitins are small, secreted proteins produced by species of the plant-pathogenic oomycete Phytophthora. They induce hypersensitive cell death in most Nicotiana species and in some cultivars of Brassica rapa and Raphanus sativus. In this study, two true-breeding Fast Cycling B. rapa lines were established that showed severe necrosis (line 7-R) or no visible response (line 18-NR) after treatment with elicitin. Unexpectedly, microscopic examination revealed localized cell death in line 18-NR plants, and expression levels of various defense-marker genes were comparable in both lines. These results suggested that both "responsive" and "nonresponsive" plants responded to elicitin but differed in the extent of the cell death response. Expression of a constitutively active form of Arabidopsis (Arabidopsis thaliana) MAP kinase kinase 4 (AtMEK4(DD)) also induced rapid development of confluent cell death in line 7-R, whereas line 18-NR showed no visible cell death. Similarly, elicitin-responsive Nicotiana species and R. sativus cultivars showed significantly stronger cell death responses following expression of AtMEK4(DD) compared with nonresponsive species/cultivars. Line 7-R also showed higher sensitivity to toxin-containing culture filtrates produced by Alternaria brassicicola, and toxin sensitivity cosegregated with elicitin responsiveness, suggesting that the downstream responses induced by elicitin and Alternaria toxin share factors that control the extent of cell death. Interestingly, elicitin responsiveness was shown to correlate with greater susceptibility to A. brassicicola (a necrotroph) in B. rapa but less susceptibility to Phytophthora nicotianae (a hemibiotroph) in Nicotiana, suggesting a more extensive cell death response could cause opposite effects on the outcomes of biotrophic versus necrotrophic plant-pathogen interactions.

Algal Proteins↗

PubMed2005

The zebrafish retinol dehydrogenase, rdh1l, is essential for intestinal development and is regulated by the tumor suppressor adenomatous polyposis coli.

Retinoic acid (RA) is a potent signaling molecule that plays important roles in multiple and diverse developmental processes. The contribution of retinoic acid to promoting the development and differentiation of the vertebrate intestine and the factors that regulate RA production in the gut remain poorly defined. Herein, we report that the novel retinol dehydrogenase, rdh1l, is required for proper gut development and differentiation. rdh1l is expressed ubiquitously during early development but becomes restricted to the gut by 3 days postfertilization. Knockdown of rdh1l results in a robust RA-deficient phenotype including lack of intestinal differentiation, which can be rescued by the addition of exogenous retinoic acid. We report that adenomatous polyposis coli (APC) mutant zebrafish harbor an RA-deficient phenotype including aberrant intestinal differentiation and that these mutants can be rescued by treatment with retinoic acid or injection of rdh1l mRNA. Further, we have found that although APC mutants are deficient in rdh1l expression, they harbor increased expression of raldh2 suggesting the control of RA production by APC is via retinol dehydrogenase activity. These results provide genetic evidence that retinoic acid is required for vertebrate gut development and that the tumor suppressor APC controls the production of RA in the gut by regulating the expression of the retinol dehydrogenase, rdh1l.

Adenomatous Polyposis Coli Protein↗

PubMed2005

Evaluation of a 7-day continuous intravenous infusion of decitabine: inhibition of promoter-specific and global genomic DNA methylation.

PURPOSE: The nucleoside analog 5-aza-2'-deoxycytidine (5-aza-CdR, decitabine) is a potent inhibitor of DNA methylation in vitro. Cellular treatment with this agent induces the re-expression of methylation-silenced genes. It remains unclear to what extent this compound inhibits DNA methylation in vivo. A clinical study was designed to examine the molecular effects and toxicity of a continuous 1-week intravenous infusion of decitabine in solid tumor patients. METHODS: Ten patients with refractory solid tumors were included in this study. Decitabine was administered at 2 mg/m(2)/d [DOSAGE ERROR CORRECTED] via continuous infusion for 168 hours. Quantitative polymerase chain reaction and high performance liquid chromatography were utilized to measure promoter-specific and global DNA methylation in peripheral-blood cells before and after treatment. RESULTS: Transient grade III/IV neutropenia (two patients) and grade II thrombocytopenia (one patient) was observed at the lowest planned dose step (2 mg/m2/d for 7 days). Nonhematologic toxicities were not observed. Quantitative polymerase chain reaction demonstrated significant MAGE-1 promoter hypomethylation by 14 days after the start of treatment in all 13 treatment cycles examined. Significant genomic DNA hypomethylation was also seen by day 14 in 11 of 13 treatment cycles analyzed. Genomic DNA methylation reverted to baseline levels by 28 to 35 days after the start of treatment, demonstrating that inhibition of DNA methylation by decitabine is transient. CONCLUSION: A 168-hour continuous infusion of decitabine is well tolerated and results in the inhibition of promoter-specific and genomic DNA methylation in vivo. This treatment schedule is suitable for evaluation of decitabine in combination with agents whose activity may be enhanced by the reversal of DNA methylation-mediated gene silencing.

Aged↗

PubMed2005

The potential immunomodulatory effects of topical retinoids.

New research has refined our understanding of the immunopathophysiology of acne. Various immune factors, including both innate and adaptive immune responses, have been implicated in the pathophysiology of inflammatory acne. Topical retinoids such as tretinoin, adapalene, and tazarotene, exhibit immunomodulatory effects that may help to explain their efficacy in the resolution of inflammatory lesions.

Acne Vulgaris↗

PubMed2005

Influence of knee joint angle on muscle properties of paralyzed and nonparalyzed human knee extensors.

Muscles of individuals with a spinal cord injury (SCI) exhibit an unexpected leftward shift in the force (torque)-frequency relationship. We investigated whether differences in torque-angle relationships between SCI and able-bodied control muscles could explain this shift. Electrically stimulated knee-extensor contractions were obtained at knee flexion angles of between 30 degrees and 90 degrees. Torque-frequency relationships were obtained at 30 degrees, 90 degrees, and optimum angle. Optimum angle was not different between groups but SCI-normalized torques were lower at the extreme angles. At all angles, SCI muscles produced higher relative torques at low stimulation frequencies. Thus, there was no evidence of a consistent change in the length of paralyzed SCI muscles, and the anomalous leftward shift in the torque-frequency relationship was not the result of testing the muscle at a relatively long length. The results provide valuable information about muscle changes occurring in various neurological disorders.

Adult↗

PubMed2005

The effects of overhearing peers discuss an authority's fairness reputation on reactions to subsequent treatment.

Fairness heuristic theory was used to examine how information from one's peers affects an individual's interpretation of, and reactions to, an authority's subsequent behavior. Participants (N=105) overheard their peers discuss an experimenter's reputation (fair, unfair, or absent) before interacting with the experimenter who behaved more versus less fairly. Results showed that the social cues biased participants' subsequent information processing: controlling for the experimenter's behavior, interactional justice mediated the effect of social cues on retaliation. Social cues and the authority's behavior also interacted to predict retaliation. Participants who were treated less fairly retaliated more after being led to expect fair treatment than did participants who heard no prior information about the experimenter.

Adolescent↗

PubMed2005

Applicant attraction to organizations and job choice: a meta-analytic review of the correlates of recruiting outcomes.

Attracting high-performing applicants is a critical component of personnel selection and overall organizational success. In this study, the authors meta-analyzed 667 coefficients from 71 studies examining relationships between various predictors with job-organization attraction, job pursuit intentions, acceptance intentions, and job choice. The moderating effects of applicant gender, race, and applicant versus nonapplicant status were also examined. Results showed that applicant attraction outcomes were predicted by job-organization characteristics, recruiter behaviors, perceptions of the recruiting process, perceived fit, and hiring expectancies, but not recruiter demographics or perceived alternatives. Path analyses showed that applicant attitudes and intentions mediated the predictor-job choice relationships. The authors discuss the implications of these findings for recruiting theory, research, and practice.

Attitude↗

PubMed2005

Strength training: isometric training at a range of joint angles versus dynamic training.

Strength training with isometric contractions produces large but highly angle-specific adaptations. To contrast the contractile mode of isometric versus dynamic training, but diminish the strong angle specificity effect, we compared the strength gains produced by isometric training at four joint angles with conventional dynamic training. Thirty-three recreationally active healthy males aged 18 - 30 years completed 9 weeks of strength training of the quadriceps muscle group three times per week. An intra-individual design was adopted: one leg performed purely isometric training at each of four joint angles (isometrically trained leg); the other leg performed conventional dynamic training, lifting and lowering (dynamically trained leg). Both legs trained at similar relative loads for the same duration. The quadriceps strength of each leg was measured isometrically (at four angles) and isokinetically (at three velocities) pre and post training. After 9 weeks of training, the increase in isokinetic strength was similar in both legs (pooled data from three velocities: dynamically trained leg, 10.7%; isometrically trained leg, 10.5%). Isometric strength increases were significantly greater for the isometrically trained leg (pooled data from four angles: dynamically trained leg, 13.1%; isometrically trained leg, 18.0%). This may have been due to the greater absolute torque involved with isometric training or a residual angle specificity effect despite the isometric training being divided over four angles.

Adaptation, Physiological↗

PubMed2005

Membrane release and destabilization of Arabidopsis RIN4 following cleavage by Pseudomonas syringae AvrRpt2.

The Arabidopsis RIN4 protein mediates interaction between the Pseudomonas syringae type III effector proteins AvrB, AvrRpm1, and AvrRpt2 and the Arabidopsis disease-resistance proteins RPM1 and RPS2. Confocal laser-scanning fluorescence microscopy following particle bombardment of tobacco leaf epidermal cells was used to examine the subcellular localization of fusions between GFP and RIN4 or several of its homologs and to examine the effects of cobombardment with AvrRpt2 or AvrRpml. This study showed that RIN4 was attached to the plasma membrane at its carboxyl terminus and that a carboxyl-terminal CCCFxFxxx prenylation or acylation (typically palmitoylation) motif, or both, was essential for this attachment. RIN4 was cleaved by AvrRpt2 at two PxFGxW motifs, one releasing a large portion of RIN4 from the plasma membrane and both exposing amino-terminal residues that destabilized the carboxyl-terminal cleavage products by targeting them for N-end ubiquitylation and proteasomal degradation. Plasma-membrane localization of RIN4 was not affected by AvrRpml. RIN4 was found to be part of a protein family comprising two full-length homologs and at least 11 short carboxyl-terminal homologs. Representatives of this family, comprising a full-length RIN4 homolog and two short carboxyl-terminal RIN4 homologs, were also attached to the plasma membrane and cleaved near their amino termini by AvrRpt2, but in contrast to RIN4, the major portions of these proteins remained on the plasma membrane. N-end degradation may play a minor role in RIN4 degradation but probably plays a major role in the degradation of RIN4 homologs and is, therefore, a major pathogenic consequence of AvrRpt2 cleavage.

Amino Acid Sequence↗

PubMed2005

The effect of sweetness on the efficacy of carbohydrate supplementation during exercise in the heat.

The aim of the present study was to investigate potential mechanisms responsible for the improvement in prolonged exercise capacity in hot environments with exogenous carbohydrate. Eight endurance-trained men (VO(2)max 60.5 +/- 2.4 ml.kg(-1).min(-1), mean +/- SE) cycled to exhaustion on three occasions at 60% VO(2)max at an ambient temperature of 35 degrees C. They ingested either a sweet 6.4% carbohydrate solution (SC), a nonsweet 6.4% carbohydrate solution (NSC), or water (W). Exercise capacity was significantly increased with SC and NSC compared to W, the improvements corresponding to 15.8% and 11.8%, respectively. No difference in exercise capacity was seen between SC and NSC solutions. Plasma glucose concentrations were higher during the SC and NSC trials compared to W, significantly so at 10 min and at fatigue. Rates of carbohydrate oxidation were higher in the SC and NSC trials, although the rates never declined below 2.1 +/- 0.2 g.min(-1) in the W trial. There was no difference in the rate of rise of rectal temperature between trials, but there was a trend for subjects to fatigue at higher temperatures during the two carbohydrate trials. In conclusion, exogenous carbohydrate, independent of sweetness, improves exercise capacity in the heat compared to water alone.

Adult↗

PubMed2005

The effect of greater tuberosity placement on active range of motion after hemiarthroplasty for acute fractures of the proximal humerus.

Union of the greater tuberosity to the humeral shaft after hemiarthroplasty for acute fractures of the proximal humerus is a critical factor in the restoration of glenohumeral function. A retrospective review was undertaken to examine 23 consecutive patients who underwent hemiarthroplasty for the treatment of acute three- and four-part fractures of the proximal humerus. The study was conducted to examine the relationship between the position of the healed greater tuberosity and postoperative range of motion. The average age of the patients was 66.5 years. The average follow up was 3.8 years with a range of 24 to 108 months. Active range of motion was measured in forward elevation, external rotation, and internal rotation. Postoperative radiographs were examined to determine the position of the united greater tuberosity in relation to the top of the replaced humeral head. The tuberosity was fixed at an average of 15.4 mm below the top of the humeral head (range: 3 to 26 mm). A radiographic assessment of a control population of 50 normal proximal humeri demonstrated an average tuberosity position of 6.7 mm (range: 2 to 12 mm) below the superior aspect of the humeral head. Polynomial regression analysis demonstrated a polynomial relationship for active range of motion and tuberosity height. ANOVA testing demonstrated statistically significant differences in all ranges of motion. Active forward elevation for Group I (3 to 9 mm) was 88 degrees, Group 11 (10 to 16 mm) was 126 degrees, and Group III (17 to 26 mm) was 85 degrees (p = 0.04). Active external rotation for Group I was 19 degrees, Group II was 48 degrees, and Group III was 29 degrees (p = 0.01). Active internal rotation for Group I was to L2, Group II was to T10, and Group III was to L2 (p = 0.01). Although many factors affect the final ranges of motion in patients who undergo prosthetic replacement for acute proximal humeral fractures we believe that placement of the greater tuberosity 10 to 16 mm below the humeral head will assist in the maximum recovery of glenohumeral motion.

Adult↗

PubMed2005

Basic fibroblast growth factor treatment for skin ulcerations in scleroderma.

We report the use of topical application of recombinant human basic fibroblast growth factor (rhbFGF) to successfully treat therapy-resistant, chronic leg ulcers in scleroderma. Endothelial cell FGF receptors are directly stimulated by bFGF; also, bFGF promotes the regeneration of capillary-rich granulation tissue. We conclude that topical bFGF may be a powerful new pharmacologic tool for treating severe skin ulcers.

Administration, Cutaneous↗

PubMed2004

Expression profiles frame the promoter specificity dilemma of the ETS family of transcription factors.

Sequence-specific DNA binding proteins that function as transcription factors are frequently encoded by gene families. Such proteins display highly conserved DNA binding properties, yet are expected to retain promoter selectivity. In this report we investigate this problem using the ets gene family, a group of metazoan genes whose members regulate cell growth and differentiation and are mutated in human cancers. We tested whether the level of mRNA can serve as a specificity determinant. The mRNA levels of the 27 paralogous human ets genes were measured in 23 tissues and cell lines. Real-time RT-PCR provided accurate measurement of absolute mRNA levels for each gene down to one copy per cell. Surprisingly, at least 16 paralogs were expressed in each cell sample and over half were expressed ubiquitously. Tissues and complementary cell lines showed similar expression patterns, indicating that tissue complexity was not a limitation. There was no unique, highly expressed gene for each cell type. Instead, one of only eight ets genes showed the highest expression in all samples. DNA binding studies illustrate both overlapping and unique specificities for ubiquitous ETS proteins. These findings establish the parameters of the promoter specificity dilemma within the ets family of transcription factors.

Binding Sites↗

PubMed2004

DU145 human prostate carcinoma invasiveness is modulated by urokinase receptor (uPAR) downstream of epidermal growth factor receptor (EGFR) signaling.

Tumor cell motility and invasion have been linked to upregulated signaling from both the epidermal growth factor receptor (EGFR) and that for urokinase-type plasminogen activator (uPAR). However, we do not know whether these events are interdependent or unrelated, despite the obvious diagnostic and therapeutic implications. Gene microarray analyses have suggested that EGFR signaling via phospholipase C-gamma (PLCgamma) induces uPAR transcription. We utilized two sublines of the DU145 human prostate carcinoma cell line that are genetically engineered to differentially activate the EGFR/PLCgamma cascade and are variously invasive in vitro and in vivo. uPAR protein levels in these cells were found to be dependent on PLC signaling, pharmacologic inhibition of PLC signaling reduced uPAR expression. To determine whether uPAR was a required element in EGFR-mediated invasion, we stably expressed uPAR cDNA in either sense or antisense orientation in the two DU145 sublines. Interestingly, uPA production was modulated in parallel, although to a lesser degree, with uPAR in these sublines. Antisense to uPAR significantly restricted invasion of the highly invasive DU145 WT cells through Matrigel and reduced aggressiveness of tumors in nude mice. Up-regulation of uPAR significantly increased the invasiveness of the moderately invasive DU145 parental (DU145 P) cells through Matrigel, but this increased invasiveness was not seen in mice. uPA activity appears to contribute to invasiveness at least through Matrigel, as antibody to uPA or amiloride limited the transmigration. These results support a model of tumor invasion promoted by autocrine EGFR signaling involving reinforcing altered gene expression, of uPAR at least, that further induces cell motility. Herein, a number of key molecules whose expression levels are interrelated, including both EGFR and uPAR, are required but none are sufficient in the absence of other keys molecules in promoting tumor progression.

Amiloride↗

PubMed2004

Adenomatous polyposis coli control of retinoic acid biosynthesis is critical for zebrafish intestinal development and differentiation.

Mutations in the APC (adenomatous polyposis coli) tumor suppressor gene cause uncontrolled proliferation and impaired differentiation of intestinal epithelial cells. Recent studies indicate that human colon adenomas and carcinomas lack retinol dehydrogenases (RDHs) and that APC regulates the expression of human RDHL. These data suggest a model wherein APC controls enterocyte differentiation by controlling retinoic acid production. However, the importance of APC and retinoic acid in mediating control of normal enterocyte development and differentiation remains unclear. To examine the relationship between APC and retinoic acid biosynthesis in normal enterocytes, we have identified two novel zebrafish retinol dehydrogenases, termed zRDHA and zRDHB, that show strong expression within the gut of developing zebrafish embryos. Morpholino knockdown of either APC or zRDHB in zebrafish embryos resulted in defects in structures known to require retinoic acid. These defects included cardiac abnormalities, pericardial edema, failed jaw and pectoral fin development, and the absence of differentiated endocrine and exocrine pancreas. In addition, APC or zRDHB morphant fish developed intestines that lacked columnar epithelial cells and failed to express the differentiation marker intestinal fatty acid-binding protein. Treatment of either APC or zRDHB morphant embryos with retinoic acid rescued the defective phenotypes. Downstream of retinoic acid production, we identified hoxc8 as a retinoic acid-induced gene that, when ectopically expressed, rescued phenotypes of APC- and zRDHB-deficient zebrafish. Our data establish a genetic link supporting a critical role for retinoic acid downstream of APC and confirm the importance of retinoic acid in enterocyte differentiation.

Adenomatous Polyposis Coli Protein↗

PubMed2004

myo-Inositol and sucrose concentrations affect the accumulation of raffinose family oligosaccharides in seeds.

Raffinose family oligosaccharides (RFOs) fulfil multiple functions in plants. In seeds, they possibly protect cellular structures during desiccation and constitute carbon reserves for early germination. Their biosynthesis proceeds by the transfer of galactose units from galactinol to sucrose. Galactinol synthase (GolS), which mediates the synthesis of galactinol from myo-inositol and UDP-galactose, has been proposed to be the key enzyme of the pathway. However, no significant relationship was detected between the extractable GolS activity and the amount of RFOs in seeds from seven pea (Pisum sativum L.) genotypes selected for high variation in RFO content. Instead, a highly significant correlation was found between the levels of myo-inositol and RFOs. Moderately strong relationships were also found between sucrose and RFO content as well as between myo-inositol and galactinol. Further evidence for a key role of myo-inositol for the synthesis of galactinol was obtained by feeding exogenous myo-inositol to intact pea seeds and by the analysis of four barley (Hordeum vulgare L.) low phytic acid mutants. In seeds of three of these mutants, the reduced demand for myo-inositol for the synthesis of phytic acid (myo-inositol 1,2,3,4,5,6-hexakisphosphate) was associated with an increased level in myo-inositol. The mutants seeds also contained more galactinol than wild-type seeds. The results suggest that the extent of RFO accumulation is controlled by the levels of the initial substrates, myo-inositol and sucrose, rather than by GolS activity alone.

Hordeum↗

PubMed2004

The tumor suppressor adenomatous polyposis coli and caudal related homeodomain protein regulate expression of retinol dehydrogenase L.

Development of normal colon epithelial cells proceeds through a systematic differentiation of cells that emerge from stem cells within the base of colon crypts. Genetic mutations in the adenomatous polyposis coli (APC) gene are thought to cause colon adenoma and carcinoma formation by enhancing colonocyte proliferation and impairing differentiation. We currently have a limited understanding of the cellular mechanisms that promote colonocyte differentiation. Herein, we present evidence supporting a lack of retinoic acid biosynthesis as a mechanism contributing to the development of colon adenomas and carcinomas. Microarray and reverse transcriptase-PCR analyses revealed reduced expression of two retinoid biosynthesis genes: retinol dehydrogenase 5 (RDH5) and retinol dehydrogenase L (RDHL) in colon adenomas and carcinomas as compared with normal colon. Consistent with the adenoma and carcinomas samples, seven colon carcinoma cell lines also lacked expression of RDH5 and RDHL. Assessment of RDH enzymatic activity within these seven cell lines showed poor conversion of retinol into retinoic acid when compared with normal cells such as normal human mammary epithelial cells. Reintroduction of wild type APC into an APC-deficient colon carcinoma cell line (HT29) resulted in increased expression of RDHL without affecting RDH5. APC-mediated induction of RDHL was paralleled by increased production of retinoic acid. Investigations into the mechanism responsible for APC induction of RDHL indicated that beta-catenin fails to repress RDHL. The colon-specific transcription factor CDX2, however, activated an RDHL promoter construct and induced endogenous RDHL. Finally, the induction of RDHL by APC appears dependent on the presence of CDX2. We propose a novel role for APC and CDX2 in controlling retinoic acid biosynthesis and in promoting a retinoid-induced program of colonocyte differentiation.

3-Hydroxysteroid Dehydrogenases↗