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Biomedical subjects

G Peters

Publications and source records attributed to G Peters.

At least 73 records · Page 4Linked to original sources
PubMed2000

Staphylococcus aureus small colony variants: formation and clinical impact.

S. aureus small-colony variants are a naturally occurring subpopulation which grow slowly and produce small colonies on routine media. They also demonstrate a number of other characteristics that are atypical for S. aureus including reduced alpha-toxin production and delayed coagulase activity. The connection of S. aureus SCVs with persistent and relapsing infections has been defined over the past decade, especially in patients with chronic osteomyelitis and in cystic fibrosis patients as demonstrated by prospective studies. While the studies with clinical isolates of SCVs suggested a link between electron transport-defective strains and persistent infections, a defined hemB mutant with the SCV phenotype provided strong additional evidence for these connections. The hemB mutant was phagocytosed by cultured endothelial cells, but did not lyse these cells, because the mutant produced very little alpha-toxin. The intracellular location may shield the SCVs from host defenses and antibiotics, thus providing one explanation for the difficulty in clearing S. aureus SCVs from host tissues.

Colony Count, Microbial↗
PubMed1999

Functional evaluation of tumour-specific variants of p16INK4a/CDKN2A: correlation with protein structure information.

Inherited mutations in the CDKN2A/INK4a/MTS1 tumour suppressor gene on chromosome 9p21 are associated with familial predisposition to melanoma and other tumour types. Nonsense and missense mutations are also found in a variety of sporadic cancers, and over 140 sequence variants have already been recorded in the literature. In assessing the relevance of these variants and for counselling members of affected families, it is important to distinguish inactivating mutations from harmless polymorphisms. Existing functional assays have frequently reached conflicting conclusions and no single test appears adequate. Here we evaluate a number of alternatives including a novel assay based on retroviral delivery of p16INK4a cDNAs into human diploid fibroblasts. Among the 17 sequence variants analysed, three distinct categories can be distinguished: those that abrogate the binding of p16INK4a to CDK4 and CDK6, those that alter the properties of the protein without preventing it from interacting with CDKs, and those that have no discernible effect on protein function. These distinctions can be rationalized by considering the impact of the amino acid changes on the three-dimensional structure of the protein.

Alleles↗
PubMed1999

Role of the alternative INK4A proteins in human keratinocyte senescence: evidence for the specific inactivation of p16INK4A upon immortalization.

The INK4A locus on human chromosome 9p21 encodes two genes that have been implicated in replicative senescence and tumor suppression, p16INK4A and p14ARF. In contrast to p16INK4A, which is up-regulated to high levels, we were unable to detect p14ARF protein in senescent human keratinocytes. Also, p53, an established target of p14ARF, did not increase, suggesting that p14ARF is not instrumental in human keratinocyte senescence. In neoplastic keratinocyte cultures, p16INK4A inactivation was invariably associated with the immortal phenotype, and there was evidence for the inactivation of p16INK4A, independent of p14ARF, in 6 of 10 lines that lacked large homozygous deletions. In contrast, we failed to detect exon 1beta mutations or p16INK4A-independent deletions. These results emphasize the previously proposed role for p16INK4A in human keratinocyte senescence but do not rule out a supporting role for p14ARF inactivation.

3T3 Cells↗
PubMed1999

Phase I trial of interferon gamma retroviral vector administered intratumorally with multiple courses in patients with metastatic melanoma.

The purpose of this study was to determine the safety and antitumor activity of IFN-gamma retroviral vector in patients with advanced melanoma. Seventeen patients (9 single courses, 8 multiple courses) received a total of 363 intratumor injections of IFN-gamma retroviral vector (1 x 10(7) PFU/ml administered at 0.3, 0.5, and 1.0 ml per cohort). No grade III/IV adverse events were attributed to study medication. Replication-competent retrovirus was not detected in any of the 17 patients by polymerase chain reaction studies. Eight patients showed elevated anti-tumor antibody responses in comparison with baseline by ELISA. One of nine patients treated with a single course had an optimal response of stable disease, compared with eight of eight multiple-injected patients. Median survival of single-injected patients was 150 days, and patients who received multiple injections have still not achieved median survival duration, with four of eight still living (p = 0.0462, Wilcoxon; p = 0.0273, log rank). We conclude that intratumor injection of IFN-gamma is safe and well tolerated. Evidence of antitumor activity is suggested in patients with advanced malignancy that received multiple injections.

Adult↗
PubMed1999

Cyclin-dependent kinase inhibitor p27Kip1 expression and interaction with other cell cycle-associated proteins in mammary carcinoma.

p27, cyclin D1, and retinoblastoma (Rb) protein have been demonstrated using immunohistochemistry in 189 cases of primary breast carcinoma with long-term follow-up. There was a statistically significant association between the expression of p27 and both cyclin D1 and the retinoblastoma gene product (pRb), corresponding to their close interactions in regulating the G1/S transition in the cell cycle. Low levels of p27 were seen in high-grade, rapidly proliferating, oestrogen receptor-negative tumours. In univariate analysis, low p27 expression was associated with a reduced relapse-free and overall survival. In multivariate analysis, p27 was not an independent predictor of survival when either histological grade or proliferative activity (S-phase fraction) was included in the model. When the combined expression of p27 and cyclin D1 was related to survival, patients with high levels of p27, regardless of their cyclin D1 status, did well, whilst those with low p27 had a poor outcome. The only exception, in the latter group, was patients with tumours expressing high levels of cyclin D1, who did as well as the high p27 group. We have shown that in clinical material p27 expression is associated with proliferative activity and while univariate analysis shows it to be a significant indicator of prognosis, this significance is lost in multivariate analysis when traditional prognostic factors are included in the model. The interest in p27 expression in mammary carcinoma lies in its behaviour when examined in combination with other G1 cell cycle regulators.

Biomarkers, Tumor↗
PubMed1999

Transforming growth factor alpha (TGF-alpha) expression in dysplastic oral leukoplakia: modulation by 13-cis retinoic acid.

BACKGROUND: Surrogate endpoint biomarkers (SEBs) are detectable molecular, cellular, and tissue changes that take place during tumorigenesis and can be modulated by a chemoprevention agent. METHOD: To identify candidate SEBs for invasive squamous cell carcinoma of the upper aerodigestive tract (SCC), we have studied the expression of transforming growth factor-alpha (TGF-alpha) and epidermal growth factor receptor (EGFr) in sequential biopsy specimens of dysplastic oral leukoplakia and adjacent normal-appearing mucosa. Biopsies were taken from patients before, during, and after treatment with 13-cis retinoic acid, a vitamin A derivative. Immunohistochemistry was performed using the Biogenex Super Sensitive Biotin-Streptavidin horseradish peroxidase detection system. RESULTS: The pretreatment expression of TGF-alpha and EGFr in dysplastic oral leukoplakia was increased when compared with their expression in adjacent normal-appearing mucosa (p = 0.001 and p = 0.01, respectively). Eleven of 14 patients enrolled in the study (78.6%) completed 3 months of treatment with 13-cis retinoic acid (1. 0 mg/kg/day). TGF-alpha expression in dysplastic oral leukoplakia, but not in adjacent normal-appearing mucosa, decreased during treatment (p < 0.05). CONCLUSIONS: TGF-alpha is a candidate SEB for future SCC chemoprevention trials.

Antineoplastic Agents↗
PubMed1999

New aspects in the molecular basis of polymer-associated infections due to staphylococci.

Coagulase-negative staphylococci, particularly Staphylococcus epidermidis, cause the majority of infections associated with both temporarily inserted and permanently implanted foreign bodies. In recent years, the pathogenesis of polymer-associated staphylococcal infection has become better understood, due in part to the characterization of further associated factors. The bacterial factors involved in the two phases of biofilm formation, i.e. the rapid adherence of bacteria to the polymer surface and the subsequent, more prolonged, accumulation phase, are presented in this review. The biofilm present on infected devices plays an important role in the pathogenicity of the infecting organism by protecting the embedded staphylococci and reducing the efficacy of host defenses and antimicrobial killing.

Bacterial Adhesion↗
PubMed1999

Pain control after thoracotomy: bupivacaine versus lidocaine in continuous extrapleural intercostal nerve blockade.

BACKGROUND: The use of a continuous bupivacaine extrapleural intercostal nerve block after posterolateral thoracotomy has been shown in randomized controlled studies to be effective in reducing postoperative pain and restoring pulmonary function. It is our hypothesis that when using a continuous infusion for nerve block, a long-acting agent (bupivacaine) is unnecessary and a shorter-acting agent (lidocaine) would offer equivalent results with less systemic toxicity. This study was designed to determine whether lidocaine was as effective as bupivacaine in a continuous extrapleural intercostal nerve block after posterolateral thoracotomy because lidocaine is a less toxic analgesic agent. The study was prospectively randomized and double-blinded. METHODS: Forty-six patients undergoing elective posterolateral thoracotomy were randomized to blindly receive bupivacaine (n = 23) or lidocaine (n = 23) by continuous infusion pump through an intraoperatively placed indwelling extrapleural catheter. Postoperative pain was assessed for 48 hours by patient-controlled morphine consumption and by linear visual analog scale. There was no statistically significant difference in age, sex, or type of operation between the two groups. RESULTS: There was no statistically significant difference between the bupivacaine and lidocaine groups in patient-controlled morphine use or in visual analog scale scores. CONCLUSIONS: Lidocaine offers equivalent pain control to bupivacaine when administered for continuous extrapleural intercostal nerve block after posterolateral thoracotomy, with less risk of systemic toxicity.

Aged↗
PubMed1999

Differential expression of and responsiveness to transforming growth factor-beta (TGF-beta) isoforms in hormone-dependent and independent lines of mouse mammary tumors.

Transforming growth factor-beta2 (TGF-beta2) and -beta3 mRNA expressions were studied in ductal hormone-dependent (HD) and -independent (HI) in vivo lines of the medroxyprogesterone acetate (MPA)-induced mammary tumor model in Balb/c mice. MPA treatment of HD tumors induced a significant decrease in TGF-beta2 and -beta3 mRNA levels. Progression to an HI phenotype of ductal tumors was associated with reduced TGF-beta2 and -beta3 expressions, as compared with their HD counterparts. Exogenously added TGF-beta1, -beta2, and -beta3 (1 ng/ml) inhibited the proliferation of primary cultures of epithelial cells from ductal HD and HI tumors. In addition, TGF-beta expression and effects were studied in the other type of MPA-induced mammary tumors, which are of lobular origin and lack steroid hormone receptors and evidence an HI behavior. These lobular HI lines showed TGF-beta2 levels similar to those found in HD lines growing in MPA-treated mice. In contrast, TGF-beta3 mRNA levels were 12- to 20-fold higher than in HD tumors. Primary cultures of lobular HI epithelial cells required either TGF-beta concentrations of 10 ng/ml to show an inhibitory response, or were completely resistant to TGF-beta inhibition. Studies of the molecular mechanisms involved in reduction or loss of TGF-beta responsiveness in lobular HI tumors showed that cell surface type II TGF-beta receptor levels were lower in these tumors than those present in HD tumors. Our results support the hypothesis that TGF-beta could play a role as an autocrine growth inhibitor in HD and HI ductal tumors. Autonomous growth of lobular HI tumors could be favored by undetectable or low TGF-beta1 and -beta2 expressions and by reduced or lost sensitivity of epithelial cells to TGF-beta's antiproliferative effects. However, the extremely high levels of TGF-beta3 expression in lobular HI tumors, in spite of reduced sensitivity to TGF-beta3 inhibitory growth effect in tumor epithelial cells, suggest a net positive role for TGF-beta3 in these tumors.

Affinity Labels↗
PubMed1999

Bloodstream infections caused by small-colony variants of coagulase-negative staphylococci following pacemaker implantation.

Small-colony variants (SCVs) of Staphylococcus aureus cause persistent and relapsing infections. Relatively little is known regarding infections caused by SCVs of coagulase-negative staphylococci. We report two cases of pacemaker electrode infections due to SCVs of Staphylococcus epidermidis and Staphylococcus capitis. Sequence analysis of a portion of the 16S rRNA gene (16S rDNA) confirmed the identity of the staphylococcal species as S. capitis and S. epidermidis. Isolates from cultures of blood obtained over at least a 2-week interval were compared by pulsed-field gel electrophoresis and found to be clonal even though the colony morphology was very different. Analysis for auxotrophism revealed hemin dependencies for all isolated SCVs. The two cases have several clinical and laboratory characteristics (which are also seen with S. aureus SCV infections) and strongly suggest that SCVs of coagulase-negative staphylococci must be actively sought, because they grow very slowly and can be easily missed.

Bacteremia↗
PubMed1999

Comparative in-vitro activities of moxifloxacin, trovafloxacin, quinupristin/dalfopristin and linezolid against staphylococci.

The antistaphylococcal activities of four newly developed antibiotics, moxifloxacin (an 8-methoxyfluoroquinolone), trovafloxacin (a naphthyridone), quinupristin/dalfopristin (a semisynthetic streptogramin) and linezolid (an oxazolidinone), were examined and compared with those of ciprofloxacin, vancomycin and teicoplanin, using an agar dilution method. A total of 245 clinical isolates of staphylococci, including a large number of clonally different methicillin-resistant strains, were tested. The new agents tested exhibited wide-spectrum antistaphylococcal activity against both methicillin-susceptible and methicillin-resistant strains. In contrast to the quinolones, the in-vitro activities of quinupristin/dalfopristin, linezolid and the glycopeptides remained almost unchanged, irrespective of the resistance phenotype for methicillin. A number of isolates with elevated quinolone MICs were observed.

Acetamides↗
PubMed1999

Use of polymerase chain reaction for postmortem diagnosis of malaria.

Delay or failure in diagnostic or therapeutic management of Plasmodiumfalciparum malaria may result in avoidable deaths, often incurring medicolegal procedures. Advanced postmortem autolytic processes and putrefication may thwart malaria diagnosis by traditional microscopic and histologic examinations. The authors describe the usefulness of polymerase chain reaction to confirm postmortem diagnosis of malaria.

Adolescent↗
PubMed1999

A lithium chloride-extracted, broad-spectrum-adhesive 42-kilodalton protein of Staphylococcus epidermidis is ornithine carbamoyltransferase.

To identify novel putative staphylococcal adhesins, lithium chloride extraction (an established method for selective surface molecule solubilization) was employed. N-terminal sequencing and functional assays identified a 42-kDa fibronectin-binding protein from Staphylococcus epidermidis as ornithine carbamoyltransferase (OCTase). However, OCTase was not recognizable extracellularly, and this fact together with the fact that LiCl induced DNA release and a decrease in viability suggests that LiCl extraction may not be the method of choice for selective surface molecule extraction from staphylococci.

Adhesins, Bacterial↗
PubMed1999

Induced expression of p16(INK4a) inhibits both CDK4- and CDK2-associated kinase activity by reassortment of cyclin-CDK-inhibitor complexes.

To investigate the mode of action of the p16(INK4a) tumor suppressor protein, we have established U2-OS cells in which the expression of p16(INK4a) can be regulated by addition or removal of isopropyl-beta-D-thiogalactopyranoside. As expected, induction of p16(INK4a) results in a G1 cell cycle arrest by inhibiting phosphorylation of the retinoblastoma protein (pRb) by the cyclin-dependent kinases CDK4 and CDK6. However, induction of p16(INK4a) also causes marked inhibition of CDK2 activity. In the case of cyclin E-CDK2, this is brought about by reassortment of cyclin, CDK, and CDK-inhibitor complexes, particularly those involving p27(KIP1). Size fractionation of the cellular lysates reveals that a substantial proportion of CDK4 participates in active kinase complexes of around 200 kDa. Upon induction of p16(INK4a), this complex is partly dissociated, and the majority of CDK4 is found in lower-molecular-weight fractions consistent with the formation of a binary complex with p16(INK4a). Sequestration of CDK4 by p16(INK4a) allows cyclin D1 to associate increasingly with CDK2, without affecting its interactions with the CIP/KIP inhibitors. Thus, upon the induction of p16(INK4a), p27(KIP1) appears to switch its allegiance from CDK4 to CDK2, and the accompanying reassortment of components leads to the inhibition of cyclin E-CDK2 by p27(KIP1) and p21(CIP1). Significantly, p16(INK4a) itself does not appear to form higher-order complexes, and the overwhelming majority remains either free or forms binary associations with CDK4 and CDK6.

CDC2-CDC28 Kinases↗