[Is there still a place for extemporaneous exam in breast cancer?]].
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Biopsy↗
Biomedical subjects
F Walker
Publications and source records attributed to F Walker.
Preclinical analysis of the analinoquinazoline AG1478, a specific small molecule inhibitor of EGF receptor tyrosine kinase.
The tyrphostin 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478) is a potent and specific inhibitor of EGFR tyrosine kinase whose favourable preclinical profile supports progression towards clinical trials. Microphysiometric evaluation revealed a short (<24 min) effective inhibition of cellular receptor response to EGF challenge in BaF/ERX cells indicating a need to maintain sustained levels of inhibitor. Initial pharmacokinetic evaluation in mice of novel AG1478 formulations in a beta-cyclodextrin (Captisol) showed monoexponential elimination from plasma (half-life 30 min) following subcutaneous administration. A two-fold dose escalation gave a 2.4-fold increase in the total AUC. Bolus i.v. and 6 h continuous infusion were investigated in rats to mimic a more clinically relevant administration regimen. Drug elimination following bolus i.v. administration was biphasic (terminal elimination half-life 30-48 min). The linear relationship between dose and AUC(0-->infinity) (r2=0.979) enabled the prediction of infusion rates and doses for sustained delivery using continuous 6 h infusions, where steady state was reached in 120 min. Plasma levels of AG1478>10 microM were achieved over the duration of the infusion. At the lowest dose, plasma drug levels after the cessation of infusion declined with a half-life of approximately 43 min. EGFR activity, measured both by autophosphorylation and downstream signalling, was inhibited in a dose-dependent manner by injection of AG1478 in mice bearing xenografts of the human glioblastoma cell line U87MG.delta2-7, which expresses a constitutively active variant of the EGF receptor. Taken together, these experiments provide essential data to assess the anti-tumour efficacy of AG1478 and will assist in the rational design of dose regimens for clinical studies.
Animals↗
[Mixed mullerian tumours of the endometrium. Four cases developed while on tamoxifen treatment].
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Antineoplastic Agents, Hormonal↗
Speed choice by drivers: the issue of driving too slowly.
Quite correctly, the majority of road safety speeding initiatives focus on drivers travelling at excessive speeds. This study, however, focused on the potential problem of driving too slowly. Six thousand, four hundred and eighty vehicles from around the Perth metropolitan area in Western Australia had their speeds recorded; observations were also made of these vehicles to identify characteristics of the driver and vehicle. In addition, a community survey with 240 members of the public was conducted to examine their attitudes towards slow drivers. As expected, results showed that older drivers drove more slowly than the other age brackets, women drove more slowly than men, and that heavily laden vehicles drove more slowly than other types of vehicles. Additionally, the slowest days were weekdays and the quickest were Saturdays. Community attitudes, generally mirrored the observational findings, and indicated that the public believed that slow driving was sometimes a safety problem causing some accidents. These data are discussed, and some possible countermeasures are briefly introduced to address the problem.
Accidents, Traffic↗
Acute effects of 40% oxygen supplementation in adults with cyanotic congenital heart disease.
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Adult↗
Vagus nerve stimulation for essential tremor: a pilot efficacy and safety trial.
OBJECTIVE: To assess the safety and efficacy of vagus nerve stimulation (VNS) for essential tremor (ET). METHODS: This was a pilot open-treatment trial at three centers, with masked videotape tremor assessments. Inclusion required a severity score of 3 or 4 on the Tremor Rating Scale (TRS) in one or both hands. At baseline, tremor was assessed with TRS and Unified Tremor Rating Assessment (UTRA), accelerometry, and a videotape protocol. The VNS device was implanted with leads placed around the left cervical vagus nerve. Stimulation was adjusted over 4 weeks before the repeat tremor assessments. Two raters masked to the study visit scored the videotapes. RESULTS: Nine subjects participated, with a mean age of 65 years and a mean age at onset of tremor of 24. Investigators rated hand tremor as mildly improved (TRS 2.3 +/- 0.7 during VNS vs 3.0 +/- 0.4 during baseline, p = 0.06). Accelerometry-measured total power improved 50.2 +/- 31.8% (p < 0.01). Videotape tremor scores were highly correlated between the masked raters and revealed no changes in tremor scores with treatment. VNS was well tolerated, with the most common adverse events being stimulation related. CONCLUSIONS: VNS was judged by investigators to mildly improve upper extremity tremor. This finding was not confirmed in videotape scoring by masked raters. VNS is not likely to have a clinically meaningful effect on ET.
Adolescent↗
[Pseudotumoral tuberculosis of the cervix].
Cervical tuberculosis is a rare pathology, which can clinically look like a cervix cancer. The biopsy re-establishes the right diagnosis. The treatment is medical. The prognosis is primarily the infertility due to frequent associated general genital tuberculosis.
Adult↗
Observer variability in the Goseki grouping of gastric adenocarcinoma in resection and biopsy specimens.
AIMS: The Goseki grouping of gastric adenocarcinoma has been suggested as a possible prognostic factor. In those centres where it is used, it may be valuable to assess the Goseki grouping of a tumour on the initial diagnostic biopsy as well as on the resection specimen since it may in theory influence management. We examined the robustness of Goseki grouping of gastric adenocarcinoma in representative sections from resection and biopsy specimens in order to assess the consistency of agreement among a group of pathologists. METHODS: A single representative block from 100 gastric resection specimens was studied using a haematoxylin and eosin and mucin (alcian blue/periodic acid-Schiff) stain. These were circulated in batches to members of a group of 12 pathologists who each completed a simple proforma confirming the presence of carcinoma and assigning a Goseki group. In a second circulation the diagnostic biopsy specimen taken prior to resection was examined in the same way. This allowed comparison of the Goseki group of the biopsy and resection specimens. RESULTS: In both studies kappa statistics showed good agreement on tubular differentiation of the carcinoma, but only moderate agreement for the intracellular mucin production, resulting in moderate agreement for the final Goseki group. Correlation between the Goseki group assigned on the biopsy and resected specimens was seen in 62% of the cases. However, the reproducibility was low (kappa 0.375). CONCLUSIONS: The Goseki grouping of resected gastric adenocarcinoma is reproducible and can be used in prognostication. Goseki grouping of biopsy specimens is of limited value in predicting the Goseki group assigned to the resected carcinoma.
Adenocarcinoma↗
Comment on a recent paper and editorial on the subject of dysplasia classification.
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Humans↗
Rapid microscale enzymic semisynthesis of epidermal growth factor (EGF) analogues.
Epidermal Growth Factor (EGF) is a small growth factor containing 53 amino acid residues capable of stimulating the proliferation of both mesenchymal and epithelial cells. Comparison of the amino acid sequences of EGF from several species, and related proteins that can bind to the EGF receptor (e.g. TGFalpha, VGF, heparin-binding EGF, and betacellulin), suggests that Leu47, which is highly conserved, is important for biological function. Additionally, we have shown previously, using a combination of trypsin and carboxypeptidase Y digestion of native murine EGF, that removal of Leu47 results in more than 100-fold decrease in both receptor binding and mitogenic activity. We now describe a micromethod for the rapid generation of C-terminally modified EGFs to investigate further the role of C-terminal residues in determining functional activity. These analogues have been generated by digesting native murine EGF with trypsin, purifying the biologically inactive, but structurally intact, EGF1-45 core by micropreparative RP-HPLC, and then reversing the action of trypsin to couple synthetic peptides (e.g. DL, DI, DF, EL, DLLW) onto the C-terminus of the EGF1-45 core. This enzymic semisynthesis method allows multiple derivatives to be generated rapidly from microgram quantities of EGF1-45 in sufficient quantities for sensitive biological and physicochemical analysis. We have validated the method by regenerating EGF1-47 from EGF1-45 with equivalent mitogenic and receptor binding activity to EGF1-47 generated from wild type EGF by digestion with trypsin and carboxypeptidase Y. We have also investigated the effect of substituting alternative normal or nonphysiological amino acids (e.g. allo-Ile) for Asp46, Leu47 or Arg48. Even small changes in these C-terminal residues reduce the mitogenic potency of the analogue.
3T3 Cells↗
Alteration of cardiac and renal functions in transgenic mice overexpressing human mineralocorticoid receptor.
The mineralocorticoid receptor (MR), a ligand-dependent transcription factor, mediates aldosterone actions in a large variety of tissues. To explore the functional implication of MR in pathophysiology, transgenic mouse models were generated using the proximal human MR (hMR) promoter to drive expression of hMR in aldosterone target tissues. Tissue-specific analysis of transgene expression in two independent transgenic animal (TG) lines by ribonuclease protection assays revealed that hMR is expressed in all mineralocorticoid-sensitive tissues, most notably in the kidney and the heart. TG exhibit both renal and cardiac abnormalities. Enlarged kidneys were histologically associated with renal tubular dilation and cellular vacuolization whose prevalence increased with aging. Renal clearance studies also disclosed a significant decrease in urinary potassium excretion rate in TG. hMR-expressing animals had normal blood pressure but developed mild dilated cardiomyopathy (increased left ventricle diameters and decreased shortening fraction), which was accompanied by a significant increase in heart rate. Differential gene expression analysis revealed a 2- to 5-fold increase in cardiac expression of atrial natriuretic peptide, serum- and glucocorticoid-induced kinase, and early growth response gene 1 as detected by microarrays; renal serum- and glucocorticoid-induced kinase was also induced significantly. Altogether, TG exhibited specific alteration of renal and cardiac functions, thus providing useful pathophysiological models to gain new insights into the tissue-specific mineralocorticoid signaling pathways.
Animals↗
Right ventricular form and function after percutaneous atrial septal defect device closure.
OBJECTIVES: We sought to assess the right heart's response to percutaneous device closure of moderate sized atrial septal defects (ASDs) in adults over a one-year follow-up period. BACKGROUND: Percutaneous ASD device closure is a safe and effective means of reducing or eliminating interatrial shunting. The response of the adult's right heart to device closure is incompletely understood. METHODS: Forty consecutive patients had 40 device implantations (32 with the CardioSeal implant and 8 with the Amplatzer device). The patients were assessed with echocardiography, chest radiography and electrocardiography before the procedure and at 1, 6 and 12 months. RESULTS: The mean ASD size was 13+/-4 mm, and the device size ranged from 33 to 40 mm for CardioSeal and 12 to 36 mm for Amplatzer. At one month, heart size (49% vs. 46%), four-chamber right ventricular (RV) size (45 vs. 41 mm), paradoxical septal motion (60% vs. 5%), QRS duration (125 vs. 119 ms), PR interval (181 vs. 155 ms) and echocardiographically determined pulmonary artery systolic pressure decreased significantly and was maintained at 12-month follow-up. At six months, right atrial length decreased from 50 to 47 mm. At one year, 29% of patients had persistent RV enlargement. CONCLUSIONS: Right heart morphology undergoes rapid improvement within one month of defect closure, with associated mechanoelectrical benefit. A small number of patients had persistent RV enlargement or pulmonary hypertension, or both, at one year. Our data support the application of transcatheter methods in achieving excellent hemodynamic and anatomic outcomes.
Adult↗
Platelet-derived growth factor requires epidermal growth factor receptor to activate p21-activated kinase family kinases.
The platelet-derived growth factor (PDGF) receptor (PDGFR) transactivates the epidermal growth factor (EGF) receptor (ErbB1) to stimulate the cell migration of fibroblasts through an unknown mechanism (Li, J., Kim, Y. N. & Bertics, P. (2000) J. Biol. Chem. 275, 2951-2958). In this paper we provide evidence that the transactivation of the EGF receptor (EGFR) by PDGFR is essential for PDGF to activate p21-activated kinase (PAK) family kinases. Fetal calf serum (10%) transiently stimulates the PAK activity in NIH 3T3 fibroblasts. The activation of PAK was completely inhibited by either PDGFR-specific inhibitor (AG1295) or EGFR-specific inhibitor (AG1478), suggesting that serum requires either the PDGF- or EGF-dependent pathway or the combination of both to activate PAK. PDGF-induced activation of PAK is completely inhibited by either AG1295 or AG1478, indicating that PDGF requires both PDGFR and EGFR for PAK activation. In support of this notion, a mouse embryo fibroblast cell line derived from the EGFR -/- mouse (from Dr. Erwin Wagner) doesn't activate PAK in response to PDGF. Expression of human EGFR in this cell line restores the ability of the PDGF to induce PAK activation. Our results indicate that PDGF activates PAK through transactivation of ErbB1.
3T3 Cells↗
Self-reported hyperarousal traits among insomnia patients.
Hyperarousal Scale scores for certain self-reported behaviors reportedly correlate with EEG arousal measures. We tested whether an insomnia subject group had different Hyperarousal Scale scores compared with hypersomnia, delayed sleep phase syndrome, procrastinator or normal subject groups. Compared with 139 normal subjects, mean scores for a group of 256 insomnia subjects was significantly 1.2 S.D. higher on Hyperarousal total scale score, 0.82 S.D. higher on React subscale score and 0.85 S.D. higher on Introspectiveness subscale score. The insomnia group median Extreme score was 2.25 times that of the normal group. These self-report findings suggest that insomnia subjects may be more responsive generally. All sleep disorder groups had increased total Hyperarousal scores, although these increases were accounted for by different scale items. The procrastinator group had Hyperarousal score patterns that generally differed from those of the other groups.
Adult↗
Isolation and identification of N-mercapto-4-formylcarbostyril, an antibiotic produced by Pseudomonas fluorescens.
Pseudomonas fluorescens strain G308 isolated from barley leaves produces a novel antibiotic substance that was purified by preparative TLC and HPLC and identified as N-mercapto-4-formylcarbostyril (Cbs) by LC/DAD, IR, LC-ES(+)/MS, LC-ES(-)/MS, GC-EI/MS, LC-HRES(+)/MS, mass isotope ratios analysis, 1H NMR and 13C NMR analysis. The purified new antibiotic compound is effective against many phytopathogenic fungi in vitro. The compound inhibited at 25 ppm spore germination and germ tube growth of the following fungi; Fusarium oxysporum f. sp. lycopersici, Fusarium culmorum, Cladosporium cucumerinum and Colletotrichum lagenarium. At concentrations up to 125 ppm, the compound did not interfere with release of zoospores from sporangia and germination of encysted zoospores of Phytophthora infestans.
Antifungal Agents↗
RING finger mutations that abolish c-Cbl-directed polyubiquitination and downregulation of the EGF receptor are insufficient for cell transformation.
The c-Cbl protooncogene can function as a negative regulator of receptor protein tyrosine kinases (RPTKs) by targeting activated receptors for polyubiquitination and downregulation. This function requires its tyrosine kinase binding (TKB) domain for targeting RPTKs and RING finger domain to recruit E2 ubiquitin-conjugating enzymes. It has therefore been proposed that oncogenic Cbl proteins act in a dominant-negative manner to block this c-Cbl activity. In testing this hypothesis, we found that although mutations spanning the RING finger abolish c-Cbl-directed polyubiquitination and downregulation of RPTKs, they do not induce transformation. In contrast, it is mutations within a highly conserved alpha-helical structure linking the SH2 and RING finger domains that render Cbl proteins oncogenic. Thus, Cbl transformation involves effects additional to polyubiquitination of RPTKs that are independent of the RING finger and its ability to recruit E2-conjugating enzymes.
3T3 Cells↗
Expression and regulation of leptin receptor proteins in afferent and efferent neurons of the vagus nerve.
Leptin, the product of the ob gene, plays a key role in the regulation of food intake via a cross-talk between hypothalamic leptin receptors and neuropeptides that affect feeding behaviour. Recent studies have shown a synergistic interaction between leptin and cholecystokinin (CCK) leading to suppression of food intake, which involves CCK-1 receptors and capsaicin-sensitive vagal fibres. In this study, we have investigated the presence of leptin receptors in afferent and efferent neurons of the vagus nerve. By using reverse transcription-polymerase chain reaction, mRNAs encoding long (Ob-Rb) and short (Ob-Ra) leptin receptor isoforms were detected in the rat nodose ganglion, which contains the cell bodies of the vagal afferent neurons. Western blot analysis confirmed the presence of leptin receptor-immunoreactive proteins in extracts from the vagal trunk. Immunohistochemistry showed the presence of leptin receptors and the leptin-induced transcription factor STAT3 in the cytoplasm of nodose ganglion cells. In cervical vagal segments, levels of leptin receptor protein displayed physiological regulation, with decreased amounts after feeding and increased levels after food restriction. In addition, leptin receptor and STAT3 immunoreactivities were detected in neurons of the nucleus of tractus solitarius (NTS) and the dorsal motor nucleus of the vagus nerve (DMNX) by immunofluorescence histochemistry. Furthermore, direct double-labelling demonstrated colocalization of Ob-Rb and STAT3 immunoreactivities in cholinergic vagal efferent cell bodies of the DMNX. It is speculated that vagal leptin receptors, apart from being activated by adipocyte-derived leptin, may also be influenced by leptin produced by the stomach. This may explain the synergistic action of leptin and CCK on neuronal activity in the NTS and on food intake.
Afferent Pathways↗