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Biomedical subjects

M Page

Publications and source records attributed to M Page.

At least 19 recordsLinked to original sources
PubMed1999

Hyperfractionated craniospinal radiation therapy for primitive neuroectodermal tumors: results of a Phase II study.

PURPOSE: To report the results of a Phase II study of hyperfractionated craniospinal radiation therapy, with and without adjuvant chemotherapy for primitive neuroectodermal brain tumors (PNETs) and malignant ependymomas. METHODS AND MATERIALS: Newly diagnosed PNET or malignant ependymomas were treated with hyperfractionated craniospinal radiation therapy. The primary tumor site was treated to a dose of 72 Gy, with 30 Gy given to the rest of the craniospinal axis. The fraction size was 1.0 Gy, given twice a day. Patients with poor risk factors also received adjuvant chemotherapy with CCNU, cisplatin, and vincristine. Patients had follow-up for survival, time to tumor progression, and patterns of relapse. RESULTS: A total of 39 patients (21 males/18 females) were treated between March 12, 1990 and October 29, 1992. The median age was 16 years (range 3-59 years). Tumor types included 25 medulloblastomas, 5 pineoblastomas, 5 cerebral PNETs, 1 spinal cord PNET, and 3 malignant ependymomas. Twenty cases were staged as poor-risk and received adjuvant chemotherapy following radiation. Three-year progression-free survival (PFS) was 60% and 63% for poor-risk and good-risk patients, respectively. Overall 3-year survival for these groups was 70% and 79%, respectively. For the 25 patients with medulloblastoma, there were 16 good-risk and 9 poor-risk patients. Three-year PFSs were 63% and 56%, respectively. The 5-year survival for good-risk medulloblastoma was 69% with 43.7% of these patients having failures outside the primary site. CONCLUSIONS: Survival in patients with good-risk medulloblastoma was no better than that seen in previous studies with single-fraction radiation, and the rate of failure outside the primary site is excessive. Those with poor-risk features had comparable survival to that seen in patients with good risk factors, but these patients were treated with chemotherapy, and the role that hyperfractionated radiation played in their outcome is uncertain.

Adolescent↗
PubMed1998

Two erbB-4 transcripts are expressed in normal breast and in most breast cancers.

ErbB-4 is a recently described member of the epidermal growth factor receptor (EGFR) family which together with erbB-3 acts as a receptor for a group of ligands known as the neuregulins (NRGs) or heregulins (HRGs). Unlike the EGFR and erbB-2 relatively little is known about the expression of erbB-4 in human tumours. Using RT-PCR and Southern blotting analysis we have investigated the expression of erbB-4 mRNA in a range of human tumour cell lines and in normal and malignant breast tissue. Using primers which amplified a 658 base pair (bp) region corresponding to part of the cytoplasmic domain of c-erbB-4 we found the receptor was expressed in some but not all breast and ovarian tumour cell lines and also in a glioma cell line. The highest level of erbB-4 expression was found in the ovarian carcinoma OVCAR-3 and the breast carcinoma T-47D. In all cell lines where the 'full-length' erbB-4 was detected, a second previously undescribed c-erbB-4 sequence was also found as a 610 bp PCR product. The alternative PCR product was identical in sequence to c-erbB-4 except for a deletion of 48 bp which encodes a consensus phosphatidylinositol 3-kinase (PI3K) binding site. This suggested that the two forms of erbB-4 might interact with different intracellular signalling pathways and therefore influence a wider variety of cellular responses to heregulin than previously thought. Expression of both erbB-4 variants was found in 7/7 normal breast tissues but only in 9/12 breast tumours analysed. In line with the terminology of Elenius et al. (1997b) we have designated the two isoforms of the C-terminal transcripts as CT-a (full-length) and CT-b which lacks the P13K binding motif. These results identify suitable cell lines for the further investigation of erbB-4 expression and function and suggest that the role of erbB-4 in breast cancer warrants further investigation with larger numbers of normal and malignant breast tissues.

Alternative Splicing↗
PubMed1998

Sleep states and neonatal pulse oximetry.

AIM: Pulse oximetry is a quick, easy, noninvasive method widely used for monitoring oxygen saturation (SaO2) in the neonatal period. The greatest recognized problem with SaO2 readings measured from the oximeter is artifact, arising from an inability to record accurately during movement. The aim of this study was to determine the proportion of pulse oximeter readings affected by movement artifact during sleep in term and preterm infants. METHOD: Polygraphic recordings were obtained from 11 term and 6 preterm infants at postconceptional ages (SD) of 39.8 (0.8) and 39.3 (1.5) weeks respectively. The polygraphic and computer recordings were divided into epochs of 30 seconds duration and identified as active sleep (AS), quiet sleep (QS), indeterminate sleep (IS), or wakefulness (AW), using electrophysiological parameters and behavioral observations. Movement artifact was identified by visual examination of polygraphic computer recordings using strict criteria. Signal containing artifact was removed from recordings and the percentage of artifact time present per recording calculated. RESULTS: Signal artifact was present in recordings of all infants studied, comprising an average state time of 19% during quiet sleep, 49% of active sleep, 49% of indeterminate sleep and 91% of wakefulness. A significant difference in the proportion of artifact present in recordings of term and preterm was observed only during quiet sleep. CONCLUSION: Movement artifact during pulse oximetry recordings is dependent on behavioral state, and overall affects up to 50% of recorded traces. A reliable and more accurate noninvasive method of recording oxygen saturation is thus needed, for use in both neonatal nurseries and in sleep studies, to aid in accurate clinical decision-making.

Female↗
PubMed1998

Effect of proteasome inhibitors on monocytic IkappaB-alpha and -beta depletion, NF-kappaB activation, and cytokine production.

We investigated the effect of proteasome inhibitors on the lipopolysaccharide (LPS)-induced expression of several monocytic cytokines, which may be dependent on the transcription factor, nuclear factor-kappaB (NF-kappaB). Exposure of human monocytic THP-1 cells to ALLN and Mu873 prevented the LPS-induced degradation of IkappaB-alpha and -beta, as did the more potent proteasome inhibitor, PSI, whereas several calpain inhibitors were ineffective. This was accompanied by the inhibition of nuclear NF-kappaB binding activity and NF-kappaB transcriptional activation. At the mRNA level, the inhibitors blocked the expression of tumor necrosis factor (TNF) and interleukin-1beta (IL-1beta), whereas IL-8 remained unaffected by ALLN and was only partially reduced by the highest dose of PSI. The latter effect appears to be due to an increase in IL-8 mRNA stability in the presence of proteasome inhibitors. Furthermore, the production of TNF was efficiently suppressed by ALLN and PSI, less by Mu873, and not at all by calpain inhibitors. In primary human blood monocytes ALLN also prevented the LPS-induced degradation of IkappaB-alpha and -beta, efficiently blocked the production of TNF and, to a lesser extent, IL-1beta, whereas that of IL-8 was not inhibited. The expression of NF-kappaB-dependent monocytic cytokines may be selectively controlled by the proteasome, offering a potential therapeutic target in inflammatory disease.

Cell Line↗
PubMed1998

IgG purification.

Explore the source record for details and available documents.

Ammonium Sulfate↗
PubMed1998

High dose oral tamoxifen and subcutaneous interferon alpha-2a for recurrent glioma.

Chemotherapeutic regimens in present use for recurrent glioma have substantial toxicity. Activity against recurrent gliomas has been reported for both tamoxifen and interferon alpha, agents that have more acceptable toxicity profiles and that can be administered in an outpatient setting. We tested the efficacy and toxicity of the combination of high-dose tamoxifen and interferon alpha in adults with recurrent glioma in a phase II trial. Eligible patients had radiographically measurable recurrent gliomas of any grade after initial radiation therapy. Interferon-alpha [6 x 10(6) U subcutaneously three times per week] and tamoxifen (240 mg/m2/day orally) were administered continuously. Treatment response was assessed at 6 week intervals using clinical and radiographic criteria. Eighteen patients (11 males and 7 females) were enrolled. Median age was 41 years (range 23-61 years). All patients had gliomas that progressed after radiation therapy and nitrosourea chemotherapy. The histologic diagnosis of the original tumor was glioblastoma multiforme in 8 patients, anaplastic astrocytoma in 5 patients, astrocytoma in 4 patients and mixed malignant glioma in 1 patient. Reversible moderate to severe neurological toxicity manifested by dizziness and unsteady gait was seen at tamoxifen doses of 240 mg/m2/day. Although the initial tamoxifen dose was reduced to 120 mg/m2/day, moderate neurotoxicity was noted at this dose as well and the trial was closed early. The combination of oral tamoxifen (120 to 240 mg/m2/day) and subcutaneous interferon-alpha [6 x 10(6) U three times per week] was associated with significant neurotoxicity in this group of recurrent glioma patients, resulting in early study closure. Of 16 evaluable patients, 12 had progressive disease after one cycle of treatment, 3 had stable disease, and there was one minor response. Gradual dose escalation may be required if similar patients are to be treated with high dose tamoxifen in conjunction with interferon.

Administration, Oral↗
PubMed1998

Characterization of the T- and B-cell immune response to a new recombinant pre-S1, pre-S2 and SHBs antigen containing hepatitis B vaccine (Hepagene); evidence for superior anti-SHBs antibody induction in responder mice.

Hepagene is a novel recombinant particle consisting of the pre-S1, pre-S2 and small surface (SHBs) antigens (Ag) of the hepatitis B virus (HBV) and is adjuvanted with alhydrogel in the final formulation. It has been primarily developed to enhance anti-SHBs antibody titres in inadequate responders, to conventional SHBsAg vaccines. Since non-compliance is also a problem with existing HBV vaccine schedules, the ability to accelerate current immunization regimens to provide more rapid protection has also been an important objective. Here we describe the T- and B-cell responses to Hepagene in two strains of responder mouse (BALB/c and SWR/J). Hepagene induced high in vitro spleen T-cell proliferative responses in both strains (max. Stimulation Index = 43), following intraperitoneal immunization. High concentrations of interferon-gamma (max. = 5000 pg/mL) were detected in the media of spleen cells cultured with non-adjuvanted Hepagene particles. SWR/J mice showed the highest serum antibody (Ab) titres to non-adjuvanted Hepagene. The presence of alhydrogel adjuvant in the vaccine formulation significantly improved the titres. Anti-pre-S1 Ab was detected in both strains of mouse but anti-pre-S2 Ab was only detected in the SWR/J strain. In BALB/c mice, the anti-Hepagene (non-adjuvanted) IgG1 Ab subclass was predominant but in SWR/J mice IgG1, IgG2a and IgG2b subclasses were of a similar magnitude. In BALB/c mice, Hepagene induced higher anti-SHBs Ab responses than Engerix-B (11097 IU/mL and 1276 IU/mL, respectively), following two doses of vaccine (10 micrograms/mouse). The vaccine therefore, induces strong cellular and humoral immune responses and these data suggest that Hepagene is an improved hepatitis B vaccine.

Animals↗
PubMed1998

Airway protection in sleeping infants in response to pharyngeal fluid stimulation in the supine position.

This study was designed to evaluate upper airway protective mechanisms in response to pharyngeal fluid stimulation in healthy term and preterm infants at term equivalent age. Five term and seven preterm infants were studied and the following recorded: sleep state, cardiorespiratory function, and swallowing. Infusions of 0.9% saline and sterile water of volumes of 0.04, 0.2, and 0.35 mL were made during active (AS) and quiet sleep (QS). The effect of these variables on apnea (> or = 2 and > or = 5 s), swallowing, and arousal was examined. After pharyngeal infusion, apnea of > or = 2 and > or = 5 s did not change from spontaneous rates for both term and preterm infants. The most common response to pharyngeal infusion was swallowing. In AS, swallowing occurred after 65 and 73% and in QS after 40 and 64% of infusions in term and preterm infants, respectively. Swallowing was volume-related and occurred significantly more often in term infants after larger infusions of 0.35 and 0.2 mL (83 and 67%) compared with the 0.04 mL (19%) and after 0.2 mL compared with 0.04 mL for preterm infants (94 and 44%). At 0.2 mL, this was significantly higher in preterm compared with term infants (p < 0.01) and was the only significant difference between these infants. In response to pharyngeal fluid stimulation, airway defense in both full-term and preterm infants is maintained primarily by swallowing with no evidence of apnea.

Deglutition↗
PubMed1998

In situ localization of paclitaxel binding structures: Labeling with a paclitaxel fluorescent analogue.

Microtubules are a major component of cell cytoskeleton. Microtubules constitute the cellular target of paclitaxel. The interaction of paclitaxel with microtubules causes an increase in tubulin polymerization and microtubules stabilization, leading to a G2/M phase cell cycle arrest and cell death by apoptosis. Three paclitaxel fluorescent analogues were prepared by introducing fluorescein or BODIPY moiety onto the 2' of the 7-carbon. These were then used to study the interaction of paclitaxel with its cellular binding site and the microtubule network was visualized directly by fluorescence microscopy. Free paclitaxel was able to inhibit 7-FITC paclitaxel binding, demonstrating that both products bind to the same site and possess similar biological properties. Using the carbon 7 derivatives, microtubules were labeled as cytoplasmic fibers extending centripedly. A few other cellular components such as nuclear membrane, nucleoli and some other cytoplasmic structures were also labeled. The labeling intensity was reduced by preincubation with free paclitaxel. The interaction of paclitaxel with microtubules was also investigated using flow cytometry. No binding of the 2'C derivative was detected, confirming that a free 2'C is a pre-requisite for paclitaxel microtubules interaction.

Journal Article↗
PubMed1998

New active paclitaxel glucuronide derivative with improved water solubility.

Poor solubility of paclitaxel constitutes an important limitation to its administration to cancer patients. In order to increase solubility, while preserving cytotoxicity, a new paclitaxel derivative substituted at the 2' position of the side chain was prepared. The first step consisted in the introduction of a glutaryl group at the 2' position by esterification of the free hydroxyl followed by an amidation with 6-amino hexanol previously attached to a glucuronide group. The new water soluble derivative was cytotoxic in vitro against an ovarian teratocarcinoma cell line.

Antineoplastic Agents, Phytogenic↗
PubMed1997

Dysregulation of monocytic nuclear factor-kappa B by oxidized low-density lipoprotein.

Nuclear factor-kappa B (NF-kappa B)/Rel transcription factors may be involved in atherosclerosis, as is suggested by the presence of activated NF-kappa B in human atherosclerotic lesions. The aim of the present study was to investigate the effects of oxidized LDL (oxLDL) on the NF-kappa B system in human THP-1 monocytic cells as well as adherent monocytes. Our results demonstrate that short-term incubation of these cells with oxLDL activated p50/p65 containing NF-kappa B dimers and induced the expression of the target gene IL-8. This activation of NF-kappa B was inhibited by the antioxidant and H2O2 scavenger pyrrolidine dithiocarbamate and the proteasome inhibitor PSI. The oxLDL-induced NF-kappa B activation was accompanied by an initial depletion of I kappa B-alpha followed by a slight transient increase in the level of this inhibitor protein. In contrast, long-term treatment with oxLDL prevented the lipopolysaccharide-induced depletion of I kappa B-alpha, accompanied by an inhibition of both NF-kappa B activation and the expression of tumor necrosis factor-alpha and interleukin-1 beta genes. These observations provide additional evidence that oxLDL is a potent modulator of gene expression and suggest that (dys)regulation of NF-kappa B/Rel is likely to play an important role in atherogenesis.

Antioxidants↗
PubMed1996

Activated transcription factor nuclear factor-kappa B is present in the atherosclerotic lesion.

Nuclear factor-kappa B (NF-kappaB)/Rel transcription factors play an important role in the inducible regulation of a variety of genes involved in the inflammatory and proliferative responses of cells. The present study was designed to elucidate the implication of NF-kappaB/Rel in the pathogenesis of atherosclerosis. Activation of the dimeric NF-kappaB complex is regulated at a posttranslational level and requires the release of the inhibitor protein IkappaB. The newly developed mAb alpha-p65mAb recognizes the IkappaB binding region on the p65 (RelA) DNA binding subunit and therefore selectively reacts with p65 in activated NF-kappaB. Using immunofluorescence and immunohistochemical techniques, activated NF-kappaB was detected in the fibrotic-thickened intima/media and atheromatous areas of the atherosclerotic lesion. Activation of NF-kappaB was identified in smooth muscle cells, macrophages, and endothelial cells. Little or no activated NF-kappaB was detected in vessels lacking atherosclerosis. Electrophoretic mobility shift assays and colocalization of activated NF-kappaB with NF-kappaB target gene expression suggest functional implications for this transcription factor in the atherosclerotic lesion. This study demonstrates the presence of activated NF-kappaB in human atherosclerotic tissue for the first time. Atherosclerosis, characterized by features of chronic inflammation and proliferative processes, may be a paradigm for the involvement of NF-kappaB/Rel in chronic inflammatory disease.

Animals↗
PubMed1996

Activation of methotrexate-phenylalanine by monoclonal antibody--carboxypeptidase A conjugate for the specific treatment of ovarian cancer in vitro.

Monoclonal antibody 4E3 directed against a glycosylated surface protein on human ovarian teratocarcinoma cells (CRL-1572 cell line) was conjugated to bovine carboxypeptidase A (CPA) using a 3400 Da polyethylene glycol chain bearing an N-hydroxysuccinimide group at both ends. The conjugate preparation was purified by fast protein liquid chromatography on a Superose 12/30 HR column. The 4E3-CPA conjugate was recovered in the third fraction by SDS-PAGE analysis. The specific binding of the 4E3-CPA conjugate to CRL-1572 cells was confirmed by a FACS analysis and the enzymatic activity of the conjugate remained while tested with hippuryl-L-phenylalanine. In vitro cytotoxic assays on CRL-1572 cells showed that the prodrug methotrexate-phenylalanine (MTX-Phe) alone was non-toxic (ID50 > 1000 ng ml-1) but was selectively converted to MTX when the cells were pretreated with 50 micrograms ml-1 4E3-CPA conjugate, which enhanced considerably the pharmacological activity of the prodrug with an ID50 of 70 ng ml-1. The co-culture assays with CRL-1572 and MRC-5 cells (human normal lung diploid fibroblast cell lines) demonstrated the specificity of the 4E3-CPA conjugate for the CRL-1572 cells since no cytotoxicity was observed on the MRC-5 cells. When both cell lines were mixed in ratios ranging from 1:10,000 to 1:5 (CRL-1572:MRC-5), the significant increase in the ID25 was correlated with the proportion of tumoral cells present in the cell inoculum. These results suggest that MTX-Phe combined with 4E3-CPA conjugate is a promising model for a more selective and localised anti-cancer chemotherapy based on the ADEPT concept.

Antibodies, Monoclonal↗