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PubMed1981

Effects of hyperthermia on cell surface charge and cell survival in mastocytoma cells.

Changes in the structure of the surface of mastocytoma cells were induced by hyperthermia and were investigated by means of cell electrophoresis. A decrease in the cell electrophoretic mobility was detected as early as 15 min after treatment at 42 degrees and progressed more rapidly under hypoxic conditions than under oxic conditions. Subsequent recovery of electrophoretic mobility at 37 degrees was dependent on the length of heat treatment and oxygenation. The surviving fraction of cells detected by their colony-forming ability and the fraction of electrophoretically recovered cells 24 hr after exposure to hyperthermia showed a good statistical correlation. It was suggested that the mechanism of electrophoretic mobility reduction by heating was the vertical translocation of hyaluronidase-sensitive charge from the peripheral layer into a deeper layer by combined use of specific enzymes and stepwise different ionic strengths. These results suggest the importance of irreparable changes of membrane conformation in the loss of colony-forming ability of heated tumor cells.

Animals↗
PubMed2005

Birth defects after prenatal exposure to antiepileptic drugs.

BACKGROUND: Exposure to antiepileptic drugs (AEDs) in the first trimester of pregnancy has been associated with an increased risk of major congenital anomalies (MCAs) in offspring. Most of the studies, however, have been fraught with methodological shortcomings, and differences in ascertainment methods and classifications prevent meaningful data pooling. Individual studies lacked the statistical power to assess comparative risks associated with specific AEDs. RECENT DEVELOPMENTS: Several larger-scale studies, including collaborative multinational registries, have been set up to compare MCA risks associated with different treatments, including newer generation AEDs. Results have largely been consistent with the notion that monotherapy with the most commonly used AEDs is associated with an increase in risk of MCAs by two to three times, and that the magnitude of risk increases in offspring exposed to polytherapy. Available evidence does not suggest that epilepsy per se is associated with a major increase in the risk of MCAs. Almost all studies have suggested that exposure to valproic acid is associated with a greater incidence of MCAs than other AEDs. Valproic acid is also the only AED for which a dose-dependency has been confirmed in several studies: the increase in risk of MCAs, compared with other AEDs, is especially evident at doses above 800-1000 mg/day. Data from the North American registry have suggested that phenobarbital may also have a higher teratogenic risk compared with AEDs other than valproic acid, but evidence remains inconclusive. Information about effects on fetuses of newer generation AEDs other than lamotrigine and oxcarbazepine is scant. Although teratogenic effects of lamotrigine and oxcarbazepine have not been established with certainty, none of the investigations to date identified any statistically significant difference in rates of MCAs between infants exposed to lamotrigine or oxcarbazepine and infants exposed to carbamazepine. In the case of lamotrigine, moreover, a positive correlation between maternal dose and rates of MCAs has been identified. WHERE NEXT?: Collaborative pregnancy registries worldwide are at work to fill remaining gaps in knowledge. Issues to be addressed include the comparative risks associated with phenobarbital, with low-dose valproic acid, with newer generation AEDs, and with specific AED combinations; the influence of potential confounders; and the interaction of AED-associated risks with other risk factors, such as genetic profiles. Large scale studies may also clarify whether individual AEDs differ in their ability to cause specific anomalies. Finally, studies are urgently needed to investigate other potential adverse effects of AED exposure, with special reference to effects on postnatal intellectual development.

Abnormalities, Drug-Induced↗
PubMed2005

DNA vaccines in sheep: CTLA-4 mediated targeting and CpG motifs enhance immunogenicity in a DNA prime/protein boost strategy.

DNA vaccines have proven to be an efficient means of inducing immune responses in small laboratory animals; however, their efficacy in large out-bred animal models has been much less promising. In addressing this issue, we have investigated the ability of ovine cytotoxic lymphocyte antigen 4 (CTLA-4) mediated targeting and ruminant specific CpG optimised plasmids, both alone and in combination, to enhance immune responses in sheep to the pro cathepsin B (FhCatB) antigen from Fasciola hepatica. In this study, CTLA-4 mediated targeting enhanced the speed and magnitude of the primary antibody response and effectively primed for a potent memory response compared to conventional DNA vaccination alone, which failed to induce a detectable immune response. While the CpG-augmentation of the CTLA-4 targeted construct did not further enhance the magnitude or isotype profile of the CTLA-4 induced antibody titres, it did result in the induction of significant antigen-specific, lymphocyte-proliferative responses that were not observed in any other treatment group, showing for the first time that significant cellular responses can be induced in sheep following DNA vaccination. In contrast, CpG-augmentation in the absence of CTLA-4 mediated targeting failed to induce a detectable immune response. This is the first study to explore the potential adjuvant effects of ruminant specific CpG motifs on DNA vaccine induced immune responses in sheep. The ability of CpG-augmented CTLA-4 mediated targeting to induce both humoral and cellular immune responses in this study suggests that this may be an effective approach for enhancing the efficacy of DNA vaccines in large out-bred animal models.

Adjuvants, Immunologic↗
PubMed1996

Blocking of iron uptake by monoclonal antibodies specific for the Neisseria meningitidis transferrin-binding protein 2.

The existence of epitopes common to different strains in the Neisseria meningitidis transferrin (Tf)-binding protein 2 (TBP2), combined with the ability of polyclonal anti-TBP2 antibodies to inhibit Tf binding and block iron uptake in this species, led to this study on the effect of anti-TBP1+2 monoclonal antibodies (MAbs) to determine the presence of epitopes inside the Tf-binding region. All MAbs used reacted exclusively with the homologous strain when tested by dot-blots of outer membrane vesicles, with the reaction being specific for TBP2 after SDS-PAGE and electroblotting. In contrast, ELISA and iron-uptake blocking assays were also positive with heterologous strains belonging to Rokbi's group II (high mol.wt TBP2). The results confirmed the two group classification proposed by Rokbi and, in contrast to other studies, indicated the existence of epitopes in the Tf-binding region that are common only to strains of Rokbi's group II. These epitopes may become denatured after drying for dot-blot assays or after SDS-PAGE and electroblotting.

Animals↗
PubMedDate not supplied

Applications of endoscopic ultrasonography in pancreatic cancer.

BACKGROUND: Accurate staging of pancreatic cancer is essential for surgical planning and for identification of locally advanced and metastatic disease that is incurable by surgery. Advances in endoscopic sonography (EUS), computed tomography (CT), and positron emission tomography have improved the accuracy of staging and reduced the number of incomplete surgical resections. Tissue acquisition is necessary in nonsurgical cases when chemoradiotherapy is considered. The complex regional anatomy of the pancreas makes cytologic diagnosis of malignancy at this region difficult without exploratory surgery. Although CT-guided fine-needle aspiration (FNA) is used for this purpose, reports of an increased risk of peritoneal dissemination of cancer cells and a false-negative rate of nearly 20% make this a poor choice. The ability to position the EUS-transducer in direct proximity to the pancreas by means of the stomach and duodenum, combined with the use of FNA, increases the specificity of EUS in detecting pancreatic malignancies. METHODS: The current literature regarding the accuracy of EUS with FNA in the evaluation of pancreatic cancer is reviewed. RESULTS: EUS accuracy ranges from 78% to 94% for tumor staging and from 64% to 82% for nodal staging. EUS also enables FNA of lesions that are too small to be identified by CT or MRI or too well encased by surrounding vascular structures to safely allow percutaneous biopsy. The accuracy for detecting invasion into the superior mesenteric artery and vein is lower than that for detecting portal or splenic vein invasion, especially for large tumors. EUS permits delivery of localized therapy such as celiac plexus neurolysis for pain control and direct intra-lesional injection of antitumor therapy. CONCLUSIONS: EUS in combination with FNA is a highly accurate method of preoperative staging of pancreatic cancer, especially those too small to be characterized by CT or MRI, and it has the ability to obtain cytological confirmation of pancreatic cancer.

Adenocarcinoma↗
PubMed1992

Effect of donor and recipient immunization protocols on primary and secondary human antibody responses in SCID mice reconstituted with human peripheral blood mononuclear cells.

We have examined the ability of mice with severe combined immunodeficiency (SCID mice) reconstituted with human peripheral blood mononuclear cells (PBMC) to generate human antibody responses after specific immunization. SCID mice reconstituted with cells from a keyhole limpet hemocyanin (KLH)-naive donor are unable to generate specific human antibody responses after immunization with that antigen. After KLH immunization, SCID mouse recipients of human PBMC from a KLH-immune subject develop specific human antibody levels exceeding those of the donor. Human antitetanus antibody titers in reconstituted, immunized mice are also equivalent to those of the donor, provided that the mice are immunized within days of human cell transplantation. The ability of reconstituted mice to generate high titers of specific human antibody is lost within 35 days of human cell reconstitution, even though titers of total human immunoglobulin (Ig) are preserved. SCID mice reconstituted with tetanus-immune donor cells fail to generate IgA responses after booster immunization, and IgM responses are low or nonexistent. These data indicate that early exposure of the adoptive recipients of human cells to antigen is required to transfer specific human humoral responses. These findings are also consistent with a requirement for persistence of antigen for the maintenance of B-cell memory. The ability to achieve specific human antibody levels equivalent to those obtained with humans indicates that reconstituted mice may be useful for the evaluation of human antibody-mediated mechanisms of resistance to infection. The data indicate, however, that cells from immunized donors will have to be used for such studies.

Animals↗
PubMed1994

Histomorphometric analysis of the repair of a segmental diaphyseal defect with ceramic and titanium fibermetal implants: effects of bone marrow.

We used a rat femoral diaphyseal defect/implant model to quantify the ingrowth of bone, cartilage, and fibrous connective tissue in a comparative study of woven sintered titanium fibermetal and porous hydroxyapatite/tricalcium phosphate ceramic implanted with and without the addition of syngeneic bone marrow cells. The patterns of tissue growth into the implants were analyzed with respect to time, type of implant, and the presence or absence of syngeneic marrow. Significantly more bone was found in ceramic implants than in fibermetal implants, with the addition of syngeneic marrow than without it, and at 4 months than at 2 months. Significantly more bone was found at both time periods in ceramic implants with bone marrow than in any other combination studied. We hypothesize that these findings resulted from interactions between the implanted material and its surroundings, specifically its ability to serve as a substratum for cell attachment, and cells in and around the defect, whether surgically implanted or arising from the soft-tissue bed.

Animals↗
PubMed1994

Analysis of neuropeptides by perfusion liquid chromatography/electrospray ion-trap mass spectrometry.

Perfusion high-performance liquid chromatography (HPLC) combined with electrospray ion trap mass spectrometry (ITMS) was evaluated for the determination of neuropeptides in plasma. Perfusion HPLC offers the capability of resolving neuropeptides spiked into plasma in 5 min compared to the 30-60 min separations performed on packed capillary C18 columns. Electrospray combined with the ITMS provides the ability to ionize these neuropeptides and mass analyze them with high sensitivity and specificity. Sub-picomole quantities of neuropeptides injected on-column could be specifically detected in a plasma matrix. The electrospray-ITMS mass spectrum of each neuropeptide showed multiply charged ions which could be used to determine or confirm their molecular weights.

Chromatography, High Pressure Liquid↗
PubMed1995

A new embryonic stem cell line from DBA/1lacJ mice allows genetic modification in a murine model of human inflammation.

The development of embryonic stem (ES) cells and their capacity to generate mice with mutations at specific loci has provided a powerful resource for functional analysis of genes in pathological processes. However, the ability to combine this technology with the large number of existing murine models of human genetic disease has been complicated by the inability to routinely generate ES cell lines from strains other than 129. Here, we report the production of a novel ES cell line derived from an inbred mouse, DBA/1lacJ. This new ES cell line undergoes homologous recombination and efficient colonization of the germline of male chimeric offspring with ES cell microinjection into C57B1/6 embryos. The DBA/1lacJ mouse is a murine model of human inflammation, therefore genetic modifications in the DBA ES cells will allow evaluation of the target gene's role in the inflammatory process.

5-Lipoxygenase-Activating Proteins↗
PubMed2006

Retrovirus vectors: toward the plentivirus?

Recombinant retroviral vectors based upon simple gammaretroviruses, complex lentiviruses, or potentially nonpathogenic spumaviruses represent relatively well characterized tools that are widely used for stable gene transfer. Different members of the Retroviridae family have developed distinct and potentially useful features related to their life cycle. These natural differences can be exploited for specialized applications in gene therapy and could conceivably be combined to create future retroviral hybrid vectors, ideally incorporating the following features: an efficient, noncytopathic packaging system with low likelihood of recombination; serum resistance; an ability to pseudotype with cell-specific envelopes; high-fidelity reverse transcription before cell entry; unrestricted cytoplasmic transport and nuclear import; an insulated expression cassette; specific chromosomal targeting; and physiologic or regulated levels of transgene expression. We envisage that, compared to contemporary vectors, a hybrid vector combining these properties would have increased therapeutic efficacy and an enhanced biosafety profile. Many of the above goals will require the inclusion of nonretroviral components into vector particles or transgenes.

Animals↗
PubMed1999

Assessment of wood utility pole climbability using psychophysical and mechanical measurements.

The issue of climbability has been raised on several occasions for more than a decade in North America. Presently, climbability is estimated from the pole hardness measured by the Pilodyn measurements (6 J). However, the use of Pilodyn measurements to discriminate the pole hardness value is criticized by climbers, who claim that the Pilodyn hardness measurement is affected by species-treatment combinations and that it does not reflect gaff penetration or climbability. Furthermore, climbability evaluations have been conducted in which test poles were climbed by linemen, and corresponding subjective ratings were recorded. However, the ability of psychophysical measurements to accurately discriminate close hardness pole values and to differentiate species-treatment combinations at specific hardness levels have not yet been fully documented. The aim of this study is to evaluate the psychophysical perception of linemen and the mechanical measurements of gaff penetration and gaff impact during the climbing of different wood species and treatment combinations in order to compare these results with Pilodyn measurements within a precise range of pole hardnesses, to study the relationships between these variables, and, finally, to propose various design guidelines for the development of a better tool for the evaluation of climbability.

Adult↗
PubMed2005

Neuropsychological deficits, syndromes, and cognitive competency in schizophrenia.

INTRODUCTION: Neuropsychological functioning connects neuropathology and symptoms in schizophrenia. Previous work suggests that deficient initiation and inhibition underlie the psychomotor poverty and disorganisation syndromes, respectively. Furthermore, although the syndromes are associated with impairments in everyday functioning, cognitive competency (CC; cognitive skills for independent living) has been neglected as an outcome. This study tested a three-level model of schizophrenia pathology (Neuropsychological dysfunction --> Syndromes --> CC), using unstructured neuropsychological tasks to measure initiation and inhibition. METHODS: Participants were 40 adults with schizophrenia. A verbal picture description and the Tinkertoy test yielded initiation and inhibition measures with good interrater reliability. Symptoms were rated using the SANS and SAPS, and an insight scale was administered. The Cognitive Competency Test utilised simulated situations to assess CC. RESULTS: Initiation failed to predict psychomotor poverty, but affected CC directly. Only one indicator of disinhibition (intermingling of personal material into speech) predicted disorganisation, which, through mediation, led to CC deficits. Insight correlated with disorganisation and contributed to CC. Unique effects of initiation, disorganisation, and insight, combined, explained 58% of CC variance. CONCLUSIONS: Partial support for the three-level model was obtained. Specific neuropsychological abilities and symptoms explain a substantial proportion of the variance in cognitive competency.

Journal Article↗
PubMed1999

Selective histocompatibility leukocyte antigen (HLA)-A2 loss caused by aberrant pre-mRNA splicing in 624MEL28 melanoma cells.

Histocompatibility leukocyte antigen (HLA)-A2 is used as a restricting element to present several melanoma-associated antigen (MAA)-derived peptides to cytotoxic T lymphocytes (CTLs). HLA-A2 antigen is selectively lost in primary melanoma lesions and more frequently in metastases. Only scanty information is available about the molecular mechanisms underlying this abnormality, in spite of its potentially negative impact on the clinical course of the disease and on the outcome of T cell-based immunotherapy. Therefore, in this study we have shown that the selective HLA-A2 antigen loss in melanoma cells 624MEL28 is caused by a splicing defect of HLA-A2 pre-mRNA because of a base substitution at the 5' splice donor site of intron 2 of the HLA-A2 gene. As a result, HLA-A2 transcripts are spliced to two aberrant forms, one with exon 2 skipping and the other with intron 2 retention. The latter is not translated because of an early premature stop codon in the retained intron. In contrast, the transcript with exon 2 skipping is translated to a truncated HLA-A2 heavy chain without the alpha(1) domain. Such a polypeptide is synthesized in vitro but is not detectable in cells, probably because of the low steady state level of the corresponding mRNA and the low translation efficiency. These results indicate that a single mutational event in an HLA class I gene is sufficient for loss of the corresponding allele. This may account, at least in part, for the high frequency of selective HLA class I allele loss in melanoma cells. Our conclusion emphasizes the need to implement active specific immunotherapy with a combination of peptides presented by various HLA class I alleles. This strategy may counteract the ability of melanoma cells with selective HLA class I allele loss to escape from immune recognition.

Alternative Splicing↗
PubMed2026

Target-Site Selection by Transcription Factors: Roles of DNA, Chromatin, and Cofactor-Mediated Regulation.

Transcription factors (TFs) are sequence-specific DNA-binding proteins that regulate gene-expression programs and cell fate. The ability of a defined combination of four TFs to reprogram differentiated cells into induced pluripotent stem cells illustrates the powerful role of TFs in determining cellular identity. However, TFs usually recognize short and degenerate DNA motifs of approximately 6-12 base pairs, generating thousands to millions of potential motif matches in mammalian genomes. In living cells, TFs occupy only a restricted subset of these sites, indicating that motif presence alone is insufficient for functional target selection. Several layers of regulation contribute to this selective occupancy, including DNA methylation, nucleosome organization, histone modifications, chromatin remodeling, TF oligomerization, TF availability and localization, and cofactors that regulate DNA-binding domains. This review outlines how DNA/chromatin features and TF-centered mechanisms contribute to target-site selection. The principal aim is to highlight DNA-binding domain-directed cofactor regulation as an underappreciated mechanism that modulates TF-DNA binding and may help explain selective genomic occupancy.

Target-site selection↗
PubMed2006

Sensitivity and specificity of immunohistochemical antibodies used to distinguish between benign and malignant pleural disease: a systematic review of published reports.

AIMS: A systematic review of published reports that have evaluated the ability of immunohistochemistry and argyrophil nucleolar organizing region (AgNOR) staining to distinguish between benign and malignant pleural disease. METHODS: Nineteen relevant papers published during the period 1979-2005 were identified. Individual results of immunohistochemistry for five diagnostic antibodies were extracted to calculate diagnostic sensitivity and specificity. results from five of these studies that had evaluated proliferation markers or AgNOR staining techniques were also summarized. RESULTS: Most antibodies demonstrated poor to moderate diagnostic ability. Desmin and epithelial membrane antigen (EMA) were the most useful, with sensitivity and specificity both above 74%. The combination of EMA and AgNOR was reported as having 95% diagnostic sensitivity. A high MCM2 labelling index also differentiated between benign and malignant pleural disease. CONCLUSIONS: Immunohistochemistry is of limited value, but newer diagnostic methods may be useful additions in this area of pathology. The diagnostic importance of histological features seen on plain tissue sections is emphasized as vital for correctly differentiating between benign pleural disease and malignant pleural mesothelioma.

Antigens, Neoplasm↗
PubMed1992

Regulation of gene expression by cytokines and virus in human cells lacking the type-I interferon locus.

A number of genes that are induced by type-I interferons are also activated by one or more other inducers, including double-stranded RNA, viruses, interferon-gamma, interleukin-1 and tumor necrosis factor. However, these inducers can also activate the expression of type-I interferons. Thus, the activation of type-I interferon-inducible genes by these other inducers could be direct, or a secondary consequence of the induction of interferon. To distinguish between these possibilities, we have used cell lines lacking all type-I interferon genes to study the direct effect of potential inducers on the expression of 14 interferon-inducible human genes. We show that double-stranded RNA, virus, interferon-gamma or tumor necrosis factor-alpha can act directly to induce specific subsets of type-I interferon-inducible genes in the absence of any possible type-I interferon involvement. The cis-acting element which confers inducibility by type-I interferon has been shown in some cases to confer inducibility by interferon-gamma, double-stranded RNA or virus as well. However, not all promoters containing such an element respond to both interferon and other inducers. Thus, the ability of a given gene to respond to different inducers most likely depends on the exact nature and specific combination of cis-acting elements present in its promoter.

Animals↗
PubMed1993

The adenovirus E1A 12S product displays functional redundancy in activating the human proliferating cell nuclear antigen promoter.

The adenovirus E1A 243R oncoprotein stimulates expression from the promoter of the human proliferating cell nuclear antigen (PCNA). To gain insight into the mechanism of activation, we analyzed deletion and point mutations of the 243R protein for their abilities to activate PCNA promoter-directed reporter gene expression upon cotransfection into HeLa cells. Large deletions that in combination span the entire protein severely impaired the ability of E1A 243R to induce PCNA expression. Smaller deletions and specific point mutations that target specific E1A-binding proteins were less deleterious to PCNA induction. The data suggest that E1A activates transcription of the PCNA gene by multiple mechanisms and that, of the known 243R-associated proteins, p300 and p107-cyclin A can mediate the response while p105-RB does not appear to participate. Presumably, the functional redundancy ensures that 243R can activate expression of this essential DNA replication protein regardless of cell type and physiological conditions.

Adenovirus E1A Proteins↗
PubMed2004

CP-64131, an aminobenzazepine with cytokine-like properties, stimulates human neutrophil functions through the p38-MAPK pathway.

CP-64131 (CP), an aminobenzazepine with cytokine-like, physiologic effects similar to granulocyte-colony stimulating factor (G-CSF) and granulocyte macrophage (GM)-CSF, increases the number of neutrophils and stimulates marrow recovery after doxirubicin ablation. CP can also function as a neutrophil agonist, like formyl-Met-leu-Phe (fMLP). In these studies, we show that CP is unique in that it stimulates the p38-mitogen-activated protein kinase (MAPK) pathway but not extracellular signal-regulated kinase (ERK)1/2 or c-jun N-terminal kinase MAPKs in human neutrophils from peripheral blood. This is in contrast to other neutrophil agonists such as fMLP, interleukin (IL)-8, or GM-CSF, which stimulate multiple MAPK pathways. Like fMLP and IL-8, CP is capable of stimulating superoxide (O2-) production, CD11b expression, and cell polarization in human neutrophils. CP-stimulated O2- production is completely dependent on p38-MAPK activation, as determined by sensitivity to the p38-MAPK inhibitor SB203580. In contrast, SB203580 only partially inhibits expression of CD11b and has no effect on cell polarization stimulated by CP. Therefore, CP treatment of neutrophils activates p38-MAPK but has effects independent of p38-MAPK activation. In human embryonic kidney 293 cells, a human kidney epithelial cell line CP stimulates p38-MAPK and modestly activates ERK1/2. The findings define CP as a novel, small molecule, which has little cellular toxicity in vitro. CP has the ability to activate specific MAPK pathways in different cell types and should prove to be an effective agonist in combination with inhibitors to study biological responses regulated by MAPKs.

Adjuvants, Immunologic↗