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Cross Infection↗
Biomedical subjects
A Bateman
Publications and source records attributed to A Bateman.
Fusogenic membrane glycoprotein-mediated tumour cell fusion activates human dendritic cells for enhanced IL-12 production and T-cell priming.
Fusogenic membrane glycoproteins (FMG) are a family of viral genes that, when expressed in tumour cells, trigger extensive cell to cell fusion and subsequent cell death. Gene therapy approaches using FMG are also potentially immunogenic, since syncitia generated ex vivo can be therapeutic as antitumour vaccines in murine models. This study has addressed the mechanisms responsible for the immunogenicity of FMG-mediated cell death, and its applicability to human immune priming. We show that fusion of human Mel888 melanoma cells following transfection with FMG can reverse the suppressive effects of Mel888 on dendritic cells (DC) phenotype, and potentiate IL-12 production by DC on activation in a cell contact-dependent manner. DC loaded with fusing, but not intact, tumour cells primed a naive, tumour-specific cytotoxic T-cell response, which was MHC class I-restricted and associated with production of high levels of IFNgamma and, later, IL-5. Fusing cells were an effective source of antigen for DC cross-priming and presentation of the melanoma-specific antigen gp100 to a specific T-cell clone. These data show, in a human system, that FMG represent an immunogenic, as well as cytotoxic, gene therapy for cancer, reversing the inhibitory effects of tumour cells on DC to potentiate IL-12 production and naive T-cell priming.
B7-2 Antigen↗
Immunosuppressive effects of radiation on human dendritic cells: reduced IL-12 production on activation and impairment of naive T-cell priming.
Dendritic cells (DC) are professional antigen-presenting cells (APC) of the immune system, uniquely able to prime naive T-cell responses. They are the focus of a range of novel strategies for the immunotherapy of cancer, a proportion of which include treating DC with ionising radiation to high dose. The effects of radiation on DC have not, however, been fully characterised. We therefore cultured human myeloid DC from CD14+ precursors, and studied the effects of ionising radiation on their phenotype and function. Dendritic cells were remarkably resistant against radiation-induced apoptosis, showed limited changes in surface phenotype, and mostly maintained their endocytic, phagocytic and migratory capacity. However, irradiated DC were less effective in a mixed lymphocyte reaction, and on maturation produced significantly less IL-12 than unirradiated controls, while IL-10 secretion was maintained. Furthermore, peptide-pulsed irradiated mature DC were less effective at naive T-cell priming, stimulating fewer effector cells with lower cytotoxicity against antigen-specific targets. Hence irradiation of DC in vitro, and potentially in vivo, has a significant impact on their function, and may shift the balance between T-cell activation and tolerization in DC-mediated immune responses.
Apoptosis↗
Radiation-induced cell death and dendritic cells: potential for cancer immunotherapy?
Dendritic cells are key orchestrators of the immune system. There is considerable interest in their use for treating cancer. Whether they initiate an effective cytotoxic response against antigen-bearing cells, or produce tolerance, depends on the context in which those antigens are presented. Ionising radiation, and the cell death it causes, has several properties that may facilitate such an effective response. A range of in-vitro and in-vivo data supports this, although potential problems exist that may require concurrent strategies.
Antigens, Neoplasm↗
Estimation of bioavailability of DL-methionine hydroxy analogue relative to DL-methionine in layers with exponential and slope-ratio models.
An experiment was conducted using molted hens to estimate the bioavailability of DL-methionine hydroxy analogue-free acid (MHA-FA) relative to DL-methionine (DLM). In this experiment, 5 supplemental levels (0.012, 0.024, 0.036, 0.048, and 0.060%) of DLM or equimolar concentrations of MHA-FA were added to a basal diet containing 14.97% protein and 0.27% methionine. The low protein diet was used to increase the sensitivity of laying hens to methionine deficiency. Feed consumption, egg production, egg mass, and egg weight increased (P < 0.05), and feed conversion decreased (P < 0.05) when DLM or MHA-FA was added to the basal diet for some supplemental methionine levels. There was no difference (P > 0.05) in feed consumption between hens fed DLM and hens fed MHA-FA. Regression analysis showed that the bioavailability of MHA-FA relative to DLM on a molar basis was 88.7% (egg production), 88.0% (egg mass), and 84.6% (egg weight) with the exponential model, and was 89.7% (egg production), 89.6% (egg mass), and 86.8% (egg weight) with the slope-ratio model. The average bioavailability of MHA-FA relative to DLM was 88% on a molar basis.
Animal Feed↗
Intratumoral expression of a fusogenic membrane glycoprotein enhances the efficacy of replicating adenovirus therapy.
We describe here a novel strategy to enhance the in vivo efficacy of replicating adenovirus therapy, using coinjection of plasmid DNA encoding a fusogenic viral glycoprotein. The combination of fusogenic membrane glycoprotein (FMG)-induced tumor cell fusion and infection with replicating adenovirus effectively treats even large established tumors at doses of plasmid DNA and virus that alone are ineffective. Adenoviral infection appears to increase the transduction of the tumor cells to a modest degree thereby boosting the FMG-mediated component of the therapy. Simultaneously, syncytial formation enhances the therapeutic effects of viral infection by increasing spread of adenoviral particles through the tumor cell population and by increasing titer of virus released from the tumor cells. This effect is due probably to release of intracellular viral particles upon tumor cell death and also to increased levels of E1A protein within syncytia, whose increased metabolic rate is associated with enhanced levels of protein expression. Cotransduction of tumor cells with replicating adenovirus and FMG-expressing vectors could either be combined within single replicating vectors or could be used in strategies using separate administration of two components, both at lower doses than required for either therapy alone.
Adenoviridae↗
The effect of increasing effort on movement economy during incremental cycling exercise in individuals early after acquired brain injury.
OBJECTIVE: To investigate the effect of increasing effort on energy cost as measured by oxygen consumption (VO2) during cycling exercise in individuals early after acquired brain injury (ABI). DESIGN: An experimental correlation design. SETTING: Specialist neurorehabilitation centre. PARTICIPANTS: Thirty-eight individuals were recruited early after acquired brain injury. Nine individuals had spasticity; Ashworth Scale >1 in either upper or lower limbs. INTERVENTION: The VO2 was measured in relation to workload during a graded exercise test. RESULTS: The VO2 increased in a linear fashion with increases in workload in 34 individuals. Only one individual with spasticity demonstrated a nonlinear relationship. CONCLUSION: Increasing the workload during cycling exercise does not disproportionately increase energy cost in most individuals with spasticity early after ABI.
Activities of Daily Living↗
Progranulin (granulin-epithelin precursor, PC-cell derived growth factor, acrogranin) in proliferation and tumorigenesis.
The granulin-epithelin precursor, progranulin, PC-cell-derived growth factor or acrogranin, is a high molecular weight secreted mitogen. It is abundantly expressed in rapidly cycling epithelial cells, in the immune system and in neurons, such as cerebellar Purkinje cells. Progranulin contributes to tumorigenesis in diverse cancers, including breast cancer, clear cell renal carcinoma, invasive ovarian carcinoma and glioblastoma. It regulates the rate of epithelial cell division in responsive epithelial cells, and confers an invasive phenotype on these cells. It is involved in the wound response. During embryogenesis, progranulin accelerates blastocyst formation, and is a growth factor for trophectodermal cells. In the neonate, progranulin, regulates the hormone-dependent virilization of the hypothalamus. It activates phosphorylation of Shc, and p44/42 MAPK (mitogen activated protein kinase) in the ERK (extracellular regulated kinase) signaling pathway; PI3K (phosophatidyl inositol-3-kinase), AKT/protein kinase B, and p70S6kinase in the phosophatidyl inositol-3-kinase pathway; and focal adhesion kinase in the adhesion/motility pathway. The signaling properties of progranulin are apparently similar to those of classic growth factors, but the functional properties of progranulin distinguish it from these molecules. Deleting the insulin-like growth factor I receptor from murine embryonic fibroblasts blocks proliferation in response to all classic growth factors, such as epidermal growth factor, or platelet-derived growth factor, whereas progranulin retains mitotic activity on these cells. The defined biological actions of progranulin probably represent a small fraction of its overall functions. Transcriptome analyses show that the progranulin gene is induced in numerous situations that vary from obesity to the transcriptional response of cells to antineoplastic drugs. Here, the biological roles of progranulin will be reviewed, with an emphasis on cancer and cell proliferation.
Animals↗
Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2).
Streptomyces coelicolor is a representative of the group of soil-dwelling, filamentous bacteria responsible for producing most natural antibiotics used in human and veterinary medicine. Here we report the 8,667,507 base pair linear chromosome of this organism, containing the largest number of genes so far discovered in a bacterium. The 7,825 predicted genes include more than 20 clusters coding for known or predicted secondary metabolites. The genome contains an unprecedented proportion of regulatory genes, predominantly those likely to be involved in responses to external stimuli and stresses, and many duplicated gene sets that may represent 'tissue-specific' isoforms operating in different phases of colonial development, a unique situation for a bacterium. An ancient synteny was revealed between the central 'core' of the chromosome and the whole chromosome of pathogens Mycobacterium tuberculosis and Corynebacterium diphtheriae. The genome sequence will greatly increase our understanding of microbial life in the soil as well as aiding the generation of new drug candidates by genetic engineering.
Bacterial Proteins↗
Use of viral fusogenic membrane glycoproteins as novel therapeutic transgenes in gliomas.
Malignant gliomas are the most common primary brain tumors in adults and, with few exceptions, have a dismal prognosis despite the therapeutic use of surgery, radiation therapy, and chemotherapy. Because CNS gliomas rarely metastasize, they represent an attractive target for gene therapy through local gene delivery. Here we report on the use of two different fusogenic membrane glycoproteins (FMGs), the measles virus proteins F and H (MV-F and MV-H) and a mutated form of the retroviral envelope protein of the gibbon ape leukemia virus (GALV.fus), as a novel class of therapeutic transgenes in gliomas. Transfection of U87 and U118 cells with MV-F and MV-H cDNA or GALV.fus cDNA led in 48 hr to massive syncytial formation followed by cell death. FMG-mediated cytotoxicity in the U87 and U118 cell lines was superior to the cytotoxicity caused by transfection with HSV-tk cDNA followed by ganciclovir (GCV) treatment at all time points. At high-density cell seeding, addition of tumor cells transfected with MV-F and H killed at least 1 log more cells than by HSV-tk + GCV treatment, indicating higher bystander effect. Similar results were obtained with GALV.fus. The mechanism of syncytial death in cultured glioma cell lines was predominantly apoptotic. Transfection of U87 cells with F + H or GALV.fus expression constructs completely suppressed their tumorigenicity. Treatment of established U87 xenografts in nude mice with a combination of F and H adenoviruses at 1:1 ratio led to complete tumor regression, significantly higher antitumor effect, and prolongation of survival as compared with control animals treated with a GFP adenovirus. In summary, the viral fusogenic membrane glycoproteins (GALV and the MV-F + MV-H combination) are potent therapeutic transgenes with potential utility in the gene therapy of gliomas.
Animals↗
Mining the draft human genome.
Now that the draft human genome sequence is available, everyone wants to be able to use it. However, we have perhaps become complacent about our ability to turn new genomes into lists of genes. The higher volume of data associated with a larger genome is accompanied by a much greater increase in complexity. We need to appreciate both the scale of the challenge of vertebrate genome analysis and the limitations of current gene prediction methods and understanding.
Animals↗
The InterPro database, an integrated documentation resource for protein families, domains and functional sites.
Signature databases are vital tools for identifying distant relationships in novel sequences and hence for inferring protein function. InterPro is an integrated documentation resource for protein families, domains and functional sites, which amalgamates the efforts of the PROSITE, PRINTS, Pfam and ProDom database projects. Each InterPro entry includes a functional description, annotation, literature references and links back to the relevant member database(s). Release 2.0 of InterPro (October 2000) contains over 3000 entries, representing families, domains, repeats and sites of post-translational modification encoded by a total of 6804 different regular expressions, profiles, fingerprints and Hidden Markov Models. Each InterPro entry lists all the matches against SWISS-PROT and TrEMBL (more than 1,000,000 hits from 462,500 proteins in SWISS-PROT and TrEMBL). The database is accessible for text- and sequence-based searches at http://www.ebi.ac.uk/interpro/. Questions can be emailed to interhelp@ebi.ac.uk.
Databases, Factual↗
CASP2 knowledge-based approach to distant homology recognition and fold prediction in CASP4.
In 1996, in CASP2, we presented a semimanual approach to the prediction of protein structure that was aimed at the recognition of probable distant homology, where it existed, between a given target protein and a protein of known structure (Murzin and Bateman, Proteins 1997; Suppl 1:105-112). Central to our method was the knowledge of all known structural and probable evolutionary relationships among proteins of known structure classified in the SCOP database (Murzin et al., J Mol Biol 1995;247:536-540). It was demonstrated that a knowledge-based approach could compete successfully with the best computational methods of the time in the correct recognition of the target protein fold. Four years later, in CASP4, we have applied essentially the same knowledge-based approach to distant homology recognition, concentrating our effort on the improvement of the completeness and alignment accuracy of our models. The manifold increase of available sequence and structure data was to our advantage, as well as was the experience and expertise obtained through the classification of these data. In particular, we were able to model most of our predictions from several distantly related structures rather than from a single parent structure, and we could use more superfamily characteristic features for the refinement of our alignments. Our predictions for each of the attempted distant homology recognition targets ranked among the few top predictions for each of these targets, with the predictions for the hypothetical protein HI0065 (T0104) and the C-terminal domain of the ABC transporter MalK (T0121C) being particularly successful. We also have attempted the prediction of protein folds of some of the targets tentatively assigned to new superfamilies. The average quality of our fold predictions was far less than the quality of our distant homology recognition models, but for the two targets, chorismate lyase (T0086) and Appr>p cyclic phosphodiesterase (T0094), our predictions achieved the top ranking.
ATP-Binding Cassette Transporters↗
A transcriptional feedback loop for tissue-specific expression of highly cytotoxic genes which incorporates an immunostimulatory component.
Transcriptional targeting of cytotoxic genes is an important way to control toxicity associated with gene transfer therapies, but supposedly, tissue-specific promoters are often either very weak and/or leaky. In addition, the phenotypic leakiness of such tissue-specific promoters is dependent upon the toxicity of the gene being used. Therefore, we devised a transcriptional feedback loop to restrict gene expression of very potent genes to melanoma cells. We screened different elements of the human tyrosinase promoter to find one which gave no detectable expression in non-melanoma cells but was active in melanoma cell lines. This weak, but highly tissue specific, element (Tyr-300) was then used as the basis for a transcriptional amplification feedback loop in which a consensus heat shock element (HSE) was cloned upstream of Tyr-300. The cytotoxic gene was cloned downstream of the HSE-Tyr-300 element along with a mutated form of the heat shock factor-1 (HSF-1) transcription factor, which no longer requires cellular stress to activate its trimerisation, nuclear localisation and transcriptional activation properties. Low levels of expression from Tyr-300 initiated expression of both the cytotoxic and the HSF-1 genes in melanoma cells. Gradual build up of HSF-1 amplified expression through binding to the HSE to give levels of cytotoxicity similar to that provided by a CMV promoter. However, no leakiness was observed in multiple non-melanoma cell lines tested. In addition to amplifying low levels of weak tissue-specific expression, the use of HSF-1 also leads to activation of endogenous stress-related genes such as hsp70. Induction of these genes, in the presence of cell killing by the cytotoxic gene, is a highly immunostimulatory event which enhances the antitumour vaccination effects of direct tumour cell destruction. Having demonstrated the compatibility of the component elements in plasmid form, we incorporated the feedback loop into a hybrid LTR-modified retroviral vector and confirmed that the system can be effective in the form of a viral vector. The format of the feedback loop described here could be exploited for any tissue type in which a highly tissue-specific element can be identified but which is itself too weak to be effective therapeutically.
Animals↗
The effect of aerobic training on rehabilitation outcomes after recent severe brain injury: a randomized controlled evaluation.
OBJECTIVE: To examine the impact of fitness training with recently brain-injured inpatients on exercise capacity and functional and psychologic outcome measures. DESIGN: A randomized controlled trial of exercise versus relaxation training for 3 months. Blind assessments were conducted before and after the end of a 12-week training program, as well as at follow-up assessment 12 weeks posttraining. SETTING: Four regional neurologic inpatient rehabilitation units. PATIENTS: Of 157 patients recruited 24 +/- 14 weeks after single-incident brain injury, 142 patients were assessed at week 12, and 128 patients at follow-up. INTERVENTIONS: Patients were randomized between cycle ergometer aerobic training and a relaxation training control condition, which was theoretically inert with respect to cardiovascular fitness. MAIN OUTCOME MEASURES: Validation of exercise training (peak work rate, peak heart rate, body mass index); mobility and physical function (modified Ashworth scale, Berg balance scale, Rivermead Mobility Index, 10-m walk velocity); disability and dependency (Barthel index, FIMtrade mark instrument, Nottingham Extended Activities of Daily Living); and psychologic function (fatigue questionnaire, Hospital Anxiety and Depression Scale). RESULTS: Significant improvements in exercise capacity (p <.05) in the exercise training group (n = 70) relative to the control group (n = 72) were not matched by greater improvements in functional independence, mobility, or psychologic function, at either 12 weeks or follow-up. CONCLUSIONS: The benefits of improved cardiovascular fitness did not appear to extend to measurable change in function or psychologic state.
Activities of Daily Living↗
HOMSTRAD: adding sequence information to structure-based alignments of homologous protein families.
summary: We describe an extension to the Homologous Structure Alignment Database (HOMSTRAD; Mizuguchi et al., Protein Sci., 7, 2469-2471, 1998a) to include homologous sequences derived from the protein families database Pfam (Bateman et al., Nucleic Acids Res., 28, 263-266, 2000). HOMSTRAD is integrated with the server FUGUE (Shi et al., submitted, 2001) for recognition and alignment of homologues, benefitting from the combination of abundant sequence information and accurate structure-based alignments. AVAILABILITY The HOMSTRAD database is available at: http://www-cryst.bioc.cam.ac.uk/homstrad/. Query sequences can be submitted to the homology recognition/alignment server FUGUE at: http://www-cryst.bioc.cam.ac.uk/fugue/.
Computational Biology↗
A novel 3' mutation in the APC gene in a family presenting with a desmoid tumour.
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Adenomatous Polyposis Coli↗
Treatment of borderline personality disorder with psychoanalytically oriented partial hospitalization: an 18-month follow-up.
OBJECTIVE: The aim of this study was to determine whether the substantial gains made by patients with borderline personality disorder following completion of a psychoanalytically oriented partial hospitalization program, in comparison to patients treated with standard psychiatric care, were maintained over an 18-month follow-up period. METHOD: Forty-four patients who participated in the original study were assessed every 3 months after completion of the treatment phase. Outcome measures included frequency of suicide attempts and acts of self-harm, number and duration of inpatient admissions, service utilization, and self-reported measures of depression, anxiety, general symptom distress, interpersonal functioning, and social adjustment. RESULTS: Patients who completed the partial hospitalization program not only maintained their substantial gains but also showed a statistically significant continued improvement on most measures in contrast to the patients treated with standard psychiatric care, who showed only limited change during the same period. CONCLUSIONS: The superiority of psychoanalytically oriented partial hospitalization over standard psychiatric treatment found in a previous randomized, controlled trial was maintained over an 18-month follow-up period. Continued improvement in social and interpersonal functioning suggests that longer-term changes were stimulated.
Borderline Personality Disorder↗