Showing papers by "University of Birmingham published in 1999"
TL;DR: It is indicated that the interaction between HIF-1 and pVHL is iron dependent, and that it is necessary for the oxygen-dependent degradation of HIF α-subunits, which may underlie the angiogenic phenotype of VHL-associated tumours.
Abstract: Hypoxia-inducible factor-1 (HIF-1) has a key role in cellular responses to hypoxia, including the regulation of genes involved in energy metabolism, angiogenesis and apoptosis. The alpha subunits of HIF are rapidly degraded by the proteasome under normal conditions, but are stabilized by hypoxia. Cobaltous ions or iron chelators mimic hypoxia, indicating that the stimuli may interact through effects on a ferroprotein oxygen sensor. Here we demonstrate a critical role for the von Hippel-Lindau (VHL) tumour suppressor gene product pVHL in HIF-1 regulation. In VHL-defective cells, HIF alpha-subunits are constitutively stabilized and HIF-1 is activated. Re-expression of pVHL restored oxygen-dependent instability. pVHL and HIF alpha-subunits co-immunoprecipitate, and pVHL is present in the hypoxic HIF-1 DNA-binding complex. In cells exposed to iron chelation or cobaltous ions, HIF-1 is dissociated from pVHL. These findings indicate that the interaction between HIF-1 and pVHL is iron dependent, and that it is necessary for the oxygen-dependent degradation of HIF alpha-subunits. Thus, constitutive HIF-1 activation may underlie the angiogenic phenotype of VHL-associated tumours. The pVHL/HIF-1 interaction provides a new focus for understanding cellular oxygen sensing.
4,845 citations
TL;DR: A number of 5-HT receptor ligands are currently utilised, or are in clinical development, to reduce the symptoms of CNS dysfunction and the functional responses attributed to each receptor in the brain are reviewed.
3,074 citations
01 Sep 1999
TL;DR: It is shown, through a considerably large literature review, that combinations between ANNs and EAs can lead to significantly better intelligent systems than relying on ANNs or EAs alone.
Abstract: Learning and evolution are two fundamental forms of adaptation. There has been a great interest in combining learning and evolution with artificial neural networks (ANNs) in recent years. This paper: 1) reviews different combinations between ANNs and evolutionary algorithms (EAs), including using EAs to evolve ANN connection weights, architectures, learning rules, and input features; 2) discusses different search operators which have been used in various EAs; and 3) points out possible future research directions. It is shown, through a considerably large literature review, that combinations between ANNs and EAs can lead to significantly better intelligent systems than relying on ANNs or EAs alone.
2,877 citations
01 Jan 1999
TL;DR: A new method of finding the fuzzy weights in fuzzy hierarchical analysis which is the direct fuzzification of the original method used by Saaty (1980) in the analytic hierarchy process is presented.
Abstract: We present a new method of finding the fuzzy weights in fuzzy hierarchical analysis which is the direct fuzzification of the original method used by Saaty (1980) in the analytic hierarchy process. We test our new procedure in two cases where there are formulas for the crisp weights. An example is presented where there are five criteria and three alternatives.
2,789 citations
Harvard University1, McGill University2, University of Birmingham3, University College London4, University of Alabama at Birmingham5, McMaster University6, Dalhousie University7, Anschutz Medical Campus8, Mount Sinai St. Luke's and Mount Sinai Roosevelt9, Hospital for Special Surgery10, University of Michigan11, Detroit Receiving Hospital12, Johns Hopkins University13, Virginia Commonwealth University14, University of Texas at San Antonio15, University of Kiel16, Royal Stoke University Hospital17, University of British Columbia18, Henry Ford Health System19, University of California, Los Angeles20
TL;DR: The American College of Rheumatology Nomenclature for NPSLE provides case definitions for 19 neuropsychiatric syndromes seen in SLE, with reporting standards and recommendations for laboratory and imaging tests.
Abstract: OBJECTIVE
To develop a standardized nomenclature system for the neuropsychiatric syndromes of systemic lupus erythematosus (NPSLE).
METHODS
An international, multidisciplinary committee representing rheumatology, neurology, psychiatry, neuropsychology, and hematology developed case definitions, reporting standards, and diagnostic testing recommendations. Before and after the meeting, clinician committee members assigned diagnoses to sets of vignettes randomly generated from a pool of 108 NPSLE patients. To assess whether the nomenclature system improved diagnostic agreement, a consensus index was developed and pre- and postmeeting scores were compared by t-tests.
RESULTS
Case definitions including diagnostic criteria, important exclusions, and methods of ascertainment were developed for 19 NPSLE syndromes. Recommendations for standard reporting requirements, minimum laboratory evaluation, and imaging techniques were formulated. A short neuropsychological test battery for the diagnosis of cognitive deficits was proposed. In the postmeeting exercise, a statistically significant improvement in diagnostic agreement was observed.
CONCLUSION
The American College of Rheumatology (ACR) Nomenclature for NPSLE provides case definitions for 19 neuropsychiatric syndromes seen in SLE, with reporting standards and recommendations for laboratory and imaging tests. It is intended to facilitate and enhance clinical research, particularly multicenter studies, and reporting. In clinical settings, consultation with other specialists may be required. It should be useful for didactic purposes but should not be used uncritically or as a substitute for a clinical diagnosis. The complete case definitions are available on the ACR World Wide Web site: http://www.rheumatology .org/ar/ar.html.
1,830 citations
Book•
01 Oct 1999
TL;DR: The techniques treated in this text represent research as elucidated by the leaders in the field and are applied to real problems, such as hilllclimbing, simulated annealing, and tabu search.
Abstract: Optimization is a pivotal aspect of software design. The techniques treated in this text represent research as elucidated by the leaders in the field. The optimization methods are applied to real problems, such as hilllclimbing, simulated annealing, and tabu search.
1,461 citations
TL;DR: It is demonstrated that ATM and the hMre11/hRad50/Nbs1 protein complex act in the same DNA damage response pathway and link hMRE11 to the complex pathology of A-T.
1,045 citations
TL;DR: The data suggest that HeLa cells, which lack the known methylation-dependent repressor MeCP2, use an alternative pathway involving MBD2 to silence methylated genes.
Abstract: Mammalian DNA is methylated at many CpG dinucleotides The
biological consequences of methylation are mediated by a family
of methyl-CpG binding proteins (1–4) The best characterized family
member is MeCP2, a transcriptional repressor that recruits histone
deacetylases (5–7) Our report concerns MBD2, which can bind
methylated DNA in vivo and in vitro4 and has been reported to
actively demethylate DNA (ref 8) As DNA methylation causes
gene silencing, the MBD2 demethylase is a candidate transcriptional
activator Using specific antibodies, however, we find here
that MBD2 in HeLa cells is associated with histone deacetylase
(HDAC) in the MeCP1 repressor complex (1,9) An affinity-purified
HDAC1 corepressor complex (10,11) also contains MBD2, suggesting
that MeCP1 corresponds to a fraction of this complex Exogenous
MBD2 represses transcription in a transient assay, and repression
can be relieved by the deacetylase inhibitor trichostatin A (TSA;
ref 12) In our hands, MBD2 does not demethylate DNA Our data suggest that HeLa cells, which lack the known methylationdependent
repressor MeCP2, use an alternative pathway involving
MBD2 to silence methylated genes
925 citations
TL;DR: Straightforward combination of the mechanisms for transcription activation at class I and class II CAP-dependent promoters permits synergistic transcription activation by multiple molecules of CAP, or by CAP and other activators.
786 citations
TL;DR: Results show that Scar and, likely, related proteins, such as the Cdc42 targets WASp and N-WASp, are endogenous activators of actin polymerization by the Arp2/3 complex.
Abstract: The Arp2/3 complex, a stable assembly of two actin-related proteins (Arp2 and Arp3) with five other subunits, caps the pointed end of actin filaments and nucleates actin polymerization with low efficiency. WASp and Scar are two similar proteins that bind the p21 subunit of the Arp2/3 complex, but their effect on the nucleation activity of the complex was not known. We report that full-length, recombinant human Scar protein, as well as N-terminally truncated Scar proteins, enhance nucleation by the Arp2/3 complex. By themselves, these proteins either have no effect or inhibit actin polymerization. The actin monomer-binding W domain and the p21-binding A domain from the C terminus of Scar are both required to activate Arp2/3 complex. A proline-rich domain in the middle of Scar enhances the activity of the W and A domains. Preincubating Scar and Arp2/3 complex with actin filaments overcomes the initial lag in polymerization, suggesting that efficient nucleation by the Arp2/3 complex requires assembly on the side of a preexisting filament—a dendritic nucleation mechanism. The Arp2/3 complex with full-length Scar, Scar containing P, W, and A domains, or Scar containing W and A domains overcomes inhibition of nucleation by the actin monomer-binding protein profilin, giving active nucleation over a low background of spontaneous nucleation. These results show that Scar and, likely, related proteins, such as the Cdc42 targets WASp and N-WASp, are endogenous activators of actin polymerization by the Arp2/3 complex.
782 citations
TL;DR: In this paper, the fraction of particulate organic carbon with a secondary origin in gas/particle conversion of volatile organic compounds was estimated from the minimum ratio between particulates organic and black carbon, which occurred during periods of reduced photochemical activity.
TL;DR: Over the 10 years, 11 beta-HSD has progressed from an enzyme merely involved in the peripheral metabolism of cortisol to a crucial pre-receptor signaling pathway in the analysis of corticosteroid hormone action.
Abstract: In mammalian tissues, at least two isozymes of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) catalyze the interconversion of hormonally active C11-hydroxylated corticosteroids (cortisol, corticosterone) and their inactive C11-keto metabolites (cortisone, 11-dehydrocorticosterone). The type 1 and type 2 11 beta-HSD isozymes share only 14% homology and are separate gene products with different physiological roles, regulation, and tissue distribution. 11 beta-HSD2 is a high affinity NAD-dependent dehydrogenase that protects the mineralocorticoid receptor from glucocorticoid excess; mutations in the HSD11B2 gene explain an inherited form of hypertension, the syndrome of apparent mineralocorticoid excess in which cortisol acts as a potent mineralocorticoid. By contrast, 11 beta-HSD1 acts predominantly as a reductase in vivo, facilitating glucocorticoid hormone action in key target tissues such as liver and adipose tissue. Over the 10 years, 11 beta-HSD has progressed from an enzyme merely involved in the peripheral metabolism of cortisol to a crucial pre-receptor signaling pathway in the analysis of corticosteroid hormone action. This review details the enzymology, molecular biology, distribution, regulation, and function of the 11 beta-HSD isozymes and highlights the clinical consequences of altered enzyme expression.
TL;DR: The experimental results show that negative correlation learning can produce neural network ensembles with good generalisation ability.
TL;DR: Treatment with rofecoxib was associated with a significantly lower incidence of PUBs than treatment with NSAIDs, based on survival analysis of time to first PUB diagnosis, using Pubs that met pre-specified criteria judged by a blinded, external adjudication committee.
Abstract: ContextNonsteroidal anti-inflammatory drug (NSAID)–induced gastrointestinal
(GI) toxic effects, such as upper GI tract perforations, symptomatic gastroduodenal
ulcers, and upper GI tract bleeding (PUBs), are thought to be attributable
to cyclooxygenase 1 (COX-1) inhibition. Rofecoxib specifically inhibits COX-2
and has demonstrated a low potential for causing upper GI injury.ObjectiveTo compare the incidence of PUBs in patients with osteoarthritis treated
with rofecoxib vs NSAIDs.DesignPrespecified analysis of all 8 double-blind, randomized phase 2b/3 rofecoxib
osteoarthritis trials conducted from December 1996 through March 1998, including
one 6-week dose-ranging study, two 6-week efficacy studies vs ibuprofen and
placebo, two 1-year efficacy studies vs diclofenac, two 6-month endoscopy
studies vs ibuprofen and placebo, and one 6-week efficacy study vs nabumetone
and placebo.SettingMultinational sites.ParticipantsOsteoarthritis patients (N = 5435; mean age, 63 years [range, 38-94
years]; 72.9% women).InterventionsRofecoxib, 12.5, 25, or 50 mg/d (n = 1209, 1603, and 545, respectively,
combined) vs ibuprofen, 800 mg 3 times per day (n = 847), diclofenac, 50 mg
3 times per day (n = 590); or nabumetone, 1500 mg/d (n = 127) (combined).Main Outcome MeasureCumulative incidence of PUBs for rofecoxib vs NSAIDs, based on survival
analysis of time to first PUB diagnosis, using PUBs that met prespecified
criteria judged by a blinded, external adjudication committee.ResultsThe incidence of PUBs over 12 months was significantly lower with rofecoxib
vs NSAIDs (12-month cumulative incidence, 1.3% vs 1.8%; P = .046; rate per 100 patient-years, 1.33 vs 2.60; relative risk,
0.51; 95% confidence interval, 0.26-1.00). The cumulative incidence of dyspeptic
GI adverse experiences was also lower with rofecoxib vs NSAIDS over 6 months
(23.5% vs 25.5%; P = .02), after which the incidence
rates converged.ConclusionIn a combined analysis of 8 trials of patients with osteoarthritis,
treatment with rofecoxib was associated with a significantly lower incidence
of PUBs than treatment with NSAIDs.
TL;DR: It is demonstrated that mutations in ATP2A2 cause Darier disease and disclose a role for this pump in a Ca2+-signalling pathway regulating cell-to-cell adhesion and differentiation of the epidermis.
Abstract: Darier disease (DD) is an autosomal-dominant skin disorder characterized by loss of adhesion between epidermal cells (acantholysis) and abnormal keratinization. Recently we constructed a 2.4-Mb, P1-derived artificial chromosome contig spanning the DD candidate region on chromosome 12q23-24.1. After screening several genes that mapped to this region, we identified mutations in the ATP2A2 gene, which encodes the sarco/endoplasmic reticulum Ca2(+)-ATPase type 2 isoform (SERCA2) and is highly expressed in keratinocytes. Thirteen mutations were identified, including frameshift deletions, in-frame deletions or insertions, splice-site mutations and non-conservative missense mutations in functional domains. Our results demonstrate that mutations in ATP2A2 cause DD and disclose a role for this pump in a Ca(2+)-signalling pathway regulating cell-to-cell adhesion and differentiation of the epidermis.
TL;DR: A review of sea-level changes during the big five mass extinctions and several lesser extinction events reveals that the majority coincide with large eustatic inflexions as discussed by the authors, with the most frequent extinctions occurring during the transgressive pulse when anoxic bottom waters often became extensive.
Journal Article•
TL;DR: It is inferred that direct T cell control of viral replicative lesions is maintained in long term carriers of EBV and is an important component of the immune response to this virus.
Abstract: EBV is a gammaherpesvirus that can establish both nonproductive (latent) and productive (lytic) infections within the cells of its host. Although T cell responses to EBV latent proteins have been well characterized, little is known about the importance of responses to lytic proteins in long term virus carriers. Here we have compared the frequencies of CD8+ T cells specific for EBV latent and lytic Ags in healthy virus carriers, using three techniques: limiting dilution analysis, enzyme-linked immunospot assay, and FACS staining with tetrameric MHC-peptide complexes. T cells specific for EBV lytic protein epitopes were readily detectable in all donors and were usually more abundant than those specific for latent epitopes. We infer that direct T cell control of viral replicative lesions is maintained in long term carriers of EBV and is an important component of the immune response to this virus. Estimates of CD8+ T cell frequencies varied considerably according to methodology; values obtained from MHC-peptide tetramer staining were, on the average, 4.4-fold higher than those obtained from enzyme-linked immunospot assays, which were, in turn, on the average, 5.3-fold higher than those obtained from limiting dilution analysis. Tetramer staining showed that as many as 5.5% circulating CD8+ T cells in a virus carrier were specific for a single EBV lytic protein epitope. Such values are much greater than previously imagined and illustrate how antigenic challenge from a persistent herpesvirus can influence the composition of the host's CD8+ T cell pool.
TL;DR: In this article, the authors show that the observed structure and evolution of X-ray-emitting clusters of galaxies seems to be at odds with this picture, and they argue that the excess entropy is a relic of the energetic winds generated by supernovae in the forming galaxies.
Abstract: It is widely believed that structure in the Universe evolves hierarchically—fluctuations in the primordial distribution of matter, amplified by gravity, collapse and merge to form progressively larger systems, culminating in the clusters of galaxies that are observed today. But the observed structure and evolution of X-ray-emitting clusters of galaxies seems to be at odds with this picture1. In particular, clusters and groups with relatively few galaxies, as well as most distant clusters, are substantially fainter in X-rays than predicted by models of hierarchical formation. Here we show that these discrepancies arise because the entropy of the hot diffuse intracluster gas near the centre of the cluster is higher than can be explained by gravitational collapse alone. We argue that the excess entropy is a relic of the energetic winds generated by supernovae in the forming galaxies. These winds also enriched the intracluster medium with elements heavier than helium. We show that such a process can account for the observed effects only if the intracluster medium is heated at modest redshifts (z ≲ 2) but before the final collapse into a cluster structure, indicating that the formation of galaxies precedes that of clusters and that most clusters have been assembled very recently.
TL;DR: A hotspot for human IFNGR1 small deletions that confer dominant susceptibility to infections caused by poorly virulent mycobacteria is reported.
Abstract: The immunogenetic basis of severe infections caused by bacille Calmette-Guerin vaccine and environmental mycobacteria in humans remains largely unknown. We describe 18 patients from several generations of 12 unrelated families who were heterozygous for 1 to 5 overlapping IFNGR1 frameshift small deletions and a wild-type IFNGR1 allele. There were 12 independent mutation events at a single mutation site, defining a small deletion hotspot. Neighbouring sequence analysis favours a small deletion model of slipped mispairing events during replication. The mutant alleles encode cell-surface IFNgamma receptors that lack the intra-cytoplasmic domain, which, through a combination of impaired recycling, abrogated signalling and normal binding to IFNgamma exert a dominant-negative effect. We thus report a hotspot for human IFNGR1 small deletions that confer dominant susceptibility to infections caused by poorly virulent mycobacteria.
TL;DR: It is almost certain that over the next few years bipolar susceptibility genes will be identified, which will have a major impact on the understanding of disease pathophysiology and will provide important opportunities to investigate the interaction between genetic and environmental factors involved in pathogenesis.
Abstract: Bipolar disorder (also known as manic depressive illness) is a complex genetic disorder in which the core feature is pathological disturbance in mood (affect) ranging from extreme elation, or mania, to severe depression usually accompanied by disturbances in thinking and behaviour. The lifetime prevalence of 1% is similar in males and females and family, twin, and adoption studies provide robust evidence for a major genetic contribution to risk. There are methodological impediments to precise quantification, but the approximate lifetime risk of bipolar disorder in relatives of a bipolar proband are: monozygotic co-twin 40-70%; first degree relative 5-10%; unrelated person 0.5-1.5%. Occasional families may exist in which a single gene plays the major role in determining susceptibility, but the majority of bipolar disorder involves the interaction of multiple genes (epistasis) or more complex genetic mechanisms (such as dynamic mutation or imprinting). Molecular genetic positional and candidate gene approaches are being used for the genetic dissection of bipolar disorder. No gene has yet been identified but promising findings are emerging. Regions of interest identified in linkage studies include 4p16, 12q23-q24, 16p13, 21q22, and Xq24-q26. Chromosome 18 is also of interest but the findings are confusing with up to three possible regions implicated. To date most candidate gene studies have focused on neurotransmitter systems influenced by medication used in clinical management of the disorder but no robust positive findings have yet emerged. It is, however, almost certain that over the next few years bipolar susceptibility genes will be identified. This will have a major impact on our understanding of disease pathophysiology and will provide important opportunities to investigate the interaction between genetic and environmental factors involved in pathogenesis. This is likely to lead to major improvements in treatment and patient care but will also raise important ethical issues that will need to be addressed.
TL;DR: This review will illustrate how, when specificity and amplification through cell signalling mechanisms are taken into account, the less significant reactions can explain many of the biological responses of exposure of cells or physiological systems to RNS.
TL;DR: F metabolism in subjects with BMIs between 20-25 kg/m2 ( group A), 25-30 kg/ m2 (group B), and more than 30kg/m3 (group C) is analyzed, finding an increased MCR for F results in an increased F secretion rate in obesity in the face of normal circulating F concentrations.
Abstract: For a given body mass index (BMI), mortality is higher in patients with central compared to generalized obesity. Glucocorticoids play an important role in determining body fat distribution, but circulating cortisol concentrations are reported to be normal in obese patients. Our recent studies show enhanced conversion of inactive cortisone (E) to active cortisol (F) through the expression of 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) in cultured omental adipose stromal cells; the autocrine production of F may be a crucial factor in the pathogenesis of central obesity. We have now analyzed F metabolism in subjects with BMIs between 20-25 kg/m2 (group A), 25-30 kg/m2 (group B), and more than 30 kg/m2 (group C; n 12 in each group; six males and six premenopausal females; aged 23-44 yr). Glucose/insulin were measured using a 75-g oral glucose tolerance test, and each subject had total body and regional fat (scapular, waist, hip, and thigh) quantified using dual energy x-ray absorptiometry. Urinary total F metabolites (measured by gas chromatography/mass spectrometry) were increased in subjects with obesity [group A, 11,176 +/- 1,530 microg/24 h (mean +/- SE); group C, 13,661 +/- 1,444], although not significantly so (P = 0.08). There was a significant reduction in the urinary tetrahydrocortisol (THF) +/- 5alpha-THF/tetrahydrocortisone (THE) and the cortol/cortolone ratio in obesity (group A vs. C, 1.06 +/- 0.08 vs. 0.84 +/- 0.04 and 0.41 +/- 0.03 vs. 0.34 +/- 0.03, respectively; both P < 0.05). Urinary free F (UFF) excretion was similar in all three groups, as was the UFF/urinary free E (UFE) ratio. The 0900 h circulating F, E, and ACTH pre- and postovernight 1-mg dexamethasone suppression values were similar in all three groups, but a reduction in the generation of serum F from dexamethasone-suppressed values after oral cortisone acetate (25 mg) was evident in both obese groups [e.g. 546 +/- 37 nmol/L in group A vs. 412 +/- 40 in group B (P < 0.05) and 388 +/- 38 in group C (P < 0.01) 180 min post-E]. Insulin resistance was present in groups B and C, but regression analysis revealed no relationship between F metabolites or the THF +/- 5alpha-THF/THE ratio and insulin action (homeostasis model assessment analysis and insulin values in the oral glucose tolerance test). There was, however, a highly significant relationship between the THF +/- 5alpha-THF/THE ratio and BMI (t = -3.44; P < 0.01) and total body fat (t = -2.27; P < 0.05). Stepwise regression analyses indicated an inverse relationship between THF+/-5alpha-THF/THE and scapular and waist fat (t = -2.25; P = 0.03) and a direct relationship with hip and thigh fat (t = 2.42; P = 0.02) in both sexes. The fall in the THF + 5alpha-THF/THE ratio but unchanged UFF/UFE ratio together with impaired F concentrations after oral E indicates inhibition of 11betaHSD1 in subjects with obesity. This results in an increased MCR for F, explaining the increased F secretion rate in obesity in the face of normal circulating F concentrations. 11BetaHSD1 activity is highly related to body fat distribution, with android or central obesity, but not gynoid obesity, associated with reduced activity in both sexes. This reduction in 11betaHSD1 activity raises new questions as to the primary role of 11betaHSD1 in the pathogenesis of insulin resistance and central obesity.
TL;DR: In this article, the MRC AML 10 trial data were used to create a prognostic index for use in risk-directed therapy decision-making for younger patients with acute myeloid leukaemia (AML).
Abstract: Data on 1711 patients, aged up to 55 years, in the MRC AML 10 trial were used to create a prognostic index for use in risk-directed therapy decision making for younger patients with acute myeloid leukaemia (AML). Two parameters, response after course 1 and cytogenetics, were strongly predictive of outcome. For patients with complete remission, partial remission and resistant disease, 5-year survival from the start of course 2 was 53%, 44% and 22% and relapse rates were 46%, 48% and 69% respectively, and for patients with favourable, intermediate and adverse karyotypic abnormalities, survival was 72%, 43% and 17% and relapse rates were 34%, 51% and 75% respectively (all P < 0.0001). Patients with FAB type M3 but no cytogenetic t(15;17) also had a low relapse rate (29%). These three factors were combined to give three risk groups: good (favourable karyotype or M3, irrespective of response status or presence of additional abnormalities), standard (neither good nor poor), poor (adverse karyotype or resistant disease, and no good-risk features). Survival for these three groups was 70%, 48% and 15% respectively and relapse rates were 33%. 50% and 78% (both P < 0.0001). The index is simple (based on just three parameters), robust (derived from 1711 patients), highly discriminatory (55% survival difference between good and poor risk) and validated, so can be applied in the clinical setting to assist with therapeutic decisions as in the current AML 12 trial.
Journal Article•
TL;DR: It is proposed that intrahepatic Th1 cytokines drive the increased expression of IFN-inducible protein-10 and monokine-induced byIFN-gamma and thereby promote the continuing recruitment of CXCR3-expressing T cells into the hepatic lobule in chronic hepatitis C infection.
Abstract: The role played by chemokines in regulating the selective recruitment of lymphocytes to different tissue compartments in disease is poorly characterized. In hepatitis C infection, inflammation confined to portal areas is associated with a less aggressive course, whereas T cell infiltration of the liver parenchyma is associated with progressive liver injury and cirrhosis. We propose a mechanism to explain how lymphocytes are recruited to hepatic lobules during bursts of necroinflammatory activity in chronic hepatitis C infection. We report here that lymphocytes infiltrating hepatitis C-infected liver express high levels of the chemokine receptors CCR5 and CXCR3. However, whereas the CCR5 ligands macrophage inflammatory protein-1α and -1β were largely confined to vessels within portal tracts, the CXCR3 ligands IFN-inducible protein-10 and monokine-induced by IFN-γ were selectively up-regulated on sinusoidal endothelium. In vitro, human hepatic sinusoidal endothelial cells secreted IFN-inducible protein-10 and monokine-induced by IFN-γ in response to stimulation with IFN-γ in combination with either IL-1 or TNF-α. This suggests that intrahepatic Th1 cytokines drive the increased expression of IFN-inducible protein-10 and monokine-induced by IFN-γ and thereby promote the continuing recruitment of CXCR3-expressing T cells into the hepatic lobule in chronic hepatitis C infection.
TL;DR: It is shown that RGD-containing peptides are able to directly induce apoptosis without any requirement for integrin-mediated cell clustering or signals, and this findings provide an alternative molecular explanation for the potent pro-apoptotic properties of RGD peptides in models of angiogenesis, inflammation and cancer metastasis.
Abstract: Synthetic peptides containing the arginine-glycine-aspartate (RGD) motif have been used extensively as inhibitors of integrin-ligand interactions in studies of cell adhesion, migration, growth and differentiation, because the RGD motif is an integrin-recognition motif found in many ligands. Here we report that RGD-containing peptides are able to directly induce apoptosis without any requirement for integrin-mediated cell clustering or signals. We show that RGD-containing peptides enter cells and directly induce autoprocessing and enzymatic activity of procaspase-3, a pro-apoptotic protein. Using the breast carcinoma cell line MCF-7, which has a functional deletion of the caspase-3 gene, we confirm that caspase-3 is required for RGD-mediated cell death. In addition to an RGD motif, pro-caspase-3 also contains a potential RGD-binding motif, aspartate-aspartate-methionine (DDM), near the site of processing to produce the p12 and p17 subunits. On the basis of the ability of RGD-DDX interactions to trigger integrin activation, we suggest that RGD peptides induce apoptosis by triggering conformational changes that promote pro-caspase-3 autoprocessing and activation. These findings provide an alternative molecular explanation for the potent proapoptotic properties of RGD peptides in models of angiogenesis, inflammation and cancer metastasis.
TL;DR: In this paper, the authors used a Bloch wave approach to show that, even for coherent dynamical scattering from a stationary lattice with no absorption, annular dark-field imaging in a scanning transmission electron microscope gives a direct incoherent structure image of the atomic-column positions of a zone-axis-aligned crystal.
TL;DR: It is proposed that rapid plasma elimination of polycation/DNA complexes results from their binding serum albumin and other proteins, perhaps due to aggregation and phagocytic capture or accumulation of the ternary complexes in fine capillary beds.
Abstract: Self-assembling polycation/DNA complexes represent a promising synthetic vector for gene delivery. However, despite considerable versatility and transfectional activity in vitro, such materials are quickly eliminated from the bloodstream following intravenous injection (plasma α half-life typically less than 5 min). For targeted systemic delivery a more prolonged plasma circulation of the vector is essential. Here we have examined factors contributing to rapid elimination of poly(L-lysine) (pLL)/DNA complexes from the bloodstream, and implicate the binding of proteins to the polyelectrolyte complexes as a likely cause for their blood clearance. pLL/DNA complexes reisolated from serum associate with several proteins, depending on their net charge, although the major band on SDS-PAGE co-migrates with albumin. Serum albumin binds to pLL/DNA complexes in vitro, forming a ternary pLL/DNA/albumin complex which regains some ethidium bromide fluorescence and fails to move during agarose electrophoresis. Albumin also causes increased turbidity of complexes, and reduces their zeta potential to the same level (−16 mV) as is measured in serum. We propose that rapid plasma elimination of polycation/DNA complexes results from their binding serum albumin and other proteins, perhaps due to aggregation and phagocytic capture or accumulation of the ternary complexes in fine capillary beds.
01 Jan 1999
TL;DR: In this paper, the arginine-glycine-aspartate (RGD) motif was used to induce apoptosis without any requirement for integrin-mediated cell clustering or signals.
Abstract: Synthetic peptides containing the arginine-glycine-aspartate (RGD) motif have been used extensively as inhibitors of integrin-ligand interactions in studies of cell adhesion, migration, growth and differentiation, because the RGD motif is an integrin-recognition motif found in many ligands. Here we report that RGD-containing peptides are able to directly induce apoptosis without any requirement for integrin-mediated cell clustering or signals. We show that RGD-containing peptides enter cells and directly induce autoprocessing and enzymatic activity of procaspase-3, a pro-apoptotic protein. Using the breast carcinoma cell line MCF-7, which has a functional deletion of the caspase-3 gene, we confirm that caspase-3 is required for RGD-mediated cell death. In addition to an RGD motif, pro-caspase-3 also contains a potential RGD-binding motif, aspartate-aspartate-methionine (DDM), near the site of processing to produce the p12 and p17 subunits. On the basis of the ability of RGD-DDX interactions to trigger integrin activation, we suggest that RGD peptides induce apoptosis by triggering conformational changes that promote pro-caspase-3 autoprocessing and activation. These findings provide an alternative molecular explanation for the potent proapoptotic properties of RGD peptides in models of angiogenesis, inflammation and cancer metastasis.
TL;DR: This work focuses on recent developments in the molecular and cell biology of Barrett's metaplasia, a heterogeneous lesion affecting the transitional zone of the gastro-esophageal junction whose associated molecular alterations may vary both in nature and temporally.
Abstract: The incidence of adenocarcinoma of the esophagus has been increasing in developing countries over the last three decades and probably reflects a genuine increase in the incidence of its recognized precursor lesion, Barrett's metaplasia. Despite advances in multimodality therapy, the prognosis for invasive esophageal adenocarcinoma is poor. An improved understanding of the molecular biology of this disease may allow improved diagnosis, therapy, and prognosis. We focus on recent developments in the molecular and cell biology of Barrett's metaplasia, a heterogeneous lesion affecting the transitional zone of the gastro-esophageal junction whose associated molecular alterations may vary both in nature and temporally. Early premalignant clones produce biological and genetic heterogeneity as seen by multiple p53 mutations, p16 mutations, aneuploidy, and abnormal methylation resulting in stepwise changes in differentiation, proliferation, and apoptosis, allowing disease progression under selective pressure. Abnormalities in expression of growth factors of the epidermal growth factor family and cell adhesion molecules, especially cadherin/catenin complexes, may occur early in invasion. Exploitation of these molecular events may lead to a more appropriate diagnosis and understanding of these lesions in the future.
TL;DR: The results suggest that carriers of ATM mutations may be at a particular risk for the development of B-CLL and this may partly explain the known genetic susceptibility to this disease.