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422 records · Page 24Linked to original sources
PubMed2004

Characterization of a nudix hydrolase from Deinococcus radiodurans with a marked specificity for (deoxy)ribonucleoside 5'-diphosphates.

BACKGROUND: Nudix hydrolases form a protein family whose function is to hydrolyse intracellular nucleotides and so regulate their levels and eliminate potentially toxic derivatives. The genome of the radioresistant bacterium Deinococcus radiodurans encodes 25 nudix hydrolases, an unexpectedly large number. These may contribute to radioresistance by removing mutagenic oxidised and otherwise damaged nucleotides. Characterisation of these hydrolases is necessary to understand the reason for their presence. Here, we report the cloning and characterisation of the DR0975 gene product, a nudix hydrolase that appears to be unique to this organism. RESULTS: The DR0975 gene was cloned and expressed as a 20 kDa histidine-tagged recombinant product in Escherichia coli. Substrate analysis of the purified enzyme showed it to act primarily as a phosphatase with a marked preference for (deoxy)nucleoside 5'-diphosphates (dGDP > ADP > dADP > GDP > dTDP > UDP > dCDP > CDP). Km for dGDP was 110 microM and kcat was 0.18 s-1 under optimal assay conditions (pH 9.4, 7.5 mM Mg2+). 8-Hydroxy-2'-deoxyguanosine 5'-diphosphate (8-OH-dGDP) was also a substrate with a Km of 170 microM and kcat of 0.13 s-1. Thus, DR0975 showed no preference for 8-OH-dGDP over dGDP. Limited pyrophosphatase activity was also observed with NADH and some (di)adenosine polyphosphates but no other substrates. Expression of the DR0975 gene was undetectable in logarithmic phase cells but was induced at least 30-fold in stationary phase. Superoxide, but not peroxide, stress and slow, but not rapid, dehydration both caused a slight induction of the DR0975 gene. CONCLUSION: Nucleotide substrates for nudix hydrolases conform to the structure NDP-X, where X can be one of several moieties. Thus, a preference for (d)NDPs themselves is most unusual. The lack of preference for 8-OH-dGDP over dGDP as a substrate combined with the induction in stationary phase, but not by peroxide or superoxide, suggests that the function of DR09075 may be to assist in the recycling of nucleotides under the very different metabolic requirements of stationary phase. Thus, if DR0975 does contribute to radiation resistance, this contribution may be indirect.

Bacterial Proteins↗
PubMed2002

Polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and risk of adult acute lymphocytic leukemia.

We previously reported that 2 polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene at positions C677T and A1298C were associated with lower risk of adult acute lymphocytic leukemia (ALL). In the present study, we have examined whether polymorphisms in other folate-metabolizing genes play a role in ALL susceptibility. Polymorphisms in methionine synthase (MS A2756G), cytosolic serine hydroxymethyltransferase (SHMT1 C1420T), and a double (2R2R) or triple (3R3R) 28-bp tandem repeat in the promoter region of thymidylate synthase (TS) were studied and found to modulate ALL risk. In a univariate analysis, SHMT1 1420CT individuals exhibited a 2.1-fold decrease in ALL risk (odds ratio [OR] = 0.48; 95% confidence interval [CI], 0.25-0.91), whereas the 1420TT genotype conferred a 3.3-fold reduction in risk (OR = 0.31; 95% CI, 0.10-0.90). Similarly, TS 2R3R individuals exhibited a 2.8-fold reduction in ALL risk (OR = 0.36; 95% CI: 0.16-0.83), while the TS 3R3R genotype conferred an even greater level of protection (OR = 0.25; 95% CI, 0.08-0.78). However, no significant associations were evident for the MS 2756AG polymorphism (OR = 0.79; 95% CI, 0.38-1.7). In addition, potential interactions between the SHMT1 and TS or MS genes were observed. TS 3R3R individuals who were SHMT1 1420CT/TT had a 13.9-fold decreased ALL risk (OR = 0.072; 95% CI, 0.0067-0.77). Further, MS 2756AG individuals who were SHMT1 1420CT/TT had a 5.6-fold reduction in ALL risk (OR = 0.18; 95% CI, 0.05-0.63). This study suggests an important role for uracil misincorporation and resultant chromosomal damage in the pathogenesis of ALL, and that genetic interactions involving low penetrance polymorphisms in folate-metabolizing genes may increase ALL risk.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1998

E2F-6: a novel member of the E2F family is an inhibitor of E2F-dependent transcription.

The E2F family of transcription factors are essential for the regulation of genes required for appropriate progression through the cell cycle. Five members of the E2F family have been previously reported, namely E2F1-5. All five are key elements in transcriptional regulation of essential genes, and they can be divided into two functional groups, those that induce S-phase progression when overexpressed in quiescent cells (E2Fs 1-3), and those that do not (E2Fs 4-5). Here, we describe the identification of a novel member of this family, which we refer to as E2F-6. E2F-6 shares significant homology with E2Fs 1-5, especially within the DNA binding, heterodimerization and marked box domains. Unlike E2Fs 1-5, E2F-6 lacks a transactivation and a pocket protein binding domain, hence, forms a unique third group within the E2F family. E2F-6 is a nuclear protein that can form heterodimers with the DP proteins (both DP-I and DP-2) in vitro and in vivo. Our results show that the complex formed between E2F-6 and the DP proteins, possesses high DNA binding activity, displaying a preference for a TTTCCCGC E2F recognition site, which is slightly different to the E2F consensus site derived from the E2 promoter (TTTCGCGC). In contrast to the other members of the E2F family, ectopic expression of E2F-6 inhibits transcription from promoters possessing E2F recognition sites rather than activating transcription. In addition, overexpression of E2F-6 suppresses the transactivational effects of coexpression of E2F-1 and DP-1. The inhibitory effect of E2F-6 is dependent on its DNA binding activity and its ability to form heterodimers with the DPs. Interestingly, ectopic expression of E2F-6 leads to accumulation of cells in S-phase. Our data suggest that E2F-6 expression delays the exit from S-phase rather than inducing S-phase, which further emphasizes the functional difference between E2F-6 and the previously known E2F family members.

Amino Acid Sequence↗
PubMed2005

Engineering and characterisation of chimeric monoclonal antibody 806 (ch806) for targeted immunotherapy of tumours expressing de2-7 EGFR or amplified EGFR.

We report the generation of a chimeric monoclonal antibody (ch806) with specificity for an epitope on the epidermal growth factor receptor (EGFR) that is different from that targeted by all other anti-EGFR therapies. Ch806 antibody is reactive to both de2-7 and overexpressed wild-type (wt) EGFR but not native EGFR expressed in normal tissues at physiological levels. Ch806 was stably expressed in CHO (DHFR -/-) cells and purified for subsequent characterisation and validated for use in preliminary immunotherapy investigations. Ch806 retained the antigen binding specificity and affinity of the murine parental antibody. Furthermore, ch806 displayed enhanced antibody-dependent cellular cytotoxicity against target cells expressing the 806 antigen in the presence of human effector cells. Ch806 was successfully radiolabelled with both iodine-125 and indium-111 without loss of antigen binding affinity or specificity. The radioimmunoconjugates were stable in the presence of human serum at 37 degrees C for up to 9 days and displayed a terminal half-life (T(1/2beta)) of approximately 78 h in nude mice. Biodistribution studies undertaken in BALB/c nude mice bearing de2-7 EGFR-expressing or amplified EGFR-expressing xenografts revealed that (125)I-labelled ch806 failed to display any significant tumour retention. However, specific and prolonged tumour localisation of (111)In-labelled ch806 was demonstrated with uptake of 31%ID g(-1) and a tumour to blood ratio of 5 : 1 observed at 7 days postinjection. In vivo therapy studies with ch806 demonstrated significant antitumour effects on established de2-7 EGFR xenografts in BALB/c nude mice compared to control, and both murine 806 and the anti-EGFR 528 antibodies. These results support a potential therapeutic role of ch806 in the treatment of suitable EGFR-expressing tumours, and warrants further investigation of the potential of ch806 as a therapeutic agent.

Animals↗
PubMed1995

The expression and release of adhesion molecules by human endothelial cell lines and their consequent binding of lymphocytes.

We report the characterization of a novel series of human endothelial cell lines (designated SGHEC) regarding the expression and release of adhesion molecules and their binding of lymphocytes. SGHEC expressed significant levels of intercellular adhesion molecule-1 (ICAM-1; CD54) which increased after stimulation with tumor necrosis factor-alpha (TNF alpha), interleukin-1 beta (IL-1 beta), or interferon-gamma (IFN-gamma). Vascular cell adhesion molecule-1 (VCAM-1; CD106) and E-selectin (CD62E) were not detectable on unstimulated SGHEC but substantial levels were expressed after stimulation with either TNF alpha or IL-1 beta but not with IFN-gamma. The increased expression of ICAM-1 and VCAM-1 was evident after 4 h stimulation and was even higher after 24 h; E-selectin was maximal after 4 h and returned almost to basal levels by 24 h. Substantial quantities of immunoreactive ICAM-1 and VCAM-1 also accumulated as soluble material in the supernatants of TNF alpha-stimulated SGHEC (VCAM-1 was substantially higher than ICAM-1), but E-selectin remained below the limits of detection. Various quantitative data suggest that this is a controlled release regulated by cytokine and provide support for a physiological function for these soluble molecules. Primary human lymphocytes and lymphoblastoid cell lines expressing lymphocyte function-associated antigen-1 (LFA-1) bound to SGHEC; this binding increased substantially after activation of either cell type. The binding was inhibited by monoclonal antibodies against LFA-1 and, to a lesser extent, ICAM-1, thus demonstrating the importance of these molecules in the observed binding; neither anti-VCAM-1 nor anti-E-selectin antibodies affected the binding. From these various data, we conclude that LFA-1/ICAM-1 interactions are partially responsible for the binding of lymphocytes to endothelial cells. The SGHEC lines should prove useful in investigating leukocyte-endothelial interactions and the mechanism of release of soluble adhesion molecules.

Cell Adhesion↗
PubMed2000

Cost-benefit analysis of drug treatment services: review of the literature*

BACKGROUND: How valuable is public investment in treatment for drug abuse and dependency in the real world of everyday practice? Does drug abuse treatment provide benefits and how are they valued? What are the costs of obtaining outcomes and benefits? Cost-benefit analysis attempts to answer these questions in a standard analytic framework. AIMS: This paper reviews cost-benefit analyses with scientific merit so that analysts will have a current picture of the state of the research. It will also give public decision-makers information with regards to the available evidence for policy purposes. METHOD: Bibliographic searches were performed. Studies were obtained through the assistance of the Parklawn Health Library system, a component of the US Public Health Service. Selected studies were from the scientific literature with the exception of eight studies published as governmental reports. RESULTS: Cost-benefit studies have fallen into the following categories: (i) planning models for delivery systems in states and cities; (ii) short-term follow-up studies of individuals, (iii) single individual programs and (iv) state system's monitoring of outcomes. In 18 cost-benefit studies, a persistent finding is that benefits exceed costs, even when not all benefits are accounted for in the analysis. Much variation is found in the implementation of cost-benefit methods, and this is detailed across discussions of effectiveness, benefits and costs. Studies have emphasized the cost savings to society from the reduction in external costs created by the behavioral consequences of addiction and drug use. DISCUSSION: Economic analysis of drug treatment requires sophisticated conceptualization and measurement. Cost-benefit analysis of drug treatment has been a significant analytical exercise since the early 1970s when the public drug treatment system was founded in the United States. CONCLUSION: Drug abuse treatment services may be considered as contributing positive economic returns to society. However, considerable work needs to be done to standardize methods used in the studies. A striking area of omission is the absence of studies for adolescents and only one for women in treatment. IMPLICATIONS FOR HEALTH CARE PROVISION AND USE: Finding a positive net social benefit should assist policy-makers with decisions related to drug abuse treatment expenditures. Additional work on allocation of budget dollars across various drug treatment services will be needed. IMPLICATIONS FOR HEALTH POLICY FORMULATION: Government agencies and other stakeholders in national health care systems must realize that cost-benefit studies are an important tool for decision-making. Rational strategies can only be addressed by examining alternatives for the efficient allocation and equitable distribution of scarce resources. IMPLICATIONS FOR FURTHER RESEARCH: Future research should focus on standardizing the methods used in the cost-benefit analysis. Extensions should examine methods related to the willingness-to-pay approach. Studies are needed for drug abuse treatment targeted to adolescents and women. More studies should be published in the scientific literature.

Journal Article↗
PubMed2004

Cytomegalovirus infection in steroid-refractory ulcerative colitis: a case-control study.

Cytomegalovirus (CMV) infection is reported to be a cause of steroid-refractory ulcerative colitis (UC), but the strength of this association has not been tested in a case control study. Controlled studies have also not been performed to determine the sensitivity of available immunohistochemical techniques to detect CMV in this setting. The pathology database at Stanford Hospital was searched for UC patients with a diagnosis of "severe colitis" between the years 1992 and 2002 and medical records were reviewed. Forty patients were identified with refractory UC, defined as poor response to highdose systemic steroids for >2 weeks. Another group of 40 patients with severe, but nonrefractory, UC was case-matched for age and year of biopsy. A series of 40 patients who underwent colectomy for reasons other than inflammatory bowel disease with representative sections of "normal" colon were selected as noncolitis controls. CMV inclusions were detected on hematoxylin and eosin (H&E) in 2 of 40 patients with refractory UC, but not in other patients. Immunohistochemistry (IHC) detected CMV in 10 of 40 (25%) patients with refractory UC and 1 of 40 (2.5%) patients with nonrefractory UC (P = 0.007). The CMV-positive cases initially identified on IHC but not on H&E were re-reviewed for viral inclusions on H&E: 3 had rare, but typical, inclusions; 3 had atypical inclusions; and 3 had no inclusions. CMV was not detected by H&E or IHC in 40 noncolitis controls. Of 10 steroid-refractory UC patients with CMV detected, 7 were refractory to cyclosporin or 6-mercaptopurine/azathioprine (70%) and 6 had undergone proctocolectomy (60%) prior to detection of the CMV. Two patients with recognized CMV infection were treated with gancyclovir, improved, and were able to taper off steroids and avoid proctocolectomy. This study provides evidence that unrecognized and therefore untreated CMV infection is significantly associated with steroid-refractory UC. Moreover, IHC is more sensitive than H&E for detection of CMV and should be considered as part of the routine evaluation of steroid-refractory UC patients, before proceeding with other medical or surgical therapy that may be unnecessary once the CMV is treated.

Adolescent↗
PubMed2000

Loss of thalamic intralaminar nuclei in progressive supranuclear palsy and Parkinson's disease: clinical and therapeutic implications.

Whilst many reports mention neurofibrillary tangle pathology in the thalamus in progressive supranuclear palsy, there has been little detailed regional analysis of the distribution and density of thalamic pathology in this disease or in other parkinsonian syndromes. The caudal intralaminar thalamic nuclei are the major thalamic regulators of the caudate nucleus and putamen, areas known to be dysfunctional in progressive supranuclear palsy and Parkinson's disease. We investigated whether these thalamic nuclei degenerate in patients with these disorders compared with age-matched, neurologically normal controls. Neurofibrillary tangle and Lewy body pathology was assessed and unbiased optical disector methods were used to quantify total neuronal number. Despite different thalamic pathology, there was a dramatic reduction in the total neuronal number in the caudal intralaminar nuclei in both progressive supranuclear palsy and Parkinson's disease (40-55% loss). In contrast, there was no loss of volume or total neuronal number in the limbic thalamic nuclei in either disease group, indicating selective degeneration of the caudal intralaminar nuclei. In Parkinson's disease, Lewy bodies were found in these regions, while in progressive supranuclear palsy abundant intracellular neurofibrillary tangles and glial tangles concentrated in the caudal intralaminar nuclei. However, tangle formation accounted for only a small proportion of cell loss (</=10%) in the thalamus in progressive supranuclear palsy. These findings have several implications. The caudal intralaminar thalamus appears to be one of three basal ganglia sites commonly affected in both progressive supranuclear palsy and Parkinson's disease. These sites are the dopaminergic substantia nigra, the cholinergic pedunculopontine tegmental nucleus and, from our results, the glutamatergic caudal intralaminar thalamus. In both diseases these sites contain characteristic but different pathologies, indicating disease-specific mechanisms of neurodegeneration. Interestingly, the proportion of remaining neurons affected by these pathologies is low. This may indicate additional (possibly common) cellular mechanisms responsible for the degeneration in these regions. Both the dopaminergic nigra and the glutamatergic caudal intralaminar thalamus are the major regulators of basal ganglia function via the caudate nucleus and putamen. The pedunculopontine tegmental nucleus has major projections to both of these regulators. These findings indicate that dysregulation of two neurotransmitter systems within the basal ganglia may underlie common parkinsonian symptoms in these disorders. For patients with Parkinson's disease, this loss of glutamate regulation may help explain some problems with dopamine replacement therapies, particularly over time. For patients with progressive supranuclear palsy, more widespread degeneration of basal ganglia structures would contribute to poor treatment outcomes.

Aged↗