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PubMed2004

Transmission and disease association of Kaposi's sarcoma-associated herpesvirus: recent developments.

PURPOSE OF REVIEW: Kaposi's sarcoma-associated herpesvirus or human herpesvirus 8, common in sub-Saharan Africa and around the Mediterranean Sea but rare in most other countries, is known to be transmitted in childhood within families in endemic regions, and through sexual contacts among high-risk groups in Western countries. Nevertheless recent developments on other modes of transmission of the virus have been made during the last years and are summarized in this review. Furthermore, recent published disease associations are discussed. RECENT FINDINGS: The last year has seen research addressing the question of parenteral transmission, sexual transmission through heterosexual contact, transmission of Kaposi's sarcoma-associated herpesvirus-infected cells from organ donors to recipient, as well as the first suggestion that host genetic factors may facilitate infection in childhood. Additional clinical manifestations of infection with the virus such as primary pulmonary hypertension and germinotropic lymphoproliferative disorder have been identified. SUMMARY: Evidence of Kaposi's sarcoma-associated herpesvirus transmission other than between homosexual adults and during childhood - namely transmission through heterosexual contact or injection drug use - is growing although these issues are still incompletely analysed and far away from being fully understood. Despite our increasing knowledge on transmission and disease associations of the virus, implications on the clinical management of associated diseases and public health have to be further evaluated in the coming years.

Disease Transmission, Infectious↗
PubMed1995

Significant reduction in methicillin-resistant Staphylococcus aureus ventilator-associated pneumonia associated with the institution of a prevention protocol.

OBJECTIVE: To determine whether the institution of a methicillin-resistant Staphylococcus aureus prevention protocol was associated with a decrease in methicillin-resistant S. aureus ventilator-associated pneumonia in long-term, acute care ventilator patients. DESIGN: A retrospective chart review comparing the number of episodes of clinical pneumonia per patient ventilator day in the 12 months preceding and 24 months following the introduction of the protocol. SETTING: University affiliated, long-term, acute care ventilator hospital. PATIENTS: Long-term, acute care ventilated patients who presented with clinical pneumonia. INTERVENTIONS: Addition of a methicillin-resistant S. aureus prevention protocol. In addition to universal precautions, the protocol consisted of mupirocin 2% ointment applied to the anterior nares, and whole body washing with chlorhexidine. All patients were given mupirocin and chlorhexidine twice weekly. Patients were cohorted in the same room if they were, or had been, infected or colonized with methicillin-resistant S. aureus in any anatomical location or at any time. This procedure replaced strict isolation of methicillin-resistant S. aureus-infected or colonized individuals. MEASUREMENTS AND MAIN RESULTS: Clinical pneumonia was diagnosed when a patient developed fever, bronchorrhea, increased white blood cell count, methicillin-resistant S. aureus isolated from the tracheal aspirate, and new or increasing infiltrate on chest roentgenograph. During the 12 months preceding the protocol, there were 0.2% episodes of methicillin-resistant S. aureus ventilator-associated pneumonia per ventilated patient day compared with 0.026% in the 24 months after the protocol (p < .001). The relative and absolute risk reductions associated with the introduction of the protocol were 87% and 6, respectively. CONCLUSIONS: The period following the institution of the protocol showed a significant reduction in episodes of clinical pneumonia compared with the 12-month period preceding the use of the protocol (p < .001). Thus, we conclude that the introduction of this protocol is associated with a significant decrease in methicillin-resistant S. aureus ventilator-associated pneumonia.

Adult↗
PubMedDate not supplied

Factors associated with failure of metronidazole in Clostridium difficile-associated disease.

GOAL: To identify patients likely to fail metronidazole as initial treatment of C. difficile infection. BACKGROUND: For moderate to severe Clostridium difficile-associated diarrhea, metronidazole is the drug of choice for treatment. Oral vancomycin is given to patients who fail metronidazole or have intolerable side effects. STUDY: Retrospective review identified all patients treated for C. difficile-associated diarrhea during hospitalization from January 2000 to September 2001. C difficile was documented by a positive toxin assay or pseudomembranes on colonoscopy. Metronidazole failure was defined as persistent symptoms of C. difficile-associated diarrhea after 5 days of uninterrupted therapy. Response was defined as improvement in symptoms at day 5 of therapy including reduction of diarrhea to <or=2 bowel movements per day. RESULTS: 119 C. difficile-associated diarrhea patients were identified, and 99 met inclusion criteria. There were 61 (62%) metronidazole responders and 38 (38%) treatment failures. Albumin <2.5g/l and intensive care unit stay at/prior to diagnosis were the only variables associated with treatment failure. The odds ratios for treatment failure were 11.7 (95% confidence interval: 4.0-31.6) and 4.1 (95% confidence interval: 1.3-12.2), respectively. When considering these 2 variables together (low albumin, intensive care unit care), the area under the receiver operating characteristic curve was 0.80 for predicting treatment failure. CONCLUSIONS: Albumin level <2.5g/l and intensive care unit stay were predictors of failure of metronidazole therapy for C. difficile-associated diarrhea. These patients may benefit from oral vancomycin therapy at outset.

Adult↗
PubMed1996

Physical association of starch biosynthetic enzymes with starch granules of maize endosperm. Granule-associated forms of starch synthase I and starch branching enzyme II.

Antibodies were used to probe the degree of association of starch biosynthetic enzymes with starch granules isolated from maize (Zea mays) endosperm. Graded washings of the starch granule, followed by release of polypeptides by gelatinization in 2% sodium dodecyl sulfate, enables distinction between strongly and loosely adherent proteins. Mild aqueous washing of granules resulted in near-complete solubilization of ADP-glucose pyrophosphorylase, indicating that little, if any, ADP-glucose pyrophosphorylase is granule associated. In contrast, all of the waxy protein plus significant levels of starch synthase I and starch branching enzyme II (BEII) remained granule associated. Stringent washings using protease and detergent demonstrated that the waxy protein, more than 85% total endosperm starch synthase I protein, and more than 45% of BEII protein were strongly associated with starch granules. Rates of polypeptide accumulation within starch granules remained constant during endosperm development. Soluble and granule-derived forms of BEII yielded identical peptide maps and overlapping tryptic fragments closely aligned with deduced amino acid sequences from BEII cDNA clones. These observations provide direct evidence that BEII exits as both soluble and granule-associated entities. We conclude that each of the known starch biosynthetic enzymes in maize endosperm exhibits a differential propensity to associate with, or to become irreversibly entrapped within, the starch granule.

1,4-alpha-Glucan Branching Enzyme↗
PubMed2006

Proviral load and immune markers associated with human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in Peru.

Human T-lymphotropic virus type 1 (HTLV-1) is the aetiological agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The objective of this study is to identify which ex vivo and in vivo markers are associated independently with HAM/TSP in a Peruvian population. Eighty-one subjects (33 men/48 women) were enrolled: 35 presented with HAM/TSP, 33 were asymptomatic HTLV-1 carriers (ACs) and 13 were HTLV-1-seronegative controls (SCs). Ex vivo markers included T cell proliferation and Th1 [interferon (IFN)-gamma], Th2 [interleukin (IL)-4, IL-5], proinflammatory [tumour necrosis factor (TNF)-alpha] and anti-inflammatory (IL-10) cytokine production in non-stimulated peripheral blood mononuclear cell (PBMC) cultures. In vivo CD4(+) T cell count, markers of Th1 [interferon-inducible protein (IP)-10] and Th2 (sCD30) activity in plasma and HTLV-1 proviral load in PBMCs were also evaluated. In univariate analysis, several markers, including T cell proliferation, IFN-gamma, IP-10, sCD30 and proviral load were associated with HAM/TSP, but in a multiple logistic regression analysis only the proviral load remained associated significantly with disease manifestation [adjusted OR 9.10 (1.24-66.91)]. Our findings suggest that HAM/TSP is associated primarily with proviral load, whereas the observed association with some immune markers seems secondary.

Adult↗
PubMed2005

The expression of p53 and bcl-2 in gastrointestinal stromal tumours is associated with anatomical site, and p53 expression is associated with grade and clinical outcome.

AIMS: To compare the expression of p53 and bcl-2 in gastrointestinal stromal tumours (GISTs) with anatomical site, National Institutes of Health (NIH) risk category (grade), pathological features, and clinical outcome. METHODS AND RESULTS: The immunohistochemical expression of p53 and bcl-2 in 105 GISTs (71 gastric, 20 small intestinal, four colonic, 10 rectal) was recorded. When all GISTs were assessed, there was p53 positivity in 28% and bcl-2 positivity in 77%. Gastric tumours had a lower prevalence of p53 positivity (20%) than intestinal (40-50%). Rectal GISTs had the lowest prevalence of bcl-2 positivity (20%) and gastric and small intestinal the highest (80% and 90%, respectively). In GISTs from all sites, p53 positivity was associated with size > 50 mm, epithelioid cell shape, nuclear atypia, mucosal invasion, and mitotic count > 5/50 high-power fields. In gastric GISTs the associations were the same, apart from size and mitotic count. In GISTs from all sites and in gastric GISTs, p53 expression correlated with NIH risk category. When GISTs from all sites were subjected to univariate survival analysis, an adverse outcome was associated with p53 positivity, NIH risk category, and several established prognostic factors. When gastric GISTs were assessed, the associations were similar although size was not prognostic. In multivariate survival analysis, p53 expression was independently prognostic for gastric GISTs in some models, while it was never independently prognostic for GISTs from all sites. Whether all GISTs or gastric GISTs were assessed, bcl-2 showed no association with clinical outcome or risk category. CONCLUSIONS: Anatomical site influences p53 and bcl-2 expression in GISTs. p53 expression is associated with NIH risk category, various pathological features, and clinical outcome, and may be independently prognostic for gastric GISTs. Bcl-2 expression has no prognostic value.

Colon↗
PubMed1994

HLA and disease associations: detecting the strongest association.

A major aim of HLA and disease association studies is to identify the causative HLA factor truly responsible for the association. This is usually difficult due to the pronounced linkage disequilibrium between most HLA determinants. The causative factor must show the strongest association compared to all other factors. Here we describe a simple analysis which can be used to identify which of two factors, say A and B, shows the strongest association. The basic data for the analysis are the entries of the two-by-four table giving the four phenotypic combinations of A and B in patients and controls, respectively. These data are analyzed in various two-by-two tables involving stratification of each of the two factors against the other. A stronger increase of factor A is established if A is significantly associated with the condition both in B-positives and in B-negatives, when this is not true for B in A-positives and A-negatives. Using simulation with control data, it is demonstrated how linkage disequilibrium may influence secondary associations. The analysis may also be used to investigate interaction between HLA factors, but linkage disequilibrium complicates the interpretation in such cases. The method is exemplified using various published data. Finally, some statistical recommendations are given. Thus, we advise that phenotype (marker) frequencies are generally used instead of gene (i.e. allele, or haplotype) frequencies. The importance of correcting p-values, the levels of significance, and the power of Fisher's exact test are discussed.

Disease Susceptibility↗
PubMed2006

Investigation of the ability of haplotype association and logistic regression to identify associated susceptibility loci.

While finely spaced markers are increasingly being used in case-control association studies in attempts to identify susceptibility loci, not enough is yet known as to the optimal spacing of such markers, their likely power to detect association, the relative merits of single marker versus multimarker analysis, or which methods of analysis may be optimal. Some investigations of these issues have used markers simulated under different theoretical models of population evolution. However the HapMap project and other sources provide real datasets which can be used to obtain a more realistic view of the performance of these approaches. SNPs around APOE and from two HapMap regions were used to obtain information regarding linkage disequilibrium (LD) relationships between polymorphisms, and these real patterns of LD were used to simulate datasets such as would be obtained in case-control studies were these SNPs to influence susceptibility to disease. The datasets obtained were analysed using tests for heterogeneity of estimated haplotype frequencies and using logistic regression analyses in which only main effects from each marker were considered. All markers surrounding the putative susceptibility locus were analysed, using sets of either 1, 2, 3 or 4 markers at a time. Some markers within 150 kb of the susceptibility locus were able to detect association. At distances less than 100 kb there was no correlation between the distance from the susceptibility locus and the strength of evidence for association. When the average inter-locus spacing is 25 kb many loci would not be detected, while when the spacing is as low as 2 kb one can be fairly confident that at least one marker will be in strong enough LD with the susceptibility locus to enable association to be detected, if the susceptibility locus has a strong enough effect relative to the sample size. With an inter-locus spacing of 4 kb some susceptibility loci did not have a marker locus in strong LD, potentially undermining the ability to detect association. There was little difference in the performance of haplotype-based analysis compared with logistic regression considering effects of each marker as separate. Multimarker analysis on occasion produced results which were much more highly significant than single marker analysis, but only very rarely. Our results support the view that if markers are randomly selected then a spacing as low as 2 kb is desirable. Multimarker analysis can sometimes be more powerful than single marker analysis so both should be performed. However, because it is rare for multimarker analysis to be much more highly significant than single marker analysis one should strongly suspect that when such results occur they may be due to mistakes in genotyping or through some other artefact. Haplotype analysis may be more prone to such problems than logistic regression, suggesting that the latter method might be preferred.

Apolipoproteins E↗
PubMed2003

Helicobacter pylori-associated chronic gastritis and unexplained iron deficiency anemia: a reliable association?

BACKGROUND AND AIM: About 35% of iron deficiency anemia cases remain unexplained after a gastrointestinal evaluation. An association between Helicobacter pylori and iron malabsorption has been suggested. The aim of this study was to determine whether H. pylori-associated chronic gastritis is linked to unexplained iron deficiency anemia in adults. METHODS: From 1996 to 2001, we identified 105 patients with unexplained iron deficiency anemia after upper endoscopy, colonoscopy, small bowel radiographic examination and duodenal biopsies. Two biopsies were obtained from the gastric antrum and two from the corpus of each patient. Gastritis status was described according to the Sydney System and H. pylori infection was assessed by an immunohistochemical test on biopsy specimens. This group was compared to a control group matched for sex and age. RESULTS: There were 76 women and 29 men (mean age 57.4 +/- 21.4 years) examined in the study. A H. pylori-associated chronic gastritis was identified in 63 cases (60%) vs. 45 cases (43%) cases in the control group (p <.01). Atrophic gastritis was significantly associated with iron deficiency anemia compared with the control group [16 (15%) vs. 6 (6%); p <.03]. In the unexplained iron deficiency anemia group, (1) patients with chronic gastritis were significantly younger (52 +/- 22 vs. 64 +/- 20 years; p <.005), and (2) chronic gastritis was not linked to sex [sex ratio (male/female): 0.5 vs. 0.34, p =.34]. The prevalence of H. pylori infection was similar between premenopausal and postmenopausal women [28 (27%) vs. 26 (25%); p =.7] with iron deficiency anemia. CONCLUSION: H. pylori infection and chronic gastritis, especially atrophic gastritis, are significantly associated with unexplained iron deficiency anemia. Relationships between H. pylori-associated chronic gastritis and unexplained iron deficiency anemia should be considered.

Adult↗
PubMed2005

Distribution of insertion- and deletion-associated genetic polymorphisms among four Mycobacterium tuberculosis phospholipase C genes and associations with extrathoracic tuberculosis: a population-based study.

The Mycobacterium tuberculosis genome contains four phospholipase C (PLC)-encoding genes, designated plcA, plcB, plcC, and plcD, respectively. Each of the four genes contributes to the overall PLC activity of M. tuberculosis. PLC is hypothesized to contribute to M. tuberculosis virulence. Infection of M. tuberculosis strains carrying a truncated plcD gene is associated with the occurrence of extrathoracic tuberculosis. However, whether the other three plc genes are also associated with extrathoracic tuberculosis remains to be assessed. We investigated the insertion- and deletion-associated genetic diversity in all four plc genes among 682 epidemiologically and clinically well-characterized M. tuberculosis clinical isolates using PCR, DNA sequencing, and Southern hybridization. Two hundred sixty-six (39%) of the 682 isolates had an interruption in at least one of the four plc genes, most often associated with an IS6110 insertion. The plcD gene interruption was the most common: it was observed in 233 (34%) of the isolates, compared to 4.7%, 4.1%, and 5.9% for plcA, plcB, and plcC gene interruption, respectively. The association between the plc gene genotypes and disease presentation was adjusted for clustering using generalized estimating equations for both bivariate and multivariate analyses. After controlling for the genotypes of the plcABC genes and the host-related risk factors, interruption in the plcD gene remained significantly associated with extrathoracic tuberculosis (odds ratio, 3.27; 95% confidence interval, 1.32 to 8.14). The data suggest that the plcD gene might play a more important role in the pathogenesis of thoracic TB than it does in the pathogenesis of extrathoracic TB.

Bacterial Proteins↗
PubMed2004

The raft-promoting property of virion-associated cholesterol, but not the presence of virion-associated Brij 98 rafts, is a determinant of human immunodeficiency virus type 1 infectivity.

Lipid rafts are enriched in cholesterol and sphingomyelin and are isolated on the basis of insolubility in detergents, such as Brij 98 and Triton X-100. Recent work by Holm et al. has shown that rafts insoluble in Brig 98 can be found in human immunodeficiency virus type 1 (HIV-1) virus-like particles, although it is not known whether raft-like structures are present in authentic HIV-1 and it is unclear whether a virion-associated raft-like structure is required for HIV replication. Independently, it was previously reported that virion-associated cholesterol is critical for HIV-1 infectivity, although the specific requirement of virion cholesterol in HIV-1 was not examined. In the present study, we have demonstrated that infectious wild-type HIV-1 contains Brij 98 rafts but only minimal amounts of Triton X-100 rafts. To directly assess the functional requirement of virion-associated rafts and various features of cholesterol on HIV-1 replication, we replaced virion cholesterol with exogenous cholesterol analogues that have demonstrated either raft-promoting or -inhibiting capacity in model membranes. We observed that variable concentrations of exogenous analogues are required to replace a defined amount of virion-associated cholesterol, showing that structurally diverse cholesterol analogues have various affinities toward HIV-1. We found that replacement of 50% of virion cholesterol with these exogenous cholesterol analogues did not eliminate the presence of Brij 98 rafts in HIV-1. However, the infectivity levels of the lipid-modified HIV-1s directly correlate with the raft-promoting capacities of these cholesterol analogues. Our data provide the first direct assessment of virion-associated Brij 98 rafts in retroviral replication and illustrate the importance of the raft-promoting property of virion-associated cholesterol in HIV-1 replication.

Centrifugation, Density Gradient↗
PubMed1997

Association between genetic polymorphism of the pepsinogen C gene and gastric body ulcer: the genetic predisposition is not associated with Helicobacter pylori infection.

BACKGROUND AND AIMS: The genetic trait plays a part in the pathogenesis of peptic ulcer disease. To identify a DNA marker for peptic ulcer disease, the association between the restriction fragment length polymorphism (RFLP) of the pepsinogen C (PGC) gene and peptic ulcer disease was investigated. PATIENTS AND METHODS: One hundred and seventy seven unrelated controls, 75 patients with gastric ulcer, and 70 with duodenal ulcer were studied. PGC-RFLP was analysed by polymerase chain reaction (PCR), and the association between PGC-RFLP and peptic ulcer disease was examined. The relation between the genetic association of PGC polymorphism with peptic ulcer and Helicobacter pylori infection was also examined. RESULTS: Four alleles, 480 (allele 1), 450 (allele 2), 400 (allele 3), and 310 bp (allele 4), were detected by PCR. The frequency of allele 4 was significantly higher in patients with gastric body ulcer than in controls (chi (2) = 9.92, p < 0.005). Genotypes containing allele 4 were significantly more frequent in patients with gastric body ulcer than in controls and patients with gastric angular or antral ulcer. The relative risk of gastric body ulcer associated with the presence of allele 4, compared with its absence, was 4.63 and was statistically significant (chi (2) = 14.84, p < 0.005). There were no significant differences in the allelic frequencies between H pylori positive and H pylori negative groups in controls, patients with gastric body ulcer, or patients with gastric angular or antral ulcer. Both in H pylori negative and H pylori positive cases, there was an increased frequency of allele 4 in patients with gastric body ulcer compared with controls. CONCLUSIONS: These results suggest that there is a significant association between this genetic polymorphism at the PGC gene locus and gastric body ulcer. There are differences in the genetic aetiology between gastric body ulcer and gastric angular or antral ulcer. PGC-RFLP may be used as a genetic marker for a genetic predisposition to gastric body ulcer; this genetic predisposition is not associated with H pylori infection.

Adult↗
PubMed1985

Identification of glycoproteins associated with elastin-associated microfibrils.

The microfibrils associated with elastic tissue have been shown to be predominantly proteinaceous. On the basis of their affinity for cationic stains, including ruthenium red, they have been assumed to be glycoprotein, but more evidence to support this claim has not been adduced. Despite repeated investigation of glycoprotein materials obtained by extraction of elastic tissues with reagents that appear to remove microfibrils, the chemical composition of elastin-associated microfibrils remains obscure. An electron microscopic study of the microfibrils in two elastin-rich tissues (bovine nuchal ligament and aorta) during their development was pursued using more specific histochemical methods. The periodic acid-alkaline bismuth stain (analogous to the periodic acid-Schiff stain for glycoproteins in light microscopy) has been adapted for this study. Specific aldehyde groups (confirmed by blocking with m-aminophenol or sodium borohydride) were identified after periodate oxidation as fine granules of bismuth stain. These were shown to localize specifically along the elastin-associated microfibrils in a finely punctate form. Staining of the amorphous elastic component did not occur except for a fine rim adjacent to the microfibrils. Lectin binding with concanavalin A (with ferritin markers) confirmed that there are glucose- or mannose-containing proteins associated with the microfibrillar component of elastic tissue. This was true of these microfibrils in all layers of the aortic wall and throughout the ligament. It was also true of mature adult tissues in which there was a lesser proportion of microfibrils. It is concluded that elastin-associated microfibrils really are associated with glycoprotein(s).

Animals↗
PubMed2000

c-erbB-2 is of independent prognostic relevance in gastric cancer and is associated with the expression of tumor-associated protease systems.

PURPOSE: The c-erbB-2 gene (encoding the protein p185) is overexpressed in diverse human cancers and has been implicated to be of prognostic value in gastric cancer. Recent studies suggest a role of p185 in tumor progression by specifically promoting the invasive capacity of tumor cells. Therefore, the present study was conducted with the following three objectives: (1) to support the prognostic value of c-erbB-2 in gastric cancer in a large prospective series using a monoclonal antibody and a highly sensitive immunohistochemical method; (2) to determine the association of c-erbB-2 expression with the expression of invasion-related genes; and (3) to perform the first overall multivariate analysis including c-erbB-2 and the invasion-related tumor-associated protease systems. PATIENTS AND METHODS: In a consecutive prospective series of 203 gastric cancer patients (median follow-up, 42 months), expression of c-erbB-2 and a panel of tumor-associated proteases and inhibitors by tumor cells were evaluated semiquantitatively (score 0 to 3) and analyzed for correlation (chi(2) test, Bonferroni-corrected). Kaplan-Meier survival analysis and multivariate Cox analysis were performed to determine the relative prognostic impact of c-erbB-2 and the invasion-related parameters. RESULTS: Kaplan-Meier analysis (log-rank statistics) revealed a significant association of increasing expression of c-erbB-2 with shorter disease-free (P =. 0023) and overall survival (P =.0160). High amounts of p185 were significantly associated with a high expression of urokinase-type plasminogen activator (uPA) (P <.010), uPA-receptor (P =.030), type-1 plasminogen activator inhibitor (PAI) (P <.010), type-2 PAI (P =.021), cathepsin D (P =.036), matrix metalloproteinase-2 (P =. 024), alpha-1-antichymotrypsin (P =.025), and alpha-2-macroglobulin (P =.017). Multivariate analysis considering these proteases/protease inhibitors, in addition to alpha-1-antitrypsin, tissue plasminogen activator, plasminogen, alpha-2-antiplasmin, and antithrombin III, and established prognostic parameters revealed that, in addition to surgical curability, pT stage, pN stage, and PAI-1, c-erbB-2 is an independent prognostic factor for overall survival of curatively resected patients (n = 139; P =.049; relative risk, 1.54; 95% confidence interval, 1.08 to 1.67) and all patients (P =.028; relative risk 1.33; 95% CI, 1.28 to 1.38). CONCLUSION: c-erbB-2 is confirmed as a new independent, functional prognostic parameter for overall survival in gastric cancer, even when a panel of invasion-related factors, including the strong prognostic parameter PAI-1, are considered. The significant correlation of p185 with several tumor-associated proteases supports the hypothesis that c-erbB-2 is a promoter of invasion and metastasis. This strongly suggests that c-erbB-2 may be a promising target for anti-invasive therapy in gastric cancer.

Adult↗
PubMed2005

Thanatos-associated protein 7 associates with template activating factor-Ibeta and inhibits histone acetylation to repress transcription.

The posttranslational modifications of histones on chromatin or a lack thereof is critical in transcriptional regulation. Emerging studies indicate a role for histone-binding proteins in transcriptional activation and repression. We have previously identified template-activating factor-Ibeta (TAF-Ibeta, also called PHAPII, SET, and I(2)(pp2A)) as a component of a cellular complex called inhibitor of acetyltransferases (INHAT) that masks histone acetylation in vitro and blocks histone acetyltransferase (HAT)-dependent transcription in living cells. TAF-Ibeta has also been shown to associate with transcription factors, including nuclear receptors, to regulate their activities. To identify novel interactors of TAF-Ibeta, we employed a yeast two-hybrid screen and identified a previously uncharacterized human protein called thanatos-associated protein-7 (THAP7), a member of a large family of THAP domain-containing putative DNA-binding proteins. In this study we demonstrate that THAP7 associates with TAF-Ibeta in vitro and map their association domains to a C-terminal predicted coiled-coil motif on THAP7 and the central region of TAF-Ibeta. Similarly, stably transfected THAP7 associates with endogenous TAF-Ibeta in intact cells. Like TAF-Ibeta, THAP7 associates with histone H3 and histone H4 and inhibits histone acetylation. The histone-interacting domain of THAP7 is sufficient for this activity in vitro. Promoter-targeted THAP7 can also recruit TAF-Ibeta and silencing mediator of retinoid and thyroid receptors/nuclear hormone receptor corepressor (NCoR) proteins to promoters, and knockdown of TAF-Ibeta by small interfering RNA relieves THAP7-mediated repression, indicating that, like nuclear hormone receptors, THAP7 may represent a novel class of transcription factor that uses TAF-Ibeta as a corepressor to maintain histones in a hypoacetylated, repressed state.

Acetylation↗
PubMed2001

Inward rectifier potassium channel Kir2.2 is associated with synapse-associated protein SAP97.

The strong inwardly rectifying potassium channels Kir2.x are involved in maintenance and control of cell excitability. Recent studies reveal that the function and localization of ion channels are regulated by interactions with members of the membrane-associated guanylate kinase (MAGUK) protein family. To identify novel interacting MAGUK family members, we constructed GST-fusion proteins with the C termini of Kir2.1, Kir2.2 and Kir2.3. GST affinity-pulldown assays from solubilized rat cerebellum and heart membrane proteins revealed an interaction between all three Kir2.x C-terminal fusion proteins and the MAGUK protein synapse-associated protein 97 (SAP97). A truncated form of the C-terminal GST-Kir2.2 fusion protein indicated that the last three amino acids (S-E-I) are essential for association with SAP97. Affinity interactions using GST-fusion proteins containing the modular domains of SAP97 demonstrate that the second PSD-95/Dlg/ZO-1 (PDZ) domain is sufficient for interaction with Kir2.2. Coimmunoprecipitations demonstrated that endogenous Kir2.2 associates with SAP97 in rat cerebellum and heart. Additionally, phosphorylation of the Kir2.2 C terminus by protein kinase A inhibited the association with SAP97. In rat cardiac ventricular myocytes, Kir2.2 and SAP97 colocalized in striated bands corresponding to T-tubules. In rat cerebellum, Kir2.2 was present in a punctate pattern along SAP97-positive processes of Bergmann glia in the molecular layer, and colocalized with astrocytes and granule cells in the granule cell layer. These results identify a direct association of Kir2.1, Kir2.2 and Kir2.3 with the MAGUK family member SAP97 that may form part of a macromolecular signaling complex in many different tissues.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Differences in tumor-associated protein levels among middle-age Flemish women in association with area of residence and exposure to pollutants.

We measured tumor-associated proteins (TAPs) and pollutants in blood, serum, and urine of 200 nonsmoking women 50-65 years of age, residing in the rural municipality of Peer or in Hoboken or Wilrijk, industrial suburbs of Antwerp, Belgium. Persons with occupational exposures or commuting to other towns were excluded. Residents from Hoboken had significantly higher levels of blood lead and serum zinc and polychlorinated biphenyls. Surprisingly, residents of Peer had significantly higher levels of serum cadmium, dioxin-like activity in blood fat, and urinary 1-hydroxypyrene. For 5 of the 12 TAPs assessed in this study, we observed significant differences in serum levels among residents of the three municipalities after adjusting for personal or lifestyle parameters. Although we found levels of internal exposure to pollutants to be quite homogeneous in Flanders, we found significantly higher levels of TAPs only in the industrial suburbs. In multiple regression with all 29 available personal, lifestyle, and internal exposure parameters, blood lead levels showed a positive association with serum levels of anti-p53, carcino-embryonic antigen (CEA), and tissue polypeptide-specific antigen (TPS) and with an index for mean TAP level (I(tap)); dioxin-like activity in serum and serum copper showed a positive association with serum CA 125 (cancer antigen 125); and serum zinc showed a positive association with serum levels of c-erbB-2 ectodomain and TPS. An index of internal exposure showed a positive association with serum levels of both CEA and anti-p53 and with I(tap). This study provides some evidence that levels of internal exposure such as those present in Flanders, in particular concerning lead, are indeed associated with biologic effects.

Aged↗
PubMed2007

Screening of 134 single nucleotide polymorphisms (SNPs) previously associated with type 2 diabetes replicates association with 12 SNPs in nine genes.

More than 120 published reports have described associations between single nucleotide polymorphisms (SNPs) and type 2 diabetes. However, multiple studies of the same variant have often been discordant. From a literature search, we identified previously reported type 2 diabetes-associated SNPs. We initially genotyped 134 SNPs on 786 index case subjects from type 2 diabetes families and 617 control subjects with normal glucose tolerance from Finland and excluded from analysis 20 SNPs in strong linkage disequilibrium (r(2) > 0.8) with another typed SNP. Of the 114 SNPs examined, we followed up the 20 most significant SNPs (P < 0.10) on an additional 384 case subjects and 366 control subjects from a population-based study in Finland. In the combined data, we replicated association (P < 0.05) for 12 SNPs: PPARG Pro12Ala and His447, KCNJ11 Glu23Lys and rs5210, TNF -857, SLC2A2 Ile110Thr, HNF1A/TCF1 rs2701175 and GE117881_360, PCK1 -232, NEUROD1 Thr45Ala, IL6 -598, and ENPP1 Lys121Gln. The replication of 12 SNPs of 114 tested was significantly greater than expected by chance under the null hypothesis of no association (P = 0.012). We observed that SNPs from genes that had three or more previous reports of association were significantly more likely to be replicated in our sample (P = 0.03), although we also replicated 4 of 58 SNPs from genes that had only one previous report of association.

Aged↗