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Results for “systematic analysis”

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PubMed2006

Biologic significance of fascin expression in clear cell renal cell carcinoma: systematic analysis of primary and metastatic tumor tissues using a tissue microarray technique.

OBJECTIVES: To investigate the biologic significance of fascin, a globular actin cross-linking protein, involved in cell adhesion and motility, in primary and metastatic renal cell carcinoma (RCC). METHODS: A total of 136 primary clear cell RCCs and 54 clear cell RCC metastases were stained immunohistochemically using a tissue microarray technique. Distinct cytoplasmic staining was considered positive, and the staining results were associated with the pT stage, Fuhrman grade, tumor size, sarcomatoid morphology, and metastasis-free survival. For multivariate testing, Cox's proportional hazards regression model was used. RESULTS: Fascin expression was noted in 13 (10%) of 136 primary and 25 (46%) of 54 metastatic RCC specimens (P <0.001). Fascin expression was associated with high tumor stage (2 [3%] of 70 pT1 versus 11 [17%] of pT2/pT3; P = 0.008), high tumor grade (3 [3%] of 88 grade 1-2 versus 10 [21%] of 48 grade 3-4; P = 0.002), and large tumor size (P <0.001). In addition, 8 (62%) of 13 RCCs with sarcomatoid morphology expressed fascin compared with 5 (4%) of 123 RCCs without sarcomatoid transformation (P <0.001). Metastatic disease was noted in 10 (77%) of 13 patients with fascin-positive RCC compared with 26 (21%) of 121 patients with fascin-negative RCC (P <0.001). Multivariate analysis revealed pT Stage 1 or greater (P <0.001, risk ratio [RR] 8.6, 95% confidence interval [CI] 2.8 to 26.5), Fuhrman grade greater than 2 (P <0.001, RR 12.7, 95% CI 4.6 to 35.4), fascin expression (P <0.001, RR 7.2, 95% CI 3.0 to 17.4), and female gender (P = 0.02, RR 2.5, 95% CI 1.1 to 5.5) as independent predictors of metastatic disease. CONCLUSIONS: Fascin immunoreactivity in RCC proved to be an independent predictor of metastatic disease and was demonstrated in almost one half of RCC metastases. Thus, fascin may be a promising molecular target for future cancer therapy.

Adult↗
PubMed2006

A systematic analysis of human CHMP protein interactions: additional MIT domain-containing proteins bind to multiple components of the human ESCRT III complex.

In Saccharomyces cerevisiae 6 closely related proteins (Did2p, Vps2p, Vps24p, Vps32p, Vps60p, Vps20p) form part of the extended ESCRT III complex. This complex is required for the formation of multivesicular bodies and the degradation of internalized transmembrane receptor proteins. In contrast the human genome encodes 10 homologous proteins (CHMP1A (approved gene symbol PCOLN3), 1B, 2A, 2B, 3 (approved gene symbol VPS24), 4A, 4B, 4C, 5, and 6). In this study we have performed a series of protein interaction experiments to generate a more comprehensive picture of the human CHMP protein-interaction network. Our results describe novel interactions between known components of the human ESCRT III complex and identify a range of putative binding partners, which may indicate new ways in which the function of human CHMP proteins may be regulated. In particular, we show that two further MIT domain-containing proteins (AMSH/STAMBP and LOC129531) interact with multiple components of the human ESCRT III complex.

Genome, Human↗
PubMed1999

Molecular systematic analysis of the order Proteocephalidea (Eucestoda) based on mitochondrial and nuclear rDNA sequences.

Two ribosomal DNA sequences were used to infer phylogenetic relationships among the Eucestoda order Proteocephalidea. A 437 bp portion of the 16S mitochondrial and a 1149 bp 5' portion of the nuclear large sub-unit rRNA molecule were sequenced for 53 proteocephalidean cestodes (representing nine subfamilies and 22 genera) and for one outgroup species. Parsimony and distance-based analyses of the two databases, alone and combined, failed to support the monophyly of the two traditionally accepted families, of numerous subfamilies (with the exception of the Rudolphielliinae and Othinoscolescinae which were validated in our analysis) and of various genera, including the genus Nomimoscolex (Woodland), Ophiotaenia (La Rue) as well as the type genus Proteocephalus (Weinland). Palaearctic Proteocephalus species nevertheless constituted a well-defined clade. The two genes globally yielded compatible results; however, the nuclear ribosomal gene provided a better resolution of relations among Proteocephalidea.

Animals↗
PubMed1976

Systematic analysis of mycotoxins by thin-layer chromatography.

The analysis of 37 mycotoxins and other fungal metabolites by thin-layer chromatography is described. Their R(F) values in eight solvent systems, colour reactions after chemical detection and detection under UV light are presented. From the R(F) values, "chromatographic spectra" which can be used as one of the characteristics for the characterization of unknown mycotoxins were constructed.

Aflatoxins↗
PubMed2003

Platelet-endothelial cell interactions during hepatic ischemia-reperfusion in vivo: a systematic analysis.

Platelets have been implicated in the pathophysiology of ischemia-reperfusion (I/R) injury. This study was designed to analyze platelet-endothelial cell interactions after I/R of the liver in vivo in dependence of the duration of ischemia and reperfusion. In C57BL/6 mice, a warm (37 degrees C) lobar hepatic ischemia was induced for 30, 60, or 90 min. Platelets were isolated from syngeneic donors, labeled ex vivo by rhodamine-6G, and infused intraarterially. Platelet-endothelial cell interactions and sinusoidal perfusion were analyzed using intravital fluorescence microscopy after 20-240 min of reperfusion. Hepatic I/R induced platelet rolling and adhesion in terminal arterioles and postsinusoidal venules as well as platelet accumulation in sinusoids already after 20 min of reperfusion. The number of platelets interacting with the endothelium was significantly increased as ischemia time was prolonged from 30 min up to 60 and 90 min. Postischemic platelet adhesion was associated with an increase in thrombin activity and a loss of platelets from the systemic circulation. Moreover, I/R-induced platelet adhesion was linearly correlated with an impairment of sinusoidal perfusion. The prolongation of reperfusion time up to 4 h did not further enhance platelet-endothelial cell interactions. These in vivo results indicate that hepatic I/R induces platelet-endothelial cell interactions in arterioles, sinusoids, and venules already during early reperfusion. The extent of these interactions is dependent on the duration of ischemia, but not on reperfusion time. Adherent platelets seem to participate in the development of sinusoidal perfusion failure in the postischemic liver.

Animals↗
PubMed2006

Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data.

BACKGROUND: Our aim was to calculate the global burden of disease and risk factors for 2001, to examine regional trends from 1990 to 2001, and to provide a starting point for the analysis of the Disease Control Priorities Project (DCPP). METHODS: We calculated mortality, incidence, prevalence, and disability adjusted life years (DALYs) for 136 diseases and injuries, for seven income/geographic country groups. To assess trends, we re-estimated all-cause mortality for 1990 with the same methods as for 2001. We estimated mortality and disease burden attributable to 19 risk factors. FINDINGS: About 56 million people died in 2001. Of these, 10.6 million were children, 99% of whom lived in low-and-middle-income countries. More than half of child deaths in 2001 were attributable to acute respiratory infections, measles, diarrhoea, malaria, and HIV/AIDS. The ten leading diseases for global disease burden were perinatal conditions, lower respiratory infections, ischaemic heart disease, cerebrovascular disease, HIV/AIDS, diarrhoeal diseases, unipolar major depression, malaria, chronic obstructive pulmonary disease, and tuberculosis. There was a 20% reduction in global disease burden per head due to communicable, maternal, perinatal, and nutritional conditions between 1990 and 2001. Almost half the disease burden in low-and-middle-income countries is now from non-communicable diseases (disease burden per head in Sub-Saharan Africa and the low-and-middle-income countries of Europe and Central Asia increased between 1990 and 2001). Undernutrition remains the leading risk factor for health loss. An estimated 45% of global mortality and 36% of global disease burden are attributable to the joint hazardous effects of the 19 risk factors studied. Uncertainty in all-cause mortality estimates ranged from around 1% in high-income countries to 15-20% in Sub-Saharan Africa. Uncertainty was larger for mortality from specific diseases, and for incidence and prevalence of non-fatal outcomes. INTERPRETATION: Despite uncertainties about mortality and burden of disease estimates, our findings suggest that substantial gains in health have been achieved in most populations, countered by the HIV/AIDS epidemic in Sub-Saharan Africa and setbacks in adult mortality in countries of the former Soviet Union. Our results on major disease, injury, and risk factor causes of loss of health, together with information on the cost-effectiveness of interventions, can assist in accelerating progress towards better health and reducing the persistent differentials in health between poor and rich countries.

Adolescent↗
PubMed1999

Optimization of retroviral-mediated gene transfer to human NOD/SCID mouse repopulating cord blood cells through a systematic analysis of protocol variables.

Retroviral transduction of human hematopoietic stem cells is still limited by lack of information about conditions that will maximize stem cell self-renewal divisions in vitro. To address this, we first compared the kinetics of entry into division of single human CD34+CD38- cord blood (CB) cells exposed in vitro to three different flt3-ligand (FL)-containing cytokine combinations. Of the three combinations tested, FL + hyperinterleukin 6 (HIL-6) yielded the least clones and these developed at a slow rate. With either FL + Steel factor (SF) + HIL-6 + thrombopoietin (TPO) or FL + SF + interleukin 3 (IL-3) + IL-6 + granulocyte-colony-stimulating factor (G-CSF), >90% of the cells that formed clones within 6 days undertook their first division within 4 days, although not until after 24 hours. These latter two, more stimulatory, cytokine combinations then were used to assess the effect of duration of cytokine exposure on the efficiency of transducing primitive CB cells with a gibbon ape leukemia virus-pseudotyped murine retroviral vector containing the enhanced green fluorescent protein (GFP) cDNA and the neomycin resistance gene. Fresh lin- CB cells exposed once to medium containing this virus plus cytokines on fibronectin-coated dishes yielded 23% GFP+ CD34+ cells and 52-57% G418-resistant CFC when assessed after 2 days. Prestimulation of the target cells (before exposing them to virus) with either the four or five cytokine combination increased their susceptibility. In both cases, the effect of prestimulation assessed using the same infection protocol was maximal with 2 days of prestimulation and resulted in 47-54% GFP+ CD34+ cells and 67-69% G418-resistant CFC. Repeated daily addition of new virus (up to three times), with assessment of the cells 2 days after the last addition of fresh virus, gave only a marginal improvement in the proportion of transduced CD34+ cells and CFC, but greatly increased the proportion of transduced LTC-IC (from 40% to >99%). Transplantation of lin- CB cells transduced using this latter 6-day protocol into NOD/SCID mice yielded readily detectable GFP+ cells in 10 of 11 mice that were engrafted with human cells. The proportion of the regenerated human cells that were GFP+ ranged from 0.2-72% in individual mice and included both human lymphoid and myeloid cells in all cases. High-level reconstitution with transduced human cells was confirmed by Southern blot analysis. These findings demonstrate that transplantable hematopoietic stem cells in human CB can be reproducibly transduced at high efficiency using a 6-day period of culture in a retrovirus-containing medium with either FL + SF + HIL-6 + TPO or FL + SF + IL-3 + IL-6 + G-CSF in which virus is added on the third, fourth, and fifth day.

ADP-ribosyl Cyclase↗
PubMed2001

Systematic analysis of acid, neutral and basic drugs in horse plasma by combination of solid-phase extraction, non-aqueous partitioning and gas chromatography-mass spectrometry.

A sample preparation method for mass chromatographic detection of doping drugs from horse plasma is described. Bond Elut Certify (1 g/6 ml) is used for the extraction of 4 ml of horse plasma. Fractionation is performed with 6 ml of CHCl3-Me2CO (8:2) and 5 ml of 1% TEA-MeOH according to its property. Simple and effective clean-up based on non-aqueous partitioning is adopted to remove co-eluted contaminants in both acid and basic fractions. Two kinds of 1-(N,N-diisopropylamino)-n-alkanes are co-injected with the sample into the GC-MS system for the calculation of the retention index. Total recoveries of 107 drugs are examined. Some data of post administration plasma are presented. This procedure achieves sufficient recoveries and clean extracts for GC-MS analysis. The method is able to detect ng/ml drug levels in horse plasma.

Animals↗
PubMed1995

Systematic analysis of the Saccharomyces cerevisiae alpha-factor containing lactam constraints of different ring size.

Eight cyclic analogs and corresponding linear homologs of the alpha-factor mating pheromone (WHWLQLKPGQPMY) of Saccharomyces cerevisiae were synthesized using solid-phase procedures on a phenylacetamidomethyl support. On-resin lactamization of the side chains of residues 7 and 10 to form rings containing from 14 to 18 atoms was effected by the BOP reagent. All peptides were highly homogeneous and gave expected molecular ions by FAB mass spectrometry. The constrained analogs had biological activities varying from 10% to less than 0.1% of that of [Nle12]-alpha-factor. In all cases, cyclic analogs with Glu in position 10 were more active than the homolog with Asp at this position. This trend was also found with the corresponding linear pheromones, suggesting that a gamma-carbonyl in position 10 is an important determinant of pheromone potency. The cyclic peptides had from 50- to 20000-fold lower affinities for the alpha-factor receptor than for [Nle12]-alpha-factor, as judged using a competition binding assay. Circular dichroism studies indicate that the cyclic lactam-containing region of cyclo7.10[Orn7, Glu10,Nle12]-alpha-factor retains a beta-turn-like structure similar to that found in the corresponding model tetrapeptide. The results show that covalently constrained analogs of the linear pheromone can maintain biological activity, despite binding poorly to the receptor, and indicate that a beta-turn-like structure in the center of the pheromone allows signal transduction.

Binding, Competitive↗
PubMed1988

Mapping the binding site of aflatoxin B1 in DNA: systematic analysis of the reactivity of aflatoxin B1 with guanines in different DNA sequences.

The mutagenic and carcinogenic chemical aflatoxin B1 (AFB1) reacts almost exclusively at the N(7)-position of guanine following activation to its reactive form, the 8,9-epoxide (AFB1 oxide). In general N(7)-guanine adducts yield DNA strand breaks when heated in base, a property that serves as the basis for the Maxam-Gilbert DNA sequencing reaction specific for guanine. Using DNA sequencing methods, other workers have shown that AFB1 oxide gives strand breaks at positions of guanines; however, the guanine bands varied in intensity. This phenomenon has been used to infer that AFB1 oxide prefers to react with guanines in some sequence contexts more than in others and has been referred to as "sequence specificity of binding". Herein, data on the reaction of AFB1 oxide with several synthetic DNA polymers with different sequences are presented, and (following hydrolysis) adduct levels are determined by high-pressure liquid chromatography. These results reveal that for AFB1 oxide (1) the N(7)-guanine adduct is the major adduct found in all of the DNA polymers, (2) adduct levels vary in different sequences, and, thus, sequence specificity is also observed by this more direct method, and (3) the intensity of bands in DNA sequencing gels is likely to reflect adduct levels formed at the N(7)-position of guanine. Knowing this, a reinvestigation of the reactivity of guanines in different DNA sequences using DNA sequencing methods was undertaken. The reactivities of 190 guanines were determined quantitatively and considered in a pentanucleotide context, 5'-WXGYZ-3', where the central, underlined G represents the reactive guanine and W, X, Y, and Z can be any of the nucleotide bases. Methods are developed to determine that the X (5'-side) base and the Y (3'-side) base are most influential in determining guanine reactivity. The influence of the bases in the 5'-position (X) is 5'-G (1.0) greater than C (0.8) greater than A (0.3) greater than T (0.2), while the influence of the bases in the 3'-position (Y) is 3'-G (1.0) greater than T (0.8) greater than C (0.4) greater than A (0.3). These rules in conjunction with molecular modeling studies (to be published elsewhere) were used to assess the binding sites that might be utilized by AFB1 oxide in its reaction with DNA.

Aflatoxin B1↗