Demonstration of the histopathological and immunohistochemical effects of a novel hemostatic agent, ankaferd blood stopper, on vascular tissue in a rat aortic bleeding model

Background: Ankaferd Blood Stopper®(ABS) is a folkloric medicinal plant extract used as a hemostatic agent in traditional Turkish medicine. This experimental study investigated the histopathological and immunohistochemical effects of ABS on vascular tissue in a rat model of aortic bleeding.Methods: Four groups of 11 Wistar albino rats were used. The abdominal aortas of the rats were wounded; an ABS-soaked tampon was applied to rats in Groups 1 and 3, and a plain gauze tampon was applied to rats in Groups 2 and 4 until the bleeding stopped. The bleeding time was recorded. Immediately following sacrificing, the arteriotomy sites from Groups 1 and 2 were removed. The abdominal incisions in Groups 3 and 4 were closed following hemostasis. On Day 7 of the study, Group 3 and 4 rats were sacrificed and the abdominal aorta arteriotomy sites were removed for histopathological and immunohistochemical evaluation.Results: The mean bleeding time in 15 animals in Groups 2 and 4 was 4.9 ± 0.6 s, and in 22 animals in Groups 1 and 3 was 3.1 ± 0.6 s. Distal aortic occlusion was not observed on either Day 1 or 7 in any group. Significantly more widespread and dense endothelial nitric oxide synthase (eNOS) staining was observed in Group 1 animals than Group 2. On Days 1 and 7 after application of ABS, histopathological changes, consisting of necrosis, inflammation, and endothelial cell loss, in the rat abdominal aortas did not differ between Groups 1 and 2. The basophilic discoloration in the ABS group on the operation day was a result of a foreign body reaction and hemosiderin-loaded histiocyte accumulation, which occurred on Day 7.Conclusions: In this study, hemostasis was successfully achieved with ABS in rat abdominal aortas. No histopathological change was found in the rat abdominal aortas between the ABS and control groups on Days 1 and 7. Further studies on the long-term effects of foreign body reactions and hemosiderin-loaded histiocyte accumulation are required. © 2010 Kandemir et al; licensee BioMed Central Ltd

Relationship between intratumoral expression of genes coding for xenobiotic-metabolizing enzymes and benefit from adjuvant tamoxifen in estrogen receptor alpha-positive postmenopausal breast carcinoma

INTRODUCTION: Little is known of the function and clinical significance of intratumoral dysregulation of xenobiotic-metabolizing enzyme expression in breast cancer. One molecular mechanism proposed to explain tamoxifen resistance is altered tamoxifen metabolism and bioavailability. METHODS: To test this hypothesis, we used real-time quantitative RT-PCR to quantify the mRNA expression of a large panel of genes coding for the major xenobiotic-metabolizing enzymes (12 phase I enzymes, 12 phase II enzymes and three members of the ABC transporter family) in a small series of normal breast (and liver) tissues, and in estrogen receptor alpha (ERα)-negative and ERα-positive breast tumors. Relevant genes were further investigated in a well-defined cohort of 97 ERα-positive postmenopausal breast cancer patients treated with primary surgery followed by adjuvant tamoxifen alone. RESULTS: Seven of the 27 genes showed very weak or undetectable expression in both normal and tumoral breast tissues. Among the 20 remaining genes, seven genes (CYP2A6, CYP2B6, FMO5, NAT1, SULT2B1, GSTM3 and ABCC11) showed significantly higher mRNA levels in ERα-positive breast tumors than in normal breast tissue, or showed higher mRNA levels in ERα-positive breast tumors than in ERα-negative breast tumors. In the 97 ERα-positive breast tumor series, most alterations of these seven genes corresponded to upregulations as compared with normal breast tissue, with an incidence ranging from 25% (CYP2A6) to 79% (NAT1). Downregulation was rare. CYP2A6, CYP2B6, FMO5 and NAT1 emerged as new putative ERα-responsive genes in human breast cancer. Relapse-free survival was longer among patients with FMO5-overexpressing tumors or NAT1-overexpressing tumors (P = 0.0066 and P = 0.000052, respectively), but only NAT1 status retained prognostic significance in Cox multivariate regression analysis (P = 0.0013). CONCLUSIONS: Taken together, these data point to a role of genes coding for xenobiotic-metabolizing enzymes in breast tumorigenesis, NAT1 being an attractive candidate molecular predictor of antiestrogen responsiveness

Prediction of HIV-1 virus-host protein interactions using virus and host sequence motifs

<p>Abstract</p> <p>Background</p> <p>Host protein-protein interaction networks are altered by invading virus proteins, which create new interactions, and modify or destroy others. The resulting network topology favors excessive amounts of virus production in a stressed host cell network. Short linear peptide motifs common to both virus and host provide the basis for host network modification.</p> <p>Methods</p> <p>We focused our host-pathogen study on the binding and competing interactions of HIV-1 and human proteins. We showed that peptide motifs conserved across 70% of HIV-1 subtype B and C samples occurred in similar positions on HIV-1 proteins, and we documented protein domains that interact with these conserved motifs. We predicted which human proteins may be targeted by HIV-1 by taking pairs of human proteins that may interact via a motif conserved in HIV-1 and the corresponding interacting protein domain.</p> <p>Results</p> <p>Our predictions were enriched with host proteins known to interact with HIV-1 proteins ENV, NEF, and TAT (p-value < 4.26E-21). Cellular pathways statistically enriched for our predictions include the T cell receptor signaling, natural killer cell mediated cytotoxicity, cell cycle, and apoptosis pathways. Gene Ontology molecular function level 5 categories enriched with both predicted and confirmed HIV-1 targeted proteins included categories associated with phosphorylation events and adenyl ribonucleotide binding.</p> <p>Conclusion</p> <p>A list of host proteins highly enriched with those targeted by HIV-1 proteins can be obtained by searching for host protein motifs along virus protein sequences. The resulting set of host proteins predicted to be targeted by virus proteins will become more accurate with better annotations of motifs and domains. Nevertheless, our study validates the role of linear binding motifs shared by virus and host proteins as an important part of the crosstalk between virus and host.</p

Origin of micro-scale heterogeneity in polymerisation of photo-activated resin composites

Photo-activated resin composites are widely used in industry and medicine. Despite extensive chemical characterisation, the micro-scale pattern of resin matrix reactive group conversion between filler particles is not fully understood. Using an advanced synchrotron-based wide-field IR imaging system and state-of-the-art Mie scattering corrections, we observe how the presence of monodispersed silica filler particles in a methacrylate based resin reduces local conversion and chemical bond strain in the polymer phase. Here we show that heterogeneity originates from a lower converted and reduced bond strain boundary layer encapsulating each particle, whilst at larger inter-particulate distances light attenuation and monomer mobility predominantly influence conversion. Increased conversion corresponds to greater bond strain, however, strain generation appears sensitive to differences in conversion rate and implies subtle distinctions in the final polymer structure. We expect these findings to inform current predictive models of mechanical behaviour in polymer-composite materials, particularly at the resin-filler interface

Identification of Tumor Suppressors and Oncogenes from Genomic and Epigenetic Features in Ovarian Cancer

The identification of genetic and epigenetic alterations from primary tumor cells has become a common method to identify genes critical to the development and progression of cancer. We seek to identify those genetic and epigenetic aberrations that have the most impact on gene function within the tumor. First, we perform a bioinformatic analysis of copy number variation (CNV) and DNA methylation covering the genetic landscape of ovarian cancer tumor cells. We separately examined CNV and DNA methylation for 42 primary serous ovarian cancer samples using MOMA-ROMA assays and 379 tumor samples analyzed by The Cancer Genome Atlas. We have identified 346 genes with significant deletions or amplifications among the tumor samples. Utilizing associated gene expression data we predict 156 genes with altered copy number and correlated changes in expression. Among these genes CCNE1, POP4, UQCRB, PHF20L1 and C19orf2 were identified within both data sets. We were specifically interested in copy number variation as our base genomic property in the prediction of tumor suppressors and oncogenes in the altered ovarian tumor. We therefore identify changes in DNA methylation and expression for all amplified and deleted genes. We statistically define tumor suppressor and oncogenic features for these modalities and perform a correlation analysis with expression. We predicted 611 potential oncogenes and tumor suppressors candidates by integrating these data types. Genes with a strong correlation for methylation dependent expression changes exhibited at varying copy number aberrations include CDCA8, ATAD2, CDKN2A, RAB25, AURKA, BOP1 and EIF2C3. We provide copy number variation and DNA methylation analysis for over 11,500 individual genes covering the genetic landscape of ovarian cancer tumors. We show the extent of genomic and epigenetic alterations for known tumor suppressors and oncogenes and also use these defined features to identify potential ovarian cancer gene candidates

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

A statistical analysis of audience sound absorption (A)

The absorption produced by the audience in concert halls is considered a random variable. Beranek's proposal [L. L. Beranek, Music, Acoustics and Architecture (Wiley, New York, 1962), p. 543] that audience absorption is proportional to the area they occupy and not to their number is subjected to a statistical hypothesis test. A two variable linear regression model of the absorption with audience area and residual area as regressor variables is postulated for concert halls without added absorptive materials. Since Beranek's contention amounts to the statement that audience absorption is independent of the seating density, the test of the hypothesis lies in categorizing halls by seating density and examining for significant differences among slopes of regression planes of the different categories. Such a test shows that Beranek's hypothesis can be accepted. It is also shown that the audience area is a better predictor of the absorption than the audience number. The absorption coefficients and their 95% confidence limits are given for the audience and residual areas. A critique of the regression model is presented