Response to combination therapy with interferon alfa-2a and ribavirin in chronic hepatitis C according to a TNF-alpha promoter polymorphism

Background. Tumor necrosis factor-alpha (TNF-alpha) is involved in the pathogenesis of chronic active hepatitis C. Polymorphisms in the promoter region of the TNF-alpha gene can alter the TNF-alpha expression and modify the host immune response. The present study aimed at the correlation of the G308A TNF-alpha polymorphism with the response to antiviral combination therapy in chronic hepatitis C. Patients and Methods: 62 patients with HCV and 119 healthy unrelated controls were genotyped for the G308A TNF-alpha promoter polymorphism. The patients received 3 x 3 million units of interferon alfa-2a and 1,0001,200 mg ribavirin daily according to their body weight. A response was defined as absence of HCV-RNA and normalization of S-ALT after 6 months of combination therapy. Results:With respect to the allele and genotype frequency, a significant difference was not observed between controls and patients with chronic hepatitis C. Furthermore, such a difference was also not observed if responders and non-responders to antiviral therapy were compared. Conclusions: The promoter polymorphism of the TNF-alpha gene investigated herein is equally distributed in healthy individuals and patients with hepatitis C and does not seem to predict the response to therapy with interferon alfa-2a and ribavirin. Copyright (C) 2003 S. Karger AG, Basel

Estimating novel potential drug targets of Plasmodium falciparum by analysing the metabolic network of knock-out strains in silico

Malaria is one of the world’s most common and serious diseases causing death of about 3 million people each year. Its most severe occurrence is caused by the protozoan Plasmodium falciparum. Biomedical research could enable treating the disease by effectively and specifically targeting essential enzymes of this parasite. However, the parasite has developed resistance to existing drugsmaking it indispensable to discover new drugs. We have established a simple computational tool which analyses the topology of the metabolic network of P. falciparum to identify essential enzymes as possible drug targets.Weinvestigated the essentiality of a reaction in the metabolic network by deleting (knocking-out) such a reaction in silico. The algorithmselected neighbouring compounds of the investigated reaction that had to be produced by alternative biochemical pathways. Using breadth first searches, we tested qualitatively if these products could be generated by reactions that serve as potential deviations of the metabolic flux. With this we identified 70 essential reactions. Our results were compared with a comprehensive list of 38 targets of approved malaria drugs. When combining our approach with an in silico analysis performed recently [Yeh, I., Hanekamp, T., Tsoka, S., Karp, P.D., Altman, R.B., 2004. Computational analysis of Plasmodium falciparum metabolism: organizing genomic information to facilitate drug discovery. Genome Res. 14, 917–924] we could improve the precision of the prediction results. Finally we present a refined list of 22 new potential candidate targets for P. falciparum, half of which have reasonable evidence to be valid targets against micro-organisms and cancer

A new approach for improving coronary plaque component analysis based on intravascular ultrasound images

Virtual histology intravascular ultrasound (VH-IVUS) is a clinically available technique for atherosclerosis plaque characterization. It, however, suffers from a poor longitudinal resolution due to electrocardiogram (ECG)-gated acquisition. This article presents an effective algorithm for IVUS image-based histology to overcome this limitation. After plaque area extraction within an input IVUS image, a textural analysis procedure consisting of feature extraction and classification steps is proposed. The pixels of the extracted plaque area excluding the shadow region were classified into one of the three plaque components of fibro-fatty (FF), calcification (CA) or necrotic core (NC) tissues. The average classification accuracy for pixel and region based validations is 75% and 87% respectively. Sensitivities (specificities) were 79% (85%) for CA, 81% (90%) for FF and 52% (82%) for NC. The kappa (kappa) = 0.61 and p value = 0.02 indicate good agreement of the proposed method with VH images. Finally, the enhancement in the longitudinal resolution was evaluated by reconstructing the IVUS images between the two sequential IVUS-VH images

Exploring the environment, magnetic fields, and feedback effects of massive high-redshift galaxies with [CII]

Massive galaxies are expected to grow through different transformative evolutionary phases where high-redshift starburst galaxies and quasars are examples of such phases. The physical mechanisms driving these phases include companion galaxy interactions, active galactic nuclei feedback, and magnetic fields. Our aim is to characterize the physical properties and the environment of the submillimeter galaxy AzTEC-3 at z = 5.3 and the lensed quasar BRI 0952-0115 at z = 4.4, to set a limit on the polarization properties, as well as placing both in the broader context of galaxy evolution. We used full polarization, sub-arcsecond-resolution, ALMA band-7 observations of both BRI 0952-0115 and AzTEC-3 and detect [CII] line emission towards both galaxies, along with companions in each field. We present an updated gravitational lensing model for BRI 0952-0115. We present infrared luminosities, star-formation rates, and [CII] line to infrared luminosity ratios for each source. The [CII] emission line profile for both BRI 0952-0115 and AzTEC-3 exhibit a broad, complex morphology, indicating the possible presence of outflows. We present evidence of a 'gas bridge' between AzTEC-3 and a companion source. Using a simple dynamical mass estimate for the sources, we suggest that both systems are undergoing minor or major mergers. No polarization is detected for the [CII], placing an upper limit below that of theoretical predictions. Our results show that high-velocity wings are detected, indicating possible signs of massive outflows; however, the presence of companion galaxies can affect the final interpretation. Furthermore, the results provide additional evidence in support of the hypothesis that massive galaxies form in overdense regions, growing through interactions. Finally, strong, ordered magnetic fields are unlikely to exist at the kiloparsec scale in the two studied sources

Program on stimulating operational private sector use of Earth observation satellite data

There are no author-identified significant results in this report

SiGe HMODFET "KAIST" micropower model and amplifier realization

Published versio

A human MAP kinase interactome.

Mitogen-activated protein kinase (MAPK) pathways form the backbone of signal transduction in the mammalian cell. Here we applied a systematic experimental and computational approach to map 2,269 interactions between human MAPK-related proteins and other cellular machinery and to assemble these data into functional modules. Multiple lines of evidence including conservation with yeast supported a core network of 641 interactions. Using small interfering RNA knockdowns, we observed that approximately one-third of MAPK-interacting proteins modulated MAPK-mediated signaling. We uncovered the Na-H exchanger NHE1 as a potential MAPK scaffold, found links between HSP90 chaperones and MAPK pathways and identified MUC12 as the human analog to the yeast signaling mucin Msb2. This study makes available a large resource of MAPK interactions and clone libraries, and it illustrates a methodology for probing signaling networks based on functional refinement of experimentally derived protein-interaction maps

Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival

Recent evidence suggests CML stem cells are insensitive to kinase inhibitors and responsible for minimal residual disease in treated patients. We investigated whether CML stem cells, in a transgenic mouse model of CML-like disease or derived from patients, are dependent on Bcr-Abl. In the transgenic model, following re-transplantation, donor-derived CML stem cells in which Bcr-Abl expression had been induced and subsequently shut off, were able to persist in vivo and re-initiate leukemia in secondary recipients upon Bcr-Abl re-expression. Bcr-Abl knockdown in human CD34+ CML cells cultured for 12 days in physiological growth factors achieved partial inhibition of Bcr-Abl and downstream targets p-CrkL and p-STAT5, inhibition of proliferation and colony forming cells, but no reduction of input cells. The addition of dasatinib further inhibited p-CrkL and p-STAT5, yet only reduced input cells by 50%. Complete growth factor withdrawal plus dasatinib further reduced input cells to 10%, however the surviving fraction was enriched for primitive leukemic cells capable of growth in long-term culture initiating cell assay and expansion upon removal of dasatinib and addition of growth factors. Together these data suggest that CML stem cell survival is Bcr-Abl kinase independent and suggest curative approaches in CML must focus on kinase-independent mechanisms of resistance

MicroRNA-519a is a novel oncomir conferring tamoxifen resistance by targeting a network of tumour-suppressor genes in ER+ breast cancer

Cataloged from PDF version of article.Tamoxifen is an endocrine therapy which is administered to up to 70% of all breast cancer patients with oestrogen receptor alpha (ERα) expression. Despite the initial response, most patients eventually acquire resistance to the drug. MicroRNAs (miRNAs) are a class of small non-coding RNAs which have the ability to post-transcriptionally regulate genes. Although the role of a few miRNAs has been described in tamoxifen resistance at the single gene/target level, little is known about how concerted actions of miRNAs targeting biological networks contribute to resistance. Here we identified the miRNA cluster, C19MC, which harbours around 50 mature miRNAs, to be up-regulated in resistant cells, with miRNA-519a being the most highly up-regulated. We could demonstrate that miRNA-519a regulates tamoxifen resistance using gain- and loss-of-function testing. By combining functional enrichment analysis and prediction algorithms, we identified three central tumour-suppressor genes (TSGs) in PI3K signalling and the cell cycle network as direct target genes of miR-519a. Combined expression of these target genes correlated with disease-specific survival in a cohort of tamoxifen-treated patients. We identified miRNA-519a as a novel oncomir in ER+ breast cancer cells as it increased cell viability and cell cycle progression as well as resistance to tamoxifen-induced apoptosis. Finally, we could show that elevated miRNA-519a levels were inversely correlated with the target genes' expression and that higher expression of this miRNA correlated with poorer survival in ER+ breast cancer patients. Hence we have identified miRNA-519a as a novel oncomir, co-regulating a network of TSGs in breast cancer and conferring resistance to tamoxifen. Using inhibitors of such miRNAs may serve as a novel therapeutic approach to combat resistance to therapy as well as proliferation and evasion of apoptosis in breast cancer. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland

A search for ferromagnetism in transition-metal-doped piezoelectric ZnO

We present the results of a computational study of ZnO in the presence of Co and Mn substitutional impurities. The goal of our work is to identify potential ferromagnetic ground states within the (Zn,Co)O or (Zn,Mn)O material systems that are also good candidates for piezoelectricity. We find that, in contrast to previous results, robust ferromagnetism is not obtained by substitution of Co or Mn on the Zn site, unless additional carriers (holes) are also incorporated. We propose a practical scheme for achieving such $p$-type doping in ZnO