Molecular Virology of Hepatitis C Virus (HCV): 2006 Update

Fascinating progress in the understanding of the molecular biology of hepatitis C virus (HCV) was achieved recently. The replicon system revolutionized the investigation of HCV RNA replication and facilitated drug discovery. Novel systems for functional analyses of the HCV glycoproteins allowed the validation of HCV receptor candidates and the investigation of cell entry mechanisms. Most recently, recombinant infectious HCV could be produced in cell culture, rendering all steps of the viral life cycle, including entry and release of viral particles, amenable to systematic analysis. In this review, we summarize recent advances and discuss future research directions

Evolving therapies in the treatment of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. The major etiologies and risk factors for HCC development are well defined and some of the steps involved in hepatocarcinogenesis have been elucidated in recent years. Therapeutic options that can be applied in curative or palliative intention are available and are dependent on the HCC stage. The therapeutic options fall into five main categories: (1) surgical interventions, including tumor resection and liver transplantation, (2) percutaneous interventions, including ethanol injection and radiofrequency thermal ablation, (3) transarterial interventions, including embolization and chemoembolization, (4) radiation therapy, and (5) drugs as well as gene and immune therapies. Until recently, no therapy existed for patients with advanced HCC. In 2007 a multikinase inhibitor (sorafenib) showed for the first time a significant increase in overall survival in patients with advanced HCC. Furthermore, several other agents that target different factors of hepatocarcinogenesis (eg, epidermal growth factor, insulin-like growth factors, hepatocyte growth factor, vascular endothelial growth factor, fibroblast growth factor, platelet-derived growth factor, and the transforming growth factors-α and -β), have emerged and been tested in clinical trials. This review gives an overview of the current therapeutic strategies and their clinical impact

Nearly Optimal Private Convolution

We study computing the convolution of a private input $x$ with a public input $h$, while satisfying the guarantees of $(\epsilon, \delta)$-differential privacy. Convolution is a fundamental operation, intimately related to Fourier Transforms. In our setting, the private input may represent a time series of sensitive events or a histogram of a database of confidential personal information. Convolution then captures important primitives including linear filtering, which is an essential tool in time series analysis, and aggregation queries on projections of the data. We give a nearly optimal algorithm for computing convolutions while satisfying $(\epsilon, \delta)$-differential privacy. Surprisingly, we follow the simple strategy of adding independent Laplacian noise to each Fourier coefficient and bounding the privacy loss using the composition theorem of Dwork, Rothblum, and Vadhan. We derive a closed form expression for the optimal noise to add to each Fourier coefficient using convex programming duality. Our algorithm is very efficient -- it is essentially no more computationally expensive than a Fast Fourier Transform. To prove near optimality, we use the recent discrepancy lowerbounds of Muthukrishnan and Nikolov and derive a spectral lower bound using a characterization of discrepancy in terms of determinants

Translation of stable hepadnaviral mRNA cleavage fragments induced by the action of phosphorothioate-modified antisense oligodeoxynucleotides

Phosphorothioate-modified antisense oligodeoxynucleotides (ASOs) are used to suppress gene expression by inducing RNase H-mediated cleavage with subsequent degradation of the target mRNA. However, previous observations suggest that ASO/RNase H can also result in the generation of stable mRNA cleavage fragments and expression of truncated proteins. Here, we addressed the underlying translational mechanisms in more detail using hepadnavirus-transfected hepatoma cells as a model system of antisense therapy. Generation of stable mRNA cleavage fragments was restricted to the ASO/RNase H pathway and not observed upon cotransfection of isosequential small interfering RNA or RNase H-incompetent oligonucleotides. Furthermore, direct evidence for translation of mRNA fragments was established by polysome analysis. Polysome-associated RNA contained cleavage fragments devoid of a 5′ cap structure indicating that translation was, at least in part, cap-independent. Further analysis of the uncapped cleavage fragments revealed that their 5′ terminus and initiation codon were only separated by a few nucleotides suggesting a 5′ end-dependent mode of translation, whereas internal initiation could be ruled out. However, the efficiency of translation was moderate compared to uncleaved mRNA and amounted to 13–24% depending on the ASO used. These findings provide a rationale for understanding the translation of mRNA fragments generated by ASO/RNase H mechanistically

Clinical response to Auron Misheil Therapy in a man with advanced multifocal hepatocellular carcinoma: A case report

<p>Abstract</p> <p>Introduction</p> <p>Auron Misheil Therapy was developed based on similarities between carcinogenesis and inflammation. Auron Misheil Therapy is a combination of natural and synthetic compounds, including anti-inflammatory drugs and insulin, expected to exhibit synergistic effects.</p> <p>Case presentation</p> <p>Here, we report the case of a 78-year-old Caucasian male patient who presented with multifocal hepatocellular carcinoma and chronic hepatitis C virus infection. Over a four-year period our patient was treated with radiofrequency ablation and transarterial chemoembolization. After these treatments there was tumor progression, with new hyperperfused lesions without evidence of extrahepatic tumor involvement. Our patient refused sorafenib therapy. Therefore, he received twice daily intramuscular injections of Auron Misheil Therapy on an outpatient basis for two months. Partial remission of the hepatic lesions was observed eight weeks after the start of treatment, and confirmed four weeks later. Unfortunately, at that time our patient refused therapy due to dizziness. During follow-up two target lesions remained stable, but one lesion increased in size. At the latest follow-up, one year later, there was still tumor control.</p> <p>Conclusion</p> <p>While the mechanisms underlying the antitumor effects of Auron Misheil Therapy are not fully understood, stable disease and remissions have been observed in different types of tumors, including hepatocellular carcinoma.</p

Registration and segmentation of multislice 3DCT images: Application to laparoscopic surgery of the upper urinary system

International audienceA clear identification of arteries, veins and urinary tracts, together with their simultaneous visualization in 3D is required when planning laparoscopic surgery on kidneys. To this aim, multiple contrast-enhanced CT scans are acquired at different times during blood circulation, but the kidney motion, among other causes, seriously hampers their direct fusion. This study aims at developing algorithms to represent in 3D, from such images, the kidney surroundings as close as possible to the surgical reality

Recalage et segmentation d'images scanographiques 3D : application à la représentation du haut appareil urinaire

National audienceDisposer en pré-opératoire d'images anatomiques les plus fiables possibles et faciles à interpréter permet d'anticiper les difficultés per-opératoires, ce qui est particulièrement important en cœliochirurgie. Les reconstructions tridimensionnelles actuelles obtenues au scanner ne permettent pas une visualisation simultanée des artères, veines et voie excrétrice : une simple fusion n'est en effet pas possible compte tenu des mouvements du rein avec la respiration. Cette étude vise à développer des algorithmes permettant cette représentation volumique la plus proche de la réalité chirurgicale

Recalage et segmentation d'images scanographiques 3D : application à la représentation du haut appareil urinaire avant coeliochirurgie

National audiencePour pouvoir anticiper les difficultés opératoires au cours d'une intervention coelioscopique, le chirurgien urologue a besoin de pouvoir étudier avant l'intervention les images anatomiques les plus fiables possibles et faciles à interpréter ; les reconstructions tridimensionnelles actuelles obtenues au scanner ne permettent pas une visualisation simultanée des artères, veines et voie excrétrice : une simple fusion n'est en effet pas possible compte tenu des mouvements du rein avec la respiration. Cette étude vise à développer des algorithmes permettant cette représentation volumique la plus proche de la réalité chirurgicale