Late-onset benefit in progressive advanced hepatocellular carcinoma with continued sorafenib therapy: a case report

<p>Abstract</p> <p>Introduction</p> <p>In the past, no effective systemic therapy has existed for patients with advanced hepatocellular carcinoma. Sorafenib, an oral multikinase inhibitor, has recently been shown to improve overall survival in patients with advanced hepatocellular carcinoma in two randomized, double-blinded, placebo-controlled trials. This drug has been approved as the first-line therapy for advanced hepatocellular carcinoma patients. We report an intriguing case of advanced hepatocellular carcinoma in which the patient achieved late- onset partial response by prolonged administration of sorafenib in spite of progressive disease.</p> <p>Case presentation</p> <p>A 54-year-old Japanese man was treated with sorafenib for multiple lung metastases after surgical resection for advanced hepatocellular carcinoma accompanied by vascular invasion of the left branch of the portal vein. Although the effective diagnosis was progressive disease, almost all sites began to reduce or disappear eight months after the diagnosis of progressive disease. A dramatic reduction in alpha-fetoprotein and des-gamma-carboxy prothrombin levels was observed. The patient finally achieved partial response and his status remains unchanged.</p> <p>Conclusions</p> <p>If tolerated, prolonged sorafenib treatment may be beneficial.</p

Identifying landslides from continuous seismic surface waves: a case study of multiple small-scale landslides triggered by Typhoon Talas, 2011

Landslides can cause devastating damage. In particular, heavy rainfall-triggered landslides pose a chain of natural hazards. However, such events are often difficult to detect, leaving the physical processes poorly understood. Here we apply a novel surface-wave detector to detect and locate landslides during the transit of Typhoon Talas 2011. We identify multiple landslides triggered by Typhoon Talas, including a landslide in the Tenryu Ward, Shizuoka prefecture, Japan, ∼400 km east from the typhoon track. The Tenryu landslide displaced a total volume of 1.2 − −1.5 × 106 m. The landslide is much smaller than those detected by using globally recorded surface waves, yet the event generated coherent seismic signals propagating up to 3000 km away. Our observations show that attributes of small and large landslides may follow the same empirical scaling relationships, indicating possible invariant failure mechanisms. Our results also suggest an alerting technology to detect and locate landslides with a sparse seismic network

Phosphorylation State-Dependent Interactions of Hepadnavirus Core Protein with Host Factors

Dynamic phosphorylation and dephosphorylation of the hepadnavirus core protein C-terminal domain (CTD) are required for multiple steps of the viral life cycle. It remains unknown how the CTD phosphorylation state may modulate core protein functions but phosphorylation state-dependent viral or host interactions may play a role. In an attempt to identify host factors that may interact differentially with the core protein depending on its CTD phosphorylation state, pulldown assays were performed using the CTD of the duck hepatitis B virus (DHBV) and human hepatitis B virus (HBV) core protein, either with wild type (WT) sequences or with alanine or aspartic acid substitutions at the phosphorylation sites. Two host proteins, B23 and I2PP2A, were found to interact preferentially with the alanine-substituted CTD. Furthermore, the WT CTD became competent to interact with the host proteins upon dephosphorylation. Intriguingly, the binding site on the DHBV CTD for both B23 and I2PP2A was mapped to a region upstream of the phosphorylation sites even though B23 or I2PP2A binding to this site was clearly modulated by the phosphorylation state of the downstream and non-overlapping sequences. Together, these results demonstrate a novel mode of phosphorylation-regulated protein-protein interaction and provide new insights into virus-host interactions

Meta-analysis of radiofrequency ablation versus hepatic resection for small hepatocellular carcinoma

<p>Abstract</p> <p>Background</p> <p>There is no clear consensus on the better therapy [radiofrequency ablation (RFA) versus hepatic resection (HR)] for small hepatocellular carcinoma (HCC) eligible for surgical treatments. This study is a meta-analysis of the available evidence.</p> <p>Methods</p> <p>Systematic review and meta-analysis of trials comparing RFA with HR for small HCC published from 1997 to 2009 in PubMed and Medline. Pooled odds ratios (OR) with 95% confidence intervals (95% CI) were calculated using either the fixed effects model or random effects model.</p> <p>Results</p> <p>One randomized controlled trial, and 9 nonrandomized controlled trials studies were included in this analysis. These studies included a total of 1411 patients: 744 treated with RFA and 667 treated with HR. The overall survival was significantly higher in patients treated with HR than in those treated with RFA at 3 years (OR: 0.56, 95% CI: 0.44-0.71), and at 5 year (OR: 0.60, 95% CI: 0.36-1.01). RFA has a higher rates of local intrahepatic recurrence compared to HR (OR: 4.50, 95% CI: 2.45-8.27). In the HR group the 1, 3, and 5 years disease -free survival rates were significantly better than in the HR-treated patients (respectively: OR: 0.54, 95% CI: 0.35-0.84; OR: 0.44, 95% CI: 0.28-0.68; OR: 0.64, 95% CI: 0.42-0.99). The postoperative morbidity was higher with HR (OR: 0.29, 95% CI: 0.13-0.65), but no significant differences were found concerning mortality. For tumors ≤ 3 cm HR did not differ significantly from RFA for survival, as reported in three NRCTs .</p> <p>Conclusions</p> <p>HR was superior to RFA in the treatment of patients with small HCC eligible for surgical treatments, particularly for tumors > 3 cm. However, the findings have to be carefully interpreted due to the lower level of evidence.</p

Regulation of the catalytic function of topoisomerase II alpha through association with RNA

Topoisomerase IIα interacts with numerous nuclear factors, through which it is engaged in diverse nuclear events such as DNA replication, transcription and the formation or maintenance of heterochromatin. We previously reported that topoisomerase IIα interacts with RNA helicase A (RHA), consistent with a recent view that topoisomerases and helicases function together. Intrigued by our observation that the RHA–topoisomerase IIα interaction is sensitive to ribonuclease A, we explored whether the RHA–topoisomerase IIα interaction can be recapitulated in vitro using purified proteins and a synthetic RNA. This work led us to an unexpected finding that an RNA-binding activity is intrinsically associated with topoisomerase IIα. Topoisomerase IIα stably interacted with RNA harboring a 3′-hydroxyl group but not with RNA possessing a 3′-phosphate group. When measured in decatenation and relaxation assays, RNA binding influenced the catalytic function of topoisomerase IIα to regulate DNA topology. We discuss a possible interaction of topoisomerase IIα with the poly(A) tail and G/U-rich 3′-untranslated region (3′-UTR) of mRNA as a key step in transcription termination

H2A.Bbd: an X-chromosome-encoded histone involved in mammalian spermiogenesis

Despite the identification of H2A.Bbd as a new vertebrate-specific replacement histone variant several years ago, and despite the many in vitro structural characterizations using reconstituted chromatin complexes consisting of this variant, the existence of H2A.Bbd in the cell and its location has remained elusive. Here, we report that the native form of this variant is present in highly advanced spermiogenic fractions of mammalian testis at the time when histones are highly acetylated and being replaced by protamines. It is also present in the nucleosomal chromatin fraction of mature human sperm. The ectopically expressed non-tagged version of the protein is associated with micrococcal nuclease-refractory insoluble fractions of chromatin and in mouse (20T1/2) cell line, H2A.Bbd is enriched at the periphery of chromocenters. The exceedingly rapid evolution of this unique X-chromosome-linked histone variant is shared with other reproductive proteins including those associated with chromatin in the mature sperm (protamines) of many vertebrates. This common rate of evolution provides further support for the functional and structural involvement of this protein in male gametogenesis in mammals

Identification of Protein Targets of Reactive Metabolites of Tienilic Acid in Human Hepatocytes

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Chemical Research in Toxicology, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/tx300103jTienilic acid (TA) is a uricosuric diuretic that was withdrawn from the market only months after its introduction because of reports of serious incidents of drug-induced liver injury including some fatalities. Its hepatotoxicity is considered to be primarily immunoallergic in nature. Like other thiophene compounds, TA undergoes biotransformation to a S-oxide metabolite which then reacts covalently with cellular proteins. To identify protein targets of TA metabolites, we incubated [14C]-TA with human hepatocytes, separated cellular proteins by 2D gel electrophoresis, and analyzed proteins in 36 radioactive spots by tryptic digestion followed by LC-MS/MS. Thirty one spots contained at least one identifiable protein. Sixteen spots contained only one of 14 non-redundant proteins which were thus considered to be targets of TA metabolites. Six of the 14 were also found in other radioactive spots that contained from 1 to 3 additional proteins. Eight of the 14 had not been reported to be targets for any reactive metabolite other than TA. The other 15 spots each contained from 2–4 identifiable proteins, many of which are known targets of other chemically reactive metabolites, but since adducted peptides were not observed, the identity of the adducted protein(s) in these spots is ambiguous. Interestingly, all the radioactive spots corresponded to proteins of low abundance, while many highly abundant proteins in the mixture showed no radioactivity. Furthermore, of approximately 16 previously reported protein targets of TA in rat liver (Methogo, R., Dansette, P. and Klarskov, K. (2007) Int. J. Mass Spectrom., 268, 284–295), only one (fumarylacetoacetase) is among the 14 targets identified in this work. One reason for this difference may be statistical, given that each study identified a small number of targets from among thousands present in hepatocytes. Another may be the species difference (i.e. rat vs. human), and still another may be the method of detection of adducted proteins (i.e. Western blot vs. C-14). Knowledge of human target proteins is very limited. Of more than 350 known protein targets of reactive metabolites, only 42 are known from human and only 21 of these are known to be targets for more than one chemical. Nevertheless, the demonstration that human target proteins can be identified using isolated hepatocytes in vitro should enable the question of species differences to be addressed more fully in the future

Dephosphorylation of Nucleophosmin by PP1β Facilitates pRB Binding and Consequent E2F1-dependent DNA Repair

We report a new pathway through which PP1β signals to nucleophosmin (NPM) in response to DNA damage. UV induces dephosphorylation of NPM at multiple sites, leading to enhancement of complex formation between NPM and retinoblastoma tumor suppressor protein and the subsequent upregulation of E2F1. Consequently, such signaling pathway potentiates the cellular DNA repair capacity

Quantitative nucleolar proteomics reveals nuclear re-organization during stress- induced senescence in mouse fibroblast

<p>Abstract</p> <p>Background</p> <p>Nucleolus is the most prominent mammalian organelle within the nucleus which is also the site for ribosomal biogenesis. There have been many reports indicating the involvement of nucleolus in the process of aging. Several proteins related to aging have been shown to localize in the nucleolus, which suggests the role of this organelle in senescence.</p> <p>Results</p> <p>In this study, we used quantitative mass spectrometry to map the flux of proteins into and out of the nucleolus during the induction of senescence in cultured mammalian cells. Changes in the abundance of 344 nucleolar proteins in sodium butyrate-induced senescence in NIH3T3 cells were studied by SILAC (stable isotope labeling by amino acids in cell culture)-based mass spectrometry. Biochemically, we have validated the proteomic results and confirmed that B23 (nucleophosmin) protein was down-regulated, while poly (ADP-ribose) polymerase (PARP) and nuclear DNA helicase II (NDH II/DHX9/RHA) were up-regulated in the nucleolus upon treatment with sodium butyrate. Accumulation of chromatin in the nucleolus was also observed, by both proteomics and microscopy, in sodium butyrate-treated cells. Similar observations were found in other models of senescence, namely, in mitoxantrone- (MTX) treated cells and primary fibroblasts from the Lamin A knockout mice.</p> <p>Conclusion</p> <p>Our data indicate an extensive nuclear organization during senescence and suggest that the redistribution of B23 protein and chromatin can be used as an important marker for senescence.</p

Nucleophosmin Phosphorylation by v-Cyclin-CDK6 Controls KSHV Latency

Nucleophosmin (NPM) is a multifunctional nuclear phosphoprotein and a histone chaperone implicated in chromatin organization and transcription control. Oncogenic Kaposi's sarcoma herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma, primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). In the infected host cell KSHV displays two modes of infection, the latency and productive viral replication phases, involving extensive viral DNA replication and gene expression. A sustained balance between latency and reactivation to the productive infection state is essential for viral persistence and KSHV pathogenesis. Our study demonstrates that the KSHV v-cyclin and cellular CDK6 kinase phosphorylate NPM on threonine 199 (Thr199) in de novo and naturally KSHV-infected cells and that NPM is phosphorylated to the same site in primary KS tumors. Furthermore, v-cyclin-mediated phosphorylation of NPM engages the interaction between NPM and the latency-associated nuclear antigen LANA, a KSHV-encoded repressor of viral lytic replication. Strikingly, depletion of NPM in PEL cells leads to viral reactivation, and production of new infectious virus particles. Moreover, the phosphorylation of NPM negatively correlates with the level of spontaneous viral reactivation in PEL cells. This work demonstrates that NPM is a critical regulator of KSHV latency via functional interactions with v-cyclin and LANA