Background: Hepatocellular carcinoma (HCC) (about 85–90% of primary liver cancer) is particularly prevalent in China because of the high prevalence of chronic hepatitis B infection. HCC is the fourth most common malignancy and the third leading cause of tumor-related deaths in China. It poses a significant threat to the life and health of Chinese people. Summary: This guideline presents official recommendations of the National Health and Family Planning Commission of the People’s Republic of China on the surveillance, diagnosis, staging, and treatment of HCC occurring in China. The guideline was written by more than 50 experts in the field of HCC in China (including liver surgeons, medical oncologists, hepatologists, interventional radiologists, and diagnostic radiologists) on the basis of recent evidence and expert opinions, balance of benefits and harms, cost-benefit strategies, and other clinical considerations. Key Messages: The guideline presents the Chinese staging system, and recommendations regarding patients with HCC in China to ensure optimum patient outcomes.
We carried out a test sample study to try to identify errors leading to irreproducibility, including incompleteness of peptide sampling, in LC-MS-based proteomics. We distributed a test sample consisting of an equimolar mix of 20 highly purified recombinant human proteins, to 27 laboratories for identification. Each protein contained one or more unique tryptic peptides of 1250 Da to also test for ion selection and sampling in the mass spectrometer. Of the 27 labs, initially only 7 labs reported all 20 proteins correctly, and only 1 lab reported all the tryptic peptides of 1250 Da. Nevertheless, a subsequent centralized analysis of the raw data revealed that all 20 proteins and most of the 1250 Da peptides had in fact been detected by all 27 labs. The centralized analysis allowed us to determine sources of problems encountered in the study, which include missed identifications (false negatives), environmental contamination, database matching, and curation of protein identifications. Improved search engines and databases are likely to increase the fidelity of mass spectrometry-based proteomics.
Core fucosylation (CF) patterns of some glycoproteins are more sensitive and specific than evaluation of their total respective protein levels for diagnosis of many diseases, such as cancers. Global profiling and quantitative characterization of CF glycoproteins may reveal potent biomarkers for clinical applications. However, current techniques are unable to reveal CF glycoproteins precisely on a large scale. Here we developed a robust strategy that integrates molecular weight cutoff, neutral loss-dependent MS 3 , database-independent candidate spectrum filtering, and optimization to effectively identify CF glycoproteins. The rationale for spectrum treatment was innovatively based on computation of the mass distribution in spectra of CF glycopeptides. The efficacy of this strategy was demonstrated by implementation for plasma from healthy subjects and subjects with hepatocellular carcinoma. Over 100 CF glycoproteins and CF sites were identified, and over 10,000 mass spectra of CF glycopeptide were found. The scale of identification results indicates great progress for finding biomarkers with a particular and attractive prospect, and the candidate spectra will be a useful resource for the improvement of database searching methods for glycopeptides. Molecular & Cellular Proteomics 8:913-923, 2009.
Acetyl-CoA carboxylase (ACC) has crucial roles in fatty acid metabolism and is an attractive target for drug discovery against diabetes, cancer and other diseases1–6. Saccharomyces cerevisiae ACC (ScACC) is crucial for the production of very-long-chain fatty acids and the maintenance of the nuclear envelope7,8. ACC contains biotin carboxylase (BC) and carboxyltransferase (CT) activities, and its biotin is linked covalently to the biotin carboxyl carrier protein (BCCP). Most eukaryotic ACCs are 250 kD, multi-domain enzymes and function as homo-dimers and higher oligomers. They contain a unique, 80 kD central region that shares no homology with other proteins. While the structures of the BC, CT and BCCP domains and other biotin-dependent carboxylase holoenzymes are known1,9–14, currently there is no structural information on the ACC holoenzyme. Here we report the crystal structure of the full-length, 500 kD holoenzyme dimer of ScACC. The structure is strikingly different from those of the other biotin-dependent carboxylases. The central region contains five domains and is important for positioning the BC and CT domains for catalysis. The structure unexpectedly reveals a dimer of the BC domain and extensive conformational differences compared to the structure of BC domain alone, which is a monomer. These structural changes explain why the BC domain alone is catalytically inactive and define the molecular mechanism for the inhibition of eukaryotic ACC by the natural product soraphen A15,16 and by phosphorylation of a Ser residue just prior to the BC domain core in mammalian ACC. The BC and CT active sites are separated by 80 Å, and the entire BCCP domain must translocate during catalysis.
Ribosomes of trypanosomatids, a family of protozoan parasites causing debilitating human diseases, possess multiply fragmented rRNAs that together are analogous to 28S rRNA, unusually large rRNA expansion segments, and r-protein variations compared with other eukaryotic ribosomes. To investigate the architecture of the trypanosomatid ribosomes, we determined the 2.5-Å structure of the Trypanosoma cruzi ribosome large subunit by single-particle cryo-EM. Examination of this structure and comparative analysis of the yeast ribosomal assembly pathway allowed us to develop a stepwise assembly model for the eight pieces of the large subunit rRNAs and a number of ancillary "glue" proteins. This model can be applied to the characterization of Trypanosoma brucei and Leishmania spp. ribosomes as well. Together with other details, our atomic-level structure may provide a foundation for structurebased design of antitrypanosome drugs.ribosome structure | Trypanosoma cruzi | biogenesis | multiply fragmented rRNA | antitrypanosome drug design
IntroductionThe aim of the study was to assess systematically the accuracies of positron emission tomography (PET), PET/computed tomography (CT), and CT in diagnosing recurrent cervical cancer.Material and methodsWe searched for articles published from January 1980 to June 2013 using the following inclusion criteria: articles were reported in English; the use of PET, interpreted with or without the use of CT; use of CT to detect recurrent cervical cancer; and histopathologic analysis and/or close clinical and imaging follow-up for at least 6 months. We extracted data to calculate sensitivity, specificity, summary receiver operating characteristic curves, and the area under the receiver operating characteristic curve (AUC) as well as test for heterogeneity.ResultsIn 23 included studies, PET had the highest pooled specificity at 92% (95% CI: 90–94), whereas PET/CT had the highest pooled sensitivity at 94% (95% CI: 90–97). The area under the curve (AUC) of PET alone, PET/CT, and CT were 0.9594, 0.9508, and 0.9363, respectively. Results of the pairwise comparison between each modality show that the specificity of PET was higher than that of PET/CT (p < 0.05). The difference in the pooled sensitivities and AUC of PET alone and PET/CT showed no statistical significance. No evidence of publication bias was found. However, evidence of heterogeneity was observed.ConclusionsThe PET/CT may be a useful supplement to current surveillance techniques, particularly for patients with negative CT imaging. However, in terms of diagnostic accuracy, interpreted CT images may have limited additional value to PET in detecting recurrent cervical cancer.
Glycosylation modifications of proteins have been attracting increasing attention due to their roles in the physiological and pathological processes of the cell. Core fucosylation (CF), one special type of glycan structure in glycoproteins, has been linked with tumorigenesis. The study of protein glycosylation has been hindered by the technical challenges caused by the microheterogeneity of glycan modifications. In commonly used methods, sugar chains on the peptide were released using endoglycosidase, and the glycan and peptides were analyzed separately with mass spectrometry. Although mass spectrometric analysis can be performed easily in this way, an increase in false positives when assigning glycosites was inevitable. Our earlier research demonstrated a strategy combining Endo F3-catalyzed partial deglycosylation with MS(3) (MS/MS/MS) scanning triggered by the neutral loss of a fucose to precisely identify CF proteins on a large scale. In this research, fragmentations of partially deglycosylated glycopeptides were studied using a triple quadrupole mass spectrometer, and a quantification method that coupled our published identification strategy with multiple reaction monitoring-mass spectrometry (MRM-MS) analysis was developed to obtain site-specific quantification information of core fucosylated peptides. To illustrate the feasibility of the quantification method, the CF peptides of target proteins in clinical serum were quantified and compared as a preliminary demonstration.
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