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[Postoperative adjuvant chemoradiotherapy in high risk stomach carcinoma].

Gastric cancer is a common cancer worldwide with a high mortality rate. Despite curative intent resection, locoregional failure as a frequent site of recurrence is responsible in part for this high mortality. Many attempts have been made to decrease the risk of recurrence after resection. Studies involving postoperative chemotherapy as a single modality have not clearly demonstrated benefit. Similarly, most studies of postoperative radiation therapy have not clearly shown an improvement in overall survival. Recently, however, a USA Intergroup study indicated a survival advantage for chemoradiation therapy compared to surgery alone for patients with locally advanced gastric cancer. "Intergroup-116" is a large-scale randomized trial designed to evaluate the role of adjuvant chemotherapy plus radiotherapy following curative intent gastric resection. The data from this study demonstrate a survival benefit with adjuvant chemoradiation that may in large part be due to better locoregional control. While many patients had a less then adequate lymph node dissection, survival was not associated with the type of lymph node dissection performed. Toxicity was acceptable. "Intergroup-116" indicates that postoperative chemoradiation should be considered as a standard care option for patients with locally advanced gastric cancer. Future studies should evaluate potentially more effective systemic therapy, molecularly-directed treatment, and possibly, whether or not more formal lymph node dissections would obviate the need for radiation.

Chemotherapy, Adjuvant↗

Liver surgery in the era of tissue-preserving resections: early and late outcome in patients with primary and secondary hepatic tumors.

During recent decades, the understanding of the segmental-oriented liver anatomy has enabled development of resection of isolated liver segments or sectors as dictated by the localization and extent of the mass lesion. These newer surgical procedures provide the advantage of maximal preservation of functional parenchyma, therefore minimizing the occurrence of postoperative liver failure and, at the same time, expanding the indications for surgery. We analyzed the results after classical hemihepatectomies and segment-based resections in a consecutive, nonselected patient group. During the 7-year period between November 1993 and November 2000, 270 patients with primary or secondary liver tumors were treated in our hospital; 167 of these patients underwent curative resections and their relevant data were entered into a statistical database. There were 77 classical hemihepatectomies and 90 tissue-preserving resections. Total mortality and morbidity for the series was 3.6% and 29.9%, respectively. Morbidity but not mortality was significantly lower after tissue-preserving resections than after classical hemihepatectomy. Median follow-up was 36 months. Survival was comparable for the two different surgical approaches for patients with secondary liver malignancies. In contrast, patients with hepatocellular carcinomas lived significantly longer after tissue-preserving resections. Tissue-preserving liver resection is a safe technique allowing maximal preservation of functional parenchyma without compromising radicality. Therefore, tissue-preserving resection is especially useful for patients with hepatocellular carcinomas and cirrhosis.

Adolescent↗

Evaluation of lateral lymph node dissection with preoperative chemo-radiotherapy for the treatment of advanced middle to lower rectal cancers.

BACKGROUND AND AIMS: This study examined rectal cancers with lateral lymph node (LN) metastases and whether lateral lymph node dissection (LLD) with or without preoperative chemo-radiotherapy (XRT) benefits patients with rectal cancer. PATIENTS AND METHODS: A total of 452 consecutive cases of curatively resected pT2, pT3, and pT4 middle to lower rectal cancers were retrospectively analyzed. Of these, 265 patients underwent curative LLD and 155 XRT. Data were evaluated with respect to the cumulative percentage of survival. RESULTS: Lateral LN metastases were identified in 7.7% of patients. Of the pT3/pT4 extraperitoneal cancer patients 13.5/18.8% had lateral LN metastases. In the treatment of middle rectal cancers and pT2 extraperitoneal cancers LLD either with or without XRT did not improve survival rate. For the treatment of pT3/pT4 extraperitoneal tumors prior to the introduction of total mesorectal excision (TME) in 1994 LLD plus XRT yielded significantly better survival and local control than conventional surgery without LLD or XRT, although LLD alone did not improve either survival or local recurrence rates. Since 1995 TME with or without subsequent LLD has yielded favorable results for the treatment of extraperitoneal tumors. CONCLUSION: For the treatment of middle rectal cancers and pT2 extraperitoneal cancers LLD either with or without XRT does not improve survival rate. For pT3/pT4 extraperitoneal tumors, which are associated with a high incidence of lateral node metastasis, combining treatment modalities such as TME followed by LLD or XRT followed by TME may be considered.

Erectile Dysfunction↗

Influential factors on tumor recurrence in head and neck cancer patients.

Alcohol consumption and cigarette smoking play a key role in the development and progression of head and neck cancer. Additionally, epidemiologic studies have given evidence that other environmental and genetic factors are relevant. We present a prospective study including 465 head and neck cancer patients. All patients were recruited between 1994 and 1998 during the initial tumor diagnosis. Three hundred twelve patients could be followed over 5 years after histologically proven curative surgical treatment. All clinical data were recorded (i.e., age, gender, TNM stage, histological grading, smoking and drinking habits) and genetic variations at loci encoding detoxifying enzymes (glutathione S-transferase and cytochrome P450); immune modulating cytokines (tumor necrosis factor) and cell cycle regulating proteins (cyclin D1) were determined. Parameters with an impact on recurrence-free survival were analyzed. A strong influence could be attributed to the tumor size at the time of presentation. Additionally, the grading of the tumor showed a strong influence (5 years recurrence free: G1: 87% and G1: 61%). Furthermore, it could be shown that the recurrence-free survival was significantly influenced by cyclin D1 genotypes (CCND1GG: P =0.01; HR=3.72) and TNF microsatellite haplotypes (TNFB1D5: P =0.043; HR=2.05). These findings are compatible with the view that genetic predisposition is important in determining recurrence-free survival after surgical treatment of head and neck cancer.

Alcohol Drinking↗

Treatment and prevention of stroke in children with sickle cell disease.

Stroke is one of the major complications in children with sickle cell disease (SCD). Ischemic stroke is associated with small asymptomatic subcortical infarcts to large territorial lesions causing major disability. Intracranial hemorrhages may be caused by aneurysm rupture or by leakage from moyamoya vessels or venous sources. There have been no acute stroke treatment studies in SCD, but hydration and exchange transfusion are often recommended. However, there is an evidence base for primary and to some extent secondary stroke prevention. Primary prevention of stroke was demonstrated in the Stroke Prevention Trial in Sickle Cell Anemia (STOP), in which children with transcranial Doppler (TCD) mean blood flow velocities of 200 cm/second (previously shown to indicate high stroke risk) or higher were randomized to either regular blood transfusions or no transfusion. The study showed a very significant 90% reduction in first stroke with transfusion. In STOP2, discontinuing transfusions after 30 months or more (even with normal TCD) resulted in a high rate of reversion to abnormal TCD values and stroke. TCD screening of all children with SCD, and initiation and maintenance of chronic transfusion to maintain hemoglobin S below 30% in the high-risk group, is the only proven prevention strategy for stroke in SCD. Hydroxyurea is being studied as secondary stroke prevention at this time. No recommendation specific to SCD regarding the use of antiplatelet agents or anticoagulants in ischemic stroke can be made. Bone marrow transplantation can be curative for SCD, and limited data support its use to prevent stroke in SCD.

Journal Article↗

GenAge: a genomic and proteomic network map of human ageing.

The aim of this work was to provide an overview of the genetics of human ageing to gain novel insights about the mechanisms involved. By incorporating findings from model organisms to humans, such as mutations that either delay or accelerate ageing in mice, we constructed the gene networks previously related to ageing: namely, the network related to DNA metabolism and the network involving the GH/IGF-1 axis. Gathering data about the interacting partners of these proteins allowed us to suggest the involvement in ageing of a number of proteins through a "guilt-by-association" methodology. To organize our data, we developed the first curated database of genes related to human ageing: GenAge. With over 200 entries, GenAge may serve as a reference database of genes related to human ageing. Moreover, we rendered the first proteomic network map of human ageing, which suggests a relationship between the genetics of development and the genetics of ageing. Our work serves as a framework upon which a systems-biology understanding of ageing can be developed. GenAge is freely available for academic purposes at: http://genomics.senescence.info/genes/.

Aging↗

Allogeneic stem cell transplantation and donor lymphocyte infusions for chronic myelomonocytic leukemia.

Prognosis in chronic myelomonocytic leukemia (CMML) is unfavorable and the optimal therapy remains uncertain. Currently, allogeneic stem cell transplantation is the only known curative therapeutic option. However, the data available are limited and restricted to small retrospective series. There is even less information on the use of donor lymphocyte infusions (DLI) for this disease. We reviewed our experience of allogeneic stem cell transplantation and DLI for adults with CMML. Seventeen consecutive adults underwent allogeneic stem cell transplantation from related (n=14) or unrelated (n=3) donors. Median age was 50 years (range 26-60). Seven patients (41%) demonstrated relapse or persistent disease at a median of 6 months (range 3-55.5). Five patients underwent DLI for morphologic relapse and one for mixed donor chimerism. Two patients achieved durable complete remissions of 15 months each. The overall transplant-related mortality was 41% (n=7). With a median follow-up of 34.5 months, three patients (18%) currently remain alive and in continuous CR. The current study demonstrates a graft-versus-leukemia effect in CMML, both for allogeneic stem cell transplantation and for DLI. Nevertheless, consistent with reported experience of others, overall outcomes remain less than optimal and unpredictable.

Adult↗

Minimising the use of sedation/anaesthesia in young children receiving radiotherapy through an effective play preparation programme.

The delivery of radiotherapy to young children is a challenging process, yet little research has been undertaken to examine practice. Many centres routinely sedate or anaesthetise young children to overcome problems relating to non-adherence to treatment. This can lead to an increased risk of clinical complications, sub-optimal nutrition, sleep disruption and is time consuming and costly. This article describes how sedation can be minimised in young children through an effective play preparation programme. To examine the effectiveness of such a programme, which had been in progress for a number of years, an audit was undertaken on a paediatric oncology unit within a regional radiotherapy centre. This took place over a 5-year period (1994-1999), on all patients aged 2-5 years. Information was collated on age, tumour type, site, duration of radiotherapy, the need for involuntary immobilisation, days requiring sedation, and whether radiotherapy was given with curative or palliative intent. Outcome data presented on 63 children suggest sedation can be minimised in this age group through the implementation of an effective play preparation programme. Of 1030 treatment days, only 111 days required sedation (10.8%), over the whole age range. No general anaesthetics were given. Only 6 patients were sedated for the whole of their treatment (9.5%), with 52 patients requiring no sedation at all (82.5%).

Journal Article↗

Phosphoproteomic analysis of Her2/neu signaling and inhibition.

Her2/neu (Her2) is a tyrosine kinase belonging to the EGF receptor (EGFR)/ErbB family and is overexpressed in 20-30% of human breast cancers. We sought to characterize Her2 signal transduction pathways further by using MS-based quantitative proteomics. Stably transfected cell lines overexpressing Her2 or empty vector were generated, and the effect of an EGFR and Her2 selective tyrosine kinase inhibitor, PD168393, on these cells was characterized. Quantitative measurements were obtained on 462 proteins by using the SILAC (stable isotope labeling with amino acids in cell culture) method to monitor three conditions simultaneously. Of these proteins, 198 showed a significant increase in tyrosine phosphorylation in Her2-overexpressing cells, and 81 showed a significant decrease in phosphorylation. Treatment of Her2-overexpressing cells with PD168393 showed rapid reversibility of the majority of the Her2-triggered phosphorylation events. Phosphoproteins that were identified included many known Her2 signaling molecules as well as known EGFR signaling proteins that had not been previously linked to Her2, such as Stat1, Dok1, and delta-catenin. Importantly, several previously uncharacterized Her2 signaling proteins were identified, including Axl tyrosine kinase, the adaptor protein Fyb, and the calcium-binding protein Pdcd-6/Alg-2. We also identified a phosphorylation site in Her2, Y877, which is located in the activation loop of the kinase domain, is distinct from the known C-terminal tail autophosphorylation sites, and may have important implications for regulation of Her2 signaling. Network modeling, which combined phosphoproteomic results with literature-curated protein-protein interaction data, was used to suggest roles for some of the previously unidentified Her2 signaling proteins.

Amino Acid Sequence↗

MPID: MHC-Peptide Interaction Database for sequence-structure-function information on peptides binding to MHC molecules.

SUMMARY: Binding of short antigenic peptides to Major histocompatibility complex (MHC) proteins is the first step in T-cell mediated immune response. To understand the structural principles governing MHC-specific peptide recognition and binding, we have developed the MHC-Peptide Interaction Database (MPID), containing sequence-structure-function information. MPID (version 1.2) contains curated x-ray crystallographic data on 86 MHC peptide complexes, with precomputed interaction parameters (solvent accessibility, hydrogen bonds, gap volume and gap index). A user-friendly web interface and query tools will facilitate the development of predictive algorithms for MHC-peptide binding from a structural viewpoint. AVAILABILITY: Freely accessible from http://surya.bic.nus.edu.sg/mpid.

Binding Sites↗

Database model and specification of GermOnline Release 2.0, a cross-species community annotation knowledgebase on germ cell differentiation.

UNLABELLED: GermOnline is a web-accessible relational database that enables life scientists to make a significant and sustained contribution to the annotation of genes relevant for the fields of mitosis, meiosis, germ line development and gametogenesis across species. This novel approach to genome annotation includes a platform for knowledge submission and curation as well as microarray data storage and visualization hosted by a global network of servers. AVAILABILITY: The database is accessible at http://www.germonline.org/. For convenient world-wide access we have set up a network of servers in Europe (http://germonline.unibas.ch/; http://germonline.igh.cnrs.fr/), Japan (http://germonline.biochem.s.u-tokyo.ac.jp/) and USA (http://germonline.yeastgenome.org/). SUPPLEMENTARY INFORMATION: Extended documentation of the database is available through the link 'About GermOnline' at the websites.

Animals↗

Dense taxonomic EST sampling and its applications for molecular systematics of the Coleoptera (beetles).

Expressed sequence tag (EST) sequences can provide a wealth of data for phylogenetic and genomic studies, but the utility of these resources is restricted by poor taxonomic sampling. Here, we use small EST libraries (<1,000 clones) to generate phylogenetic markers across a broad sample of insects, focusing on the species-rich Coleoptera (beetles). We sequenced over 23,000 ESTs from 34 taxa, which produced 8,728 unique sequences after clustering nonredundant sequences. Between taxa, the sequences could be grouped into 731 gene clusters, with the largest corresponding to mitochondrial DNA transcripts and gene families chymotrypsin, actin, troponin, and tubulin. While levels of paralogy were high in most gene clusters, several midsized clusters including many ribosomal protein (RP) genes appeared to be free of expressed paralogs. To evaluate the utility of EST data for molecular systematics, we curated available transcripts for 66 RP genes from representatives of the major groups of Coleoptera. Using supertree and supermatrix approaches for phylogenetic analysis, the results were consistent with the emerging phylogenetic conclusions about basal relationships in Coleoptera. Numerous small EST libraries from a taxonomically densely sampled lineage can provide a core set of genes that together act as a scaffold in phylogenetic reconstruction, comparative genomics, and studies of gene evolution.

Animals↗

The ribosomal database project.

The Ribosomal Database Project (RDP) is a curated database that offers ribosome data along with related programs and services. The offerings include phylogenetically ordered alignments of ribosomal RNA (rRNA) sequences, derived phylogenetic trees, rRNA secondary structure diagrams and various software packages for handling, analyzing and displaying alignments and trees. The data are available via ftp and electronic mail. Certain analytic services are also provided by the electronic mail server.

Databases, Factual↗

EpoDB: a prototype database for the analysis of genes expressed during vertebrate erythropoiesis.

EpoDB is a database of genes expressed in vertebrate red blood cells. It is also a prototype for the creation of cell and tissue-specific databases from multiple external sources. The information in EpoDB obtained from GenBank, SWISS-PROT, Transfac, TRRD and GERD is curated to provide high quality data for sequence analysis aimed at understanding gene regulation during erythropoiesis. New protocols have been developed for data integration and updating entries. Using a BLAST-based algorithm, we have grouped GenBank entries representing the same gene together. This sequence similarity protocol was also used to identify new entries to be included in EpoDB. We have recently implemented our database in Sybase (relational tables) in addition to SICStus Prolog to provide us with greater flexibility in asking complex queries that utilize information from multiple sources. New additions to the public web site (http://www.cbil.upenn.edu/epodb) for accessing EpoDB are the ability to retrieve groups of entries representing different variants of the same gene and to retrieve gene expression data. The BLAST query has been enhanced by incorporating BLASTView, an interactive and graphical display of BLAST results. We have also enhanced the queries for retrieving sequence from specified genes by the addition of MEME, a motif discovery tool, to the integrated analysis tools which include CLUSTALW and TESS.

Animals↗

MaizeGDB, the community database for maize genetics and genomics.

The Maize Genetics and Genomics Database (MaizeGDB) is a central repository for maize sequence, stock, phenotype, genotypic and karyotypic variation, and chromosomal mapping data. In addition, MaizeGDB provides contact information for over 2400 maize cooperative researchers, facilitating interactions between members of the rapidly expanding maize community. MaizeGDB represents the synthesis of all data available previously from ZmDB and from MaizeDB-databases that have been superseded by MaizeGDB. MaizeGDB provides web-based tools for ordering maize stocks from several organizations including the Maize Genetics Cooperation Stock Center and the North Central Regional Plant Introduction Station (NCRPIS). Sequence searches yield records displayed with embedded links to facilitate ordering cloned sequences from various groups including the Maize Gene Discovery Project and the Clemson University Genomics Institute. An intuitive web interface is implemented to facilitate navigation between related data, and analytical tools are embedded within data displays. Web-based curation tools for both designated experts and general researchers are currently under development. MaizeGDB can be accessed at http://www.maizegdb.org/.

Computational Biology↗

PIRSF: family classification system at the Protein Information Resource.

The Protein Information Resource (PIR) is an integrated public resource of protein informatics. To facilitate the sensible propagation and standardization of protein annotation and the systematic detection of annotation errors, PIR has extended its superfamily concept and developed the SuperFamily (PIRSF) classification system. Based on the evolutionary relationships of whole proteins, this classification system allows annotation of both specific biological and generic biochemical functions. The system adopts a network structure for protein classification from superfamily to subfamily levels. Protein family members are homologous (sharing common ancestry) and homeomorphic (sharing full-length sequence similarity with common domain architecture). The PIRSF database consists of two data sets, preliminary clusters and curated families. The curated families include family name, protein membership, parent-child relationship, domain architecture, and optional description and bibliography. PIRSF is accessible from the website at http://pir.georgetown.edu/pirsf/ for report retrieval and sequence classification. The report presents family annotation, membership statistics, cross-references to other databases, graphical display of domain architecture, and links to multiple sequence alignments and phylogenetic trees for curated families. PIRSF can be utilized to analyze phylogenetic profiles, to reveal functional convergence and divergence, and to identify interesting relationships between homeomorphic families, domains and structural classes.

Amino Acid Motifs↗

Entrez Gene: gene-centered information at NCBI.

Entrez Gene (www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene) is NCBI's database for gene-specific information. It does not include all known or predicted genes; instead Entrez Gene focuses on the genomes that have been completely sequenced, that have an active research community to contribute gene-specific information, or that are scheduled for intense sequence analysis. The content of Entrez Gene represents the result of curation and automated integration of data from NCBI's Reference Sequence project (RefSeq), from collaborating model organism databases, and from many other databases available from NCBI. Records are assigned unique, stable and tracked integers as identifiers. The content (nomenclature, map location, gene products and their attributes, markers, phenotypes, and links to citations, sequences, variation details, maps, expression, homologs, protein domains and external databases) is updated as new information becomes available. Entrez Gene is a step forward from NCBI's LocusLink, with both a major increase in taxonomic scope and improved access through the many tools associated with NCBI Entrez.

Databases, Genetic↗

Nuclear Receptor Signaling Atlas (www.nursa.org): hyperlinking the nuclear receptor signaling community.

The nuclear receptor signaling (NRS) field has generated a substantial body of information on nuclear receptors, their ligands and coregulators, with the ultimate goal of constructing coherent models of the biological and clinical significance of these molecules. As a component of the Nuclear Receptor Signaling Atlas (NURSA)--the development of a functional atlas of nuclear receptor biology--the NURSA Bioinformatics Resource is developing a strategy to organize and integrate legacy and future information on these molecules in a single web-based resource (www.nursa.org). This entails parallel efforts of (i) developing an appropriate software framework for handling datasets from NURSA laboratories and (ii) designing strategies for the curation and presentation of public data relevant to NRS. To illustrate our approach, we have described here in detail the development of a web-based interface for the NURSA quantitative PCR nuclear receptor expression dataset, incorporating bioinformatics analysis which provides novel perspectives on functional relationships between these molecules. We anticipate that the free and open access of the community to a platform for data mining and hypothesis generation strategies will be a significant contribution to the progress of research in this field.

Animals↗