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Future vision of the GDB human genome database.

In 1973, scientists assembled at the first Human Gene Mapping Workshop to discuss the 64 human genes mapped at that time. In 1989, the GDB Human Genome Database was created to store information on 1, 700 mapped human genes. Ten years later, as the human genome project closes in on the release of the complete DNA sequence holding as many as 100,000 human genes, GDB is evolving to continue to meet the needs of the scientific community. Well known as a resource for data which has been stringently reviewed as part of the curation process, GDB prepares to continue to provide a compilation of the human genome including maps, map objects, polymorphisms, and mutations. As more sites across the Internet are established to share biological information, it becomes increasingly burdensome for the scientist to collect data from all sources of a particular domain. In an attempt to reduce this burden, GDB continues to load data from large genome centres and accept submissions from researchers around the world. Moreover, GDB looks to provide a mechanism to link gene-related information to the human reference sequence. In doing this, GDB plans to establish federated linkages with "boutique" databases around the world that could contain enormous amounts of valuable information about specific genes or chromosomes.

Computer Simulation↗

Quantitative information management for the biochemical computation of cellular networks.

Understanding complex protein networks within cells requires the ability to develop quantitative models and to numerically compute the properties and behavior of the networks. To carry out such computational analysis, it is necessary to use modeling tools and information management systems (IMSs) where the quantitative data, associated to its biological context, can be stored, curated, and reliably retrieved. We have focused on the biochemical computation of cellular interactions and developed an IMS that stores both quantitative information on the cellular components and their interactions, and the basic reactions governing those interactions. This information can be used to construct pathways and eventually large-scale networks. This system, SigPath, is available on the Internet (http://www.sigpath.org). Key features of the approach include (i) the use of background information (for example, names of molecules, aliases, and accession codes) to ease data submission and link this quantitative database with other qualitative databases, (ii) a strategy to allow refinement of information over time by multiple users, (iii) the development of a data representation that stores both qualitative and quantitative information, and (iv) features to assist contributors and users in assembling custom quantitative models from the information stored in the IMS. Currently, models assembled in SigPath can be automatically exported to several computing environments, such as Kinetikit/Genesis, Virtual Cell, Jarnac/JDesigner, and JSim. We anticipate that, when appropriately populated, such a system will be useful for large-scale quantitative studies of cell-signaling networks and other cellular networks. SigPath is distributed under the GNU General Public License.

Animals↗

[Significance of selected preventive, therapeutic and rehabilitation services reflected in a population survey].

BACKGROUND: Statutory health insurance bodies in Germany are experiencing increasing deficits, which raises the demand for rationalising health benefits. This, however, requires the establishment of priorities unless absolutely necessary benefits have to be cut. In other words, we must examine the preferences, expectations and experiences of the insured population. Within the framework of this study, we tried to find out the preferences and assessment of health services by the German population in the Lübeck region. DESIGN: Mail survey (questionnaire and two reminders) to register the preferences and attitudes to guaranteed medical services in the light of threatening deficits. The random sample was drawn by the residents' registration office in Lübeck, the criteria being an age of between 25 and 64 years, German nationality and principle domicile in Lübeck. INSTRUMENT: Postal questionnaire with 7 pages including 9 question complexes on the importance of preventive, curative and rehabilitative health services with 88 items and personal data. RESULTS: We succeeded in contacting 992 persons and achieved a response rate of 64.1%. 67% of the participants (n = 634) conveyed about their opinion on economic decisions in health care. 12% refused any involvement. In respect of importance and the cost of medical interventions, preventive, curative and rehabilitative interventions for children have highest priority. In the curative and rehabilitative sphere the emphasis lies on the severity of the illness. Interventions with controversial effectiveness were rated less important by the respondents and hence these should not be financed by the health insurance companies in every case, in the opinion of the persons who had been questioned. CONCLUSIONS: The evaluation shows that most participants could cope quite well with this questionnaire and were ready to be involved in decisions concerning health care. Like the participants of Ann Bowling's survey about the investigation of preferences in the UK, our respondents give medical interventions for children (independent from the medical sector) a higher priority. Mit vorang. Satz weicht die engl. Zusammenfassung von der dt. Zusammenfassung ab Apart from this it is obvious that interventions with controversial effectivity should not be covered by the health insurance companies to the same extent as those with established effectivity, which is, in a way, in contrast to valid German legal regulations.

Adolescent↗

MINT: a Molecular INTeraction database.

Protein interaction databases represent unique tools to store, in a computer readable form, the protein interaction information disseminated in the scientific literature. Well organized and easily accessible databases permit the easy retrieval and analysis of large interaction data sets. Here we present MINT, a database (http://cbm.bio.uniroma2.it/mint/index.html) designed to store data on functional interactions between proteins. Beyond cataloguing binary complexes, MINT was conceived to store other types of functional interactions, including enzymatic modifications of one of the partners. Release 1.0 of MINT focuses on experimentally verified protein-protein interactions. Both direct and indirect relationships are considered. Furthermore, MINT aims at being exhaustive in the description of the interaction and, whenever available, information about kinetic and binding constants and about the domains participating in the interaction is included in the entry. MINT consists of entries extracted from the scientific literature by expert curators assisted by 'MINT Assistant', a software that targets abstracts containing interaction information and presents them to the curator in a user-friendly format. The interaction data can be easily extracted and viewed graphically through 'MINT Viewer'. Presently MINT contains 4568 interactions, 782 of which are indirect or genetic interactions.

Amino Acid Sequence↗

GDB: the Human Genome Database.

The Genome Database (GDB, http://www.gdb.org ) is a public repository of data on human genes, clones, STSs, polymorphisms and maps. GDB entries are highly cross-linked to each other, to literature citations and to entries in other databases, including the sequence databases, OMIM, and the Mouse Genome Database. Mapping data from large genome centers and smaller mapping efforts are added to GDB on an ongoing basis. The database can be searched by a variety of methods, ranging from keyword searches to complex queries. Major functionality extensions in the last year include the ongoing computation of integrated human genome maps, called Comprehensive Maps, and the use of those maps to support positional queries and graphic displays. The capabilities of the GDB map viewer (Mapview) have been extended to include map printing and the graphical display of ad hoc query results. The HUGO Nomenclature Committee continues to curate the proposed and official gene symbols and related data in collaboration with GDB. As genome research shifts its emphasis from mapping to sequencing and functional analysis, the scope of the GDB schema is being extended. We are in the process of adding representations of gene function and expression, and improving our representation of human polymorphism and mutation.

Animals↗

The number of metastatic lymph nodes: a promising prognostic determinant for gastric carcinoma in the latest edition of the TNM classification.

BACKGROUND: The number of metastatic regional lymph nodes determines the new pN categories in the 5th edition of the TNM classification. STUDY DESIGN: Our retrospective study was conducted to compare the new method of defining lymph node status with the conventional classification, consisting of the anatomic extent of lymph node metastases, a well-established prognostic factor. The study was based on clinical data for 493 patients with gastric carcinomas who underwent potentially curative operations and had histologically confirmed nodal metastases. These patients were stratified into 1) n categories according to the Japanese Classification of Gastric Carcinoma, 2) the new pN categories, and 3) the pN categories determined by the number of metastatic perigastric nodes resected by standard D1 gastrectomy. Survival data were analyzed for each group. RESULTS: The number of metastatic nodes after D2 lymphadenectomy reflected prognosis well and was shown by multivariate analysis to be a strong independent prognostic factor. When the classification was performed limited to the metastatic perigastric nodes, stage migration was evident, but the variable remained competent as a prognostic indicator. CONCLUSIONS: The number of metastatic nodes is a promising determinant in the new international stage classification.

Adult↗

Do older men benefit from curative therapy of localized prostate cancer?

PURPOSE: Prior decision-analytic models are based on outdated or suboptimal efficacy, patient preference, and comorbidity data. We estimated life expectancy (LE) and quality-adjusted life expectancy (QALE) associated with available treatments for localized prostate cancer in men aged >/= 65 years, adjusting for Gleason score, patient preferences, and comorbidity. METHODS: We evaluated three treatments, using a decision-analytic Markov model: radical prostatectomy (RP), external beam radiotherapy (EBRT), and watchful waiting (WW). Rates of treatment complications and pretreatment incontinence and impotence were derived from published studies. We estimated treatment efficacy using three data sources: cancer registry cohort data, pooled case series, and modern radiotherapy studies. Utilities were obtained from 141 prostate cancer patients and from published studies. RESULTS: For men with well-differentiated tumors and few comorbidities, potentially curative therapy (RP or EBRT) prolonged LE up to age 75 years but did not improve QALE at any age. For moderately differentiated cancers, potentially curative therapy resulted in LE and QALE gains up to age 75 years. For poorly differentiated disease, potentially curative therapy resulted in LE and QALE gains up to age 80 years. Benefits of potentially curative therapy were restricted to men with no worse than mild comorbidity. When cohort and pooled case series data were used, RP was preferred over EBRT in all groups but was comparable to modern radiotherapy. CONCLUSION: Potentially curative therapy results in significantly improved LE and QALE for older men with few comorbidities and moderately or poorly differentiated localized prostate cancer. Age should not be a barrier to treatment in this group.

Aged↗

Number of lymph nodes examined and prognosis of TNM stage II colorectal cancer.

The diagnosis of a lymph node-negative colorectal carcinoma should imply a good prognosis; however, the outcomes for TNM stage II patients remain variable. Few studies have examined the relationship of the number of lymph nodes examined to the prognosis of this stage. The aim of this study was to determine whether the number of lymph nodes examined has an effect on prognosis of a relatively large sample of patients undergoing curative surgery for stage II colorectal cancer at a single institution. Data on patients who underwent surgery for colorectal cancer between January 1980 and April 2000 were prospectively collected in a database. Patients with TNM stage II or stage III tumours who were treated with curative intent were removed. Patients over 80 years of age were excluded from the survival analysis. Survival comparisons were made using Kaplan-Meier curves and the log-rank test. Multivariate analysis was performed using a Cox regression model. A total of 625 cases of TNM stage II cases and, for comparison purposes, 415 stage III cases, were analysed. Lymph node retrieval in stage II cases was affected by the patient's age (P=0.04) and gender (P=0.02), tumour grade (P<0.0001), tumour site (P<0.0001), and necessity to carry out extended resection (P<0.0001). In stage III cases, lymph node retrieval was affected by patient age (P<0.0001), tumour grade (P=0.02), and tumour site (P=0.002). Decreased lymph node detection was associated with increasing hazard ratios among the 480 TNM stage II patients under 80 years of age, but not among the 345 patients with TNM stage III tumours. Five year survival rate for patients with stage III tumours with only 1-3 positive lymph nodes (52.6%) was similar to that of patients with stage II tumour who had nine or fewer lymph nodes examined (51.3%). These results demonstrate that the prognosis of TNM stage II colorectal cancer is dependent on the number of lymph nodes examined. Patients with few nodes examined have a poorer prognosis. It is possible that a smaller number of lymph nodes examined reflects a diminished immune response. It can be presumed that those patients with stage II tumour with only a few nodes examined should be offered postoperative chemotherapy on a routine basis.

Aged↗

[Prospective assessment of glycopeptides prescriptions in a general hospital].

OBJECTIVE: The authors had for aim to analyze the indications, quality, and volumes of glycopeptide (GP) prescriptions in all in-patient units of a general hospital. CLINICAL MATERIAL AND METHODOLOGY: A 4 month prospective study assessed the compliance of curative and prophylactic treatment prescriptions administered according to guidelines. The assessment criteria were as follows: prescription indicated or not, prescription modalities (administration of loading dose, performing of serum tests, dosage appropriateness, appropriateness with antibiogram data when available). RESULTS: Over the 46 assessed prescriptions, 84.7% were curative treatments (N = 39), whereas 15.2% (N = 7) were written out for surgical antibioprophylaxis. The prescription incidence and density were, respectively, 0.60 prescription/100 admissions and 20.8 DDJ/1000 hospitalization days, i.e. 24% of the total antibiotics budget. Prescriptions were always indicated for surgical antibioprophylaxis, but met standards in only 14% of cases. As for curative prescriptions, treatments were appropriate in 56.5% of cases, but only 18% met standards. GP use modalities proved incorrect at various levels: non existing load dose and lack of serum tests, subinhibiting daily doses, no dose lowering when possible, exaggerated duration of surgical antibioprophylaxis. Average GP serum levels were 16 mg/L and were higher than the target level in no more than 40% of properly prescribed treatments. CONCLUSION: Prescription modalities and treatment monitoring must be improved, given the development of bacterial resistance.

Anti-Bacterial Agents↗

Clinical Variant Interpretation with the Integrative Genomics Viewer (IGV) for Molecular Pathologists.

The integrative genomics viewer (IGV) is a pivotal tool in clinical genomics, enabling the visualization and interpretation of complex sequencing data. Bringing clinical knowledge to bear with visual evaluation of sequencing results is the primary means by which molecular pathologists and other professionals assess and finalize cases. A variety of software tools can assist, but their relationship to the underlying data must be understood and applied systematically. This study includes essential background on next-generation sequencing (NGS) data file types (e.g., FASTQ, BAM, VCF) with a discussion of their format and purpose. We then describe features of IGV that derive nuances from these files. We utilize a series of curated practical cases based on clinical vignettes through which the reader will interact with clinical NGS sequencing data using the IGV software to review various types of clinically relevant variants relative to the human reference genome. These clinical vignettes have been curated to describe examples of some of the complexities of interpretation of genomic data, and how utilizing IGV as part of a routine workflow can provide additional interpretive information for variants beyond routine bioinformatic software algorithm variant calls. The visual inspection of genomic variants utilizing the tools within IGV can unmask subtle contextual cues (i.e., variant allele frequency, strand bias, tissue-specific context) that can influence the interpretation of genomic variants. Although this study focuses on using IGV for the detection and interpretation of somatic variants, the provided applications can be extrapolated for use in the germline setting, including analysis of complex variants and detection of mosaicism.

Humans↗

Follow-up of colorectal cancer patients after resection with curative intent-the GILDA trial.

PURPOSE: Surgery remains the primary treatment of colorectal cancer. Data are lacking to delineate the optimal surveillance strategy following resection. A large-scale multi-center European study is underway to address this issue (Gruppo Italiano di Lavoro per la Diagnosi Anticipata-GILDA). METHODS: Following primary surgery with curative intent, stratification, and randomization at GILDA headquarters, colon cancer patients are then assigned to a more intensive or less intensive surveillance regimen. Rectal cancer patients undergoing curative resection are similarly randomized, with their follow-up regimens placing more emphasis on detection of local recurrence. Target recruitment for the study will be 1500 patients to achieve a statistical power of 80% (assuming an alpha of 0.05 and a hazard-rate reduction of >24%). RESULTS: Since the trial opened in 1998, 985 patients have been randomized from 41 centers as of February 2004. There were 496 patients randomized to the less intensive regimens, and 489 randomized to the more intensive regimens. The mean duration of follow-up is 14 months. 75 relapses (15%) and 32 deaths (7%) had been observed in the two more intensive follow-up arms, while 64 relapses (13%) and 24 deaths (5%) had been observed in the two less intensive arms as of February 2004. CONCLUSIONS: This trial should provide the first evidence based on an adequately powered randomized trial to determine the optimal follow-up strategy for colorectal cancer patients. This trial is open to US centers, and recruitment continues.

Adolescent↗

Evidence supports adjuvant radiotherapy in selected patients with rectal cancer.

BACKGROUND: Much recent data have been published on the risk of local recurrence (LR) following curative surgery for rectal cancer and the impact of adjuvant radiation therapy (RT). With improvements in surgical technique apparently reducing the risk of LR, the relevance of older data upon which the current recommendations for adjuvant RT are based has been questioned. METHODS: A focused review was undertaken of the published literature on the risk of LR following surgery for rectal cancer and the impact of adjuvant radiation. In particular the authors attempt to define how accurately the risk for an individual patient can be predicted, trends in reported LR rates over the time period of randomized trials, and the relevance of changing surgical and RT techniques. RESULTS: Many of the perceived differences in published results can be explained by variations in study entry criteria, length of follow up and data recording. Comparisons between studies are most accurate when defined subsets of patients, such as those with stage III disease, followed for the same period of time, are considered. In parallel with improvements in surgical technique, which may have reduced the risk of LR, modifications to RT delivery have resulted in recent series not reporting an increased mortality in those patients treated with modern RT techniques. CONCLUSION: All of the available evidence supports the use of adjuvant RT in selected patients with rectal cancer. Ongoing studies will better define individual patient risk and the risk-benefit ratio of adjuvant RT.

Humans↗

The SWISS-PROT protein sequence data bank and its new supplement TREMBL.

SWISS-PROT is a curated protein sequence database which strives to provide a high level of annotation (such as the description of the function of a protein, its domain structure, post-translational modifications, variants, etc), a minimal level of redundancy and a high level of integration with other databases. Recent developments of the database include: an increase in the number and scope of model organisms; cross-references to seven additional databases; a variety of new documentation files; the creation of TREMBL, and unannotated supplement to SWISS-PROT. This supplement consists of entries in SWISS-PROT-like format derived from the translation of all coding sequences (CDS) in the EMBL nucleotide sequence database, except CDS already included in SWISS-PROT.

Amino Acid Sequence↗

Nephron-sparing surgery.

The curative management of renal cell carcinoma remains surgical. Recent advances in imaging and increased use of cross-sectional imaging modalities have led to an increased detection of incidental renal cell carcinomas. There is little debate regarding the role of nephron-sparing surgery (NSS) when absolutely indicated. Radical nephrectomy is still considered by many as the treatment of choice for localized renal cell carcinoma in the setting of a normal contralateral kidney. However, there is growing evidence that in the correct patient, the use of NSS in this setting is justified. Therefore, the indications of NSS have evolved in the past decade. Recent data indicate that radical nephrectomy and NSS provide effective and equivalent curative treatment for most renal cell carcinomas, especially those 4 cm or smaller. These data, along with new, refined surgical techniques, new studies regarding the biology of renal cell carcinoma and true incidence of occult multifocality, and earlier diagnosis make NSS an attractive consideration for the practicing urologist.

Carcinoma, Renal Cell↗

Colonoscopy after curative resection of colorectal cancer.

Colonoscopy is generally considered to be an important part of the follow-up program for patients who have undergone curative resection of colorectal cancer. However, there are few data available concerning the frequency with which colonoscopy should be performed and for what length of time after operation. Since 1978, our policy has been to examine the colon annually in these patients using colonoscopy alternating with barium enema. We have evaluated the results in 100 patients over a four-year period. Based on size and histology, the significant colonoscopic findings were new colon cancers in three patients and 11 polyps demonstrating increased risk for malignancy in nine patients. This represents an interval yield of 3% per year. From these results and other reports, we recommend that these patients undergo total colonoscopy in the perioperative period to identify and remove synchronous lesions of the colon, and that examination of the remaining colon should be performed annually, preferably with colonoscopy, for at least the first four years after curative resection.

Barium Sulfate↗

In vitro sensitivity of Plasmodium falciparum to lumefantrine in north-western Thailand.

Lumefantrine (benflumetol) belongs to the class-2 blood schizontocidal compounds. In combination with artemether it serves as an alternative drug for treating chloroquine-resistant infections with Plasmodium falciparum. In view of activity correlations with mefloquine, it is important to monitor the parasite's intrinsic sensitivity to lumefantrine in areas with multi-drug resistant P. falciparum, the objective of this study. The observations were carried out in 2002 at Mae Sot, northwestern Thailand, near the border to Myanmar. The 41 successfully in-vitro tested parasite isolates yielded a geometric mean cut-off concentration of schizont maturation of 237.54 nM, and EC50, EC90 and EC90 values of 15.13 nM, 86.71 nM and 359.97 nM, respectively. As compared to the findings of 1998 and 1999, the susceptibility to lumefantrine has increased, possibly due to the improved therapeutic response of mefloquine-resistant P. falciparum infections to combined treatment with artesunate + mefloquine. The EC9o and EC99 data of 2002 for lumefantrine in the study area suggest fully curative clinical-parasitological efficacy.

Adolescent↗

Finding function: evaluation methods for functional genomic data.

BACKGROUND: Accurate evaluation of the quality of genomic or proteomic data and computational methods is vital to our ability to use them for formulating novel biological hypotheses and directing further experiments. There is currently no standard approach to evaluation in functional genomics. Our analysis of existing approaches shows that they are inconsistent and contain substantial functional biases that render the resulting evaluations misleading both quantitatively and qualitatively. These problems make it essentially impossible to compare computational methods or large-scale experimental datasets and also result in conclusions that generalize poorly in most biological applications. RESULTS: We reveal issues with current evaluation methods here and suggest new approaches to evaluation that facilitate accurate and representative characterization of genomic methods and data. Specifically, we describe a functional genomics gold standard based on curation by expert biologists and demonstrate its use as an effective means of evaluation of genomic approaches. Our evaluation framework and gold standard are freely available to the community through our website. CONCLUSION: Proper methods for evaluating genomic data and computational approaches will determine how much we, as a community, are able to learn from the wealth of available data. We propose one possible solution to this problem here but emphasize that this topic warrants broader community discussion.

Algorithms↗

A QTL resource and comparison tool for pigs: PigQTLDB.

During the past decade, efforts to map quantitative trait loci (QTL) in pigs have resulted in hundreds of QTL being reported for growth, meat quality, reproduction, disease resistance, and other traits. It is a challenge to locate, interpret, and compare QTL results from different studies. We have developed a pig QTL database (PigQTLdb) that integrates available pig QTL data in the public domain, thus, facilitating the use of this QTL data in future studies. We also developed a pig trait classification system to standardize names of traits and to simplify organization and searching of the trait data. These steps made it possible to compare primary data from diverse sources and methods. We used existing pig map databases and other publicly available data resources (such as PubMed) to avoid redundant developmental work. The PigQTLdb was also designed to include data representing major genes and markers associated with a large effect on economically important traits. To date, over 790 QTL from 73 publications have been curated into the database. Those QTL cover more than 300 different traits. The data have been submitted to the Entrez Gene and the Map Viewer resources at NCBI, where the information about markers was matched to marker records in NCBI's UniSTS database. Having these data in a public resource like NCBI allows regularly updated automatic matching of markers to public sequence data by e-PCR. The submitted data, and the results of these calculations, are retrievable from NCBI via Entrez Gene, Map Viewer, and UniSTS. Efforts were undertaken to improve the integrated functional genomics resources for pigs.

Animals↗