The Genome Sequence DataBase: towards an integrated functional genomics resource

During 1998 the primary focus of the Genome Sequence DataBase (GSDB; http://www.ncgr.org/gsdb ) located at the National Center for Genome Resources (NCGR) has been to improve data quality, improve data collections, and provide new methods and tools to access and analyze data. Data quality has been improved by extensive curation of certain data fields necessary for maintaining data collections and for using certain tools. Data quality has also been increased by improvements to the suite of programs that import data from the International Nucleotide Sequence Database Collaboration (IC). The Sequence Tag Alignment and Consensus Knowledgebase (STACK), a database of human expressed gene sequences developed by the South African National Bioinformatics Institute (SANBI), became available within the last year, allowing public access to this valuable resource of expressed sequences. Data access was improved by the addition of the Sequence Viewer, a platform-independent graphical viewer for GSDB sequence data. This tool has also been integrated with other searching and data retrieval tools. A BLAST homology search service was also made available, allowing researchers to search all of the data, including the unique data, that are available from GSDB. These improvements are designed to make GSDB more accessible to users, extend the rich searching capability already present in GSDB, and to facilitate the transition to an integrated system containing many different types of biological data

The utility of Aspirin in dukes C and high risk dukes B colorectal cancer - The ASCOLT study: study protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>High quality evidence indicates that aspirin is effective in reducing colorectal polyps; and numerous epidemiological studies point towards an ability to prevent colorectal cancer. However the role of Aspirin as an adjuvant agent in patients with established cancers remains to be defined. Recently a nested case-control study within the Nurses Health cohort suggested that the initiation of Aspirin <it>after </it>the diagnosis of colon cancer reduced overall colorectal cancer specific mortality. Although this data is supportive of Aspirin's biological activity in this disease and possible role in adjuvant therapy, it needs to be confirmed in a randomized prospective trial.</p> <p>Methods/Design</p> <p>We hypothesize through this randomized, placebo-controlled adjuvant study, that Aspirin in patients with dukes C or high risk dukes B colorectal cancer (ASCOLT) can improve survival in this patient population over placebo control. The primary endpoint of this study is Disease Free Survival and the secondary Endpoint is 5 yr Overall Survival. This study will randomize eligible patients with Dukes C or high risk Dukes B colorectal cancer, after completion of surgery and standard adjuvant chemotherapy (+/- radiation therapy for rectal cancer patients) to 200 mg Aspirin or Placebo for 3 years. Stratification factors include study centre, rectal or colon cancer stage, and type of adjuvant chemotherapy (exposed/not exposed to oxaliplatin). After randomization, patient will be followed up with 3 monthly assessments whilst on study drug and for a total of 5 years. Patients with active peptic ulcer disease, bleeding diathesis or on treatment with aspirin or anti-platelet agents will be excluded from the study.</p> <p>Discussion</p> <p>This study aims to evaluate Aspirin's role as an adjuvant treatment in colorectal cancer. If indeed found to be beneficial, because aspirin is cheap, accessible and easy to administer, it will positively impact the lives of many individuals in Asia and globally.</p> <p>Trials Registration</p> <p>Clinicaltrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00565708">NCT00565708</a></p

Suppression of Radiation-Induced Salivary Gland Dysfunction by IGF-1

Radiation is a primary or secondary therapeutic modality for treatment of head and neck cancer. A common side effect of irradiation to the neck and neck region is xerostomia caused by salivary gland dysfunction. Approximately 40,000 new cases of xerostomia result from radiation treatment in the United States each year. The ensuing salivary gland hypofunction results in significant morbidity and diminishes the effectiveness of anti-cancer therapies as well as the quality of life for these patients. Previous studies in a rat model have shown no correlation between induction of apoptosis in the salivary gland and either the immediate or chronic decrease in salivary function following gamma-radiation treatment.A significant level of apoptosis can be detected in the salivary glands of FVB mice following gamma-radiation treatment of the head and neck and this apoptosis is suppressed in transgenic mice expressing an activated mutant of Akt (myr-Akt1). Importantly, this suppression of apoptosis in myr-Akt1 mice preserves salivary function, as measured by saliva output, three and thirty days after gamma-radiation treatment. In order to translate these studies into a preclinal model we found that intravenous injection of IGF1 stimulated activation of endogenous Akt in the salivary glands in vivo. A single injection of IGF1 prior to exposure to gamma-radiation diminishes salivary acinar cell apoptosis and completely preserves salivary gland function three and thirty days following irradiation.These studies suggest that apoptosis of salivary acinar cells underlies salivary gland hypofunction occurring secondary to radiation of the head and neck region. Targeted delivery of IGF1 to the salivary gland of patients receiving head and neck irradiation may be useful in reducing or eliminating xerostomia and restoring quality of life to these patients

Developmental Programming Mediated by Complementary Roles of Imprinted Grb10 in Mother and Pup

Developmental programming links growth in early life with health status in adulthood. Although environmental factors such as maternal diet can influence the growth and adult health status of offspring, the genetic influences on this process are poorly understood. Using the mouse as a model, we identify the imprinted gene Grb10 as a mediator of nutrient supply and demand in the postnatal period. The combined actions of Grb10 expressed in the mother, controlling supply, and Grb10 expressed in the offspring, controlling demand, jointly regulate offspring growth. Furthermore, Grb10 determines the proportions of lean and fat tissue during development, thereby influencing energy homeostasis in the adult. Most strikingly, we show that the development of normal lean/fat proportions depends on the combined effects of Grb10 expressed in the mother, which has the greater effect on offspring adiposity, and Grb10 expressed in the offspring, which influences lean mass. These distinct functions of Grb10 in mother and pup act complementarily, which is consistent with a coadaptation model of imprinting evolution, a model predicted but for which there is limited experimental evidence. In addition, our findings identify Grb10 as a key genetic component of developmental programming, and highlight the need for a better understanding of mother-offspring interactions at the genetic level in predicting adult disease risk

Pregnancy and Breast Cancer: when They Collide

Women of childbearing age experience an increased breast cancer risk associated with a completed pregnancy. For younger women, this increase in breast cancer risk is transient and within a decade after parturition a cross over effect results in an ultimate protective benefit. The post-partum peak of increased risk is greater in women with advanced maternal age. Further, their lifetime risk for developing breast cancer remains elevated for many years, with the cross over to protection occurring decades later or not at all. Breast cancers diagnosed during pregnancy and within a number of years post-partum are termed pregnancy-associated or PABC. Contrary to popular belief, PABC is not a rare disease and could affect up to 40,000 women in 2009. The collision between pregnancy and breast cancer puts women in a fear-invoking paradox of their own health, their pregnancy, and the outcomes for both. We propose two distinct subtypes of PABC: breast cancer diagnosed during pregnancy and breast cancer diagnosed post-partum. This distinction is important because emerging epidemiologic data highlights worsened outcomes specific to post-partum cases. We reported that post-partum breast involution may be responsible for the increased metastatic potential of post-partum PABC. Increased awareness and detection, rationally aggressive treatment, and enhanced understanding of the mechanisms are imperative steps toward improving the prognosis for PABC. If we determine the mechanisms by which involution promotes metastasis of PABC, the post-partum period can be a window of opportunity for intervention strategies

Metastatic canine mammary carcinomas can be identified by a gene expression profile that partly overlaps with human breast cancer profiles

<p>Abstract</p> <p>Background</p> <p>Similar to human breast cancer mammary tumors of the female dog are commonly associated with a fatal outcome due to the development of distant metastases. However, the molecular defects leading to metastasis are largely unknown and the value of canine mammary carcinoma as a model for human breast cancer is unclear. In this study, we analyzed the gene expression signatures associated with mammary tumor metastasis and asked for parallels with the human equivalent.</p> <p>Methods</p> <p>Messenger RNA expression profiles of twenty-seven lymph node metastasis positive or negative canine mammary carcinomas were established by microarray analysis. Differentially expressed genes were functionally characterized and associated with molecular pathways. The findings were also correlated with published data on human breast cancer.</p> <p>Results</p> <p>Metastatic canine mammary carcinomas had 1,011 significantly differentially expressed genes when compared to non-metastatic carcinomas. Metastatic carcinomas had a significant up-regulation of genes associated with cell cycle regulation, matrix modulation, protein folding and proteasomal degradation whereas cell differentiation genes, growth factor pathway genes and regulators of actin organization were significantly down-regulated. Interestingly, 265 of the 1,011 differentially expressed canine genes are also related to human breast cancer and, vice versa, parts of a human prognostic gene signature were identified in the expression profiles of the metastatic canine tumors.</p> <p>Conclusions</p> <p>Metastatic canine mammary carcinomas can be discriminated from non-metastatic carcinomas by their gene expression profiles. More than one third of the differentially expressed genes are also described of relevance for human breast cancer. Many of the differentially expressed genes are linked to functions and pathways which appear to be relevant for the induction and maintenance of metastatic progression and may represent new therapeutic targets. Furthermore, dogs are in some aspects suitable as a translational model for human breast tumors in order to identify prognostic molecular signatures and potential therapeutic targets.</p