In this issue, we are putting cancer in the spotlight and will focus on how Ingenuity Systems' solutions are helping scientists in the cancer field achieve their research goals. You’ll find some recent examples of oncology research conducted by your fellow IPA users in the Publications section, as well as some highlights from this summer’s annual AACR and ASCO meetings.

Along with our usual Tips on how to maximize your experience with IPA, this issue we’re introducing the IPA Brain Teaser. Test your IPA knowledge! Be the first person to submit the correct answer and we’ll send you a prize.

It has been a busy few months, so we also want to update you on various activities and events Ingenuity Systems has been involved in, including the Ingenuity Systems User Group Meeting. To read more about it, skip to the Events section.

We have also had a recent Content Update in IPA, and will bring you up to speed on the benefits in the Product Updates section.

Thanks for joining us for another issue of the Ingenuity Insider. As always, if you have comments or recommendations for us, don’t hesitate to contact us at support@ingenuity.com.

Best Regards,
The Ingenuity Team

Publication Highlights

Identification of a PAX-FKHR Gene

A Modular Analysis of Breast Cancer

Re-Expression of the Retinoblastoma-Binding Protein

More Publications

Ingenuity Pathways Analysis fuels research presented at annual AACR and ASCO Meetings

Ingenuity Pathways Analysis provides cancer researchers with access to a wealth of information on genes involved in cancer-related processes and pathways, targets of chemotherapeutic drugs, as well as the tools necessary to discover new cancer targets and markers of disease and drug efficacy. A review of the abstracts published from this year’s annual meetings of the American Association for Cancer Research (AACR) and the American Society of Clinical Oncology (ASCO) provides a good indication of how integral Ingenuity Pathways Analysis has become in the workflows of cancer researchers. IPA was used by a variety of research teams from industry, government and academia in order to accomplish research goals ranging from basic science to clinical applications.

Research presented at the AACR and ASCO annual meetings indicate that IPA helped guide genomic and proteomic studies focused on:

• Understanding mechanism of action of chemotherapeutics
• Validating in vitro metastatic models of angiogenesis and human cancer
• Discovering clinically relevant markers
• Guiding selection of molecular targets for individual patients
• Discriminating tumors resistant to and susceptible to therapy
• Identifying pathways perturbed in metastatic vs. non-metastatic tumors
• Developing a systems biology approach linking the physiology of human cancer to the human genome

This research was conducted by a number of Ingenuity customers and their collaborators, including scientists at:

• Dana-Farber Cancer Institute
• Duke University Medical Center
• Fred Hutchinson Cancer Research Center
• Genomics Institute of the Novartis Research Foundation
• Lilly Research Labs
• Mayo Clinic
• NCI/NIH
• Response Genetics Inc.
• Roche Molecular Diagnostics
• UT MD Anderson Cancer Center

All of this research is referenced on our website. To read more about any of these particular studies just go to the following link:
(http://www.ingenuity.com/solutions/pdf/Bibliography.pdf) and search with the term “AACR” or ASCO”.

Identification of a PAX-FKHR Gene Expression Signature that Defines Molecular Classes and Determines the Prognosis of Alveolar Rhabdomyosarcomas. Cancer Res. 2006 Jul 15;66(14):6936-46. Davicioni E, Finckenstein FG, Shahbazian V, Buckley JD, Triche TJ, Anderson MJ.

A Modular Analysis of Breast Cancer Reveals a Novel Low-Grade Molecular Signature in Estrogen Receptor–Positive Tumors. Clin Cancer Res. 2006 Jun 1;12(11 Pt 1):3288-96.

Re-Expression of the Retinoblastoma-Binding Protein 2-Homolog 1 Reveals Tumor-Suppressive Functions in Highly Metastatic Melanoma Cells. J Invest Dermatol. 2006 Apr 27; [Epub ahead of print]. Roesch A, Becker B, Schneider-Brachert W, Hagen I, Landthaler M, Vogt T.

Progression-Specific Genes Identified by Expression Profiling of Matched Ductal Carcinomas In situ and Invasive Breast Tumors, Combining Laser Capture Microdissection and Oligonucleotide Microarray Analysis. Cancer Res. 2006; 66(10): p. 5278-5286. Christina S. Schuetz, Michael Bonin, Susan E. Clare, Kay Nieselt, Karl Sotlar, Michael Walter, Tanja Fehm, Erich Solomayer, Olaf Riess, Diethelm Wallwiener, Raffael Kurek, and Hans J. Neubauer.

Ingenuity Network-Assisted Transcription Profiling: Identification of a New Pharmacologic Mechanism for MK886. Clin Cancer Res. 2006 Mar 15;12(6):1820-7. Mayburd AL, Martlinez A, Sackett D, Liu H, Shih J, Tauler J, Avis I, Mulshine JL.

Global gene expression associated with hepatocarcinogenesis in adult male mice induced by in utero arsenic exposure. Environ Health Perspect. 2006 Mar;114(3):404-11. Liu J, Xie Y, Ducharme DM, Shen J, Diwan BA, Merrick BA, Grissom SF, Tucker CJ, Paules RS, Tennant R, Waalkes MP.

Analysis of the interaction of extracellular matrix and phenotype of bladder cancer cells. BMC Cancer. 2006 Jan 13;6:12. Dozmorov MG, Kyker KD, Saban R, Knowlton N, Dozmorov I, Centola MB, Hurst RE.

Major carcinogenic pathways identified by gene expression analysis of peritoneal mesotheliomas following chemical treatment in F344 rats. Toxicol Appl Pharmacol. 2006 Feb 3; [Epub ahead of print] Kim Y, Ton TV, Deangelo AB, Morgan K, Devereux TR, Anna C, Collins JB, Paules RS, Crosby LM, Sills RC.

Significance of Murine Retroviral Mutagenesis for Identification of Disease Genes in Human Acute Myeloid Leukemia. Cancer Research 66, 622-626, January 15, 2006. Erkeland SJ, Verhaak RGW, Valk, PJM, Delwel R, Lowenberg B, Touw IP.

Gene expression profiling of localized esophageal carcinomas: association with pathologic response to preoperative chemoradiation. J Clin Oncol. 2006 Jan 10;24(2):259-67. Epub 2005 Dec 12. Luthra R, Wu TT, Luthra MG, Izzo J, Lopez-Alvarez E, Zhang L, Bailey J, Lee JH, Bresalier R, Rashid A, Swisher SG, Ajani JA.

Identification of novel transcriptional networks in response to treatment with the anticarcinogen 3H-1,2-dithiole-3-thione. Physiol Genomics. 2006 Jan 12;24(2):144-53. Epub 2005 Nov 29. Huang Y, Yan J, Lubet R, Kensler TW, Sutter TR.

Drug Discovery and Development Summit
Phoenix, AZ
November 27-28, 2007

Molecular Medicine Tri-Conference
Moscone North Convention Center
San Francisco, CA
February 27 - March 2, 2007
Booth 302

Save the Date!
European Ingenuity Systems User Group Meeting
Basel, Switzerland
April 26-27, 2007

Ingenuity Systems User Group Meeting
Redwood City, CA
TBD

Training Schedule

IPA as a Knowledge and Discovery Tool
November 16, 7:00 am

IPA Case Studies
November 30, 7:00 am

Using IPA for Expression Data Analysis
December 7, 10:00 am

IPA as a Knowledge and Discovery Tool
December 14, 10:00 am

IPA Case Studies
December 21, 10:00 am

Ingenuity’s User Group Meeting (Boston, July 2006)

The Ingenuity Systems’ User Group Meeting was by all accounts a great success! We are already gearing up for the 2007 User Group Meeting series in the United States and in Europe (see “Save the Date ” above). Some of the highlights mentioned by IPA users that attended the meeting included hearing their peers present their research and IPA workflows as well as getting previews and tips on new features in IPA. From the Ingenuity Team’s perspective, highlights included meeting users face to face and hearing feedback straight from the source, and also seeing IPA “power users” pass their knowledge on to newer IPA users.

Thanks again to all of the speakers and attendees. Your participation really made the event a great success. We look forward to seeing you at the next User Group Meetings.

Did you know that using Advanced Search, My Lists and the Overlay List tool you can easily identify the subsets of proteins that localize to a particular compartment of the cytoplasm? For example – if you would like to be able to identify all mitochoindrial enzymes within a network, create a My List by first searching with the protein family term “enzyme” and the subcellular location term “mitochondria”. Select all of the genes returned by the search and save them as a list. You can now reference this list and flag mitochondrial enzymes any time you are viewing a Network or Pathway.

Use this tip any time you need to generate a category of genes that you would like to identify and flag within a Network or My Pathway.

Each issue of the Ingenuity Insider we will post a question or two related to Ingenuity Pathways Analysis. The first person to email the answer to the Brain Teaser will be announced in the next issue of the Ingenuity Insider along with their answer. As an additional incentive, a prize will be awarded to the first correct answer received. Send your answer to support@ingenuity.com. All emails must include the following subject line: "Ingenuity Insider Brain Teaser" along with your contact information (so we can send your prize).

Brain Teaser Question:
What are the peptidases and growth factors that are associated with angiogenesis in Ingenuity Pathways Analysis? Which of those proteins are the targets of FDA APPROVED drugs?

Additional CNS content:

We’ve received some feedback from our customers requesting additional content to support workflows focused on central nervous system (CNS) research. We make every effort to respond to our customers’ content suggestions, and as a result have expanded our content acquisition efforts to include several additional neuroscience journals.

We increased our coverage of CNS-related content by targeting content from the following journals:

• Journal of Neuroscience
• British Journal of Pharmacology
• Molecular Pharmacology
• Hypertension
• Circulation
• Circulation Research

We also curated the following pathways and added them to IPA’s extensive library of signaling and metabolic pathways:

• Synaptic Long-Term Potentiation
• Synaptic Long-Term Depression
• Axonal Guidance Signaling
• Huntington’s Disease Signaling
• Amyotrophic Lateral Sclerosis (ALS) Signaling

New microRNA content:

In this content update we have also included findings involving microRNAs (miRNAs). In addition to these findings we have added all known miRNAs to the Ingenuity Knowledge Base, enabling our customers to map miRNAs from their expression experiments in IPA.

The addition of miRNA content is particularly relevant to our customers focused on cancer research, as recent studies of miRNA expression profiles in cancer have identified miRNAs that are differentially regulated in tumors, suggesting a link between miRNAs and oncogenesis. IPA’s support of miRNA workflows provides cancer researchers with an additional tool for the discovery of cancer diagnostics.

New clinical candidate and approved drugs, info on drug metabolism:

With this latest content release, our customers will have access to additional content on clinical candidates and FDA approved drugs, as well as the metabolic pathway “Metabolism of Xenobiotics by Cytochrome p450”.

If you have a suggestion regarding additional content you would like to see in IPA, please feel free to forward your requests (new pathways, expanded information on diseases or genes, etc.) by using the e-mail link highlighted above on the IPA landing page.

Improved Integration Between Entrez Gene and IPA

Entrez Gene is one of the most widely used searchable databases of genes and has become integrated into the workflow of nearly every scientist studying the molecular basis of disease. We would like our customers to be able to immediately answer questions regarding pathways, molecular interactions, cellular functions, regulatory events, etc. that a gene is involved in, as soon as these questions come to mind. As a result, we are now providing direct links for IPA customers from Entrez Gene records to corresponding Gene View pages in IPA.

To take advantage of this improved workflow when in Entrez Gene, select the “Link Out” option from the Display menu in Entrez Gene (see graphic below), and click on the Ingenuity Pathways Analysis link. You will be taken directly to the species-specific (human, mouse or rat) Gene View page in IPA, where your exploration of that gene can continue.

Ingenuity Insider Quick Tip from your Customer Support Team

Ingenuity Systems periodically updates the content available in IPA. To see the impact the new content has on your research, we recommend that you rerun your analysis after each content update. The analysis in your workspace is not automatically updated after new content is added to the Ingenuity Pathways Knowledge Base (IPKB).

Additionally, Functional Analysis results for a particular dataset might also change. The top 500 functions with a p-value of 0.05 or less are displayed in the Functions tab of your analysis results. When content is added to the Ingenuity Pathways Knowledge Base, the significance of a particular function may change with some functions rising in relevance to that dataset, others falling or being eliminated from the results.
		The Ingenuity Systems Customer Support Team, Jaya Ramkumar, Amy Mendenhall, Carmela Jaravata and Kent Hillyer - absent from the photo are Jinah Kim and Jyothi Paniyadi.