Application of virtual screening to the discovery of novel nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with potential for the treatment of cancer and axonopathies.

NAMPT may represent a novel target for drug discovery in various therapeutic areas, including oncology and inflammation. Additionally, recent work has suggested that targeting NAMPT has potential in treating axon degeneration. In this work, publicly available X-ray co-crystal structures of NAMPT and the structures of two known NAMPT inhibitors were used as the basis for a structure- and ligand-based virtual screening campaign. From this, two novel series of NAMPT inhibitors were identified, one of which showed a statistically significant protective effect when tested in a cellular model of axon degeneration

Optogenetic regulation of site-specific subtelomeric DNA methylation

Telomere length homeostasis, critical for chromosomal integrity and genome stability, is controlled by intricate molecular regulatory machinery that includes epigenetic modifications. Here, we examine site-specific and spatiotemporal alteration of the subtelomeric methylation of CpG islands using optogenetic tools to understand the epigenetic regulatory mechanisms of telomere length maintenance. Human DNA methyltransferase3A (DNMT3A) were assembled selectively at chromosome ends by fusion to cryptochrome 2 protein (CRY2) and its interacting complement, the basic helix loop helix protein-1 (CIB1). CIB1 was fused to the telomere-associated protein telomere repeat binding factor-1 (TRF1), which localized the protein complex DNMT3A-CRY2 at telomeric regions upon excitation by blue-light monitored by single-molecule fluorescence analyses. Increased methylation was achieved selectively at subtelomeric CpG sites on the six examined chromosome ends specifically after blue-light activation, which resulted in progressive increase in telomere length over three generations of HeLa cell replications. The modular design of the fusion constructs presented here allows for the selective substitution of other chromatin modifying enzymes and for loci-specific targeting to regulate the epigenetic pathways at telomeres and other selected genomic regions of interest

THE INDIANA CENTER FOR BREAST CANCER RESEARCH: PROGRESS REPORT

poster abstractThe mission of IUPUI breast cancer center is to address prevention, early detection, and treatment of breast cancer through translational projects, supportive cores, and synergistic programs. This poster details our efforts improve resources for breast cancer research and efforts to develop multi-PI investigator proposals. The Signature Center Initiative has developed two web resources: the Breast Cancer Prognostics Database (BCDB) to study prognostic implications of genes of interest in publically available breast cancer databases and PROGmiR, a microRNA database. The BCDB can be used to study overall, recurrence free and metastasis free survival in large patient series. PROGmiR allows investigators to study the prognostic importance of microRNAs. PROGmiR has recently been published and has been accessed by investigators from several countries. The signature center has also devoted considerable efforts in developing tumor tissue resource. Tissue Bank includes a total sample of N = 500 cases with 30% non-Caucasian cases from Wishard Memorial Hospital. Currently 237 cases have been assembled into a Tissue Microarray with clinical and follow up data. The breast cancer center has funded three pilot projects. Drs. Clark Wells, S. Badve, and G. Sandusky are collaborating on the project: “Histologic Analysis of the Protein Levels of Amot130, AmotL1 and YAP in Normal, Hyperplastic and Invasive Breast Cancer Tissues”. This project is investigating localized protein expression in paraffin-embedded tissues to associate expression levels with disease subtype and patient outcome. Dr. David Gilley and his group are collaborating on the project: “Luminal mammary progenitors are a unique site of telomere dysfunction”. This project is investigating the relationship between telomere dysfunction and breast cancer tumorigenesis. In the third project, Dr. Theresa Guise will be investigating the mechanisms of cancer-associated cachexia. Several multi-PI proposals are under preparation and one proposal with Drs. Nakshatri and Kathy Miller as PIs is currently under review

The Indiana Center for Breast Cancer Research: Progress towards a SPORE Proposal

poster abstractAbstract The Indiana Center for Breast Cancer Research (ICBCR) was funded under the IUPUI Signature Center Initiative in 2010. Its mission is to address the full range of prevention, early detection, and treatment of breast cancer through translational projects, supportive cores, and synergistic programs. This poster details our efforts to date towards applying for a National Cancer Institute Specialized Program of Research Excellence (SPORE) in January 2013. The proposed IU Breast Cancer SPORE will include 4-5 individual research projects, 3 cores, developmental research and career development programs. The SPORE Biostatistics and Bioinformatics core has developed the Breast Cancer Prognostics Database (BCDB), an online tool to study prognostic implications of genes of interest in publically available breast cancer databases. The BCDB can be used to study overall, recurrence free and metastasis free survival in large patient series. Supporting the SPORE Biospecimen/Pathology core, the IU Breast Cancer Tissue Bank includes a total sample of N = 500 cases with 30% non-Caucasian cases from Wishard Memorial Hospital. Currently there are N = 333 cases with tissue microarray data and complete clinical data with an additional 200 cases pending tissue confirmation. Dr. Clark D. Wells together with S. Badve and G. Sandusky are collaborating on the project: “Histologic Analysis of the Protein Levels of Amot130, AmotL1 and YAP in Normal, Hyperplastic and Invasive Breast Cancer Tissues”, a candidate SPORE individual research project. This project is investigating localized protein expression in paraffin-embedded tissues to associate expression levels with disease subtype and patient outcome. Dr. David P. Gilley together with N. Kannan, N. Huda, L. Tu, R. Droumeva, R. Brinkman, J. Emerman, S. Abe, and C. Eaves, are collaborating on the project: “Luminal mammary progenitors are a unique site of telomere dysfunction”, a candidate SPORE developmental research project. This project is investigating the relationship between telomere dysfunction and breast cancer tumorigenesis. These SPORE projects and cores were discussed at the IUSCC Breast Cancer Program retreat held on 1/13/12. Two additional planning meetings were held on 1/5 and 2/23. A timeline was generated to include final project selection in April, internal review in June, external review in August-September, and draft completion by 12/1, to meet the 1/20/13 NIH receipt deadline

DMAPT inhibits NF-κB activity and increases sensitivity of prostate cancer cells to X-rays in vitro and in tumor xenografts in vivo

Constitutive activation of the pro-survival transcription factor NF-κB has been associated with resistance to both chemotherapy and radiation therapy in many human cancers, including prostate cancer. Our lab and others have demonstrated that the natural product parthenolide can inhibit NF-κB activity and sensitize PC-3 prostate cancers cells to X-rays in vitro; however, parthenolide has poor bioavailability in vivo and therefore has little clinical utility in this regard. We show here that treatment of PC-3 and DU145 human prostate cancer cells with dimethylaminoparthenolide (DMAPT), a parthenolide derivative with increased bioavailability, inhibits constitutive and radiation-induced NF-κB binding activity and slows prostate cancer cell growth. We also show that DMAPT increases single and fractionated X-ray-induced killing of prostate cancer cells through inhibition of DNA double strand break repair and also that DMAPT-induced radiosensitization is, at least partially, dependent upon the alteration of intracellular thiol reduction-oxidation chemistry. Finally, we demonstrate that the treatment of PC-3 prostate tumor xenografts with oral DMAPT in addition to radiation therapy significantly decreases tumor growth and results in significantly smaller tumor volumes compared to xenografts treated with either DMAPT or radiation therapy alone, suggesting that DMAPT might have a potential clinical role as a radiosensitizing agent in the treatment of prostate cancer

Modify the redefined: strategic human resource development maturity at a crossroads

This integrative literature review reports on strategic human resource development (SHRD) models that examine the strategic embeddedness of HRD (SHRD maturity) in organizations. A review and critique of all existing SHRD models is provided, exemplifying their limitations and building upon their strengths to inform a modified SHRD framework. The latter suggests an enhanced set of strategic components to assess SHRD maturity. This paper further outlines how SHRD aspirations can be practiced within complex, dynamic, and continually changing business and economic environments. The SHRD literature is advanced by new insights on how HRD scholars and practitioners could assess and enhance the maturity of their HRD interventions in the context of constantly changing (dynamic) environments. The modified SHRD framework further contributes to the academic literature with its enhanced set of strategic characteristics, as well as with its SHRD pointers, all of which can offer a better evaluation of SHRD maturity during periods of business and economic complexity and uncertainty

Indiana Center for Breast Cancer Research

poster abstractThe mission of IUPUI breast cancer signature center is to address prevention, early detection, and treatment of breast cancer through translational projects, supportive cores, and synergistic programs. This poster details our efforts improve resources for breast cancer research and efforts to develop multi-PI investigator proposals. The Signature Center has developed two web resources: the Breast Cancer Prognostics Database (PROGgene) to study prognostic implications of genes of interest in publically available breast cancer databases and PROGmiR, a microRNA database. The PROGgene can be used to study overall, recurrence free and metastasis free survival in large patient series. PROGmiR allows investigators to study the prognostic importance of microRNAs. Both PROGgene and PROGmiR have recently been published and accessed by investigators from >10 countries. The signature center has also devoted considerable efforts in developing tumor tissue resource. Tissue Bank includes a total sample of N = 600 cases with 30% non-Caucasian cases. Currently 460 cases have been assembled into a Tissue Microarray with clinical and follow up data. Expression pattern of AP2γ, a potential marker of breast cancer progression, has been analyzed in a TMA with ~170 cases. The breast cancer signature center has funded four pilot projects and projects for the fourth round of funding are currently under review. Drs. Clark Wells received funding for the project “Histologic Analysis of the Protein Levels of Amot130, AmotL1 and YAP in Normal, Hyperplastic and Invasive Breast Cancer Tissues”, which resulted in a publication in PNAS. Dr. David Gilley and his group received funding for the project: “Luminal mammary progenitors are a unique site of telomere dysfunction”, which was published in Stem Cell Reports. In the third project, Dr. Theresa Guise is investigating the mechanisms of cancer-associated muscular dysfunction with a future plan for a clinical trial. Drs. Ken Nephew and Milan Radovich received funding to obtain preliminary results for a multi-PI R01 or P01, which will explore genomics and epigenomics of breast cancer using clinical trial materials. Progress made by the signature center was integral in our request to Vera Bradley Foundation for Breast Cancer. This foundation has recently committed $15 million for the breast cancer program, which will be used to develop three themes of research with a focus on personalized therapies to improve outcome in breast cancer patients

UN Peace operations and conflicting legitimacies

Analyses of UN peacekeeping increasingly consider legitimacy a key factor for success, conceiving of it as a resource that operations should seek and use in the pursuit of their goals. However, these analyses rarely break down legitimacy by source. Because the UN is an organization with multiple identities and duties however, different legitimacy sources—in particular output and procedural legitimacy—and the UN’s corresponding legitimation practices come into conflict in the context of peacekeeping. Drawing on a range of examples and a specific case of the UN mission in Congo, this article argues that looking at different legitimacy sources and linking them to the institutional identity of the UN is thus critical and it shows how the UN’s in contradictory legitimation practices can reduce overall legitimacy perceptions