bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA53: Challenges of implementing interventions in “small populations.”
Authors: Srinivasan Shobha , Moser Richard P. , Willis Gordon , Riley William , Alexander Mark 
Published: October 2015

Abstract
The ability to harness the benefits of big data has had a revolutionary impact on science, with its focus on the volume and variety of data sources and application of both traditional and innovative analytic methods appropriate for large, aggregated datasets. We are concerned, however, about the opposite: small data for which the size, dispersion, or accessibility of the population of interest makes it difficult to obtain adequate sample sizes to test specific research questions. Data from these groups, however, are critical if we want to include health-related issues across all populations in cancer research.
An example of the potential negative ramifications of not including underrepresented groups in research or inappropriately aggregating them across groups-- comes from the study of racial and ethnic health disparities and issues of equity in the US. Intervention research often does not include a wide range of racial/ethnic subgroups; so it is not feasible to test whether an intervention created specifically for the majority group is also efficacious for the subgroups. Likewise, the ability to test whether an intervention can be altered for a particular subgroup is also often not possible. Epidemiologic and surveillance research usually involves the inclusion of “minority or underserved populations” in addition to white/non-Hispanic white (NHW) groups. While this has allowed for a better understanding of these smaller populations and provides some progress toward addressing health inequities, there remain pockets of communities that are severely underrepresented within the broader minority and underserved populations.
Citation Format: Shobha Srinivasan, Richard P. Moser, Gordon Willis, William Riley, Mark Alexander. Challenges of implementing interventions in “small populations.” [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr IA53.
Abstract PR13: Disparities in centrosomal profiles: Prediction of metastatic risk in African American and European American breast cancer patients
Authors: Wright Nikita , Pannu Vaishali , Rida Padmashree , Mittal Karuna , Klimov Sergey , Yada Farida N. , Reid Michelle D. , Cantuaria Guilherme , Aneja Ritu 
Published: October 2015

Abstract
Centrosome amplification has long been established as a hallmark of cancer. More than 80% of invasive breast tumors display this cellular trait. Centrosomal aberrations underlie chromosome instability (CIN) thus corroborating the extensive clonal intratumoral heterogeneity existent within breast lesions that fuels tumor evolution. Sub-clonal heterogeneity drives emergence of aggressive clones with a propensity to migrate and invade, resulting in tumor dissemination and metastases. Thus, centrosome amplification is a critical driver of tumor progression and metastases. Although numerous studies have linked centrosomal overload to tumor aggressiveness, no studies have yet quantified this cell-biological feature to establish a well-defined relationship between the severity and extent of centrosome amplification and tumor aggressiveness. Utilizing an innovative and rationally-guided approach, we have derived an algorithm that allows the precise quantitation of the frequency and severity of both structural and numerical aberrations in supernumerary centrosomes present in clinical samples. Our novel method thus uncovers previously unrecognized differences in the centrosomal profiles of grade-matched breast tumors from African-American (AA) (n=71) and European American (EA) (n=104) women. Our data demonstrate that AA breast tumors exhibit higher numeral, structural and total centrosome amplification scores than grade-matched EA tumors. Interestingly, tumors displaying lymph node and distant metastasis exhibited higher structural amplification than grade-matched non-metastatic tumors. Hence, our novel quantification tool offers valuable information that can potentially predict the risk of AA breast tumors rapidly progressing to metastatic disease and uncovers a hitherto unappreciated organelle-specific disparity marker among racially distinct breast tumors.
This abstract was also presented as Poster B6.
Citation Format: Nikita Wright, Vaishali Pannu, Padmashree Rida, Karuna Mittal, Sergey Klimov, Farida N. Yada, Michelle D. Reid, Guilherme Cantuaria, Ritu Aneja. Disparities in centrosomal profiles: Prediction of metastatic risk in African American and European American breast cancer patients. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr PR13.
Abstract A33: Utilizing insulin the treatment of prostate cancer with BKM120 abrogates the therapeutic effect of PI3K pathway inhibition
Authors: Wang Lily C. , Kim Sunnie S. , Nanus David M. , Cantley Lewis C. 
Published: October 2015

Abstract
Genetic aberrations in PTEN, the negative regulator of phosphoinositide 3-kinase (PI3K) signaling, are common in prostate cancers (PCA) with high Gleason Scores and correlate with adverse outcome. Currently, PI3K inhibitors, as single agents and in combination, have entered Phase I and II clinical trials for metastatic castrate resistant PCA. Alpha-specific and pan-PI3K inhibitors cause hyperglycemia as an on-target side effect by blocking insulin-dependent PI3K signaling in the liver and muscle and patients develop hyperinsulinemia in response to hyperglycemia, and insulin treatment is often needed to manage drug-induced hyperglycemia. Using human and murine prostate cancer cell lines, we examined the effect of adding insulin to BKM120 treatment on PI3K pathway activation.
Using human prostate cancer cell lines LNCaP and PC3 which both express insulin receptor (IR) and IGF-1 receptor (IGF-1R), we found downregulation of the PI3K pathway by BKM120 treatment and upregulation of the PI3K pathway by insulin treatment, as assessed by AKT phosphorylation. In both cell lines, the PI3K pathway is reactivated when insulin is added to BKM120 treatment. Using cells derived from PTEN-/-P53-/- murine PCA which express low levels of IR and IGF-1R, we found minimal activation of the PI3K pathway with insulin, either alone or in combination with BKM120. Conversely, using cells derived from Myc-overexpressing mice which express high levels of IR and IGF-1R, we found robust activation of the PI3K pathway with insulin treatment. More importantly, while BKM120 abolished PI3K activity in the Myc-overexpressing cells, the addition of insulin to BKM120 resulted in the reactivation of the PI3K pathway to the level of PI3K pathway activity without BKM120 treatment. Together these findings suggest that the use of insulin in combination with BKM120 abrogates the therapeutic effect of PI3K inhibition. In addition, they indicate that PCAs that have high levels of IR and/or IGF-1 expression are particularly sensitive to PI3K inhibitors as well as insulin reactivation of the PI3K pathway.
Citation Format: Lily C. Wang, Sunnie S. Kim, David M. Nanus, Lewis C. Cantley. Utilizing insulin the treatment of prostate cancer with BKM120 abrogates the therapeutic effect of PI3K pathway inhibition. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr A33.
Abstract A39: PI3K inhibition in preclinical models of HNSCC
Authors: Hedberg Matthew Louis , Li Hua , Zeng Yan , Grandis Jennifer Rubin 
Published: October 2015

Abstract
Head and neck squamous cell carcinoma (HNSCC) is characterized by alteration of the PI3K pathway; especially mutation and/or amplification of the oncogene PIK3CA, and these alterations are enriched in HNSCC associated with human papilloma virus infection (HPV(+)HNSCC). We sought to test the hypothesis that HNSCC cells/tumors with mutant or amplified PIK3CA are more sensitive to anti-tumor effects of PI3K pathway inhibitors, including BKM-120 and BYL-719, and to assess the effect of HPV status on the efficacy of these agents. Proliferation assays and immunobloting were employed to examine the effects on growth and signaling of BKM-120 and BYL-719 administration to HNSCC cell lines with endogenous PIK3CA mutation, gene amplification, or WT, unamplified PIK3CA. The cytotoxic effects of BKM-120 and BYL-719 were comparable in a panel of 8 HNSCC cell lines, with IC50s in the micromolar range. BYL-719 demonstrated greater cytotoxic activity in cell lines with endogenous PIK3CA alterations compared with cells harboring endogenous WT, unamplified PIK3CA. Treatment with BKM-120 decreased the levels of phosphorylated AKT in a dose-dependent fashion to a greater degree in PIK3CA altered cells than in PIK3CA WT cells. In contrast, BYL-719 treatment inhibited phosphorylation of AKT in both PIK3CA altered and PIK3CA WT HNSCC cells, with comparable efficacy. Phosphorylation of S6 and MTOR however, was inhibited by BYL-719 to a greater degree in PIK3CA altered cell lines vs. PIK3CA WT cell lines. More than half of all HPV(+)HNSCC harbor some form of PI3K alteration; generally PIK3CA mutation or amplification. However, there is a paucity of HPV(+)HNSCC cell lines, and no cell lines to date derived from HPV(+)HNSCC tumors contain PIK3CA mutations. Although we included two HPV(+)HNSCC cell lines in our studies, neither are known to harbor endogenous PIK3CA mutations, and they did not appear to be more sensitive to PI3K pathway targeting with BKM-120 or BYL-719. Our in vivo treatment experiments, utilizing patient derived xenografts (PDX) of varying HPV and PIK3CA status, demonstrate that the growth of HPV(+)HNSCC tumors can be inhibited by BYL-719 treatment to a greater degree than the growth of HPV(-)HNSCC tumors. These cumulative findings suggest that PI3K inhibition may represent an effective therapeutic strategy in the subset of HNSCC patients whose tumors harbor PI3K alteration. As the PI3K pathway is the most commonly altered mitogenic pathway in HNSCC; the completion of this work, and its extension into clinical trials, will likely have translational significance.
Citation Format: Matthew Louis Hedberg, Hua Li, Yan Zeng, Jennifer Rubin Grandis. PI3K inhibition in preclinical models of HNSCC. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr A39.
Abstract B04: NPM1: A new downstream effector of PI3K-AKT-mTOR pathway in prostate cancer?
Authors: Boudra Rafik , Loubeau Gaelle , Lours-Calet Corinne , Dejoussineau Cyrille , Morel Laurent , Beaudoin Claude 
Published: October 2015

Abstract
Nucleophosmin NPM1 is a molecular chaperone involved in many aspect of cellular physiology, eg. ribosomal biogenesis and cell cycle regulation. NPM1 is overexpressed in numerous types of solid tumors, including prostate cancer but the underlying molecular mechanisms are largely unknown. Using both cell lines and transgenic mouse models, we show that NPM1 expression is significantly increased in cells where the PI3K-AKT-mTOR pathway is activated through PTEN deletion. This overexpression is reversed when cells are treated with the pharmacological inhibitor of mTOR rapamycin. In accordance, transfection of small interfering RNA (siRNA) directed against mTOR leads to mTOR and NPM1 downregulation in these cells. In vivo, we found that NPM1 is overexpressed in PTEN knock-out murine prostate, and a one week treatment of these mice with rapamycin leads to NPM1 downregulation. Chromatin Immunoprecipitation (ChIP) assays show that mTOR is localized on NPM1 proximal promoter, close to a binding site for the transcription factor Ying-Yang 1 (YY1). mTOR binding on the chromatin seems to be constitutive, since rapamycin treatment did not alter its localization. mTOR could therefore regulates NPM1 expression by phosphorylating others factors involved in NPM1 gene expression, as previously described (Cunningham et al., 2007). We have previously shown that NPM1 overexpression enhance the migration and invasion abilities of prostate cancer cells (Loubeau et al., 2014). Moreover, NPM1 overexpression in mouse prostate epithelium leads to p27 protein downregulation and cyclin E upregulation, two molecular features of aggressive human prostate cancer. We thus propose that NPM1 could be a downstream effector of PI3K-AKT-mTOR pathway, supporting prostate cancer progression by altering expression of a set of genes involved in cellular homeostasis and proliferation.
Citation Format: Rafik Boudra, Gaelle Loubeau, Corinne Lours-Calet, Cyrille Dejoussineau, Laurent Morel, Claude Beaudoin. NPM1: A new downstream effector of PI3K-AKT-mTOR pathway in prostate cancer? [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B04.
Abstract B19: Short chain fatty acids suppress mTOR activation in colon cancer cells via the long noncoding RNA rhabdomyosarcoma 2 associated transcript
Authors: Wang Jiuhui , Nie Daotai 
Published: October 2015

Abstract
Short chain fatty acids (SCFAs), derived from dietary fiber bacterial fermentation in the colon, exert multiple effects on colonic functions including tumor suppressing activities. Our previous studies found that SCFAs can induce autophagy in colon cancer cells via suppressing mTOR activities, but the mechanism involved is not well understood. Herein we identify rhabdomyosarcoma 2 associated transcript (RMST), a long non-coding RNA, and protein tyrosine phosphatase non-receptor type 7(PTPN7) as key mediators for SCFAs to suppress mTOR signaling. SCFAs induce the expression of RMST in colon cancer cells. RMST by itself is sufficient to suppress mTOR signaling and sensitize colon cancer cells to SCFAs induction of autophagy. Through profiling, PTPN7 was identified as an effector for both RMST and SCFAs to suppress mTOR signaling. RMST increases the expression of PTPN7 by recruiting RNAPII to its promoter region. The data delineate a novel RMST-PTPN7 cellular pathway, enlisted by SCFAs, to modulate mTOR activities.
Citation Format: Jiuhui Wang, Daotai Nie. Short chain fatty acids suppress mTOR activation in colon cancer cells via the long noncoding RNA rhabdomyosarcoma 2 associated transcript. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B19.
Abstract B23: The 5 UTR of many oncogenes and transcription factors encodes a targetable dependence on the eIF4A RNA helicase
Authors: Singh Kamini , Wolfe Andrew L. , Zhong Yi , Rätsch Gunnar , Wendel Hans-Guido 
Published: October 2015

Abstract
We report a mechanism of translational control that is determined by a requirement for eIF4A RNA helicase activity and underlies the anticancer effects of Silvestrol and related compounds. Briefly, activation of cap-dependent translation contributes to T-cell leukemia (T-ALL) development and maintenance. Accordingly, inhibition of translation initiation factor eIF4A with Silvestrol produces powerful therapeutic effects against T-ALL in vivo. We used transcriptome-scale ribosome footprinting on Silvestrol-treated T-ALL cells to identify Silvestrol-sensitive transcripts and the hallmark features of eIF4A-dependent translation. These include a long 5 UTR and a 12-mer sequence motif that encodes a guanine quartet (CGG)4. RNA folding algorithms as well as experimental evidences pinpoint the (CGG)4 motif as a common site of RNA G-quadruplex structures within the 5 UTR. In T-ALL these structures mark approximately eighty highly Silvestrol-sensitive transcripts that include key oncogenes and transcription factors and contribute to the drug's anti-leukemic action. Hence, the eIF4A-dependent translation of G-quadruplex containing transcripts emerges as a gene-specific and therapeutically targetable mechanism of translational control.
Citation Format: Kamini Singh, Andrew L. Wolfe, Yi Zhong, Gunnar Rätsch, Hans-Guido Wendel. The 5 UTR of many oncogenes and transcription factors encodes a targetable dependence on the eIF4A RNA helicase. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B23.
Abstract B28: Rictor/mTORC2 drives formation, progression, and therapeutic resistance of HER2-amplified breast cancers
Authors: Morrison Meghan M. , Jones Bayley A. , Hicks Donna J. , Sanchez Violeta , Estrada Valeria M. , Williams Michelle M. , Brantley-Sieders Dana , Cook Rebecca S. 
Published: October 2015

Abstract
Although HER2-targeted therapies substantially improve the outcome for patients with HER2-amplified breast cancer, resistance to HER2 targeting is frequently observed. HER2-amplified tumors depend on the HER2-mediated activation of the phosphatidylinositol-3kinase (PI3K)/Akt pathway, which becomes reactivated in many therapeutically resistant HER2-amplified tumors. We investigated the mTOR complexes mTORC1 and mTORC2 as potential therapeutic targets in HER2-amplified breast cancers, based on their roles as activators (mTORC2) or effectors (mTORC1) of Akt. We found that genomic gains in Rictor, encoding a necessary mTORC2 cofactor, correlated with poor survival in breast cancer patients, while genomic gains in Raptor, an mTORC1 cofactor, did not. Rictor protein levels were increased in invasive breast cancers as compared to ductal carcinoma in situ (DCIS). Conditional Rictor gene ablation decreased growth, cell survival and invasion of human HER2-amplified breast cancer cells by blocking Akt signaling. Treatment of HER2 positive cells with the HER2/EGFR inhibitor Lapatinib caused Rictor upregulation. However, Rictor knockdown improved cell killing in Lapatinib-treated cells and impaired Akt signaling and cell survival in Lapatinib-resistant HER2 positive breast cancer cells. Together, these results demonstrate the pivotal role of mTORC2 in HER2-amplified breast cancers and support efforts to develop mTORC2-targeted therapies.
Citation Format: Meghan M. Morrison, Bayley A. Jones, Donna J. Hicks, Violeta Sanchez, Valeria M. Estrada, Michelle M. Williams, Dana Brantley-Sieders, Rebecca S. Cook. Rictor/mTORC2 drives formation, progression, and therapeutic resistance of HER2-amplified breast cancers. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B28.
Abstract B37: Mechanisms of acquired resistance to the PI3K inhibitor GDC-0941 in breast cancer cell lines
Authors: Edgar Kyle A. , Hwu Ling , Walter Kimberly , Lackner Mark , Friedman Lori S. , Wallin Jeffrey J. 
Published: October 2015

Abstract
Alterations of the phosphoinositide-3 kinase (PI3K)/Akt signaling pathway occur broadly in cancer via multiple mechanisms including mutation of the PIK3CA gene or loss of the tumor suppressor PTEN. The dysregulation of this pathway has been implicated in tumor initiation, cell growth and survival, invasion and angiogenesis, thus, PI3K is a promising therapeutic target for cancer. There are several PI3K inhibitors in clinical trials and the current study was intended to investigate preclinical mechanisms of acquired resistance to GDC-0941, a class I selective PI3K inhibitor. GDC-0941 resistant pools and clones were generated in both EVSA-T and HCC-1954 breast cancer cell lines by treating cells with increasing concentrations of drug. We found that resistant clones from both lines demonstrated marked increase of downstream PI3K pathway signaling and upregulation of the MAPK pathway, through two different mechanisms. In HCC-1954, autocrine signaling to EGFR was observed in the resistant clones and resulted in increased dependency on the downstream factor c-Myc. EVSA-T clones with acquired resistance to GDC-0941 had elevated HER2 copy number and protein expression levels. A corresponding increase in phosphorylation of HER2 binding partner ErbB3 was also discovered in the EVSA-T resistance cells. In both cases sensitivity to PI3K inhibition was restored by blocking the activated upstream receptor tyrosine kinase, EGFR for HCC-1954 and HER2 for EVSA-T. Additionally both models were re-sensitized to GDC-0941 by blocking downstream signaling of the MAPK pathway. These preclinical data may provide rationale for combination therapy with PI3K inhibitors in the clinic.
Citation Format: Kyle A. Edgar, Ling Hwu, Kimberly Walter, Mark Lackner, Lori S. Friedman, Jeffrey J. Wallin. Mechanisms of acquired resistance to the PI3K inhibitor GDC-0941 in breast cancer cell lines. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B37.