bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract SY29-03: The impact of aerobic exercise on breast cancer progression
Authors: Nelson Erik R. 
Published: August 2018

Abstract
In 1924, Otto Warburg first postulated that cancer was caused by altered metabolism, specifically the reliance of cancer cells on glycolysis. Since then, this altered metabolism has been recognized as a "hallmark of cancer," with numerous studies supporting this. It is now clear that pathologies resulting in perturbed homeostasis at the level of the organism, such as obesity, diabetes, and hypercholesterolemia, are also associated with tumor progression. Since aerobic exercise is known to alter systemic homeostasis, we reasoned that it may also impact tumor progression. In this regard, emerging epidemiologic evidence indicates an inverse correlation between exercise and the onset of many forms of cancer, including breast cancer. Intriguingly, several studies have found that self-reported physical activity is associated with decreased recurrence. We have now directly tested the impact of exercise on the progression of breast cancer, using several murine models of mammary cancer, finding that exercise significantly reduces tumor growth and metastasis. Subsequent work has been focused on delineating the molecular mechanisms by which exercise hinders the progression of breast cancer. We will discuss these results and present our current understanding of how exercise influences tumor pathophysiology. Collectively, our work suggests that aerobic exercise may offer an effective complementary adjunct therapy with current standard of care.
Citation Format: Erik R. Nelson. The impact of aerobic exercise on breast cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY29-03.
Abstract 17: In situ immune expression signatures before and after ipilimumab therapy for relapsed acute myeloid leukemia after allogeneic stem cell transplantation
Authors: Bachireddy Pavan , Davids Matthew S. , Rooney Michael S. , Bowden Michaela , Zhou Chensheng W. , Rodig Scott J. , Ho Vincent , Antin Joseph , Koreth John , Alyea Edwin , Soiffer Robert J. , Wu Catherine J. 
Published: August 2018

Abstract
Immune evasion may facilitate hematologic relapse after allogeneic hematopoietic stem cell transplantation (allo-SCT). We recently demonstrated that CTLA4 blockade with ipilimumab reinvigorates a graft-versus-leukemia effect to induce complete remissions of acute myeloid leukemia (AML) relapsing after allo-SCT. Here, we hypothesized that immune subpopulation dynamics and activation states inferred from in situ gene expression changes within the leukemic microenvironment are informative of clinical outcome. We undertook an in situ transcriptomic characterization of paired, pre/post ipilimumab leukemic biopsies from five samples with relapsed, extramedullary AML. We performed a response-to-treatment expression analysis for each patient and found three immune patterns corresponding to three clinical response patterns following ipilimumab (durable response, relapse, and primary resistance). Durable responses were characterized by a diverse infiltration of activated cytotoxic T lymphocytes, B cells, and macrophages. In contrast, primary resistance was associated with both marked infiltration of CD8 T cells deficient in T-cell receptor signaling, activation, or cytolytic activity and absent infiltration of other immune effectors. Interestingly, the sample with transient response and eventual relapse demonstrated pre- and post-treatment immunologically “inflamed” states that were strongly downregulated during clinical relapse. In situ gene expression analyses of leukemic biopsies before and after ipilimumab therapy suggest that specific patterns of immune population dynamics and activation states underlie diverse clinical outcomes.
Citation Format: Pavan Bachireddy, Matthew S. Davids, Michael S. Rooney, Michaela Bowden, Chensheng W. Zhou, Scott J. Rodig, Vincent Ho, Joseph Antin, John Koreth, Edwin Alyea, Robert J. Soiffer, Catherine J. Wu. In situ immune expression signatures before and after ipilimumab therapy for relapsed acute myeloid leukemia after allogeneic stem cell transplantation [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr 17.
Abstract 50: Small molecule Ring1B-Bmi1 inhibitor attenuates PRC1 E3 ligase activity and targets leukemia stem cells self-renewal
Authors: Shukla Shirish , Gray Felicia , Ying Weijiang , Cho Hyoje , Zhao Qingjie , Miao Hongzhi , Miao Hongzhi , Purohit Trupta , Guzman Monica , Grembecka Jolanta , Cierpicki Tomasz 
Published: August 2018

Abstract
Polycomb group proteins, Ring1B and Bmi1 constitute catalytic component of Poly-comb Repressive Complex 1(PRC1) and execute gene silencing through histone H2A lysine119 ubiquitination (H2AK119ub). Bmi1 is overexpressed in a wide range of human cancers and has been implicated in regulation of leukemic stem cells (LSCs) self-renewal capacity. LSCs are refractory to the conventional therapies and eventually lead to the disease relapse. Small-molecule inhibitors of the Ring1B-Bmi1 E3 ligase activity have not been reported to date, but are highly desired as potential therapeutic agents to target LSCs. In the present study, employing fragment-based screening and extensive medicinal chemistry optimization, we developed WY332 that binds to Ring1B-Bmi1 with low micromolar affinity. Extensive characterization of the WY332 demonstrated selective reduction in Ring1B-Bmi1 mediated H2AK119ub levels in vitro and in leukemic cells whereas structurally similar and less potent compound displayed similar effect at much higher concentrations. Treatment of model cell lines, TEX and M9:ENL1, enriched in leukemia initiating cells show that the reduction in H2AK119ub levels is associated with induction of cellular differentiation and altered colony-forming potential. Further, gene expression analysis of TEX cells treated with WY332 indicated reprogramming of CD34+ cells and revealed significant increase in expression of genes suppressed in LSCs. In addition, WY332 treatment led to a marked increase in CD11b expression and significantly decreased CD34 expression in TEX cells. Evaluation of WY332 in patients' derived primary AML cells further revealed reprogramming of gene expression profile and phenotypic markers associated with LSCs self-renewal property. Overall, these compounds represent the novel small-molecule inhibitors of Ring1B-Bmi1 which inhibit E3 ubiquitin ligase activity and impair leukemic stem cell self-renewal capacity.
Citation Format: Shirish Shukla, Felicia Gray, Weijiang Ying, Hyoje Cho, Qingjie Zhao, Hongzhi Miao, Hongzhi Miao, Trupta Purohit, Monica Guzman, Jolanta Grembecka, Tomasz Cierpicki. Small molecule Ring1B-Bmi1 inhibitor attenuates PRC1 E3 ligase activity and targets leukemia stem cells self-renewal [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr 50.
Abstract IA09: Targeting the CRL4CRBN E3 ligases for treatment of hematologic cancers
Authors: Chopra Rajesh 
Published: August 2018

Abstract
Manipulation of the ubiquitin-proteasome system to achieve targeted degradation of proteins within cells using chemical tools and drugs has the potential to transform pharmacologic and therapeutic approaches in cancer and other diseases. Thalidomide and its analogues lenalidomide and pomalidomide exert their mechanism of action through the modulation of the CRL4CRBN E3 ligase family. Binding of the thalidomide to analogues Cereblon (CRBN) results in the degradation of neomorphic protein such as Aiolos and iKaros in multiple myeloma. This degradation explains the antitumor activity as well as the immunomodulatory effects of these drugs. The degradation of multiple context-specific proteins by the thalidomide analogues provides a means to uncover new cell biology as well as generate future drug molecules against currently undruggable targets. In parallel, the development of larger bifunctional molecules that bring together highly specific protein targets in complexes with Cereblon, von Hippel-Lindau or other E3 ligases to promote ubiquitin-dependent degradation has progressed to generate selective chemical compounds with potent effects in cells and in vivo models, providing valuable tools for biological target validation and with future potential for therapeutic use. This presentation will survey recent breakthroughs achieved in these two complementary methods, with a greater focus of CRL4CRBN modulation.
Citation Format: Rajesh Chopra. Targeting the CRL4CRBN E3 ligases for treatment of hematologic cancers [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr IA09.
Abstract IA15: Genetic predisposition to hematopoietic malignancies
Authors: Godley Lucy A. 
Published: August 2018

Abstract
There is a growing appreciation for the impact of baseline genetic variants in the development of hematopoietic malignancies, and the germline risk factors that make an individual more susceptible to developing bone marrow-derived cancers are being defined through highly informative families and next-generation sequencing with increasing frequency. At the University of Chicago, we use a rigorous pipeline for clinical testing of individuals comprising next-generation sequencing-based molecular testing to detect point mutations as well as microarrays to detect chromosomal rearrangements. Overall, we are now able to identify the causative germline mutation in about 20% of cases, a level commensurate with other cancer risk clinics, but hinting that additional predisposition alleles remain to be discovered. Many of our patients/families also contribute to research by banking samples for future studies designed to identify new predisposition syndromes. This presentation will include a discussion of the new insights into hematopoietic biology that can be appreciated by studying these emerging predisposition syndromes.
Citation Format: Lucy A. Godley. Genetic predisposition to hematopoietic malignancies [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr IA15.
Abstract A31: Mutant p53 increases integrin-ECM interactions in early HGSOC
Authors: Lecker Laura SM , Trevisan Caterina , Delaine-Smith Robin , Maniati Eleni , Pearce Oliver , Meinert Christoph , Iwanicki Marcin , Drapkin Ronny , Loessner Daniela , Balkwill Frances 
Published: August 2018

Abstract
Until recently, it was thought that high-grade serous ovarian cancer (HGSOC) arises from the ovarian surface epithelium (OSE). Now, it has become clear that the epithelium of the fallopian tube fimbriae is the starting point of many HGSOCs. Serous tubal intraepithelial carcinomas (STICs) are suggested to be the earliest form of HGSOC and show mutations in the p53 gene. Part of the neoplastic transformation into invasive HGSOC may be the initial adhesion of STIC cells to the surface of the ovary as a first site of metastasis. To examine the role of mutant p53 immortalized fallopian tube secretory epithelial (FTSE) cells in the early onset of HGSOC, we used mechanically tunable hydrogels and developed a protocol to obtain decellularized human ovary scaffolds for 3D cell cultures. Stable expression of mutant p53 in FTSE cells promoted adhesion to hydrogel matrices and invasion into decellularized ovary scaffolds. Next, we sought to analyze the extracellular matrix (ECM) landscape of human fallopian tube and ovary tissues and identified proteins with a high affinity to integrin αvβ3. Mutant p53 FTSE cells had increased levels of integrin αvβ3 and decreased adhesive potential upon integrin αvβ3 blockage compared to wild-type FTSE cells. The results indicate that FTSE cells expressing mutant p53 upregulate integrin expression, which in turn alters their tissue-specific ECM interactions. Our findings give new insights in the early onset of HGSOC and may help to understand the role of p53 in the cells of origin of HGSOC.
Citation Format: Laura SM Lecker, Caterina Trevisan, Robin Delaine-Smith, Eleni Maniati, Oliver Pearce, Christoph Meinert, Marcin Iwanicki, Ronny Drapkin, Daniela Loessner, Frances Balkwill. Mutant p53 increases integrin-ECM interactions in early HGSOC. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A31.
Abstract B08: Urinary PGE-M levels and risk of ovarian cancer
Authors: Barnard Mollie E. , Eliassen A. Heather , Rosner Bernard A. , Terry Kathryn L. , Milne Ginger L. , Tworoger Shelley S. 
Published: August 2018

Abstract
Introduction: Prostaglandin E2 (PGE2) is thought to influence ovarian carcinogenesis by increasing cell proliferation, tumor cell invasiveness, and angiogenesis. PGE-M is the major metabolite of PGE2 and a marker of systemic PGE2 production. Prior research has reported positive associations between urinary PGE-M and risk of colorectal, gastric, lung, pancreatic, and breast cancer; however, this is the first study to evaluate the association between urinary PGE-M and risk of ovarian cancer.
Methods: We conducted a prospective case-control study nested in the Nurses’ Health Study (NHS) and NHSII cohorts. We included 194 cases of invasive epithelial ovarian cancer and 387 matched controls. All cases were diagnosed between the time of urine specimen collection (1996-97 NHSII; 2000-2002 NHS) and the end of follow-up (2015). Controls were selected using incidence density sampling and matched to cases on year of birth, menopausal status at collection and diagnosis, date and time of day of collection, hormone therapy use at collection, and fasting status. We measured PGE-M levels using LC/MS methods, and used the PGE-M distribution among controls to identify tertile cutpoints. We estimated the association between prediagnosis urinary PGE-M (in tertiles) and risk of ovarian cancer using conditional logistic regression.
Results: We observed a suggestively lower risk of ovarian cancer for those with the highest PGE-M levels in NHS (OR=0.66; 95%CI=0.36-1.21; p-trend=0.15; n=123 cases), and no association in NHSII (OR=1.15; 95%CI=0.50-2.67; p-trend=0.75; n=71 cases). When results from the two cohorts were pooled, we observed nonsignificant, lower odds of ovarian cancer among those in the highest tertile of PGE-M compared to the lowest tertile (OR=0.80; 95%CI=0.50-1.27; p-trend=0.34), particularly after restricting our analysis to study participants who provided first morning urine samples (OR=0.68; 95%CI=0.40-1.14; p-trend=0.13). However, when we examined quartiles, no clear association was observed, although power was limited.
Conclusions: Overall, our results suggest that higher prediagnosis PGE-M levels are not associated with an increased risk of ovarian cancer. Further analyses are under way to evaluate the potential for effect modification by menopausal status, BMI, and NSAID use.
Citation Format: Mollie E. Barnard, A. Heather Eliassen, Bernard A. Rosner, Kathryn L. Terry, Ginger L. Milne, Shelley S. Tworoger. Urinary PGE-M levels and risk of ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B08.
Abstract B25: Hormone receptor expression and response in ovarian tumors of low malignant potential
Authors: Taylor Sarah E. , Andersen Courtney L. , Bhargava Rohit , Tseng George , Oesterreich Steffi , Edwards Robert P. , Lee Adrian V. 
Published: August 2018

Abstract
Objective: Primary treatment for ovarian low malignant potential (LMP) tumors is surgical resection with little proven effect of cytotoxic chemotherapy. New therapeutic strategies are needed to prevent and treat recurrence. The objective of this study is to investigate the role of hormone receptors in ovarian low malignant potential tumors.
Methods: We obtained formalin-fixed, paraffin embedded (FFPE) tissue samples from patients with ovarian LMP tumors. Clinicopathologic data were collected for all available specimens. Immunohistochemistry (IHC) was performed to determine protein expression. Gene expression was measured using the NanoString nCounter platform. Differences in expression between histologic subtypes were by t-test, followed by a Bonferroni adjustment for multiple comparisons (p&lt;0.01).
Results: Thirty-eight patients were included in this study. The histologic subtypes were divided between 20 serous and 18 mucinous tumors. All serous tumors were ERα and PR positive by IHC and 6 of 20 (30%) were ERβ positive. Only one of the 18 mucinous tumors (5.6%) was positive for both ERα and PR, and all the samples were negative for ERβ. ERβ mRNA levels were elevated in the mucinous LMP tumors and ERα mRNA was higher in the serous samples. ERα and PR protein expression correlated with mRNA expression of ESR1 (r2=0.5606) and PR (r2=0.42), respectively. ERβ expression did not correlate with mRNA expression of ESR2 (r2=0.038). Measurement of estrogen-regulated genes and genes involved in ER signaling (n=236) revealed a clear separation of serous from mucinous subtypes, with 44 genes showing a statistically significant difference (p&lt;0.01) between the serous and mucinous subtypes.
Conclusion: High levels of ERα, PR, and downstream ERα targets in serous LMP tumors suggest hormone responsiveness and that these tumors are potentially treatable with endocrine therapy. Mucinous tumors largely did not express hormone receptors. In light of this, differences in gene expression observed are more likely attributable to underlying lineage differences than differences in estrogen signaling. Additional large-scale analyses are warranted to better understand the differences between subtypes and to identify avenues for targeted therapy in mucinous LMPs.
Citation Format: Sarah E. Taylor, Courtney L. Andersen, Rohit Bhargava, George Tseng, Steffi Oesterreich, Robert P. Edwards, Adrian V. Lee. Hormone receptor expression and response in ovarian tumors of low malignant potential. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B25.
Abstract B71: New directions in gynecologic cancer research utilizing Text Information Extraction System (TIES) Cancer Research Network
Authors: Linkov Faina Y. , Schwenk Melissa , Davis Michael , Edwards Robert , Becich Michael 
Published: August 2018

Abstract
Gynecologic cancers pose significant morbidity and mortality burden for US women. Endometrial cancer is the most common gynecologic malignancy in the US, while ovarian cancer is one of the deadliest. Since research funding for some of the gynecologic malignancies has been limited, novel research on the existing datasets needs to be harnessed to improve the health of the women affected by these conditions. We aim to evaluate if Text Information Extraction System (TIES) Cancer Research Network, a federated network that facilitates data and biospecimen sharing among member institutions, has capabilities for conducting research in the area of gynecologic cancers.
TIES system provides effective tools for searching deidentified structured and unstructured data for gynecologic cancers with capabilities to explore pathology and radiology records. We used TIES system to identify records of patients with ovarian, endometrial, and cervical cancers. We used temporal search features to identify patients who developed ovarian tumors after being diagnosed with endometrial tumors. We examined records for completeness of information on diagnosis, age, and procedure year.
We found that TIES system has 13,762 records for endometrial cancer, 7,692 records for ovarian cancer, and 10,826 records for cervical cancer for Pittsburgh site. 306 records have been identified for patients who had both ovarian and endometrial malignancies. Nearly 100% of the records had information on age of the patient, year of the procedure, and exact diagnosis.
TIES is a promising tool for conducting research in the area of gynecologic malignancies, especially for rare diseases such as concurrent endometrial and ovarian cancers. Existing data repositories like TIES need to be further explored for novel research questions in the area of gynecologic cancer.
Citation Format: Faina Y. Linkov, Melissa Schwenk, Michael Davis, Robert Edwards, Michael Becich. New directions in gynecologic cancer research utilizing Text Information Extraction System (TIES) Cancer Research Network. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B71.
Abstract IA10: Deconstructing and reconstructing the ovarian cancer microenvironment
Authors: Balkwill Frances R. 
Published: August 2018

Abstract
The tumor microenvironment (TME) is critical for cancer growth and spread. However, the relationships between molecular components of the TME and higher-order features, tissue stiffness, extent of disease, and cellularity are not known. Using clinical samples of metastatic high-grade serous ovarian cancer (HGSOC) that ranged from minimal to extensive disease, we have defined RNA and protein profiles that evolved with these higher-order features.
We obtained a unique profile of the evolving metastatic microenvironment of HGSOC that includes data not only on gene expression and proteomics but also cytokine/chemokine expression, ECM organization, and biophysical properties. This “deconstruction” of a metastatic microenvironment provides a critical reference for our mouse model systems and a template for reconstruction of 3D multicellular human ovarian cancer models as will be detailed in this presentation.
Although our work was conducted on omental metastases of HGSOC, we found evidence for a conserved mechanism that may be relevant to many human solid tumors: a pattern of matrix-associated gene expression that we termed the matrix index. In the HGSOC samples, the matrix index significantly associated with various leukocyte signaling pathways of cells associated with poor prognosis including Th2 cells and macrophage-associated genes and correlated with extent of disease and tissue stiffness. Interrogating transcriptional datasets from a wide range of human solid cancers, including HGSOC, we found that the matrix index had prognostic significance irrespective of patient age, stage of disease, or first response to therapy. This led us to suggest that there may be a common matrix response to human cancer.
Citation Format: Frances R. Balkwill. Deconstructing and reconstructing the ovarian cancer microenvironment. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA10.