bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B034: Time to treatment and overall survival among men with localized prostate cancer
Authors: Pierre-Victor Dudith , Pinsky Paul , Martin Iman K. , McCaskill-Stevens Worta 
Published: February 2019

Abstract
Background: Prostate cancer is the second most common cancer diagnosed among men in the United States. Delays from the time of confirmed diagnosis to primary treatment are more common for prostate compared to other malignancies. The objective of this study was to investigate factors associated with time to treatment and the effect of time to treatment on overall survival among men with early-stage prostate cancer.
Methods: From the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, men diagnosed with localized prostate cancer who received treatment within a year of diagnosis were selected for analysis (N=6,349). Selected men had date of diagnosis, treatment date, and mortality status as of 2012. We investigated sociodemographic and clinical factors associated with time to treatment using Cox regression. We also used Cox regression to examine the effect of time to treatment on overall survival. Covariates included Gleason score, PSA level, age at diagnosis, employment status, education level, race, marital status, and comorbidity burden.
Results: The median time to treatment was 73 (IQR: 44-120) days. Demographic factors associated with longer time to treatment included being Black (adjusted hazard ratio (aHR)= 0.85, 95%CI: 0.76-0.95), having some college education (aHR= 0.91, 95%CI: 0.85-0.97), and having a baccalaureate degree or a post-baccalaureate degree (aHR= 0.89, 95% CI: 0.84-0.95). Clinical factors associated with longer time to treatment were being diagnosed at an older age (aHR= 0.86, 95%CI:0.80-0.93 for age of 70-74 years and aHR= 0.80, 95%CI: 0.74-0.87 for 75 year and older) and having an elevated PSA level (HR=0.89, 95%CI: 0.81-0.94 for third PSA quartile (6.11-9.0) and HR=0.87, 95%CI: 0.81-0.94 for fourth PSA quartile (9.0 and above). Gleason score and comorbidity burden were not associated with time to treatment. Being married (aHR=1.11, 95%CI: 1.03-1.19) and being retired (aHR=1.09, 95%CI:1.034-1.16) were associated with shorter time to treatment. After adjusting for sociodemographic and clinical characteristics, time to treatment did not have a significant effect on overall survival.
Conclusions: College education, being Black, older age at diagnosis, and higher PSA levels were associated with longer time to treatment. Being married and being retired were associated with shorter time to treatment. Longer time to treatment was not associated with overall mortality among PLCO men with localized prostate cancer.
Citation Format: Dudith Pierre-Victor, Paul Pinsky, Iman K. Martin, Worta McCaskill-Stevens. Time to treatment and overall survival among men with localized prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B034.
Abstract B038: Convergent hormone therapy resistance mediated by stress/dormancy-like pathways in prostate cancer
Authors: Ware Kathryn E. , Gupta Santosh , Eng Jared , Foo Wen-Chi , Crawford Lorin , Austin Garland , Puviindran Bhairavy , Freedman Jennifer , Patierno Steven R. , Zhang Tian , Corcoran David , Pierobon Mariaelena , Petricoin Emanuel , Somarelli Jason A. , Armstong Andrew J. 
Published: February 2019

Abstract
Background: Novel agents that inhibit the androgen receptor (AR), including abiraterone acetate and enzalutamide, have significantly prolonged life in many men with metastatic castration-resistant prostate cancer (mCRPC). However, after 1-2 years of therapy acquired resistance to these drugs is nearly universal. Therefore, identifying mechanisms of resistance and innovative therapies to treat enzalutamide-resistant disease represents a major unmet clinical need.
Methods: In this study, we developed four enzalutamide-resistant cell lines and analyzed each cell line by RNA-seq and phospho-proteomics to identify common pathways deregulated during disease progression to enzalutamide resistance. We manipulated p38 levels and activity in order to determine its mechanistic relationship to resistance. We measured p38 activity in metastatic biopsies from men with both hormone-sensitive and metastatic prostate cancer.
Results: At the nexus of acquired enzalutamide resistance in four independently derived prostate cancer model systems, we identified a convergent mechanism of resistance through activation of the p38 stress response/dormancy pathway. Enzalutamide-resistant cells are sensitized to p38 inhibition, and enzalutamide- sensitive cells developed resistance to enzalutamide with constitutive activation of p38 signaling. Enzalutamide-resistant cells have sustained AR activity, which is blocked with genetic or small-molecule p38 inhibition, indicating that p38 promotes AR activity in the absence of ligand binding. Finally, we found common activation of p38 in lymph node, visceral, and bone metastases from men with mCRPC.
Conclusions: We have identified the stress response/dormancy p38-signaling pathway as a common mechanism driving enzalutamide resistance. Most importantly, p38 is a targetable pathway activated in tumors from men with mCRPC, suggesting that novel therapeutic strategies could be applied to prolong the lives of men with metastatic, drug-resistant prostate cancer.
Citation Format: Kathryn E. Ware, Santosh Gupta, Jared Eng, Wen-Chi Foo, Lorin Crawford, Garland Austin, Bhairavy Puviindran, Jennifer Freedman, Steven R. Patierno, Tian Zhang, David Corcoran, Mariaelena Pierobon, Emanuel Petricoin, Jason A. Somarelli, Andrew J. Armstong. Convergent hormone therapy resistance mediated by stress/dormancy-like pathways in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B038.
Abstract B061: Alternative RNA splicing and prostate cancer aggressiveness
Authors: Abo Muthana Al , Patierno Steven R. , Freedman Jennifer A. 
Published: February 2019

Abstract
Prostate cancer (PCa) is the most common cancer in men in the United States. Aggressive pathology, metastasis, and drug resistance of cancer cells are the most important prognostic factors for patients with PCa. African Americans (AAs) suffer disproportionately from PCa, with higher aggressiveness, progression, and mortality. A recently published analysis involving our laboratory reported more than 2,500 alternatively RNA spliced (ARS) genes between AA and white PCa biopsy tissue specimens. Subsequent analysis revealed that, among the race-related ARS genes in PCa tissue, 19 are also ARS in breast, lung, and liver cancer. Several of the genes that are ARS across multiple tumor types are important for cancer aggressiveness, including CD44, FN1, and LMO7. We designed PCR primers to further explore the expression of LMO7 variants in preclinical models of white and AA PCa, and found that a LMO7 variant that skips exons 10, 11, and 12 is predominantly expressed in VCaP (white) and MDA PCA 2b (AA) PCa cell lines. In addition, we detected a unique race-related LMO7 splicing event that excludes exons 10 and 11, but preserves exon 12. This event is detected in MDA PCA 2b cells, but not in VCaP cells. Importantly, both of these LMO7 splicing events are in-frame and are not frameshifts leading to truncated or extended C-terminal proteins. These LMO7 variants translate to proteins of 1297 amino acids (missing 344 amino acids coded by skipped exons 10, 11, and 12) and 1287 amino acids (missing 334 amino acids coded by skipped exons 10 and 11), which differ from the full-length LMO7 variant that translates to a protein of 1631 amino acids. Interestingly, the enrichment of these variants in cancer cells suggests an important regulatory role for the amino acids encoded by the skipped exons. Further work to study the impact of LMO7 variants as well as other candidate RNA splice variants on PCa aggressiveness is ongoing, using gene overexpression, gene depletion, and splicing manipulation by siRNA or CRISPR-cas, followed by assessment of resulting alterations in growth, migration, invasion, and drug sensitivity. In summary, we have identified genes that undergo race-related ARS in multiple tumor types and novel ARS events that may functionally contribute to increased tumor aggressiveness, including that of PCa in AA men.
Citation Format: Muthana Al Abo, Steven R. Patierno, Jennifer A. Freedman. Alternative RNA splicing and prostate cancer aggressiveness [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B061.
Abstract B062: Proteomic characterization of the secretome from prostate cancer and bone progenitor cell coculture
Authors: Anselmino Nicolás , Páez Alejandra , Vickers Sofía Lage , Cotignola Javier , Valacco Pía , Gueron Geraldine , Vázquez Elba 
Published: February 2019

Abstract
Prostate cancer (PCa) is one of the most frequent sites of primary tumor development in human beings. PCa tumor cells tend to disseminate to and form metastatic lesions in the bone. Given the evident prevalence and clinical significance of bone metastases, unraveling the mechanisms exploited by cancer to form these destructive lesions is of critical interest. This is partly due to the fact that the metastatic cascade encompasses many rate-limiting steps demanding tumor cells to employ new mechanisms at each stage.
Our work aimed at evaluating which soluble factors could mediate the chemical crosstalk between PCa cells and bone progenitor cells. For this purpose, we used coculture transwell systems of PC3 (human PCa cells) with the preosteoclastic Raw264.7 or preosteoblastic MC3T3 cell lines (murine cells), where cells shared the culture media (CMs) without physical contact for 24h.
We employed mass spectrometry—nanoLC-MS/MS(Orbitrap) —for the secretome analysis of the CMs. The obtained spectra were analyzed with the Proteome Discover Software and compared with both human and murine protein databases. Results highlight a differential secretome profile released to the CM when tumor cells are grown in coculture compared to controls. These results could potentially explain the altered mRNA expression levels assessed by RTqPCR in PCa cells growing in coculture, displaying significant upregulation for HO-1 ANXA2, ANXA2R, OPG, and PTHrP (p&lt;0.05). Of note, coculture secretomes showcase highly bone-associated proteins released by tumoral cells such as periostin, cartilage oligomeric matrix protein, OPN, BMP and ILGF-II, IL-7, FGF, Mx-1—involved in prostate carcinogenesis—compared to controls, evidencing a misregulated microenvironment.
These results may offer a better understanding of the molecular affinity between PCa cells and the bone microenvironment, allowing the improvement of PCa patient prognosis
Citation Format: Nicolás Anselmino, Alejandra Páez, Sofía Lage Vickers, Javier Cotignola, Pía Valacco, Geraldine Gueron, Elba Vázquez. Proteomic characterization of the secretome from prostate cancer and bone progenitor cell coculture [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B062.
Abstract B071: Circulating tumor cells as liquid biopsies of skeletal metastases from prostate cancer
Authors: Josefsson Andreas , Larsson Karin , Åhs Daniel , Brisby Helena , Damber Jan-Erik , Welén Karin 
Published: February 2019

Abstract
Background: Circulating tumor cells (CTC) are promising biomarkers in advanced prostate cancer. Since they are seeded from metastases, they may also serve as liquid biopsies for skeletal metastases that are difficult to sample. The aim of the present study was to evaluate to which extent CTCs reflect the phenotype of skeletal metastases, and thereby their potential to serve as a clinical tool in individualizing treatment of metastatic prostate cancer.
Materials and Method: CTC and tissue from skeletal metastases were sampled from 22 patients (8 GnRH-naïve and 14 castration-resistant) during surgery for spinal cord compression symptoms. CTCs were sampled prior to removal of metastatic tissue, and isolated with AdnaTest ProstateCancerSelect/Detect (Qiagen). Resulting cDNA was preamplified in a multiplex reaction and analyzed for expression of 37 genes related to prostate cancer progression and metastasis with qPCR. RNA was extracted from the metastatic tissue with RNeasy Plus Universal Mini kit (Qiagen), and gene expression was assessed in the same way as for CTCs. EPCAM expression level was used as internal control to enable normalization to epithelial content (CTCs or tumor tissue) of the samples. Correlation of detected signals between matched CTC and tissue was calculated with Pearson correlations.
Results: 12 of the 37 genes displayed expression patterns that were correlating in paired CTC and metastatic samples. Using this subset of genes, the metastases could be grouped similarly to when all 37 genes were included in hierarchical clustering analyses. Using a smaller subset of genes and patients, defined by gene detection frequency in CTC samples, hierarchical clustering of gene expression in CTCs could group the patients similar to when expression data from the metastases were used. In addition, a subset of genes discriminating GnRH-naïve from castration-resistant metastases could be analyzed in CTCs, where it, to a large extent, could identify the same groups of patients.
Conclusion: This study shows that gene expression patterns in CTCs can reflect those of metastases. However, careful selection of the genes to include is important. In addition, insufficient detection sensitivity in CTC analyses limits the range of the genes to be analyzed with current methodology. Taken together, the results imply that CTC phenotyping is a promising tool for individualized therapy in metastatic prostate cancer.
Citation Format: Andreas Josefsson, Karin Larsson, Daniel Åhs, Helena Brisby, Jan-Erik Damber, Karin Welén. Circulating tumor cells as liquid biopsies of skeletal metastases from prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B071.
Abstract B073: Stat5a/b blockade sensitizes prostate cancer to radiation through inhibition of Rad51 and DNA repair
Authors: Maranto Cristina , Udhane Vindhya , Dagvadorj Ayush , Hoang David T. , Gu Lei , Alexeev Vitali , Malas Kareem , Cardenas Karmel , Koptyra Mateusz , Brody Jonathan R. , Rodeck Ulrich , Bergom Carmen , Iczkowski Ken A. , Jacobsohn Ken , See William , Schmitt Sara M. , Nevalainen Marja T. 
Published: February 2019

Abstract
Purpose: The standard treatment for organ-confined prostate cancer (PC) is surgery or radiation, and locally advanced PC is typically treated with radiotherapy alone or in combination with androgen-deprivation therapy. Here, we investigated whether Stat5a/b participates in regulation of double-strand DNA break repair in PC, and if Stat5 inhibition may provide a novel strategy to sensitize PC to radiation therapy.
Experimental Design: Stat5a/b regulation of DNA repair in PC was evaluated by comet assay and clonogenic survival assay, followed by assays specific to homologous recombination (HR) DNA repair and nonhomologous end-joining (NHEJ) DNA repair. For HR DNA repair, Stat5a/b regulation of Rad51 and the mechanisms underlying the regulation were investigated in PC cells, xenograft tumors, and patient-derived PCs ex vivo in 3D explant cultures. Stat5a/b induction of Rad51 and HR DNA repair and responsiveness to radiation were evaluated in vivo in mice bearing PC xenograft tumors.
Results: Stat5a/b is critical for Rad51 expression in PC via Jak2-dependent mechanisms by inducing Rad51 mRNA levels. Consistent with this, genetic knockdown of Stat5a/b suppressed HR DNA repair while not affecting NHEJ DNA repair. Pharmacologic Stat5a/b inhibition potently sensitized PC cell lines and PC tumors to radiation, while not affecting radiation sensitivity of the neighboring tissues.
Conclusion: This work introduces a novel concept of a pivotal role of Jak2-Stat5a/b signaling for Rad51 expression and HR DNA repair in PC. Inhibition of Jak2-Stat5a/b signaling sensitizes PC to radiation and, therefore, may provide an adjuvant therapy for radiation to reduce radiation-induced damage to the neighboring tissues.
Citation Format: Cristina Maranto, Vindhya Udhane, Ayush Dagvadorj, David T. Hoang, Lei Gu, Vitali Alexeev, Kareem Malas, Karmel Cardenas, Mateusz Koptyra, Jonathan R. Brody, Ulrich Rodeck, Carmen Bergom, Ken A. Iczkowski, Ken Jacobsohn, William See, Sara M. Schmitt, Marja T. Nevalainen. Stat5a/b blockade sensitizes prostate cancer to radiation through inhibition of Rad51 and DNA repair [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B073.
Abstract B075: The role of TET1 and hydroxymethylation in high-risk prostate cancer
Authors: Smeets Elien , Spans Lien , Prekovic Stefan , Broeck Thomas Van den , Moris Lisa , Gevaert Thomas , Helsen Christine , Joniau Steven , Claessens Frank 
Published: February 2019

Abstract
The Ten-eleven translocation (TET) proteins are dioxygenases that catalyze the oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) as part of the DNA demethylation pathway. Gene silencing through cytosine methylation contributes to cancer formation, but how hydroxymethylation affects gene expression is largely unknown. In this work, TET1 and genomic hydroxymethylation were investigated in a high-risk prostate cancer cohort for which exome sequencing data are available (1).
Immunohistochemical analysis of tumor versus nontumor prostate biopsies from high-risk prostate cancer showed a strong reduction of genome-wide 5hmC and milder but still significant reduction of 5mC levels in prostate cancer tissue compared to control tissue. Copy number analysis of high-risk prostate cancer showed a loss of the TET1 genomic region in 6 out of 39 samples of our cohort. As expected, the mRNA levels of TET1 were decreased in these tumor samples. Recently, an alternative promoter of TET1 was discovered. This promoter generates a novel isoform lacking the CXXC-domain, which is called TET1ALT (2). We therefore performed functional analyses of the two TET1 promoters in prostate cancer cells. Interestingly, the promoter controlling expression of the endogenous full-length TET1 is less active in prostate cancer cell line PC-3, while the alternative promoter generating TET1ALT is more active in these cells. This is shown by luciferase constructs driven by the two promoter regions.
In conclusion, our findings indicate that there is a drop in (hydroxy)methylation levels in high-risk prostate cancer that correlates with decreased TET1 expression levels and in some cases by a copy number loss of TET1. We are currently working on a more detailed analysis of TET1 promoter usage and control. This will unravel the regulation of hydroxymethylation in prostate cancer, which is crucial for the understanding of prostate cancer development and progression.
References:
1. Spans L, Van den Broeck T, Smeets E, et al. Genomic and epigenomic analysis of high-risk prostate cancer reveals changes in hydroxymethylation and TET1. Oncotarget 2016;7(17):24326-38.
2. Good CR, Madzo J, Patel B, et al. A novel isoform of TET1 that lacks a CXXC domain is overexpressed in cancer. Nucleic Acids Res 2017;45(14):8269-81.
Citation Format: Elien Smeets, Lien Spans, Stefan Prekovic, Thomas Van den Broeck, Lisa Moris, Thomas Gevaert, Christine Helsen, Steven Joniau, Frank Claessens. The role of TET1 and hydroxymethylation in high-risk prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B075.
Abstract B077: 3D reconstruction and machine learning-based analysis of prostate cancer from histologic images
Authors: Ruusuvuori Pekka , Valkonen Mira , Kartasalo Kimmo , Visakorpi Tapio , Nykter Matti , Latonen Leena 
Published: February 2019

Abstract
Prostate cancer is multifocal in nature, and histologic grading is the key clinical prognostic factor. Imaging-based tools are required for decreasing the subjectivity of histologic grading, providing quantitative information of the tissue and the pathologic changes in it, and to allow quantitative associations of histologic alterations with other types of information collected from the tissues, such as genomic data.
To enable imaging-based diagnosis, methods for quantifying both the naturally occurring heterogeneity of normal tissue and morphologic changes due to pathology need to be developed. On the other hand, accurate distinction of early pathologic changes from natural variation could provide novel information about development of tumors. Furthermore, the 3-dimensional evolution and growth patterns of tumors should be considered as, traditionally, histologic scoring mostly relies on individual tissue sections extracted from their spatial context.
To build nonsubjective histologic analysis tools, and to model the multifocality of prostate cancer within the organ, we use analysis of histologic images to quantitatively describe prostate cancer. We present an approach for 1) imaging the whole organ into digital pathology slides, 2) reconstruction of the 3D structure of the organ based on the histologic images, and 3) both feature-based and deep learning-based quantitative analysis of the digital images. Our approach enables characterization of tissue morphology with numerical descriptors, enabling subsequent analysis, such as determining the likelihood of pathologic changes. Our current efforts show how heterogeneity in prostate tissue due to spatial location or cancer can be quantified with image-derived features. In addition, we use mouse prostate as a model to visualize and reconstruct a whole organ from high-resolution whole-slide images, and combine tissue type classification in the 3D reconstruction. Further development of these methods and their application for human samples will improve our understanding of human prostate pathologies and cancer evolution within the 3D environment of the organ.
Citation Format: Pekka Ruusuvuori, Mira Valkonen, Kimmo Kartasalo, Tapio Visakorpi, Matti Nykter, Leena Latonen. 3D reconstruction and machine learning-based analysis of prostate cancer from histologic images [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B077.