bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B15: A cancer-specific detection of serum CA125 improves differential diagnosis of epithelial ovarian cancer from benign conditions
Authors: Huhtinen Kaisa , Gidwani Kamlesh , Kekki Henna , Hynninen Johanna , Salminen Liina , Perheentupa Antti , Poutanen Matti , Auranen Annika , Grenman Seija , Lamminmäki Urpo , Carpén Olli , Pettersson Kim 
Published: August 2018

Abstract
Introduction: We have developed an assay that distinguishes CA125 originating from malignant and benign sources. The assay combines conventional immunoassay with the detection of carbohydrates differentially glycosylated in epithelial ovarian cancer (EOC). These glycans can be detected using carbohydrate-reactive lectins. Our recent data showed that CA125 detection using MGL-lectin improves the discrimination of cancerous CA125 from CA125 of endometriosis patients (Gidwani et al., Clin.Chem 2016). The current study extends CA125MGL measurements to a broader sample set and longitudinal collections during EOC treatment and follow-up.
Methods: MGL lectin coated onto fluorescent europium-chelate-doped 97-nm nanoparticles was used for detection of the CA125 that was captured on an anti-CA125 antibody immobilized on microtitration wells. Serum samples from high-grade serous EOC or patients with varying benign conditions and healthy controls were analyzed.
Results: CA125MGL specifically recognized the CA125 isoform produced by EOC, whereas the recognition of CA125 from nonmalignant conditions was reduced. Serum CA125MGL measurement discriminated better patients with EOC from benign conditions compared with conventional immunoassay. Importantly, discrimination was particularly improved for marginally increased CA125 values that are common in benign conditions. Our data also showed earlier detection of EOC progression, suggesting that the CA125MGL also has potential to improve earlier diagnosis of EOC.
Conclusions: The CA125MGL concept could help reduce the false-positive rates of conventional CA125 immunoassays. It carries further potential to improve early diagnosis of EOC as well as follow-up of treatment response. Finally, using appropriate combinations of lectins and antibodies, applying the test concept presented here can also be explored for other diagnostic targets, where changes in glycosylation are indicative of an ongoing disease process.
Citation Format: Kaisa Huhtinen, Kamlesh Gidwani, Henna Kekki, Johanna Hynninen, Liina Salminen, Antti Perheentupa, Matti Poutanen, Annika Auranen, Seija Grenman, Urpo Lamminmäki, Olli Carpén, Kim Pettersson. A cancer-specific detection of serum CA125 improves differential diagnosis of epithelial ovarian cancer from benign conditions. [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 B15.
Abstract B37: Prevention of epithelial ovarian cancer by eliciting P4/RIPK1-dependent necroptosis
Authors: Bitler Benjamin , Yamamoto Tomomi , Bales Elise , Watson Zachary , Behbakht Kian , Johnson Joshua 
Published: August 2018

Abstract
High-grade serous epithelial ovarian cancer (HGSOC) is the deadliest gynecologic disease, commonly diagnosed in peri/postmenopausal women. Annually, HGSOC accounts for over 140,000 deaths worldwide. Because we lack effective early detection methods, over 75% of HGSOC are diagnosed at stages III/IV, with abysmal 5-year survival rates of 37/25%, respectively. Recently, progesterone (P4) was observed to promote the elimination of p53-null cells from the fallopian tube by inducing necroptosis, a regulatable form of non-apoptotic cell death. Activation of necroptosis depends on activation of receptor-interacting kinase proteins 1 and 3 (RIPK1 and RIPK3). Several additional factors suggest that P4 may have a key protective role versus HGSOC; protection versus tumorigenesis is reduced at the time of menopause due to decreasing P4 levels. Several studies examining the use of a synthetic progesterone (medroxyprogesterone acetate, MPA) observed decreases in the incidence of HGSOC. Also, MPA had a significant clinical benefit in 20-40% of pretreated ovarian cancer patients. Further, 75% of HGSOC have decreased expression of progesterone receptor (PGR). With lower P4 at menopause, p53 mutated fallopian tube epithelial cells may therefore escape necroptosis and progress to HGSOC. All of the above information led to our hypothesis that activating P4 signaling will induce necroptosis in HGSOC tumor cells.
Examining The Cancer Genome Atlas (TCGA) database for regulators of necroptosis, we found that increased expression of the P4 receptor (PGR), necroptosis effectors TNFα, and RIPK1/3 corresponded to significantly higher overall survival in 484 HGSOC cases. Using OVSAHO (BRCA2-deleted) cells, we show that P4 and/or TNFα treatment increases TNFα, RIPK1, and RIPK3 expression. In OVSAHO cells, we observed a significant decrease in cell number following treatment with P4 and/or TNFα. Also, we confirmed that P4 treatment was able to induce a necroptotic response distinct from classical apoptosis. Upon examination of normal fallopian tube tissue, borderline tumors, and advanced HGSOC, we detected expression of necroptosis effectors RIPK1 and 3, suggesting an intact necroptosis pathway. These observations point towards an HGSOC prevention strategy that favors the elimination of “founder” cells by activating necroptosis downstream of P4. These data may be particularly useful for the management of BRCA1/2 mutant patients, as these women experience menopause significantly earlier than noncarriers.
Citation Format: Benjamin Bitler, Tomomi Yamamoto, Elise Bales, Zachary Watson, Kian Behbakht, Joshua Johnson. Prevention of epithelial ovarian cancer by eliciting P4/RIPK1-dependent necroptosis. [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 B37.
Abstract B57: Adhesion and beyond: CD44 in ovarian cancer spheroids
Authors: Sacks Joelle D. , Main Hilal Gurler , Muralidhar Goda G. , Elfituri Osama , Xu Hao-Liang , Kajdacsy-Balla Andre A. , Barbolina Maria V. 
Published: August 2018

Abstract
Epithelial ovarian carcinoma (EOC) metastasis is characterized by the shedding of malignant cells from the surface of the primary tumor and their implantation onto the peritoneal surface lining the abdominal cavity in addition to more distant sites. This shedding of malignant cells from the primary site results as either single cells or free-floating multicellular aggregates, known as spheroids, in the ascites. Although single cells and spheroids may potentially seed metastases, considerable evidence now suggests that the aggregation of cells is important for anchorage-independent cell survival and growth, and spheroid formation may represent an important intermediate survival mechanism to facilitate EOC dissemination. Recent studies have uncovered human transmembrane cell adhesion molecule CD44 standard (CD44s) isoform expression correlating with high-grade and advanced-stage ovarian carcinoma. Moreover, it has also been suggested that CD44s may be an important mediator of ovarian cancer cell implantation in the peritoneal cavity, enhancing the metastatic potential of ovarian cancer cells. Thus, we investigated the functional significance of CD44 standard by means of in vitro culture experiments with ovarian cancer spheroids. After characterizing 8 EOC cell lines, a spectrum of CD44 expression was observed and two cell lines with high CD44s (ES-2 and SKOV-3) and two cell lines low in CD44s (OVCAR-4 and OVSAHO) were chosen for further testing. Interestingly, the high CD44s-expressing cell lines formed larger spheroids that adhered significantly faster to a monolayer of primary mesothelial cells. Stable knockdown of CD44 using CRISPR/Cas9 in these 2 cell lines reduced spheroid formation, suggesting that differential expression of CD44 standard plays a role in cell-cell adhesion. When ES-2 CD44-/- cells were injected i.p. into athymic nude mice, decreased ascites production and mesentery tumor burden were observed as well as increased overall survival. However, CD44 knockdown also significantly increased metastasis to the lung, suggesting a suppressive role for CD44 in EOC metastasis as well. These in vivo data imply that CD44 enhances the metastatic potential in ovarian cancer spheroids influencing peritoneal tumor growth while suppressing metastasis to lung tissue.
Citation Format: Joelle D. Sacks, Hilal Gurler Main, Goda G. Muralidhar, Osama Elfituri, Hao-Liang Xu, Andre A. Kajdacsy-Balla, Maria V. Barbolina. Adhesion and beyond: CD44 in ovarian cancer spheroids. [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 B57.
Abstract IA23: How does the immune system contend with intratumoral heterogeneity in ovarian cancer?
Authors: Nelson Brad H. 
Published: August 2018

Abstract
The presence of tumor-infiltrating T cells and B cells is associated with markedly prolonged survival in high-grade serous ovarian cancer (HGSC), yet we have only a rudimentary understanding of how the immune system contends with the continually evolving tumor genome. HGSC exhibits extensive spatial heterogeneity at diagnosis, and tumors undergo dramatic changes in response to treatment. In long-term survivors, the immune system presumably deploys mechanisms that successfully respond to these changes. With better understanding, it may be possible to exploit these mechanisms to create more effective immunotherapies.
We have shown that the most prognostically favorable immune responses involve both cytolytic and antibody-based mechanisms, suggesting important cooperative interactions between the T cell and B cell branches of the immune system. By studying serial tumor samples, we have uncovered extensive temporal dynamics of the antitumor immune response. We found that neoadjuvant chemotherapy can enhance preexisting immune responses yet generally fails to initiate responses in tumors that lack immune infiltrates at baseline. Indeed, with better understanding, these immunologically inert or “cold” tumors may represent an attractive therapeutic opportunity, as they can express high levels of tumor-specific antigens with corresponding systemic T-cell and antibody responses.
Currently, we are looking at the issue of spatial heterogeneity by subjecting tumor samples collected from different anatomical locations to comprehensive genomic and immunologic analyses, including mutational profiling, RNA-seq, TCR/BCR-seq, and multi-plexed immunohistochemistry. This work is providing novel insights into the relationship between the clonal architecture of tumors and antitumor immunity. Our findings to date indicate that tumor deposits with a high degree of clonal heterogeneity generally have low densities of immune infiltrates, suggesting a means by which tumor evolutionary processes are insulated from immunologic attack. Furthermore, TCR-seq experiments are providing early evidence that T-cell clones track with individual tumor clones across space, suggesting that the immune system contends with intratumoral heterogeneity by battling each tumor clone individually. The presentation will address the implications of these findings on the design of more effective immunotherapies for HGSC and related cancers.
Citation Format: Brad H. Nelson. How does the immune system contend with intratumoral heterogeneity in 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 IA23.
Abstract A30: Preclinical study of a combination of mocetinostat (HDAC inhibitor) and 5-AZA-dC (decitabine) in chondrosarcoma
Authors: Sheikh Tahir N. , Patwardhan Parag , Schwartz Gary K. 
Published: August 2018

Abstract
Chondrosarcomas are the second most frequently occurring type of bone malignancy, and account for approximately 25% of all bone sarcomas. They are often highly aggressive neoplasms that rapidly progress and eventually recur and give distant metastases. They are largely considered to be resistant to conventional chemotherapy and radiotherapy. Previous reports have shown that the interaction of DNA methylation and histone modification regulates gene expression, and targeting these mechanisms could be a potentially novel approach to treat cancer. In the present study, we hypothesized that concurrent inhibition of histone acetylation and DNA methylation could result in decreased viability of chondrosarcoma cells. To test this, we used a panel of chondrosarcoma cell lines including IDH wild type (CH2879), IDH1 mutant (JJ012), and IDH2 mutant (SW1353) cell line. Results from our in vitro proliferation assay showed that combination of sub-IC50 concentrations of the DNA methyltransferase (DNMT) inhibitor decitabine (5-AZA-dC) and a spectrum-selective class I and IV histone deacetylase (HDAC) inhibitor mocetinostat (MGCD0103) resulted in decreased cell viability, which appears to be at least additive, in all the three chondrosarcoma cell lines when compared to either of the two drugs alone. Western blot analysis showed induction of cleaved Poly-ADP Ribose Polymerase (PARP) as well as cleaved caspase 3, known markers of apoptosis. Consistent with augmented DNA damage, combination of decitabine and MG103 markedly increased the levels of phospho-H2AX, a DNA damage marker, and proapoptotic BH3-only proteins such as Bim. Combination treatment also resulted in increased induction of histone acetylation (AcH3 and AcH4) and increased expression of E-cadherin, an important tumor suppressor gene. Cell cycle analysis showed induction of sub-G1 population phase in combination treatment. Previous reports have shown that CpG methylation is a critical event in transcriptional repression of hypermethylated genes in cancer. To this end, we show that combination treatment with mocetinostat and 5-AZA-dC results in downregulation of (H3K9) methylation. Taken together, our data strongly suggest that combination treatment with mocetinostat and decitabine is a novel treatment approach and merits evaluation in the treatment of chondrosarcoma.
Citation Format: Tahir N. Sheikh, Parag Patwardhan, Gary K. Schwartz. Preclinical study of a combination of mocetinostat (HDAC inhibitor) and 5-AZA-dC (decitabine) in chondrosarcoma [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr A30.
Abstract B19: Tumor-suppressive activities associated to MIR10A-5p expression in developmental sarcomas
Authors: Herrero-Martin David , Rello-Varona Santiago , Garcia-Monclus Silvia , Huertas-Martinez Juan , Almacellas-Rabaiget Olga , Helman Lee J. , Tirado Oscar M. 
Published: August 2018

Abstract
Ewing sarcoma (ES) and alveolar rhabdomyosarcoma (ARMS) are pediatric sarcomas characterized by tumor-specific translocations. Besides acting as a direct modulator of transcription, fusion proteins appear to exert its oncogenic functions by epigenetic modifications on the transcriptome. Therefore, the identification of specific DNA methylation markers would be helpful for understanding their pathogenetic mechanism as well as for developing new therapeutic strategies. By using the Illumina Infinium HumanMethylation450 we have analyzed the methylome of ES and ARMS tumors and cell lines. ES and ARMS samples showed, among other epigenetic alterations, differential hypermethylation in the promoter of MIR10A-5p, thus suggesting an inhibition of its expression. Expression of MIR10A-5p is effectively low in ES and ARMS cell lines and patient samples and the treatment with the epigenetic modifier 5-aza restores its expression. MIR10A-5p stable overexpression in two ES (A673 and TC252) and two ARMS (Rh4 and RMS13) cell lines reduces proliferation, diminishes clonogenic growth, and decreases cellular migration. Cell death induced by MIR10A-5p reintroduction is only achieved in the p53wt ES cell line TC252. Proteomic profile of A673 MIR10A-5p cells is altered as assessed by iTRAQ. Protein kinase CRKL is one of the proteins downregulated due to MIR10A-5p reintroduction. Indeed, CRKL expression is also reduced in the other three MIR10A-5p stable overexpression models. Doxycycline-induced silencing of CRKL in ARMS cell line Rh30 provokes cell growth reduction in vitro and in vivo, G0/G1 arrest, and a decrease in the clonogenic capacity (Yeung CL et al., 2013). Interestingly, the migratory ability of Rh30 and A673 CRKL-silenced cells is also impaired. Thus, our results uncover MIR10A-5p as a putative tumor suppressor in ES and ARMS, suggesting a link between MIR10A-5p and CRKL. Further characterization of the oncogenic role of CRKL and the molecular mechanisms associated to MIR10A-5p tumor-suppressor activities in ES and ARMS is ongoing.
Citation Format: David Herrero-Martin, Santiago Rello-Varona, Silvia Garcia-Monclus, Juan Huertas-Martinez, Olga Almacellas-Rabaiget, Lee J. Helman, Oscar M. Tirado. Tumor-suppressive activities associated to MIR10A-5p expression in developmental sarcomas [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr B19.
Abstract IA08: Analysis of a histiocytic carcinoma in the dog: The canine's utility in fetching disease genes
Authors: Parker Heidi G. , Cadieu Edouard , Shearin Abigail , Rutteman Gerard , Ostrander Elaine A. 
Published: August 2018

Abstract
Histiocytic sarcoma (HS) is a rare human hematopoietic neoplasm that accounts for less than 1% of hematolymphoid cancers and occurs either concurrently with or subsequently to B- or T-lymphoblastic lymphoma and other B-cell cancers. As such, its genetic etiology has been difficult to establish. HS in dogs, by comparison, shows strong breed specificity with 20% of flat-coated retrievers and 25% of Bernese mountain dogs (BMD) estimated to develop the disease in their lifetime. These two affected breeds share no recent common ancestors and display differences in disease presentation, offering a unique system in which to investigate the genetic predisposition and progression of HS. Our lab has previously undertaken genome wide association study (GWAS) on both BMD and FCR collected in North America and Europe and identified four significantly associated loci, two in BMD and two in FCR. In each breed, only one locus was segregating with disease in the American population while both were present in the European populations. There were no loci in common between the two breeds. Fine mapping of the common BMD HS locus on canine chromosome (CFA) CFA11 revealed a single haplotype spanning the MTAP (methylthioadenosine phosphorylase) gene and part of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene, which was present in 96% of BMD with HS. The European BMD also showed a significant locus on CFA14 that may be approaching fixation in the American dogs based on allele frequency calculations. We have done targeted resequencing of the CFA14 locus in a subset of European BMD and are in the process of filtering the identified mutations. Promising candidate genes in this region include GRM8, which inhibits the cyclic AMP cascade in the central nervous system and has shown to be involved in several of cancers; POT1, which is involved in telomere length maintenance and protection; and HYAL4, a hyaluronidase potentially involved in extracellular matrix degradation. In addition, the laboratory has generated 30x sequence from two HS cases and a control BMD, two FCR cases, and a control and low pass sequence from 16 dogs (8 cases and controls) in order to identify the likely causative mutations in each of the associated loci as well as breed specific mutations that may predispose the dogs to aggressive cancers.
Citation Format: Heidi G. Parker, Edouard Cadieu, Abigail Shearin, Gerard Rutteman, Elaine A. Ostrander. Analysis of a histiocytic carcinoma in the dog: The canine's utility in fetching disease genes [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr IA08.
Abstract IA15: Using gene expression analyses to identify MPNST therapeutics
Authors: Ratner Nancy 
Published: August 2018

Abstract
Malignant peripheral nerve sheath tumors (MPNST) are rare soft tissue sarcomas that are a major source of mortality in neurofibromatosis type 1 (NF1) patients. In NF1 patients, these devastating sarcomas often develop in existing benign neurofibroma. We hypothesized that some over-expressed genes in solid tumors would be driver genes and/or mark critical pathways and therapeutic targets. In one approach to identify MPNST driver genes we targeted 130 genes up-regulated in neurofibroma and MPNSTs versus normal cells in a lentiviral short hairpin (sh) RNA screen. A counter-screen in RAS mutant cells excluded common RAS-pathway driven genes. We identified 7 genes specific for survival of MPSNT cells, including the transcription factor MEIS1. In a second approach, we targeted known oncogenes that were expressed at higher levels in MPNST than in normal cells, including Aurora Kinase A. MPNST responded to the Aurora A kinase inhibitor alisertib, and the combination of alisertib and HSV1716, a virus derived from HSV-1 and attenuated by deletion of RL1, exhibited significantly increased antitumor efficacy compared to either monotherapy. Supported by NIH-NS-084855 (N.R. and Largaespada, D.), NS-28840 (N.R.), and NS-086219 (N.R. and Cripe, T.P.).
Citation Format: Nancy Ratner. Using gene expression analyses to identify MPNST therapeutics [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr IA15.