bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract NTOC-114: ARID1A DEFICIENCY IN OVARIAN CLEAR CELL CARCINOMAS UP–REGULATES OXIDATIVE STRESS AND SENSITIZES CELLS TO ROS–INDUCING AGENTS
Authors: Kwan Suet-Yan , Cheng Xuanjin , Kwan Suet-Ying , Izaguirre Daisy I. , Tsang Yvonne T.M. , Choi Jong-Sun , Kwan Hoi-Shan , Gershenson David M. , Wong Kwong-Kwok 
Published: June 2017

Abstract
Inactivating mutations in AT-rich interaction domain 1A (ARID1A) are most frequently found in ovarian clear cell carcinomas (OCCC) and ovarian endometrioid carcinomas (OEC). The functional roles of ARID1A are not completely understood and there are limited therapeutic strategies that specifically target ARID1A-mutant cancers. Given that ARID1A expression is lost in cancer, ARID1A mutations cannot be targeted directly and novel therapeutic strategies are required to target ARID1A-mutant cancers.
In this study, drug responses between ARID1A-wildtype and ARID1A-mutant cell lines were compared using the ‘Genomics of Drug Sensitivities in Cancer’ database. From this analysis, we found that ARID1A-mutant cell lines are more sensitive to elesclomol, which is a reactive oxygen species (ROS)-inducing agent. This finding was validated using a panel of well-characterized ovarian and endometrial cancer cell lines. ARID1A-mutant OCCC cell lines exhibited lower IC50 values and higher apoptotic rates when treated with elesclomol. Knockdown and re-expression of ARID1A in ovarian cancer cells showed that ARID1A is required to protect cancer cells from oxidative stress. In the absence of ARID1A, intracellular ROS levels were increased as determined by flow cytometry. Immunostaining of 4-hydroxy-2-nonenals (4-HNE), one of the products from lipid peroxidation induced by ROS, in OCCC patient samples indicated an up-regulation of oxidative stress in the tumor.
We also found that ARID1A negatively regulates the expression of NRF2 which is the major regulator of the antioxidant response in the cell. Knockdown of NRF2 in ovarian cancer cell lines revealed that NRF2 expression may be preferentially required for protection from oxidative stress and cell proliferation in ARID1A-mutant cells. Analysis using The Cancer Genome Atlas (TCGA) UCEC dataset revealed that ARID1A-mutant tumor samples have higher expression of NRF2 and NRF2-target genes.
In summary, this study revealed novel roles of ARID1A in protecting ovarian cancer cells against oxidative stress. In the absence of ARID1A, NRF2 is up-regulated and may be required to compensate for ARID1A deficiency. These findings suggest that ARID1A-mutant ovarian cancer cells may be targeted for treatment with ROS-inducing agents and NRF2 inhibitors.
Citation Format: Suet-Yan Kwan, Xuanjin Cheng, Suet-Ying Kwan, Daisy I. Izaguirre, Yvonne T.M. Tsang, Jong-Sun Choi, Hoi-Shan Kwan, David M. Gershenson and Kwong-Kwok Wong. ARID1A DEFICIENCY IN OVARIAN CLEAR CELL CARCINOMAS UP–REGULATES OXIDATIVE STRESS AND SENSITIZES CELLS TO ROS–INDUCING AGENTS [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-114.
Abstract NTOC-116: THE TUMOUR SUPPRESSOR PROTEIN OPCML ACTS AS A SENSITIZING AGENT IN ANTI–EGFR/HER2 THERAPY AND CISPLATIN TREATMENT IN OVARIAN CANCER
Authors: Zanini E , Louis LS , Antony J , Okon I , McKie AB , Recchi C , Gabra H 
Published: June 2017

Abstract
Ovarian cancer is a very heterogeneous disease characterised by lack of oncogene addition and occurrence of resistance to platinum-based treatment. The opioid-binding cell adhesion molecule (OPCML) is a glycosylphosphatidylinositol (GPI) anchored protein that was found to be epigenetically inactivated in 83% of ovarian cancers and demonstrated to act as a tumour suppressor gene (TSG) by negatively regulating a spectrum of receptor tyrosine kinases (RTKs), such as ErbB2/HER2, FGFR1, EphA2 and Axl, and their related downstream signalling. We propose that OPCML can sensitise cells to drugs that target these RTKs and, given the profound effect of OPCML on the AKT signaling, we also propose that OPCML can sensitize cells to platinum-based therapy.
In particular, here we confirm by in vitro pull-downs and mammalian 2-hybrid studies that OPCML physically interacts with HER2 but not with EGFR. As HER2 is the obligate and preferred partner of EGFR, we propose that OPCML can sensitize cells to drugs that target either EGFR or both EGFR and HER2 when HER2 is over-expressed in the system. SK-OV-3 and OV90 cells were stably transduced to express OPCML and treated with either Erlotinib or Lapatinib for IC50 studies and analysis of the downstream signalling pathways. We found that OPCML was able to significantly sensitize only the cells with high HER2 expression (SK-OV-3) to both Erlotinib and Lapatinib. Proliferation and apoptosis assays were also carried out in OPCML-expressing SK-OV-3 cells after treatment with Cisplatin, showing how OPCML expression sensitizes the cells to the drug by increasing Caspase 3/7 activation.
Overall, we show that OPCML expression is associated with a better response to two drugs that target the EGFR/HER2 system, Erlotinib and Lapatinib, when HER2 is over-expressed in the cells. Similarly, cells expressing OPCML are sensitised also to Cisplatin. These results are particularly relevant in view of the development of OPCML as a therapeutic that could prove to be an effective adjuvant to both RTK-specific and platinum-based therapies.
Citation Format: Zanini E, Louis LS, Antony J, Okon I, McKie AB, Recchi C, Gabra H. THE TUMOUR SUPPRESSOR PROTEIN OPCML ACTS AS A SENSITIZING AGENT IN ANTI–EGFR/HER2 THERAPY AND CISPLATIN TREATMENT IN OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-116.
Abstract NTOC-117: CD73 BLOCKADE OVERCOMES RESISTANCE TO AGONISTIC ANTI-CD137 ANTIBODY THERAPY IN OVARIAN CANCER
Authors: Chen Siqi , Fan Jie , Dominguez Donye , Lei Qin , Long Alan , Fang Deyu , Zhang Bin 
Published: June 2017

Abstract
Agonist antibodies (Ab) directed against costimulatory molecule CD137 (4-1BB) on the surface of antigen-primed T-lymphocytes are currently in various stages of pre-clinical and clinical development in advanced ovarian cancers, though therapeutic benefit has been limited as single agents. Here, we identified a novel mechanism of tumor-reactive CD8+ T cell unresponsiveness in ovarian cancer driven by the upregulation of CD73 (ecto-5′-nucleotidase), which prevents CD8+ T cell activity from engagement of the CD137 costimulatory molecule. Accordingly, CD73-deificient mice treated with anti-CD137 Ab survived significantly longer wild-type mice against an ovarian tumor challenge. To explore the therapeutic relevance of these observations, we combined anti-CD137 and anti-CD73 Ab to treat mice with established ovarian cancers. This combination therapy induced tumor regression associated with enhanced antitumor CD8+ T cell responses and reduced CD4+Foxp3+ regulatory T cells number and function. Mechanistically, CD137 engagement-triggered antitumor T cell activity was diminished in response to microenvironmental transforming growth factor-β (TGF-β) that was essential for CD73 induction. Furthermore, extracellular adenosine generation by CD73 abrogated T cell activity through A2BR activation in the face of agonistic anti-CD137 treatment. Our study demonstrates that CD73 blockade has critical implications for effective clinical targeting of CD137 and possibly other costimulatory molecules.
Note: This abstract was not presented at the conference.
Citation Format: Siqi Chen, Jie Fan, Donye Dominguez, Qin Lei, Alan Long, Deyu Fang, Bin Zhang. CD73 BLOCKADE OVERCOMES RESISTANCE TO AGONISTIC ANTI-CD137 ANTIBODY THERAPY IN OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-117.
Abstract TMEM-034: THE HEAT SHOCK TRANSCRIPTION FACTOR HSF1 INDUCES OVARIAN CANCER EPITHELIAL-MESENCHYMAL TRANSITION IN A 3D SPHEROID GROWTH MODEL
Authors: Paullin Trillitye , Powell Chase , Menzie Chris , Hill Robert , Martyniuk Christopher , Westerheide Sandy D. 
Published: June 2017

Abstract
Ovarian cancer is the most lethal gynecological cancer, with over 200,000 women diagnosed each year and over half of those cases leading to death. These poor statistics are related to a lack of early symptoms and inadequate screening techniques. This results in the cancer going undetected until later stages when the tumor has metastasized through a process that requires the epithelial to mesenchymal transition (EMT). In lieu of traditional monolayer cell culture, EMT and cancer progression in general is best characterized through the use of 3D spheroid models. Compared to other cancers, ovarian cancer has very limited treatment options to date, with cisplatin and paclitaxel being the most common and efficient. Recently, a significant increase in heat shock factor 1 (HSF1) expression has been found in highly malignant ovarian cancer. HSF1 is the regulator of the heat shock response (HSR) and promotes the transcription of heat shock proteins (HSPs). Previous studies have shown that HSF1-induced chaperone activity may act to stabilize multiple oncogenes within many different cancer types. This leads to cancer proliferation, reduced apoptosis, and metastasis. In this study, we examine gene expression changes through microarray analysis in spheroid versus monolayer ovarian cancer cells treated with TGFβ to induce EMT. Interestingly, EMT and stress response pathways, including the heat shock response, were all significantly affected by 3D growth. HSF1 knockdown was utilized in both 2D and 3D cultures to further study this response. HSF1 knockdown is shown to inhibit ovarian cancer progression in both monolayer and spheroid model cells. Moreover, HSF1 knockdown in spheroid cells has a significantly greater impact on EMT markers than it does in 2D cultures. This indicates HSF1 may be a utilized as a target for chemotherapeutics in ovarian cancer patients and could potentially have implications in other such hormonal cancers.
Citation Format: Trillitye Paullin, Chase Powell, Chris Menzie, Robert Hill, Christopher Martyniuk, and Sandy D. Westerheide. THE HEAT SHOCK TRANSCRIPTION FACTOR HSF1 INDUCES OVARIAN CANCER EPITHELIAL-MESENCHYMAL TRANSITION IN A 3D SPHEROID GROWTH MODEL [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr TMEM-034.
Abstract TMEM-038: THE CULTIVATION AND PARTITIONING OF INVASIVE OVARIAN CANCER CELLS AFTER THEIR ISOLATION FROM WHOLE BLOOD
Authors: Veeramallu Uday K. 
Published: June 2017

Abstract
Ovarian cancer patients suffer from high rates of recurrence and mortality. Circulating tumor cells (CTCs) can serve as a minimally invasive tool to improve the clinical management of such cancer patients. Hence there is growing interest in the isolation, characterization and in vitro culture of CTCs. To this end, the porous membrane cell separators developed by MetaCell s.r.o. provide a simple solution. Ovarian cancer cell line models OVCAR3 and SKOV3 were studied by gene expression profiling and immunostaining for the expression of EPCAM, EGFR, HER2, MET and certain other novel therapeutic targets. Cultivation of the cancer cells after their spike recovery from either cell culture medium or from whole blood was explored using MetaCellTM separators. The cells growing on the separator membranes housed in multi-well culture plates was conveniently visualized with vital cell stains. The SKOV3 cells, but not the OVCAR3 cells, were found to migrate through the membrane pores and populate the well bottoms of the culture plates. This can be attributed to the more plastic and invasive nature of SKOV3 cells as characterized by high Vimentin and low EPCAM expression levels. This is akin to the profile exhibited by highly invasive cancer cells that have undergone epithelial to mesenchymal transition (EMT) and that are implicated in the metastatic spread of cancer in patients. Furthermore, the invasive cells growing on the culture plate well bottoms were found to still stain positively for the therapeutic targets of interest. This cultivation device thus offers the ability to selectively interrogate the more invasive sub-populations within the highly heterogeneous CTCs that are typically seen in cancer patients. After the isolation and cultivation of CTCs, if the partitioned invasive cells remain addressable for the therapeutic target under consideration, the patients are more likely to respond to that therapy for the arrest of metastatic disease. In this context, the MetaCellTM separators have the potential to serve as very effective adjunctive aids for the selection and monitoring of ovarian cancer patients for treatment with targeted therapies.
Citation Format: Uday K. Veeramallu, M.S. THE CULTIVATION AND PARTITIONING OF INVASIVE OVARIAN CANCER CELLS AFTER THEIR ISOLATION FROM WHOLE BLOOD [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr TMEM-038.
Abstract TMEM-118: ROLES OF T-LAK CELL-ORIGINATED KINASE (TOPK) AND THE MICROENVIRONMENT IN DRIVING OVARIAN CANCER PROGRESSION
Authors: Eckert Mark A. , Coscia Fabian , Pan Shawn , Chiang Chun-Yi , McGregor Stephanie , Lastra Ricardo , Yamada S. Diane , Mann Matthias , Lengyel Ernst 
Published: June 2017

Abstract
Ovarian cancer (OvCa) therapy is confounded by late detection and a lack of effective therapeutics. After debulking surgery, most patients initially respond to platinum-based chemotherapeutics, however their tumors inevitably develop resistance and recur. Developing new treatments for OvCa will depend on a thorough understanding of OvCa biology. We recently identified T-LAK cell-originated kinase (TOPK), a serine-threonine kinase, as highly expressed in OvCa. A member of the cancer/testis antigen (CTA) family, TOPK is induced by mutant TP53 and is expressed in early, in situ serous tubal intraepithelial carcinoma lesions. Targeting TOPK with a small-molecule inhibitor in a mouse model of OvCa led to significant reductions in tumor burden. To better understand the interplay between TOPK and the tumor and stroma in ovarian cancer progression, we performed compartment-resolved, quantitative shotgun proteomics on microdissected tumor and stromal samples across a hypothetical progression series of ovarian cancer from in situ STIC to omental metastases. With a highly-sensitive platform, we were able to accurately quantify proteins across the progression series and confirmed expression of known tumor and stromal markers in the data set. Interestingly, we observed a conserved stromal response associated with metastasis. This signature included both genes known to play a role in cancer-associated fibroblasts, as well as proteins with no previously described roles in the tumor stroma. Many components of the signature are also representative of the previously described “mesenchymal” subgroup of ovarian cancer. In vitro and in vivo functional assays have confirmed essential roles for several of these proteins in regulating the cancer-associated fibroblast phenotype. This work establishes TOPK as a potential therapeutic target for ovarian cancer and emphasizes the importance of compartment resolved studies in understanding the individual roles of the tumor and stroma in ovarian cancer progression.
Citation Format: Mark A. Eckert, Fabian Coscia, Shawn Pan, Chun-Yi Chiang, Stephanie McGregor, Ricardo Lastra, S. Diane Yamada, Matthias Mann, and Ernst Lengyel. ROLES OF T-LAK CELL-ORIGINATED KINASE (TOPK) AND THE MICROENVIRONMENT IN DRIVING OVARIAN CANCER PROGRESSION [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr TMEM-118.
Taxonomic revision of the speckled crabs, genus Arenaeus Dana, 1851 (Brachyura: Portunidae) based on morphological and molecular data
Authors: ZUPOLINI LUCAS L. , MAGALHÃES TATIANA , PILEGGI LEONARDO G. , MANTELATTO FERNANDO L. 
Published: June 2017

The family Portunidae Rafinesque, 1815 presents a series of taxonomic problems such as paraphyletic groups, synonymizations, and unresolved complexes of cryptic species. Arenaeus Dana, 1851, encompasses only two species with mirrored distributions along the coasts of the Americas. Despite of comprising two widespread species, there is a scarcity of information on their biology and ecology and on the relationships with other genera in the family. Because of the lack of studies comprising both species and the imprecise or erroneous taxonomic descriptions for the species of Arenaeus, we conducted a thorough taxonomic revision of the genus and used data from fragments of the 16S rRNA and the cytochrome oxidase I (COI) genes to investigate the validity of Arenaeus cribrarius (Lamarck, 1818) and Arenaeus mexicanus (Gerstaecker, 1856). A range of easily discernible and objective characteristics distinguish the species, including the number of rostral teeth, the number of carpal spines, and the presence of a spine on the epistome region. This last feature, although never properly addressed in the literature, was diagnostic in discriminating the taxa. Results of molecular analyses also supported the separate identity of the two species. Assemblages generated in COI analyses reflected no geographic pattern or geographic partitioning, suggesting that dispersion and gene flow could be sufficiently high to hinder genetic differentiation through the extensive distribution range of the Atlantic species, A. cribrarius. Furthermore, molecular results and morphological analyses may indicate a closer relationship among particular groups of portunids and Arenaeus. Morphology of the carapace and of the first male gonopods may be the most prominent characteristics supporting such view. We have shed light on the status of the genus Arenaeus and its members, clarified some taxonomical issues, and provide an identification key for the species.
Evaluating the Use of Electronic Health Records for Type 2 Diabetes Surveillance in 2 California Counties, 2010-2014
Authors: Richardson Maxwell J. , Van Den Eeden Stephen K. , Roberts Eric , Ferrara Assiamira , Paulukonis Susan , English Paul 
Published: June 2017

Objectives: Electronic health records (EHRs) and electronic laboratory records (ELRs) are increasingly seen as a rich source of data for performing public health surveillance activities and monitoring community health status. Their potential for surveillance of chronic illness, however, may be underused. Our objectives were to (1) evaluate the use of EHRs and ELRs for diabetes surveillance in 2 California counties and (2) examine disparities in diabetes prevalence by geography, income, and race/ethnicity. Methods: We obtained data on a clinical diagnosis of diabetes and hemoglobin A1c (HbA1c) test results for adult members of Kaiser Permanente Northern California living in Contra Costa County or Solano County at any time during 2010-2014. We evaluated the validity of using HbA1c test results to determine diabetes prevalence, using clinical diagnoses as a gold standard. We estimated disparities in diabetes prevalence by combining HbA1c test results with US Census data on income, race, and ethnicity. Results: When compared with a clinical diagnosis of diabetes, data on a patient’s 5-year maximum HbA1c value ≥6.5% yielded the best combination of sensitivity (87.4%) and specificity (99.2%). The prevalence of 5-year maximum HbA1c ≥6.5% decreased with increasing median family income and increased with greater proportions of residents who were either non-Hispanic black or Hispanic. Conclusions: Timely diabetes surveillance data from ELRs can be used to document disparities, target interventions, and evaluate changes in population health. ELR data may be easier to access than a patient’s entire EHR, but outcome metric validation with diabetes diagnoses would need to be ongoing. Future research should validate ELR and EHR data across multiple providers.
A review of CD19-targeted immunotherapies for relapsed or refractory acute lymphoblastic leukemia
Authors: DasGupta Ryan K , Marini Bernard L , Rudoni Joslyn , Perissinotti Anthony J 
Published: June 2017

Aim Novel immunotherapies have generated high response rates and unique adverse effects among patients with relapsed or refractory acute lymphoblastic leukemia. Therapies engaging endogenous T-cells against acute lymphoblastic leukemia are emerging for children and adults with various poor prognostic factors, thus accurate knowledge of immunotherapies is necessary for their effective implementation in the future. In this review, we evaluate clinical trial data regarding chimeric antigen receptor T-cells and blinatumomab, for the treatment of relapsed or refractory acute lymphoblastic leukemia. Summary In the relapsed or refractory setting, response rates rapidly diminish after subsequent lines of chemotherapy and cumulative toxicities may cause significant patient harm. Immunotherapies provide an approach to improve response rates and minimize traditional toxicities via novel mechanisms of action. Two therapies targeting CD19 antigens expressed on B-cell acute lymphoblastic leukemia lineages, chimeric antigen receptor T-cells, and blinatumomab have induced complete remissions among high-risk patient populations, especially those refractory to multiple therapies. Adverse effects such as cytokine release syndrome and neurologic sequelae remain serious precautions of each therapy. Conclusion Knowledge of immunotherapy mechanisms and clinical outcomes associated with immunotherapies is critical for the optimization of treating patients with relapsed or refractory acute lymphoblastic leukemia. Future use of chimeric antigen receptor T-cells and blinatumomab demands proper assessment of a patient’s disease and treatment history in addition to unique monitoring and supportive care interventions.
Agreement analysis comparing iPad LCVA and Sloan testing in multiple sclerosis patients
Authors: Sattarnezhad Neda , Farrow Samantha , Kimbrough Dorlan , Glanz Bonnie , Healy Brian , Chitnis Tanuja 
Published: June 2017

Background: Visual symptoms are common in multiple sclerosis (MS). Low-contrast visual acuity (LCVA) testing using Sloan charts has demonstrated increased sensitivity for visual deficits compared to high-contrast acuity testing. Computerized testing of visual acuity may facilitate use in the clinic setting. Objectives: To evaluate the agreement between an iPad-based and Sloan testing of LCVA in a cohort of MS patients. Methods: A total of 38 patients with relapsing-remitting MS were enrolled after providing informed written consent at Partners MS Center, Brigham and Women’s hospital. Monocular LCVA was measured using retroilluminated Sloan chart and iPad-based LogMAR chart. Number of correct letters and agreement between two measurements were assessed for each eye using Bland–Altman analysis and paired t-test. Results: For both eyes, there was no significant difference in number correct between the two measurements using a paired t-test, and there was high correlation between two measurements (oculus dextrus (OD) r = 0.89, p < 0.001; oculus sinister (OS) r = 0.78, p < 0.001). The limits of agreement were −7.9 to +8.5 letters for the right eye and −10.9 to +11.2 letters for the left eye. Conclusion: An iPad-based LCVA test shows good agreement with Sloan testing in MS patients.