bluuebunny/crossref_metadata_2025 huggingface dataset:
Pasteurized Autograft-Prosthesis Composite Reconstruction May Not Be a Viable Primary Procedure for Large Skeletal Defects after Resection of Sarcoma
Authors: Lee Seung Yong , Jeon Dae-Geun , Cho Wan Hyeong , Song Won Seok , Kong Chang-Bae , Kim Bum Suk
Published: June 2017

Background. Among various types of composite biological reconstruction, pasteurized autograft-prosthesis composite (PPC) is popular when allograft is unavailable. Previous limited cohort study indicated result comparable to tumor prosthesis. However, as case number and follow-up increase, we experienced more complications than anticipated. We questioned the usefulness of PPC as a viable reconstructive option. Methods. We reviewed 142 PPCs and analyzed overall and location-related survival and factors associated with the failure of PPC. Results. Twenty-year survival rate of 142 PPCs was 39.8 ± 10.0%. Fifty-two (36.6%) of 142 PPCs showed failure. Among various locations, the proximal femur showed best survival: 78.0 ± 9.9%. Final status of the 52 failed PPCs was modular tumor prosthesis in 23 (43%), arthrodesis in 11 (21%), pseudarthrosis in 7 (13%), amputation in 7 (13%), and allograft-prosthesis composite in 4 (8%). Tumor volume > 200 cc (p=0.001), pasteurization length ≤ 10 cm (p=0.002), male sex (p=0.02), and locations in pelvis or tibia (p=0.029) were poor prognostic factors. Conclusions. Long-term survival of PPCs was below expectations. Despite the complexity of the procedure, there is little survival gain over tumor prosthesis. PPC may be indicated when a modular prosthesis is not readily available.
Serum Gamma-Glutamyl Transferase and Ferritin Synergistically Associated with the Rate of Chronic Kidney Disease
Authors: Chen Tao , Ren Yan , Gao Yun , Tian Haoming
Published: June 2017

The present study investigated the effects of GGT and SF on the risk of CKD. 1024 participants (436 men and 588 women) were divided into three groups according to GGT and SF levels: group 1 (both GGT and SF not in the fourth quartile), group 2 (only GGT or SF in the fourth quartile), and group 3 (both GGT and SF in the fourth quartile). The risks of CKD in different levels of GGT and SF and in groups 2-3 compared with group 1 were analyzed by multiple logistic regression. GGT or SF in the highest quartile was associated with increased risk of CKD. Such associations attenuated after adjustment for confounding factors. The incidences of CKD, especially albuminuria, increased across the three groups. Correspondingly, malondialdehyde (MDA) levels gradually increased from group 1 to group 3. The risks of CKD were higher in groups 2 and 3 than that in group 1. In group 3, the increased rate was independent of age, BMI, alcohol drinking, diabetes mellitus, hypertension, hypertriglyceridemia, and metabolic syndrome (odds ratios from 1.887 to 2.293,P<0.05). In summary, this study suggested that GGT and SF synergistically influence the rate of CKD.
Colonic Oxidative and Mitochondrial Function in Parkinson’s Disease and Idiopathic REM Sleep Behavior Disorder
Authors: Morén C. , González-Casacuberta Í. , Navarro-Otano J. , Juárez-Flores D. , Vilas D. , Garrabou G. , Milisenda J. C. , Pont-Sunyer C. , Catalán-García M. , Guitart-Mampel M. , Tobías E. , Cardellach F. , Valldeoriola F. , Iranzo A. , Tolosa E.
Published: June 2017

Objective. To determine potential mitochondrial and oxidative alterations in colon biopsies from idiopathic REM sleep behavior disorder (iRBD) and Parkinson’s disease (PD) subjects. Methods. Colonic biopsies from 7 iRBD subjects, 9 subjects with clinically diagnosed PD, and 9 healthy controls were homogenized in 5% w/v mannitol. Citrate synthase (CS) and complex I (CI) were analyzed spectrophotometrically. Oxidative damage was assessed either by lipid peroxidation, through malondialdehyde and hydroxyalkenal content by spectrophotometry, or through antioxidant enzyme levels of superoxide dismutase-2 (SOD2), glutathione peroxidase-1 (Gpx1), and catalase (CAT) by western blot. The presence of mitochondrial DNA (mtDNA) deletions was assessed by long PCR and electrophoresis. Results. Nonsignificant trends to CI decrease in both iRBD (45.69±18.15; 23% decrease) and PD patients (37.57±12.41; 37% decrease) were found compared to controls (59.51±12.52, p: NS). Lipid peroxidation was maintained among groups (iRBD: 27.46±3.04, PD: 37.2±3.92, and controls: 31.71±3.94; p: NS). Antioxidant enzymes SOD2 (iRBD: 2.30±0.92, PD: 1.48±0.39, and controls: 1.09±0.318) and Gpx1 (iRBD 0.29±0.12, PD: 0.56±0.33, and controls: 0.38±0.16) did not show significant differences between groups. CAT was only detected in 2 controls and 1 iRBD subject. One iRBD patient presented a single mtDNA deletion.
How to Use CA-125 More Effectively in the Diagnosis of Deep Endometriosis
Authors: Oliveira Marco Aurelio Pinho , Raymundo Thiers Soares , Soares Leila Cristina , Pereira Thiago Rodrigues Dantas , Demôro Alessandra Viviane Evangelista
Published: June 2017

Deep infiltrative endometriosis (DIE) is a severe form of the disease. The median time interval from the onset of symptoms to diagnosis of endometriosis is around 8 years. In this prospective study patients were divided into two groups: cases (34 DIE patients) and control (20 tubal ligation patients). The main objective of this study was to evaluate the performance of CA-125 measurement in the menstrual and midcycle phases of the cycle, as well as the difference in its levels between the two phases, for the early diagnosis of DIE. Area Under the Curve (AUC) of CA-125 in menstrual phase and of the difference between menstrual and midcycle phases had the best performance (both with AUC = 0.96), followed by CA-125 in the midcycle (AUC = 0.89). The ratio between menstrual and midcycle phases had the worst performance. CA-125 may be useful for the diagnosis of deep endometriosis, especially when both are collected during menstruation and in midcycle. These may help to decrease the long interval until the definitive diagnosis of DIE. Multicentric studies with larger samples should be performed to better evaluate the cost-effectiveness of measuring CA-125 in two different phases of the menstrual cycle.
KITD816V Induces SRC-Mediated Tyrosine Phosphorylation of MITF and Altered Transcription Program in Melanoma
Authors: Phung Bengt , Kazi Julhash U. , Lundby Alicia , Bergsteinsdottir Kristin , Sun Jianmin , Goding Colin R. , Jönsson Göran , Olsen Jesper V. , Steingrímsson Eiríkur , Rönnstrand Lars
Published: June 2017

The oncogenic D816V mutation of the KIT receptor is well characterized in systemic mastocytosis and acute myeloid leukemia. Although KITD816V has been found in melanoma, its function and involvement in this malignancy is not understood. Here we show that KITD816V induces tyrosine phosphorylation of MITF through a triple protein complex formation between KIT, MITF, and SRC family kinases. In turn, phosphorylated MITF activates target genes that are involved in melanoma proliferation, cell-cycle progression, suppression of senescence, survival, and invasion. By blocking the triple protein complex formation, thus preventing MITF phosphorylation, the cells became hypersensitive to SRC inhibitors. We have therefore delineated a mechanism behind the oncogenic effects of KITD816V in melanoma and provided a rationale for the heightened SRC inhibitor sensitivity in KITD816V transformed cells.

Implications: This study demonstrates that an oncogenic tyrosine kinase mutant, KITD816V, can alter the transcriptional program of the transcription factor MITF in melanoma Mol Cancer Res; 15(9); 1265–74. ©2017 AACR.
Abstract AP03: OVARIAN CANCER AND PULP AND PAPER MANUFACTURING IN THE US: A GEOSPATIAL ANALYSIS
Authors: Hanchette Carol L.
Published: June 2017

The goals of this research were to: 1) utilize geographic and geostatistical methods available in geographic information systems (GIS) software to gain an in-depth understanding of the spatial distribution of ovarian cancer incidence rates, at national, state and county levels; and2) based on patterns identified from the first goal, conduct a preliminary assessment of the hypothesized association between ovarian cancer occurrence and pulp and paper manufacturing.

We used the following approaches: 1) exploratory spatial data analysis of 2008-2012 ovarian cancer incidence at the county level – choropleth mapping, trend surface analysis, spatial autocorrelation and hot spot analysis;2) exploratory spatial data analysis of pulp and paper production sites, using EPA's Toxic Release Inventory data from 1988-2012;3) geographically weighted regression analysis to examine the relationship between ovarian cancer incidence and toxic emissions to air and surface water; and4) preliminary fate and transport modeling of a case study area (Wisconsin) to examine river effluent and atmospheric dispersion of chemical by-products.

Results indicate that there is a strong north-to-south trend (i.e. higher rates in the north) in ovarian cancer incidence at both state and county levels. This coincides with historically higher numbers of pulp and paper mills in northern states. Exceptions to this overall trend are statistically significant multi-county clusters of high rates in Georgia and Alabama, both of which have high levels of pulp and paper production. The hypothesis is weakly supported by geographically weighted regression, when migration patterns are taken into account. In conclusion, this research indicates that there is some support, at an ecological level, for the hypothesized association between ovarian cancer incidence rates and pulp and paper production.

Citation Format: Carol L. Hanchette, PhD. OVARIAN CANCER AND PULP AND PAPER MANUFACTURING IN THE US: A GEOSPATIAL ANALYSIS [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 AP03.
Abstract AP04: THE MOLECULAR DETECTION OF CIRCULATING TUMOR CELLS IN THE BLOOD OF OVARIAN CANCER PATIENTS
Authors: Obermayr Eva , Maritschnegg Elisabeth , Speiser Paul , Schuster Eva , Holzer Barbara , Pecha Nina , Zeillinger Robert
Published: June 2017

PURPOSE OF THE STUDY: The detection of circulating tumor cells (CTCs) in the blood of cancer patients has raised considerable interest over the last decade as a promising biomarker of minimal residual disease in various solid tumors. Although hematogenous spread has not been deemed a major issue for ovarian cancer, there are several studies demonstrating the presence and prognostic impact of CTCs in ovarian cancer patients. Recently, we developed a protocol for the enrichment of CTCs from ovarian cancer blood samples, achieving a high purity of the target cells and enabling high specificity.

EXPERIMENTAL PROCEDURES: Blood samples were enriched using a density gradient centrifugation (OncoQuick, Greiner Bio–One) followed by a micro–fluidic based isolation of the target cells using the Parsortix™ system (Angle plc.). The captured target cells were lysed, RNA was extracted (RNeasy Micro Kit, Qiagen) and transcribed into cDNA (ssVILO, Life Technologies). After a pre–amplification step (PreAmp Master Mix, Life Technologies), the transcript levels of selected genes (EpCAM, PPIC, TUSC3, EMP2, LAMB1, MAL2, FN1) were measured using RT–qPCR. Additionally, density gradient enriched cells were immuno–fluorescently stained targeting CK8/18/19, PPIC, TP53 and CD45.

SUMMARY: By combining a density gradient based pre–enrichment and the micro–fluidic Parsortix™ technology we achieved an up to 106–fold depletion of blood cell contamination. The analysis of CTC–related transcripts in the enriched samples indicated the presence of CTCs in 78% of the ovarian cancer blood samples taken at primary diagnosis (N=15) and in 80% of the samples taken at relapse (N=9). Concordant results of immuno–fluorescent staining and RT–qPCR were obtained in just 30% of ovarian cancer samples. By adding further 22 RT–qPCR markers, 92% of all cancer patients (n=13) and 100% of the ovarian cancer patients (n=7) were classified as being CTC–positive by RT–qPCR.

CONCLUSIONS: In conclusion, we developed a protocol which enabled the detection of CTC–related transcripts in the majority of ovarian cancer blood samples, which is a clear improvement in sensitivity as compared to earlier studies employing density gradient centrifugation as the only enrichment step. Our results are currently validated in the large cohort of platinum resistant ovarian cancer patients provided by a multi–center Gannet53 study.

Citation Format: Eva Obermayr, Elisabeth Maritschnegg, Paul Speiser, Eva Schuster, Barbara Holzer, Nina Pecha, Robert Zeillinger. THE MOLECULAR DETECTION OF CIRCULATING TUMOR CELLS IN THE BLOOD OF OVARIAN CANCER PATIENTS [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 AP04.
Abstract MIP-070: THE IMPACT OF HBO1 IN OVARIAN CANCER
Authors: Quintela M. , Francis L. , Sieglaff D.H. , Webb P. , Conlan S.
Published: June 2017

Epithelial ovarian cancer (OC) is now the fifth leading cause of cancer death among women in the U.S. and the leading cause of death in gynecological cancers. OC comprises a variety of tumor types (histotypes) that differ in morphology, prognosis, etiology and molecular biology. Despite the knowledge of OC heterogeneity, current treatment strategies are very similar, and unfortunately, very ineffectual. New approaches, to inhibit OC growth and progression are therefore being sought, with few obvious targets for directed therapy. Currently, large–scale gene expression, DNA copy number and mutational screens have not been able to pinpoint new high frequency drugable targets.

Epigenetic therapy conceives a whole genome approach, potentially circumventing the reliance on therapies that target infrequently mutated genes. Histone acetyl–transferases like GCN5 and PCAF have been targeted in cancer previously, and the main purpose of this study is to assess the role of one such acetyl–transferase, Histone acetyl–transferase binding to origin of replication complex 1” (HBO1, also known as KAT7 and MYST2) in the progression of OC. HBO1 is a histone acetyltransferase (HAT) that plays important roles in diverse molecular processes including DNA replication, transcription and DNA repair. Importantly, HBO1 is overexpressed in primary cancers (breast, testis, ovarian), although the molecular basis of its role is still unclear.

To better understand HBO1's role in OC, we characterized its expression in well–defined OC cell lines both at the mRNA and protein level. Observed in vitro patterns of HBO1 expression correlate well with previous observations; HBO1 is overexpressed in several OC cell lines. Interestingly, the serous histotype generally shows the highest expression. Thus far, we have now analyzed HBO1's downstream regulatory pathways in several OC cell lines through use of siRNA knock–down coupled to microarray analysis. Comparisons of the various datasets have revealed pathways common to all cell lines studied, as well as distinction.

Our approach aims to identify known epigenomic signatures that may be associated with HBO1 binding and downstream signaling which may drive differentiation toward the most advanced stages of the disease. Translating this new information through epigenetic targeting and structural inhibition may lead to novel, next–generation therapies for this most complex of disease presentations.

Citation Format: M.Quintela, L.Francis, D.H.Sieglaff, P.Webb, S.Conlan. THE IMPACT OF HBO1 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 MIP-070.
Abstract MIP-072: IDENTIFICATION OF THE SIGNALING PATHWAYS DOWNSTREAM OF PTEN LOSS IN FALLOPIAN TUBE LEADING TO INITIATION AND PROGRESSION OF HGSOC
Authors: Russo Angela , Burdette Joanna E.
Published: June 2017

High-grade serous ovarian carcinoma (HGSOC) is the most common histotype of ovarian cancer with the highest mortality rate. The lethality of these tumors is due mainly to the difficulty in detecting the disease at early stages. The findings of early lesions in the fallopian tube suggest that HGSOC may originate from the fallopian tube epithelium (FTE) and metastasize to the ovary. Recent transgenic animal models of FTE-derived HGSOC have pointed out the critical role of loss of PTEN (phosphatase and tensin homolog) in generating HGSOC when in combination with p53 mutation and alteration of BRCA1/2, but not by itself.

Our lab was the first to show that deletion of PTEN alone in FTE is sufficient to lead to tumor formation and peritoneal dissemination suggesting that the importance of PTEN in the early events of the tumorigenic cascade may have been underestimated. Indeed, it has been found that loss of PTEN is a common alteration in STIC lesions. Recent studies revealed that loss of PTEN is predicted to be much more common (30% more) in HGSOC when the DNA contribution from stroma is excluded from tumor DNA analysis.

The understanding of the sequence of the molecular alterations behind the genesis of HGSOC from FTE remains poorly defined and pivotal to early detection of HGSOC. The purpose of this study was to identify the markers of cancer initiation and progression altered upon loss of PTEN in FTE. Our data revealed increased mRNA levels of signaling components of the non-canonical (βcatenin-independent) WNT pathway. βcatenin was indeed not activated upon loss of PTEN, however inhibition of the WNT canonical and non-canonical pathway blocked PTEN-induced migration and ovarian colonization suggesting that the WNT non-canonical pathway is mediating loss of PTEN-induced tumorigenesis.

Citation Format: Angela Russo, Joanna E. Burdette. IDENTIFICATION OF THE SIGNALING PATHWAYS DOWNSTREAM OF PTEN LOSS IN FALLOPIAN TUBE LEADING TO INITIATION AND PROGRESSION OF HGSOC [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 MIP-072.
Abstract NTOC-109: MULTI–FUNCTIONAL RNA NANOPARTICLES FOR TARGETED DELIVERY OF THERAPEUTIC DRUGS FOR OVARIAN CANCER
Authors: Thiviyanathan Varatharasa , Li Xin , Pi Fengmei , Zhang Hui , Wang Hongyu , Haque Farzin , Gorenstein David , Guo Peixuan
Published: June 2017

Targeted delivery of therapeutic drugs and imaging agents remains a promising option in the treatment and diagnosis of ovarian cancer. We have developed a new class of affinity ligands that specifically recognize the ovarian cancer cells. We are using these ligands as homing devices to deliver the therapeutic drugs to ovarian cancer cells using multifunctional nanoparticles made up of RNA molecules. The affinity ligands, called Aptamers, are short, chemically modified DNA oligonucleotides and are emerging as attractive alternatives for monoclonal antibodies. Using cell-SELEX methods, we screened a large combinatorial library and have isolated two DNA thioaptamers that specifically bind human ovarian cancer cells. These thioaptamers, named ENDO 28 and ENDO 31, showed specific binding and tissue penetration towards human ovarian cancer vasculature tissue. Using mass-spectroscopy based proteomics, we have identified Annexin A2, a membrane protein upregulated in various tumor types, as the protein target for ENDO28 and ENDO31. We have assembled RNA nanoparticles using the pRNA-three way junction (3WJ) platform and conjugated the ENDO28 thioaptamer as the targeting ligand. This multifunctional RNA nanoparticle (ENDO28-RNA NP) is used to carry Doxorubicin to specifically to ovarian cancer cells. Our results showed the ENDO28 containing RNA nanoparticles delivered the Doxorubicin to the Annexin A2(+)ve ovarian cancer cells, while the control nanoparticles failed to deliver. We further tested the specificity of ENDO28-RNA NP, by using Annexin A2 (-ve) cell lines (HEK293T). Our results showed that the ENDO28 containing RNA NPs do not deliver Doxorubicin to HEK293T cells, further supporting that ENDO28 can be used for targeted delivery therapeutic drugs to ovarian cancer cells, while sparing the normal cells. Our ultimate goal is the development of patient-optimized aptamer-nanoparticle delivery systems for chemotherapy and molecular diagnostics imaging.

Citation Format: Varatharasa Thiviyanathan,, Xin Li, Fengmei Pi, Hui Zhang, Hongyu Wang, Farzin Haque, David Gorenstein and Peixuan Guo. MULTI–FUNCTIONAL RNA NANOPARTICLES FOR TARGETED DELIVERY OF THERAPEUTIC DRUGS FOR 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-109.
Abstract NTOC-110: UNEXPECTED ROLES FOR KDM4A: PROTEIN SYNTHESIS AND MTOR INHIBITOR SENSITIVITY
Authors: Rechem Capucine Van , Black Joshua C. , Greninger Patricia , Zhao Yang , Boukhali Myriam , Donado Carlos , Aryee Martin J. , Burrowes Paul d. , Ladd Brendon , Gräslund Susanne , Haas Wilhelm , Christiani David C. , Benes Cyril H. , Whetstine Johnathan R.
Published: June 2017

Single nucleotide polymorphisms (SNPs) occur within chromatin-modulating factors; however, little is known about how these variants within the coding sequence impact cancer progression or treatment. Therefore, there is a need to establish their biochemical and/or molecular contribution, their use in sub-classifying patients and their impact on therapeutic response. We demonstrate that coding SNP-A482 within the lysine tri-demethylase KDM4A/JMJD2A associates with differential outcome in cancer patients and promotes KDM4A protein turnover. Interestingly, homozygous SNP-482 cells have increased mTOR inhibitor sensitivity. mTOR inhibitors significantly reduce SNP-A482 protein levels, which parallels the increased drug sensitivity observed with KDM4A depletion. Furthermore, we demonstrate that KDM4A interacts with the translation initiation complex and impacts the distribution of translation initiation factors within polysome fractions. Upon KDM4A depletion, protein synthesis was reduced and there was enhanced protein synthesis suppression with mTOR inhibitors, which paralleled an increased sensitivity to these drugs. Lastly, we demonstrate that JIB-04, a JmjC demethylases inhibitor, suppresses translation initiation and enhances mTOR inhibitor sensitivity. These data highlight an unexpected role for KDM4A in regulating protein synthesis, in modulating mTOR inhibitor sensitivity and suggest potential novel therapeutic applications for this class of enzyme.

Citation Format: Capucine Van Rechem, Joshua C. Black, Patricia Greninger, Yang Zhao, Myriam Boukhali, Carlos Donado, Martin J. Aryee, Paul d. Burrowes, Brendon Ladd, Susanne Gräslund, Wilhelm Haas, David C. Christiani, Cyril H. Benes and Johnathan R. Whetstine. UNEXPECTED ROLES FOR KDM4A: PROTEIN SYNTHESIS AND MTOR INHIBITOR SENSITIVITY [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-110.
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

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

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

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

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

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

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.
The Use of Mouse Asthma Models to Successfully Discover and Develop Novel Drugs
Authors: Epstein Michelle M. , Tilp Cornelia , Erb Klaus J.
Published: June 2017

The past 20 years have seen a proliferation of scientific data on the pathophysiology of asthma. Most of these data were generated in mice using tool reagents, gene-deficient or transgenic animals. In contrast, studies on disease pathogenesis in patients are scarce. Previously, a good novel antiasthma target for drug development was one that abrogated asthma in mice when it was knocked out, neutralized or induced asthma when it was overexpressed. This type of approach led to many drug candidates that worked in mice but unfortunately failed in patients, thereby demonstrating that the results of experiments in mice are not always predictive of clinical efficacy. Currently, there is active debate about the use of mouse models in drug discovery. In this review, we summarize the obstacles and challenges faced when using experimental mouse models of asthma in drug discovery. We propose that the initial selection of a novel drug target begins with defining the unmet medical need and specific patient population, followed by a thorough evaluation of available human data, and, only then, well-planned and executed mouse asthma experiments. Using this approach, we argue that mouse models lend support for the target when the models are tailored for the specific asthma patient population, and that targeted, reliable, and predictive mouse models can indeed improve and accelerate the drug discovery process.
A Case of Rhegmatogenous Retinal Detachment at Late Stage following Endogenous Bacterial Endophthalmitis
Authors: Kimura Daisaku , Sato Takaki , Suzuki Hiroyuki , Kohmoto Ryohsuke , Fukumoto Masanori , Tajiri Kensuke , Kobayashi Takatoshi , Kida Teruyo , Ikeda Tsunehiko
Published: June 2017

Purpose: To report a case of rhegmatogenous retinal detachment in the late stage, despite the fact that it had previously been halted after intravitreal injection of an antimicrobial agent against endogenous bacterial endophthalmitis (EBE). Case: This study involved a 62-year-old male who had previously been diagnosed with septicemia due to liver abscess and the detection of Klebsiella pneumoniae in a culture of his liver abscess, and who underwent ophthalmic examination after his conjunctival hyperemia had failed to improve. Visual acuity could not be measured due to his general condition being poor and his declining level of consciousness. Slit lamp examination revealed bilateral iritis and cataracts, and the fundus was invisible due to vitreous opacity. Ultrasonic B-mode examination showed subretinal abscess and exudative retinal detachment, leading to the diagnosis of EBE. Vitreous injections of antibiotics were administered to both of his eyes. His right eye became affected by phthisis bulbi, but the condition in his left eye subsided, leaving a scarred lesion near the macula. However, complete retinal detachment occurred in his left eye approximately 10 months after the vitreous injection. During vitreous surgery, proliferative membrane formation was observed in the posterior pole area, and an irregular retinal break was detected in the scar margin caused by the traction of the proliferative membrane. After vitreous surgery, the retina was reattached under silicone oil. Conclusion: In cases of EBE, even if the inflammation has previously subsided, strict follow-up examinations are necessary, since complications such as rhegmatogenous retinal detachment may occur at a late stage.
Can In-Bag Manual Morcellation Represent an Alternative to Uncontained Power Morcellation in Laparoscopic Myomectomy? A Randomized Controlled Trial
Authors: Frascà Clarissa , Degli Esposti Eugenia , Arena Alessandro , Tuzzato Gianmarco , Moro Elisa , Martelli Valentina , Seracchioli Renato
Published: June 2017

Aims: The study aimed to evaluate feasibility and safety of in-bag manual morcellation compared to uncontained power morcellation during laparoscopic myomectomy. Methods: A total of 72 women undergoing laparoscopic myomectomy were randomized into 2 treatment groups: 34 patients underwent in-bag manual morcellation (experimental group) and 38 were submitted to uncontained power morcellation (control group). The primary end point was the comparison of morcellation operative time (MOT). Total operative time (TOT), rate of intraoperative complication, and postoperative outcomes in the 2 groups were regarded as secondary outcomes. Results: Mean MOT and TOT were longer in the experimental group than in the control one (MOT: 9.47 ± 5.05 vs. 6.16 ± 7.73 min; p = 0.01; TOT: 113.24 ± 28.12 vs. 96.74 ± 33.51 min; p = 0.01). No intraoperative complications occurred in either group and no cases of bag disruption or laparotomic conversion were recorded. No significant difference in hemoglobin drop, hospital stay, and postoperative outcomes was reported between groups. Conclusion: In-bag manual morcellation appears a safe and feasible procedure and, despite slightly longer operative time, could represent an alternative to uncontained power morcellation.
Desenvolvimento de impressora 3D de coordenadas polares
Authors: Yoshikawa Mariana Wong , Branco Kalenin De Moraes
Published: June 2017

Com a crescente tendência de personalização de produtos de geometrias cada vez mais complexas, as impressoras 3D proporcionam uma grande versatilidade e têm sido utilizadas cada vez mais por diversos setores da sociedade, seja as de uso profissional por parte das empresas, quanto as de uso pessoal, pela comunidade em geral. Com um processo de fabricação chamado de tecnologia aditiva, as impressoras 3D tornam-se populares para diversos usuários. Com o intuito de tornar esta tecnologia mais acessível para a população, foi desenvolvida uma impressora 3D de coordenadas polares, com a vantagem de possuir uma quantidade menor de componentes que as impressoras 3D de coordenadas cartesianas.
Reconhecimento de Sinais da Libras por Visão Computacional
Authors: Ono Koroishi Giovanna , Vieira Louzada Silva Bruna
Published: June 2017

O reconhecimento automático linguagens de sinais promete facilitar a comunicação entre surdos e o restante da população. As tecnologias atuais esbarram em obstáculos como dificuldade de rastreio das mãos e reconhecimento de poses. Este projeto estuda uma abordagem probabilística para a identificação de sinais da LIBRAS com um sensor RGBD. Essa identificação é baseada na classificação SematosÊmica da linguagem. Durante o projeto, foi implementado um identificador automático de sinais da LIBRAS que captura o vídeo através do sensor Kinect, segmenta o objeto de interesse (a mão direita) e calcula a probabilidade dos sinais. O principal desafio do trabalho foi reconhecer as configurações de mão e para solucioná-lo utilizou-se modelos estruturados em nuvens de pontos e o algoritmo de ICP. O projeto mostrou que essa abordagem torna viável o reconhecimento automático, pois obteve-se 65% de acerto entre 48 testes envolvendo 12 sinais diferentes, mesmo com as limitações de recursos e tempo existentes.
Regulatory T-Cell Augmentation or Interleukin-17 Inhibition Prevents Calcineurin Inhibitor–Induced Hypertension in Mice
Authors: Chiasson Valorie L. , Pakanati Abhinandan R. , Hernandez Marcos , Young Kristina J. , Bounds Kelsey R. , Mitchell Brett M.
Published: June 2017

The immunosuppressive calcineurin inhibitors cyclosporine A and tacrolimus alter T-cell subsets and can cause hypertension, vascular dysfunction, and renal toxicity. We and others have reported that cyclosporine A and tacrolimus decrease anti-inflammatory regulatory T cells and increase proinflammatory interleukin-17–producing T cells; therefore, we hypothesized that inhibition of these effects using noncellular therapies would prevent the hypertension, endothelial dysfunction, and renal glomerular injury induced by calcineurin inhibitor therapy. Daily treatment of mice with cyclosporine A or tacrolimus for 1 week significantly decreased CD4
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regulatory T cells in the spleen and lymph nodes, as well as induced hypertension, vascular injury and dysfunction, and glomerular mesangial expansion in mice. Daily cotreatment with all-trans retinoic acid reported to increase regulatory T cells and decrease interleukin-17–producing T cells, prevented all of the detrimental effects of cyclosporine A and tacrolimus. All-trans retinoic acid also increased regulatory T cells and prevented the hypertension, endothelial dysfunction, and glomerular injury in genetically modified mice that phenocopy calcineurin inhibitor–treated mice (FKBP12-Tie2 knockout). Treatment with an interleukin-17–neutralizing antibody also increased regulatory T-cell levels and prevented the hypertension, endothelial dysfunction, and glomerular injury in cyclosporine A–treated and tacrolimus-treated mice and FKBP12-Tie2 knockout mice, whereas an isotype control had no effect. Augmenting regulatory T cells and inhibiting interleukin-17 signaling using noncellular therapies prevents the cardiovascular and renal toxicity of calcineurin inhibitors in mice.