bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association betweenCOL11A1(rs1337185) andADAMTS5(rs162509) gene polymorphisms and lumbar spine pathologies in Chinese Han population: an observational study
Authors: Jiang Hua , Yang Qinghua , Jiang Jie , Zhan Xinli , Xiao Zengming 
Published: June 2017

ObjectivesA previous study identified a significant association between several single nucleotide polymorphisms (SNPs) and lumbar disc degeneration (LDD) in Indians. To validate the association between these SNPs and specific lumbar spine pathologies, we performed a case–control study in Chinese Han population.DesignAn observational study.SettingUniversity Hospital in Nanning, China.ParticipantsThis study included 428 patients with LDD and 400 normal controls.Outcome measuresPatients with LDD were classified into four subgroups, including disc herniation only (subgroup 1), discopathies or/and osteochondrosis associated with disc herniation (subgroup 2), spinal stenosis or/and spondylolisthesis (subgroup 3) and degenerative scoliosis (subgroup 4). This study was conducted by examining two aspects: environmental factors and SNP genotyping. The environmental factors were evaluated with a questionnaire survey including questions about body mass index, smoking habits, the physical demands of their job and exposure to vibrations. Rs1337185, rs5275, rs5277, rs7575934, rs3213718 and rs162509 were genotyped using a PCR-based invader assay.ResultsThe physical workload was significantly higher in patients with lumbar spine pathologies than in the normal controls (p=0.035). The genotype and allele frequencies of rs1337185 and rs162509 were significantly different between the patients with LDD and the normal controls. In rs1337185, a significant association was found between the C allele (risk allele) and the presence of disc herniation (OR=1.80; 95% CI 1.21 to 2.68; p=0.003,adjustedp=0.012) and the presence of spinal stenosis and spondylolisthesis (OR=1.92; 95% CI 1.29 to 2.89; p=0.001, adjusted p=0.004). In rs162509, the G allele represented 1.58-fold increased risk to suffer from disc herniation (OR=1.58; 95% CI 1.20 to 2.09; p=0.001, adjusted p=0.004).ConclusionThe SNPs rs1337185 inCOL11A1and rs162509 inADAMTS5are associated with susceptibility to LDD. The C allele of rs1337185 is risky for patients who are affected by lumbar pathologies such as disc herniation, stenosis and spondylolisthesis. The G allele of rs16250 represents a risk factor for the development of disc herniation.
Effect of vitamin D3on the antimicrobial activity of human airway surface liquid: preliminary results of a randomised placebo-controlled double-blind trial
Authors: Vargas Buonfiglio Luis G , Cano Marlene , Pezzulo Alejandro A , Vanegas Calderon Oriana G , Zabner Joseph , Gerke Alicia K , Comellas Alejandro P 
Published: June 2017

IntroductionVitamin D3supplementation has been reported to prevent lung infections and increase the gene expression of antimicrobial peptides such as cathelicidin. We investigated the effect of vitamin D3supplementation on the antimicrobial activity of airway surface liquid (ASL) in human subjects. Since smoking can increase the risk of respiratory infections, we also investigated the effect of smoking in the cathelicidin response to vitamin D3in human airway epithelia in vitro.MethodsThis study is a subanalysis of single-centre community-based randomised placebo-controlled double-blind trial. Participants were randomised to receive 1000 international units per day of oral vitamin D3or identical placebo for 90 days. Blood and ASL samples were collected preintervention and postintervention. 105 participants were originally enrolled, 86 completed the trial, and due to low protein concentration in the samples, 40 participants were finally analysed. Our primary outcome was ASL antimicrobial activity. We also considered secondary outcomes including changes in serum concentration of 25-hydroxyvitamin D3(25(OH)D3), 1,25-hydroxyvitamin D3, calcium and parathyroid hormone (PTH). In addition, we studied the effect of cigarette smoke extract (CSE) exposure to primary human airway epithelial cell cultures on the gene expression of cathelicidin in response to vitamin D3and expression of CYP27B1 (1-alpha hydroxylase), responsible for vitamin D3activation.ResultsVitamin D3supplementation significantly increased both ASL antimicrobial activity and serum concentration of 25(OH)D3. In a subgroup analysis, we found that smokers did not increase their baseline antimicrobial activity in response to vitamin D3. Exposure to CSE on human airway epithelia decreased baseline CYP27B1 gene expression and cathelicidin response to 25(OH)D3.ConclusionVitamin D3supplementation for 90 days increases ASL antimicrobial activity. Data from this preliminary study suggest that smoking may alter the ability of airway epithelia to activate vitamin D3and increase the gene expression of cathelicidin antimicrobial peptide.Trial registration numberNCT01967628; Post-results.
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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.