bluuebunny/crossref_metadata_2025 huggingface dataset:
Galilean covariance, Casimir effect and Stefan–Boltzmann law at finite temperature
Authors: Ulhoa S. C. , Santos A. F. , Khanna Faqir C.
Published: June 2017

The Galilean covariance, formulated in 5-dimensions space, describes the nonrelativistic physics in a way similar to a Lorentz covariant quantum field theory being considered for relativistic physics. Using a nonrelativistic approach the Stefan–Boltzmann law and the Casimir effect at finite temperature for a particle with spin zero and 1/2 are calculated. The thermo field dynamics is used to include the finite temperature effects.
Muscle Lipid Metabolism: Role of Lipid Droplets and Perilipins
Authors: Morales Pablo Esteban , Bucarey Jose Luis , Espinosa Alejandra
Published: June 2017

Skeletal muscle is one of the main regulators of carbohydrate and lipid metabolism in our organism, and therefore, it is highly susceptible to changes in glucose and fatty acid (FA) availability. Skeletal muscle is an extremely complex tissue: its metabolic capacity depends on the type of fibers it is made up of and the level of stimulation it undergoes, such as acute or chronic contraction. Obesity is often associated with increased FA levels, which leads to the accumulation of toxic lipid intermediates, oxidative stress, and autophagy in skeletal fibers. This lipotoxicity is one of the most common causes of insulin resistance (IR). In this scenario, the “isolation” of certain lipids in specific cell compartments, through the action of the specific lipid droplet, perilipin (PLIN) family of proteins, is conceived as a lifeguard compensatory strategy. In this review, we summarize the cellular mechanism underlying lipid mobilization and metabolism inside skeletal muscle, focusing on the function of lipid droplets, the PLIN family of proteins, and how these entities are modified in exercise, obesity, and IR conditions.
Subchronic Infection of Porphyromonas gingivalis and Tannerella forsythia Stimulates an Immune Response but Not Arthritis in Experimental Murine Model
Authors: Hernández-Aguas Jorday , Montiel-Hernández José Luis , De La Garza-Ramos Myriam A. , Ruiz-Ramos Rosa Velia , Escamilla García Erandi , Guzmán-García Mario Alberto , Ayón-Haro Esperanza Raquel , Garza-Elizondo Mario Alberto
Published: June 2017

Studies have proposed that Porphyromonas gingivalis (Pg) and Tannerella forsythia (Tf) promote a nonspecific inflammatory response that could produce systemic disease. Oral inoculation of Pg and Tf on the immune and arthritis response was evaluated in BALB/C mice divided into four groups: (1) sham; (2) food contaminated with Pg/Tf; (3) complete Freund’s adjuvant (CFA) + Pg/Tf; and (4) CFA alone. CFA was administered subcutaneously on days 1 and 14. The arthritis response was monitored for 21 days after day 14 of CFA administration. IL-1β and IL-6 were determined in serum. T cell activation was evaluated by CD25 in salivary lymph nodes or mouse spleen. Pad inflammation appeared by day 19 in the CFA group, but animals with bacteria inoculation presented a delay. A significant increase in IL-6 was found in Groups 3 and 4, but not with respect to IL-1β. We observed an increase in CD25 in cells derived from cervical nodes and in animals with bacteria inoculation and CFA. A local immune response was observed in mice inoculated with Pg and Tf (T cell activation); a systemic response was observed with CFA. Since pad inflammation was delayed by bacterial inoculation this suggests that local T cell activation could decrease pad inflammation.
Changes in Body Water Caused by Sleep Deprivation in Taeeum and Soyang Types in Sasang Medicine: Prospective Intervention Study
Authors: Hong Seung Min , Kim Byung Joo , Shin Seungwon , Hwang Minwoo
Published: June 2017

Background. There is a negative relationship between sleep deprivation and health. However, no study has investigated the effect of sleep deprivation on individuals with different body composition. The aim of this study was to determine the differential effect of sleep deprivation in individuals with different body compositions (fluid) according to Soyang type (SY) and Taeeum type (TE). Methods. Sixty‐two cognitively normal, middle‐aged people with normal sleep patterns were recruited from the local population. The duration of participants’ sleep was restricted to 4 h/day during the intervention phase. To examine the physiological changes brought on by sleep deprivation and recovery, 10 ml of venous blood was obtained. Results. Total Body Water (TBW) and Extracellular Water (ECW) were significantly different between the groups in the intervention phase. Physiological parameters also varied from the beginning of the resting phase to the end of the experiment. Potassium levels changed more in SY than TE individuals. Conclusion. Participants responded differently to the same amount of sleep deprivation depending on their Sasang constitution types. This study indicated that SY individuals were more sensitive to sleep deprivation and were slower to recover from the effects of sleep deprivation than TE individuals.
Salinomycin Exerts Anticancer Effects on PC-3 Cells and PC-3-Derived Cancer Stem Cells In Vitro and In Vivo
Authors: Zhang Yunsheng , Liu Luogen , Li Fang , Wu Tao , Jiang Hongtao , Jiang Xianxun , Du Xiaobo , Wang Yi
Published: June 2017

Salinomycin is an antibiotic isolated from Streptomyces albus that selectively kills cancer stem cells (CSCs). However, the antitumor mechanism of salinomycin is unclear. This study investigated the chemotherapeutic efficacy of salinomycin in human prostate cancer PC-3 cells. We found that cytotoxicity of salinomycin to PC-3 cells was stronger than to nonmalignant prostate cell RWPE-1, and exposure to salinomycin induced G2/M phage arrest and apoptosis of PC-3 cells. A mechanistic study found salinomycin suppressed Wnt/β-catenin pathway to induce apoptosis of PC-3 cells. An in vivo experiment confirmed that salinomycin suppressed tumorigenesis in a NOD/SCID mice xenograft model generated from implanted PC-3 cells by inhibiting the Wnt/β-catenin pathway, since the total β-catenin protein level was reduced and the downstream target c-Myc level was significantly downregulated. We also showed that salinomycin, but not paclitaxel, triggered more apoptosis in aldehyde dehydrogenase- (ALDH-) positive PC-3 cells, which were considered as the prostate cancer stem cells, suggesting that salinomycin may be a promising chemotherapeutic to target CSCs. In conclusion, this study suggests that salinomycin reduces resistance and relapse of prostate tumor by killing cancer cells as well as CSCs.
Jacalin Has Chemopreventive Effects on Colon Cancer Development
Authors: Geraldino Thais Herrero , Modiano Patricia , Veronez Luciana Chain , Flória-Santos Milena , Garcia Sergio Britto , Pereira-da-Silva Gabriela
Published: June 2017

Colorectal cancer, which is one of the most common causes of cancer-related deaths worldwide, has a slow natural history that provides a great opportunity for prevention strategies. Plant-derived natural products have received considerable attention because of their inherent colorectal cancer chemopreventive effects. The plant lectin jacalin specifically recognizes the tumor-associated Thomsen-Friedenreich antigen and has antiproliferative effects on human colon cancer cells, highlighting its potential antitumor activity. To evaluate jacalin’s potential application in colorectal cancer chemoprevention, we studied its effects on the early stages of carcinogenesis. Balb/c mice were given 4 intrarectal deposits of 0.1 ml solution of Methyl-N′-Nitro-N-Nitroso-Guanidine (5 mg/ml) twice a week (with a 3-day interval) for 2 weeks. Starting 2 weeks before carcinogen administration, animals were treated orally with jacalin (0.5 and 25 μg) three times a week (on alternate weekdays) for 10 weeks. We show that jacalin treatment reduced the number of preneoplastic lesions in carcinogen-exposed mice. This anticarcinogenic activity was associated with decreased colonic epithelial cell proliferation and stromal COX-2 expression and with increased intestinal production of TNF-α. Our results demonstrate that jacalin is able to modulate the early stages of colon carcinogenesis and emphasize its promising chemopreventive activity in colorectal cancer.
Nyctanthes arbor-tristis Ameliorated FCA‐Induced Experimental Arthritis: A Comparative Study among Different Extracts
Authors: Uroos Maliha , Abbas Zaigham , Sattar Shumaila , Umer Nigarish , Shabbir Arham , Shafiq-ur-Rehman  , Sharif Ahsan
Published: June 2017

Nyctanthes arbor-tristis (NAT) is commonly used traditionally for the treatment of rheumatism and inflammatory diseases. Current study evaluates the antiarthritic potential of NAT using Freund’s adjuvant‐induced arthritic rat model. Treatments with methanolic, ethyl acetate, and n‐hexane extracts were continued for consecutive 20 days. Macroscopic arthritic scoring and water displacement plethysmometry were used to evaluate arthritic development. Hematological and biochemical parameters were investigated and ankle joints were processed for histopathological evaluation. Qualitative phytochemical analysis and GC‐MS analysis were conducted for identification of constituents. NAT extracts suppressed arthritic scoring, paw edema, infiltration of inflammatory cells, pannus formation, and bone erosion. The plant extracts ameliorated total leukocytes and platelet counts and nearly normalized red blood cells (RBC) counts and hemoglobin (Hb) content. The extracts were found safe in terms of hepatotoxicity and nephrotoxicity as determined by aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine, and urea levels. Comparative analysis showed that ethyl acetate extract produced the highest inhibition of paw edema. The major constituents found in ethyl acetate extract can be classified into three major classes, that is, terpenes, terpenoids, fatty acids, and iridoid glycosides. Current study showed that Nyctanthes arbor-tristis ameliorated experimental rheumatoid arthritis and ethyl acetate extract possessed the highest inhibitory activity.
Prognostic Impact of miR-224 and RAS Mutations in Medullary Thyroid Carcinoma
Authors: Cavedon Elisabetta , Barollo Susi , Bertazza Loris , Pennelli Gianmaria , Galuppini Francesca , Watutantrige-Fernando Sara , Censi Simona , Iacobone Maurizio , Benna Clara , Vianello Federica , Zovato Stefania , Nacamulli Davide , Mian Caterina
Published: June 2017

Little is known about the function of microRNA-224 (miR-224) in medullary thyroid cancer (MTC). This study investigated the role of miR-224 expression in MTC and correlated it with mutation status in sporadic MTCs. A consecutive series of 134 MTCs were considered. Patients had a sporadic form in 80% of cases (107/134). In this group, REarranged during transfection (RET) and rat sarcoma (RAS) mutation status were assessed by direct sequencing in the tumor tissues. Quantitative real-time polymerase chain reaction was used to quantify mature hsa-miR-224 in tumor tissue. RAS (10/107 cases, 9%) and RET (39/107 cases, 36%) mutations were mutually exclusive in sporadic cases. miR-224 expression was significantly downregulated in patients with the following: high calcitonin levels at diagnosis (p=0.03, r=−0.3); advanced stage (p=0.001); persistent disease (p=0.001); progressive disease (p=0.002); and disease-related death (p=0.0001). We found a significant positive correlation between miR-224 expression and somatic RAS mutations (p=0.007). Patients whose MTCs had a low miR-224 expression tended to have a shorter overall survival (log-rank test p=0.005). On multivariate analysis, miR-224 represented an independent prognostic marker. Our data indicate that miR-224 is upregulated in RAS-mutated MTCs and in patients with a better prognosis and could represent an independent prognostic marker in MTC patients.
Evaluation of Paracervical Block and IV Sedation for Pain Management during Hysteroscopic Polypectomy: A Randomized Clinical Trial
Authors: Asgari Zahra , Razavi Maryam , Hosseini Reihaneh , Nataj Masoumeh , Rezaeinejad Mahroo , Sepidarkish Mahdi
Published: June 2017

Background. The aim of this study was to compare the effectiveness of paracervical block (PB) and IV sedation (IVS) on women’s pain perception during operative hysteroscopy. Methods. A total of 84 patients with uterine polyps were randomized to either PB or IV sedation or general anesthesia (GA) as control group. In PB group, the patients received oral diazepam 10 mg and 100 mg diclofenac Na suppository 60 min before surgery and 10 cc of 2% buffered lidocaine was injected at cervix. Conscious sedation was performed with the IV administration of 2-3 mg/kg/h propofol 1% and midazolam 0.02 mg/kg and fentanyl (1-2 μg/kg) with o2 4-5 lit/min via face mask. Results. There were no significant differences between groups on VAS score at 3 hours after operation (PB: 1.22 ± (1.31), IVS: 1.10 ± (1.68), GA: 1.29 ± (2.03), P=0.671) and during recovery (PB: 0.85 ± (1.06), IVS: 0.68 ± (1.33), GA: 1.21 ± (2.04), P=0.458). There was no difference between PB (3.33 ± (2.81)) and IVS (2.31 ± (2.63)) groups at hysteroscopy (P=0.182). Patients undergoing IVS reported lower VAS score than PB group at dilation and curettage, although the difference was not statistically significant (PB: 2.59 ± (1.78), IVS: 1.72 ± (2.34), P=0.051). Moreover, patients undergoing IVS obtained lower VAS score than PB group at polypectomy, while the difference was not statistically significant (PB: 1.81 ± (1.52), IVS: 1.10 ± (1.32), P=0.073). Conclusion. The finding of the present study revealed that IVS and PB showed the same effect in reducing pain during and after gynecological surgical procedures. The study was registered in Iranian Registry of Clinical Trial with the number IRCT2016031426855N3, on April 28, 2016.
Isolation and Characterization of Yeasts Able to Assimilate Sugarcane Bagasse Hemicellulosic Hydrolysate and Produce Xylitol Associated with Veturius transversus (Passalidae, Coleoptera, and Insecta)
Authors: Matos Italo Thiago Silveira Rocha , Assunção Enedina Nogueira , Carmo Edson Junior do , Soares Verena Makaren , Astolfi-Filho Spartaco
Published: June 2017

Yeasts are an important component of insect gut microbial content, playing roles such as degradation of polymers and toxic compounds, biological control, and hormone, vitamin, and digestive enzyme production. The xylophagous beetle gut is a hyperdiverse habitat and a potential source of new species with industrial abilities such as enzyme production, pentose fermentation, and biodetoxification. In this work, samples of Veturius transversus (Passalidae, Coleoptera, and Insecta) were collected from the Central Amazon Rainforest. Their guts were dissected and a total of 20 microbial colonies were isolated using sugarcane bagasse hemicellulosic hydrolysate. They were identified as having 10 distinct biochemical profiles, and genetic analysis allowed identification as three clades in the genera Candida, Williopsis, and Geotrichum. All colonies were able to assimilate D-xylose and 18 were able to produce xylitol, especially a strain of Geotrichum, with a maximum yield of 0.502 g·g−1. These results agree with a previous prediction that the microbial community associated with xylophagous insects is a promising source of species of biotechnological interest.
Natural Scaffolds for Regenerative Medicine: Direct Determination of Detergents Entrapped in Decellularized Heart Valves
Authors: Dettin Monica , Zamuner Annj , Naso Filippo , Monteleone Antonella , Spina Michele , Gerosa Gino
Published: June 2017

The increasing urgency for replacement of pathological heart valves is a major stimulus for research on alternatives to glutaraldehyde-treated grafts. New xenogeneic acellular heart valve substitutes that can be repopulated by host cells are currently under investigation. Anionic surfactants, including bile acids, have been widely used to eliminate the resident cell components chiefly responsible for the immunogenicity of the tissue, even if detergent toxicity might present limitations to the survival and/or functional expression of the repopulating cells. To date, the determination of residual detergent has been carried out almost exclusively on the washings following cell removal procedures. Here, a novel HPLC-based procedure is proposed for the direct quantification of detergent (cholate, deoxycholate, and taurodeoxycholate) residues entrapped in the scaffold of decellularized porcine aortic and pulmonary valves. The method was demonstrated to be sensitive, reproducible, and extendable to different types of detergent. This assessment also revealed that cell-depleted heart valve scaffolds prepared according to procedures currently considered for clinical use might contain significant amount of surfactant.
Active Control for Multinode Unbalanced Vibration of Flexible Spindle Rotor System with Active Magnetic Bearing
Authors: Qiao Xiaoli , Hu Guojun
Published: June 2017

The unbalanced vibration of the spindle rotor system in high-speed cutting processes not only seriously affects the surface quality of the machined products, but also greatly reduces the service life of the electric spindle. However, since the unbalanced vibration is often distributed on different node positions, the multinode unbalanced vibration greatly exacerbates the difficulty of vibration control. Based on the traditional influence coefficient method for controlling the vibration of a flexible rotor, the optimal influence coefficient control method with weights for multinode unbalanced vibration of flexible electric spindle rotors is proposed. The unbalanced vibration of all nodes on the whole spindle rotor is used as the control objective function to achieve optimal control. The simulation results show that the method has an obvious control effect on multinode unbalanced vibration.
Abstract MIP-050: NON–CODING GENETIC ABERRATIONS IN HIGH GRADE SEROUS OVARIAN CANCER
Authors: Chaluvally–Raghavan Pradeep
Published: June 2017

BACKGROUND

The 3q26.2 loci amplification is present in a large proportion of high grade serous ovarian cancer (HGSOC) is less frequently curable disease in the clinic. The 3q26.2 loci, which is present in at least 35% of HGSOC, is large and structurally complex suggesting that multiple coding genes of the amplicon contribute to tumor initiation and progression either alone or through cooperative activity. Our high resolution SNP array mapping of 3q26.2 amplicon identified microRNAs miR569 and miR551b are highly amplified in addition to the coding genes in a large set of ovarian cancer samples. Potential role of miR569 and miR551b are not characterized previously in the context of ovarian cancer. Herein our studies provide new mechanisms underlying the oncogenic role of microRNAs amplified in 3q26 in ovarian cancer.

RESULTS

We demonstrated a strong correlation between 3q26.2 amplification and overexpression of miR569 in patient's samples of ovarian cancer. Using target based analysis, AGOCLIP methods, cellular and molecular approaches, we have demonstrated that 3q26 microRNAs altered the expression of TP53INP1, P53AIP1, and STAT3, which are critical regulators of survival and proliferation of ovarian cancer cells. Employing in silico and in vitro experiments, we have showed that miR569 directly targets and inhibited the expression of p53 induced tumor suppressor gene TP53INP1. miRNAs are thought to primarily downregulate the gene expression by binding 3'UTR of target genes. Our recent results identified a novel action of microRNAs, that miR551b can bind to the promoter of STAT3 and activate STAT3 transcription by recruiting transcription factors and RNA–Polymerase–II to the promoter. In sum, the discovery of miRNAs and lncRNAs as potent regulators of RNA stability and translation, dramatically changed our understanding of the mechanisms controlling the gene expression and protein levels. We are expecting that our studies will identify new biomarkers and novel targets for therapy.

Citation Format: Pradeep Chaluvally–Raghavan, PhD. NON–CODING GENETIC ABERRATIONS IN HIGH GRADE SEROUS 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-050.
Abstract MIP-068: TUMOR–PROMOTING EFFECTS OF THE OVARIAN CANCER MUCIN, MUC16, ARE ASSOCIATED WITH SUPPRESSION OF INNATE IMMUNITY
Authors: Felder Mildred , Kapur Arvinder , Rakhmilevich Alexander L. , Qu Xiaoyi , Connor Joseph , Patankar Manish S.
Published: June 2017

The membrane-spanning mucin MUC16 promotes proliferation and metastasis of ovarian cancer cells. Here, we demonstrate that mice implanted with MUC16-knockdown human ovarian tumors show greater than two-fold increase in survival as compared to controls with tumors that express this mucin. While the lower survival of mice bearing MUC16-positive tumors is reportedly attributable to the ability of MUC16 to increase proliferation and metastasis, we also show that murine NK cells and macrophages are more efficient at lysing MUC16-knockdown cells. Macrophages showed infiltration in the MUC16-knockdown tumors but were restricted to the surrounding stroma in MUC16-positive tumors. In vitro cytotoxicity assays with NK cells and macrophages isolated from mice stimulated with agonistic anti-CD40 antibody showed 2-3-fold increased activity against the MUC16-knockdown cells as compared to matching target cells expressing this mucin. Finally, knockdown of MUC16 increased the susceptibility of cancer cells to ADCC and lysis by KS-IL2, an immunocytokine investigated as a treatment for ovarian cancer. Collectively our results support a role for MUC16 in promoting tumor growth. The ability of murine innate cells to selectively target MUC16-knockdown cells indicates that in vivo experiments investigating the biology of this mucin should be interpreted taking into account its immunomodulating activity as well as its growth promoting properties.

Citation Format: Mildred Felder, Arvinder Kapur, Alexander L. Rakhmilevich, Xiaoyi Qu2, Joseph Connor, and Manish S. Patankar. TUMOR–PROMOTING EFFECTS OF THE OVARIAN CANCER MUCIN, MUC16, ARE ASSOCIATED WITH SUPPRESSION OF INNATE IMMUNITY [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-068.
Abstract NTOC-078: ENGINEERING ADOPTIVE T CELL THERAPY FOR EFFICACY IN OVARIAN CANCER
Authors: Anderson Kristin G. , Bates Breanna M. , Chiu Edison Y. , Greenberg Philip D.
Published: June 2017

Over 20,000 women are diagnosed with ovarian cancer annually—more than half will die within 5 years and this rate has changed very little in the last 20 years, highlighting the need for innovative therapies. Reprogramming immune system cells to target and kill cancer cells represents a promising new treatment strategy. Immune T cells have the potential to control tumor growth without toxicity to healthy tissues when engineered to target proteins uniquely overexpressed in tumors. Recent technological advances have helped identify and validate Wilms' Tumor Antigen 1 (WT1) and mesothelin (MSLN) as valid antigen targets for ovarian cancer; these proteins contribute to malignant and invasive phenotypes and have limited expression in healthy cells. In preclinical studies using either patient-derived cell lines or the mouse ID8 ovarian tumor model, we show that T cells engineered to express either a WT1- or MSLN- specific high-affinity T cell receptor (TCR) can kill human and murine ovarian tumor cells in vitro. Moreover, in a disseminated in vivo murine model, adoptively transferred TCRengineered T cells preferentially accumulated within established ID8 tumors, delayed ovarian tumor growth, and prolonged mouse survival. However, our data also reveal that the tumor microenvironment (TME) limits the persistence and killing capacity of the engineered T cells. Cellular and molecular analyses of human tumor specimens show human therapy will face similar obstacles posed by the TME. Ongoing studies will be discussed that are exploring strategies to overcome elements common to the human and murine TME, including direct modulation of the environment and T cell engineering to promote T cell survival and function.

Citation Format: Kristin G. Anderson, Breanna M. Bates, Edison Y. Chiu, Philip D. Greenberg. ENGINEERING ADOPTIVE T CELL THERAPY FOR EFFICACY 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-078.
Abstract NTOC-096: INTRAPERITONEAL CHEMOTHERAPY AFTER PRIMARY OR INTERVAL DEBULKING SURGERY FOR ADVANCED EPITHELIAL OVARIAN CANCER
Authors: Lee Jessica , Curtin John P , Muggia Franco M , Pothuri Bhavana , Boyd Leslie R. , Chern Jing-Yi , Frey Melissa K , Blank Stephanie V
Published: June 2017

PURPOSE: To evaluate the outcomes of intraperitoneal (IP) chemotherapy compared with those of intravenous (IV) chemotherapy in patients with advanced ovarian cancer treated either with neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS) or with primary debulking surgery (PDS).

METHODS: Patients diagnosed with FIGO stage III or IV epithelial ovarian, fallopian tube or primary peritoneal carcinoma treated at our institutions with PDS or NACT and IDS from 2006-2014 were identified. Covariates were compared using chi-square analyses, t-tests and Mann-Whitney tests. Survival rates were calculated using the Kaplan-Meier method and compared with log rank tests and Cox multivariate regression models.

RESULTS: Sixty one patients received NACT and underwent IDS with residual disease of ≤ 1 cm; 40 patients (65.6%) received IP chemotherapy and 21 patients (34.4%) were given IV chemotherapy after IDS. The median number of chemotherapy cycles was three (range 3-8), and 34 patients (85.0%) completed the prescribed dose of IP chemotherapy. The median progression free survival was 16.5 months in the IP group and 15.0 months in the IV group (p = 0.88). The estimated median overall survival was 64.0 months in the IP group and 42.0 months in the IV group (p = 0.12).

During the same study period, 148 patients underwent optimal PDS after which 93 patients (83.6%) received IP chemotherapy and 55 patients (37.2%) were given IV chemotherapy. Patients after IP chemotherapy had improved survival outcomes when compared to patients after IV chemotherapy. The median progression free survival was 29.0 months after IP chemotherapy and 16.0 months after IV chemotherapy (p < 0.0001) and the median overall survival was 93.0 months after IP chemotherapy and 43.0 months after IV chemotherapy (p < 0.0001).

CONCLUSIONS: Although IP chemotherapy after PDS showed improved survival, IP chemotherapy after NACT and IDS, while tolerable with high rates of completion, did not demonstrate a survival advantage over IV chemotherapy in our patients.

Citation Format: Jessica Lee MD, John P Curtin MD, Franco M Muggia MD, Bhavana Pothuri MD, Leslie R. Boyd MD, Jing-Yi Chern MD, Melissa K Frey MD, Stephanie V Blank MD. INTRAPERITONEAL CHEMOTHERAPY AFTER PRIMARY OR INTERVAL DEBULKING SURGERY FOR ADVANCED EPITHELIAL 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-096.
Abstract NTOC-111: TARGETING COMPONENTS OF THE STAT3 SIGNALING PATHWAY FOR OVARIAN CANCER THERAPY: IMPLICATIONS FROM 3D CULTURE SYSTEMS
Authors: Walker Sarah R. , Zhang Yixi , Liu Suhu , Giaccone Zachary T. , Frank David A.
Published: June 2017

High grade serous ovarian cancer remains deadly for countless women; therefore, better treatment options are necessary. To identify new targeted therapies for this disease, it is necessary to delineate critical signaling pathways that are driving the pathogenesis of ovarian cancer. Since ovarian cancer in patients grows as three dimensional clusters, particularly within the peritoneum, we examined signaling pathways that were activated with 3D culture in vitro. Comparing the growth of ovarian cancer cell lines in 2D and 3D, we found that the transcription factor STAT3 consistently becomes activated in 3D culture systems. Ovarian cancer cells that lack STAT3 activation when grown in 2D acquire STAT3 activation when grown in 3D. Additionally, ovarian cancer cell lines that have constitutively active STAT3 when grown in 2D display enhanced STAT3 activation when these cells are grown in 3D. STAT3 is often activated through autocrine or paracrine mechanisms via cytokine receptors interacting with the transmembrane signal transducing molecule GP130 and intracellular Jak kinases. Once activated, these kinases tyrosine phosphorylate STAT3, which then translocates to the nucleus, binds to cognate DNA binding sites, and regulates genes that are involved in migration, invasion, and survival. We have found that not only is STAT3 tyrosine phosphorylated in cells grown in 3D, but that STAT3 is functionally active such that STAT3 DNA binding and target gene expression is enhanced in ovarian cancer cells grown in 3D versus 2D. We next determined if STAT3 signaling was necessary for ovarian cancer cell growth in 3D. Using RNA interference directed to STAT3 or GP130, we found that both proteins are necessary for the 3D growth of ovarian cancer cells. In addition, we have found that cells grown in 3D are more resistant to cytotoxic drugs; therefore, we wanted to determine if inhibiting STAT3 would enhance the response to conventional chemotherapy. Using both chemical biology and computational approaches, we have identified small molecule inhibitors of STAT3 that target a number of distinct points in the STAT3 activation pathway. We have found that a subset of these compounds disrupt the morphology of ovarian cancer spheroids. Furthermore, combination of these inhibitors with paclitaxel leads to enhanced loss of viability of cells grown in 3D, raising the possibility of using STAT3 inhibitors alone or in combination with chemotherapeutic drugs for the treatment of ovarian cancer.

Citation Format: Sarah R. Walker, Yixi Zhang, Suhu Liu, Zachary T. Giaccone, and David A. Frank. TARGETING COMPONENTS OF THE STAT3 SIGNALING PATHWAY FOR OVARIAN CANCER THERAPY: IMPLICATIONS FROM 3D CULTURE SYSTEMS [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-111.
Abstract NTOC-119: VCP INHIBITORS INDUCE ENDOPLASMIC RETICULUM (ER) STRESS AND SYNERGISTICALLY KILL OVARIAN CANCER CELLS IN COMBINATION WITH SALUBRINAL OR MIFEPRISTONE
Authors: Bastola Prabhakar , Schoenen Frank J. , Chien Jeremy
Published: June 2017

Valosin-containing protein (VCP) or p97, a member of AAA-ATPase protein family, has been linked to several cellular functions including endoplasmic reticulum associated degradation (ERAD), cell division, golgi-membrane reassembly and autophagy. Recent studies have indicated VCP as one of the vulnerabilities in ovarian cancer. Here, we show that treatment with CB-5083, an orally bioavailable compound derived from previously identified quinazoline scaffold-based VCP inhibitor ML240, contributes to cytotoxicity in high-grade serous or clear cell ovarian cancer cell lines. CB-5083 treatment results in increased unfolded protein response (UPR), accumulation of cell cycle proteins as a result of inhibition of proteosomal degradation, cell cycle arrest at G1, and subsequent cell death mediated by both intrinsic and extrinsic apoptotic pathways. These results support an emerging concept that ER stress pathway can be therapeutically targeted in ovarian cancer.

Since CB-5083 induces CHOP-dependent apoptosis, we tested the extent to which VCP inhibitors act synergistically with salubrinal, a compound that inhibits GADD34 and enhances eIF2α phosphorylation. Results from Sulforadamine B and clonogenic assays indicate that VCP inhibitors and salubrinal act synergistically across various concentrations of drug combination. Based on recent studies indicating that mifepristone, a steroidal antagonist to progesterone and glucocorticoid, induce ER stress and subsequent cell death, we also tested the potential drug synergies between VCP inhibitors and mifepristone. Our results indicate these drugs act synergistically across various concentrations in ovarian cancer cells. Analysis of TCGA RNA-sequencing datasets indicate VCP expression is down-regulated in cisplatin-resistant tumor samples compared to cisplatin-sensitive cancer. This data is consistent with the fact that tumors with lower expression of VCP shows significant association with poor progression-free survival and overall survivor. Finally, our results indicate that cells with lower expression of VCP are more sensitive to VCP inhibitors than those with higher expression. Considering that cisplatin-resistant tumor samples have lower expression of VCP, VCP inhibitors may be a good therapeutic candidate to treat cisplatin-resistant ovarian cancer. Collectively, our results provide evidence that VCP inhibitors can be used as a single agent and can be synergized with compounds that prolong or induce ER stress in ovarian cancer.

Citation Format: Prabhakar Bastola, Frank J. Schoenen, Jeremy Chien. VCP INHIBITORS INDUCE ENDOPLASMIC RETICULUM (ER) STRESS AND SYNERGISTICALLY KILL OVARIAN CANCER CELLS IN COMBINATION WITH SALUBRINAL OR MIFEPRISTONE [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-119.
Abstract TMEM-017: COLLAGEN TYPE XI ALPHA 1 (COL11A1) IS A NOVEL STROMAL MEDIATOR OF CHEMORESISTANCE
Authors: Rada Miran , Eldred Catherine , Sage Jessica , Orsulic Sandra , Cheon Dong-Joo
Published: June 2017

Despite an initial satisfactory response to platinum and taxane-based regimens, approximately 80% of ovarian cancer patients will succumb to chemoresistant recurrent disease. Thus, there is a dire need to understand the mechanism by which tumor cells develop resistance to subsequent therapies after first-line cisplatin treatment.

We previously identified that collagen type XI, alpha 1 (COL11A1) is a novel biomarker associated with poor survival, metastasis, and chemoresistance in ovarian cancer. COL11A1 is expressed in a subset of α-SMA-positive cancer-associated fibroblasts (CAFs) adjacent to tumor cells. COL11A1 expression in peritumoral CAFs increases during ovarian cancer progression, with the highest expression in recurrent tumors. However, the functional significance of stromal COL11A1 in ovarian cancer progression and chemoresistance is largely unknown.

To determine the role of stromal COL11A1 in chemoresistance, we generated COL11A1-overexpressing TRS3 ovarian fibroblasts, co-cultured them with A2780 and OVCAR3 ovarian cancer cells, and measured cancer cell sensitivity to cisplatin. Our data showed that ovarian cancer cells become resistant to cisplatin when cultured in direct contact with COL11A1-overexpressing fibroblasts as well as in fibroblast conditioned media. Furthermore, full-length COL11A1 protein, extracted from A204 cell line, increased cisplatin resistance in ovarian cancer cells, suggesting that COL11A1 is sufficient to induce chemoresistance. Interestingly, culture of cancer cells on full-length COL11A1 protein resulted in increased number of ALDHhigh cancer stem-like cells and activation of Akt, the principal mediator of pro-survival signaling. To further dissect the mechanism by which COL11A1 leads to cisplatin resistance in tumor cells, we performed RNA-seq analysis of tumor cells after COL11A1 overexpression. Our data showed that COL11A1 did not change the levels of genes involved in cisplatin transport and DNA repair pathway in cancer cells, which are well-established mechanisms to confer cisplatin resistance. Rather, COL11A1 increased the expression of pro-inflammatory genes, some of which are known to confer chemoresistance in ovarian cancer. Consistently, our Western data showed that COL11A1 activates NF-kB signaling in cancer cells, a central pathway regulating pro-inflammatory genes. Collectively, our data suggest that COL11A1 contributes to chemoresistance possibly due to an increased survival of ALDHhigh cancer stem-like cells through activation of pro-inflammatory signaling.

Citation Format: Miran Rada, Catherine Eldred, Jessica Sage, Sandra Orsulic and Dong-Joo Cheon. COLLAGEN TYPE XI ALPHA 1 (COL11A1) IS A NOVEL STROMAL MEDIATOR OF CHEMORESISTANCE [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-017.
Abstract TMEM-018: IN VITRO MODELS OF HGSC BASED ON MURINE OVIDUCTAL EPITHELIAL ORGANOIDS
Authors: Zhai Yali , Fearon Eric R. , Cho Kathleen R.
Published: June 2017

Mouse models of high-grade serous carcinoma (HGSC) arising from oviductal epithelium provide excellent in vivo systems with which to define the cellular and molecular events associated with HGSC development and progression. However, tumors in mice typically develop over months rather than weeks, and tumor progression in vivo cannot be easily monitored. Murine organoid models that closely mimic the biology of fallopian tube epithelium would facilitate research exploring HGSC pathogenesis.

We have developed Ovgp1-iCreERT2 mice in which the Ovgp1 promoter controls expression of tamoxifen (TAM)-inducible Cre recombinase in the oviductal epithelium – the murine equivalent of human fallopian tube epithelium. We have established long-term, 3-dimensional oviductal epithelial organoid cultures from Ovgp1-iCreERT2;R26LSL-EYFP double transgenic mice, and show that the organoids contain both ciliated and secretory cells, and express oviductal epithelial markers including cytokeratin 8, ER, PAX8 and OVGP1. Organoids treated in vitro with 4-hydroxy-tamoxifen (4-OH-TAM) activate the EYFP reporter.

Oviductal epithelial organoids established from Ovgp1-iCreERT2;Brca1del/fl; Trp53mut/fl;Rb1fl/fl (BPR) mice and treated in vitro with 4-OH-TAM show selection for the recombined tumor suppressor gene alleles by passage 6, accompanied by morphological and behavioral changes associated with neoplastic transformation. Stable organoid cultures can also be established from the oviductal epithelium of BPR mice treated in vivo with Tamoxifen (TAM).

We show that long-lived 3-dimensional organoids can be generated from normal oviductal tissue; can undergo Cre-mediated recombination in vitro to inactivate tumor suppressor genes relevant to human HGSC pathogenesis; and can acquire properties associated with neoplastic transformation in a relatively short period of time (weeks). As we have already generated Ovgp1-iCreERT2 mice with various combinations of constitutional and Cre-inducible mutant tumor suppressor gene (Trp53, Rb1, Brca1, Pten, Nf1, Apc) and oncogene (PIK3CA, KRAS) alleles, the roles of specific genetic alterations in HGSC pathogenesis can be explored in a relatively rapid and controlled experimental system.

Citation Format: Yali Zhai, Eric R. Fearon, and Kathleen R. Cho. IN VITRO MODELS OF HGSC BASED ON MURINE OVIDUCTAL EPITHELIAL ORGANOIDS [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-018.
Abstract TMEM-029: AGING INCREASES SUSCEPTIBILITY TO OVARIAN CANCER METASTASIS IN A MURINE ALLOGRAFT MODEL
Authors: Loughran Elizabeth , Leonard Annemarie , Phan Ryan , Tarwater Laura , Hilliard Tyvette , Asem Marwa , Liu Yueying , Yang Jing , Klymenko Yuliya , Johnson Jeff , Shi Zonggao , Leevy Matthew , Ravosa Matthew , Stack M. Sharon
Published: June 2017

Ovarian cancer (OvCa) is the leading gynecological malignancy in women in the United States. OvCa metastasizes uniquely, spreading through the peritoneal cavity and generating widespread metastatic sites. The vast majority of OvCa cases occur in women over 40 and the median age at diagnosis is 63 (SEER). Despite age being a significant risk factor for the development of OvCa, there is a paucity of studies addressing the role of aging in OvCa metastasis. To our knowledge, there are no reports utilizing old mice to investigate the effects of age on metastasis in vivo. We designed a study using a C57BL/6 model of aging where young (Y) mice are 3-6 months of age and aged (A) mice are 20-23 months of age, corresponding to young (20-30 years) and aged (60-67 years) humans. Using the C57BL/6 syngeneic ID8 mouse ovarian surface epithelial cell line, we tested the effect of aging on metastatic success in vivo. An allograft study was carried out with Y and A mice that were intraperitoneally injected with 3.7x106 ID8 RFP-tagged cells. The mice were imaged once a week starting at 4.5 weeks post injection and were sacrificed for dissection at 8 weeks post injection. Live imaging suggested OvCa metastasis was more efficient in the aged animals than in the young animals. After dissection, the abdominal organs were imaged ex vivo and tumor burden was quantified. The aged mice displayed heavier tumor burden in the gonadal fat compared to the young. Interestingly, no difference in metastasis to the omentum was detected. To investigate why gonadal fat is more receptive to metastasis in the aged animals, periovarian adipose from 4 young and 4 aged healthy non-tumor bearing mice was isolated for RNAseq analysis. Several immune pathways involving B cells were found to be significantly upregulated in the RNA from aged animals. Studies will be conducted to elucidate the status of B cells in aging periovarian adipose, including immunohistochemistry for CD45 and other B cell markers upregulated in the RNAseq dataset.

Citation Format: Elizabeth Loughran, Annemarie Leonard, Ryan Phan, Laura Tarwater, Tyvette Hilliard, Marwa Asem, Yueying Liu, Jing Yang, Yuliya Klymenko, Jeff Johnson, Zonggao Shi, Matthew Leevy, Matthew Ravosa and M. Sharon Stack. AGING INCREASES SUSCEPTIBILITY TO OVARIAN CANCER METASTASIS IN A MURINE ALLOGRAFT 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-029.
Abstract TMEM-033: DEVELOPING A MONKEY MODEL FOR SPONTANEOUS TYPE I OVARIAN CANCER
Authors: Felder Mildred , Kapur Arvinder , Simmons Heather , Abbott David , Patankar Manish S.
Published: June 2017

The goal of this research project is to investigate if Non-Human Primates (NHP) can serve as model for endometriosis-associated Type I ovarian cancer. Endometriosis is a spontaneously occurring condition in both women and rhesus macaques. Endometriosis is likely caused by aberrant retrograde menstruation of endometrial epithelium that implants and grows on the serosal surfaces of the ovaries, uterus, urinary bladder, intestines and abdominal peritoneum. Several studies have shown direct association between endometriosis and two histological subtypes of Type I ovarian cancer- clear cell ovarian carcinoma (CCOC) and low grade serous endometrioid ovarian cancer (EnOC). Genetically altered mouse models for Type I and II ovarian cancer and are contributing significantly to our understanding of the biology of this malignancy. Since rodents do not have menstrual cycles, there are no mouse models for spontaneous endometriosis and Type I ovarian tumors. On the other hand, between 10-30% of female rhesus macaques of reproductive age develop endometriosis. A survey of pathology reports at the Wisconsin National Primate Research Center (WNPRC) identified cases of ovarian and peritoneal neoplasia in monkeys that also had endometriosis. This is a typical feature of CCOC and EnOC in humans where tumors are found adjacent to atypical endometriotic lesions. We are conducting immunohistological analysis to study the molecular phenotype of endometriosis and the ovarian and peritoneal neoplasia in the rhesus macaque. We will discuss our findings on the expression of important molecular markers of ovarian cancer (CA125, EpCAM, mesothelin, ARID1A, and others) in the non-human primate reproductive organs as well as in endometriotic explants and in ovarian and peritoneal neoplasms from the female rhesus. The data we will present and our on-going efforts to sequence the genome and transcriptome of normal and aberrant reproductive tissue samples of female rhesus monkeys will be essential in determining if the rhesus can be used as a model for CCOC and EnOC.

Citation Format: Mildred Felder, Arvinder Kapur, Heather Simmons, David Abbott, and Manish S. Patankar. DEVELOPING A MONKEY MODEL FOR SPONTANEOUS TYPE I 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 TMEM-033.
Ureteroscopic Lithotripsy versus Laparoscopic Ureterolithotomy or Percutaneous Nephrolithotomy in the Management of Large Proximal Ureteral Stones: A Systematic Review and Meta-Analysis
Authors: Wu Tao , Duan Xi , Chen Shulin , Yang Xuesong , Tang Tielong , Cui Shu
Published: June 2017

Objectives: To provide a systematic review and meta-analysis of studies comparing ureterolithotripsy (URS) with percutaneous nephrolithotripsy (PCNL) or laparoscopic ureterolithotomy (LU) techniques for the management of large proximal ureteral stones (diameter greater than 10 mm). Methods: A literature search was performed using PubMed, EMBASE, EBSCO, Web of Science, and Cochrane Library to identify suitable studies until November 2016. We used weighted mean difference to measure operative time and hospital stay, OR to measure stone free rate (SFR), and complication rate. Subgroup analyses were assessed for heterogeneity. Results: Fourteen publications strictly met our eligibility criteria of which 7 were randomized control studies (RCTs) and 7 non-RCTs. Meta-analysis of extractable data showed that LU and PCNL had higher SFR than URS. URS led to a similar hospital stay like that of LU. However, it had a shorter operative time and lower complication rate than LU. When we compared URS with PCNL, we found a shorter hospital stay in the URS group. However, there was no significant difference in terms of the operative time and complication rate between URS and PCNL. Conclusion: URS should be considered standard therapy for treating large proximal ureteral stones.
Patients with Fever of Unknown Origin and Splenomegaly: Diagnostic Value of Splenectomy and Preoperative Risk Factors Suggestive of Underlying Lymphomas
Authors: Zhang Lu , Zhang Wei , Cai Huacong , Cao Xinxin , Chen Miao , Li Jian , Zhu Tienan , Duan Minghui , Wang Shujie , Han Bing , Zhou Daobin
Published: June 2017

Background: We reviewed patients with fever of unknown origin (FUO) and splenomegaly and assessed the diagnostic value of splenectomy and measured risk factors suggestive of an underlying lymphoma. Methods: FUO patients (n = 83) who had splenomegaly and underwent splenectomy were enrolled into this retrospective single-center study. Clinical presentations were documented and risk factors suggestive of an underlying lymphoma were tested. Results: Seventy-four patients (89.2%) had a diagnosis of lymphoma or not after splenectomy and follow-up. Of those (55.4%) diagnosed with lymphoma, 29 had B-cell non-Hodgkin lymphoma and 12 had T-cell non-Hodgkin lymphoma. The remaining 33 (44.6%) had diseases other than lymphoma. Using multivariate logistic analysis, the following 3 independent risk factors were found to be related to a final diagnosis of lymphoma: age (continuous) (HR 1.086; 95% CI 1.033-1.141; p = 0.001), massively enlarged spleen (HR 7.797; 95% CI 1.267-47.959; p = 0.027), and enlarged intra-abdominal lymph nodes (HR 63.925; 95% CI 7.962-513.219; p < 0.001). The calibration of the model was satisfactory (p = 0.248 using the Hosmer-Lemeshow test), and the discrimination power was good (area under the receiver operating characteristic curve 0.925; 95% CI 0.863-0.987). Conclusions: Splenectomy is an effective diagnostic procedure for patients with FUO and splenomegaly and lymphoma is a common cause. Older age, a massively enlarged spleen, and enlarged intra-abdominal lymph nodes are risk factors suggesting an underlying lymphoma, and surgery for high-risk patients should be considered.