bluuebunny/crossref_metadata_2025 huggingface dataset:
Preparation of Sulfur-Free Exfoliated Graphite by a Two-Step Intercalation Process and Its Application for Adsorption of Oils
Authors: He Jun , Song Laizhou , Yang Hongxia , Ren Xiaohui , Xing Lifei
Published: June 2017

The sulfur-free exfoliated graphite (EG) was prepared by a two-step chemical oxidation process, using natural flake graphite (NFG) as the precursor. The first chemical intercalation process was carried out at a temperature of 30°C for 50 min, with the optimum addition of NFG, potassium permanganate, and perchloric acid in a weight ratio of 1 : 0.4 : 10.56. Then, in the secondary intercalation step, dipotassium phosphate was employed as the intercalating agent to further increase the exfoliated volume (EV) of EG. NFG, graphite intercalation compound (GIC), and EG were characterized by scanning electron microscope (SEM), energy dispersive spectrometer (EDS), X-ray diffractometer (XRD), Fourier transform infrared spectrometer (FTIR), BET surface area, and porosity analyzer. Also, the uptakes of crude oil, diesel oil, and gasoline by EG were determined. Results show that perchloric acid and hydrogen phosphate are validated to enter into the interlayer of graphite flake. The obtained EG possesses a large exfoliated volume (EV) and has an excellent affinity to oils; thus, the material has rapid adsorption rates and high adsorption capacities for crude oil, diesel oil, and gasoline.
An In Vitro Model of Gastric Inflammation and Treatment with Cobalamin
Authors: Elliott T. R. , Guildford A. L.
Published: June 2017

Pernicious anaemia (PA) is an autoimmune condition where antibodies target intrinsic factor and parietal cells, reducing the patient’s ability to absorb cobalamin promoting atrophic gastritis. Treatment guidelines are based on excretion data of hydroxocobalamin from healthy individuals obtained 50 years ago. This manuscript describes the use of phorbol 12-myristate 13-acetate (PMA) to stimulate low grade inflammation in an epithelial colorectal cell line to assess the efficacy of methylcobalamin and hydroxocobalamin. Nitric oxide increased significantly in cells exposed to higher doses of PMA (100 ng/ml, 150 ng/ml, and 200 ng/ml) accompanied by a loss of the characteristic cobblestone morphology with no negative effect on cell activity or viability. A significant reduction in nitric oxide production was associated with the addition of 200 pg/ml hydroxocobalamin, alongside a return to the characteristic cobblestone morphology. This study highlights the use of PMA to promote low grade inflammation in human cell lines to model gastric inflammation associated with autoimmunity; furthermore it raises questions regarding the concentration of cobalamin administered clinically to restore cell functionality, feasibly allowing the patient to receive reduced quantity of the vitamin more regularly, providing the patient with levels which are akin to dietary intake.
The Ratio of C-Reactive Protein/Albumin is a Novel Inflammatory Predictor of Overall Survival in Cisplatin-Based Treated Patients with Metastatic Nasopharyngeal Carcinoma
Authors: Sun Peng , Chen Cui , Xia Yi , Bi Xiwen , Liu Panpan , Zhang Fei , Yang Hang , An Xin , Jiang Wenqi , Wang Fenghua
Published: June 2017

The C-reactive protein/albumin (CRP/Alb) ratio has been recently identified as a prognostic factor in various cancers, whereas its role remains unclear in metastatic nasopharyngeal carcinoma (NPC). The current study retrospectively analyzed 148 patients with metastatic NPC who underwent cisplatin-based chemotherapy and further evaluated the prognostic value of the CRP/Alb ratio and its association with clinical characteristics in these patients. The optimal cut-off value was 0.189 for the CRP/Alb ratio. The high CRP/Alb ratio was significantly associated with elevated NLR, platelet-to-lymphocyte ratio (PLR), and EBV-DNA levels and decreased haemoglobin level (all p<0.05). The results of multivariate analysis showed that the CRP/Alb ratio was an independent prognostic factor of overall survival. Patients with a high CRP/Alb ratio (≥0.189) had a 1.867 times (p=0.024, 95% CI=1.085–3.210) greater risk of mortality compared with those with a low CRP/Alb ratio (<0.189). In addition, combining the CRP/Alb ratio with GPS could accurately discriminate the prognosis of our patients. Our results suggested that the CRP/Alb ratio is a feasible and inexpensive tool for predicting survival outcomes and is a valuable coadjutant for the GPS to further identify differences in survivals of patients with metastatic NPC.
Subthalamic Nucleus Deep Brain Stimulation in Early Stage Parkinson’s Disease Is Not Associated with Increased Body Mass Index
Authors: Millan Sarah H. , Hacker Mallory L. , Turchan Maxim , Molinari Anna L. , Currie Amanda D. , Charles David
Published: June 2017

Previous studies suggest that deep brain stimulation of the subthalamic nucleus (STN-DBS) for Parkinson’s disease (PD) leads to weight gain. This study analyzes changes in body mass index (BMI) in 29 subjects from a prospective, single-blind trial of DBS in early stage PD (age 50–75, Hoehn & Yahr stage II off medication, treated with antiparkinsonian medications for ≥6 months but <4 years, and without a history of motor fluctuations, dyskinesias, or dementia). Subjects were randomized to DBS plus optimal drug therapy (DBS+ODT;n=15) or ODT (n=14) and followed for 24 months. Weight and height were recorded at baseline and each follow-up visit and used to calculate BMI. BMIs were compared within and between groups using nonparametrict-tests. Mean BMI at baseline was 29.7 in the ODT group and 32.3 in the DBS+ODT group (p>0.05). BMI change over two years was not different between the groups (p=0.62, ODT = −0.89; DBS+ODT = −0.17). This study suggests that STN-DBS is not associated with weight gain in subjects with early stage PD. This finding will be tested in an upcoming FDA-approved phase III multicenter, randomized, double-blind, placebo-controlled, pivotal clinical trial evaluating DBS in early stage PD (ClinicalTrials.gov identifierNCT00282152).
Abstract AP13: NF-KAPPAB CLASSICAL VERSUS ALTERNATIVE PATHWAYS SUPPORT DISTINCT POPULATIONS OF OVARIAN CANCER TUMOR-INITIATING CELLS
Authors: House Carrie D. , Jordan Elizabeth A. , Annunziata Christina M.
Published: June 2017

Ovarian cancer is the most lethal gynecological malignancy in the United States with high morbidity and mortality due to recurrence and chemoresistance. Our data suggest tumor-initiating cells (TICs) play an important role in disease biology. We previously showed that a subset of ovarian cancer cells depends on NF-kappaB signaling, and that expression of NF-kappaB proteins is associated with poor survival. Given that NF-kappaB expression correlates with a poor outcome in ovarian cancer, and NF-kappaB activity supports drug resistance and tumorigenicity, we hypothesize that NF-kappaB supports a TIC program responsible for ovarian cancer relapse. To investigate this pathway in TICs, we designed a novel method to enrich for TICs from cell lines and patient samples by culturing non-adherent, floating cells in stem cell conditions defined by low attachment flasks and serum free media. Preliminary data confirm that these cells have higher stem cell marker expression, are chemoresistant, and are more tumorigenic in nude mice compared to their adherent counterparts. These TIC-enriched culture conditions enhance NF-kappaB expression and activity. More specifically, alternative NF-kappaB signaling through the RelB transcription factor supports TIC populations by regulating aldehyde dehydrogenase (ALDH), an enzyme with high activity in TICs. Using an inducible shRNA targeting RelB we show that spheroid formation, ALDH expression and activity, chemoresistance, and tumorigenesis in both subcutaneous and intrabursal xenograft models, significantly decreased in the absence of RelB. Interestingly, loss of classical NF-kappaB signaling, through an shRNA targeting the RelA transcription factor, was less effective in targeting TICs, but more effective at targeting a proliferative subpopulation with high Ki67 staining. We conclude that classical and alternative NF-kappaB signaling support ovarian tumor cells with distinct phenotypes and the collaboration of these pathways may be critical for supporting tumor repopulation following chemotherapy. Current studies will measure system level changes induced by these shRNAs, and identify a gene signature specific to each NF-kappaB pathway in ovarian TICs. Clarifying the nuances of NF-kappaB signaling in TICs will increase our understanding of ovarian cancer recurrence and further focus therapeutic strategies to prevent relapse.

Citation Format: Carrie D. House, Elizabeth A. Jordan, Christina M. Annunziata. NF-KAPPAB CLASSICAL VERSUS ALTERNATIVE PATHWAYS SUPPORT DISTINCT POPULATIONS OF OVARIAN CANCER TUMOR-INITIATING CELLS [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 AP13.
Abstract AP26: SMAC–MIMETIC TREATMENT ENHANCES ANTITUMOR EFFECT OF STANDARD CHEMOTHERAPY IN OVARIAN CANCERS EXPRESSING LOW CASPASE 8 IN VITRO AND IN VIVO
Authors: Hernandez Lídia , Annunziata Christina M.
Published: June 2017

Ovarian cancer is the most lethal gynecological cancer in the US. Standard treatment consists of surgery followed by chemotherapies relying on apoptotic tumor cell death. Most women with advanced stage disease will relapse, suggesting that this disease is characterized by primary and acquired resistance to chemotherapy, and targeted approaches to treatment are greatly needed. We recently demonstrated that low Caspase 8 expression levels in ovarian cancers correlated with resistance to chemotherapy, and a subpopulation of ovarian cancer patients with low Caspase 8 levels exhibits poorer overall survival after standard of care treatment. We hypothesized that the loss of Caspase 8 function reduces the cancer cells' ability to undergo apoptosis when exposed to standard chemotherapy. Here we show that combination treatment with Smac-mimetics targets tumor cells with low Caspase 8 and induces necroptotic cell death. We investigated the in vitro sequential effect of Smac-mimetic added to carboplatin + paclitaxel treatment of ovarian cancer cells expressing wild type, low and mutant Caspase 8 levels, which resulted in a 2-4fold enhancement of cell death. In vivo treatment of mice bearing subcutaneous or intraperitoneal ovarian xenografts showed greater aggressiveness of Caspase 8 deficient vs wild-type tumors; combined treatment with chemotherapy and Smac-mimetic resulted in over 50% decrease in low-Caspase 8 xenograft growth, as well as enhanced overall survival of the mice. Subpopulations of women with low Caspase 8 ovarian cancers that resist apoptosis could benefit from treatments which promote non-apoptotic forms of cell death, such as Smac-mimetic induced necroptosis. Clinical validation of such approaches are needed to increase the effectiveness of current standard ovarian cancer treatment.

Citation Format: Lídia Hernandez and Christina M. Annunziata. SMAC–MIMETIC TREATMENT ENHANCES ANTITUMOR EFFECT OF STANDARD CHEMOTHERAPY IN OVARIAN CANCERS EXPRESSING LOW CASPASE 8 IN VITRO AND IN VIVO [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 AP26.
Abstract DPOC-009: DETECTION OF A CLINICALLY OCCULT OVARIAN CARCINOMA BY NEW DIAGNOSTIC TOOLS – A CASE REPORT
Authors: Maritschnegg Elisabeth , Obermayr Eva , Holzer Barbara , Gleeson Noreen , Heitz Florian , Massuger Leon , Telsnigg Gunda Pristauz , Rosenthal Adam , Trillsch Fabian , Nieuwenhuysen Els Van , Zikan Michael , Speiser Paul , Zeillinger Robert
Published: June 2017

75% of ovarian cancer (OC) cases are detected at an advanced stage. State–of–the–art diagnostic tools don't show sufficient sensitivity, especially in diagnosing early–stage disease. Still, due to lack in alternatives, these methods are used for monitoring BRCA mutation carriers, who face a high penetrance of OC.

A 41–year old BRCA1 mutation carrier decided to undergo risk–reducing bilateral salpingo–oophorectomy (rrBSO), currently the only effective way of reducing the OC risk. The day before surgery, 20ml of peripheral blood were drawn to test for the presence of circulating tumor cells (CTCs) by applying a microfluidic device (Parsortix system) and subsequent qPCR. Furthermore, a lavage of the uterine cavity was performed as previously described. According to state–of–the–art techniques, no signs of cancer were present. However, microscopic malignant lesions at both ovaries and the right diaphragm were observed, and final histopathology revealed FIGO IIIB serous OC. Multiple precursor lesions (STICs) were observed in the fallopian tube. qPCR of preoperative enriched cell fraction indicated the presence of CTCs. Analysis of the lavage sample using TP53 mutation analysis revealed 17% mutant allelic fraction. The same mutation was identified in different STIC and invasive lesions.

This case shows that early detection of high–grade serous OC does not necessarily translate into a stage shift, but easier to resect disease. Considering the lag–time between STIC to clinically–overt OC development, both described methods present an opportunity for monitoring high–risk patients to delay rrBSO. Both methods proved to be able to diagnose occult OC, and even carry the potential of detecting STICs.

Citation Format: Elisabeth Maritschnegg, Eva Obermayr, Barbara Holzer, Noreen Gleeson, Florian Heitz, Leon Massuger, Gunda Pristauz Telsnigg, Adam Rosenthal, Fabian Trillsch, Els Van Nieuwenhuysen, Michael Zikan, Paul Speiser, Robert Zeillinger. DETECTION OF A CLINICALLY OCCULT OVARIAN CARCINOMA BY NEW DIAGNOSTIC TOOLS – A CASE REPORT [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 DPOC-009.
Abstract IS02: BCAM-AKT2 FUSION GENE LEADS TO A CONSTITUTIVELY ACTIVATED AKT2 FUSION KINASE IN HGSC
Authors: Yen Laising
Published: June 2017

High-grade serous ovarian cancer (HGSC) is among the most lethal forms of cancer in women. Excessive genomic rearrangements, which are expected to create fusion oncogenes, are the hallmark of this cancer. Using high-throughput RNAseq, we identify a cancer-specific gene fusion between BCAM, a membrane adhesion molecule, and AKT2, a key kinase in the PI3K signaling pathway. This fusion is present in 7% of patient cancers tested, a significant frequency considering the highly heterogeneous nature of this malignancy. We provide direct evidence that BCAM-AKT2 is translated into an in-frame fusion protein in the patient's tumor. The resulting AKT2 fusion kinase is membrane-associated, constitutively phosphorylated, and activated as a functional kinase in cells, suggesting a new mechanism of AKT2 kinase activation in HGSC. This recurrent genomic alteration is a potential therapeutic target and marker of a clinically relevant subtype for tailored therapy of HGSC.

Citation Format: Laising Yen. BCAM-AKT2 FUSION GENE LEADS TO A CONSTITUTIVELY ACTIVATED AKT2 FUSION KINASE IN HGSC [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 IS02.
Abstract NTOC-080: NANOOLAPARIB: AN INTRAPERITONEAL PARP INHIBITOR THERAPY FOR OVARIAN CANCER
Authors: Baldwin Paige , Ohman Anders , Dinulescu Daniela , Sridhar Srinivas
Published: June 2017

PURPOSE: PARP inhibitor therapy for ovarian cancer exploits the concept of synthetic lethality by taking advantage of defects in DNA damage repair pathways. Currently Olaparib is the only FDA-approved PARP inhibitor and is available as an oral dosage, which has plenty of advantages, but requires the drug to undergo first pass metabolism, inactivating a significant fraction of the dose. We have developed a nanoparticle delivery system to allow for local delivery of Olaparib directly to the intraperitoneal cavity.

METHODS: NanoOlaparib was characterized in vitro in regards to size, charge, drug loading and release before testing on a panel of ovarian cancer cell lines, including KURAMOCHI, SKOV3, OVSAHO, JHOS2, PA1, COV318, 403 and 404, derived from tumors of Brca2-/-, Pten-/-, Tp53-/- mice, and 4306 and 4412, developed from conditional KrasLSL-G12D/+, Pten-/- mice, to elucidate sensitivity profiles and ensure comparable activity to the free drug. 404 cells, derived from Brca2-/-, Tp53-/-, Pten-/- genetically engineered mouse models, were utilized to develop an IP spread xenograft model to test NanoOlaparib in vivo. Animals were treated with NanoOlaparib or oral Olaparib daily for 4 weeks. Tumor burden was monitored weekly via bioluminescence imaging.

RESULTS: NanoOlaparib shows comparable efficacy in vitro to free Olaparib. The murine cell lines were the most sensitive to the treatment regardless of BRCA status, suggesting that Pten deletions are just as susceptible to PARP inhibitor therapy as the BRCA mutations. The average fold change in bioluminescence for NanoOlaparib decreased, while it increased for oral Olaparib. The oral Olaparib animals had widely varied responses, with some animals' tumors shrinking and others never responding. All NanoOlaparib tumors shrank initially, however, severe toxicity was noted after 3 weeks of treatment.

CONCLUSIONS: NanoOlaparib toxicity in vivo was observed with daily dosing likely due to the sustained release of the drug in comparison to the much more rapid clearance of the oral drug. While the NanoOlaparib was toxic, it provided a much more uniform response to the treatment than the oral Olaparib. It is clear that because this strategy provides 100% of the dose to the disease site with a sustained delivery it is no longer necessary to administer daily. This suggests that NanoOlaparib changes the pharmacokinetics to allow for a lower dose to be administered. A modified dosing regime is to be tested with the goal of lowering the toxicity while still maintaining therapeutic efficacy.

Citation Format: Paige Baldwin, Anders Ohman, Daniela Dinulescu, Srinivas Sridhar. NANOOLAPARIB: AN INTRAPERITONEAL PARP INHIBITOR THERAPY 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-080.
Abstract NTOC-087: DYNAMIC REPROGRAMMING OF THE KINOME OVERCOMES BET PROTEIN INHIBITION IN OVARIAN CANCER
Authors: Kurimchak Alison M. , Shelton Claude , Duncan Kelly E. , Johnson Katherine J. , Brown Jennifer , O'Brien Shane , Gabbasov Rashid , Fink Lauren S. , Li Yuesheng , Lounsbury Nicole , Abou-Gharbia Magid , Childers Wayne E. , Connolly Denise C. , Chernoff Jonathan , Peterson Jeffrey R. , Duncan James S.
Published: June 2017

High-grade serous ovarian carcinoma (HGS-OvCa) is the most common and deadly form of ovarian cancer, and currently lacks effective targeted therapies. Recently, proteins involved in chromatin remodeling such as the BET bromodomain protein BRD4 have emerged as an exciting new class of targets for the treatment of cancer. Targeted BRD4 inhibition has been shown to cause tumor regression and apoptosis in a number of cancers, including HGS-OvCa. Consequently, small molecule BET bromodomain inhibitors (BETi) are actively being pursued in clinical trials. In our preliminary studies, we discovered that the BET inhibitor JQ1 dramatically reduced MYC protein levels resulting in inhibited cell growth and survival in a panel of HGS-OvCa cell lines. Importantly, although JQ1 initially caused significant growth arrest and apoptosis, the majority of HGS-OvCa cell lines acquired drug resistance. Detailed molecular characterization of JQ1- resistant HGS-OvCa cells showed the return of MYC protein levels accompanied by elevated PI3K-AKT activity, suggesting the acquired resistance stems from activated kinase signaling. Our laboratory has designed a novel mass spectrometry approach that globally measures kinase activity to identify the kinase networks responsible for drug resistance. Using this technology, we analyzed global kinase activity in JQ1-resistant cells and observed the activation of several receptor-tyrosine kinases (RTKs), including EGFR, FGFRs and IGF1R known to strongly drive PI3K-AKT pro-survival signaling pathways. These findings suggest that BETi therapies may have limited success as single agent therapies due to “adaptive kinome reprogramming” and will likely require combination strategies involving inhibitors targeting protein kinases and BET bromodomain proteins.

Citation Format: Alison M. Kurimchak, Claude Shelton, Kelly E. Duncan, Katherine J. Johnson, Jennifer Brown, Shane O'Brien, Rashid Gabbasov, Lauren S. Fink, Yuesheng Li, Nicole Lounsbury, Magid Abou-Gharbia, Wayne E. Childers, Denise C. Connolly, Jonathan Chernoff, Jeffrey R. Peterson, James S. Duncan. DYNAMIC REPROGRAMMING OF THE KINOME OVERCOMES BET PROTEIN INHIBITION 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-087.
Abstract NTOC-091: INVOLVEMENT OF TIE–1 TYROSINE KINASE RECEPTOR IN CHEMO–RESISTANCE: POTENTIAL OF TIE1 AS A NOVEL THERAPEUTIC TARGET
Authors: Ishibashi Masumi , Toyoshima Masafumi , Egiz Mahy , Zhang Xuewei , Minato Junko , Shigeta Shogo , Kitatani Kazuyuki , Yaegashi Nobuo
Published: June 2017

OBJECTIVES: Platinum-resistance is one of the most challenging difficulties in the treatment of ovarian cancer patients. To overcome this problem, we have explored a target molecule which can conquer platinum-resistance of ovarian cancer cells utilizing a functional genomics approach.

MATERIALS AND METHODS: High-throughput functional siRNA screening was designed to target 6550 genes in cisplatin-resistant A2780 CP ovarian cancer cells. Cell viability was assessed by luminescent cell viability assay. After identifying a candidate molecule, cisplatin uptake was determined by atomic absorption spectrometry. DNA damages were determined by the western blotting and immunofluorescent staining using γH2AX antibodies.

RESULTS: Through a functional screening, receptor tyrosine kinase TIE 1 was identified as a top candidate gene, of which inhibition give rise to enhancement of cisplatin sensitivity in ovarian cancer cells. Conversely, over-expression of TIE 1 gene significantly decreased susceptibility to cisplatin-induced cell death without affecting cisplatin uptake. DNA damages induced by cisplatin was significantly suppressed in TIE 1 over-expressed cells, raising novel potential mechanisms of TIE 1 in nucleotide excision repair system that removes chemicals adduct to DNA. In addition, over-expression of TIE 1 increased the expression of XPC, which is responsible for nucleotide excision repair.

CONCLUSION: We have identified TIE 1 as a molecular target to overcome platinum-resistance in ovarian cancer cells. TIE 1 contribute platinum- resistance in ovarian cancer cells by promoting XPC-dependent DNA repairing system.

Citation Format: Masumi Ishibashi, Masafumi Toyoshima, Mahy Egiz, Xuewei Zhang, Junko Minato, Shogo Shigeta, Kazuyuki Kitatani, Nobuo Yaegashi. INVOLVEMENT OF TIE–1 TYROSINE KINASE RECEPTOR IN CHEMO–RESISTANCE: POTENTIAL OF TIE1 AS A NOVEL THERAPEUTIC TARGET [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-091.
Abstract NTOC-115: ASSOCIATION BETWEEN NUCLEAR SYK PHOSPHORYLATION AND EGFR/ERBB2 PATHWAY AND POOR SURVIVAL IN HIGH GRADE SEROUS OVARIAN CANCER
Authors: Yu Yu , Ardighieri Laura , Suryo Rahmanto Yohan , Chen Lin Y. , Tessarollo Nayara G. , Mizushima Taichi , Ayhan Ayse , Davidson Ben , Wang Tian L. , Shih Ie M
Published: June 2017

BACKGROUND: Spleen tyrosine kinase (SYK) has emerged as a cancer associated kinase of which aberrant activity contributes to tumor development and drug resistance in several types of human cancer including ovarian carcinoma. To better understand the mechanism how the SYK pathway participates in tumor progression, we studied the biochemistry and transcriptional regulation of SYK in high-grade ovarian serous carcinoma.

METHODS: Immunohistochemical analyses were performed for phosphorylated SYK (Y525/526) and total SYK levels in 42 primary serous ovarian carcinomas and 112 tumor ascites formalin-fixed paraffin embedded tissues. The relative expression of SYK long and short isoforms in peritoneal ascites and cell lines were examined by reverse transcriptase-PCR. Transcriptome analysis of gene regulated by SYK inhibition was carried out using Illumina Human HT-12 v4 arrays. Results from array was analyzed for upstream regulators. IHC data was correlated with pEGFR (Y1197) and pERBB2 (Y877) nuclear expression. Association with survival was determined by Kaplan-Meier analysis and the log-rank test.

RESULTS: We observed that active phosphorylated SYK (p-SYK, Y525/526) is mainly localized in the nucleus and cytoskeleton in cell lines and tissues. Investigation of SYK mRNA spliced variants in ascites tumors showed predominant SYK long isoform expression, consistent with its nuclear localization. Survival analyses revealed that intense nuclear p-SYK correlated with poor overall survival in two ovarian carcinoma cohorts. Patients with relatively high p-SYK in the nucleus had approximately half the median survival compared to those with undetectable or low nuclear p-SYK. SYK inhibition affected changes in gene expression that are downstream of ERBB2 and EGFR signaling. Correlation analyses in tissues suggested a relationship between p-SYK and pERBB2 or pEGFR signaling.

CONCLUSIONS: Our results suggest that activation of the SYK pathway leads to its phosphorylation and localization in cell nucleus. SYK activity plays a role in regulating EGFR and ERBB2 phosphorylation and activation. Thus, SYK may regulate tumor-promoting gene transcription through cross-talks with the EGFR/ERBB2 pathways.

Citation Format: Yu, Yu; Ardighieri, Laura; Suryo Rahmanto, Yohan; Chen, Lin Y.; Tessarollo, Nayara G.; Mizushima, Taichi; Ayhan, Ayse; Davidson, Ben; Wang, Tian L., and Shih Ie M. ASSOCIATION BETWEEN NUCLEAR SYK PHOSPHORYLATION AND EGFR/ERBB2 PATHWAY AND POOR SURVIVAL 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 NTOC-115.
Autobiographical Memory in Bipolar Disorder and Its Link to Neuropsychological Functioning
Authors: Quinlivan Esther , Dallacker Mattea , Renneberg Babette , Strasser Elisa , Fiebig Jana , Stamm Thomas J.
Published: June 2017

Objective: The aim of this study was to examine the specificity of autobiographical memory (AM) in bipolar disorder (BD) and to investigate the association between AM and neuropsychological functions. Method: Twenty bipolar patients and 22 matched healthy controls (HCs) were included in this study. AM was assessed with an extended version of the Autobiographical Memory Test (AMT) including rejection cue words. A neuropsychological test battery was used to examine verbal memory, executive functions, and attention. Results: Across both groups, the number of specific memories in the AMT was significantly smaller in response to rejection cue words and positive cue words than in response to negative cue words. Participants with BD and HCs did not differ significantly in neuropsychological measures. Across both groups, scores of verbal memory, executive functions, and attention were significantly correlated with specificity of retrieved memories. Limitations: Although our clinical sample consisted of clinically stable outpatients, 6 out of 20 patients were not rated as euthymic but as mildly depressed. All BD patients were medicated. Conclusion: Contrary to previous results, patients with BD did not differ in the number of specific memories compared to an HC group. Our findings suggest that neuropsychological functioning is associated with AMT specificity. Further research is required to gain a better understanding of the underlying mechanisms which may influence the ease of memory retrieval.
Effect of Anesthesia on the Developing Brain: Infant and Fetus
Authors: Andropoulos Dean B.
Published: June 2017

The potential for commonly used anesthetics and sedatives to cause neuroapoptosis and other neurodegenerative changes in the developing mammalian brain has become evident in animal studies over the past 15 years. This concern has led to a number of retrospective studies in human infants and young children, and some of these studies observed an association between exposure to general anesthesia as an infant, and later neurobehavioral problems in childhood. This association is particularly evident for prolonged or repeated exposures. Because of the significant growth of fetal interventions requiring sedation and analgesia for the fetus, or because of maternal anesthetic effects, this concern about anesthetic neurotoxicity is relevant for the fetus. The potential for anesthetic neurotoxicity is the most important clinical and research problem in the field of pediatric anesthesiology. This review will first briefly summarize the rapid brain growth and development in the fetus and neonate. Next, animal model data of anesthetic neurotoxicity in the fetus and neonate will be presented, followed by a review of recent human clinical anesthetic neurotoxicity trials. Finally, the rationale for studying dexmedetomidine as a potential neuroprotectant agent in anesthetic neurotoxicity will be reviewed along with study design for two human clinical trials involving dexmedetomidine.
A Role of Remote Organs Effect in Acute Kidney Injury Outcome
Authors: Dépret François , Prud'homme Mathilde , Legrand Matthieu
Published: June 2017

Acute kidney injury (AKI) has been associated with both short- and long-term outcomes. To date, there is still a debate whether the increase risk of morbidity and mortality is directly due to AKI occurrence. There is, however, a potential causal impact of AKI on outcome, but evidence of this association is yet lacking. The hypothesis of remote organ damage and dysfunction (heart, lung, liver, brain, etc.) has emerged over the last decade and may explain the reason for the potential negative impact of AKI on outcome. The aim of this review was to describe findings concerning the remote effect of AKI in animal models and human studies.
Femtosecond Laser in situ Keratomileusis Flap Creation in Narrow Palpebral Fissure Eyes without Suction
Authors: Chang John S.M. , Law Antony K.P. , Ng Jack C.M. , Cheng May S.Y.
Published: June 2017

Purpose: To evaluate a surgical technique used in eyes with narrow palpebral fissure undergoing femtosecond laser flap creation without suction during laser in situ keratomileusis (LASIK). Methods: All data of 2 patient groups were collected through chart review. Group 1 consisted of 6 eyes with narrow palpebral fissure in which the suction ring was manually fixated and femtosecond laser was applied accordingly. Thirty comparison cases were randomly drawn from among eyes that underwent a standard LASIK procedure matched for age and preoperative refraction (group 2). Only 1 eye of each patient was selected to compare the refractive and visual outcomes between groups. Results: In all group 1 eyes, the flaps were created successfully with manual fixation of the suction ring without suction. No eyes lost 2 or more lines of vision. No significant difference was found in the safety and refractive outcomes between groups. Conclusion: Manual fixation of the suction ring in eyes with narrow palpebral fissure without suction was feasible for flap creation during LASIK.
Catastrophic Thermal Corneoscleral Injury Treated with Transplantation of Donor Scleral Graft
Authors: Kase Satoru , Ohguchi Takeshi , Ishida Susumu
Published: June 2017

Background: The aim of this study is to report a patient with senile cataract developing severe thermal corneoscleral injury during phacoemulsification, which was treated with a donor scleral graft. Case: Severe thermal corneoscleral injury occurred during phacoemulsification in the right eye of a 74-year-old male. His medical history was prostate hypertrophy. Visual acuity was hand motion and the intraocular pressure was 3 mm Hg OD. There was heavy corneal stromal opacity with intraocular fluid leakage. The patient underwent transplantation of a donor scleral graft to the burn site. Histologically, the injured sclera showed coagulation necrosis without inflammatory cell infiltration. An intraocular lens was eventually fixed in the ciliary sulcus 7 months later. His visual acuity remains at 2/20 OD. Conclusions: Transplantation of the donor scleral grafts is useful to close the wound in catastrophic thermal injury.
Breast Cancer Metastasis Masquerading as the Great Masquerader: Sebaceous Cell Carcinoma
Authors: Martin Jonathan , Fung Maxwell A. , Lin Lily Koo
Published: June 2017

Objective: We describe the case of a patient with metastatic breast cancer who presented with eyelid margin thickening and madarosis more suggestive of sebaceous cell carcinoma than metastatic disease. Histopathology confirmed metastatic breast adenocarcinoma. Case Report: A 59-year-old woman with a known history of metastatic breast carcinoma actively enrolled in a clinical trial presented with a thickened right upper eyelid margin with madarosis and without ulceration. Although the possibility of metastasis was considered, a biopsy was performed to ensure the patient did not have a primary eyelid malignancy such as sebaceous cell carcinoma given her immunocompromised state. Histopathology revealed metastatic breast adenocarcinoma. Conclusions: To the authors’ best knowledge, metastatic breast carcinoma presenting as eyelid margin thickening without ulceration has not previously been reported. Eyelid metastasis is rare, and this patient’s clinical presentation was found to be unusual as well. It is important to establish metastatic disease even in a small focus such as the eyelid, as it may alter disease management.
Mortality of Stroke and Its Subtypes in China: Results from a Nationwide Population-Based Survey
Authors: Chen Zhenghong , Jiang Bin , Ru Xiaojuan , Sun Haixin , Sun Dongling , Liu Xiangtong , Li Yichong , Li Di , Guo Xiuhua , Wang Wenzhi
Published: June 2017

Background: In China, stroke is the leading cause of death and contributes to a heavy disease burden. However, a nationwide population-based survey of the mortality of stroke and its subtypes is lacking for this country. Methods: Data derived from the National Epidemiological Survey of Stroke in China, which was a multistage, stratified clustering sampling-designed, cross-sectional survey, were analyzed. Mortality rate analyses were performed for 476,156 participants ≥20 years old from September 1, 2012 to August 31, 2013. Results: Of the 476,156 participants in the investigated population, 364 died of ischemic stroke, 373 of hemorrhagic stroke, and 21 of stroke of undetermined pathological type. The age-standardized mortality rates per 100,000 person-years among those aged ≥20 years were 114.8 for total stroke, 56.5 for ischemic stroke, and 55.8 for hemorrhagic stroke. The age-standardized mortality rates of total stroke, ischemic stroke, and hemorrhagic stroke were all higher in rural areas than those in urban areas. The stroke mortality rate was higher in the northern regions than in the south. An estimated 1.12 million people aged ≥20 years in China died of stroke during the period from September 1, 2012 to August 31, 2013. Conclusions: The burden of stroke in China is still heavy. Greater attention should be paid to improve strategies for preventing stroke.
Resolução comentada da questão 1 da P1 de 2015 da disciplina PME3230 - Mecânica dos Fluidos I
Authors: Cancian Caio Garcia
Published: June 2017

A primeira questão da P1 de 2015 da disciplina PME3230 - Mecânica dos Fluidos I obteve um índice de acerto extremamente baixo, essencialmente pela necessidade de possuir certo domínio de técnicas básicas de resolução de equações diferenciais. No entanto, essas técnicas só foram aprendidas no curso de cálculo em um momento mais avançado do semestre. Por isso, esse texto busca resolver essa questão da prova, de modo a explicitar quais eram esses conhecimentos extras necessários para poder resolvê-la corretamente.
Cytochrome b5 Reductase 3 Modulates Soluble Guanylate Cyclase Redox State and cGMP Signaling
Authors: Rahaman Mizanur M. , Nguyen Anh T. , Miller Megan P. , Hahn Scott A. , Sparacino-Watkins Courtney , Jobbagy Soma , Carew Nolan T. , Cantu-Medellin Nadiezhda , Wood Katherine C. , Baty Catherine J. , Schopfer Francisco J. , Kelley Eric E. , Gladwin Mark T. , Martin Emil , Straub Adam C.
Published: June 2017

Rationale:

Soluble guanylate cyclase (sGC) heme iron, in its oxidized state (Fe
3+
), is desensitized to NO and limits cGMP production needed for downstream activation of protein kinase G–dependent signaling and blood vessel dilation.

Objective:

Although reactive oxygen species are known to oxidize the sGC heme iron, the basic mechanism(s) governing sGC heme iron recycling to its NO-sensitive, reduced state remain poorly understood.

Methods and Results:

Oxidant challenge studies show that vascular smooth muscle cells have an intrinsic ability to reduce oxidized sGC heme iron and form protein–protein complexes between cytochrome b5 reductase 3, also known as methemoglobin reductase, and oxidized sGC. Genetic knockdown and pharmacological inhibition in vascular smooth muscle cells reveal that cytochrome b5 reductase 3 expression and activity is critical for NO-stimulated cGMP production and vasodilation. Mechanistically, we show that cytochrome b5 reductase 3 directly reduces oxidized sGC required for NO sensitization as assessed by biochemical, cellular, and ex vivo assays.

Conclusions:

Together, these findings identify new insights into NO–sGC–cGMP signaling and reveal cytochrome b5 reductase 3 as the first identified physiological sGC heme iron reductase in vascular smooth muscle cells, serving as a critical regulator of cGMP production and protein kinase G–dependent signaling.
Paramedic Initiation of Neuroprotective Agent Infusions
Authors: Shkirkova Kristina , Starkman Sidney , Sanossian Nerses , Eckstein Marc , Stratton Samuel , Pratt Frank , Conwit Robin , Hamilton Scott , Sharma Latisha , Liebeskind David , Restrepo Lucas , Valdes-Sueiras Miguel , Saver Jeffrey L.
Published: June 2017

Background and Purpose—

Paramedic use of fixed-size lumen, gravity-controlled tubing to initiate intravenous infusions in the field may allow rapid start of neuroprotective therapy for acute stroke. In a large, multicenter trial, we evaluated its efficacy in attaining target serum levels of candidate neuroprotective agent magnesium sulfate and the relation of achieved magnesium levels to outcome.

Methods—

The FAST-MAG phase 3 trial (Field Administration of Stroke Therapy – Magnesium) randomized 1700 patients within 2 hours of onset to paramedic-initiated, a 15-minute loading intravenous infusion of magnesium or placebo followed by a 24-hour maintenance dose. The drug delivery strategy included fixed-size lumen, gravity-controlled tubing for field drug administration, and a shrink-wrapped ambulance kit containing both the randomized field loading and hospital maintenance doses for seamless continuation.

Results—

Among patient randomized to active treatment, magnesium levels in the first 72 hours were assessed 987 times in 572 patients. Mean patient age was 70 years (SD±14 years), and 45% were women. During the 24-hour period of active infusion, mean achieved serum level was 3.91 (±0.8), consistent with trial target. Mg levels were increased by older age, female sex, lower weight, height, body mass index, and estimated glomerular filtration rate, and higher blood urea nitrogen, hemoglobin, and higher hematocrit. Adjusted odds for clinical outcomes did not differ by achieved Mg level, including disability at 90 days, symptomatic hemorrhage, or death.

Conclusions—

Paramedic infusion initiation using gravity-controlled tubing permits rapid achievement of target serum levels of potential neuroprotective agents. The absence of association of clinical outcomes with achieved magnesium levels provides further evidence that magnesium is not biologically neuroprotective in acute stroke.
Women's Struggles to Practice Medicine in Antebellum America: The Troubled Career of Boston Physician Harriot Kezia Hunt
Authors: Glenn Myra C.
Published: June 2017

This essay discusses the failed efforts of Boston physician and woman's rights activist Harriot Kezia Hunt to study at Harvard's Medical School in 1847 and 1850. It explores the fractious and gendered nature of medicine in antebellum America and concerns about professionalism, gender roles, student retention, and interracial mixing at Harvard.
Understanding Taiwan’s Agricultural Protectionism
Authors: Schmidt Hernandez Fernando Mariano
Published: June 2017

The following article aims to discern whether partial protectionism in Taiwan’s meat markets can still be explained as a function of Taiwan’s ‘strong state argument’, which was developed to understand the nation’s policies between the 1960s and 1980s. In spite of a weak international position, Taiwan has been able to sustain a policy of agricultural protection, based on the unitary rationality of its domestic bureaucratic units and a centralised process of decision-making. The institutional path dependence witnessed in agricultural trade policy can help explain why, for example, Taiwan is able to ban imports of agricultural items from the United States and Japan, which are two of Taiwan’s largest supporters in the international arena. The article analyses the domestic structure of agricultural market access decision-making, in order to shed light on how this structure is used to leverage trade-offs in other areas where Taiwan’s bargaining position is weaker, given its international status; and thus it revises Taiwan’s strong state argument as causal towards explaining agricultural protectionism.
Melchor Cano and the Spirituality of St. Ignatius Loyola: The Censura y parecer contra el Insituto de los Padres Jesuitas
Authors: O’Reilly Terence
Published: June 2017

The leading critic in Spain of the early Society of Jesus and its founder was the Dominican theologian Melchor Cano, who believed that the spirituality of Ignatius and his companions was a form of illuminism. During the 1550s he set out his reasons for thinking this in his Censura y parecer contra el Insituto de los Padres Jesuitas, a document he intended to show to the pope. It survives in a number of manuscripts, one of them in the British Library in London. The present article traces the history of the text, which was long considered lost, and examines its portrayal of Ignatius, the Spiritual Exercises, and the Society. It concludes with a critical edition of the British Library manuscript.
The Jesuit College Ballets: What We Know and What’s Next
Authors: Rock Judith
Published: June 2017

The existence and nature of the seventeenth- and eighteenth-century ballets produced at Jesuit colleges in Catholic Europe, most often in France and German-speaking lands, is better known now, in the United States and in France, than it was several decades ago. Researchers have come to understand much more about the ballets, their motivation and widespread production, and their professionalism. The Jesuit college ballets are a rich nexus of art, theology, philosophy, and culture. Looking again at what we already know reveals questions that need to be addressed in future research. The most fruitful future research is likely to come from scholars committed to interdisciplinary work, including some physical understanding of dance as an art form. As with any phenomenon involving the meeting of an art form and theology, historians of the art form and historians of the theology tend to know and be interested in very different things. And their colleagues, historians of culture, may be interested in yet something else. As scholars approach a variety of possible future Jesuit college ballet projects, this interdisciplinary challenge can illumine more completely the commitments and intentions of the ballets’ Jesuit producers, as well as the ballets’ influence on their surrounding cultures, and the cultures’ shaping of the ballets.
A review of the taxonomy and osteology of the Rhombophryne serratopalpebrosa species group (Anura: Microhylidae) from Madagascar, with comments on the value of volume rendering of micro-CT data to taxonomists
Authors: SCHERZ MARK D. , HAWLITSCHEK OLIVER , ANDREONE FRANCO , RAKOTOARISON ANDOLALAO , VENCES MIGUEL , GLAW FRANK
Published: June 2017

Over the last three years, three new species of saw-browed diamond frogs (Rhombophryne serratopalpebrosa species group)—a clade of cophyline microhylid frogs native to northern and eastern Madagascar—have been described. We here review the taxonomy of these frogs based on a new multi-gene phylogeny of the group, which confirms its monophyly but is insufficiently resolved to clarify most intra-group relationships. We confirm Rhombophryne guentherpetersi (Guibé, 1974) to be a member of this group, and we re-describe it based on its type series and newly collected material; the species is characterised by small superciliary spines (overlooked in its original description), as well as large tibial glands and an unusually laterally compressed pectoral girdle. We go on to describe two new species of this group from northern Madagascar: both R. diadema sp. nov. from the Sorata Massif and R. regalis sp. nov. from several sites in the northeast of the island possess three superciliary spines, but they are characterised by several subtle morphological and osteological differences. The new species are separated from all known congeners by an uncorrected pairwise distance of at least 5.1% in a ca. 550 bp fragment of the 16S rRNA gene. In order to highlight the significance of the skeleton in the taxonomy of this group, we provide a detailed description of its generalized osteology based on volume-rendered micro-CT scans of all described members, revisiting already-described skeletons of some species, and describing the skeletons of R. guentherpetersi, R. coronata, and the new taxa for the first time. Use of volume rendering, instead of surface rendering of micro-CT data, resulted in some discrepancies due to the properties of each method. We discuss these inconsistencies and their bearing on the relative value of surface and volume rendering in the taxonomist’s toolkit. We argue that, while surface models are more practical for the reader, volumes are generally a more objective representation of the data. Thus, taxonomic description work should be based on volume rendering when possible, with surface models presented as an aid to the reader.
Review of the genus Bythonia Oman 1936 with description of a new species and new record from Venezuela (Hemiptera, Cicadellidae, Iassinae)
Authors: GAIANI MARCO A.
Published: June 2017

Bythonia freytagi sp. nov. is diagnosed and described from northern Venezuela. Bythonia rugosa is recorded for the first time in Venezuela from the southern state of Amazonas. The presence of both species of Bythonia in Venezuela represent the first occurrences of this genus north of the Equator. Comments on the relationships of the described species are made and two species groups are proposed. A checklist and key to the known species of the genus are provided.