bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract POSTER-CTRL-1217: Human placental lactogen-functionalized bimodal imaging probe for human ovarian cancer detection
Authors: Zhang Yilin , Sundaram Karthik M. , Li Nan-Sheng , Piccirilli Joseph A. , Lengyel Ernst 
Published: August 2015

Abstract
The early detection of ovarian cancer (OvCa) is a challenge because the postmenopausal ovaries are hidden in the peritoneal cavity and current imaging technologies lack the ability to differentiate between benign and malignant masses. Our goal is to improve the detection and imaging of OvCa utilizing cancer cell-targeted, bimodal fluorescent and paramagnetic micelles that effectively detect malignant tumors. The human prolactin receptor (PrlR) is expressed in 98% of malignant ovarian tumors, but is not expressed in benign ovarian tumors or fallopian tubes. Therefore, we conjugated the maleimide-functional micelles to a thiol group of human placental lactogen (hPL), a ligand of PrlR, to specifically target OvCa cells. The micelles were 20-nm in diameter with a favorable surface charge (-5.8mV) characterized by dynamic light scattering, zeta potential, and transmission electron microscopy (TEM). After conjugation to hPL, hPL-micelles displayed an increased molecular weight and particle size as assessed by SDS-PAGE, MALDI-TOF, and size exclusion chromatography. Microscopic and cytometric analyses demonstrated that hPL-micelles were more efficiently internalized in human primary OvCa cells and OvCa cell lines than unconjugated micelles. The knockdown of PrlR using shRNA in OvCa cell lines or the triple mutation of hPL significantly inhibited uptake of hPL-fluorophore conjugates, suggesting receptor-mediated endocytosis. Furthermore, the Xenogen IVIS small animal imaging system detected a greater accumulation of hPL-micelles than of unconjugated micelles in the human ovarian tumor xenograft, confirming the enhanced imaging of OvCa through targeted delivery. Given the low prevalence of OvCa and the current unsatisfactory imaging modalities, “receptor-dependent imaging” through hPL-decorated bimodal micelles has the potential to improve detection of OvCa through enhanced specificity.
Citation Format: Yilin Zhang, Karthik M. Sundaram, Nan-Sheng Li, Joseph A. Piccirilli, Ernst Lengyel. Human placental lactogen-functionalized bimodal imaging probe for human ovarian cancer detection [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-CTRL-1217.
Abstract POSTER-THER-1413: Targeting constitutively-activated STAT3 in hypoxic ovarian cancer
Authors: McCann Georgia A , ElNaggar Adam , Naidu Shan , Rath Kellie S , Tierney Brent J , Suarez Adrian , Cohn David E , Selvendiran Karuppaiyah 
Published: August 2015

Abstract
Background: Tumor hypoxia, a feature of many solid tumors including ovarian cancer, is associated with resistance to therapies. We previously demonstrated that hypoxic exposure results in increased expression of phosphorylated signal transducer and activator of transcription 3 (pSTAT3). We hypothesized that the activation of STAT3 could lead to chemotherapeutic resistance in ovarian cancer cells in hypoxic conditions.
Methods: The increase of pSTAT3 Tyr705 in the hypoxic regions of human epithelial ovarian cancer (EOC) specimens was determined by HIF-1α and CD-31 staining. In vitro mutagenesis studies of pSTAT3 Tyr705 were used to demonstrate the necessity for cell survival and proliferation under hypoxic conditions. In addition, S1PR1, a regulator of STAT3 transcription via the JAK/STAT pathway, is highly expressed in hypoxic ovarian cancer cells (HOCCs). This association was evaluated with knock down of S1PR1 in HOCCs. HOCCs were treated with our novel STAT3 inhibitor, HO-3867.
Results: pSTAT3 Tyr705 is increased in the hypoxic regions of EOC specimens. In vitro mutagenesis studies proved that pSTAT3 Tyr705 is necessary for cell survival and proliferation under hypoxic conditions. Knock down of S1PR1 in HOCCs reduced pSTAT3 Tyr705 levels and was associated with decreased cell survival. Treatment of HOCCs with the STAT3 inhibitor HO-3867 resulted in a rapid and dramatic decrease in pSTAT3 Tyr705 levels as a result of ubiquitin proteasome degradation. There was decreased expression of the STAT3-target proteins Bcl-xL, cyclin D2, and VEGF in all HO-3867 treated cells.
Conclusions: These findings suggest that activation of STAT3 Tyr705 promotes cell survival and proliferation in HOCCs, and that S1PR1 is involved in the initiation of STAT3 activation. Therefore, targeting hypoxia-mediated STAT3 activation represents a therapeutic option for ovarian cancer and other solid tumors.
Citation Format: Georgia A McCann, MD, Adam ElNaggar, MD, Shan Naidu, MS; Kellie S Rath, MD; Brent J Tierney, MD; Adrian Suarez, MD; David E Cohn, MD; Karuppaiyah Selvendiran, PhD. Targeting constitutively-activated STAT3 in hypoxic ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1413.
Abstract POSTER-THER-1425: Novel small molecules overcoming platinum drug resistance in ovarian cancer cells
Authors: Qian Wei , Wang Jingnan , Edwards Robert , Wipf Peter , Houten Bennett Van 
Published: August 2015

Abstract
After stage, platinum drug resistance is the single most important factor in determining prognosis in ovarian cancer. Overcoming platinum drug resistance by pharmacological manipulations represents a major challenge in the current clinical practice for the management of ovarian cancer. We discovered a novel drug combination approach using platinum agents with mdivi-1 (mitochondrial division inhibitor 1) that is able to synergistically induce rapid apoptosis in platinum-resistant ovarian cancer cells, including established cisplatin-resistant ovarian cancer cell lines as well as primary cancer cells derived from ovarian cancer patients. We also identified that the synergism between cisplatin and mdivi-1 is not dependent on Drp1 (a mitochondrial fission protein and the reported target of mdivi-1), as mdivi-1 enhances cisplatin toxicity in Drp1 knockout mouse embryonic fibroblast (MEF) cells. In order to improve the compound properties of mdivi-1, we performed a structure activity relationship (SAR) study of mdivi-1 and assembled and screened a small library of structurally related compounds. We were able to identify more potent novel small molecules that synergize with platinum agents. We found that short-term exposure of cells to the combination of cisplatin and those novel compounds is sufficient to reduce cell viability, while cisplatin alone treatment only slightly inhibited cell proliferation in cisplatin-resistant ovarian cancer cells. We further identified that mdivi-1 and its structurally related novel small molecules, when combined with cisplatin, induce a synergistic increase of replication stress and DNA damage, causing upregulation of a pro-apoptotic Bcl-2 family protein Noxa. These small molecules also repress mitochondrial respiration and the combination with cisplatin triggers substantial mitochondrial dysfunction including mitochondrial uncoupling. DNA replication stress and mitochondrial dysfunction converge on the induction of mitochondrial outer membrane permeabilization (MOMP) proceeding robust mitochondrial apoptotic signaling, bypassing a Bax/Bak-dependent mechanism. Since apoptosis induced by cisplatin alone relies on Bax/Bak-dependent MOMP, and inefficient activation of Bax/Bak-dependent MOMP is often associated with cisplatin resistance, the combination of cisplatin and mdivi-1 family compounds represents a novel strategy in overcoming platinum resistance. We thus present a novel platinum-based combination approach in the treatment of platinum resistant ovarian cancer.
Citation Format: Wei Qian, Jingnan Wang, Robert Edwards, Peter Wipf, Bennett Van Houten. Novel small molecules overcoming platinum drug resistance in ovarian cancer cells [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1425.
Abstract POSTER-THER-1429: Selection of DNA aptamers for an ovarian cancer cell line using high-throughput sequencing
Authors: Whelan Rebecca J. , Kapur Arvinder , Felder Mildred , Shallcross Jamie , Nie Jeff , Patankar Manish S. 
Published: August 2015

Abstract
Humanized antibodies have been extensively investigated as therapeutic as well as diagnostic agents. While the antigen specificity offered by antibodies makes them very attractive for such theranostic applications, their large-scale synthesis can be challenging and expensive. We are therefore investigating alternate strategies to develop agents that can be used for in vivo monitoring as well as for treatment of epithelial ovarian tumors. One approach is to develop Single Stranded DNA aptamers that selectively bind to ovarian cancer cells. The ssDNA aptamers can be synthesized using template-driven or de novo chemical synthetic approaches to manufacture agents at a large scale and low cost. The challenge however, is to develop aptamers that are specific to ovarian cancer cells. In the current study, we report a streamlined approach that incorporates the cell-based Systematic Evolution of Ligands by Exponential Enrichment (cell-SELEX) with DNASeq technology to select aptamers that recognize ovarian cancer cells. An ssDNA aptamer library composed of ~1015 sequences was subjected to ten iterative rounds of selection against the ovarian cancer cell line OVCAR-3. Aptamers from each round were amplified by asymmetric PCR and subjected to high-throughput sequencing. Eight ssDNA aptamers enriched through the selection process were identified by DNASeq and subsequent bioinformatics analysis and their selectivity and affinity for OVCAR-3 cells was determined by flow cytometry. Two of these aptamers (Apt-1 and Apt-8) showed significant binding to OVCAR-3 cells with Kd of 24 and 28 nM, respectively. Secondary structure analysis using mfold indicated that Apt-1 and Apt-8 had defined secondary structures resulting from ordered base pairing of the ssDNA. The inclusion of high-throughput sequencing techniques has therefore allowed rapid identification of theranostic aptamers from an large randomized library of ssDNA sequences. Our ongoing experiments are focused on coupling of the ovarian cancer cell-specific ssDNA aptamers to contrast agents or cytotoxic drugs. The ssDNA aptamers coupled to contrast agents are specifically being investigated for in vivo imaging of ovarian cancer masses in the peritoneum whereas the aptamers coupled to drugs can be used for the treatment of ovarian cancer.
Citation Format: Rebecca J. Whelan, Arvinder Kapur, Mildred Felder, Jamie Shallcross, Jeff Nie, Manish S. Patankar. Selection of DNA aptamers for an ovarian cancer cell line using high-throughput sequencing [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1429.
Abstract POSTER-THER-1440: Targeted delivery of doxorubicin loaded nanobins to ovarian cancer cells through the urokinase plasminogen activator system
Authors: Zhang Yilin , Swindell Elden P. , Hankins Patrick L. , Kenny Hilary A. , O'Halloran Thomas V. , Mazar Andrew P. , Lengyel Ernst 
Published: August 2015

Abstract
The therapeutic efficacy of antitumor drugs is often limited by non-specific, systematic delivery. Here we report a novel targeted delivery platform designed by coupling liposomal nanobins (NB) with the urokinase plasminogen activator receptor (u-PAR) antibody (ATN-658). The urokinase system is overexpressed in epithelial ovarian cancer (OvCa) cells and is expressed only at low levels in normal cells. Doxorubicin (Dox), a FDA approved antitumor drug, had been loaded into the nanobins as a payload. The size and surface charge of the nanobins were optimized to facilitate specific binding to u-PAR expressing OvCa cells. Confocal and transmission electron microscopy showed that ATN-658-NB(Dox) was internalized in OvCa cells in a receptor-dependent manner and was released from endosomes as a function of time. This uptake could be blocked by stably down-regulating u-PAR expression in the OvCa cells using shRNA. In an orthotopic ovarian cancer model, athymic mice treated with ATN-658-NB(Dox) had a significantly greater reduction in tumor burden (0.06±0.01g versus 0.1±0.01g; p&lt;0.001) than mice treated with NB(Dox), which was corroborated by in vivo fluorescence imaging results. A survival study showed that targeted nanobins prolonged the survival of mice by 3 days (43 days versus 40 days, median survival) as compared to untargeted nanobins. Immunoblot analysis of tumor sections showed that targeted nanobins induced apoptosis (cleaved caspase 3) and inhibited proliferation (Ki-67) more efficiently when compared to untargeted nanobins. Furthermore, tumor-targeted delivery of ATN-658-ND(Dox) was confirmed by ex vivo fluorescence imaging, FACS analysis, and confocal microscopy. Taken together, our findings show that receptor-mediated delivery of targeted nanobins to cancer cells could serve as a novel approach to ovarian cancer treatment.
Citation Format: Yilin Zhang, Elden P. Swindell, Patrick L. Hankins, Hilary A. Kenny, Thomas V. O’Halloran, Andrew P. Mazar, Ernst Lengyel. Targeted delivery of doxorubicin loaded nanobins to ovarian cancer cells through the urokinase plasminogen activator system [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1440.
EGFR Kinase Domain Duplication (EGFR-KDD) Is a Novel Oncogenic Driver in Lung Cancer That Is Clinically Responsive to Afatinib
Authors: Gallant Jean-Nicolas , Sheehan Jonathan H. , Shaver Timothy M. , Bailey Mark , Lipson Doron , Chandramohan Raghu , Brewer Monica Red , York Sally J. , Kris Mark G. , Pietenpol Jennifer A. , Ladanyi Marc , Miller Vincent A. , Ali Siraj M. , Meiler Jens , Lovly Christine M. 
Published: August 2015

Abstract
Oncogenic EGFR mutations are found in 10% to 35% of lung adenocarcinomas. Such mutations, which present most commonly as small in-frame deletions in exon 19 or point mutations in exon 21 (L858R), confer sensitivity to EGFR tyrosine kinase inhibitors (TKI). In analyzing the tumor from a 33-year-old male never-smoker, we identified a novel EGFR alteration in lung cancer: EGFR exon 18–25 kinase domain duplication (EGFR-KDD). Through analysis of a larger cohort of tumor samples, we detected additional cases of EGFR-KDD in lung, brain, and other cancers. In vitro, EGFR-KDD is constitutively active, and computational modeling provides potential mechanistic support for its auto-activation. EGFR-KDD–transformed cells are sensitive to EGFR TKIs and, consistent with these in vitro findings, the index patient had a partial response to the EGFR TKI afatinib. The patient eventually progressed, at which time resequencing revealed an EGFR-dependent mechanism of acquired resistance to afatinib, thereby validating EGFR-KDD as a driver alteration and therapeutic target.
Significance: We identified oncogenic and drug-sensitive EGFR-KDD that is recurrent in lung, brain, and soft-tissue cancers and documented that a patient with metastatic lung adenocarcinoma harboring the EGFR-KDD derived significant antitumor response from treatment with the EGFR inhibitor afatinib. Findings from these studies will be immediately translatable, as there are already several approved EGFR inhibitors in clinical use. Cancer Discov; 5(11); 1155–63. ©2015 AACR.
This article is highlighted in the In This Issue feature, p. 1111
A New Method of Comparing Forcing Agents in Climate Models*
Authors: Kravitz Ben , MacMartin Douglas G. , Rasch Philip J. , Jarvis Andrew J. 
Published: August 2015

Abstract
The authors describe a new method of comparing different climate forcing agents (e.g., CO2 concentration, CH4 concentration, and total solar irradiance) in climate models that circumvents many of the difficulties associated with explicit calculations of efficacy. This is achieved by introducing an explicit feedback loop external to a climate model that adjusts one forcing agent to balance another while keeping global-mean surface temperature constant. The convergence time of this feedback loop can be adjusted, allowing for comparisons of forcing agents to be achieved with relatively short simulations. Comparisons between forcing agents are highly linear in concordance with predicted scaling relationships; for example, the global-mean climate response to a doubling of the CO2 concentration is equivalent to that of a 2.1% change in total solar irradiance. This result is independent of the magnitude of the forcing agent (within the range of radiative forcings considered here) and is consistent across two different climate models.
The Effect of Midlatitude Transient Eddies on Monsoonal Southerlies over Eastern China
Authors: Park Hyo-Seok , Lintner Benjamin R. , Boos William R. , Seo Kyong-Hwan 
Published: August 2015

Abstract
The strengthening of monsoonal southerlies over East Asia is associated with the westward intensification of the North Pacific subtropical high. Previous work has shown that the seasonal-mean position and strength of subtropical highs are affected by tropical and subtropical diabatic heating. Here it is shown that the synoptic-time-scale strengthening of southerlies over eastern China is dynamically tied to extratropical eddy activity. Composite analysis based on strong southerly wind events highlights an antecedent baroclinic wave train propagating southeastward into eastern China from extratropical central Asia. This wave train generates quasigeostrophic ascent over eastern China that is associated with heavy precipitation. The anomalously cold upper-tropospheric conditions associated with the wave train decrease static stability throughout the lower and middle troposphere in eastern China, while low-level moistening enhances equivalent potential temperature. It is proposed that the resulting reductions in dry and moist static stability intensify the eddy-induced precipitating ascent. These results illustrate how East Asian monsoon circulation and precipitation can be enhanced by the interaction of midlatitude baroclinic waves with the moist subtropical monsoon region.
Reduction of Nonuniform Beamfilling Effects by Multiple Constraints: A Simulation Study
Authors: Short David A. , Meneghini Robert , Emory Amber E. , Schwaller Mathew R. 
Published: August 2015

AbstractA spaceborne precipitation radar samples the vertical structure of precipitating hydrometeors from the top down. The viewing geometry and operating frequency result in certain limitations and opportunities. Among the limitations is attenuation of the radar signal that can cause the measured radar reflectivity factor to be substantially less than the desired quantity, the true radar reflectivity factor. Another error source is the spatial variability in precipitation rates that occurs at scales smaller than the sensor field of view (FOV), giving rise to the nonuniform beamfilling (NUBF) effect. The opportunities arise when the radar return from the surface can be used to obtain constraints on the path-integrated attenuation (PIA) for use in hybrid attenuation correction algorithms. The surface return can also provide some information on the degree of NUBF at off-nadir viewing angles. In this paper ground-based radar data are used to simulate spaceborne radar data at nadir and off-nadir viewing angles at Ku band and Ka band and to test attenuation correction algorithms in the presence of nonuniform beamfilling. The cross-FOV gradient in PIA is found to be an important characteristic for describing the performance of attenuation correction algorithms.
A Randomized Controlled Trial Comparing Intranasal Midazolam and Chloral Hydrate for Procedural Sedation in Children
Authors: Stephen Marie Christy Sharafine , Mathew John , Varghese Ajoy Mathew , Kurien Mary , Mathew George Ani 
Published: August 2015

ObjectivesTo evaluate the efficacy and safety of intranasal midazolam and chloral hydrate syrup for procedural sedation in children.Study DesignProspective randomized placebo‐controlled trial (double blind, double dummy).SettingTertiary care hospital over 18 months.Subjects and MethodsEighty‐two children, 1 to 6 years old, undergoing auditory brainstem response testing were randomized to receive either intranasal midazolam with oral placebo or chloral hydrate syrup with placebo nasal spray. Intranasal midazolam was delivered at 0.5 mg/kg (100 mcg per spray) and oral syrup at 50 mg/kg. Children not sedated at 30 minutes had a second dose at half the initial dose. The primary outcomes measured were safety and efficacy. Secondary outcomes were time to onset of sedation, parental separation, nature of parental separation, parental satisfaction, audiologist’s satisfaction, time to recovery, and number of attempts.ResultsForty‐one children were in each group, and no major adverse events were noted. The chloral hydrate group showed earlier onset of sedation (66%) compared with the intranasal midazolam group (33%). Significant difference in time to recovery was noted in the chloral hydrate group (78 minutes) versus the intranasal midazolam group (108 minutes). The parents’ and audiologist’s satisfaction was higher for chloral hydrate (95% and 75%) than for intranasal midazolam (49% and 29%, respectively). Overall, sedation was 95% with chloral hydrate versus 51% with intranasal midazolam. Both drugs maintained sedation.ConclusionsIntranasal midazolam and chloral hydrate are both safe and efficacious for pediatric procedural sedation. Chloral hydrate was superior to intranasal midazolam, with an earlier time to onset of sedation, a faster recovery, better satisfaction among parents and the audiologist, and successful sedation.