bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of β-Lactam/β-Lactamase Inhibitor Combinations for the Treatment of Bloodstream Infection Due to Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae in Hematological Patients with Neutropenia
Authors: Gudiol Carlota , Royo-Cebrecos Cristina , Abdala Edson , Akova Murat , Álvarez Rocío , Maestro-de la Calle Guillermo , Cano Angela , Cervera Carlos , Clemente Wanessa T. , Martín-Dávila Pilar , Freifeld Alison , Gómez Lucía , Gottlieb Thomas , Gurguí Mercè , Herrera Fabián , Manzur Adriana , Maschmeyer Georg , Meije Yolanda , Montejo Miguel , Peghin Maddalena , Rodríguez-Baño Jesús , Ruiz-Camps Isabel , Sukiennik Teresa C. , Tebe Cristian , Carratalà Jordi 
Published: June 2017

ABSTRACT
β-Lactam/β-lactamase inhibitors (BLBLIs) were compared to carbapenems in two cohorts of hematological neutropenic patients with extended-spectrum-β-lactamase (ESBL) bloodstream infection (BSI): the empirical therapy cohort (174 patients) and the definitive therapy cohort (251 patients). The 30-day case fatality rates and other secondary outcomes were similar in the two therapy groups of the two cohorts and also in the propensity-matched cohorts. BLBLIs might be carbapenem-sparing alternatives for the treatment of BSI due to ESBLs in these patients.
Upregulation of Apoptosis Pathway Genes in Peripheral Blood Mononuclear Cells of HIV-Infected Individuals with Antiretroviral Therapy-Associated Mitochondrial Toxicity
Authors: Foli Yram , Ghebremichael Musie , Li Min , Paintsil Elijah 
Published: June 2017

ABSTRACT
A case-control study of the effect of antiretroviral therapy (ART) on apoptosis pathway genes comprising 16 cases (HIV infected with mitochondrial toxicity) and 16 controls (HIV uninfected) was conducted. A total of 26 of 84 genes of the apoptosis pathway were differentially expressed. Two of the upregulated genes, DFFA and TNFRSF1A, classified 75% of study participants correctly as either a case or control. Thus, apoptosis may be in the causal pathway of ART-associated mitochondrial toxicity. These two genes could be markers for detecting and monitoring ART-induced mitochondrial toxicity.
Pharmacodynamic Optimization for Treatment of Invasive Candida auris Infection
Authors: Lepak Alexander J. , Zhao Miao , Berkow Elizabeth L. , Lockhart Shawn R. , Andes David R. 
Published: June 2017

ABSTRACT

Candida auris
is an emerging multidrug-resistant threat. The pharmacodynamics of three antifungal classes against nine
C. auris
strains was explored using a murine invasive candidiasis model. The total drug median pharmacodynamic (PD) target associated with net stasis was a fluconazole AUC/MIC (the area under the concentration-time curve over 24 h in the steady state divided by the MIC) of 26, an amphotericin B
C
max
/MIC (maximum concentration of drug in serum divided by the MIC) of 0.9, and a micafungin AUC/MIC of 54. The micafungin PD targets for
C. auris
were ≥20-fold lower than those of other
Candida
species in this animal model. Clinically relevant micafungin exposures produced the most killing among the three classes.
In Vitro
Antibiofilm Activity of Eucarobustol E against Candida albicans
Authors: Liu Rui-Huan , Shang Zhi-Chun , Li Tian-Xiao , Yang Ming-Hua , Kong Ling-Yi 
Published: June 2017

ABSTRACT

Formyl-phloroglucinol meroterpenoids (FPMs) are important types of natural products with various bioactivities. Our antifungal susceptibility assay showed that one of the
Eucalyptus robusta
-derived FPMs, eucarobustol E (EE), exerted a strong inhibitory effect against
Candida albicans
biofilms at a concentration of 16 μg/ml. EE was found to block the yeast-to-hypha transition and reduce the cellular surface hydrophobicity of the biofilm cells. RNA sequencing and real-time reverse transcription-PCR analysis showed that exposure to 16 μg/ml of EE resulted in marked reductions in the levels of expressions of genes involved in hyphal growth (
EFG1
,
CPH1
,
TEC1
,
EED1
,
UME6
, and
HGC1
) and cell surface protein genes (
ALS3
,
HWP1
, and
SAP5
). Interestingly, in response to EE, genes involved in ergosterol biosynthesis were downregulated, while the farnesol-encoding gene (
DPP3
) was upregulated, and these findings were in agreement with those from the quantification of ergosterol and farnesol. Combined with the obvious elevation of negative regulator genes (
TUP1
,
NRG1
), we speculated that EE's inhibition of carbon flow to ergosterol triggered the mechanisms of the negative regulation of hyphal growth and eventually led to biofilm inhibition.
Patient level cost of diabetes self-management education programmes: an international evaluation
Authors: Doyle Gerardine , O'Donnell Shane , Quigley Etáin , Cullen Kate , Gibney Sarah , Levin-Zamir Diane , Ganahl Kristin , Müller Gabriele , Muller Ingrid , Maindal Helle Terkildsen , Chang Wushou Peter , Van Den Broucke Stephan 
Published: June 2017

ObjectivesThe objective of this study was to examine the value of time-driven activity-based costing (TDABC) in understanding the process and costs of delivering diabetes self-management education (DSME) programmes in a multicountry comparative study.SettingOutpatient settings in five European countries (Austria, Denmark, Germany, Ireland, UK) and two countries outside Europe, Taiwan and Israel.ParticipantsProviders of DSME programmes across participating countries (N=16) including healthcare professionals, administrators and patients taking part in DSME programmes.Primary and secondary measuresPrimary measure: time spent by providers in the delivery of DSME and resources consumed in order to compute programme costs. Secondary measures: self-report measures of behavioural self-management and diabetes disease/health-related outcomes.ResultsWe found significant variation in costs and the processes of how DSME programmes are provided across and within countries. Variations in costs were driven by a combination of price variances, mix of personnel skill and efficiency variances. Higher cost programmes were not found to have achieved better relative outcomes. The findings highlight the value of TDABC in calculating a patient level cost and potential of the methodology to identify process improvements in guiding the optimal allocation of scarce resources in diabetes care, in particular for DSME that is often underfunded.ConclusionsThis study is the first to measure programme costs using estimates of the actual resources used to educate patients about managing their medical condition and is the first study to map such costs to self-reported behavioural and disease outcomes. The results of this study will inform clinicians, managers and policy makers seeking to enhance the delivery of DSME programmes. The findings highlight the benefits of adopting a TDABC approach to understanding the drivers of the cost of DSME programmes in a multicountry study to reveal opportunities to bend the cost curve for DSME.
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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.