bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dual Src and MEK Inhibition Decreases Ovarian Cancer Growth and Targets Tumor Initiating Stem-Like Cells
Authors: Simpkins Fiona , Jang Kibeom , Yoon Hyunho , Hew Karina E. , Kim Minsoon , Azzam Diana J. , Sun Jun , Zhao Dekuang , Ince Tan A. , Liu Wenbin , Guo Wei , Wei Zhi , Zhang Gao , Mills Gordon B. , Slingerland Joyce M. 
Published: June 2018

Abstract
Purpose: Rational targeted therapies are needed for treatment of ovarian cancers. Signaling kinases Src and MAPK are activated in high-grade serous ovarian cancer (HGSOC). Here, we tested the frequency of activation of both kinases in HGSOC and the therapeutic potential of dual kinase inhibition.
Experimental Design: MEK and Src activation was assayed in primary HGSOC from The Cancer Genome Atlas (TGGA). Effects of dual kinase inhibition were assayed on cell-cycle, apoptosis, gene, and proteomic analysis; cancer stem cells; and xenografts.
Results: Both Src and MAPK are coactivated in 31% of HGSOC, and this associates with worse overall survival on multivariate analysis. Frequent dual kinase activation in HGSOC led us to assay the efficacy of combined Src and MEK inhibition. Treatment of established lines and primary ovarian cancer cultures with Src and MEK inhibitors saracatinib and selumetinib, respectively, showed target kinase inhibition and synergistic induction of apoptosis and cell-cycle arrest in vitro, and tumor inhibition in xenografts. Gene expression and proteomic analysis confirmed cell-cycle inhibition and autophagy. Dual therapy also potently inhibited tumor-initiating cells. Src and MAPK were both activated in tumor-initiating populations. Combination treatment followed by drug washout decreased sphere formation and ALDH1+ cells. In vivo, tumors dissociated after dual therapy showed a marked decrease in ALDH1 staining, sphere formation, and loss of tumor-initiating cells upon serial xenografting.
Conclusions: Selumetinib added to saracatinib overcomes EGFR/HER2/ERBB2–mediated bypass activation of MEK/MAPK observed with saracatinib alone and targets tumor-initiating ovarian cancer populations, supporting further evaluation of combined Src–MEK inhibition in clinical trials. Clin Cancer Res; 24(19); 4874–86. ©2018 AACR.
Functional Parameters Derived from Magnetic Resonance Imaging Reflect Vascular Morphology in Preclinical Tumors and in Human Liver Metastases
Authors: Kannan Pavitra , Kretzschmar Warren W. , Winter Helen , Warren Daniel , Bates Russell , Allen Philip D. , Syed Nigar , Irving Benjamin , Papiez Bartlomiej W. , Kaeppler Jakob , Markelc Bosjtan , Kinchesh Paul , Gilchrist Stuart , Smart Sean , Schnabel Julia A. , Maughan Tim , Harris Adrian L. , Muschel Ruth J. , Partridge Mike , Sharma Ricky A. , Kersemans Veerle 
Published: June 2018

Abstract
Purpose: Tumor vessels influence the growth and response of tumors to therapy. Imaging vascular changes in vivo using dynamic contrast-enhanced MRI (DCE-MRI) has shown potential to guide clinical decision making for treatment. However, quantitative MR imaging biomarkers of vascular function have not been widely adopted, partly because their relationship to structural changes in vessels remains unclear. We aimed to elucidate the relationships between vessel function and morphology in vivo.
Experimental Design: Untreated preclinical tumors with different levels of vascularization were imaged sequentially using DCE-MRI and CT. Relationships between functional parameters from MR (iAUC, Ktrans, and BATfrac) and structural parameters from CT (vessel volume, radius, and tortuosity) were assessed using linear models. Tumors treated with anti-VEGFR2 antibody were then imaged to determine whether antiangiogenic therapy altered these relationships. Finally, functional–structural relationships were measured in 10 patients with liver metastases from colorectal cancer.
Results: Functional parameters iAUC and Ktrans primarily reflected vessel volume in untreated preclinical tumors. The relationships varied spatially and with tumor vascularity, and were altered by antiangiogenic treatment. In human liver metastases, all three structural parameters were linearly correlated with iAUC and Ktrans. For iAUC, structural parameters also modified each other's effect.
Conclusions: Our findings suggest that MR imaging biomarkers of vascular function are linked to structural changes in tumor vessels and that antiangiogenic therapy can affect this link. Our work also demonstrates the feasibility of three-dimensional functional–structural validation of MR biomarkers in vivo to improve their biological interpretation and clinical utility. Clin Cancer Res; 24(19); 4694–704. ©2018 AACR.
Cancer-Stimulated CAFs Enhance Monocyte Differentiation and Protumoral TAM Activation via IL6 and GM-CSF Secretion
Authors: Cho Haaglim , Seo Youngha , Loke Kin Man , Kim Seon-Wook , Oh Seong-Min , Kim Jun-Hyeong , Soh Jihee , Kim Hyoen Sik , Lee Hyunju , Kim Jin , Min Jung-Joon , Jung Da-Woon , Williams Darren Reece 
Published: June 2018

AbstractPurpose: M2-type TAMs are increasingly implicated as a crucial factor promoting metastasis. Numerous cell types dictate monocyte differentiation into M2 TAMs via a complex network of cytokine-based communication. Elucidating critical pathways in this network can provide new targets for inhibiting metastasis. In this study, we focused on cancer cells, CAFs, and monocytes as a major node in this network.Experimental Design: Monocyte cocultures with cancer-stimulated CAFs were used to investigate differentiation into M2-like TAMs. Cytokine array analyses were employed to discover the CAF-derived regulators of differentiation. These regulators were validated in primary CAFs and bone marrow-derived monocytes. Orthotopic, syngeneic colon carcinoma models using cotransplanted CAFs were established to observe effects on tumor growth and metastasis. To confirm a correlation with clinical evidence, meta-analyses were employed using the Oncomine database.Results: Our coculture studies identify IL6 and GM-CSF as the pivotal signals released from cancer cell–activated CAFs that cooperate to induce monocyte differentiation into M2-like TAMs. In orthotopic, syngeneic colon carcinoma mouse models, cotransplanted CAFs elevated IL6 and GM-CSF levels, TAM infiltration, and metastasis. These pathologic effects were dramatically reversed by joint IL6 and GM-CSF blockade. A positive correlation between GM-CSF and IL6 expression and disease course was observed by meta-analyses of the clinical data.Conclusions: Our studies indicate a significant reappraisal of the role of IL6 and GM-CSF in metastasis and implicate CAFs as the “henchmen” for cancer cells in producing an immunosuppressive tumor ecological niche. Dual targeting of GM-CSF and IL6 is a promising new approach for inhibiting metastasis. Clin Cancer Res; 24(21); 5407–21. ©2018 AACR.
Arsenic Trioxide and Sorafenib Induce Synthetic Lethality of FLT3-ITD Acute Myeloid Leukemia Cells
Authors: Wang Rui , Li Ying , Gong Ping , Gabrilove Janice , Waxman Samuel , Jing Yongkui 
Published: June 2018

Abstract
Acute myeloid leukemia (AML) with Fms-related tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation is notoriously hard to treat. We identified two drugs that together form an effective combination therapy against FLT3-ITD AML. One of the drugs, Sorafenib, an inhibitor of FLT3-ITD and other kinase activity, produces an impressive but short-lived remission in FLT3-ITD AML patients. The second, arsenic trioxide (ATO), at therapeutically achievable concentrations, reduces the level of FLT3-ITD and Mcl-1 proteins, and induces apoptosis in leukemic cell lines and in primary cells expressing FLT3-ITD. We linked this relative sensitivity to ATO to low levels of reduced glutathione. While producing proapoptotic effects, ATO treatment also has an unwanted effect whereby it causes the accumulation of the phosphorylated (inactive) form of glycogen synthase kinase 3β (GSK3β), a kinase necessary for apoptosis. When ATO is combined with Sorafenib, GSK3β is activated, Mcl-1 is further reduced, and proapoptotic proteins Bak and Bax are activated. Mice xenografted with FLT3-ITD MOLM13 cell line treated with the Sorafenib/ATO combination have significantly improved survival. This combination has potential to improve the therapeutic outcome of FLT3-ITD–targeted therapy of AML patients. Mol Cancer Ther; 17(9); 1871–80. ©2018 AACR.
Targeting Notch1 and IKKα Enhanced NF-κB Activation in CD133+ Skin Cancer Stem Cells
Authors: Quan Xin Xin , Hawk Nga Voong , Chen Weiping , Coupar Jamie , Lee Steven K. , Petersen David W. , Meltzer Paul S. , Montemarano Andrew , Braun Martin , Chen Zhong , Van Waes Carter 
Published: June 2018

Abstract
Cancer stem–like cells are hypothesized to be the major tumor-initiating cell population of human cutaneous squamous cell carcinoma (cSCC), but the landscape of molecular alterations underpinning their signaling and cellular phenotypes as drug targets remains undefined. In this study, we developed an experimental pipeline to isolate a highly enriched CD133+CD31−CD45−CD61−CD24− (CD133+) cell population from primary cSCC specimens by flow cytometry. The CD133+ cells show enhanced stem–like phenotypes, which were verified by spheroid and colony formation in vitro and tumor generation in vivo. Gene expression profiling of CD133+/− cells was compared and validated, and differentially expressed gene signatures and top pathways were identified. CD133+ cells expressed a repertoire of stemness and cancer-related genes, including NOTCH and NOTCH1-mediated NF-κB pathway signaling. Other cancer-related genes from WNT, growth factor receptors, PI3K/mTOR, STAT pathways, and chromatin modifiers were also identified. Pharmacologic and genetic targeting of NOTCH1, IKKα, RELA, and RELB modulated NF-κB transactivation, the CD133+ population, and cellular and stemness phenotypes. Immunofluorescent staining confirmed colocalization of CD133+ and IKKα expression in SCC tumor specimens. Our functional, genetic, and pharmacologic studies uncovered a novel linkage between NOTCH1, IKKα, and NF-κB pathway activation in maintaining the CD133+ stem SCC phenotypes. Studies investigating markers of activation and modulators of NOTCH, IKK/NF-κB, and other pathways regulating these cancer stem gene signatures could further accelerate the development of effective therapeutic strategies to treat cSCC recurrence and metastasis. Mol Cancer Ther; 17(9); 2034–48. ©2018 AACR.
A Quinoline-Based DNA Methyltransferase Inhibitor as a Possible Adjuvant in Osteosarcoma Therapy
Authors: Manara Maria Cristina , Valente Sergio , Cristalli Camilla , Nicoletti Giordano , Landuzzi Lorena , Zwergel Clemens , Mazzone Roberta , Stazi Giulia , Arimondo Paola B. , Pasello Michela , Guerzoni Clara , Picci Piero , Nanni Patrizia , Lollini Pier-Luigi , Mai Antonello , Scotlandi Katia 
Published: June 2018

AbstractThe identification of new therapeutic strategies against osteosarcoma, the most common primary bone tumor, continues to be a primary goal to improve the outcomes of patients refractory to conventional chemotherapy. Osteosarcoma originates from the transformation of mesenchymal stem cells (MSC) and/or osteoblast progenitors, and the loss of differentiation is a common biological osteosarcoma feature, which has strong significance in predicting tumor aggressiveness. Thus, restoring differentiation through epigenetic reprogramming is potentially exploitable for therapeutic benefits. Here, we demonstrated that the novel nonnucleoside DNMT inhibitor (DNMTi) MC3343 affected tumor proliferation by blocking osteosarcoma cells in G1 or G2–M phases and induced osteoblastic differentiation through the specific reexpression of genes regulating this physiologic process. Although MC3343 has a similar antiproliferative effect as 5azadC, the conventional FDA-approved nucleoside inhibitor of DNA methylation, its effects on cell differentiation are distinct. Induction of the mature osteoblast phenotype coupled with a sustained cytostatic response was also confirmed in vivo when MC3343 was used against a patient-derived xenograft (PDX). In addition, MC3343 displayed synergistic effects with doxorubicin and cisplatin (CDDP), two major chemotherapeutic agents used to treat osteosarcoma. Specifically, MC3343 increased stable doxorubicin bonds to DNA, and combined treatment resulted in sustained DNA damage and increased cell death. Overall, this nonnucleoside DNMTi is an effective novel agent and is thus a potential therapeutic option for patients with osteosarcoma who respond poorly to preadjuvant chemotherapy. Mol Cancer Ther; 17(9); 1881–92. ©2018 AACR.
Reappraisal of Reported Genes for Sudden Arrhythmic Death
Authors: Hosseini S. Mohsen , Kim Raymond , Udupa Sharmila , Costain Gregory , Jobling Rebekah , Liston Eriskay , Jamal Seema M. , Szybowska Marta , Morel Chantal F. , Bowdin Sarah , Garcia John , Care Melanie , Sturm Amy C. , Novelli Valeria , Ackerman Michael J. , Ware James S. , Hershberger Ray E. , Wilde Arthur A.M. , Gollob Michael H. ,   On behalf of the National Institutes of Health Clinical Genome Resource Consortium
Published: June 2018

Background:
Implicit in the genetic evaluation of patients with suspected genetic diseases is the assumption that the genes evaluated are causative for the disease based on robust scientific and statistical evidence. However, in the past 20 years, considerable variability has existed in the study design and quality of evidence supporting reported gene-disease associations, raising concerns of the validity of many published disease-causing genes. Brugada syndrome (BrS) is an arrhythmia syndrome with a risk of sudden death. More than 20 genes have been reported to cause BrS and are assessed routinely on genetic testing panels in the absence of a systematic, evidence-based evaluation of the evidence supporting the causality of these genes.

Methods:
We evaluated the clinical validity of genes tested by diagnostic laboratories for BrS by assembling 3 gene curation teams. Using an evidence-based semiquantitative scoring system of genetic and experimental evidence for gene-disease associations, curation teams independently classified genes as demonstrating limited, moderate, strong, or definitive evidence for disease causation in BrS. The classification of curator teams was reviewed by a clinical domain expert panel that could modify the classifications based on their independent review and consensus.

Results:

Of 21 genes curated for clinical validity, biocurators classified only 1 gene (
SCN5A
) as definitive evidence, whereas all other genes were classified as limited evidence. After comprehensive review by the clinical domain Expert panel, all 20 genes classified as limited evidence were reclassified as disputed with regard to any assertions of disease causality for BrS.

Conclusions:
Our results contest the clinical validity of all but 1 gene clinically tested and reported to be associated with BrS. These findings warrant a systematic, evidence-based evaluation for reported gene-disease associations before use in patient care.
Bioimpedance and New‐Onset Heart Failure: A Longitudinal Study of >500 000 Individuals From the General Population
Authors: Lindholm Daniel , Fukaya Eri , Leeper Nicholas J. , Ingelsson Erik 
Published: June 2018

Background
Heart failure constitutes a high burden on patients and society, but although lifetime risk is high, it is difficult to predict without costly or invasive testing. We aimed to establish new risk factors of heart failure, which potentially could enable early diagnosis and preemptive treatment.

Methods and Results

We applied machine learning in
the UK
Biobank in an agnostic search of risk factors for heart failure in 500 451 individuals, excluding individuals with prior heart failure. Novel factors were then subjected to several in‐depth analyses, including multivariable Cox models of incident heart failure, and assessment of discrimination and calibration. Machine learning confirmed many known and putative risk factors for heart failure and identified several novel candidates. Mean reticulocyte volume appeared as one novel factor and leg bioimpedance another, the latter appearing as the most important new marker. Leg bioimpedance was lower in those who developed heart failure during an up to 9.8‐year follow‐up. When adjusting for known heart failure risk factors, leg bioimpedance was inversely related to heart failure (hazard ratio [95%
confidence interval
], 0.60 [0.48–0.73] and 0.75 [0.59–0.94], in age‐ and sex‐adjusted and fully adjusted models, respectively, comparing the upper versus lower quartile). A model including leg bioimpedance, age, sex, and self‐reported history of myocardial infarction showed good discrimination for future heart failure hospitalization (Concordance index [C‐index]=0.82) and good calibration.

Conclusions
Leg bioimpedance is inversely associated with heart failure incidence in the general population. A simple model of exclusively noninvasive measures, combining leg bioimpedance with history of myocardial infarction, age, and sex provides accurate predictive capacity.
A Call for a Permissible Plurality Within Theory-Building in a Time of Excess
Authors: Hermann Adrian 
Published: June 2018

AbstractTheory in a Time of Excess(Equinox 2017) serves as a useful starting point to argue for a plural understanding of theory in the study of religion. While the existing conversation often implies that there is only one acceptable way of theorizing, it seems useful to distinguish between (at least) three understandings of theory—and a fourth potentially “illegitimate” one. These four forms (discourse theories, creative theories, scientific theories, and essentialist theories) are all present in the volume. Different theoretical approaches can learn from each other and expose their respective blind spots, which is the main reason to further a meta-theoretical debate about a permissible plurality within theory-building. Rather than a call to “just get along” under one big tent, this critical attitude implies that we should strive to better profile all four of these forms of theorizing in order to discuss their potential place in our discipline.
Foundlings in the Greco-Roman world: Status and the (im)possibility of adoption
Authors: Kacprzak Agnieszka , Nowak Maria 
Published: June 2018

Summary
The present article offers a commentary on two passages from the Gnomon of idios logos: § 41 (BGU V 1210, ll. 115-116), which pertains to a quarter of the inheritance left by an Egyptian who adopted a child picked up from a dump-hill, and § 107 (BGU V 1210, ll. 238-239), which repeats the same rule with regard to everyone, regardless of their civic status. The following problems are subject to our investigation: 1) Which specific type of adoption was expressed by the verb υἱοποιέομαι in § 41? 2) Why does the adoption of foundlings not appear in documentary sources? 3) What was the scope of the cited provisions? The article offers a survey of the legal status of exposed children and (im)possibilities of their adoption in law and legal practices in Roman, Greek and Egyptian sources.
The scholastics on negotiatio and the just price: medieval and early modern ideas in Theologians and contract law
Authors: Bukała Marcin W. 
Published: June 2018

Summary
The aim of the article is to highlight some crucial aspects of the just price concept and the differences between the medieval foundations and the late scholastic views on the topic. The paper refers especially to Wim Decock’s discourses on the ideas of ‘fairness in exchange’ in the book Theologians and contract law, The moral transformation of the ius commune (ca. 1500-1650) (Leiden 2013). The discussion concerns chiefly such issues as: role of Thomas Aquinas’s concepts (1), value in economic exchange (2), relativity in exchange (3), the distinction between furtum and turpe lucrum (4), changing views on the common good in the scholastic ethics of economic life, e.g. in the discussion of ‘Merchant of Rhodes’ casus (5).
Unique static discharge events on two CentriMag® (2nd Gen) ECMO patients causing console failure
Authors: Wise Robert K. , Waldhausen Sherry M. , Nguyen Van T. , Palanzo David A. , Baer Larry D. 
Published: June 2018

The use of ECMO for cardiovascular support continues to increase in the United States and around the world. It is not a benign endeavor as serious complications may occur. We present our experience of two second generation CentriMag® (Abbott formerly Thoratec Inc.) console failures that occurred while transporting the patients to other areas of the hospital. In each incident, the patients were immediately placed on back-up units and the transport continued. No patient complications could be attributed to the failures. An investigation by Abbott engineers traced the failure to a static build-up and discharge caused by a non-manufacturer-approved metal rod that was utilized to mount the external monitor. The static discharge caused a disruption of electrical continuity between the control system and the motor, stopping the motor as well as the monitoring system. Removal of the mounting rod prevented replication of the situation in the lab. We have removed the rod from our clinical units and have not experienced any other pump failures.
Effect of inflow cannula side-hole number on drainage flow characteristics: flow dynamic analysis using numerical simulation
Authors: Goto Takeshi , Tanabe Tsubasa , Inamura Takao , Shirota Minori , Fumoto Koji , Saito Yoshiaki , Fukuda Wakako , Fukuda Ikuo , Daitoku Kazuyuki , Minakawa Masahito 
Published: June 2018

Background: Venous drainage in cardiopulmonary bypass is a very important factor for safe cardiac surgery. However, the ideal shape of venous drainage cannula has not been determined. In the present study, we evaluated the effect of side-hole number under fixed total area and venous drainage flow to elucidate the effect of increasing the side-hole numbers. Method: Computed simulation of venous drainage was performed. Cannulas were divided into six models: an end-hole model (EH) and models containing four (4SH), six (6SH), eight (8SH), 10 (10SH) or 12 side-holes (12SH). Total orifice area of the side-holes was fixed to 120 mm2 on each side-hole cannula. The end-hole orifice area was 36.3 mm2. The total area of the side-holes was kept constant when the number of side-holes was increased. Result: The mean venous drainage flow rate of the EH, 4SH, 6SH, 8SH, 10SH and 12SH was 2.57, 2.52, 2.51, 2.50, 2.49, 2.41 L/min, respectively. The mean flow rate decreased in accordance with the increased number of side-holes. Conclusion: We speculate that flow separation at the most proximal site of the side-hole induces stagnation of flow and induces energy loss. This flow separation may hamper the main stream from the end-hole inlet, which is most effective with low shear stress. The EH cannula was associated with the best flow rate and flow profile. However, by increasing side-hole numbers, flow separation occurs on each side-hole, resulting in more energy loss than the EH cannula and flow rate reduction.