bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trabectedin Is Active against Malignant Pleural Mesothelioma Cell and Xenograft Models and Synergizes with Chemotherapy and Bcl-2 Inhibition In Vitro
Authors: Hoda Mir A. , Pirker Christine , Dong Yawen , Schelch Karin , Heffeter Petra , Kryeziu Kushtrim , van Schoonhoven Sushilla , Klikovits Thomas , Laszlo Viktoria , Rozsas Anita , Ozsvar Judit , Klepetko Walter , Döme Balazs , Grusch Michael , Hegedüs Balazs , Berger Walter 
Published: August 2016

Abstract
Malignant pleural mesothelioma (MPM) is characterized by widespread resistance to systemic therapy. Trabectedin is an antineoplastic agent targeting both the malignant cells and the tumor microenvironment that has been approved for the treatment of advanced soft tissue sarcoma and ovarian cancer. In this preclinical study, we evaluated the antineoplastic potential of trabectedin as a single agent and in drug combination approaches in human MPM. Therefore, we utilized an extended panel of MPM cell lines (n = 6) and primary cell cultures from surgical MPM specimens (n = 13), as well as nonmalignant pleural tissue samples (n = 2). Trabectedin exerted a dose-dependent cytotoxic effect in all MPM cell cultures in vitro when growing as adherent monolayers or nonadherent spheroids with IC50 values ≤ 2.6 nmol/L. Nonmalignant mesothelial cells were significantly less responsive. The strong antimesothelioma activity was based on cell-cycle perturbation and apoptosis induction. The activity of trabectedin against MPM cells was synergistically enhanced by coadministration of cisplatin, a drug routinely used for systemic MPM treatment. Comparison of gene expression signatures indicated an inverse correlation between trabectedin response and bcl-2 expression. Accordingly, bcl-2 inhibitors (Obatoclax, ABT-199) markedly synergized with trabectedin paralleled by deregulated expression of the bcl-2 family members bcl-2, bim, bax, Mcl-1, and bcl-xL as a consequence of trabectedin exposure. In addition, trabectedin exerted significant antitumor activity against an intraperitoneal MPM xenograft model. Together, these data suggest that trabectedin exerts strong activity in MPM and synergizes with chemotherapy and experimental bcl-2 inhibitors in vitro. Thus, it represents a promising new therapeutic option for MPM. Mol Cancer Ther; 15(10); 2357–69. ©2016 AACR.
BPR1J373, an Oral Multiple Tyrosine Kinase Inhibitor, Targets c-KIT for the Treatment of c-KIT–Driven Myeloid Leukemia
Authors: Chen Li-Tzong , Chen Chiung-Tong , Jiaang Weir-Torn , Chen Tsai-Yun , Butterfield Joseph H. , Shih Neng-Yao , Hsu John Tsu-An , Lin Hui-You , Lin Sheng-Fung , Tsai Hui-Jen 
Published: August 2016

Abstract
Acute myelogenous leukemia (AML) carrying t(8;21)(q22;q22) or inv(16)/t(16;16)(p13;q22) is classified as core binding factor (CBF)-AML and accounts for approximately 15% of AML. c-KIT mutation can be detected in 17%∼46% of CBF-AML and is associated with poor prognosis. c-KIT mutation is a crucial hit and cooperates with AML1-ETO resulting from t(8;21)(q22;q22) to cause overt AML. Tyrosine kinase inhibitors (TKI) targeting c-KIT, such as imatinib, has been used successfully to treat c-KIT driven gastrointestinal stromal tumors. However, the effect of TKI on c-KIT–driven leukemia, including CBF-AML and systemic mastocytosis (SM), has not been satisfactory. BPR1J373 is a 5-phenylthiazol-2-ylamine-pyriminide derivative targeting multiple tyrosine kinases. It was shown to inhibit cell proliferation and induce apoptosis in AML cells with constitutively activated c-KIT via inhibiting c-KIT phosphorylation and its downstream signals. The compound induced apoptosis by the mitochondrial intrinsic pathway through upregulation of proapoptotic proteins Bax and Bak and caspase 8 and 9 activation in c-KIT mutant Kasumi-1 cells. Furthermore, it induced cell-cycle arrest via targeting aurora kinase B in c-KIT wild-type KG-1 cells. The antitumor response of BPR1J373 was also shown in subcutaneously grafted SCID mice. BPR1J373 was shown to effectively suppress c-KIT phosphorylation of D816V mutation by treating c-KIT–null COS-1 cells transfected with c-KIT D816V mutant plasmid. In conclusion, BPR1J373 inhibits cell proliferation of c-KIT–driven AML cells via induction of apoptosis and cell-cycle arrest. It is also effective for multiple drug–resistant c-KIT D816V mutation. BPR1J373 deserves further development for clinical use in c-KIT–driven myeloid leukemia. Mol Cancer Ther; 15(10); 2323–33. ©2016 AACR.
Differential Response to Low-Dose Dopamine or Low-Dose Nesiritide in Acute Heart Failure With Reduced or Preserved Ejection Fraction
Authors: Wan Siu-Hin , Stevens Susanna R. , Borlaug Barry A. , Anstrom Kevin J. , Deswal Anita , Felker G. Michael , Givertz Michael M. , Bart Bradley A. , Tang W.H. Wilson , Redfield Margaret M. , Chen Horng H. 
Published: August 2016

Background—
The ROSE AHF trial (Renal Optimization Strategies Evaluation in Acute Heart Failure) found that when compared with placebo, neither low-dose dopamine (2 µg/kg per minute) nor low-dose nesiritide (0.005 μg/kg per minute without bolus) enhanced decongestion or preserved renal function in AHF patients with renal dysfunction. However, there may be differential responses to vasoactive agents in AHF patients with reduced versus preserved ejection fraction (EF). This post hoc analysis examined potential interaction between treatment effect and EF (EF ≤40% versus >40%) on the ROSE AHF end points.

Methods and Results—

ROSE AHF enrolled AHF patients (n=360; any EF) with renal dysfunction. The coprimary end points were cumulative urine volume and the change in serum cystatin-C in 72 hours. The effect of dopamine (interaction
P
=0.001) and nesiritide (interaction
P
=0.039) on urine volume varied by EF group. In heart failure with reduced EF, urine volume was higher with active treatment versus placebo, whereas in heart failure with preserved EF, urine volume was lower with active treatment. The effect of dopamine and nesiritide on weight change, sodium excretion, and incidence of AHF treatment failure also varied by EF group (interaction
P
<0.05 for all). There was no interaction between vasoactive treatment’s effect and EF on change in cystatin-C. Compared with placebo, dopamine was associated with improved clinical outcomes in heart failure with reduced EF and worse clinical outcomes in heart failure with preserved EF. With nesiritide, there were no differences in clinical outcomes when compared with placebo in both heart failure with reduced EF and heart failure with preserved EF.

Conclusions—
In this post hoc analysis of ROSE AHF, the response to vasoactive therapies differed in patients with heart failure with reduced EF and heart failure with preserved EF. Investigations of AHF therapies should assess the potential for differential responses in AHF with preserved versus reduced EF.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01132846.
Very Long–Term (10 to 14 Year) Outcomes After Percutaneous Coronary Intervention Versus Coronary Artery Bypass Grafting for Multivessel Coronary Artery Disease in the Bare-Metal Stent Era
Authors: Shiomi Hiroki , Yamaji Kyohei , Morimoto Takeshi , Shizuta Satoshi , Nakatsuma Kenji , Higami Hirooki , Furukawa Yutaka , Nakagawa Yoshihisa , Kadota Kazushige , Ando Kenji , Sakata Ryuzo , Okabayashi Hitoshi , Hanyu Michiya , Shimamoto Mitsuomi , Nishiwaki Noboru , Komiya Tatsuhiko , Kimura Takeshi 
Published: August 2016

Background—
Many of the previous randomized trials comparing percutaneous coronary intervention (PCI) with coronary artery bypass grafting (CABG) in patients with multivessel coronary artery disease reported equivalent or better survival with CABG as compared with PCI at 5-year follow-up. However, 5-year follow-up might be too short to evaluate the true differences in long-term clinical outcomes between PCI and CABG.

Methods and Results—

Among 8934 patients enrolled in the extended 10- to 14-year follow-up study of the CREDO-Kyoto registry cohort-1 (Coronary Revascularization Demonstrating Outcome study in Kyoto) conducted in the bare-metal stent era, 5152 (PCI: n=3490 and CABG: n=1662) patients had multivessel coronary artery disease without left main disease. Median follow-up duration was 11.2 (interquartile range: 10.2–12.2) years. The cumulative 10-year incidence of all-cause death was not significantly different between PCI and CABG (32.2% versus 31.7%; log-rank
P
=0.93). After adjusting for confounders, however, the mortality risk of PCI was significantly higher than that of CABG (hazard ratio, 1.19 [95% confidence interval, 1.02–1.39];
P
=0.03). Within 5 years after the index procedure, the risk for all-cause death was significantly higher after PCI than after CABG (hazard ratio, 1.41; 95% CI, 1.12–1.79;
P
=0.004). By a landmark analysis at 5 years, however, the cumulative 10-year incidence of and adjusted risk for all-cause death beyond 5 years were not significantly different between PCI and CABG (19.3% versus 20.0%; log-rank
P
=0.22 and hazard ratio, 1.02, 95% confidence interval, 0.83–1.26;
P
=0.82).

Conclusions—
CABG as compared with PCI was associated with better 10-year survival in patients with multivessel coronary artery disease. However, the benefit of CABG compared with PCI on late mortality beyond 5 years was not observed in this study.
Absorb Bioresorbable Vascular Scaffold in Complex Coronary Bifurcation Interventions
Authors: Bennett Johan , Vanhaverbeke Maarten , Vanden Driessche Nina , Adriaenssens Tom , Hiltrop Nick , Desmet Walter , Sinnaeve Peter , Dubois Christophe 
Published: August 2016

Background—
Although bioresorbable scaffolds offer potential advantages compared with metallic drug-eluting stents in the treatment of complex coronary bifurcation lesions, there are concerns that the polymeric scaffold integrity may be compromised. This in vivo study sought to provide insights about the feasibility of performing complex bifurcation stenting with Absorb bioresorbable vascular scaffolds (Abbott Vascular, Santa Clara, CA).

Methods and Results—
Twenty New Zealand white rabbits underwent stenting of the nondiseased aortoiliac bifurcation with bioresorbable vascular scaffolds using provisional (PS, n=5), culotte (n=5), modified-T (n=5), or T-and protrusion (n=5) stenting techniques. Angiography, optical coherence tomography, and microcomputed tomography were performed. Angiographic results were excellent without evidence of dissection or side branch (SB) compromise. PS optimally opened the SB ostium without deforming the main vessel (MV) bioresorbable vascular scaffolds, avoiding malapposition, and revealing a single connector fracture in 1 of 5 cases on microcomputed tomography. Culotte stenting resulted in complete bifurcation coverage with extensive segments of double-layered struts and inappropriately apposed struts at the bifurcation level in 3 of 5 cases. On microcomputed tomography, there was MV and SB scaffold distortion at the bifurcation with single strut fractures in 4 of 5 and double fractures in 1 of 5. Modified-T and T-and protrusion resulted in complete bifurcation coverage and in minimal double-strut layers at the neocarina. On microcomputed tomography, no strut fractures were present after modified-T, whereas in 3 of 5 T-and protrusion procedures single strut fractures were noted.

Conclusions—
Bifurcation stenting using bioresorbable vascular scaffolds is feasible with excellent angiographic results. PS with additional T-and protrusion whenever needed seems a reasonable approach. Whenever a 2-stent technique is planned, modified T-stenting appears the most promising.
Significantly higher rates of multiple and proximally located adenomas among patients with diabetes mellitus: A cross‐sectional population‐based study
Authors: de Kort Sander , Bouwens Mariëlle WE , Weijenberg Matty P , Janssen‐Heijnen Maryska LG , de Bruïne Adriaan P , Riedl Robert , Masclee Ad AM , Sanduleanu Silvia 
Published: August 2016

BackgroundDiabetes mellitus (DM) is associated with a greater risk for colorectal cancer (CRC).ObjectiveThe objective of this article is to examine the endoscopic phenotype and histopathology of colorectal polyps in patients with vs without DM.MethodsWe conducted a cross‐sectional study of patients who underwent colonoscopy at our university hospital and who completed a questionnaire. We collected endoscopy and histopathology data regarding colorectal adenomas and serrated polyps. Cox regression analyses were used to estimate adjusted prevalence ratios (PRs).ResultsWe examined a total of 3654 patients (mean age (SD): 62 (12) years, 47% males). Of them, 360 (9.9%) had DM. Overall, the prevalence of colorectal adenomas (42% vs 32%, p  < 0.01), multiple (≥3) adenomas (12% vs 7%, p  = 0.01) and proximal adenomas (30% vs 19%, p  < 0.01) was higher in patients with vs without DM. Multivariable analysis showed that the prevalence of adenomas (PR 1.17, 95% CI; 1.02–1.34), multiple (PR 1.37, 95% CI; 1.00–1.86) and proximal (PR 1.37, 95% CI; 1.16–1.62) adenomas was higher in patients with vs without DM, especially in men.ConclusionPatients with DM harbor more frequently multiple and proximal adenomas than those without DM. Close colonoscopic surveillance of DM patients is important to maximize the effectiveness of colonoscopic CRC prevention.
General continuous-time Markov model of sequence evolution via insertions/deletions: are alignment probabilities factorable?
Authors: Ezawa Kiyoshi 
Published: August 2016

Abstract
Background
Insertions and deletions (indels) account for more nucleotide differences between two related DNA sequences than substitutions do, and thus it is imperative to develop a stochastic evolutionary model that enables us to reliably calculate the probability of the sequence evolution through indel processes. Recently, indel probabilistic models are mostly based on either hidden Markov models (HMMs) or transducer theories, both of which give the indel component of the probability of a given sequence alignment as a product of either probabilities of column-to-column transitions or block-wise contributions along the alignment. However, it is not a priori clear how these models are related with any genuine stochastic evolutionary model, which describes the stochastic evolution of an entire sequence along the time-axis. Moreover, currently none of these models can fully accommodate biologically realistic features, such as overlapping indels, power-law indel-length distributions, and indel rate variation across regions.

Results
Here, we theoretically dissect the ab initio calculation of the probability of a given sequence alignment under a genuine stochastic evolutionary model, more specifically, a general continuous-time Markov model of the evolution of an entire sequence via insertions and deletions. Our model is a simple extension of the general “substitution/insertion/deletion (SID) model”. Using the operator representation of indels and the technique of time-dependent perturbation theory, we express the ab initio probability as a summation over all alignment-consistent indel histories. Exploiting the equivalence relations between different indel histories, we find a “sufficient and nearly necessary” set of conditions under which the probability can be factorized into the product of an overall factor and the contributions from regions separated by gapless columns of the alignment, thus providing a sort of generalized HMM. The conditions distinguish evolutionary models with factorable alignment probabilities from those without ones. The former category includes the “long indel” model (a space-homogeneous SID model) and the model used by Dawg, a genuine sequence evolution simulator.

Conclusions
With intuitive clarity and mathematical preciseness, our theoretical formulation will help further advance the ab initio calculation of alignment probabilities under biologically realistic models of sequence evolution via indels.
Exendin-4 enhances the differentiation of Wharton’s jelly mesenchymal stem cells into insulin-producing cells through activation of various β-cell markers
Authors: Kassem Dina H. , Kamal Mohamed M. , El-Kholy Abd El-Latif G. , El-Mesallamy Hala O. 
Published: August 2016

Abstract
Background
Diabetes mellitus is a devastating metabolic disease. Generation of insulin-producing cells (IPCs) from stem cells, especially from Wharton’s jelly mesenchymal stem cells (WJ-MSCs), has sparked much interest recently. Exendin-4 has several beneficial effects on MSCs and β cells. However, its effects on generation of IPCs from WJ-MSCs specifically have not been studied adequately. The purpose of this study was therefore to investigate how exendin-4 could affect the differentiation outcome of WJ-MSCs into IPCs, and to investigate the role played by exendin-4 in this differentiation process.

Methods
WJ-MSCs were isolated, characterized and then induced to differentiate into IPCs using two differentiation protocols: protocol A, without exendin-4; and protocol B, with exendin-4. Differentiated IPCs were assessed by the expression of various β-cell-related markers using quantitative RT-PCR, and functionally by measuring glucose-stimulated insulin secretion.

Results
The differentiation protocol B incorporating exendin-4 significantly boosted the expression levels of β-cell-related genes Pdx-1, Nkx2.2, Isl-1 and MafA. Moreover, IPCs generated by protocol B showed much better response to variable glucose concentrations as compared with those derived from protocol A, which totally lacked such response. Furthermore, exendin-4 alone induced early differentiation markers such as Pdx-1 and Nkx2.2 but not Isl-1, besides inducing late markers such as MafA. In addition, exendin-4 showed a synergistic effect with nicotinamide and β-mercaptoethanol in the induction of these markers.

Conclusions
Exendin-4 profoundly improves the differentiation outcome of WJ-MSCs into IPCs, possibly through the ability to induce the expression of β-cell markers.
Leadership Perspectives on Operationalizing the Learning Health Care System in an
Integrated Delivery System
Authors: Psek Wayne , Davis F. Daniel , Gerrity Gloria , Stametz Rebecca , Bailey-Davis Lisa , Henninger Deb , Sellers Dorothy , Darer Jonathan 
Published: August 2016

Introduction: Healthcare leaders need operational strategies that support
organizational learning for continued improvement and value generation. The learning
health system (LHS) model may provide leaders with such strategies; however, little is
known about leaders’ perspectives on the value and application of system-wide
operationalization of the LHS model. The objective of this project was to solicit and
analyze senior health system leaders’ perspectives on the LHS and learning activities in
an integrated delivery system.Methods: A series of interviews were conducted with 41
system leaders from a broad range of clinical and administrative areas across an
integrated delivery system. Leaders’ responses were categorized into
themes.Findings: Ten major themes emerged from our conversations with leaders. While
leaders generally expressed support for the concept of the LHS and enhanced system-wide
learning, their concerns and suggestions for operationalization where strongly aligned
with their functional area and strategic goals.Discussion: Our findings suggests that
leaders tend to adopt a very pragmatic approach to learning. Leaders expressed a
dichotomy between the operational imperative to execute operational objectives
efficiently and the need for rigorous evaluation. Alignment of learning activities with
system-wide strategic and operational priorities is important to gain leadership support
and resources. Practical approaches to addressing opportunities and challenges
identified in the themes are discussed.Conclusion: Continuous learning is an ongoing,
multi-disciplinary function of a health care delivery system. Findings from this and
other research may be used to inform and prioritize system-wide learning objectives and
strategies which support reliable, high value care delivery.
Adult respiratory distress syndrome
Authors: Cutts S , Talboys R , Paspula C , Prempeh EM , Fanous R , Ail D 
Published: August 2016

Adult respiratory distress syndrome (ARDS) has now been described as a sequela to such diverse conditions as burns, amniotic fluid embolism, acute pancreatitis, trauma, sepsis and damage as a result of elective surgery in general. Patients with ARDS require immediate intubation, with the average patient now being ventilated for between 8 and 11 days. While the acute management of ARDS is conducted by the critical care team, almost any surgical patient can be affected by the condition and we believe that it is important that a broader spectrum of hospital doctors gain an understanding of the nature of the pathology and its current treatment.
Mineralogy, Geochemistry, and Genesis of Sepiolite and Palygorskite in Neogene Lacustrine Sediments, Eskişehir Province, West Central Anatolia, Turkey
Authors: Kadir Selahattin , Erkoyun Hülya , Eren Muhsin , Huggett Jennifer , Önalgil Nergis 
Published: August 2016

AbstractSepiolite and palygorskite are common as layers and nodules in the Neogene lacustrine sediments of the Eskişehir area. This study aims to determine their mineralogical and geochemical characteristics, plus the distribution of these economically important sepiolite and palygorskite deposits within the lacustrine environment. Using these data the research goes on to discuss the environmental conditions for their formation. Sepiolite and palygorskite layers are associated with dolomite, marlstone, and argillaceous limestone. The sepiolite nodules (meerschaum), which are former magnesite gravels, are observed in the Upper Miocene reddish-brown fluvial deposits derived from the ophiolite and its fractureinfills at the northern margin of the basin. Sepiolite and palygorskite are only sparsely associated with dolomite and accessory magnesite, quartz, feldspar, and amphibole. Sepiolite and palygorskite fibers formed as oriented platy fan, interwoven, and knitted aggregates in the absence of dolomite indicated precipitation from supersaturated solution. Sepiolite and palygorskite fibers edging dolomite crystals postdate dolomite and formed through precipitation in a vadose environment under semi-arid to arid climatic conditions. High values of Mg+Fe+Ni and enrichment of light rare earth elements (LREE) relative to middle rare earth elements (MREE) and heavy rare earth elements (HREE), Sr content, depletion of Rb+Ba and K, and negligible negative Eu anomalies all reflect the derivation from the Paleozoic metamorphic and Upper Cretaceous ophiolitic rocks. Locally, Upper Miocene to Lower Pliocene volcanic, volcanoclastic, and fluvio-lacustrine sedimentary rocks supplied the required Si, Mg, Al, and Fe for precipitation of Al-sepiolite and Mg-palygorskite with average structural formulae of Si11.91Al0.09O30Mg6.60Al0.78Fe0.13 (OH)4Na0.12K0.06(OH2)4·nH2O and Si7.74Al0.26O20Mg2.52Al1.13Fe0.38(OH)2(OH2)4Na0.32K0.14 Ca0.12·nH2O, respectively. In contrast to the layered sepiolites, the absence of Al and high Ni content in sepiolite nodules suggest formation through replacement of magnesite gravels at shallow burial in an alkal ine environment. The calculated meerschaum sepiol ite chemical formula i s: Si12.02O30Mg7.87Fe0.01(OH)4Na0.13K0.03(OH2)4·nH2O.
Performativity, role reversal and disruptions in Joshua Oppenheimer’s The Act of Killing
Authors: Mayor Christine 
Published: August 2016

Abstract
The Act of Killing (2012) has been both praised for its innovative approach to documentary film-making and criticized for its historical ‘inaccuracies’ and potential ethical problems. This article offers a new reading of the documentary through a drama therapy lens, highlighting the performativity of the perpetrators and history itself, the power of role reversals towards collective healing by bringing one closer to the horror of their actions, and the importance of disrupting traditional genocide narratives for the viewing audience. This analysis points to new directions in working directly with perpetrators of mass violence and trauma.