bluuebunny/crossref_metadata_2025_split huggingface dataset:
New Strategies in Esophageal Carcinoma: Translational Insights from Signaling Pathways and Immune Checkpoints
Authors: Wang Victoria E. , Grandis Jennifer R. , Ko Andrew H. 
Published: July 2016

Abstract
Esophageal cancer remains a highly lethal malignancy in which relatively modest therapeutic advances have been made over the past several decades. Cytotoxic therapy remains the mainstay of treatment for both advanced esophageal adenocarcinoma and squamous cell carcinoma (SCC), with incremental benefit conferred by antibodies targeting HER2 and VEGFR in selected patients. However, intrinsic or acquired resistance in this disease almost invariably occurs and remains a major challenge. Moreover, although large-scale exome and whole-genome sequencing efforts have identified a variety of somatic mutations and copy number variations, particularly amplifications, in esophageal cancer, the ability to translate these findings successfully into actionable therapeutic approaches has been elusive. More recently, immunotherapeutic strategies, most notably immune checkpoint inhibitors, have demonstrated benefit to a subset of patients with both esophageal adenocarcinoma and SCC and represent an area of active clinical investigation. In this article, we discuss some of the insights derived from past trials of esophageal cancer, highlight ongoing research efforts in this arena, and emphasize the need to refine our approach to treating patients based on distinct anatomic, histologic, and molecular features. Clin Cancer Res; 22(17); 4283–90. ©2016 AACR.
Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor
Authors: Zook Phillip , Pathak Harsh B. , Belinsky Martin G. , Gersz Lawrence , Devarajan Karthik , Zhou Yan , Godwin Andrew K. , von Mehren Margaret , Rink Lori 
Published: July 2016

Abstract
Purpose: Gastrointestinal stromal tumors (GIST) generally harbor activating mutations in the receptor tyrosine kinase KIT or in the related platelet-derived growth factor receptor alpha (PDGFRA). GIST treated with imatinib mesylate or second-line therapies that target mutant forms of these receptors generally escape disease control and progress over time. Inhibiting additional molecular targets may provide more substantial disease control. Recent studies have implicated the PI3K/AKT pathway in the survival of imatinib mesylate–resistant GIST cell lines and tumors.
Experimental Design: Here, we performed in vitro and in vivo studies evaluating the novel combination of imatinib mesylate with the AKT inhibitor MK-2206 in GIST. Whole-transcriptome sequencing (WTS) of xenografts was performed to explore the molecular aspects of tumor response to this novel combination and to potentially identify additional therapeutic targets in GIST.
Results: This drug combination demonstrated significant synergistic effects in a panel of imatinib mesylate–sensitive and -resistant GIST cell lines. Furthermore, combination therapy provided significantly greater efficacy, as measured by tumor response and animal survival, in imatinib mesylate–sensitive GIST xenografts as compared with treatment with imatinib mesylate or MK-2206 alone. WTS implicated two neural genes, brain expressed X-linked 1 and neuronal pentraxin I, whose expression was significantly upregulated in combination-treated tumors compared with tumors treated with the two monotherapies.
Conclusions: These studies provide strong preclinical justification for combining imatinib mesylate with an AKT inhibitor as a front-line therapy in GIST. In addition, the WTS implicated the BCL-2/BAX/BAD apoptotic pathway as a potential mechanism for this enhanced combination effect. Clin Cancer Res; 23(1); 171–80. ©2016 AACR.
HGF/Met Signaling in Head and Neck Cancer: Impact on the Tumor Microenvironment
Authors: Hartmann Stefan , Bhola Neil E. , Grandis Jennifer R. 
Published: July 2016

AbstractStudies to date have revealed several major molecular alterations that contribute to head and neck squamous cell carcinoma (HNSCC) initiation, progression, metastatic spread, and therapeutic failure. The EGFR is the only FDA-approved therapeutic target, yet responses to cetuximab have been limited. Activation and cross-talk of cellular receptors and consequent activation of different signaling pathways contribute to limited activity of blockade of a single pathway. The hepatocyte growth factor (HGF) receptor, Met, has been implicated in HNSCC tumorigenesis and EGFR inhibitor resistance. HGF, the sole ligand of Met, is overexpressed in the tumor microenvironment. The role of HGF/Met signaling in proliferation, metastasis, and angiogenesis has been investigated in HNSCC, leading to clinical trials with various Met inhibitors and HGF antibodies. However, the role of the HGF/Met signaling axis in mediating the tumor microenvironment has been relatively understudied in HNSCC. In this review, we discuss the functional roles of Met and HGF in HNSCC with a focus on the tumor microenvironment and the immune system. Clin Cancer Res; 22(16); 4005–13. ©2016 AACR.
Long Noncoding RNA MALAT1 Promotes Aggressive Pancreatic Cancer Proliferation and Metastasis via the Stimulation of Autophagy
Authors: Li Le , Chen Hua , Gao Yue , Wang Yong-Wei , Zhang Guang-Quan , Pan Shang-Ha , Ji Liang , Kong Rui , Wang Gang , Jia Yue-Hui , Bai Xue-Wei , Sun Bei 
Published: July 2016

Abstract
Recently, pancreatic ductal adenocarcinoma (PDAC) has emerged as one of the most aggressive malignant tumors with the worst prognosis. Previous studies have demonstrated that long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is increased in pancreatic cancer and is identified as a diagnostic biomarker. Nonetheless, the molecular mechanism of elevated MALAT1 levels and tumor aggressiveness remains unknown. In this study, MALAT1 was found to be highly expressed in PDAC tissues, and elevated expression was associated with poorer prognoses. In addition, MALAT1 was positively linearly correlated with the expression of LC3B mRNA. Furthermore, several molecules involved in cellular autophagic flux were modulated following the downregulation of MALAT1, including LC3, P62, and LAMP-2. Mechanistically, we found that MALAT1 interacted with RNA binding protein HuR, and silencing of MALAT1 greatly enhanced the posttranscriptional regulation of TIA-1 and had further effects on inhibiting autophagy. MALAT1 was speculated to regulate tumorigenesis via HuR-TIA-1–mediated autophagic activation. Hence, we investigated the biological properties of MALAT1 in terms of tumor proliferation and metastasis by promoting autophagy in vitro. In brief, these data demonstrate that MALAT1 could facilitate the advanced progression of tumors in vivo. Our study highlights the new roles of MALAT1 on protumorigenic functioning and anticancer therapy via activating autophagy in pancreatic cancer. Mol Cancer Ther; 15(9); 2232–43. ©2016 AACR.
Covalent Targeting of Fibroblast Growth Factor Receptor Inhibits Metastatic Breast Cancer
Authors: Brown Wells S. , Tan Li , Smith Andrew , Gray Nathanael S. , Wendt Michael K. 
Published: July 2016

Abstract
Therapeutic targeting of late-stage breast cancer is limited by an inadequate understanding of how tumor cell signaling evolves during metastatic progression and by the currently available small molecule inhibitors capable of targeting these processes. Herein, we demonstrate that both β3 integrin and fibroblast growth factor receptor-1 (FGFR1) are part of an epithelial–mesenchymal transition (EMT) program that is required to facilitate metastatic outgrowth in response to fibroblast growth factor-2 (FGF2). Mechanistically, β3 integrin physically disrupts an interaction between FGFR1 and E-cadherin, leading to a dramatic redistribution of FGFR1 subcellular localization, enhanced FGF2 signaling and increased three-dimensional (3D) outgrowth of metastatic breast cancer cells. This ability of β3 integrin to drive FGFR signaling requires the enzymatic activity of focal adhesion kinase (FAK). Consistent with these mechanistic data, we demonstrate that FGFR, β3 integrin, and FAK constitute a molecular signature capable of predicting decreased survival of patients with the basal-like subtype of breast cancer. Importantly, covalent targeting of a conserved cysteine in the P-loop of FGFR1–4 with our newly developed small molecule, FIIN-4, more effectively blocks 3D metastatic outgrowth as compared with currently available FGFR inhibitors. In vivo application of FIIN-4 potently inhibited the growth of metastatic, patient-derived breast cancer xenografts and murine-derived metastases growing within the pulmonary microenvironment. Overall, the current studies demonstrate that FGFR1 works in concert with other EMT effector molecules to drive aberrant downstream signaling, and that these events can be effectively targeted using our novel therapeutics for the treatment of the most aggressive forms of breast cancer. Mol Cancer Ther; 15(9); 2096–106. ©2016 AACR.
Relationship of Annular Sizing Using Multidetector Computed Tomographic Imaging and Clinical Outcomes After Self-Expanding CoreValve Transcatheter Aortic Valve Replacement
Authors: Popma Jeffrey J. , Gleason Thomas G. , Yakubov Steven J. , Harrison J. Kevin , Forrest John K. , Maini Brijeshwar , Ruiz Carlos E. , Pinto Duane S. , Costa Marco , Resar Jon , Conte John , Crestanello Juan , Chang Yanping , Oh Jae K. , Reardon Michael J. , Adams David H. 
Published: July 2016

Background—
Multidetector computed tomography is useful for determining the appropriate transcatheter heart valve (THV) size in patients with severe aortic stenosis who are suboptimal surgical candidates. The relationship between adherence to the recommended CoreValve sizing algorithm and clinical outcomes is not known.

Methods and Results—

We evaluated 1023 patients with severe aortic stenosis deemed high or extreme risk for surgery treated with the CoreValve THV. All patients underwent preprocedural multidetector computed tomography, and the scans were reviewed at a central analysis center using standardized software. Compliance to a recommended sizing algorithm was used to identify patients with below-range, in-range, and above-range THV sizing. A device annular sizing ratio (DAR) was also calculated based on the native annulus perimeter and perimeter of the selected THV. Clinical end points included the presence of paravalvular aortic regurgitation evaluated by an independent echocardiographic laboratory. Adherence to the sizing algorithm was highest with a 31-mm THV (92.6%) and lowest with the 23-mm THV (38.5%). Below-range sizing was associated with a higher rate of moderate or severe paravalvular aortic regurgitation (15.3%) than in-range (6.5%) or above-range (10.0%;
P
<0.001) sizing. Higher DARs were associated with lower rates of moderate or severe paravalvular aortic regurgitation: DAR ≤10%, 17.6%; DAR 10% to 15%, 9.9%; DAR 15% to 20%, 6.3%; and DAR >20%, 4.9%;
P
<0.001. There was no increase in clinical events associated with higher DARs.

Conclusions—
Adherence to a sizing algorithm guided by multidetector computed tomography resulted in lower rates of paravalvular aortic regurgitation after self-expanding transcatheter valve replacement without an increase in complications.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01240902.
The art of good governance: how images from the past provide inspiration for modern practice
Authors: de Graaf Gjalt , van Asperen Hanneke 
Published: July 2016

Since the early 1990s, discourse on ‘good governance’ has become more prevalent. What ‘good governance’ means and entails, however, and when we can speak of ‘good’ governance in this discourse, is not always clear. Many scholars in public administration and other social sciences writing about good governance have used visual interpretations of good governance from centuries ago to illustrate their case in point. Here, we also use pictures from the past – Lorenzetti’s Sienese frescoes to be more precise – yet, not as an illustration, but as the core of the argument. Our main research question is: how can Lorenzetti’s frescoes of Good Governance inspire our modern-day conception of good governance? We conclude that good governance is governance by good governors, and good governors are governors guided by benevolence. We end with a discussion of what that entails for modern-day governance practice. Points for practitioners Governance without integrity violations is not necessarily good governance. Benevolence is needed for that.
The Contribution of Hugo Chávez to an Understanding of Post-Neoliberalism
Authors: Spanakos Anthony Petros , Pantoulas Dimitris 
Published: July 2016

When Hugo Chávez was president, he pronounced the death of many things—the constitution, the old “partyarchy,” Venezuela’s “Fourth Republic,” and the Free Trade Area of the Americas, among others. Since his own death in 2013, scholars, activists, and citizens have contributed to a rich discussion of his legacy. Part of that legacy is an understanding of post-neoliberalism that recognizes its competing and contradictory components, some of them seeking to complement, improve, and reverse neoliberal policies or overcome neoliberal logics and others constituting important remnants of neoliberalism. Durante su presidencia, Hugo Chávez declaró la muerte de muchas cosas: la constitución, el viejo “partidocracia,” la Cuarta República de Venezuela y el Tratado de Libre Comercio de las Américas, entre otros. Desde su muerte en 2013, un grupo variado de estudiosos, activistas y ciudadanos ha llevado a cabo una rica discusión sobre su legado. Una parte importante de su legado es el entender que el post-neoliberalismo tiene componentes contrapuestos y contradictorios, y reconocer que algunos de ellos buscan complementar, mejorar y revertir las políticas neoliberales o superar la lógica neoliberal y otros importantes vestigios constituyentes del neoliberalismo.
¿Por qué no les callan?
Authors: Burges Sean W. , Chodor Tom , Emerson R. Guy 
Published: July 2016

On October 7, 2012, Hugo Chávez was comfortably reelected president of Venezuela. Just days before the vote, the impression given by major international print media was that it would be close, an assessment that proved to be at best optimistic. Western media coverage of the election in Venezuela was designed to skew the result toward the opposition, and this effort singularly failed. The “propaganda model” advanced by Herman and Chomsky is now faltering in the Americas, and the region is acting in a manner that is increasingly free of influence from the United States. Venezuela thus stands as a case of the citizenry actively and independently asserting its political agency despite clear attempts to redirect its thinking and decision making. El 7 de octubre de 2012, Hugo Chávez fue cómodamente reelegido presidente de Venezuela. Justo antes de las elecciones, los principales medios periodísticos internacionales daban por sentado que la votación iba a ser cerrada, una apreciación que resultó ser en el mejor de los casos optimista. La cobertura de las elecciones en Venezuela por parte de los medios occidentales estaba diseñada para sesgar los resultados a favor de la oposición, un esfuerzo que fracasó rotundamente. El “modelo de propaganda” propuesto por Herman y Chomsky está tambaleándose en las Américas, y la región está actuando de una manera cada vez más libre de la influencia de los Estados Unidos. Venezuela, por lo tanto, se erige como un ejemplo de un grupo de ciudadanos que de forma activa e independiente reafirma su voluntad política a pesar de unos claros intentos por desviar su pensamiento y su poder de decisión.
Sealing and Unsealing Uruguay’s Transitional Politics of Oblivion
Authors: Fried Amilivia Gabriela 
Published: July 2016

Three decades after state terror in Uruguay, counter memory making has endured in successive waves despite the official politics of oblivion, a transitional politics based on the denial of state abuses, absence of redress for victims, and impunity for perpetrators of the crimes of state terrorism. The Uruguayan case illustrates the impossibility of foreclosing memory through political engineering and the unsustainability of blanket impunity. It also highlights the long-term effects of ongoing social mobilization for memory and personal memorialization after social trauma and offers a sociocultural and intersubjective approach to the understanding of the generation of social memory after massive political violence. Tres décadas después del terrorismo de estado en el Uruguay, la construcción de la contramemoria ha resistido en oleadas sucesivas a pesar de una política oficial del olvido, una política de transición basada en la negación de los abusos del estado, la ausencia de reparaciones para las víctimas y la impunidad para los responsables de los crímenes del terrorismo de estado. El caso uruguayo ilustra la imposibilidad de impedir la construcción de la memoria por medio de la ingeniería política y la falta de viabilidad de una impunidad general. También pone de manifiesto los efectos a largo plazo de una continua movilización social por la memoria y la memorialización personal después del trauma social y ofrece un enfoque sociocultural e intersubjetivo para entender la generación de la memoria social después de periodos de enorme violencia política.
Attempts at Neoliberal Urban Planning in Postearthquake Chile: Master Plans for Reconstruction
Authors: Imilan Walter , González Luis Eduardo 
Published: July 2016

Urban and regional reconstruction after the February 27, 2010, earthquake and tsunami in Chile was organized by master plans at the local level. These plans, based on public-private partnerships, can be considered an innovation as an instrument of postdisaster reconstruction. They emerged as a commitment to privatization of urban planning in Chile. An analysis of two master plans based on field research carried out between 2011 and 2014 reveals that they had limited impact because of weak public-private ties, lack of comprehensiveness, and lack of legitimacy. They can be read as failed attempts at neoliberal deepening at the level of urban and regional administration. Después del terremoto y del sunami del 27 de febrero de 2010 en Chile la reconstrucción urbana y regional fue organizada usando planes maestros a nivel local. Estos planes, con base en alianzas público-privadas, pueden considerarse una innovación como instrumento de reconstrucción posterior a un desastre. Surgieron como una transigencia con la privatización de la planificación urbana en Chile. El análisis de dos planes maestros con base en el trabajo de campo que se llevó a cabo entre 2011 y 2014 revela que esos planes tuvieron un impacto limitado debido a la debilidad de los lazos entre el sector público y el sector privado, la falta de un enfoque amplio y la falta de legitimidad. Se pueden entender como esfuerzos fallidos de la profundización neoliberal al nivel de la administración urbana y regional.
Does the method of botulinum neurotoxin injection for limb spasticity affect outcomes? A systematic review
Authors: Chan Aaron K , Finlayson Heather , Mills Patricia B 
Published: July 2016

Objective: To systematically review randomized controlled trials of botulinum neurotoxin for limb spasticity to determine whether different injection techniques affect spasticity outcomes. Methods: MEDLINE, EMBASE, CINAHL, and Cochrane Central Register of Controlled Trials electronic databases were searched for English language human randomized controlled trials from 1990 to 13 May 2016. Studies were assessed in duplicate for data extraction and risk of bias using the Physiotherapy Evidence Database scale and graded according to Sackett’s levels of evidence. Results: Nine of 347 studies screened met selection criteria. Four categories of botulinum neurotoxin injection techniques were identified: (1) injection localization technique; (2) injection site selection; (3) injectate volume; (4) injection volume and site selection. There is level 1 evidence that: ultrasound, electromyography, and electrostimulation are superior to manual needle placement; endplate injections improve outcomes vs. multisite quadrant injections; motor point injections are equivalent to multisite injections; high volume injections are similar to low volume injections; and high volume injections distant from the endplate are more efficacious than low volumes closer to the endplate. Conclusion: Level 1 evidence exists for differences in treatment outcomes using specific botulinum neurotoxin injection techniques. Findings are based on single studies that require independent replication and further study.
‘Because it’s the wife who has to look after the man’: A descriptive qualitative study of older women and the intersection of gender and the provision of family caregiving at the end of life
Authors: Williams Lisa Ann , Giddings Lynne S , Bellamy Gary , Gott Merryn 
Published: July 2016

Background: Research indicates that women are the primary family caregivers for others at life’s end and, because of ageing populations, will keep fulfilling this role as they age. Yet, little is known about how the gendered nature of caregiving contributes to older women’s understandings of providing care. Aim: To explore how gender norms constructed older women’s views about the appropriate roles of women and men in providing palliative and end-of-life care for family members. Design: Six focus groups were conducted with 39 community dwelling older adults (36 women and 3 men) using two vignettes to prompt discussion about experience of end of life caring and attitudes towards Advance Care Planning. This article reports on data gathered from female participants’ reactions to Vignette 1 which prompted significant discussion regarding the intersection of gender and older women’s caregiving experience. Setting/participants: A total of 36 women in the age ranges of ‘50–59 years’ through to ‘90–99 years’ from New Zealand. Results: Three themes regarding gender and caregiving were identified: the expectation women will care, women’s duty to care and women’s construction of men in relation to caregiving and illness. The women adhered to stereotypical gender norms that regard women as primary caregivers. There was little connection between the burden they associated with caregiving and this gender construction. Conclusion: The expectation that older women will provide end-of-life care even when experiencing considerable burden is an unacknowledged outcome of gender norms that construct women as caregivers.
Mephedrone and 3,4-methylenedioxy-methamphetamine: Comparative psychobiological effects as reported by recreational polydrug users
Authors: Jones Lewis , Reed Phil , Parrott Andrew 
Published: July 2016

Aims: The purpose of this study was to compare the effects of mephedrone and 3,4-methylenedioxy-methamphetamine (MDMA), as reported by young recreational polydrug users. Methods: 152 MDMA users and 81 mephedrone users were recruited through snowballing on social network sites. They completed a standard online questionnaire for either mephedrone or MDMA. The questions covered the average amount taken per session, the longest duration of usage in the last 12-months, subjective effects while on-drug, and recovery effects in the days afterwards. Results: Mephedrone users reported a significantly longer maximum session of use than MDMA users. Mephedrone users also reported a significantly greater average amount used per session. The majority of on-drug subjective ratings did not differ between drugs, with similar increases in entactogenic effects. Although mephedrone users did report significantly more frequent issues with sleeping, anger and anxiety. In relation to recovery, mephedrone users reported more frequent craving, nasal irritation, paranoia, and relationship difficulties. Mephedrone users also rated general recovery effects as more severe over the seven-day period following use, taking more days to feel normal. Conclusions: The acute effects of MDMA and mephedrone were broadly similar. However, the recovery period for mephedrone was more enduring, possibly due to the longer duration of acute session usage.