bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activation of EIF4E by Aurora Kinase A Depicts a Novel Druggable Axis in Everolimus-Resistant Cancer Cells
Authors: Katsha Ahmed , Wang Lihong , Arras Janet , Omar Omar M. , Ecsedy Jeffrey , Belkhiri Abbes , El-Rifai Wael 
Published: January 2017

Abstract
Purpose: Aurora kinase A (AURKA) is overexpressed in several cancer types, making it an attractive druggable target in clinical trials. In this study, we investigated the role of AURKA in regulating EIF4E, cap-dependent translation, and resistance to mTOR inhibitor, RAD001 (everolimus).
Experimental Design: Tumor xenografts and in vitro cell models of upper gastrointestinal adenocarcinomas (UGC) were used to determine the role of AURKA in the activation of EIF4E and cap-dependent translation. Overexpression, knockdown, and pharmacologic inhibition of AURKA were used in vitro and in vivo.
Results: Using in vitro cell models, we found that high protein levels of AURKA mediate phosphorylation of EIF4E and upregulation of c-MYC. Notably, we detected overexpression of endogenous AURKA in everolimus-resistant UGC cell models. AURKA mediated phosphorylation of EIF4E, activation of cap-dependent translation, and an increase in c-MYC protein levels. Targeting AURKA using genetic knockdown or a small-molecule inhibitor, alisertib, reversed these molecular events, leading to a decrease in cancer cell survival in acquired and intrinsic resistant cell models. Mechanistic studies demonstrated that AURKA binds to and inactivates protein phosphatase 2A, a negative regulator of EIF4E, leading to phosphorylation and activation of EIF4E in an AKT-, ERK1/2-, and mTOR-independent manner. Data from tumor xenograft mouse models confirmed that everolimus-resistant cancer cells are sensitive to alisertib.
Conclusions: Our results indicate that AURKA plays an important role in the activation of EIF4E and cap-dependent translation. Targeting the AURKA–EIF4E–c-MYC axis using alisertib is a novel therapeutic strategy that can be applicable for everolimus-resistant tumors and/or subgroups of cancers that show overexpression of AURKA and activation of EIF4E and c-MYC. Clin Cancer Res; 23(14); 3756–68. ©2017 AACR.
Metabolic Profiling in Formalin-Fixed and Paraffin-Embedded Prostate Cancer Tissues
Authors: Cacciatore Stefano , Zadra Giorgia , Bango Clyde , Penney Kathryn L. , Tyekucheva Svitlana , Yanes Oscar , Loda Massimo 
Published: January 2017

AbstractMetabolite profiling has significantly contributed to a deeper understanding of the biochemical metabolic networks and pathways in cancer cells. Metabolomics-based biomarker discovery would greatly benefit from the ability to interrogate retrospective annotated clinical specimens archived as formalin-fixed, paraffin-embedded (FFPE) material. Mass spectrometry–based metabolomic analysis was performed in matched frozen and FFPE human prostate cancers as well as isogenic prostate cancer cell lines. A total of 352 and 460 metabolites were profiled in human tissues and cell lines, respectively. Classes and physical–chemical characteristics of the metabolites preserved in FFPE material were characterized and related to their preservation or loss following fixation and embedding. Metabolite classes were differentially preserved in archival FFPE tissues, regardless of the age of the block, compared with matched frozen specimen, ranging from maximal preservation of fatty acids (78%) to loss of the majority of peptides and steroids. Generally, FFPE samples showed a decrease of metabolites with functional groups, such as carboxamide. As an adjunct technique, metabolic profiles were also obtained in situ from FFPE tissue sections where metabolites were extracted in a manner that preserves tissue architecture. Despite the fact that selected metabolites were not retained after processing, global metabolic profiles obtained from FFPE can be used to predict biologic states and study biologic pathways. These results pave the way for metabolomics-based biomarker discovery/validation utilizing retrospective and clinically annotated FFPE collections.Implications: Metabolic profiles can be performed in archival tissue and may be used to complement other profiling methods such as gene expression for biomarker discovery or pathway analysis in the assessment of biologic states. Mol Cancer Res; 15(4); 439–47. ©2017 AACR.
Implantation of the Subcutaneous Implantable Cardioverter-Defibrillator
Authors: Brouwer Tom F. , Miller Marc A. , Quast Anne-Floor B.E. , Palaniswamy Chandrasekar , Dukkipati Srinivas R. , Reddy Vivek , Wilde Arthur A. , Willner Jonathan M. , Knops Reinoud E. 
Published: January 2017

Background—
Alternative techniques to the traditional 3-incision subcutaneous implantation of the subcutaneous implantable cardioverter-defibrillator may offer procedural and cosmetic advantages. We evaluate 4 different implant techniques of the subcutaneous implantable cardioverter-defibrillator.

Methods and Results—

Patients implanted with subcutaneous implantable cardioverter-defibrillators from 2 hospitals between 2009 and 2016 were included. Four implantation techniques were used depending on physician preference and patient characteristics. The 2- and 3-incision techniques both place the pulse generator subcutaneously, but the 2-incision technique omits the superior parasternal incision for lead positioning. Submuscular implantation places the pulse generator underneath the serratus anterior muscle and subfascial implantation underneath the fascial layer on the anterior side of the serratus anterior muscle. Reported outcomes include perioperative parameters, defibrillation testing, and clinical follow-up. A total of 246 patients were included with a median age of 47 years and 37% female. Fifty-four patients were implanted with the 3-incision technique, 118 with the 2-incision technique, 38 with submuscular, and 37 with subfascial. Defibrillation test efficacy and shock lead impedance during testing did not differ among the groups; respectively,
P
=0.46 and
P
=0.18. The 2-incision technique resulted in the shortest procedure duration and time-to-hospital discharge compared with the other techniques (
P
<0.001). A total of 18 complications occurred, but there were no significant differences between the groups (
P
=0.21). All infections occurred in subcutaneous implants (3-incision, n=3; 2-incision, n=4). In the 2-incision group, there were no lead displacements.

Conclusions—
The presented implantation techniques are feasible alternatives to the standard 3-incision subcutaneous implantation, and the 2-incision technique resulted in shortest procedure duration.
Functional Tricuspid Regurgitation Caused by Chronic Atrial Fibrillation
Authors: Utsunomiya Hiroto , Itabashi Yuji , Mihara Hirotsugu , Berdejo Javier , Kobayashi Sayuki , Siegel Robert J. , Shiota Takahiro 
Published: January 2017

Background—
Functional tricuspid regurgitation (TR) with a structurally normal tricuspid valve (TV) may occur secondary to chronic atrial fibrillation (AF). However, the clinical and echocardiographic differences according to functional TR subtypes are unclear. Therefore, characterization of functional TR because of chronic AF (AF-TR) remains undetermined.

Methods and Results—

To investigate the prevalence of AF-TR, 437 patients with moderate to severe TR underwent 3-dimensional (3D) transesophageal echocardiography. TR severity was determined by the averaged vena contracta width on apical and parasternal inflow views. The prevalence of AF-TR was 9.2%, whereas that of functional TR because of left-sided heart disease was 45.3%. Clinical features of AF-TR included advanced age, female sex, greater right atrial than left atrial enlargement and lower systolic pulmonary artery pressure compared with left-sided heart disease-TR with sinus rhythm (all
P
<0.05). In 3D TV assessment, patients with AF-TR had a larger TV annular area with weaker annular contraction (both
P
<0.001) but a smaller tethering angle (
P
<0.001) despite a similar leaflet coaptation status compared with patients with left-sided heart disease-TR with sinus rhythm. On multivariable analysis, only the TV annular area in midsystole (coefficient, 0.059; 95% confidence interval, 0.041–0.078 per 100 mm
2
;
P
<0.001) was associated with TR severity in AF-TR. The annular area was more closely correlated with the right atrial volume than right ventricular end-systolic volume in AF-TR (
P
<0.001).

Conclusions—
AF-TR is not rare and is associated with advanced age and right atrial enlargement. TV deformations and their association with right heart remodeling differ between AF-TR and left-sided heart disease-TR. Our results suggest that in patients with TR secondary to AF, TV annuloplasty should be effective because this entity has annular dilatation without leaflet deformation.
Multiyear Droughts and Pluvials over the Upper Colorado River Basin and Associated Circulations
Authors: Abatan Abayomi A. , Gutowski William J. , Ammann Caspar M. , Kaatz Laurna , Brown Barbara G. , Buja Lawrence , Bullock Randy , Fowler Tressa , Gilleland Eric , Gotway John Halley 
Published: January 2017

Abstract
This study analyzes spatial and temporal characteristics of multiyear droughts and pluvials over the southwestern United States with a focus on the upper Colorado River basin. The study uses two multiscalar moisture indices: standardized precipitation evapotranspiration index (SPEI) and standardized precipitation index (SPI) on a 36-month scale (SPEI36 and SPI36, respectively). The indices are calculated from monthly average precipitation and maximum and minimum temperatures from the Parameter-Elevation Regressions on Independent Slopes Model dataset for the period 1950–2012. The study examines the relationship between individual climate variables as well as large-scale atmospheric circulation features found in reanalysis output during drought and pluvial periods. The results indicate that SPEI36 and SPI36 show similar temporal and spatial patterns, but that the inclusion of temperatures in SPEI36 leads to more extreme magnitudes in SPEI36 than in SPI36. Analysis of large-scale atmospheric fields indicates an interplay between different fields that yields extremes over the study region. Widespread drought (pluvial) events are associated with enhanced positive (negative) 500-hPa geopotential height anomaly linked to subsidence (ascent) and negative (positive) moisture convergence and precipitable water anomalies. Considering the broader context of the conditions responsible for the occurrence of prolonged hydrologic anomalies provides water resource managers and other decision-makers with valuable understanding of these events. This perspective also offers evaluation opportunities for climate models.
MRMS QPE Performance East of the Rockies during the 2014 Warm Season
Authors: Cocks Stephen B. , Zhang Jian , Martinaitis Steven M. , Qi Youcun , Kaney Brian , Howard Kenneth 
Published: January 2017

Abstract
Multi-Radar Multi-Sensor (MRMS) quantitative precipitation estimation (QPE) radar only (Q3RAD), Q3RAD local gauge corrected (Q3gc), dual polarization (Dual Pol), legacy Precipitation Processing System (PPS), and National Centers for Environmental Prediction (NCEP) stage IV product performance were evaluated for data collected east of the Rockies during the 2014 warm season. For over 22 000 radar QPE–gauge data pairs, Q3RAD had a higher correlation coefficient (0.85) and a lower mean absolute error (9.4 mm) than the Dual Pol (0.83 and 10.5 mm, respectively) and PPS (0.79 and 10.8 mm, respectively). Q3RAD performed best when the radar beam sampled precipitation within or above the melting layer because of its use of a reflectivity mosaic corrected for brightband contamination. Both NCEP stage IV and Q3gc showed improvement over the radar-only QPEs; while stage IV exhibited the lower errors, the performance of Q3gc was remarkable considering the estimates were automatically generated in near–real time. Regional analysis indicated Q3RAD outperformed Dual Pol and PPS over the southern plains, Southeast/mid-Atlantic, and Northeast. Over the northern United States, Q3RAD had a higher wet bias below the melting layer than both Dual Pol and PPS; within and above the melting layer, Q3RAD exhibited the lowest errors. The Q3RAD wet bias was likely due to MRMS’s overestimation of tropical rain areas in continental regions and applying a high yield reflectivity–rain-rate relationship. An adjustment based on precipitation climatology reduced the wet bias errors by ~22% and will be implemented in the operational MRMS in the fall of 2016.
Three Years Experience of Adults Admitted to Hospital in North-East Scotland with E.Coli O157
Authors: Cadwgan A.M. , Laing R.B.S. , Dargie L. , Beadsworth M. , Mackenzie A. R. , Douglas J.G. 
Published: January 2017

To describe the epidemiology, clinical features, treatment and outcomes of adults with E. coli O157 infection presenting to Aberdeen Royal Infirmary over a three year period. Methods: A retrospective casenote review. Results: Thirty-two confirmed cases of E. coli O157 infection were admitted between 1997 and 2000. The median age was 58 years (range 16–93). Ten patients (31%) were from the city of Aberdeen and 22 (69%) from surrounding rural areas. Twenty-seven patients (85%) presented between May and October. The source of infection was unknown or unconfirmed in all cases. Bloody diarrhoea was present in 30 (94%). Leucocytosis was present in 18 (63%) but only four patients (13%) had a fever. Six of the 32 patients (19%) developed Haemolytic-Uraemic Syndrome (HUS) of whom 2 died. Ten patients received antibiotics of whom two developed HUS. Twenty-seven of the 32 (85%) had made a full recovery by time of discharge, three (9%) had impaired renal function and two (6%) died in hospital. Conclusion: E. coli O157 infection tends to occur sporadically in rural areas in North East Scotland. It is not usually associated with fever. Infection occurs more commonly in the summer and autumn. HUS complicates infection in almost one fifth of patients.
Local Steroid Therapy in Painful Orthopaedic Conditions
Authors: Goldie I. 
Published: January 2017

Local corticosteroid therapy is often used in the treatment of a variety of painful orthopaedic conditions such as rheumatoid arthritis, osteoarthritis, peritendinitis, tendinous and ligamentous disorders and bursitis. Steroids have a direct biological activity of two kinds one pertaining to tissue repair, the other to tissue destruction. All tissue components, vessels, cellular compartment and ground substance are affected by steroids. The most important role of these agents in repair is their anti-inflammatory property. They can however be shown to destroy the fundamental building stones of connective tissue, cartilage and bone. This destructive action appears to be dose-dependent. Clinical appraisal varies. Both beneficial and deleterious effects have been noted. Local steroid therapy has a part to play in rheumatoid arthritis and in soft tissue disorders, but would appear to be of questionable value in patients with osteoarthritis.
Sex and the Surgeon's Knife: The Family Court's Dilemma … Informed Consent and the Specter of Iatrogenic Harm to Children with Intersex Characteristics
Authors: Gurney Karen 
Published: January 2017

“When I use a word,” Humpty Dumpty said, in a rather scornful tone, “it means just what I choose it to mean, neither more nor less.””The question is,” said Alice, “whether you can make words mean so many different things.””The question is,” said Humpty Dumpty, “which is to be master - that's all.”—Lewis Carroll“Sex” is a complex thing. The word conjures up many images according to how it is used. When narrowed to the context of the law, however, a person’s sex can be broken down into three primary categories: biological sex, common law sex, and legal sex.Biological sex has traditionally been determined according to the presence or absence of genitals and gonads (phenotype), and the configuration of the sex chromosomes (karyotype).
The Patient Life: Can Consumers Direct Health Care?
Authors: Schneider Carl E. , Hall Mark A. 
Published: January 2017

AbstractThe ultimate aim of health care policy is good care at good prices. Managed care failed to achieve this goal through influencing providers, so health policy has turned to the only market-based option left: treating patients like consumers. Health insurance and tax policy now pressure patients to spend their own money when they select health plans, providers, and treatments. Expecting patients to choose what they need at the price they want, consumerists believe that market competition will constrain costs while optimizing quality. This classic form of consumerism is today's health policy watchword.This article evaluates consumerism and the regulatory mechanism of which it is essentially an example — legally mandated disclosure of information. We do so by assessing the crucial assumptions about human nature on which consumerism and mandated disclosure depend. Consumerism operates in a variety of contexts in a variety of ways with a variety of aims. To assess so protean a thing, we ask what a patient's life would really be like in a consumerist world The literature abounds in theories about how medical consumers should behave. We look for empirical evidence about how real people actually buy health plans, choose providers, and select treatments.We conclude that consumerism, and thus mandated disclosure generally, are unlikely to accomplish the goals imagined for them. Consumerism's prerequisites are too many and too demanding. First, consumers must have choices that include the coverage, care-takers, and care they want. Second, reliable information about those choices must be available. Third, information must be put before consumers, especially by doctors. Fourth, consumers must receive the information. Fifth, the information must be complete and comprehensible enough for consumers to use it. Sixth, consumers must understand what they are told. Seventh, consumers must be willing to analyze the information. Eighth, consumers must actually analyze the information and do so well enough to make good choices.Our review of the empirical evidence concludes that these prerequisites cannot be met reliably most of the time. At every stage people encounter daunting hurdles. Like so many other dreams of controlling costs and giving patients control, consumerism is doomed to disappoint. This does not mean that consumerist tools should never be used. It means they should not be used unadvisedly or lightly, but discreetly, advisedly, soberly, and in the fear of error.
From Concierge Medicine to Patient-Centered Medical Homes: International Lessons & the Search for a Better Way to Deliver Primary Health Care in the U.S.
Authors: Majette Gwendolyn Roberts 
Published: January 2017

Primary care is crucial to the United States health care system. It is essential to the provision of high quality care; including the ability to reach health outcomes, ensure patient satisfaction, and facilitate efficient resource use. Primary care also places strong “emphasis on health promotion, disease prevention, and care of the chronically ill.”Physicians have introduced two business models in their attempts to improve the delivery of primary care: Concierge Medicine (“CM”) and the Patient Centered Medical Home (“PCMH”). Both models provide personalized, comprehensive preventive care services.CM is a private medical practice in which the physician charges patients an annual fee to be a patient in the practice. In exchange, the physician limits the number of patients in order to offer more personalized services and amenities such as: direct access through email or cell phone, same day or next day appointments, longer, more personalized appointments, house calls, and physician accompaniment to a specialist.
Autism in the U.S.: Social Movement and Legal Change
Authors: Caruso Daniela 
Published: January 2017

AbstractThe social movement surrounding autism in the U.S. has been rightly defined a ray of light in the history of social progress. The movement is inspired by a true understanding of neuro-diversity and is capable of bringing about desirable change in political discourse. At several points along the way, however, the legal reforms prompted by the autism movement have been grafted onto preexisting patterns of inequality in the allocation of welfare, education, and medical services. In a context most recently complicated by economic recession, autism-driven change bears the mark of political and legal fragmentation. Distributively, it yields ambivalent results that have not yet received systemic attention. This article aims to fill this analytical vacuum by offering, first, a synoptic view of the several legal transformations brought about or advocated for by the autism movement and, second, a framework for investigating their distributive consequences.
You Can't Say That on Television: Constitutional Analysis of a Direct-to-Consumer Pharmaceutical Advertising Ban
Authors: Mulligan Lia 
Published: January 2017

In one year, you will watch roughly sixteen hours of pharmaceutical advertisements. Sometime during those sixteen hours, you may recognize in yourself the symptoms portrayed in the advertisements. You may even wonder whether you would benefit from a particular drug. But will you visit your doctor with the fear that you may be suffering from a previously undiagnosed disease? Will you encourage your doctor to prescribe the medication you saw in the advertisements? Will your insurance cover the costs of your medication? More importantly, will you even need the medication at all?The trend in the pharmaceutical industry to increase yearly spending on direct-to-consumer pharmaceutical advertising (DTCA) seems almost disrespectful considering the magnitude of the healthcare crisis in which the United States is currently embroiled. This notion is inflamed when accounting for the fact that (arguably) one of the biggest problems in our healthcare system is the amount of money spent on healthcare each year.
Confronting the Vector of Tobacco-Related Disease
Authors: Allen Matthew 
Published: January 2017

It has been estimated that the use of tobacco kills nearly 6 million people each year, with most deaths occurring in low- and middle-income countries. This disparity is expected to increase over the next few decades. On the basis of current trends, tobacco use will kill more than 8 million people worldwide per annum by 2030, with eighty percent of those premature deaths occurring in low- and middle-income countries. The significant burden of morbidity and mortality associated with tobacco use is well documented and proven and will not be repeated here.The evidence base for addressing the tobacco epidemic domestically, regionally, and globally has developed in a systematic fashion over the past five decades. Effective measures for tobacco control are now well known and have been canvassed widely in the published literature.