bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Ubiquitin-like Protein FAT10 Stabilizes eEF1A1 Expression to Promote Tumor Proliferation in a Complex Manner
Authors: Liu Xiuxia , Chen Leifeng , Ge Jin , Yan Chen , Huang Zixi , Hu Junwen , Wen Chongyu , Li Ming , Huang Da , Qiu Yumin , Hao Haibin , Yuan Rongfa , Lei Jun , Yu Xin , Shao Jianghua 
Published: June 2016

Abstract
Human HLA-F adjacent transcript 10 (FAT10) is the only ubiquitin-like protein that can directly target substrates for degradation by proteasomes, but it can also stabilize the expression of certain substrates by antagonizing ubiquitination, through mechanisms as yet uncharacterized. In this study, we show how FAT10 stabilizes the translation elongation factor eEF1A1, which contributes to cancer cell proliferation. FAT10 overexpression increased expression of eEF1A1, which was sufficient to promote proliferation of cancer cells. Mechanistic investigations revealed that FAT10 competed with ubiquitin (Ub) for binding to the same lysines on eEF1A1 to form either FAT10–eEF1A1 or Ub–eEF1A1 complexes, respectively, such that FAT10 overexpression decreased Ub–eEF1A1 levels and increased FAT10–eEF1A1 levels. Overall, our work establishes a novel mechanism through which FAT10 stabilizes its substrates, advancing understanding of the biological function of FAT10 and its role in cancer. Cancer Res; 76(16); 4897–907. ©2016 AACR.
Molecular Landscape of Acquired Resistance to Targeted Therapy Combinations in BRAF-Mutant Colorectal Cancer
Authors: Oddo Daniele , Sennott Erin M. , Barault Ludovic , Valtorta Emanuele , Arena Sabrina , Cassingena Andrea , Filiciotto Genny , Marzolla Giulia , Elez Elena , van Geel Robin M.J.M. , Bartolini Alice , Crisafulli Giovanni , Boscaro Valentina , Godfrey Jason T. , Buscarino Michela , Cancelliere Carlotta , Linnebacher Michael , Corti Giorgio , Truini Mauro , Siravegna Giulia , Grasselli Julieta , Gallicchio Margherita , Bernards René , Schellens Jan H.M. , Tabernero Josep , Engelman Jeffrey A. , Sartore-Bianchi Andrea , Bardelli Alberto , Siena Salvatore , Corcoran Ryan B. , Di Nicolantonio Federica 
Published: June 2016

Abstract
Although recent clinical trials of BRAF inhibitor combinations have demonstrated improved efficacy in BRAF-mutant colorectal cancer, emergence of acquired resistance limits clinical benefit. Here, we undertook a comprehensive effort to define mechanisms underlying drug resistance with the goal of guiding development of therapeutic strategies to overcome this limitation. We generated a broad panel of BRAF-mutant resistant cell line models across seven different clinically relevant drug combinations. Combinatorial drug treatments were able to abrogate ERK1/2 phosphorylation in parental-sensitive cells, but not in their resistant counterparts, indicating that resistant cells escaped drug treatments through one or more mechanisms leading to biochemical reactivation of the MAPK signaling pathway. Genotyping of resistant cells identified gene amplification of EGFR, KRAS, and mutant BRAF, as well as acquired mutations in KRAS, EGFR, and MAP2K1. These mechanisms were clinically relevant, as we identified emergence of a KRAS G12C mutation and increase of mutant BRAF V600E allele frequency in the circulating tumor DNA of a patient at relapse from combined treatment with BRAF and MEK inhibitors. To identify therapeutic combinations capable of overcoming drug resistance, we performed a systematic assessment of candidate therapies across the panel of resistant cell lines. Independent of the molecular alteration acquired upon drug pressure, most resistant cells retained sensitivity to vertical MAPK pathway suppression when combinations of ERK, BRAF, and EGFR inhibitors were applied. These therapeutic combinations represent promising strategies for future clinical trials in BRAF-mutant colorectal cancer. Cancer Res; 76(15); 4504–15. ©2016 AACR.
GON4L Drives Cancer Growth through a YY1–Androgen Receptor–CD24 Axis
Authors: Agarwal Neeraj , Dancik Garrett M. , Goodspeed Andrew , Costello James C. , Owens Charles , Duex Jason E. , Theodorescu Dan 
Published: June 2016

Abstract
In principle, the inhibition of candidate gain-of-function genes defined through genomic analyses of large patient cohorts offers an attractive therapeutic strategy. In this study, we focused on changes in expression of CD24, a well-validated clinical biomarker of poor prognosis and a driver of tumor growth and metastasis, as a benchmark to assess functional relevance. Through this approach, we identified GON4L as a regulator of CD24 from screening a pooled shRNA library of 176 candidate gain-of-function genes. GON4L depletion reduced CD24 expression in human bladder cancer cells and blocked cell proliferation in vitro and tumor xenograft growth in vivo. Mechanistically, GON4L interacted with transcription factor YY1, promoting its association with the androgen receptor to drive CD24 expression and cell growth. In clinical bladder cancer specimens, expression of GON4L, YY1, and CD24 was elevated compared with normal bladder urothelium. This pathway is biologically relevant in other cancer types as well, where CD24 and the androgen receptor are clinically prognostic, given that silencing of GON4L and YY1 suppressed CD24 expression and growth of human lung, prostate, and breast cancer cells. Overall, our results define GON4L as a novel driver of cancer growth, offering new biomarker and therapeutic opportunities. Cancer Res; 76(17); 5175–85. ©2016 AACR.
Durable Complete Response from Metastatic Melanoma after Transfer of Autologous T Cells Recognizing 10 Mutated Tumor Antigens
Authors: Prickett Todd D. , Crystal Jessica S. , Cohen Cyrille J. , Pasetto Anna , Parkhurst Maria R. , Gartner Jared J. , Yao Xin , Wang Rong , Gros Alena , Li Yong F. , El-Gamil Mona , Trebska-McGowan Kasia , Rosenberg Steven A. , Robbins Paul F. 
Published: June 2016

AbstractImmunotherapy treatment of patients with metastatic cancer has assumed a prominent role in the clinic. Durable complete response rates of 20% to 25% are achieved in patients with metastatic melanoma following adoptive cell transfer of T cells derived from metastatic lesions, responses that appear in some patients to be mediated by T cells that predominantly recognize mutated antigens. Here, we provide a detailed analysis of the reactivity of T cells administered to a patient with metastatic melanoma who exhibited a complete response for over 3 years after treatment. Over 4,000 nonsynonymous somatic mutations were identified by whole-exome sequence analysis of the patient's autologous normal and tumor cell DNA. Autologous B cells transfected with 720 mutated minigenes corresponding to the most highly expressed tumor cell transcripts were then analyzed for their ability to stimulate the administered T cells. Autologous tumor-infiltrating lymphocytes recognized 10 distinct mutated gene products, but not the corresponding wild-type products, each of which was recognized in the context of one of three different MHC class I restriction elements expressed by the patient. Detailed clonal analysis revealed that 9 of the top 20 most prevalent clones present in the infused T cells, comprising approximately 24% of the total cells, recognized mutated antigens. Thus, we have identified and enriched mutation-reactive T cells and suggest that such analyses may lead to the development of more effective therapies for the treatment of patients with metastatic cancer. Cancer Immunol Res; 4(8); 669–78. ©2016 AACR.
Circulating Proneurotensin Concentrations and Cardiovascular Disease Events in the Community
Authors: Januzzi James L. , Lyass Asya , Liu Yuyin , Gaggin Hanna , Trebnick April , Maisel Alan S. , D’Agostino Ralph B. , Wang Thomas J. , Massaro Joseph , Vasan Ramachandran S. 
Published: June 2016

Objective—
Neurotensin is a peptide whose receptor (sortilin receptor 1) is linked to cardiovascular disease (CVD) development. We hypothesized concentrations of proneurotensin (stable profragment of neurotensin) would predict incident cardiovascular events in community-based subjects.

Approach and Results—

Blood samples from 3439 participants in the Framingham Heart Study (FHS) Offspring cohort (mean age 59.2 years, 47.1% male) were tested for proneurotensin. Primary outcome of interest was incident hard CVD (myocardial infarction, stroke, and cardiovascular death); interaction between proneurotensin concentration with sex, low-density lipoprotein concentrations, and sortilin receptor 1 single-nucleotide polymorphisms was sought. At baseline, those in the highest log-proneurotensin quartile were younger and heavier (
P
<0.001); across proneurotensin quartiles, more prevalent hard CVD (from 3% to 7%;
P
<0.001) and diabetes mellitus (from 6% to 14%;
P
<0.001) were present. In age- and sex-adjusted models, log-proneurotensin concentrations predicted incident hard CVD (hazard ratio [HR], 1.24 per SD change in log-proneurotensin; 95% confidence intervals [CIs], 1.11–1.39;
P
<0.001), a finding that remained on adjustment for standard CVD risk factors (HR, 1.13; 95% CI, 1.01–1.27;
P
=0.03). Elevated log-proneurotensin concentrations were associated with shorter time to first event (
P
=0.02). We found no effect modification by sex, low-density lipoprotein concentration, or sortilin receptor 1 single-nucleotide polymorphisms. Concentrations of proneurotensin were modestly associated with left ventricular mass and coronary artery calcium in these subjects.

Conclusions—
Higher concentrations of proneurotensin are associated with a greater risk of incident cardiovascular events in the community. This association did not vary according to sex, baseline low-density lipoprotein, or sortilin receptor 1 genotype.
Intima–Media Thickness Is Linearly and Continuously Associated With Systolic Blood Pressure in a Population‐Based Cohort (STANISLAS Cohort Study)
Authors: Ferreira João Pedro , Girerd Nicolas , Bozec Erwan , Machu Jean Loup , Boivin Jean‐Marc , London Gérard M. , Zannad Faiez , Rossignol Patrick 
Published: June 2016

Background

Carotid intima–media thickness (
cIMT
) is a noninvasive marker of cardiovascular risk. The
cIMT
may be increased in patients with harmonisation, but little is known regarding the functional form of the association between blood pressure (
BP
) and
cIMT
in hypertensive and nonhypertensive persons. We aimed to define the shape of the association between
BP
and
cIMT
.

Methods and Results

We studied
cIMT
and ambulatory
BP
monitoring data from a single‐center, cross‐sectional, population‐based study involving 696 adult participants from the
STANISLAS
cohort, a familial longitudinal cohort from the Nancy region of France. Participants with
a
history of hypertension were more likely to have a
cIMT
>900 μm and had higher mean
cIMT
(both
P
<0.001). The risk of
cIMT
>900 μm increased linearly with higher 24‐hour and daytime systolic
BP
in participants both with and without history of hypertension. The relationship between systolic
BP
and the risk of
cIMT
>900 μm was not dependent on
hypertension
status (all
P
for interaction >0.10). In multivariable analysis adjusted on cardiovascular risk factors, each 5‐mm Hg increase in systolic
BP
was associated with an 8‐μm increase in
cIMT
(β=8.249 [95% CI 2.490–14.008],
P
=0.005). In contrast, the association between diastolic
BP
and
cIMT
was weaker and not significant.

Conclusions

Systolic BP is linearly and continuously associated with higher
cIMT
in both hypertensive and nonhypertensive persons, suggesting a detrimental effect of
BP
on the vascular tree prior to overt hypertension. Similarly, it suggests a detrimental effect of
BP
at the higher end of the normal range in treated hypertensive patients.

Clinical Trial Registration

URL
:
https://www.clinicaltrials.gov/
. Unique identifier:
NCT
01391442.
Coding of Visual, Auditory, Rule, and Response Information in the Brain: 10 Years of Multivoxel Pattern Analysis
Authors: Woolgar Alexandra , Jackson Jade , Duncan John 
Published: June 2016

Abstract
How is the processing of task information organized in the brain? Many views of brain function emphasize modularity, with different regions specialized for processing different types of information. However, recent accounts also highlight flexibility, pointing especially to the highly consistent pattern of frontoparietal activation across many tasks. Although early insights from functional imaging were based on overall activation levels during different cognitive operations, in the last decade many researchers have used multivoxel pattern analyses to interrogate the representational content of activations, mapping out the brain regions that make particular stimulus, rule, or response distinctions. Here, we drew on 100 searchlight decoding analyses from 57 published papers to characterize the information coded in different brain networks. The outcome was highly structured. Visual, auditory, and motor networks predominantly (but not exclusively) coded visual, auditory, and motor information, respectively. By contrast, the frontoparietal multiple-demand network was characterized by domain generality, coding visual, auditory, motor, and rule information. The contribution of the default mode network and voxels elsewhere was minor. The data suggest a balanced picture of brain organization in which sensory and motor networks are relatively specialized for information in their own domain, whereas a specific frontoparietal network acts as a domain-general “core” with the capacity to code many different aspects of a task.
Linking Theoretical Decision-making Mechanisms in the Simon Task with Electrophysiological Data: A Model-based Neuroscience Study in Humans
Authors: Servant Mathieu , White Corey , Montagnini Anna , Burle Borís 
Published: June 2016

AbstractA current challenge for decision-making research is in extending models of simple decisions to more complex and ecological choice situations. Conflict tasks (e.g., Simon, Stroop, Eriksen flanker) have been the focus of much interest, because they provide a decision-making context representative of everyday life experiences. Modeling efforts have led to an elaborated drift diffusion model for conflict tasks (DMC), which implements a superimposition of automatic and controlled decision activations. The DMC has proven to capture the diversity of behavioral conflict effects across various task contexts. This study combined DMC predictions with EEG and EMG measurements to test a set of linking propositions that specify the relationship between theoretical decision-making mechanisms involved in the Simon task and brain activity. Our results are consistent with a representation of the superimposed decision variable in the primary motor cortices. The decision variable was also observed in the EMG activity of response agonist muscles. These findings provide new insight into the neurophysiology of human decision-making. In return, they provide support for the DMC model framework.
Distinct Neural Suppression and Encoding Effects for Conceptual Novelty and Familiarity
Authors: Reggev Niv , Bein Oded , Maril Anat 
Published: June 2016

Abstract
Like yin and yang, novelty and familiarity are typically described as separate-yet-complementary aspects of an experience, two ends of a single continuum. However, novelty and familiarity are also multifaceted. For instance, novelty can sometimes result in enhanced mnemonic performance, whereas at other times familiarity is better remembered. As previous investigations focused primarily on the experimental aspect of novelty, the mechanisms supporting conceptual novelty (the novel combination of two previously unrelated existing concepts) remain unclear. Importantly, conceptual novelty can be recognized as such only when compared with preexperimental familiar knowledge, regardless of experimental status. Here we applied a combined repetition suppression/subsequent memory fMRI paradigm, focusing on the conceptual aspect of novelty and familiarity as the subject matter. Conceptual novelty was characterized by sustained neural activity; familiarity, on the other hand, exhibited repetition effects in multiple cortical regions, a subset of which was modulated by successful encoding. Subsequent memory of novelty was associated only with activation differences in a distinct set of regions, including the hippocampus and medial cortical regions. These results suggest that conceptual novelty (a) does not (easily) trigger the repetition suppression phenomenon but requires sustained neural recruitment and (b) activates dedicated encoding mechanisms. Conceptual familiarity, in contrast, allows rapid neural processing that depends upon existing neural representations. Overall, these findings challenge the definition of novelty as a unitary concept. Furthermore, they bear important implications for research into the neural bases of knowledge representation and recognition memory.
Semantic Structural Alignment of Neural Representational Spaces Enables Translation between English and Chinese Words
Authors: Zinszer Benjamin D. , Anderson Andrew J. , Kang Olivia , Wheatley Thalia , Raizada Rajeev D. S. 
Published: June 2016

AbstractTwo sets of items can share the same underlying conceptual structure, while appearing unrelated at a surface level. Humans excel at recognizing and using alignments between such underlying structures in many domains of cognition, most notably in analogical reasoning. Here we show that structural alignment reveals how different people's neural representations of word meaning are preserved across different languages, such that patterns of brain activation can be used to translate words from one language to another. Groups of Chinese and English speakers underwent fMRI scanning while reading words in their respective native languages. Simply by aligning structures representing the two groups' neural semantic spaces, we successfully infer all seven Chinese–English word translations. Beyond language translation, conceptual structural alignment underlies many aspects of high-level cognition, and this work opens the door to deriving many such alignments directly from neural representational content.
The Effects of Climate Change on Seasonal Snowpack and the Hydrology of the Northeastern and Upper Midwest United States
Authors: Demaria Eleonora M. C. , Roundy Joshua K. , Wi Sungwook , Palmer Richard N. 
Published: June 2016

AbstractThe potential effects of climate change on the snowpack of the northeastern and upper Midwest United States are assessed using statistically downscaled climate projections from an ensemble of 10 climate models and a macroscale hydrological model. Climate simulations for the region indicate warmer-than-normal temperatures and wetter conditions for the snow season (November–April) during the twenty-first century. However, despite projected increases in seasonal precipitation, statistically significant negative trends in snow water equivalent (SWE) are found for the region. Snow cover is likely to migrate northward in the future as a result of warmer-than-present air temperatures, with higher loss rates in northern latitudes and at high elevation. Decreases in future (2041–95) snow cover in early spring will likely affect the timing of maximum spring peak streamflow, with earlier peaks predicted in more than 80% of the 124 basins studied.
An Index to Distinguish Surface- and Subsurface-Intensified Vortices from Surface Observations
Authors: Assassi C. , Morel Y. , Vandermeirsch F. , Chaigneau A. , Pegliasco C. , Morrow R. , Colas F. , Fleury S. , Carton X. , Klein P. , Cambra R. 
Published: June 2016

AbstractIn this study, the authors first show that it is difficult to reconstruct the vertical structure of vortices using only surface observations. In particular, they show that the recent surface quasigeostrophy (SQG) and interior and surface quasigeostrophy (ISQG) methods systematically lead to surface-intensified vortices, and those subsurface-intensified vortices are thus not correctly modeled. The authors then investigate the possibility of distinguishing between surface- and subsurface-intensified eddies from surface data only, using the sea surface height and the sea surface temperature available from satellite observations. A simple index, based on the ratio of the sea surface temperature anomaly and the sea level anomaly, is proposed. While the index is expected to give perfect results for isolated vortices, the authors show that in a complex environment, errors can be expected, in particular when strong currents exist in the vicinity of the vortex. The validity of the index is then analyzed using results from a realistic regional circulation model of the Peru–Chile upwelling system, where both surface and subsurface eddies coexist. The authors find that errors are mostly associated with double-core eddies (aligned surface and subsurface cores) and that the index can be useful to determine the nature of mesoscale eddies (surface or subsurface intensified) from surface (satellite) observations. However, the errors reach 24%, and some possible improvements of the index calculations are discussed.
Recognizing citizens in municipal management: an exploratory study based on a content analysis of municipal websites in the province of Quebec
Authors: Divay Gérard , Micheau Maud 
Published: June 2016

This article explores the usefulness of a recognition framework for the study of the relationship between municipal administrations and citizens. Within the organizational science literature, employee recognition has been shown to enhance their commitment to their organization. In a context where public authorities consistently seek to improve levels of civic engagement, could this conclusion be applied to the relationship between municipalities and their constituents? Following a review of the literature, we present the results of a content analysis of the websites of Quebec municipalities whose populations are greater than 20,000. Three modes of recognition are identified: personalized attention, value confirmation, and gratitude. Recognition practices are also found to vary between municipalities. Our study opens new pragmatic and theoretical horizons in the area of municipal management. Points for practitioners Managers know that showing recognition toward their employees is not only a sign of respect, but a means to mobilize employee commitment to their organization. This article explores the value of this finding for the field of municipal management and, specifically, to the study of the relationship between municipal managers and citizens. Should serving citizens not ultimately mean recognizing their individual identities, civic capacities, and contribution to their community’s vitality?
Distinct role of heme oxygenase-1 in early- and late-stage intracerebral hemorrhage in 12-month-old mice
Authors: Zhang Zhen , Song Yuejia , Zhang Ze , Li Danyang , Zhu Hong , Liang Rui , Gu Yunhe , Pang Yuxin , Qi Jiping , Wu He , Wang Jian 
Published: June 2016

Intracerebral hemorrhage (ICH) is a devastating form of stroke with high morbidity and mortality. Heme oxygenase-1 (HO-1), the key enzyme in heme degradation, is highly expressed after ICH, but its role is still unclear. In this study, we used an HO-1 inducer and inhibitor to test the role of HO-1 in different stages of ICH in vivo and in vitro. In the early stage of ICH, high HO-1 expression worsened the outcomes of mice subjected to the collagenase-induced ICH model. HO-1 increased brain edema, white matter damage, neuronal death, and neurobehavioral deficits. Furthermore, elevated HO-1 increased inflammation, oxidative stress, matrix metalloproteinase-9/2 activity, and iron deposition. In the later stage of ICH, long-term induction of HO-1 increased hematoma absorption, angiogenesis, and recovery of neurologic function. We conclude that HO-1 activation mediates early brain damage after ICH but promotes neurologic function recovery in the later stage of ICH.