bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reciprocal intralimb transfer of skilled isometric force production
Authors: Rajan Vikram A. , Hardwick Robert M. , Celnik Pablo A. 
Published: May 2019

Motor control theories propose that the same motor plans can be employed by different effectors (e.g., the hand and arm). Skills learned with one effector can therefore “transfer” to others, which has potential applications in clinical situations. However, evidence from adaptation suggests this effect is not reciprocal; learning can be generalized from proximal to distal effectors (e.g., arm to hand), but not from distal to proximal effectors (e.g., hand to arm). We propose that skill learning may not follow the same pattern, because it relies on multiple learning processes beyond error detection and correction. Participants learned a skill task involving the production of isometric forces. We assessed their ability to perform the task with the hand and arm. One group then trained to perform the task using only their hand, whereas a second group trained using only their arm. In a final assessment, we found that participants who trained with either effector improved their skill in performing the task with both their hand and arm. There was no change in a control group that did not train between assessments, indicating that gains were related to the training, not the multiple assessments. These results indicate that in contrast to adaptation, motor skills can generalize from both proximal to distal effectors and from distal to proximal effectors. We propose this is due to differences in the processes underlying skill acquisition as compared with adaptation. NEW & NOTEWORTHY Prior research indicates that motor learning transfers from proximal to distal effectors, but not vice versa. However, this work focused on adapting existing behavior; we questioned whether different results would occur during learning of new motor skills. We found that the benefits of training on a skill task with either the hand or arm transferred across both effectors. This highlights important differences between adaptation and skill learning, and may allow therapeutic benefits for patients with impairments in specific effectors.
Liquid Biopsy: Is There an Advantage to Analyzing Circulating Exosomal DNA Compared to cfDNA or Are They the Same?
Authors: Kahlert Christoph 
Published: May 2019

Abstract
Cancer is one of the leading causes of death worldwide. This life-threatening disease requires novel strategies for the early detection and therapy response prediction. Circulating DNA was first described 70 years ago. However, only the recent evolution in the PCR-based sequencing techniques allow the minimally invasive molecular profiling of circulating mutant DNA from small-volume “liquid biopsies” such as blood, urine, or saliva. In this article, we aim to summarize the fast-growing evidence for cfDNA and exosomal DNA as minimally invasive diagnostic markers in solid tumors and to highlight their opposing diagnostic advantages and disadvantages.
Nischarin Regulates Secretion of Exosomes and Cancer Progression
Authors: McAndrews Kathleen M. , Kalluri Raghu 
Published: May 2019

Abstract
The intercellular exchange of exosomes may play a regulatory function in tumor progression and metastasis. Maziveyi and colleagues demonstrated that Nischarin regulated the secretion of exosomes from breast cancer cells. Loss of Nischarin expression increased exosome production and promoted tumor cell growth and migration, supporting that Nischarin can influence the behavior of surrounding cancer cells. This study identified a novel function of the tumor suppressor Nischarin in exosome biology and cancer progression.
See related article by Maziveyi et al., p. 2152
Evaluating Correlates of Awareness of the Association between Drinking Too Much Alcohol and Cancer Risk in the United States
Authors: Wiseman Kara P. , Klein William M.P. 
Published: May 2019

Abstract

Background:
Awareness that alcohol consumption is associated with cancer is low in the United States, and predictors of awareness are not well understood.

Methods:
Data from the 2017 Health Information National Trends Survey (HINTS 5 Cycle 1) were used to describe knowledge of the association between drinking too much alcohol and cancer (“Yes,” aware of the association; “No”; or “Don't know”) among 3,009 adults. Weighted multinomial multivariable logistic regression determined personal characteristics (e.g., demographic characteristics, health-related self-efficacy, cancer beliefs, and information seeking) associated with reporting “Yes” or “Don't know” compared with “No.”

Results:
Thirty-eight percent of the U.S. population believed there was an association (38.36%), 36.17% were uncertain, and 25.47% believed there was no association. People believing that everything causes cancer and people who had ever looked up information about cancer had 1.61 and 1.80 higher odds of reporting “Yes” [95% confidence intervals (CI), 1.08–2.42 and 1.27–2.57, respectively]. Compared with people who were completely confident in their ability to take care of their health, people only somewhat confident had 2.32 higher odds of reporting “Don't know” (95% CI, 1.30–4.14). Younger age was negatively associated with reporting “Don't know.”

Conclusions:
Awareness of the association between alcohol and cancer is low in the United States. Personal characteristics associated with awareness differed between reporting “Yes” and “Don't know,” and there were few associations between demographic characteristics and awareness.

Impact:
A significant knowledge gap exists in the population. Broad reaching public health media campaigns, particularly those that increase information seeking, are needed to increase awareness.
Vitamin D Modifies the Incidence of Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation Depending on the Vitamin D Receptor (VDR) Polymorphisms
Authors: Carrillo-Cruz Estrella , García-Lozano José R. , Márquez-Malaver Francisco J. , Sánchez-Guijo Fermín M. , Montero Cuadrado Isabel , Ferra i Coll Christelle , Valcárcel David , López-Godino Oriana , Cuesta Marian , Parody Rocío , López-Corral Lucía , Alcoceba Miguel , Caballero-Velázquez Teresa , Rodríguez-Gil Alfonso , Bejarano-García José A. , Ramos Teresa Lopes , Pérez-Simón José A. 
Published: May 2019

AbstractPurpose:The biologically active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3 (vit D), has immunoregulatory properties via binding vitamin D receptor (VDR). In a prospective trial, we previously reported a reduction in the incidence of chronic GvHD (cGvHD) among patients who received vit D after allogeneic stem cell transplantation (allo-HSCT; Clinical Trials.gov: NCT02600988). Here we analyze the role of patients and donors' VDR SNPs on the immunomodulatory effect of vit D.Patients and Methods:Patients undergoing allo-HSCT were included in a prospective phase I/II clinical trial (Alovita) in three consecutive cohorts: control (without vit D), low-dose (1,000 IU/day), and high-dose (5,000 IU/day) groups. Vit D was given from day −5 until +100 after transplant. Genotyping of four SNPs of the VDR gene, FokI, BsmI, ApaI, and TaqI, were performed using TaqMan SNP genotyping assays.Results:We observed a decrease in the incidence of overall cGvHD at 1 year after allo-HSCT depending on the use or not of vit D among patients with FokI CT genotype (22.5% vs 80%, P = 0.0004) and among those patients without BsmI/ApaI/TaqI ATC haplotype (22.2% vs 68.8%, P = 0.0005). In a multivariate analysis, FokI CT genotype significantly influenced the risk of cGvHD in patients treated with vit D as compared with the control group (HR 0.143, Pinteraction &lt; 0.001).Conclusions:Our results show that the immunomodulatory effect of vit D depends on the VDR SNPs, and patients carrying the FokI CT genotype display the highest benefit from receiving vit D after allo-HSCT.
Intrinsic Resistance to MEK Inhibition through BET Protein–Mediated Kinome Reprogramming in NF1-Deficient Ovarian Cancer
Authors: Kurimchak Alison M. , Shelton Claude , Herrera-Montávez Carlos , Duncan Kelly E. , Chernoff Jonathan , Duncan James S. 
Published: May 2019

Abstract

Mutation or deletion of Neurofibromin 1 (NF1), an inhibitor of RAS signaling, frequently occurs in epithelial ovarian cancer (EOC), supporting therapies that target downstream RAS effectors, such as the RAF–MEK–ERK pathway. However, no comprehensive studies have been carried out testing the efficacy of MEK inhibition in NF1-deficient EOC. Here, we performed a detailed characterization of MEK inhibition in NF1-deficient EOC cell lines using kinome profiling and RNA sequencing. Our studies showed MEK inhibitors (MEKi) were ineffective at providing durable growth inhibition in NF1-deficient cells due to kinome reprogramming. MEKi-mediated destabilization of FOSL1 resulted in induced expression of receptor tyrosine kinases (RTK) and their downstream RAF and PI3K signaling, thus overcoming MEKi therapy. MEKi synthetic enhancement screens identified BRD2 and BRD4 as integral mediators of the MEKi-induced RTK signatures. Inhibition of bromo and extra terminal (BET) proteins using BET bromodomain inhibitors blocked MEKi-induced RTK reprogramming, indicating that BRD2 and BRD4 represent promising therapeutic targets in combination with MEKi to block resistance due to kinome reprogramming in NF1-deficient EOC.

Implications:
Our findings suggest MEK inhibitors will likely not be effective as single-agent therapies in NF1-deficient EOC due to kinome reprogramming. Cotargeting BET proteins in combination with MEKis to block reprogramming at the transcriptional level may provide an epigenetic strategy to overcome MEKi resistance in NF1-deficient EOC.
Programmed Cell Death Ligand-1 (PD-L1) and CD8 Expression Profiling Identify an Immunologic Subtype of Pancreatic Ductal Adenocarcinomas with Favorable Survival
Authors: Danilova Ludmila , Ho Won Jin , Zhu Qingfeng , Vithayathil Teena , De Jesus-Acosta Ana , Azad Nilofer S. , Laheru Daniel A. , Fertig Elana J. , Anders Robert , Jaffee Elizabeth M. , Yarchoan Mark 
Published: May 2019

Abstract
Immune-checkpoint therapy has failed to demonstrate meaningful clinical benefit in unselected cases of pancreatic adenocarcinoma (PDAC), but a subset of PDACs are known to upregulate pathways involved in acquired immune suppression. Further delineation of immunologic subtypes of PDAC is necessary to improve clinical trial designs and identify patients who might benefit from immune-checkpoint therapy. We used clinical survival and RNA expression data from The Cancer Genome Atlas (TCGA) to investigate the relationship between immune-modulating pathways and immune subset markers and their impact on survival in PDAC patients. Of the adaptive immune-resistance pathways, expression of PD-L1 and IDO1 was individually associated with poor survival. Although CD8 expression alone was not correlated with survival, the combination of PD-L1− and high CD8 expression identified a subtype with favorable survival. We further extended these observations using an independent PDAC cohort from our institution via IHC, again observing that the PD-L1−/CD8high subtype was associated with positive prognosis. Although PDAC is regarded as a poorly immunogenic cancer type, these findings infer that T-cell infiltration in the absence of adaptive immune-resistance pathways is a feature of long-term survival in PDAC and imply the importance of developing future immunotherapeutic strategies based on data-supported biomarkers to refine patient selection.
The Highs and Lows of Immune-Checkpoint Blockade in Lymphoma
Authors: Ansell Stephen M. 
Published: May 2019

Abstract
Immunologic approaches to treating patients with cancer have shown promise, and immune-checkpoint blockade has been particularly successful. In many solid tumors, the presence of intratumoral immune cells has been predictive of a response to therapy, and blockade of inhibitory signals that dampen an effective antitumor response has resulted in clinical benefit for patients. Lymphoid malignancies, including Hodgkin lymphoma and non-Hodgkin lymphoma, are cancers of the immune system, and in these diseases, the malignant cells interact with the immune system and commonly provide signals that regulate immune function. Therefore, many of the immunologic lessons learned from solid tumors may not directly translate to lymphoid malignancies, and the mechanisms of effective antitumor responses in these diseases may be different. In Hodgkin lymphoma, for example, immune-checkpoint blockade has resulted in response rates of 65% to 75%. In contrast, in non-Hodgkin lymphoma, responses to immune-checkpoint blockade in phase II trials have been seen in fewer than 10% of patients, and the reasons for this substantial difference are largely unknown. Combination approaches are likely needed, particularly in the various subtypes of non-Hodgkin lymphoma, and combinations that include cytotoxic agents seem more effective than combinations of immunologic therapies. Successful therapeutic combinations in lymphomas may require an approach that simultaneously blocks inhibitory immune signals, provides direct activation of the immune response, and directly inhibits the malignant clone.
Pilhagem territorial, precarização do trabalho e degradação do sujeito que trabalha: reflexões a partir da produção de celulose no Brasil
Authors: Perpetua Guilherme Marini , Thomaz Junior Antonio 
Published: May 2019

Como resultado de uma singular combinação de fatores internos e externos, particularmente atuantes a partir do início dos anos 2000, a economia e o território do Brasil sofreram um avanço inaudito da produção de commodities agropecuárias e minerais. Nesse contexto, a produção de celulose despontou como um dos principais produtos exportados, territorializando-se em diferentes regiões por meio de megaempreendimentos que vinculam fábricas a imensas áreas de monocultivo de eucalipto. O objetivo do presente artigo é desvelar a dinâmica do trabalho no interior do recente processo de territorialização do capital arbóreo-celulósico no Brasil, com foco na precarização do trabalho e nos riscos e agravos à saúde dos trabalhadores. A pesquisa combinou procedimentos metodológicos quantitativos e qualitativos, investigando empiricamente os casos de três regiões: Porto Seguro (BA), Três Lagoas (MS) e Imperatriz (MA).
Cidade, história e segregação socioespacial no romance O moleque Ricardo, de José Lins do Rego
Authors: Hollanda Bernardo Buarque de , Matos Regiane 
Published: May 2019

O artigo detém-se no exame do quarto romance de autoria do escritor José Lins do Rego, procurando mostrar de que maneira, nele, o narrador se desvencilha da paisagem canavieira do interior do Nordeste, e apresenta como locus central de sua ficção o cenário de uma grande cidade nordestina, mais precisamente, a Recife do início dos anos 1920. Procura-se evidenciar a maneira pela qual o escritor deslinda a ambiência turbulenta e excludente de uma cidade grande, com seus tipos urbanos subalternos, com a exploração social do trabalho e com seus conflitos políticos.
RACHS‐ANZ: A Modified Risk Adjustment in Congenital Heart Surgery Model for Outcome Surveillance in Australia and New Zealand
Authors: McSharry Brent , Straney Lahn , Alexander Janet , Gentles Tom , Winlaw David , Beca John , Millar Johnny , Shann Frank , Wilkins Barry , Numa Andrew , Stocker Christian , Erickson Simon , Slater Anthony ,   the Australian and New Zealand Intensive Care Society Paediatric Study Group and Centre for Outcomes and Resource Evaluation
Published: May 2019

Background

Outcomes for pediatric cardiac surgery are commonly reported from international databases compiled from voluntary data submissions. Surgical outcomes for all children in a country or region are less commonly reported. We aimed to describe the bi‐national population‐based outcome for children undergoing cardiac surgery in Australia and New Zealand and determine whether the Risk Adjustment for Congenital Heart Surgery (
RACHS
) classification could be used to create a model that accurately predicts
in‐hospital mortality
in this population.

Methods and Results

The study was conducted in all children's hospitals performing cardiac surgery in Australia and New Zealand between January 2007 and December 2015. The performance of the original
RACHS
‐1 model was assessed and compared with an alternative
RACHS
‐
ANZ
(Australia and New Zealand) model, developed balancing discrimination with parsimonious variable selection. A total of 14 324 hospital admissions were analyzed. The overall hospital mortality was 2.3%, ranging from 0.5% for
RACHS
category 1 procedures, to 17.0% for
RACHS
category 5 or 6 procedures. The original
RACHS
‐1 model was poorly calibrated with death overpredicted (1161 deaths predicted, 289 deaths observed). The
RACHS
‐
ANZ
model had better performance in this population with excellent discrimination (Az‐
ROC
of 0.830) and acceptable Hosmer and Lemeshow goodness‐of‐fit (
P
=0.216).

Conclusions

The original
RACHS
‐1 model overpredicts mortality in children undergoing heart surgery in the current era. The
RACHS
‐
ANZ
model requires only 3 risk variables in addition to the
RACHS
procedure category, can be applied to a wider range of patients than
RACHS
‐1, and is suitable to use to monitor regional pediatric cardiac surgery outcomes.
Association of High Birth Weight With Incident Heart Failure in the ARIC Study
Authors: Rashid Abdirahim , Agarwala Anandita , Novak Eric , Brown David L. 
Published: May 2019

Background

Traditional risk factors for heart failure––coronary heart disease, hypertension, diabetes mellitus, obesity, and smoking––only account for about 50% of cases. Thus, the identification of novel risk factors is of significant public health importance. As high birth weight infants are at increased risk for obesity and diabetes mellitus later in life, which are both risk factors for the development of heart failure, we sought to assess the association of high birth weight with incident heart failure in the
ARIC
(Atherosclerosis Risk in Communities) study.

Methods and Results

The ARIC study is a biracial prospective community‐based investigation of 15 792 individuals aged 45 to 64 years at baseline. Study participants who were born premature or born a twin were excluded from this analysis, resulting in 9820 participants who provided either their birth weight category (low, medium, high) or exact birth weight. After adjusting for differences in demographics, risk factors, and comorbidities, compared with medium birth weight, those with high birth weight had a significantly increased risk of incident heart failure (hazard ratio, 1.27; 95%
CI
, 1.05–1.54 [
P
=0.014]). The hazard for all‐cause mortality for high birth weight compared with medium birth weight was 1.16 (95%
CI
, 0.99–1.34;
P
=0.06). There was no association of high birth weight with myocardial infarction (hazard ratio, 1.06; 95%
CI
, 0.84–1.34 [
P
=0.6]).

Conclusions
High birth weight was associated with a significantly increased hazard of incident heart failure independent of traditional risk factors and a trend toward an increased hazard of death. A history of high birth weight should be ascertained in young adults for primordial prevention of heart failure and in older adults for primary prevention.
Defective Renal Angiotensin III and AT
2
Receptor Signaling in Prehypertensive Spontaneously Hypertensive Rats
Authors: Kemp Brandon A. , Howell Nancy L. , Keller Susanna R. , Gildea John J. , Shao Weijian , Navar Luis Gabriel , Carey Robert M. 
Published: May 2019

Background

Previous studies demonstrated that angiotensin (Ang)
III
, not Ang
II
, is the predominant endogenous agonist for Ang type‐2 receptor (
AT
2
R)‐induced natriuresis in normal rats, and that hypertensive 12‐week‐old spontaneously hypertensive rats (
SHR
) lack natriuretic responses to Ang
III
. This study tested whether prehypertensive
SHR
already have defective Ang
III
‐induced natriuresis and determined possible mechanisms.

Methods and Results

Female and male normotensive 4‐week‐old
SHR
and Wistar Kyoto rats were studied after 24‐hour systemic
AT
1
R blockade. Left kidneys received 30 minute renal interstitial infusions of vehicle followed by Ang
III
(3.5, 7.0, 14, and 28 nmol/kg per min; each dose for 30 minutes). Right kidneys received vehicle infusions. In 4‐week‐old Wistar Kyoto rats, renal interstitial Ang
III
increased urine sodium (Na
+
) excretion but failed to induce natriuresis in 4‐week‐old
SHR
. Renal Ang
III
levels were similar between Wistar Kyoto rats and
SHR
, making increased Ang
III
degradation as a possible cause for defective natriuresis in
SHR
unlikely. In Wistar Kyoto rats, renal interstitial Ang
III
induced translocation of
AT
2
Rs to apical plasma membranes of renal proximal tubule cells. Simultaneously, Ang
III
induced retraction of the major Na
+
transporter Na
+
‐H
+
exchanger‐3 (
NHE
‐3) from apical membranes and internalization of Na
+
/K
+
ATP
ase (
NKA
) from basolateral membranes of renal proximal tubule cells. Consistent with
NHE
‐3 and
NKA
retraction, Ang
III
increased
pS
er
552
‐
NHE
‐3 and decreased
pS
er
23
‐
NKA
. In contrast, in
SHR
, intrarenal Ang
III
failed to induce
AT
2
R translocation,
NHE
‐3 or
NKA
retraction,
pS
er
552
‐
NHE
‐3 phosphorylation, or
pS
er
23
‐
NKA
dephosphorylation.

Conclusions

These results indicate impaired Ang
III
/
AT
2
R signaling as a possible primary defect in prehypertensive
SHR
.
Prognostic Implications of Door‐to‐Balloon Time and Onset‐to‐Door Time on Mortality in Patients With ST‐Segment–Elevation Myocardial Infarction Treated With Primary Percutaneous Coronary Intervention
Authors: Park Jonghanne , Choi Ki Hong , Lee Joo Myung , Kim Hyun Kuk , Hwang Doyeon , Rhee Tae‐Min , Kim Jihoon , Park Taek Kyu , Yang Jeong Hoon , Song Young Bin , Choi Jin‐Ho , Hahn Joo‐Yong , Choi Seung‐Hyuk , Koo Bon‐Kwon , Chae Shung Chull , Cho Myeong Chan , Kim Chong Jin , Kim Ju Han , Jeong Myung Ho , Gwon Hyeon‐Cheol , Kim Hyo‐Soo ,   The KAMIR‐NIH (Korea Acute Myocardial Infarction Registry–National Institutes of Health) Investigators
Published: May 2019

Background
In patients with ST‐segment–elevation myocardial infarction, timely reperfusion therapy with door‐to‐balloon (D2B) time <90 minutes is recommended by the current guidelines. However, whether further shortening of symptom onset‐to‐door (O2D) time or D2B time would enhance survival of patients with ST‐segment–elevation myocardial infarction remains unclear. Therefore, the current study aimed to evaluate the prognostic impact of O2D or D2B time in patients with ST‐segment–elevation myocardial infarction who underwent primary percutaneous coronary intervention.

Methods and Results

We analyzed 5243 patients with ST‐segment–elevation myocardial infarction were treated at 20 tertiary hospitals capable of primary percutaneous coronary intervention in Korea. The association between O2D or D2B time with all‐cause mortality at 1 year was evaluated. The median O2D time was 2.0 hours, and the median D2B time was 59 minutes. A total of 92.2% of the total population showed D2B time ≤90 minutes. In univariable analysis, 1‐hour delay of D2B time was associated with a 55% increased 1‐year mortality, whereas 1‐hour delay of O2D time was associated with a 4% increased 1‐year mortality. In multivariable analysis, D2B time showed an independent association with mortality (adjusted hazard ratio, 1.90; 95%
CI
, 1.51–2.39;
P
<0.001). Reducing D2B time within 45 minutes showed further decreased risk of mortality compared with D2B time >90 minutes (adjusted hazard ratio, 0.30; 95%
CI
, 0.19–0.42;
P
<0.001). Every reduction of D2B time by 30 minutes showed continuous reduction of 1‐year mortality (90 to 60 minutes: absolute risk reduction, 2.4%; number needed to treat, 41.9; 60 to 30 minutes: absolute risk reduction, 2.0%; number needed to treat, 49.2).

Conclusions
Shortening D2B time was significantly associated with survival benefit, and the survival benefit of shortening D2B time was consistently observed, even <60 to 90 minutes.