bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transglutaminase 2 Maintains Hepatocyte Growth Factor Signaling to Enhance the Cancer Cell Phenotype
Authors: Chen Xi , Adhikary Gautam , Shrestha Suruchi , Xu Wen , Keillor Jeffrey W. , Naselsky Warren , Eckert Richard L. 
Published: September 2021

Abstract

Transglutaminase 2 (TG2) is a key epidermal squamous cell carcinoma cancer cell survival protein. However, how TG2 maintains the aggressive cancer phenotype is not well understood. The present studies show that TG2, which is highly expressed in epidermal cancer stem–like cells (ECS cells), maintains hepatocyte growth factor (HGF) signaling to drive an aggressive ECS cell cancer phenotype. Inhibiting TG2 reduces MET tyrosine kinase receptor expression and activity and attenuates the cancer cell phenotype. Moreover, inhibition of TG2 or HGF/MET function reduces downstream MEK1/2 and ERK1/2 activity, and this is associated with reduced cancer cell spheroid formation, invasion, and migration, and reduced stem and EMT marker expression. Treatment of TG2 knockdown cells with HGF partially restores the aggressive cancer phenotype, confirming that MET signaling is downstream of TG2. MET knockout reduces ERK1/2 signaling, doubles the time to initial tumor appearance, and reduces overall tumor growth. These findings suggest that TG2 maintains HGF/MET and MAPK (MEK1/2 and ERK1/2) signaling to drive the aggressive ECS cell cancer phenotype and tumor formation, and that TG2-dependent MET signaling may be a useful anti-cancer target.

Implications:
TG2 is an important epidermal squamous cell carcinoma stem cell survival protein. We show that TG2 activates an HGF/MET, MEK1/2 ERK1/2 signaling cascade that maintains the aggressive cancer phenotype.
Circulating Tumor DNA in Lymphoma: Principles and Future Directions
Authors: Roschewski Mark , Rossi Davide , Kurtz David M. , Alizadeh Ash A. , Wilson Wyndham H. 
Published: September 2021

AbstractLymphomas are heterogeneous tumors with striking genetic diversity and variable outcomes even within pathologic diagnoses. Treatment response assessment relies on radiologic and nuclear scans, which cannot detect disease at the molecular level. Molecular tumor analyses require invasive tissue biopsies that cannot accurately capture spatial tumor heterogeneity within each patient. Circulating tumor DNA (ctDNA) is a minimally invasive and highly versatile biomarker that overcomes fundamental limitations of imaging scans and tissue biopsies and may aid clinical decision-making in lymphoma. In this review, we highlight the key established principles regarding ctDNA in lymphoma and emphasize the important research questions and future directions.Significance:ctDNA is an emerging biomarker for lymphomas that noninvasively provides genotypic information and can measure the effectiveness of treatment by detecting the presence of minimal residual disease. Key principles have emerged related to ctDNA for lymphoma, but further studies are needed to standardize its use and establish clinical utility.
Vascular Smooth Muscle Cell Subpopulations and Neointimal Formation in Mouse Models of Elastin Insufficiency
Authors: Lin Chien-Jung , Hunkins Bridget M. , Roth Robyn A. , Lin Chieh-Yu , Wagenseil Jessica E. , Mecham Robert P. 
Published: September 2021

Objective:
Using a mouse model of Eln (elastin) insufficiency that spontaneously develops neointima in the ascending aorta, we sought to understand the origin and phenotypic heterogeneity of smooth muscle cells (SMCs) contributing to intimal hyperplasia. We were also interested in exploring how vascular cells adapt to the absence of Eln.

Approach and Results:

We used single-cell sequencing together with lineage-specific cell labeling to identify neointimal cell populations in a noninjury, genetic model of neointimal formation. Inactivating Eln production in vascular SMCs results in rapid intimal hyperplasia around breaks in the ascending aorta’s internal elastic lamina. Using lineage-specific
Cre
drivers to both lineage mark and inactivate Eln expression in the secondary heart field and neural crest aortic SMCs, we found that cells with a secondary heart field lineage are significant contributors to neointima formation. We also identified a small population of secondary heart field-derived SMCs underneath and adjacent to the internal elastic lamina. Within the neointima of SMC-Eln knockout mice, 2 unique SMC populations were identified that are transcriptionally different from other SMCs. While these cells had a distinct gene signature, they expressed several genes identified in other studies of neointimal lesions, suggesting that some mechanisms underlying neointima formation in Eln insufficiency are shared with adult vessel injury models.

Conclusions:
These results highlight the unique developmental origin and transcriptional signature of cells contributing to neointima in the ascending aorta. Our findings also show that the absence of Eln, or changes in elastic fiber integrity, influences the SMC biological niche in ways that lead to altered cell phenotypes.
Cardiotoxicity of Cancer Treatments: Focus on Anthracycline Cardiomyopathy
Authors: Nishi Masahiro , Wang Ping-yuan , Hwang Paul M. 
Published: September 2021

Significant progress has been made in developing new treatments and refining the use of preexisting ones against cancer. Their successful use and the longer survival of cancer patients have been associated with reports of new cardiotoxicities and the better characterization of the previously known cardiac complications. Immunotherapies with monoclonal antibodies against specific cancer-promoting genes, chimeric antigen receptor T cells, and immune checkpoint inhibitors have been developed to fight cancer cells, but they can also show off-target effects on the heart. Some of these cardiotoxicities are thought to be due to nonspecific immune activation and inflammatory damage. Unlike immunotherapy-associated cardiotoxicities which are relatively new entities, there is extensive literature on anthracycline-induced cardiomyopathy. Here, we provide a brief overview of the cardiotoxicities of immunotherapies for the purpose of distinguishing them from anthracycline cardiomyopathy. This is especially relevant as the expansion of oncological treatments presents greater diagnostic challenges in determining the cause of cardiac dysfunction in cancer survivors with a history of multiple cancer treatments including anthracyclines and immunotherapies administered concurrently or serially over time. We then provide a focused review of the mechanisms proposed to underlie the development of anthracycline cardiomyopathy based on experimental data mostly in mouse models. Insights into its pathogenesis may stimulate the development of new strategies to identify patients who are susceptible to anthracycline cardiomyopathy while permitting low cardiac risk patients to receive optimal treatment for their cancer.

Graphic Abstract:
A graphic abstract is available for this article.
Practice Patterns and Patient Outcomes After Widespread Adoption of Remote Heart Failure Care
Authors: Yuan Neal , Botting Patrick G. , Elad Yaron , Miller Shaun J. , Cheng Susan , Ebinger Joseph E. , Kittleson Michelle M. 
Published: September 2021

Background:
An unprecedented shift to remote heart failure outpatient care occurred during the coronavirus disease 2019 (COVID-19) pandemic. Given challenges inherent to remote care, we studied whether remote visits (video or telephone) were associated with different patient usage, clinician practice patterns, and outcomes.

Methods:
We included all ambulatory cardiology visits for heart failure at a multisite health system from April 1, 2019, to December 31, 2019 (pre-COVID) or April 1, 2020, to December 31, 2020 (COVID era), resulting in 10 591 pre-COVID in-person, 7775 COVID-era in-person, 1009 COVID-era video, and 2322 COVID-era telephone visits. We used multivariable logistic and Cox proportional hazards regressions with propensity weighting and patient clustering to study ordering practices and outcomes.

Results:

Compared with in-person visits, video visits were used more often by younger (mean 64.7 years [SD 14.5] versus 74.2 [14.1]), male (68.3% versus 61.4%), and privately insured (45.9% versus 28.9%) individuals (
P
<0.05 for all). Remote visits were more frequently used by non-White patients (35.8% video, 37.0% telephone versus 33.2% in-person). During remote visits, clinicians were less likely to order diagnostic testing (odds ratio, 0.20 [0.18–0.22] video versus in-person, 0.18 [0.17–0.19] telephone versus in-person) or prescribe β-blockers (0.82 [0.68–0.99], 0.35 [0.26–0.47]), mineralocorticoid receptor antagonists (0.69 [0.50–0.96], 0.48 [0.35–0.66]), or loop diuretics (0.67 [0.53–0.85], 0.45 [0.37–0.55]). During telephone visits, clinicians were less likely to prescribe ACE (angiotensin-converting enzyme) inhibitor/ARB (angiotensin receptor blockers)/ARNIs (angiotensin receptor-neprilysin inhibitors; 0.54 [0.40–0.72]). Telephone visits but not video visits were associated with higher rates of 90-day mortality (1.82 [1.14–2.90]) and nonsignificant trends towards higher rates of 90-day heart failure emergency department visits (1.34 [0.97–1.86]) and hospitalizations (1.36 [0.98–1.89]).

Conclusions:
Remote visits for heart failure care were associated with reduced diagnostic testing and guideline-directed medical therapy prescription. Telephone but not video visits were associated with increased 90-day mortality.
Contraction Patterns of the Right Ventricle Associated with Different Degrees of Left Ventricular Systolic Dysfunction
Authors: Surkova Elena , Kovács Attila , Tokodi Márton , Lakatos Bálint Károly , Merkely Béla , Muraru Denisa , Ruocco Alessandro , Parati Gianfranco , Badano Luigi P. 
Published: September 2021

Background:
The functional adaptation of the right ventricle (RV) to the different degrees of left ventricular (LV) dysfunction remains to be clarified. We sought to (1) assess the changes in RV contraction pattern associated with the reduction of LV ejection fraction (EF) and (2) analyze whether the assessment of RV longitudinal, radial, and anteroposterior motion components of total RVEF adds prognostic value.

Methods:
Consecutive patients with left-sided heart disease who underwent clinically indicated transthoracic echocardiography were enrolled in a single-center prospective observational study. Adverse outcome was defined as heart failure hospitalization or cardiac death. Cross-sectional analysis using the baseline 3-dimensional echocardiography studies was performed to quantify the relative contribution of the longitudinal, radial, and anteroposterior motion components to total RVEF.

Results:

We studied 292 patients and followed them for 6.7±2.2 years. In patients with mildly and moderately reduced LVEF, the longitudinal and the anteroposterior components of RVEF decreased significantly, while the radial component increased resulting in preserved total RVEF (RVEF: 50% [46%–54%] versus 47% [44%–52%] versus 46% [42%–49%] in patients with no, mild, or moderate LV dysfunction, respectively; data presented as median and interquartile range). In patients with severe LV systolic dysfunction (n=34), a reduction in all 3 RV motion components led to a significant drop in RVEF (30% [25%-39%],
P
<0.001). In patients with normal RVEF (>45%), the anteroposterior component of total RVEF was a significant and independent predictor of outcome (hazard ratio, 0.960 [CI, 0.925–0.997],
P
<0.001).

Conclusions:
In patients with left-sided heart disease, there is a significant remodeling of the RV associated with preservation of the RVEF in patients with mild or moderate LV dysfunction. In patients with normal RVEF, the measurement of the anteroposterior component of RV motion provided independent prognostic value.
Learning at Variable Attentional Load Requires Cooperation of Working Memory, Meta-learning, and Attention-augmented Reinforcement Learning
Authors: Womelsdorf Thilo , Watson Marcus R. , Tiesinga Paul 
Published: September 2021

Abstract
Flexible learning of changing reward contingencies can be realized with different strategies. A fast learning strategy involves using working memory of recently rewarded objects to guide choices. A slower learning strategy uses prediction errors to gradually update value expectations to improve choices. How the fast and slow strategies work together in scenarios with real-world stimulus complexity is not well known. Here, we aim to disentangle their relative contributions in rhesus monkeys while they learned the relevance of object features at variable attentional load. We found that learning behavior across six monkeys is consistently best predicted with a model combining (i) fast working memory and (ii) slower reinforcement learning from differently weighted positive and negative prediction errors as well as (iii) selective suppression of nonchosen feature values and (iv) a meta-learning mechanism that enhances exploration rates based on a memory trace of recent errors. The optimal model parameter settings suggest that these mechanisms cooperate differently at low and high attentional loads. Whereas working memory was essential for efficient learning at lower attentional loads, enhanced weighting of negative prediction errors and meta-learning were essential for efficient learning at higher attentional loads. Together, these findings pinpoint a canonical set of learning mechanisms and suggest how they may cooperate when subjects flexibly adjust to environments with variable real-world attentional demands.
Bilingualism, Executive Function, and the Brain: Implications for Autism
Authors: Romero Celia , Uddin Lucina Q. 
Published: September 2021

Abstract
Autism spectrum disorder (ASD) is associated with marked heterogeneity with respect to the development of executive function abilities. The bilingual advantage refers to the observation that individuals who speak two languages perform better on executive function tasks than monolinguals under some circumstances. There is not yet consensus, however, as to whether this advantage can be reliably demonstrated, nor is there consensus regarding under which conditions it emerges. Bilingual and monolingual children with ASD have comparable developmental outcomes, particularly in the areas of core ASD symptoms, cognitive function, and language. Still, despite the potential advantages that bilingualism may confer, clinicians commonly advise against providing a bilingual environment for children with ASD. The purpose of the present review is to provide an up-to-date assessment of the limited literature on bilingualism in children with ASD in order to inform evidence-based practice. Studies suggest a potential bilingual advantage in ASD in the areas of nonverbal intelligence quotient, adaptive functioning, and expressive vocabulary. A limited yet growing literature provides preliminary evidence for enhanced executive function ability in some children with ASD. Taken together, current evidence suggests that although a bilingual advantage may not be universally present in typical development, it may manifest under specific circumstances, conferring advantage for populations in which executive function is compromised. Further work is needed to develop consistent, evidence-based guidelines around language recommendations for families of children with ASD and to better understand the cognitive and brain mechanisms giving rise to the bilingual advantage in clinical developmental populations.
Evolution of the Moat Associated with the Secondary Eyewall Formation in a Simulated Tropical Cyclone
Authors: Qin Nannan , Wu Liguang , Liu Qingyuan 
Published: September 2021

Abstract
Previous studies have focused on the formation and maintenance of spiral rainbands in the secondary eyewall formation (SEF) of tropical cyclones (TCs). However, the evolution of the moat, a region with weak precipitation separating spiral rainbands from the inner eyewall, is also essential for the SEF. In this study, a semi-idealized numerical experiment is conducted to understand the SEF by focusing on the evolution of the moat. In the simulated TC, a secondary eyewall forms around 32 h, and then intensifies and replaces the inner eyewall at 46 h. It is found that the occurrence and subsequent evolution of the moat in the simulated TC are closely associated with the inner-eyewall structure. As the eyewall updraft becomes strong and the eyewall anvil is well developed, the upper-level inflow develops below the eyewall anvil in response to the diabatic warming in the eyewall anvil. The warming-induced inflow causes a drying effect and promotes the sublimation cooling below the anvil, inducing strong subsidence between the inner eyewall and the spiral rainband through the resulting negative buoyancy. Moreover, the resulting subsidence is enhanced by the compensated downward motion in the outer edge of the inner eyewall. Further analysis indicates that the rapidly decreasing vertical shear of environmental wind and the rapid filamentation zone outside the inner eyewall also play important role in the axisymmetrization of the rainband and the moat subsidence. Our results demonstrate that an intense inner eyewall with a wide upper-level anvil is favorable for the SEF in an environment with decreasing vertical wind shear.
Clustering of Climate Change Impacts on Ocean Waves in the Northwest Atlantic
Authors: Goharnejad Hamid , Perrie Will , Toulany Bash , Casey Mike , Zhang Minghong 
Published: September 2021

Abstract
The provision of reliable results from numerical wave models implemented over vast ocean areas can be considered as a time-consuming process. In this regard, the estimation of areas with maximum similarity in wave climate spatial areas and the determination of associated representative point locations for these areas can play an important role in climate research and in engineering applications. To deal with this issue, we apply a state-of-the-art clustering method, Geo-SOM, to determine geographical areas with similar wave regimes, in terms of mean wave direction (MWD), mean wave period (T0), and significant wave height (Hs). Although this method has many strengths, a weakness is related to detection and accounting of the most extreme and rare events. To resolve this deficiency, an initial preprocessing method (called PG-Geo-SOM) is applied. To evaluate the performance of this method, extreme wave parameters, including Hs and T0, are calculated. We simulate the present climate, represented as 1979 to 2017, compared to the future climate, 2060–98, following the Intergovernmental Panel on Climate Change (IPCC) future scenario RCP8.5 in the northwestern Atlantic Ocean. In this approach, the wave parameter data are divided into distinct groups, or clusters, motivated by their geographical positions. For each cluster, the centroid spatial point and the time series of data are extracted, for Hs, MWD, and T0. Extreme values are estimated for 5-, 10-, 25-, 50-, and 100-yr return periods, using Gumbel, exponential, and Weibull stochastic models, for both present and future climates. Results show that for parameter T0, the impact of climate change for the study area is a decreasing trend, while for Hs, in coastal and shelf areas up to about 1000 km from the coastline, increasing trends are estimated, and in open-ocean areas, far from the coast, decreasing trends are obtained.
‘Depression is not a familiar word’: A mixed-methods approach to describe the experience of primary care nurses treating depression in rural Guatemala
Authors: Stryker Shanna D , Kishton Rachel , Nichols Beatrice , Hargraves Daniel , Goodnow Keesha , Doarn Charles R , Brown Jennifer L 
Published: September 2021

Background: As the burden of mental health disorders continues to increase worldwide, there is significant need to describe the cultural variations in presentation, diagnosis and treatment of these diseases. An understanding of these variations can lead to the development of more effective programs to manage these conditions. In Guatemala, depression is the second-leading cause of disability and yet mental health treatment resources are scarce, particularly for indigenous individuals. Aims: The primary research aim was to describe primary care nurses’ explanatory models of depression in their clinical work in indigenous communities in Guatemala. A secondary research aim was to describe training and resources which would support and empower these nurses, in order to lessen risk for burnout. Methods: A cross-sectional mixed methods survey was designed to elicit nurses’ perspectives on the presentation, cause and treatment of depression in the communities they serve, as well as their clinical and emotional comfort in working with depressed individuals. Two subsequent focus groups gathered qualitative commentary which informed training and resource recommendations. Theoretical thematic analysis was used to generate codes and themes from focus group transcripts and survey responses. Results: Guatemalan primary care nurses described symptoms of depression in their cultural context, identified socioeconomic factors which contribute to depression in their communities, and detailed treatment preferences. Limited referral options and concern for privacy made connecting patients to mental health care difficult. Nurses emphasized the need for community education on depression and for supplemental mental health resources which would increase their capacity to identify and treat depression. Conclusions: Primary care nurses in Guatemala identify and treat depression despite limited resources. Further investigations should focus on creating training modalities which include front-line nurses, given their critical role in the health system.
Early Intervention Orientation and Mobility: A Delphi Study of the Content of the Birth to 6 Orientation and Mobility Skills Inventory (B6OMSI)
Authors: Baguhn Sarahelizabeth 
Published: September 2021

Introduction: The objective of this research was to identify the appropriate content for an orientation and mobility (O&M) assessment for young children. It is necessary to have a reliable and valid assessment tool to evaluate whether young children are making adequate gains in response to early intervention efforts in O&M. Very little literature exists on the O&M needs of children aged birth to 6 years because of the roots in adult rehabilitation of the field of O&M. Methods: A group of expert-level professionals in the field of early intervention O&M engaged in a consensus process to establish face validity and content validity of the assessment items, which was accomplished using a Delphi study to identify relevant topics for assessment as a first step in developing a research-based assessment tool. Cutoffs for agreement were established prior to analysis, with 90% consensus for face and content validity of a high-stakes assessment that allows the score on the assessment to serve as a snapshot of a child’s progress. Results: All skills and concepts on the assessment were validated, and seven new items were added. Discussion: The resultant assessment tool is comprehensive in measuring the areas of O&M for young children that specialists found useful for determining the need for services and monitoring progress, does not contain extraneous test questions, and can stand alone as a snapshot of student progress. One item was added to the background information portion of the assessment tool because of its usefulness to some practitioners despite a consensus level below 90%. Future research should seek to establish construct validity and reliability measures. Implications for practitioners: Orientation and mobility specialists can begin using the updated item tool with improved content validity available from the New Mexico School for the Blind website.