bluuebunny/crossref_metadata_2025_split huggingface dataset:
Defining the Energetic Basis for a Conformational Switch Mediating Ligand-Independent Activation of Mutant Estrogen Receptors in Breast Cancer
Authors: Mayne Christopher G. , Toy Weiyi , Carlson Kathryn E. , Bhatt Trusha , Fanning Sean W. , Greene Geoffrey L. , Katzenellenbogen Benita S. , Chandarlapaty Sarat , Katzenellenbogen John A. , Tajkhorshid Emad 
Published: May 2021

AbstractAlthough most primary estrogen receptor (ER)–positive breast cancers respond well to endocrine therapies, many relapse later as metastatic disease due to endocrine therapy resistance. Over one third of these are associated with mutations in the ligand-binding domain (LBD) that activate the receptor independent of ligand. We have used an array of advanced computational techniques rooted in molecular dynamics simulations, in concert with and validated by experiments, to characterize the molecular mechanisms by which specific acquired somatic point mutations give rise to ER constitutive activation. By comparing structural and energetic features of constitutively active mutants and ligand-bound forms of ER-LBD with unliganded wild-type (WT) ER, we characterize a spring force originating from strain in the Helix 11–12 loop of WT-ER, opposing folding of Helix 12 into the active conformation and keeping WT-ER off and disordered, with the ligand-binding pocket open for rapid ligand binding. We quantify ways in which this spring force is abrogated by activating mutations that latch (Y537S) or relax (D538G) the folded form of the loop, enabling formation of the active conformation without ligand binding. We also identify a new ligand-mediated hydrogen-bonding network that stabilizes the active, ligand-bound conformation of WT-ER LBD, and similarly stabilizes the active conformation of the ER mutants in the hormone-free state.Implications:Our investigations provide deep insight into the energetic basis for the structural mechanisms of receptor activation through mutation, exemplified here with ER in endocrine-resistant metastatic breast cancers, with potential application to other dysregulated receptor signaling due to driver mutations.
Local Anti–PD-1 Delivery Prevents Progression of Premalignant Lesions in a 4NQO-Oral Carcinogenesis Mouse Model
Authors: Shi Yewen , Xie Tong-xin , Leach David G. , Wang Bingbing , Young Simon , Osman Abdullah A. , Sikora Andrew G. , Ren Xiaoyong , Hartgerink Jeffrey D. , Myers Jeffrey N. , Rangel Roberto 
Published: May 2021

Abstract

Although the principle of systemic treatment to prevent the progression of oral premalignant lesions (OPL) has been demonstrated, there remains a lack of consensus about an optimal approach that balances clinical efficacy with toxicity concerns. Recent advances in cancer therapy using approaches targeting the tumor immune microenvironment (TIME) including immune-checkpoint inhibitors indicate that these agents have significant clinically activity against different types of cancers, including oral cancer, and therefore they may provide an effective oral cancer prevention strategy for patients with OPLs. Our past work showed that systemic delivery of a monoclonal antibody to the programmed death receptor 1 (PD-1) immune checkpoint can inhibit the progression of OPLs to oral cancer in a syngeneic murine oral carcinogenesis model. Here we report a novel approach of local delivery of a PD-1 immune-checkpoint inhibitor loaded using a hydrogel, which significantly reduces the progression of OPLs to carcinomas. In addition, we detected a significant infiltration of regulatory T cells associated with oral lesions with p53 mutation, and a severe loss of expression of STING, which correlated with a decreased infiltration of dendritic cells in the oral lesions. However, a single local dose of PD-1 inhibitor was found to restore stimulator of interferon response cGAMP interactor 1 (STING) and CD11c expression and increase the infiltration of CD8+ T cells into the TIME irrespective of the p53 mutational status. Overall, we provide evidence for the potential clinical value of local delivery of biomaterials loaded with anti–PD-1 antibodies to prevent malignant progression of OPLs.

Prevention Relevance:
Oral cancer is an aggressive disease, with an overall survival rate of 50%. Preinvasive histologic abnormalities such as tongue dysplasia represent an early stage of oral cancer; however, there are no treatments to prevent oral carcinoma progression. Here, we combined biomaterials loaded with an immunotherapeutic agent preventing oral cancer progression.
Impact of Patient Adherence to Stool-Based Colorectal Cancer Screening and Colonoscopy Following a Positive Test on Clinical Outcomes
Authors: Fendrick A. Mark , Fisher Deborah A. , Saoud Leila , Ozbay A. Burak , Karlitz Jordan J. , Limburg Paul J. 
Published: May 2021

Abstract

Colorectal cancer–screening models commonly assume 100% adherence, which is inconsistent with real-world experience. The influence of adherence to initial stool-based screening [fecal immunochemical test (FIT), multitarget stool DNA (mt-sDNA)] and follow-up colonoscopy (after a positive stool test) on colorectal cancer outcomes was modeled using the Colorectal Cancer and Adenoma Incidence and Mortality Microsimulation Model. Average-risk individuals without diagnosed colorectal cancer at age 40 undergoing annual FIT or triennial mt-sDNA screening from ages 50 to 75 were simulated. Primary analyses incorporated published mt-sDNA (71%) or FIT (43%) screening adherence, with follow-up colonoscopy adherence ranging from 40% to 100%. Secondary analyses simulated 100% adherence for stool-based screening and colonoscopy follow-up (S1), published adherence for stool-based screening with 100% adherence to colonoscopy follow-up (S2), and published adherence for both stool-based screening and colonoscopy follow-up after positive mt-sDNA (73%) or FIT (47%; S3). Outcomes were life-years gained (LYG) and colorectal cancer incidence and mortality reductions (per 1,000 individuals) versus no screening. Adherence to colonoscopy follow-up after FIT had to be 4%–13% higher than mt-sDNA to reach equivalent LYG. The theoretical S1 favored FIT versus mt-sDNA (LYG 316 vs. 297; colorectal cancer incidence reduction 68% vs. 64%; colorectal cancer mortality reduction 76% vs. 72%). The more realistic S2 and S3 favored mt-sDNA versus FIT (S2: LYG 284 vs. 245, colorectal cancer incidence reduction 61% vs. 50%, colorectal cancer mortality reduction 69% vs. 59%; S3: LYG 203 vs. 113, colorectal cancer incidence reduction 43% vs. 23%, colorectal cancer mortality reduction 49% vs. 27%, respectively). Incorporating realistic adherence rates for colorectal cancer screening influences modeled outcomes and should be considered when assessing comparative effectiveness.

Prevention Relevance:
Adherence rates for initial colorectal cancer screening by FIT or mt-sDNA and for colonoscopy follow-up of a positive initial test influence the comparative effectiveness of these screening strategies. Using adherence rates based on published data for stool-based testing and colonoscopy follow-up yielded superior outcomes with an mt-sDNA versus FIT-screening strategy.
IL11: A Specific Repressor of Tumor-Specific CD4+ T Cells
Authors: van der Burg Sjoerd H. 
Published: May 2021

Abstract
CD4+ T helper 1 (Th1) cells have a key role in tumor immunity by producing effector cytokines that orchestrate the tumoricidal effects of cytotoxic T lymphocytes, natural killer cells, and macrophages and directly exert tumor growth control via the induction of tumor cell senescence and inhibition of angiogenesis. In this issue, Huynh and colleagues report a new role for IL11 in fostering tumor outgrowth by suppressing the effector mechanisms of intratumoral CD4+ Th1 cells.
See related article by Huynh et al., p. 735.
Multiomic Profiling in Black and White Populations Reveals Novel Candidate Pathways in Left Ventricular Hypertrophy and Incident Heart Failure Specific to Black Adults
Authors: Katz Daniel H. , Tahir Usman A. , Ngo Debby , Benson Mark D. , Gao Yan , Shi Xu , Nayor Matthew , Keyes Michelle J. , Larson Martin G. , Hall Michael E. , Correa Adolfo , Sinha Sumita , Shen Dongxiao , Herzig Matthew , Yang Qiong , Robbins Jeremy M. , Chen Zsu-Zsu , Cruz Daniel E. , Peterson Bennet , Vasan Ramachandran S. , Wang Thomas J. , Wilson James G. , Gerszten Robert E. 
Published: May 2021

Background:
Increased left ventricular (LV) mass is associated with adverse cardiovascular events including heart failure (HF). Both increased LV mass and HF disproportionately affect Black individuals. To understand the underlying mechanisms, we undertook a proteomic screen in a Black cohort and compared the findings to results from a White cohort.

Methods:
We measured 1305 plasma proteins using the SomaScan platform in 1772 Black participants (mean age, 56 years; 62% women) in JHS (Jackson Heart Study) with LV mass assessed by 2-dimensional echocardiography. Incident HF was assessed in 1600 participants. We then compared protein associations in JHS to those observed in White participants from FHS (Framingham Heart Study; mean age, 54 years; 56% women).

Results:

In JHS, there were 110 proteins associated with LV mass and 13 proteins associated with incident HF hospitalization with false discovery rate <5% after multivariable adjustment. Several proteins showed expected associations with both LV mass and HF, including NT-proBNP (N-terminal pro-B-type natriuretic peptide; β=0.04;
P
=2×10
−8
; hazard ratio, 1.48;
P
=0.0001). The strongest association with LV mass was novel: LKHA4 (leukotriene-A4 hydrolase; β=0.05;
P
=5×10
−15
). This association was confirmed on an alternate proteomics platform and further supported by related metabolomic data. Fractalkine/CX3CL1 (C-X3-C Motif Chemokine Ligand 1) showed a novel association with incident HF (hazard ratio, 1.32;
P
=0.0002). While established biomarkers such as cystatin C and NT-proBNP showed consistent associations in Black and White individuals, LKHA4 and fractalkine were significantly different between the two groups.

Conclusions:
We identified several novel biological pathways specific to Black adults hypothesized to contribute to the pathophysiologic cascade of LV hypertrophy and incident HF including LKHA4 and fractalkine.
CalTrack: High-Throughput Automated Calcium Transient Analysis in Cardiomyocytes
Authors: Psaras Yiangos , Margara Francesca , Cicconet Marcelo , Sparrow Alexander J. , Repetti Giuliana G. , Schmid Manuel , Steeples Violetta , Wilcox Jonathan A.L. , Bueno-Orovio Alfonso , Redwood Charles S. , Watkins Hugh C. , Robinson Paul , Rodriguez Blanca , Seidman Jonathan G. , Seidman Christine E. , Toepfer Christopher N. 
Published: May 2021

Rationale:
Calcium transient analysis is central to understanding inherited and acquired cardiac physiology and disease. Although the development of novel calcium reporters enables assays of CRISPR/Cas-9 genome-edited induced pluripotent stem cell–derived cardiomyocytes and primary adult cardiomyocytes, existing calcium-detection technologies are often proprietary and require specialist equipment, whereas open-source workflows necessitate considerable user expertise and manual input.

Objective:
We aimed to develop an easy to use open-source, adaptable, and automated analysis pipeline for measuring cellular calcium transients, from image stack to data output, inclusive of cellular identification, background subtraction, photobleaching correction, calcium transient averaging, calcium transient fitting, data collation, and aberrant behavior recognition.

Methods and Results:

We developed CalTrack, a MatLab-based algorithm, to monitor fluorescent calcium transients in living cardiomyocytes, including isolated single cells or those contained in 3-dimensional tissues or organoids, and to analyze data acquired using photomultiplier tubes or employing line scans. CalTrack uses masks to segment cells allowing multiple cardiomyocyte transients to be measured from a single field of view. After automatically correcting for photobleaching, CalTrack averages and fits a string of transients and provides parameters that measure time to peak, time of decay, tau, peak fluorescence/baseline fluorescence (F
max
/F
0
), and others. We demonstrate the utility of CalTrack in primary and induced pluripotent stem cell–derived cell lines in response to pharmacological compounds and in phenotyping cells carrying hypertrophic cardiomyopathy variants.

Conclusions:
CalTrack, an open-source tool that runs on a local computer, provides automated high-throughput analysis of calcium transients in response to development, genetic or pharmacological manipulations, and pathological conditions. We expect that CalTrack analyses will accelerate insights into physiological and abnormal calcium homeostasis that influence diverse aspects of cardiomyocyte biology.
Anterior Cerebral Artery Stroke: Role of Collateral Systems on Infarct Topography
Authors: Thirugnanachandran Tharani , Beare Richard , Mitchell Melissa , Wong Chloe , Vuong Jason , Singhal Shaloo , Slater Lee-Anne , Hilton James , Sinnott Mathew , Srikanth Velandai , Ma Henry , Phan Thanh 
Published: May 2021

Background and Purpose:
The circle of Willis (CoW) and leptomeningeal anastomoses play an important role in transforming infarct topography following middle cerebral artery occlusion. Their role in infarct topography following anterior cerebral artery occlusion is not well understood. The aim of this study was to evaluate the role of the CoW and leptomeningeal anastomoses in modifying regional variation in infarct topography following occlusion of the anterior cerebral artery and its branches.

Methods:
Perfusion and magnetic resonance imaging of patients with anterior cerebral artery stroke and evidence of vessel occlusion were segmented and manually registered to standard brain template for voxel-wise comparison. Next, a computer model of the cerebral arteries was formulated as network of nodes connected by cylindrical pipes. The experiments included occlusion of successive branches of the anterior cerebral artery while the configurations of the CoW were varied.

Results:
Forty-seven patients with a median age of 77.5 years (interquartile range, 68.0–84.5 years) were studied. The regions with the highest probabilities of infarction were the superior frontal gyrus (probability =0.26) and anterior cingulate gyrus (probability =0.24). The regions around the posterior cingulate gyrus (probability =0.08), paracentral lobule (probability =0.05), precuneus and superior parietal lobule (probability =0.03) had a low probability of infarction. Following occlusions distal to the anterior communicating artery, the computer model demonstrated an increase in flow (>30%) in neighboring cortical arteries with leptomeningeal anastomoses.

Conclusions:
Traditionally the CoW has been regarded as the primary collateral system. However, our computer model shows that the CoW is only helpful in redirecting flow following proximal vessel occlusions (pre-anterior communicating artery). More important are leptomeningeal anastomoses, which play an essential role in distal vessel occlusions, influencing motor outcome by modifying the posterolateral extent of infarct topography.
Regional radiomics similarity networks (R2SNs) in the human brain: Reproducibility, small-world properties and a biological basis
Authors: Zhao Kun , Zheng Qiang , Che Tongtong , Martin Dyrba , Li Qiongling , Ding Yanhui , Zheng Yuanjie , Liu Yong , Li Shuyu 
Published: May 2021

Abstract
A structural covariance network (SCN) has been used successfully in structural magnetic resonance imaging (sMRI) studies. However, most SCNs have been constructed by a unitary marker that is insensitive for discriminating different disease phases. The aim of this study was to devise a novel regional radiomics similarity network (R2SN) that could provide more comprehensive information in morphological network analysis. R2SNs were constructed by computing the Pearson correlations between the radiomics features extracted from any pair of regions for each subject. We further assessed the small-world properties of R2SNs, and we evaluated the reproducibility in different datasets and through test-retest analysis. The relationships between the R2SNs and general intelligence/interregional coexpression of enriched genes were also explored. R2SNs could be replicated in different datasets, regardless of the use of different feature subsets. R2SNs showed high reproducibility in the test-retest analysis (intraclass correlation coefficient &gt; 0.7). In addition, the small-word property (σ &gt; 2) and the high correlation between gene expression (R = 0.29, p &lt; 0.001) and general intelligence were determined for R2SNs. Furthermore, the results have also been repeated in the Brainnetome atlas. R2SNs provide a novel, reliable, and biologically plausible method to understand human morphological covariance based on sMRI.
Technology, Media Literacy, and the Human Subject
Authors: Lewis Richard S. 
Published: May 2021

What does it mean to be media literate in today’s world? How are we transformed by the many media infrastructures around us? We are immersed in a world mediated by information and communication technologies (ICTs). From hardware like smartphones, smartwatches, and home assistants to software like Facebook, Instagram, Twitter, and Snapchat, our lives have become a complex, interconnected network of relations. Scholarship on media literacy has tended to focus on developing the skills to access, analyze, evaluate, and create media messages without considering or weighing the impact of the technological medium—how it enables and constrains both messages and media users. Additionally, there is often little attention paid to the broader context of interrelations which affect our engagement with media technologies.
This book addresses these issues by providing a transdisciplinary method that allows for both practical and theoretical analyses of media investigations. Informed by postphenomenology, media ecology, philosophical posthumanism, and complexity theory the author proposes both a framework and a pragmatic instrument for understanding the multiplicity of relations that all contribute to how we affect—and are affected by—our relations with media technology. The author argues persuasively that the increased awareness provided by this posthuman approach affords us a greater chance for reclaiming some of our agency and provides a sound foundation upon which we can then judge our media relations. This book will be an indispensable tool for educators in media literacy and media studies, as well as academics in philosophy of technology, media and communication studies, and the post-humanities.
National identification, a social cure for COVID-19? Evidence from 67 countries
Authors: Bonetto Eric , Delouvée Sylvain , Mahfud Yara , Adam-Troian Jais 
Published: May 2021

Background: Social distancing and mass quarantines were implemented worldwide in response to the current COVID-19 pandemic. Prior research has shown that such measures bear negative consequences for population mental health and well-being. Conversely, a growing body of evidence suggests that feeling positively identified with a group is associated with physical and mental health benefits. Aims: This study tested whether national identification could promote wellbeing and physical health during the COVID-19 pandemic. Method: We used survey data conducted among 67 countries ( N = 46,450). Results: Mixed-model analyses revealed that national identity was associated with wellbeing – despite adjustment on social belonging, COVID-19 perceived risk, exposure and ideology. This effect did not extend to physical health. Conclusions: These results suggest that the mere feeling of belonging to a national group may have mental health benefits. We discuss the implications of our findings within the social cure framework and their relevance for population mental health under COVID-19.
‘Saying goodbye’ during the COVID-19 pandemic: A document analysis of online newspapers with implications for end of life care
Authors: Selman Lucy E , Sowden Ryann , Borgstrom Erica 
Published: May 2021

Background: News media create a sense-making narrative, shaping, reflecting and enforcing cultural ideas and experiences. Reportage of COVID-related death and bereavement illuminates public perceptions of, and responses to, the COVID-19 pandemic. Aim: We aimed to explore British newspaper representations of ‘saying goodbye’ before and after a COVID-related death and consider clinical implications. Design: Document analysis of UK online newspaper articles published during 2 week-long periods in March–April 2020. Data sources: The seven most-read online newspapers were searched: The Guardian, The Daily Mail, The Telegraph, The Mirror, The Sun, The Times and The Metro. Fifty-five articles discussed bereavement after a human death from COVID-19, published during 18/03–24/03/2020 (the UK’s transition into lockdown) or 08/04–14/04/2020 (the UK peak of the pandemic’s first wave). Results: The act of ‘saying goodbye’ (before, during and after death) was central to media representations of COVID bereavement, represented as inherently important and profoundly disrupted. Bedside access was portrayed as restricted, variable and uncertain, with families begging or bargaining for contact. Video-link goodbyes were described with ambivalence. Patients were portrayed as ‘dying alone’ regardless of clinician presence. Funerals were portrayed as travesties and grieving alone as unnatural. Articles focused on what was forbidden and offered little practical guidance. Conclusion: Newspapers portrayed COVID-19 as disruptive to rituals of ‘saying goodbye’ before, during and after death. Adaptations were presented as insufficient attempts to ameliorate tragic situations. More nuanced and supportive reporting is recommended. Clinicians and other professionals supporting the bereaved can play an important role in offering alternative narratives.
Shear wave elastography evaluation in predicting the success of ultrasound-guided saline enema hydrostatic reduction technique in ileocolic intussusception
Authors: Akdulum İsmail , Gürün Enes , Akyüz Melih , Tiken Ramazan , Oral Hayrunnisa , Kaya Cem , Boyunaga Öznur Leman 
Published: May 2021

Background Intussusception is the invagination of the proximal intestinal segment into the distal portion. Reduction procedures with fluid or air have been used as the primary treatment of choice in clinically stable children. Purpose To evaluate the role of intestinal wall elasticity measurements by shear wave elastography (SWE) to predict the success of ultrasound-guided saline enema (USGSE) reduction. Methods USGSE was performed, if not contraindicated otherwise, after the diagnosis of ileocecal intussusception via the ultrasound (US). The length and diameter of the intussusception and the median stiffness of the intestine were measured before USGSE. Results Seventeen children were diagnosed with ileocolic intussusception via grayscale US assessment. Two children whose SWE images became artifacts due to inadaptability were excluded from the study. Thus, the study involved 15 patients (9 boys, 6 girls; age range = 11–48 months). There was no statistically significant association between age and median stiffness measurement in kilopascal (kPa). ( P > 0.05). A moderate positive correlation was observed between the median stiffness measurement (kPa) and the length of intussusception (r = 0.547; P = 0.035). There was no statistically significant relationship between median stiffness measurement (kPa) and short-axis diameter of intussusception ( P > 0.05). Conclusions Stiffness assessment of the intestinal wall in ileocolic intussusception during the US examination, which is the gold standard in the intussusception assessment, can be used as a new criterion for predicting the performance of the USGSE technique and might be useful in making decisions regarding the clinical management of ileocolic intussusception.