tbuckley/cabot-search huggingface dataset:
Mesenchymal Lineage Heterogeneity Underlies Nonredundant Functions of Pancreatic Cancer–Associated Fibroblasts
Authors: Erin J. Helms, Mark W. Berry, R. Crystal Chaw, Christopher C. DuFort, Duanchen Sun, M. Kathrina Onate, Chet Oon, Sohinee Bhattacharyya, Hannah Sanford-Crane, Wesley Horton, Jennifer M. Finan, Ariana Sattler, Rosemary Makar, David W. Dawson, Zheng Xia, Sunil R. Hingorani, Mara H. Sherman
Journal: Cancer Discovery (2021)

Cancer-associated fibroblast (CAF) heterogeneity is increasingly appreciated, but the origins and functions of distinct CAF subtypes remain poorly understood. The abundant and transcriptionally diverse CAF population in pancreatic ductal adenocarcinoma (PDAC) is thought to arise from a common cell of origin, pancreatic stellate cells (PSC), with diversification resulting from cytokine and growth factor gradients within the tumor microenvironment. Here we analyzed the differentiation and function of PSCs during tumor progression in vivo. Contrary to expectations, we found that PSCs give rise to a numerically minor subset of PDAC CAFs. Targeted ablation of PSC-derived CAFs within their host tissue revealed nonredundant functions for this defined CAF population in shaping the PDAC microenvironment, including production of specific extracellular matrix components and tissue stiffness regulation. Together, these findings link stromal evolution from distinct cells of origin to transcriptional heterogeneity among PDAC CAFs and demonstrate unique functions for CAFs of a defined cellular origin. SIGNIFICANCE: By tracking and ablating a specific CAF population, we find that a numerically minor CAF subtype from a defined cell of origin plays unique roles in establishing the pancreatic tumor microenvironment. Together with prior studies, this work suggests that mesenchymal lineage heterogeneity and signaling gradients diversify PDAC CAFs.See related commentary by Cukierman, p. 296.This article is highlighted in the In This Issue feature, p. 275.
Correlation Between Markers of Bone Turnover and Vitamin D Levels in Patients with Monoclonal Gammopathy of Undetermined Significance (MGUS)
Authors: Brea C. Lipe, Tara L. Lin, Omar S. Aljitawi, Abdulraheem Yacoub, Ruben Reyes, Suman Kambhampati, Peter van Veldhuizen, Joseph R. Mikhael
Journal: Blood (2014)
Abstract P030: Traditional Cardiovascular Risk Factors Are Associated With Being Hypertensive At Rheumatoid Arthritis Diagnosis: Results From The Canadian Early Arthritis Cohort
Authors: Brook Hadwen, Saverio Stranges, Neil Klar, Vivian Bykerk, Susan Bartlett, Louis Bessette, Gilles Boire, Glen Hazlewood, Carol Hitchon, Edward Keystone, Bindee Kuriya, Janet Pope, Carter Thorne, Diane Tin, Marie-France Valois, Orit Schieir, Lillian Barra
Journal: Circulation (2022)

Introduction: Rheumatoid arthritis (RA) is an autoimmune disease causing chronic inflammation of the joints. RA patients have increased risk of hypertension (HTN). The aim of this study was to determine prevalence of HTN at RA diagnosis as well as demographic, behavioral, and clinical characteristics associated with HTN. Hypothesis: We assessed the hypothesis that a large proportion of RA patients are hypertensive at RA diagnosis and that worse disease activity is associated with HTN. Methods: Data from the Canadian Early Arthritis Cohort was used. This is an inception cohort of RA patients across Canada. Data on HTN was collected according to patient/physician-report or use of anti-hypertensive drugs. Prevalence of HTN was calculated. A multivariate logistic regression model was built using likelihood ratio test for the total sample and while stratifying by sex, including variables on age, race, BMI, education, smoking, alcohol, disease activity and comorbidities. Results: The sample included 2052 RA patients. Mean(±SD) for age was 55(14) years and RA symptom duration 5.6(2.9) months, 71% (1438 of 2028) were female and 85% (1709 of 2010) were Caucasian. HTN was reported in 26% (537 of 2052) of subjects, 23% (327 of 1438) of females and 35% (205 of 590) of men. All results of logistic regression are in table 1. In multivariable analysis for the total sample, older age, overweight and obese BMI, diabetes and hyperlipidemia were associated with HTN. For females, excess alcohol consumption was also associated with HTN. In males, only older age, diabetes and hyperlipidemia were associated with HTN. Conclusions: One in four RA patients were hypertensive at RA diagnosis. Traditional risk factors that have been found in the general population were also associated with HTN in RA patients at diagnosis. Whether other characteristics are associated with HTN later in the RA disease course will be explored in further analysis.
Maturation of hiPSC-derived cardiomyocytes promotes adult alternative splicing of SCN5A and reveals changes in sodium current associated with cardiac arrhythmia
Authors: Giulia Campostrini, Georgios Kosmidis, Dorien Ward-van Oostwaard, Richard Paul Davis, Loukia Yiangou, Daniele Ottaviani, Christiaan Cornelis Veerman, Hailiang Mei, Valeria Viktorovna Orlova, Arthur Arnold Maria Wilde, Connie Rose Bezzina, Arie Otto Verkerk, Christine Lindsay Mummery, Milena Bellin
Journal: Cardiovascular Research (2022)

Abstract Aims Human-induced pluripotent stem cell-cardiomyocytes (hiPSC-CMs) are widely used to study arrhythmia-associated mutations in ion channels. Among these, the cardiac sodium channel SCN5A undergoes foetal-to-adult isoform switching around birth. Conventional hiPSC-CM cultures, which are phenotypically foetal, have thus far been unable to capture mutations in adult gene isoforms. Here, we investigated whether tri-cellular cross-talk in a three-dimensional (3D) cardiac microtissue (MT) promoted post-natal SCN5A maturation in hiPSC-CMs. Methods and results We derived patient hiPSC-CMs carrying compound mutations in the adult SCN5A exon 6B and exon 4. Electrophysiological properties of patient hiPSC-CMs in monolayer were not altered by the exon 6B mutation compared with isogenic controls since it is not expressed; further, CRISPR/Cas9-mediated excision of the foetal exon 6A did not promote adult SCN5A expression. However, when hiPSC-CMs were matured in 3D cardiac MTs, SCN5A underwent isoform switch and the functional consequences of the mutation located in exon 6B were revealed. Up-regulation of the splicing factor muscleblind-like protein 1 (MBNL1) drove SCN5A post-natal maturation in microtissues since its overexpression in hiPSC-CMs was sufficient to promote exon 6B inclusion, whilst knocking-out MBNL1 failed to foster isoform switch. Conclusions Our study shows that (i) the tri-cellular cardiac microtissues promote post-natal SCN5A isoform switch in hiPSC-CMs, (ii) adult splicing of SCN5A is driven by MBNL1 in these tissues, and (iii) this model can be used for examining post-natal cardiac arrhythmias due to mutations in the exon 6B. Translational perspective The cardiac sodium channel is essential for conducting the electrical impulse in the heart. Postnatal alternative splicing regulation causes mutual exclusive inclusion of fetal or adult exons of the corresponding gene, SCN5A. Typically, immature hiPSCCMs fall short in studying the effect of mutations located in the adult exon. We describe here that an innovative tri-cellular three-dimensional cardiac microtissue culture promotes hiPSC-CMs maturation through upregulation of MBNL1, thus revealing the effect of a pathogenic genetic variant located in the SCN5A adult exon. These results help advancing the use of hiPSC-CMs in studying adult heart disease and for developing personalized medicine applications.
Advancing precision medicine for acute respiratory distress syndrome
Authors: Jeremy R Beitler, B Taylor Thompson, Rebecca M Baron, Julie A Bastarache, Loren C Denlinger, Laura Esserman, Michelle N Gong, Lisa M LaVange, Roger J Lewis, John C Marshall, Thomas R Martin, Daniel F McAuley, Nuala J Meyer, Marc Moss, Lora A Reineck, Eileen Rubin, Eric P Schmidt, Theodore J Standiford, Lorraine B Ware, Hector R Wong, Neil R Aggarwal, Carolyn S Calfee
Journal: The Lancet Respiratory Medicine (2021)
Indication-Specific Generic Uptake of Imatinib Demonstrates the Impact of Skinny Labeling
Authors: Bryan S. Walsh, Aaron S. Kesselheim, Ameet Sarpatwari, Benjamin N. Rome
Journal: Journal of Clinical Oncology (2022)

Generic competition can be delayed if brand-name manufacturers obtain additional patents on supplemental uses. The US Food and Drug Administration allows generic drug manufacturers to market versions with skinny labels that exclude patent-protected indications. This study assessed whether use of generic versions of imatinib varied between indications included and excluded from the skinny labels.In this cross-sectional study, we identified adult patients covered by commercial insurance or Medicare Advantage plans who initiated imatinib from February 2016 (first generic availability) to September 2020. Generic versions were introduced with skinny labels that included indications covering treatment of chronic myelogenous leukemia (CML) but excluded treatment of gastrointestinal stromal tumors (GISTs) because of remaining patent protections. Logistic regression was used to determine whether use of generic versus brand-name imatinib differed between patients with a diagnosis of CML or GIST, adjusting for demographics, insurance type, prior use of brand-name drugs, and calendar month.Among 2,000 initiators, 934 (47%) had CML and 686 (34%) had GIST. Within 3 years after generics entered the market, more than 90% of initiators in both groups used generic imatinib. Initiation of generic imatinib was slightly lower among patients with GIST than among patients with CML (85% v 88%; adjusted odds ratio 0.56; 95% CI, 0.39 to 0.80; P ≤ .001).Generic versions of imatinib were dispensed frequently for indications both included (CML) and excluded (GIST) from the skinny labeling, although patients with GIST were slightly less likely to receive a generic version. The skinny labeling pathway allowed generics to enter the market before patent protection for treating patients with GIST expired, facilitating lower drug prices.
Preventing heart failure: a position paper of the Heart Failure Association in collaboration with the European Association of Preventive Cardiology
Authors: Massimo F. Piepoli, Marianna Adamo, Andrea Barison, Reinaldo B. Bestetti, Jan Biegus, Michael Böhm, Javed Butler, Jonathan Carapetis, Claudio Ceconi, Ovidiu Chioncel, Andrew Coats, Maria G. Crespo‐Leiro, Giovanni de Simone, Heinz Drexel, Michele Emdin, Dimitros Farmakis, Martin Halle, Stephane Heymans, Tiny Jaarsma, Ewa Jankowska, Mitja Lainscak, Carolyn S.P. Lam, Maja‐Lisa Løchen, Yuri Lopatin, Aldo Maggioni, Benedetta Matrone, Marco Metra, Katharine Noonan, Ileana Pina, Eva Prescott, Giuseppe Rosano, Petar M. Seferovic, Karen Sliwa, Simon Stewart, Alicia Uijl, Ilonca Vaartjes, Roel Vermeulen, W. M. Monique Verschuren, Maurizio Volterrani, Stephan von Haehling, Arno Hoes
Journal: European Journal of Heart Failure (2022)
Increased 68Ga-FAPI Uptake in Active Atherosclerotic Plaque
Authors: Zhi Hu, Xiao Yang, Zhouxiang You, Yue Chen, Huipan Liu
Journal: Clinical Nuclear Medicine (2022)

Abstract A 67-year-old man with esophageal cancer was included in a clinical trial of a 68 Ga-FAPI PET/CT study on tumors (ChiCTR2100044131). Increased tracer uptake was noted in the esophageal cancer with esophagitis. In addition, active coronary atherosclerotic plaque also revealed increased FAPI activity.
Histopathological Features of Parathyroid Adenoma and 18F-Choline Uptake in PET/MR of Primary Hyperparathyroidism
Authors: Virginia Liberini, Gregoire B. Morand, Niels J. Rupp, Erika Orita, Désirée Deandreis, Martina Broglie Däppen, Marlena Hofbauer, Alexander Maurer, Lars Husmann, Cäcilia E. Mader, Hannes Grünig, Abdullah A. Alharbi, Michael Messerli, Martin W. Huellner
Journal: Clinical Nuclear Medicine (2022)

The aim of this study was to assess the relationship between the histopathological properties of hyperfunctioning parathyroids and parathyroid 18F-choline uptake.A total of 31 parathyroid adenomas were retrospectively analyzed in patients with primary hyperparathyroidism and preoperative 18F-choline PET/MR. PET/MR parameters of parathyroid glands (SUVmax and target-to-background ratio in early-phase [EP] and late-phase [LP]), MRI volume, preoperative parathyroid hormone (PTH) serum concentration, and postoperative histopathology (predominant cell type and growth pattern of adenoma cells, location and size of adenoma) were assessed. The relationship of PET/MR parameters, PTH, and histological parameters was determined using linear regression, Spearman correlation and Kruskal-Wallis test.The median volume of parathyroid adenoma was 421.78 ± 142.46 mm3 (46.39-4412.69). Adenomas were predominantly composed of chief, water-clear, and oncocytic/oxyphilic cells in 27/31, 2/31, and 2/31 cases, respectively. The growth pattern was predominantly solid, follicular, and trabecular in 18/31, 8/31, and 5/31, respectively. The SUVmax was 6.71 ± 3.39 in EP and 6.91 ± 3.97 in LP. Follicular growth pattern had slightly higher EP SUVmax (trabecular: 4.12 ± 0.56; solid: 6.62 ± 3.19; follicular: 8.56 ± 3.96; P = 0.046). Spearman correlation showed strong positive correlation between volume and both EP and LP SUVmax (0.626; P = 0.0001 and 0.576; P = 0.0001, respectively). Linear regression analysis revealed significant correlation between PTH level and EP and LP SUVmax (both P = 0.001); in contrast, no correlation was found between PTH level and both cell type and growth pattern.Our findings suggest that 18F-choline uptake of parathyroid adenomas might be associated both with the histological growth pattern and adenoma volume, but not with a specific cell type.
Large Pleural Effusion
Authors: Wajahat Khatri, Michael Polydefkis, Joban Vaishnav, Elie Saad, Lilja B. Solnes, Steven P. Rowe
Journal: Clinical Nuclear Medicine (2022)

Transthyretin cardiac amyloidosis (ATTR and ATTRv) is an underrecognized cause of heart failure that results from myocardial deposition of misfolded protein (TTR or prealbumin). The diagnosis can be confirmed by uptake of 99m Tc-pyrophosphate ( 99m Tc-PYP) in the heart with serologic studies to rule out light chain disease. We present the case of a 70-year-old woman who underwent a 99m Tc-PYP scan. The patient had a large right-sided pleural effusion that lowered counts in the right chest on planar imaging, interfered with ratio-based grading of PYP uptake, and highlighted the importance of obtaining SPECT/CT for problem-solving in cases where uptake ratios may be spurious.
The disintegrated theory of consciousness: Sleep, waking, and meta-awareness
Authors: Antonio Zadra, Daniel J Levitin
Journal: Behavioral and Brain Sciences (2022)

Abstract The study of sleep and wakefulness can inform debates about the nature of consciousness. We argue that sleep and wakefulness fall along a multidimensional continuum and that inconsistencies and paradoxes with the accounts put forth by Merker et al. and Tononi can be understood in terms of a pervasive false dichotomy between these two states.
Network Analysis Identifies Regulators of Basal-Like Breast Cancer Reprogramming and Endocrine Therapy Vulnerability
Authors: Sea R. Choi, Chae Young Hwang, Jonghoon Lee, Kwang-Hyun Cho
Journal: Cancer Research (2021)

Abstract Basal-like breast cancer is the most aggressive breast cancer subtype with the worst prognosis. Despite its high recurrence rate, chemotherapy is the only treatment for basal-like breast cancer, which lacks expression of hormone receptors. In contrast, luminal A tumors express ERα and can undergo endocrine therapy for treatment. Previous studies have tried to develop effective treatments for basal-like patients using various therapeutics but failed due to the complex and dynamic nature of the disease. In this study, we performed a transcriptomic analysis of patients with breast cancer to construct a simplified but essential molecular regulatory network model. Network control analysis identified potential targets and elucidated the underlying mechanisms of reprogramming basal-like cancer cells into luminal A cells. Inhibition of BCL11A and HDAC1/2 effectively drove basal-like cells to transition to luminal A cells and increased ERα expression, leading to increased tamoxifen sensitivity. High expression of BCL11A and HDAC1/2 correlated with poor prognosis in patients with breast cancer. These findings identify mechanisms regulating breast cancer phenotypes and suggest the potential to reprogram basal-like breast cancer cells to enhance their targetability. Significance: A network model enables investigation of mechanisms regulating the basal-to-luminal transition in breast cancer, identifying BCL11A and HDAC1/2 as optimal targets that can induce basal-like breast cancer reprogramming and endocrine therapy sensitivity.
A tumor-derived type III collagen-rich ECM niche regulates tumor cell dormancy
Authors: Julie S. Di Martino, Ana Rita Nobre, Chandrani Mondal, Isra Taha, Eduardo F. Farias, Elana J. Fertig, Alexandra Naba, Julio A. Aguirre-Ghiso, Jose Javier Bravo-Cordero
Journal: Nature Cancer (2021)
Interpreting Deep Machine Learning Models: An Easy Guide for Oncologists
Authors: Jose P. Amorim, Pedro H. Abreu, Alberto Fernandez, Mauricio Reyes, Joao Santos, Miguel H. Abreu
Journal: IEEE Reviews in Biomedical Engineering (2021)

Healthcare agents, in particular in the oncology field, are currently collecting vast amounts of diverse patient data. In this context, some decision-support systems, mostly based on deep learning techniques, have already been approved for clinical purposes. Despite all the efforts in introducing artificial intelligence methods in the workflow of clinicians, its lack of interpretability - understand how the methods make decisions - still inhibits their dissemination in clinical practice. The aim of this article is to present an easy guide for oncologists explaining how these methods make decisions and illustrating the strategies to explain them. Theoretical concepts were illustrated based on oncological examples and a literature review of research works was performed from PubMed between January 2014 to September 2020, using "deep learning techniques," "interpretability" and "oncology" as keywords. Overall, more than 60% are related to breast, skin or brain cancers and the majority focused on explaining the importance of tumor characteristics (e.g. dimension, shape) in the predictions. The most used computational methods are multilayer perceptrons and convolutional neural networks. Nevertheless, despite being successfully applied in different cancers scenarios, endowing deep learning techniques with interpretability, while maintaining their performance, continues to be one of the greatest challenges of artificial intelligence.
Psychologists should learn structural specification and experimental econometrics
Authors: Don Ross
Journal: Behavioral and Brain Sciences (2022)

Abstract The most plausible of Yarkoni's paths to recovery for psychology is the least radical one: psychologists need truly quantitative methods that exploit the informational power of variance and heterogeneity in multiple variables. If they drop ambitions to explain entire behaviors, they could find a box full of design and econometric tools in the parts of experimental economics that don't ape psychology.
<i>Dnmt3a</i>-Mutant Hematopoietic Stem Cell Rewire IFNγ Signaling to Gain Clonal Advantage
Authors: Marco De Dominici, James DeGregori
Journal: Blood Cancer Discovery (2022)

Summary: Dnmt3a-mutant stem cells gain a competitive advantage via upregulation of a Txnip–p53–p21 axis and protection from IFNγ induced exhaustion. See related article by Zhang et al., p. 220 (5).
Electronic Alerts to Improve Heart Failure Therapy in Outpatient Practice
Authors: Lama Ghazi, Yu Yamamoto, Ralph J. Riello, Claudia Coronel-Moreno, Melissa Martin, Kyle D. O’Connor, Michael Simonov, Joanna Huang, Temitope Olufade, James McDermott, Ravi Dhar, Silvio E. Inzucchi, Eric J. Velazquez, F. Perry Wilson, Nihar R. Desai, Tariq Ahmad
Journal: Journal of the American College of Cardiology (2022)

The use of guideline-directed medical therapy (GDMT) is underprescribed in patients with heart failure with reduced ejection fraction (HFrEF). This study sought to examine whether targeted and tailored electronic health record (EHR) alerts recommending GDMT in eligible patients with HFrEF improves GDMT use. PROMPT-HF (PRagmatic trial Of Messaging to Providers about Treatment of Heart Failure) was a pragmatic, EHR-based, cluster-randomized comparative effectiveness trial. A total of 100 providers caring for patients with HFrEF were randomized to either an alert or usual care. The alert notified providers of individualized GDMT recommendations along with patient characteristics. The primary outcome was an increase in the number of GDMT classes prescribed at 30 days postrandomization. Providers were surveyed on knowledge of guidelines and user experience. The study enrolled 1,310 ambulatory patients with HFrEF from April to October 2021. Median age was 72 years; 31% were female; 18% were Black; and median left ventricular ejection fraction was 32%. At baseline, 84% of participants were receiving β-blockers, 71% received a renin-angiotensin-aldosterone system inhibitor, 29% received a mineralocorticoid receptor antagonist, and 11% received a sodium-glucose cotransporter-2 inhibitor. The primary outcome occurred in 176 of 685 (26%) participants in the alert arm vs 117 of 625 (19%) in the usual care arm, thus increasing GDMT class prescription by >40% after alert exposure (adjusted relative risk: 1.41; 95% CI: 1.03-1.93; P = 0.03). The number of patients needed to alert to result in an increase in addition of GDMT classes was 14. A total of 79% of alerted providers agreed that the alert was effective at enabling improved prescription of medical therapy for HF. A real-time, targeted, and tailored EHR-based alerting system for outpatients with HFrEF led to significantly higher rates of GDMT at 30 days when compared with usual care. This low-cost intervention can be rapidly integrated into clinical care and accelerate adoption of high-value therapies in heart failure. (PRagmatic trial Of Messaging to Providers about Treatment of Heart Failure [PROMPT-HF; NCT04514458])
197P Lung cancer in lung transplant recipients
Authors: M. Svorcova, L. Valentova-Bartakova, J. Havlin, L.C. Mendez, J. Vachtenheim, K. Vyskocilova, T. Kotowski, J. Pozniak, J. Kolarik, J. Simonek, R. Lischke
Journal: Annals of Oncology (2022)