tbuckley/cabot-search huggingface dataset:
Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease
Authors: Tiantian Guo, Denghong Zhang, Yuzhe Zeng, Timothy Y. Huang, Huaxi Xu, Yingjun Zhao
Journal: Molecular Neurodegeneration (2020)

Abstract Alzheimer’s disease (AD) is the most common neurodegenerative disorder seen in age-dependent dementia. There is currently no effective treatment for AD, which may be attributed in part to lack of a clear underlying mechanism. Studies within the last few decades provide growing evidence for a central role of amyloid β (Aβ) and tau, as well as glial contributions to various molecular and cellular pathways in AD pathogenesis. Herein, we review recent progress with respect to Aβ- and tau-associated mechanisms, and discuss glial dysfunction in AD with emphasis on neuronal and glial receptors that mediate Aβ-induced toxicity. We also discuss other critical factors that may affect AD pathogenesis, including genetics, aging, variables related to environment, lifestyle habits, and describe the potential role of apolipoprotein E (APOE), viral and bacterial infection, sleep, and microbiota. Although we have gained much towards understanding various aspects underlying this devastating neurodegenerative disorder, greater commitment towards research in molecular mechanism, diagnostics and treatment will be needed in future AD research.
Abstract 10608: Cellular Basis of Urotensin II Produced Enhanced Inhibition on Left Ventricular Contractile Functional Performance in Diabetes Mellitus
Authors: Xiaowei Zhang, Tiankai Li, Peng Zhou, Michael F Callahan, Che Ping Cheng, Heng-Jie Cheng
Journal: Circulation (2018)

Background: Diabetes mellitus (DM) increases the risk for the development of diabetic cardiomyopathy (DCM) and leads to heart failure. DM is associated with increased levels of circulating urotensi...
Reply to Fekkar <i>et al.</i>: Fungal Infection during COVID-19: Does <i>Aspergillus</i> Mean Secondary Invasive Aspergillosis?
Authors: Robbert G. Bentvelsen, Andreas L. E. van Arkel, Tom A. Rijpstra, Huub N. A. Belderbos, Peter van Wijngaarden, Paul E. Verweij
Journal: American Journal of Respiratory and Critical Care Medicine (2020)
US Spending Associated With Transition From Daily to 3-Times-Weekly Glatiramer Acetate
Authors: Benjamin N. Rome, Frazer A. Tessema, Aaron S. Kesselheim
Journal: JAMA Internal Medicine (2020)

Market exclusivity for daily injections of glatiramer acetate, a disease-modifying therapy for multiple sclerosis, expired in 2015. In 2014, the manufacturer launched an alternate 3-times-weekly version that was widely adopted, sustaining market dominance of brand-name glatiramer until late 2017.To estimate excess US spending associated with the transition from daily to 3-times-weekly glatiramer.This economic evaluation estimated total US glatiramer spending from January 1, 2011, to June 30, 2019, using a national cohort from 3 data sources that collectively represent approximately 40% of the US glatiramer market: Medicare Part D, Medicaid, and a claims database of commercially insured and Medicare Advantage patients.Calendar quarter.Outcomes were quarterly US glatiramer spending, estimated as price × use. Manufacturer list prices for generic products and estimates of net (postrebate) prices for brand-name products were used. Linear regression and interrupted time series models were used to compare spending trends in 3 periods: before generic competition (2011-2015), during generic competition for daily glatiramer (2015-2017), and during generic competition for daily and 3-times-weekly glatiramer (2017-2019).From 2011 to 2015, US glatiramer spending increased to $962 million per quarter and did not decrease with generic competition of only daily glatiramer (2015-2017). After generic competition began for 3-times-weekly glatiramer in 2017, prices decreased by 47% to 64%, and spending decreased to $508 million per quarter in 2019 (P < .001 for slope). The delay in decreased spending from 2015 to 2017 was associated with excess spending of $4.3 billion to $6.5 billion.These findings suggest that 2.5 years of delayed generic competition related to introduction of a new version of branded glatiramer acetate was associated with $4.3 billion to $6.5 billion in excess spending. Extended market exclusivity from introducing a new version of an existing brand-name drug can yield manufacturer returns out of proportion to the level of investment or risk involved; more limited incentives could encourage incremental innovations to existing drugs at a lower societal cost.
Spontaneous Intracranial Hypotension With Brain Sagging Attributable to a Cerebrospinal Fluid–Venous Fistula
Authors: Vinil N. Shah, William P. Dillon
Journal: JAMA Neurology (2020)

This case report describes a 44-year-old man who presented with positional headaches and other symptoms and was found to have spontaneous intracranial hypotension because of a cerebrospinal fluid–venous fistula.
Inference of Chromosome-Length Haplotypes Using Genomic Data of Three or a Few More Single Gametes
Authors: Ruidong Li, Han Qu, Jinfeng Chen, Shibo Wang, John M Chater, Le Zhang, Julong Wei, Yuan-Ming Zhang, Chenwu Xu, Wei-De Zhong, Jianguo Zhu, Jianming Lu, Yuanfa Feng, Weiming Chen, Renyuan Ma, Sergio Pietro Ferrante, Mikeal L Roose, Zhenyu Jia
Journal: Molecular Biology and Evolution (2020)

Compared with genomic data of individual markers, haplotype data provide higher resolution for DNA variants, advancing our knowledge in genetics and evolution. Although many computational and experimental phasing methods have been developed for analyzing diploid genomes, it remains challenging to reconstruct chromosome-scale haplotypes at low cost, which constrains the utility of this valuable genetic resource. Gamete cells, the natural packaging of haploid complements, are ideal materials for phasing entire chromosomes because the majority of the haplotypic allele combinations has been preserved. Therefore, compared with the current diploid-based phasing methods, using haploid genomic data of single gametes may substantially reduce the complexity in inferring the donor's chromosomal haplotypes. In this study, we developed the first easy-to-use R package, Hapi, for inferring chromosome-length haplotypes of individual diploid genomes with only a few gametes. Hapi outperformed other phasing methods when analyzing both simulated and real single gamete cell sequencing data sets. The results also suggested that chromosome-scale haplotypes may be inferred by using as few as three gametes, which has pushed the boundary to its possible limit. The single gamete cell sequencing technology allied with the cost-effective Hapi method will make large-scale haplotype-based genetic studies feasible and affordable, promoting the use of haplotype data in a wide range of research.
Abstract NT-093: THE N6-METHYLATION OF ADENOSINE (M6A) IN FZD10 MRNA CONTRIBUTES TO RESISTANCE TO PARP INHIBITOR
Authors: Takeshi Fukumoto, Hengrui Zhu, Sergey Karakashev, Timothy Nacarelli, Nail Fatkhutdinov, Shuai Wu, Andrew V. Kossenkov, Louise Showe, Stephanie Jean, Lin Zhang, Rugang Zhang
Journal: Clinical Cancer Research (2019)

Abstract Chemical modifications of RNAs have emerged as a new layer of epigenetic gene regulation. N6-methyladenosine (m6A) is the most abundant chemical modification of messenger RNA. The m6A modification affects RNA fate and functions such as RNA stability. Despite the high initial clinical response rates to PARP inhibitors in BRCA1/2-mutated epithelial ovarian cancers, PARP inhibitor (PARPi) resistance remains a major challenge. The role of m6A modification in PARPi resistance has not previously been explored. Here we show that m6A modification of FZD10 mRNA contributes to PARPi resistance by upregulating the Wnt/β-catenin pathway in BRCA-mutated EOC cells. Global m6A profile reveals a significant increase in m6A modification in FZD10 mRNA. This correlates with an increase in FZD10 mRNA stability and an upregulation of the Wnt/β-catenin pathway in PARPi resistant cells. FZD10 knockdown or inhibition of the Wnt/β-catenin sensitizes the resistant cells to PAPRi. Mechanistically, downregulation of m6A demethylases FTO and ALKBH5 is sufficient to increase FZD10 mRNA m6A modification and reduce PARPi sensitivity. Moreover, PAPRi and Wnt/β-catenin inhibitor showed synergistic suppression of growth of PAPRi resistant cancer both in vitro and in vivo in a xenograft ovarian cancer mouse model. Our results show that m6A contributes to PAPRi resistance in BRCA-deficient EOC cells by upregulating the Wnt/β-catenin pathway through stabilizing FZD10. They also suggest that inhibition of Wnt/β-catenin pathway represents a potential strategy to overcome PARPi resistance. Citation Format: Takeshi Fukumoto, Hengrui Zhu, Sergey Karakashev, Timothy Nacarelli, Nail Fatkhutdinov, Shuai Wu, Andrew V. Kossenkov, Louise Showe, Stephanie Jean, Lin Zhang, Rugang Zhang. THE N6-METHYLATION OF ADENOSINE (M6A) IN FZD10 MRNA CONTRIBUTES TO RESISTANCE TO PARP INHIBITOR [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-093.
A Woman in Her 40s With Dilated Cardiomyopathy and Abdominal Contractions
Authors: Hai-Long Dai, Xue-Feng Guang, Wei-Hua Zhang
Journal: JAMA Cardiology (2020)

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Lung recruitment before surfactant administration in extremely preterm neonates with respiratory distress syndrome (IN-REC-SUR-E): a randomised, unblinded, controlled trial
Authors: Giovanni Vento, Maria Luisa Ventura, Roberta Pastorino, Anton H van Kaam, Virgilio Carnielli, Filip Cools, Carlo Dani, Fabio Mosca, Graeme Polglase, Paolo Tagliabue, Luca Boni, Francesco Cota, Milena Tana, Chiara Tirone, Claudia Aurilia, Alessandra Lio, Simonetta Costa, Vito D'Andrea, Mariella Lucente, Gabriella Nigro, Lucio Giordano, Vincenzina Roma, Paolo E Villani, Francesca P Fusco, Valeria Fasolato, Maria Rosa Colnaghi, Piero G Matassa, Valentina Vendettuoli, Chiara Poggi, Antonio Del Vecchio, Flavia Petrillo, Pasqua Betta, Carmine Mattia, Giampaolo Garani, Agostina Solinas, Eloisa Gitto, Vincenzo Salvo, Giancarlo Gargano, Eleonora Balestri, Fabrizio Sandri, Giovanna Mescoli, Stefano Martinelli, Laura Ilardi, Elena Ciarmoli, Sandra Di Fabio, Eugenia Maranella, Carolina Grassia, Gaetano Ausanio, Vincenzo Rossi, Angela Motta, Lucia G Tina, Kim Maiolo, Stefano Nobile, Hubert Messner, Alex Staffler, Federica Ferrero, Ilaria Stasi, Luisa Pieragostini, Isabella Mondello, Cristina Haass, Chiara Consigli, Stefania Vedovato, Alessandra Grison, Gianfranco Maffei, Giuseppe Presta, Roberto Perniola, Marcello Vitaliti, Maria P Re, Mario De Curtis, Viviana Cardilli, Paola Lago, Francesca Tormena, Luigi Orfeo, Camilla Gizzi, Luca Massenzi, Diego Gazzolo, Maria Chiara M Strozzi, Roberto Bottino, Federica Pontiggia, Alberto Berardi, Isotta Guidotti, Caterina Cacace, Valerio Meli, Lorenzo Quartulli, Antonio Scorrano, Alessandra Casati, Lidia Grappone, J Jane Pillow
Journal: The Lancet Respiratory Medicine (2020)
Two-Pore Domain Potassium Channels as Drug Targets: Anesthesia and Beyond
Authors: Alistair Mathie, Emma L. Veale, Kevin P. Cunningham, Robyn G. Holden, Paul D. Wright
Journal: The Annual Review of Pharmacology and Toxicology (2020)

Two-pore domain potassium (K2P) channels stabilize the resting membrane potential of both excitable and nonexcitable cells and, as such, are important regulators of cell activity. There are many conditions where pharmacological regulation of K2P channel activity would be of therapeutic benefit, including, but not limited to, atrial fibrillation, respiratory depression, pulmonary hypertension, neuropathic pain, migraine, depression, and some forms of cancer. Up until now, few if any selective pharmacological regulators of K2P channels have been available. However, recent publications of solved structures with small-molecule activators and inhibitors bound to TREK-1, TREK-2, and TASK-1 K2P channels have given insight into the pharmacophore requirements for compound binding to these sites. Together with the increasing availability of a number of novel, active, small-molecule compounds from K2P channel screening programs, these advances have opened up the possibility of rational activator and inhibitor design to selectively target K2P channels.
Harnessing Expressed Single Nucleotide Variation and Single Cell RNA Sequencing To Define Immune Cell Chimerism in the Rejecting Kidney Transplant
Authors: Andrew F. Malone, Haojia Wu, Catrina Fronick, Robert Fulton, Joseph P. Gaut, Benjamin D. Humphreys
Journal: Journal of the American Society of Nephrology (2020)

Significance Statement The combination of exome sequencing with single-cell RNA sequencing can reveal the recipient versus donor origin of each immune cell within human kidney allografts. This approach greatly improves upon previous techniques used to identify and describe leukocyte chimerism within a complex organ, such as Y chromosome identification for sex-mismatched transplants. Exome sequencing and single-cell RNA sequencing of single nucleotide variants indicated that donor-origin macrophages may contribute to the alloimmune response through antigen presentation and signaling, whereas donor-origin T cells remain quiescent. Therefore, teaming these techniques can paint a portrait of the chimerism that may lie behind rejection of a donor kidney. Background In solid organ transplantation, donor-derived immune cells are assumed to decline with time after surgery. Whether donor leukocytes persist within kidney transplants or play any role in rejection is unknown, however, in part because of limited techniques for distinguishing recipient from donor cells. Methods Whole-exome sequencing of donor and recipient DNA and single-cell RNA sequencing (scRNA-seq) of five human kidney transplant biopsy cores distinguished immune cell contributions from both participants. DNA-sequence comparisons used single nucleotide variants (SNVs) identified in the exome sequences across all samples. Results Analysis of expressed SNVs in the scRNA-seq data set distinguished recipient versus donor origin for all 81,139 cells examined. The leukocyte donor/recipient ratio varied with rejection status for macrophages and with time post-transplant for lymphocytes. Recipient macrophages displayed inflammatory activation whereas donor macrophages demonstrated antigen presentation and complement signaling. Recipient-origin T cells expressed cytotoxic and proinflammatory genes consistent with an effector cell phenotype, whereas donor-origin T cells appeared quiescent, expressing oxidative phosphorylation genes. Finally, both donor and recipient T cell clones within the rejecting kidney suggested lymphoid aggregation. The results indicate that donor-origin macrophages and T cells have distinct transcriptional profiles compared with their recipient counterparts, and that donor macrophages can persist for years post-transplantation. Conclusions Analysis of single nucleotide variants and their expression in single cells provides a powerful novel approach to accurately define leukocyte chimerism in a complex organ such as a transplanted kidney, coupled with the ability to examine transcriptional profiles at single-cell resolution. Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/JASN/2020_08_07_JASN2020030326.mp3
Association Between Universal Masking in a Health Care System and SARS-CoV-2 Positivity Among Health Care Workers
Authors: Xiaowen Wang, Enrico G. Ferro, Guohai Zhou, Dean Hashimoto, Deepak L. Bhatt
Journal: JAMA (2020)

This study describes SARS-CoV-2 PCR test positivity among health care workers before, during, and after implementation of a policy requiring universal masking of all health care workers and patients in a large health care system in Massachusetts.
Is Coronary Artery Disease Inevitable in Type 2 Diabetes? From a Glucocentric to a Holistic View on Patient Management
Authors: Giulia Ferrannini, Anna Norhammar, Viveca Gyberg, Linda Mellbin, Lars Rydén
Journal: Diabetes Care (2020)

Type 2 diabetes represents a major threat to global health mainly because of its strong link to atherosclerotic vascular disease. From position 15 among the 20 leading causes of loss of disability-adjusted life-years in 2000, type 2 diabetes climbed to position 8 in 2016. The fact that ischemic heart disease and stroke, conditions for which diabetes is a major risk factor, hold the two leading positions confirms that diabetes is an important threat to health (1). Combining this information with a predicted increase in adults living with diabetes from 9.3% of the global population (463 million) in 2019 to 10.9% (700 million) in 2045, the majority with type 2 diabetes, further underlines that this menace is truly of an immense magnitude. In addition, impaired glucose tolerance (IGT) has been shown to be a risk factor for cardiovascular disease. The proportion of IGT is estimated to increase from 7.5% (374 million) of the adult population in 2019 to 8.6% (548 million) in 2045, with the largest increase in low- to middle-income countries. Of great concern is that about one-half of people with type 2 diabetes are undiagnosed, varying from 38% in high-income countries to 67% in low-income countries, limiting the possibility to prevent the development of diabetes-related complications. Diabetes already puts a strain on health economics; diabetes-related expenditure was estimated to be US$760 billion in 2019 and is expected to increase to US$845 billion in 2045 (2), with costs associated with cardiovascular complications dominating (3).

Cardiovascular complications of diabetes were unknown until the Nobel Prize–awarded discovery of insulin a century ago allowed people with diabetes to survive longer (4). Not until the 1960s–1970s did the first reports on an increased cardiovascular risk associated with diabetes make their appearance from several research groups (5–8). One of the first long-term …
Single-Cell RNA Expression Profiling of ACE2, the Receptor of SARS-CoV-2
Authors: Yu Zhao, Zixian Zhao, Yujia Wang, Yueqing Zhou, Yu Ma, Wei Zuo
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Abstract  A novel coronavirus SARS-CoV-2 was identified in Wuhan, Hubei Province, China in December of 2019. According to WHO report, this new coronavirus has resulted in 76,392 confirmed infections and 2,348 deaths in China by 22 February, 2020, with additional patients being identified in a rapidly growing number internationally. SARS-CoV-2 was reported to share the same receptor, Angiotensin-converting enzyme 2 (ACE2), with SARS-CoV. Here based on the public database and the state-of-the-art single-cell RNA-Seq technique, we analyzed the ACE2 RNA expression profile in the normal human lungs. The result indicates that the ACE2 virus receptor expression is concentrated in a small population of type II alveolar cells (AT2). Surprisingly, we found that this population of ACE2-expressing AT2 also highly expressed many other genes that positively regulating viral entry, reproduction and transmission. This study provides a biological background for the epidemic investigation of the COVID-19, and could be informative for future anti-ACE2 therapeutic strategy development.
Abstract IA16: Accelerating innovation for children with cancer in the new regulatory environment
Authors: Gilles Vassal
Journal: Cancer Research (2020)

Abstract Over the last 20 years, several pieces of regulation have been launched, in the US and in Europe, to mandate and incentivize the development of safe and effective medicines for children. It has been a success in several pediatric specialties such as rheumatology, infection diseases, cardiovascular diseases, allergy, and several rare pediatric diseases. In oncology, the landscape of pediatric drug development has significantly changed, but very few new anticancer medicines have been approved for the treatment of pediatric malignancies over the last 10 years as compared to the high number of anticancer drugs approved for the treatment of cancer in adults: dinutuximab for neuroblastoma, blinatumomab and tisagenlecleucel for acute lymphoblastic leukemia, and larotrectinib for NTRK positive malignancies. So far, the regulations mandated the pediatric development of any drug if the indicated disease in adults occurred in children. If not, a waiver was issued and the company did not have to study the drug in children. In oncology, malignancies in children and in adults are different, but the same drugs are used to treat both, and often the same biologic alterations (targets) are found in both adult and pediatric malignancies. Too many oncology drugs have been waived. In addition, the pediatric trials of oncology products as part of Pediatric Investigation Plans and Pediatric Study Plans started late in the life cycle of product development and often close to or after the marketing authorization. There is a crucial need to improve and accelerate new drug development for children and adolescents with cancer. The goal is to drive pediatric oncology drug developments through science (using biology, preclinical evaluation, and precision medicine), to better meet patients’ unmet medical needs and to facilitate prioritization among all compounds in development. The FDA Race for Children Act is setting a new regulatory environment that will improve the situation by asking pediatric development of oncology products if their target is “directed at a molecular target that the Secretary determines to be substantially relevant to the growth or progression of a pediatric cancer.” In addition, over the last 5 years, the value of having all stakeholders, i.e. academia, parents, industry and regulators, working together has been demonstrated by ACCELERATE, the international multistakeholder platform (www.accelerate-platform.org). Accelerating innovation for pediatric cancers is urgently needed and feasible in the new regulatory environment and requires international cooperation of all stakeholders. Citation Format: Gilles Vassal. Accelerating innovation for children with cancer in the new regulatory environment [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr IA16.
Association of Dysregulated Central Pain Processing and Response to Disease–Modifying Antirheumatic Drug Therapy in Rheumatoid Arthritis
Authors: Andrew C. Heisler, Jing Song, Lutfiyya N. Muhammad, Alyssa Wohlfahrt, Wendy Marder, Marcy B. Bolster, Clifton O. Bingham, Daniel J. Clauw, Dorothy D. Dunlop, Tuhina Neogi, Yvonne C. Lee
Journal: Arthritis & Rheumatology (2020)

To determine the association between dysregulated central pain processing and treatment response in rheumatoid arthritis (RA).