tbuckley/cabot-search huggingface dataset:
LPA<sub>3</sub>-mediated lysophosphatidic acid signaling promotes postnatal heart regeneration in mice
Authors: Fang Wang, Si Liu, Jianqiu Pei, Lin Cai, Ning Liu, Tian Liang, Xiaoxuan Dong, Xiangfeng Cong, Jerold Chun, Jinghai Chen, Shengshou Hu, Xi Chen
Journal: Theranostics (2020)

Background: Lysophosphatidic acid (LPA) is a small glycerophospholipid that acts as a potent extracellular signal in various biological processes and diseases. Our previous work demonstrated that the expression of the LPA receptors LPA1 and LPA3 is elevated in the early postnatal heart. However, the role of this stage-specific expression of LPA1 and LPA3 in the heart is unknown. Methods and Results: By using LPA3 and LPA1 knockout mice, and neonatal SD rats treated with Ki16425 (LPA1/LPA3 inhibitor), we found that the number of proliferating cardiomyocytes, detected by coimmunostaining pH3, Ki67 or BrdU with cardiac troponin T, was significantly decreased in the LPA3 knockout mice and the Ki16425-treated rats but not in the LPA1 knockout mice during the first week of postnatal life. Using a myocardial infarction (MI) model, we found that cardiac function and the number of proliferating cardiomyocytes were decreased in the neonatal LPA3 KO mice and increased in the AAV9-mediated cardiac-specific LPA3 overexpression mice. By using lineage tracing and AAV9-LPA3, we further found that LPA3 overexpression in adult mice enhances cardiac function and heart regeneration as assessed by pH3-, Ki67-, and Aurora B-positive cardiomyocytes and clonal cardiomyocytes after MI. Genome-wide transcriptional profiling and additional mechanistic studies showed that LPA induces cardiomyocyte proliferation through the PI3K/AKT, BMP-Smad1/5, Hippo/YAP and MAPK/ERK pathways in vitro, whereas only ERK was confirmed to be activated by LPA-LPA3 signaling in vivo. Conclusion: Our study reports that LPA3-mediated LPA signaling is a crucial factor for cardiomyocyte proliferation in the early postnatal heart. Cardiac-specific LPA3 overexpression improved cardiac function and promoted cardiac regeneration after myocardial injury induced by MI. This finding suggested that activation of LPA3 potentially through AAV-mediated gene therapy might be a therapeutic strategy to improve the outcome after MI.
Abstract 15751: Detecting the Onset of Contraction Using High Frame Rate Strain Rate Images
Authors: Martin V Andersen, Cooper Moore, Johannes Struiijk, Kristine Arges, Melissa LeFevre, Peter Søgaard, Joseph Kisslo, Samuel Schmidt, Olaf T von Ramm
Journal: Circulation (2018)

Introduction: Deriving timing data from high frame rate ultrasound images can be difficult, as the image quality decreases as frame rate increases. However, higher temporal resolution increases the...
Noninvasive assessment and therapeutic monitoring of drug-resistant colorectal cancer by MR molecular imaging of extradomain-B fibronectin
Authors: Amita Vaidya, Nadia Ayat, Megan Buford, Helen Wang, Aman Shankardass, Yiqing Zhao, Hannah Gilmore, Zhenghe Wang, Zheng-Rong Lu
Journal: Theranostics (2020)

Antineoplastic resistance represents a multifaceted challenge for cancer therapy and diagnostics. Extensive molecular heterogeneity, even within neoplasms of the same type, can elicit distinct outcomes of administering therapeutic pressures, frequently leading to the development of drug-resistant populations. Improved success of oncotherapies merits the exploration of precise molecular imaging technologies that can detect not only anatomical but also molecular changes in tumors and their microenvironment, early on in the treatment regimen. To this end, we developed magnetic resonance molecular imaging (MRMI) strategies to target the extracellular matrix oncoprotein, extradomain-B fibronectin (EDB-FN), for non-invasive assessment and therapeutic monitoring of drug-resistant colorectal cancer (CRC).
Circulating long-non coding RNA LIPCAR and left ventricular diastolic function in patients with uncomplicated type 2 diabetes mellitus
Authors: D.D. Calvo, F. Schottmer, C. Bang, R. Toro, R.W. van der Meer, L.J. Rijzewijk, J.W.A. Smit, H.J. Lamb, V. Llorente-Cortes, T. Thum
Journal: Cardiovascular Research (2016)
Covid-19: US should end Gilead’s monopoly on producing remdesivir, report says
Authors: Janice Hopkins Tanne
Journal: BMJ (2020)

The US government should end the shortage of the antiviral drug remdesivir by eliminating Gilead’s monopoly, says a report from Public Citizen, a national non-profit organisation that represents consumers’ interests.1

Remdesivir, an unapproved investigational drug that is used in patients with severe covid-19, is in short supply and rationed. Doctors and politicians at a press conference on 8 September called on the Trump administration to use existing laws to increase supplies of the drug by ending Gilead’s monopoly. This would allow other companies to make generic versions of the drug and permit imports of generic versions from foreign manufacturers. Gilead would earn licensing fees from generic manufacturers. Gilead has licensed some generic manufacturers to sell remdesivir in low and middle income countries, but the agreements are narrow and limited, says …
PTWAS: investigating tissue-relevant causal molecular mechanisms of complex traits using probabilistic TWAS analysis
Authors: Yuhua Zhang, Corbin Quick, Ketian Yu, Alvaro Barbeira, Francesca Luca, Roger Pique-Regi, Hae Kyung Im, Xiaoquan Wen
Journal: Genome biology (2020)

Abstract We propose a new computational framework, probabilistic transcriptome-wide association study (PTWAS), to investigate causal relationships between gene expressions and complex traits. PTWAS applies the established principles from instrumental variables analysis and takes advantage of probabilistic eQTL annotations to delineate and tackle the unique challenges arising in TWAS. PTWAS not only confers higher power than the existing methods but also provides novel functionalities to evaluate the causal assumptions and estimate tissue- or cell-type-specific gene-to-trait effects. We illustrate the power of PTWAS by analyzing the eQTL data across 49 tissues from GTEx (v8) and GWAS summary statistics from 114 complex traits.
Loss of FBXW7-mediated degradation of BRAF elicits resistance to BET inhibitors in adult T cell leukemia cells
Authors: Chien-Hung Yeh, Marcia Bellon, Fang Wang, Hong Zhang, Liwu Fu, Christophe Nicot
Journal: Molecular Cancer (2020)

Human T cell leukemia virus type 1 (HTLV-1)-associated adult T cell leukemia (ATL) has a very poor prognosis with a median survival of 8 months and a 4-year overall survival of 11% for acute ATL. Present treatment options are limited and there is no curative therapy for ATL. Ubiquitin ligase FBXW7 is commonly mutated or functionally inactivated in human cancers. Consistent with the notion that FBXW7 controls the degradation of many oncoproteins, loss of FBXW7 has been linked to increased drug resistance or sensitivity in cancer cells.In this study, we have characterized FBXW7 mutants previously identified in HTLV-I-infected ATL patient samples. TET-inducible ATL cells carrying wild type or mutated FBXW7 were analyzed for target degradation and for drug sensitivity.Our results demonstrate that mutations in FBXW7 can selectively disrupt ubiquitination and proteasome degradation of target proteins: c-MYC, cyclin E and MCL1. Both c-MYC and MYCN were highly expressed in uncultured ATL patient's samples and ATL-derived cell lines; and ATL cells demonstrated sensitivity to BET inhibitors in vitro and in vivo. High-throughput reverse phase protein array revealed BRAF as a novel target of FBXW7 and further experiments showed that mutations in FBXW7 preventing degradation of BRAF provided resistance to BET inhibitors. In contrast to R465, hot spot FBXW7 mutations at R505C retained degradation of BRAF but not NOTCH1, c-MYC, cyclin E, or MCL1. Finally, a combination therapy using BET inhibitors along with a BRAF or an ERK inhibitor prevented tumor cell resistance and growth.Our results suggest that FBXW7 status may play an important role in drug therapy resistance of cancer cells. Genetic characterization of FBXW7 may be one factor included in future personalized cancer treatment identification.
Next-generation tissue-engineered heart valves with repair, remodelling and regeneration capacity
Authors: Emanuela S. Fioretta, Sarah E. Motta, Valentina Lintas, Sandra Loerakker, Kevin K. Parker, Frank P. T. Baaijens, Volkmar Falk, Simon P. Hoerstrup, Maximilian Y. Emmert
Journal: Nature Reviews Cardiology (2020)
Racial/Ethnic Variation in Nasal Gene Expression of Transmembrane Serine Protease 2 (<i>TMPRSS2</i>)
Authors: Supinda Bunyavanich, Chantal Grant, Alfin Vicencio
Journal: JAMA (2020)

This cross-sectional study used nasal epithelium collected in 2015-2018 to compare expression of TMPRSS2, a facilitator of SARS-CoV-2 viral entry and spread, among Asian, Black, Latino, and White patients as well as patients of mixed race/ethnicity within a New York City health system.
STARR-seq identifies active, chromatin-masked, and dormant enhancers in pluripotent mouse embryonic stem cells
Authors: Tianran Peng, Yanan Zhai, Yaser Atlasi, Menno ter Huurne, Hendrik Marks, Hendrik G. Stunnenberg, Wout Megchelenbrink
Journal: Genome biology (2020)

Enhancers are distal regulators of gene expression that shape cell identity and control cell fate transitions. In mouse embryonic stem cells (mESCs), the pluripotency network is maintained by the function of a complex network of enhancers, that are drastically altered upon differentiation. Genome-wide chromatin accessibility and histone modification assays are commonly used as a proxy for identifying putative enhancers and for describing their activity levels and dynamics.
GetOrganelle: a fast and versatile toolkit for accurate de novo assembly of organelle genomes
Authors: Jian-Jun Jin, Wen-Bin Yu, Jun-Bo Yang, Yu Song, Claude W. dePamphilis, Ting-Shuang Yi, De-Zhu Li
Journal: Genome biology (2020)

Abstract GetOrganelle is a state-of-the-art toolkit to accurately assemble organelle genomes from whole genome sequencing data. It recruits organelle-associated reads using a modified “baiting and iterative mapping” approach, conducts de novo assembly, filters and disentangles the assembly graph, and produces all possible configurations of circular organelle genomes. For 50 published plant datasets, we are able to reassemble the circular plastomes from 47 datasets using GetOrganelle. GetOrganelle assemblies are more accurate than published and/or NOVOPlasty-reassembled plastomes as assessed by mapping. We also assemble complete mitochondrial genomes using GetOrganelle. GetOrganelle is freely released under a GPL-3 license ( https://github.com/Kinggerm/GetOrganelle ).
Immunization with nanogram doses of a replicon DNA vaccine encoding Phl p 5 effectively prevents from allergic reactions
Authors: Maximilian Gabler, Sandra Scheiblhofer, Kerstin Kern, Wolfgang W. Leitner, C Hauser-Kronberger, R. Valenta, Josef Thalhamer, Richard Weiss, Cornelia Hauser-Kronberger
Journal: Journal of Allergy and Clinical Immunology (2006)
Microfluidic production and characterization of biofunctionalized giant unilamellar vesicles for targeted intracellular cargo delivery
Authors: Oskar Staufer, Silvia Antona, Dennis Zhang, Júlia Csatári, Martin Schröter, Jan-Willi Janiesch, Sebastian Fabritz, Imre Berger, Ilia Platzman, Joachim P. Spatz
Journal: Biomaterials (2020)

Lipid-based vesicles have found widespread applications in the life sciences, allowing for fundamental insights into membrane-based processes in cell biology and as carrier systems for drug delivery purposes. So far, mostly small unilamellar vesicles (SUVs) with diameters of ~100 nm have been applied as carrier systems for biomedical applications. Despite this progress, several systematic limitations have arisen due to SUV dimensions, e.g., the size and total amount of applicable cargo is limited. Giant unilamellar vesicles (GUVs) might offer a pragmatic alternative for efficient cargo delivery. However, due to the lack of reliable high-throughput production technologies for GUV-carrier systems, only little is known about their interaction with cells. Here we present a microfluidic-based mechanical droplet-splitting pipeline for the production of carrier-GUVs with diameters of ~2 μm. The technology developed allows for highly efficient cargo loading and unprecedented control over the biological and physicochemical properties of GUV membranes. By generating differently charged (between −31 and + 28 mV), bioligand-conjugated (e.g. with E-cadherin, NrCam and antibodies) and PEG-conjugated GUVs, we performed a detailed investigation of attractive and repulsive GUV-cell interactions. Fine-tuning of these interactions allowed for targeted cellular GUV delivery. Moreover, we evaluated strategies for intracellular GUV cargo release by lysosomal escape mediated by the pH sensitive lipid DOBAQ, enabling cytoplasmic transmission. The presented GUV delivery technology and the systematic characterization of associated GUV-cell interactions could provide a means for more efficient drug administration and will pave the way for hitherto impossible approaches towards a targeted delivery of advanced cargo such as microparticles, viruses or macromolecular DNA-robots.
Germ cell tumors and associated hematologic malignancies evolve from a common shared precursor
Authors: Justin Taylor, Mark T.A. Donoghue, Caleb Ho, Kseniya Petrova-Drus, Hikmat A. Al-Ahmadie, Samuel A. Funt, Yanming Zhang, Umut Aypar, Pavitra Rao, Shweta S. Chavan, Michael Haddadin, Roni Tamari, Sergio Giralt, Martin S. Tallman, Raajit K. Rampal, Priscilla Baez, Rajya Kappagantula, Satyajit Kosuri, Ahmet Dogan, Satish K. Tickoo, Victor E. Reuter, George J. Bosl, Christine A. Iacobuzio-Donahue, David B. Solit, Barry S. Taylor, Darren R. Feldman, Omar Abdel-Wahab
Journal: Journal of Clinical Investigation (2020)

Germ cell tumors (GCTs) are the most common cancer in men between the ages of 15 and 40. Although most patients are cured, those with disease arising in the mediastinum have distinctly poor outcomes. One in every 17 patients with primary mediastinal nonseminomatous GCTs develop an incurable hematologic malignancy and prior data intriguingly suggest a clonal relationship exists between hematologic malignancies and GCTs in these cases. To date, however, the precise clonal relationship between GCTs and the diverse additional somatic malignancies arising in such individuals have not been determined. Here, we traced the clonal evolution and characterized the genetic features of each neoplasm from a cohort of 15 patients with GCTs and associated hematologic malignancies. We discovered that GCTs and hematologic malignancies developing in such individuals evolved from a common shared precursor, nearly all of which harbored allelically imbalanced p53 and/or RAS pathway mutations. Hematologic malignancies arising in this setting genetically resembled mediastinal GCTs rather than de novo myeloid neoplasms. Our findings argue that this scenario represents a unique clinical syndrome, distinct from de novo GCTs or hematologic malignancies, initiated by an ancestral precursor that gives rise to the parallel evolution of GCTs and blood cancers in these patients.
Vitamin A controls the allergic response through T follicular helper cell as well as plasmablast differentiation
Authors: Josephine Scholz, Julia Kuhrau, Frederik Heinrich, Gitta Anne Heinz, Andreas Hutloff, Margitta Worm, Guido Heine
Journal: Allergy (2020)

Abstract Background Vitamin A regulates the adaptive immune response and a modulatory impact on type I allergy is discussed. The cellular mechanisms are largely unknown. Objective To determine the vitamin A‐responding specific lymphocyte reaction in vivo. Methods Antigen‐specific B and T lymphocytes were analyzed in an adoptive transfer airway inflammation mouse model in response to 9‐cis retinoic acid (9cRA) and after lymphocyte‐specific genetic targeting of the receptor RARα. Flow cytometry, quantitative PCR, next‐generation sequencing, and specific Ig‐ELISA were used to characterize the cells functionally. Results Systemic 9cRA profoundly enhanced the specific IgA‐secreting B‐cell frequencies in the lung tissue and serum IgA while reducing serum IgE concentrations. RARα overexpression in antigen‐specific B cells promoted differentiation into plasmablasts at the expense of germinal center B cells. In antigen‐specific T cells, RARα strongly promoted the differentiation of T follicular helper cells followed by an enhanced germinal center response. Conclusions 9cRA signaling via RARα impacts the allergen‐specific immunoglobulin response directly by the differentiation of B cells and indirectly by promoting T follicular helper cells.
Identification of functional cooperative mutations of <i>GNAO1</i> in human acute lymphoblastic leukemia
Authors: Lili Song, Bo Yu, Yi Yang, Jianwei Liang, Yingwen Zhang, Lixia Ding, Tianyi Wang, Xinyu Wan, Xiaomin Yang, Jingyan Tang, Shengyue Wang, Benshang Li, Yanxin Li, Haizhong Feng
Journal: Blood (2020)
Comparative Effectiveness of the Sodium–Glucose Cotransporter 2 Inhibitor Empagliflozin Versus Other Antihyperglycemics on Risk of Major Adverse Kidney Events
Authors: Yan Xie, Benjamin Bowe, Andrew K. Gibson, Janet B. McGill, Yan Yan, Geetha Maddukuri, Ziyad Al-Aly
Journal: Diabetes Care (2020)

To examine the comparative effectiveness of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin and other non-SGLT2i antihyperglycemics on the risk of major adverse kidney events (MAKE) of estimated glomerular filtration rate (eGFR) decline >50%, end-stage kidney disease, or all-cause mortality.
Pigmented Fungiform Papillae of the Tongue
Authors: Casey L Ross, Christina Ring, Sherry Yang
Journal: JAMA Dermatology (2020)

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Covid-19: Shooting for the moon
Authors: Kamran Abbasi
Journal: BMJ (2020)

What happens if a moonshot fails?John F Kennedy's moonshot didn't fail.It eventually got a man to the moon eight years later, and even if it hadn't succeeded the world might not have been much different.Our exclusive news story revealed that the rocket scientists in the UK's Cabinet Office are planning their own moonshot: to introduce mass testing for covid-19 on a scale that beats every other country. 1 The financial commitment for mass population testing will be huge, considering an outlay of £500m (€550m; $650m) to merely support initial experiments. 2What if you spend billions on a moonshot to defeat covid-19 and you miss?
Cardiopulmonary Resuscitation–associated Lung Edema (CRALE). A Translational Study
Authors: Aurora Magliocca, Emanuele Rezoagli, Davide Zani, Martina Manfredi, Daria De Giorgio, Davide Olivari, Francesca Fumagalli, Thomas Langer, Leonello Avalli, Giacomo Grasselli, Roberto Latini, Antonio Pesenti, Giacomo Bellani, Giuseppe Ristagno
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Cardiopulmonary resuscitation is the cornerstone of cardiac arrest (CA) treatment. However, lung injuries associated with it have been reported.Objectives: To assess 1) the presence and characteristics of lung abnormalities induced by cardiopulmonary resuscitation and 2) the role of mechanical and manual chest compression (CC) in its development.Methods: This translational study included 1) a porcine model of CA and cardiopulmonary resuscitation (n = 12) and 2) a multicenter cohort of patients with out-of-hospital CA undergoing mechanical or manual CC (n = 52). Lung computed tomography performed after resuscitation was assessed qualitatively and quantitatively along with respiratory mechanics and gas exchanges.Measurements and Main Results: The lung weight in the mechanical CC group was higher compared with the manual CC group in the experimental (431 ± 127 vs. 273 ± 66, P = 0.022) and clinical study (1,208 ± 630 vs. 837 ± 306, P = 0.006). The mechanical CC group showed significantly lower oxygenation (P = 0.043) and respiratory system compliance (P < 0.001) compared with the manual CC group in the experimental study. The variation of right atrial pressure was significantly higher in the mechanical compared with the manual CC group (54 ± 11 vs. 31 ± 6 mm Hg, P = 0.001) and significantly correlated with lung weight (r = 0.686, P = 0.026) and respiratory system compliance (r = -0.634, P = 0.027). Incidence of abnormal lung density was higher in patients treated with mechanical compared with manual CC (37% vs. 8%, P = 0.018).Conclusions: This study demonstrated the presence of cardiopulmonary resuscitation-associated lung edema in animals and in patients with out-of-hospital CA, which is more pronounced after mechanical as opposed to manual CC and correlates with higher swings of right atrial pressure during CC.
Epithelial-to-Mesenchymal Transition is a Cause of Both Intrinsic and Acquired Resistance to KRAS G12C Inhibitor in KRAS G12C–Mutant Non–Small Cell Lung Cancer
Authors: Yuta Adachi, Kentaro Ito, Yuko Hayashi, Ryo Kimura, Tuan Zea Tan, Rui Yamaguchi, Hiromichi Ebi
Journal: Clinical Cancer Research (2020)

Abstract Purpose: KRAS is among the most commonly mutated oncogene in cancer including non–small cell lung cancer (NSCLC). In early clinical trials, inhibitors targeting G12C-mutant KRAS have achieved responses in some patients with NSCLC. Possible intrinsic and acquired resistance mechanisms to KRAS G12C inhibitors are not fully elucidated and will likely become important to identify. Experimental Design: To identify potential resistance mechanisms, we defined the sensitivity of a panel of KRAS G12C–mutant lung cancer cell lines to a KRAS G12C inhibitor, AMG510. Gene set enrichment analyses were performed to identify pathways related to the sensitivity, which was further confirmed biochemically. In addition, we created two cell lines that acquired resistance to AMG510 and the underlying resistance mechanisms were analyzed. Results: KRAS expression and activation were associated with sensitivity to KRAS G12C inhibitor. Induction of epithelial-to-mesenchymal transition (EMT) led to both intrinsic and acquired resistance to KRAS G12C inhibition. In these EMT-induced cells, PI3K remained activated in the presence of KRAS G12C inhibitor and was dominantly regulated by the IGFR–IRS1 pathway. We found SHP2 plays a minimal role in the activation of the PI3K pathway in contrast to its critical role in the activation of the MAPK pathway. The combination of KRAS G12C inhibitor, PI3K inhibitor, and SHP2 inhibitor resulted in tumor regressions in mouse models of acquired resistance to AMG510. Conclusions: Our findings suggest that EMT is a cause of both intrinsic and acquired resistance by activating the PI3K pathway in the presence of KRAS G12C inhibitor.