tbuckley/cabot-search huggingface dataset:
Lung CD4+ T-cells in patients with lung fibrosis produce pro-fibrotic interleukin-13 together with interferon-γ
Authors: Liv I.B. Sikkeland, Shuo-Wang Qiao, Thor Ueland, Ole Myrdal, Łukasz Wyrożemski, Pål Aukrust, Frode L. Jahnsen, Tone Sjåheim, Johny Kongerud, Øyvind Molberg, May Brit Lund, Espen S. Bækkevold
Journal: European Respiratory Journal (2020)

Progressive fibrosing interstitial lung diseases (PF-ILD) have poor prognosis and survival, and their pathogenesis is not well understood [1]. Mechanistically, lung fibrosis is thought to result from distorted wound-healing following tissue insults and inflammation, leading to scar formation by excess deposition of extracellular matrix proteins and destruction of lung architecture [2]. The fibrotic process is complex, and CD4+ T cells are likely involved by their production of a wide range of cytokines and growth factors that promote fibroblast proliferation and differentiation, collagen production, and stimulate production of pro-fibrotic mediators by tissue macrophages [3]. However, CD4+ T cells in PF-ILD are poorly characterised. To this end, we performed a detailed analysis of phenotype, cytokine production and clonality of T cells from the lungs [bronchoalveolar lavage (BAL)] of PF-ILD patients. We found that BAL from PF-ILD lungs contained high numbers of clonally expanded CD4+ T cells that produced an unusual combination of interferon (IFN) γ and pro-fibrotic interleukin (IL)-13. Such cells were not found in patient blood or in control BAL samples. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Sikkeland reports grants from Norwegian Respiratory Society sponsored by Boehringer Ingelheim, during the conduct of the study;. Conflict of interest: Dr. Qiao has nothing to disclose. Conflict of interest: Dr. Ueland has nothing to disclose. Conflict of interest: Dr. Myrdal has nothing to disclose. Conflict of interest: Dr. Wyrozemski has nothing to disclose. Conflict of interest: Dr. Aukrust has nothing to disclose. Conflict of interest: Dr. Jahnsen has nothing to disclose. Conflict of interest: Dr. Sjåheim reports personal fees from Boehringer Ingelheim and Roche, outside the submitted work;. Conflict of interest: Dr. Kongerud has nothing to disclose. Conflict of interest: Dr. Molberg has nothing to disclose. Conflict of interest: Dr. Lund has nothing to disclose. Conflict of interest: Dr. Bækkevold has nothing to disclose.
Abstract 405: A Personalized, 3D Printed <i>in vitro</i> Model of Vascular Anastomosis in Single Ventricle Heart Defects
Authors: Martin L Tomov, Bowen Jing, Akaash Kumar, Katherine Do, Alexander Cetnar, Sai Raviteja Bhamidipati, Lilanni Perez, Nicki Panoskaltsis, Tim C SLESNICK, Reza Avaz, Athanasios MANTALARIS, Brooks Lindsey, Holly Bauser-Heaton, Vahid Serpooshan
Journal: Circulation Research (2020)

Single ventricle physiology is a complex disease state requiring multiple open-heart surgeries to achieve stable hemodynamics. For patients with abnormalities in the pulmonary arteries (PAs), these must be remedied before the patient can be a candidate for such palliations. Transcatheter techniques could rescue this subset of single ventricle patients through intervascular PA connections, allowing a high-risk population to ultimately achieve stable pulmonary blood flow. However, there is currently no in vitro platform to model transcatheter processes for anastomosis, particularly to palliate single ventricle defects. This project utilizes 3D bioprinting and perfusion bioreactor technologies to develop a functional in vitro biological device to model severely stenotic PAs of single ventricle patients. Human endothelial (ECs) &amp; smooth muscle (SMCs) cells embedded in extracellular matrix bioink are used in a multi-material bioprinting approach to create 3D bilayer vascular structures with controlled geometry and flow. In collaboration with CHOA Cardiac Catheterization Laboratory , stent devices are deployed in the printed model to re-establish intervascular connection. Healthy, stenotic, and stented tissues are cultured via a bioreactor and analyzed for flow hemodynamics by echo PIV and 4D MR imaging. Cell viability, proliferation, and endothelialization of printed vessels, plus EC-SMC interplay were closely monitored pre- and post- anastomosis, to identify the effect of geometry and flow on cellular overgrowth. This advanced planning enables a subset of single ventricle patients, otherwise not eligible, to ultimately accept further palliative strategies.
Pan-cancer single-cell RNA-seq identifies recurring programs of cellular heterogeneity
Authors: Gabriela S. Kinker, Alissa C. Greenwald, Rotem Tal, Zhanna Orlova, Michael S. Cuoco, James M. McFarland, Allison Warren, Christopher Rodman, Jennifer A. Roth, Samantha A. Bender, Bhavna Kumar, James W. Rocco, Pedro A. C. M. Fernandes, Christopher C. Mader, Hadas Keren-Shaul, Alexander Plotnikov, Haim Barr, Aviad Tsherniak, Orit Rozenblatt-Rosen, Valery Krizhanovsky, Sidharth V. Puram, Aviv Regev, Itay Tirosh
Journal: Nature Genetics (2020)
Dynamic single-cell RNA sequencing identifies immunotherapy persister cells following PD-1 blockade
Authors: Kartik Sehgal, Andrew Portell, Elena V. Ivanova, Patrick H. Lizotte, Navin R. Mahadevan, Jonathan R. Greene, Amir Vajdi, Carino Gurjao, Tyler Teceno, Luke J. Taus, Tran C. Thai, Shunsuke Kitajima, Derek Liu, Tetsuo Tani, Moataz Noureddine, Christie J. Lau, Paul T. Kirschmeier, David Liu, Marios Giannakis, Russell W. Jenkins, Prafulla C. Gokhale, Silvia Goldoni, Maria Pinzon-Ortiz, William D. Hastings, Peter S. Hammerman, Juan J. Miret, Cloud P. Paweletz, David A. Barbie
Journal: Journal of Clinical Investigation (2020)

Resistance to oncogene-targeted therapies involves discrete drug-tolerant persister cells, originally discovered through in vitro assays. Whether a similar phenomenon limits efficacy of programmed cell death 1 (PD-1) blockade is poorly understood. Here, we performed dynamic single-cell RNA-Seq of murine organotypic tumor spheroids undergoing PD-1 blockade, identifying a discrete subpopulation of immunotherapy persister cells (IPCs) that resisted CD8+ T cell-mediated killing. These cells expressed Snai1 and stem cell antigen 1 (Sca-1) and exhibited hybrid epithelial-mesenchymal features characteristic of a stem cell-like state. IPCs were expanded by IL-6 but were vulnerable to TNF-α-induced cytotoxicity, relying on baculoviral IAP repeat-containing protein 2 (Birc2) and Birc3 as survival factors. Combining PD-1 blockade with Birc2/3 antagonism in mice reduced IPCs and enhanced tumor cell killing in vivo, resulting in durable responsiveness that matched TNF cytotoxicity thresholds in vitro. Together, these data demonstrate the power of high-resolution functional ex vivo profiling to uncover fundamental mechanisms of immune escape from durable anti-PD-1 responses, while identifying IPCs as a cancer cell subpopulation targetable by specific therapeutic combinations.
Feasibility, and Efficacy of Donor-Derived cd19-Targeted Car t-Cell Therapy in Refractory/Relapsed(r/r)b-Cell Acute Lymphoblastic Leukemia (b-all) Patients
Authors: Xian Zhang, Junfang Yang, Wenqian Li, Gailing Zhang, Yunchao Su, Yanze Shi, Dan Song, Min Zhang, Jiujiang He, Li Xu, Liyuan Qiu, Xin-An Lu, Fei Wu, Jianqiang Li, Dandan Chen, Xiangqun Li, Ziyu Li, Jingjing Li, Peihua Lu
Journal: Blood (2020)
A Randomized Open-Label, Phase 3 Study to Evaluate Imetelstat Versus Best Available Therapy (BAT) in Patients with Intermediate-2 or High-Risk Myelofibrosis (MF) Refractory to Janus Kinase (JAK) Inhibitor
Authors: John Mascarenhas, Claire Harrison, Jean-Jacques Kiladjian, Ruben Mesa, Rami S. Komrokji, Steffen Koschmieder, Alessandro M. Vannucchi, Tymara Berry, Laurie Sherman, Souria Dougherty, Libo Sun, Fei Huang, Ying Wan, Faye Feller, Aleksandra Rizo, Srdan Verstovsek
Journal: Blood (2020)
Abstract 336: Interleukin 4 and 13 Signaling in Myeloid Cells Regulates Cardiac Regeneration
Authors: Santiago Alvarez, Samantha Paddock, Caitlin Omeara
Journal: Circulation Research (2020)

Introduction: Heart failure is a very important disease in the United States and worldwide, with a projected prevalence of 8 million by 2030. Current therapy partially decreases progression; however, mortality continues to be high, and progression to terminal HF is still significant, requiring heart transplant and other interventions that further increase morbidity and overall disease burden and costs. Therefore, the need to develop new therapies that target HF progression. Our prior work and published studies demonstrate that IL13 promotes cardiac regeneration, however, the mechanism mediating this response is currently unknown. IL13 and IL4 share a common receptor, and both cytokines are known to polarize macrophages into a pro-reparative phenotype. Here, we hypothesize that IL4/13 signaling in myeloid cells promotes heart regeneration after cardiac injury. Methods and Results: We compared cardiac regeneration in IL4Ra null/FLOXed (IL4Rα-/fl) and IL4Rα-/fl lysosome M Cre littermate mice, knocking out IL4Rα in myeloid cells. We performed apical resection on postnatal day 1 (P1) mice and assessed cardiac regeneration by histological analysis. We found that mice lacking IL4Ra in myeloid cells (IL4rafl/-, LysMCre) had significantly impaired cardiac regenerative capacity compared to Cre negative littermate controls. We also performed gene expression analysis by qPCR in whole hearts collected at 2dpi to quantify macrophages markers. Cre positive mice trended higher for expression of arginase 1 and mannose receptor 1 (p=0.055 and 0.057, respectively; student t-test) compared to Cre negative littermates. Conclusions and Discussion: Lack of IL4/13 signaling in myeloid cells impairs cardiac regeneration after injury in neonatal mice and modulated expression of immune markers. To confirm these results, flow cytometry to quantify immune cell infiltration can be performed. Other components that limit damage extension can also be assessed, like angiogenesis and cardiomyocyte proliferation. Our data suggest that IL4/IL13 signaling polarizes myeloid cells to a pro-reparative state in the neonatal heart. Additional studies are required to delineate the specific cell population mediating this response.
Role of Aneuploidy in Transcriptional Regulation and Clinical Prognosis in Relapsed and/or Refractory Multiple Myeloma (RRMM)
Authors: Christopher T Su, Liying Chen, Jason Chen, Brian Parkin, Avery Polk, Malathi Kandarpa, Craig E. Cole, Erica Campagnaro, Josh Vo, Dan Robinson, Yi-Mi Wu, Moshe Talpaz, Jennifer Yesil, Daniel Auclair, P. Leif Bergsagel, Arul Chinnaiyan, Veerabhadran Baladandayuthapani, J Christine Ye
Journal: Blood (2020)
PWD/Ph-Encoded Genetic Variants Modulate the Cellular Wnt/β-Catenin Response to Suppress <i>Apc</i>Min-Triggered Intestinal Tumor Formation
Authors: Alexandra L. Farrall, Matthias Lienhard, Christina Grimm, Heiner Kuhl, Susanna H.M. Sluka, Marta Caparros, Jiri Forejt, Bernd Timmermann, Ralf Herwig, Bernhard G. Herrmann, Markus Morkel
Journal: Cancer Research (2020)

Abstract Genetic predisposition affects the penetrance of tumor-initiating mutations, such as APC mutations that stabilize β-catenin and cause intestinal tumors in mice and humans. However, the mechanisms involved in genetically predisposed penetrance are not well understood. Here, we analyzed tumor multiplicity and gene expression in tumor-prone ApcMin/+ mice on highly variant C57BL/6J (B6) and PWD/Ph (PWD) genetic backgrounds. (B6 × PWD) F1 APCMin offspring mice were largely free of intestinal adenoma, and several chromosome substitution (consomic) strains carrying single PWD chromosomes on the B6 genetic background displayed reduced adenoma numbers. Multiple dosage-dependent modifier loci on PWD chromosome 5 each contributed to tumor suppression. Activation of β-catenin–driven and stem cell–specific gene expression in the presence of ApcMin or following APC loss remained moderate in intestines carrying PWD chromosome 5, suggesting that PWD variants restrict adenoma initiation by controlling stem cell homeostasis. Gene expression of modifier candidates and DNA methylation on chromosome 5 were predominantly cis controlled and largely reflected parental patterns, providing a genetic basis for inheritance of tumor susceptibility. Human SNP variants of several modifier candidates were depleted in colorectal cancer genomes, suggesting that similar mechanisms may also affect the penetrance of cancer driver mutations in humans. Overall, our analysis highlights the strong impact that multiple genetic variants acting in networks can exert on tumor development. Significance: These findings in mice show that, in addition to accidental mutations, cancer risk is determined by networks of individual gene variants.
Light-induced release of the cardioprotective peptide angiotensin-(1–9) from thermosensitive liposomes with gold nanoclusters
Authors: Julian Bejarano, Aldo Rojas, Andrea Ramírez-Sagredo, Ana L. Riveros, Francisco Morales-Zavala, Yvo Flores, Jaime A. Riquelme, Fanny Guzman, Eyleen Araya, Mario Chiong, María Paz Ocaranza, Javier O. Morales, María Gabriela Villamizar Sarmiento, Gina Sanchez, Sergio Lavandero, Marcelo J. Kogan
Journal: Journal of Controlled Release (2020)
Opportunities of Genome Imaging for Genetic Diagnosis in Acute Lymphoblastic Leukemia
Authors: Jolien De Bie, Barbara Dewaele, Olga Gielen, Katrina Rack, Johan A. Maertens, Heidi Segers, Joris Vermeesch, Kim De Keersmaecker, Jan Cools, Lucienne Michaux
Journal: Blood (2020)
Hitting Gliomas When They Are Down: Exploiting IDH-Mutant Metabolic Vulnerabilities
Authors: Christopher J. Pirozzi, Hai Yan
Journal: Cancer Discovery (2020)

Abstract Summary: Tumors mutated in IDH1 tend to have lower levels of the essential substrate NAD+. In this issue of Cancer Discovery, Nagashima and colleagues exploit this metabolic sensitivity by devising a combinatorial therapy that both further reduces the pools as well as sequesters the remaining substrate in PAR chains, sensitizing the cells to temozolomide and PARG inhibition. See related article by Nagashima et al., p. 1672.
Abstract 523: Analysis of Mesenchymal Stem Cell Proteomes In Situ in the Ischemic Heart
Authors: Junjie Yang, Dunzheng Han, Gangjian Qin
Journal: Circulation Research (2020)

Cell therapy for myocardial infarction is promising but largely unsuccessful partially due to a lack of mechanistic understanding. Techniques enabling identification of stem cell-specific proteomes in situ in the injured heart may shed light on how the administered cells respond to the injured microenvironment and exert reparative effects. To identify the proteomes of the transplanted mesenchymal stem cells (MSCs) in the infarcted myocardium, we sought to engineer a mutant methionyl-tRNA synthetase (MetRS L274G ) in MSC, which charges the methionine analogue azidonorleucine (ANL) to tRNA and subsequently to nascent proteins, permitting isolation of ANL-labeled MSC proteomes from ischemic hearts by ANL-alkyne based click reaction. Murine MSCs were transduced with lentivirus MetRS L274G and supplemented with ANL; the ANL-tagged nascent proteins were visualized by bio-orthogonal non-canonical amino-acid tagging, spanning all molecular weights and by fluorescent non-canonical amino-acid tagging, displaying strong fluorescent signal. Then, the MetRS L274G -transduced MSCs were administered to the infarcted or Sham heart in mice receiving ANL treatment. The MSC proteomes were isolated from the left ventricle by click reaction at days 1, 3, and 7 after cell administration, identified by LC/MS. Among all identified proteins (in Sham and MI hearts, three time-points each), 648 were shared by all 6 groups, accounting for 82±5% of total proteins in each group, and their GO terms are enriched under mitochondrion, extracellular exosomes, oxidation-reduction process and poly(A) RNA binding. Notably, 35, 131 and 84 proteins were significantly up-regulated and 12, 38 and 27 proteins were down-regulated in the infarcted vs. Sham heart at the three time-points, respectively; these proteins are pronounced in the GO terms of extracellular microvesicles, inflammatory response and apoptosis and in the KEGG pathways of complements and coagulation cascades, lysosomes, and regulators of actin cytoskeleton. MetRS L274G expression allows successful identification of MSC-specific nascent proteins in the infarcted hearts, which reflect the functional states, adaptive response, and reparative effects of MSCs that may be leveraged to improve cardiac repair.
Abstract 410: Transthyretin Amyloid Fibrils Deposited in the Microenvironment Alter Cardiac Myocyte and Fibroblast Function and Cytoskeletal Structure
Authors: Kyle Dittloff, Antonio Iezzi, Kathrin Banach, Brenda Russell
Journal: Circulation Research (2020)

Age-related wild type transthyretin amyloidosis (ATTRwt) is a systemic condition that is characterized by deposition of amyloidogenic fibrils of misfolded transthyretin (TTR) in various organ systems. This disease manifests as an infiltrative cardiomyopathy hallmarked by extracellular deposition of misfolded TTR fibrils in the cardiac tissue, leading to cardiac dysfunction and heart failure with preserved ejection fraction (HFpEF); this disease is underdiagnosed and may affect 25% of elderly men and women. We hypothesize that deposition of amyloidogenic TTR fibrils alters cardiomyocyte contractility and sarcomere structure via modulation of cell growth due to altered microenvironmental features such as substrate stiffness. Recombinant TTR fibrils were deposited on glass substrates or substrates mimicking the stiffness of the healthy myocardium (10kPa). Neonatal rat ventricular myocytes exhibited decreased rate of linear contractility via line scan kymography and altered cytoskeletal structure when exposed to deposited TTR fibrils, with greater maladaptive effects seen on 10kPa substrates. Isolated adult mouse atrial cardiomyocytes plated on TTR fibril-containing substrates had attenuated calcium transient amplitude and a prolonged decay constant, consistent with lower amplitude. We also hypothesize that deposited TTR fibrils induce cardiac fibroblast activation and promote progression of fibrosis. Isolated cardiac fibroblasts grown on TTR-coated glass showed a reorganization of the F-actin cytoskeleton, with preferential distribution to the cell periphery. Barrier removal tests after confluence resulted in significantly faster migration velocity of fibroblasts cultured on TTR fibrils. Increased reduction of MTS tetrazolium by a colorimetric assay suggests a significant TTR-related increase in the proliferation rate of cells. Together, results suggest that amyloidogenic TTR fibrils may affect cardiac myocyte and fibroblast structure and function through both chemical and mechanical pathways. As recently approved therapies for ATTRwt are cost-prohibitive and are intended to slow disease progression only, better understanding of disease mechanisms may elucidate novel therapeutic targets.
FRI0106 The assessment of glomerular filtraton rate during the treatment of patients with lupus nephritis
Authors: H Seleskovic, S Mulic, N Kapidzic Basic, M Hukic, A Cickusic, M Smajic
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> The deterioration of renal function is one of the most important prognostic predictors in lupus nephritis (LN). <h3>Objectives</h3> To determine glomerular filtration rate (GFR) in patients (pts) with LN and to clarify the characteristics of renal haemodynamics during the treatment of LN. <h3>Methods</h3> Thirty three clinically active pts with LN underwent glomerular filtration rate (GFR) clearance study by using radionucleotide compound Tc-99 m diethylamine-pentoacetic acid (DTPA). All pts had definite clinical evidence of active LN, including urinary and immunological abnormalities. Twenty of pts underwent renal biopsies (66%). GFR was studied in 30 female and 3 male pts (average 39 years and duration of disease average 5 years) in two occasions over an interval of 3 to 6 months during treatment with cotricosteroids (Cs) and cytotoxic drugs (Ct). <h3>Results</h3> GFR-DTPA clearance was in range from 11 to 157 ml/min, mean 87.42 ml/min (normal &gt;100 ml/min), in repeated measurements it was in range from 13 to 147 ml/min, mean GFR (94.33) was slightly but not significantly better. We divided pts into four groups. First group of 12 pts had values in normal range, second group of 11 pts showed an improvement in GFR from mean 64.33 to 95.50 ml/min. Mean GFR second values from third group of 6 pts (18%) were as low as in first measurements (mean 51.83), and a fall in GFR (mean 106 to 70.25 ml/min) was notified only in 4 pts (12%) as a result of deterioration of glomerular function. <h3>Conclusion</h3> During the undergoing treatment over an interval of 3 to 6 month we kept GFR in pts with LN in normal range at 12 pts (37%). Average GFR increased significantly (p &lt; 0.05) at 11 pts (33%). The treatment LN with Cs and Ct is useful for saving renal function, and could be able to prevent the progression LN to renal failure.
New Zealanders vote to legalise assisted dying for terminally ill adults
Authors: Clare Dyer
Journal: BMJ (2020)

New Zealanders have voted overwhelmingly for a law legalising assisted dying, which has already been passed by the country’s legislature.

The End of Life Choice Act was supported by 65.2% of the public, the preliminary results of a nationwide referendum showed. The act was approved by parliament in 2019, but its implementation was delayed until the public had a say through the binding referendum.

Due to come into effect in November 2021, the law will enable terminally ill, mentally competent adults in the final months of life to request assistance from a medical …
Impact of Differences in Time from Diagnosis to Treatment on DLBCL Response and Survival Outcomes: A VA Study
Authors: Ryan A. Williams, Madison H. Williams, Jean Pierre Blaize, Snegha Ananth, David Gregorio, Gerardo Manuel Rosas, Michael M. Song, Brian Warnecke, Abhishek Pandya, Lakene Raissa Djoufack Djoumessi, Vivian Dee, Phillip Nazarewicz, Juan J. Toro, Kathleen Franklin, Michael Mader, Zohra Nooruddin
Journal: Blood (2020)
Response and Survival Outcomes with Hypomethylating Agents in Patients with Chronic Myelomonocytic Leukemia Based on Disease Phenotype and Risk Categories
Authors: Jorge M. Ramos Perez, Veronica A Guerra, Danielle Hammond, Kelly S. Chien, Rashmi Kanagal-Shamanna, Kiran Naqvi, Koji Sasaki, Shilpa Paul, Tapan M. Kadia, Courtney D. DiNardo, Marina Konopleva, Naval Daver, Farhad Ravandi, Naveen Pemmaraju, Nicholas J. Short, Koichi Takahashi, Zeev E. Estrov, Sherry A. Pierce, Hagop M. Kantarjian, Guillermo Garcia-Manero, Guillermo Montalban-Bravo
Journal: Blood (2020)