tbuckley/cabot-search huggingface dataset:
Rapid design and development of CRISPR-Cas13a targeting SARS-CoV-2 spike protein
Authors: Lin Wang, Junhu Zhou, Qixue Wang, Yunfei Wang, Chunsheng Kang
Journal: Theranostics (2020)

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide epidemic of the lethal respiratory coronavirus disease (COVID-19), necessitating urgent development of specific and effective therapeutic tools.Among several therapeutic targets of coronaviruses, the spike protein is of great significance due to its key role in host invasion.Here, we report a potential anti-SARS-CoV-2 strategy based on the CRISPR-Cas13a system.Methods: A comprehensive set of bioinformatics methods, including sequence alignment, structural comparison, and molecular docking, was utilized to identify a SARS-CoV-2-spike(S)-specific segment.A tiling crRNA library targeting this specific RNA segment was designed, and optimal crRNA candidates were selected using in-silico methods.The efficiencies of the crRNA candidates were tested in human HepG2 and AT2 cells.Results: The most effective crRNA sequence inducing a robust cleavage effect on S and a potent collateral cleavage effect were identified.Conclusions: This study provides a rapid design pipeline for a CRISPR-Cas13a-based antiviral tool against SARS-CoV-2.Moreover, it offers a novel approach for anti-virus study even if the precise structures of viral proteins are indeterminate.
Abstract 292: Hypoxia Induced Formation of Immunoproteasome Instigates Rejection of Allogeneic Mesenchymal Stem Cells in the Ischemic Heart
Authors: Ejlal Abu-El-Rub, Weiang Yan, Niketa Sareen, Keshav N Alagarsamy, Alireza Rafieerad, Sanjiv Dhingra
Journal: Circulation Research (2020)

Bone marrow derived allogeneic (donor derived) mesenchymal stem cells (MSCs) are considered to be prominent cell type for cardiac repair following a damage due to ischemic heart disease. Even though the outcome of initial allogeneic MSCs based clinical trials was encouraging, the overall enthusiasm lately has declined due to poor survival of transplanted cells in the ischemic heart. We reported in a rat model of myocardial infarction that allogeneic-MSCs became immunogenic after 5 weeks of transplantation and were rejected by host immune system that led to poor survival of implanted cells. The immunoprivilege of MSCs is preserved by absence of cell surface antigen, human leukocyte antigen (HLA) - DRα. We found that in normoxic MSCs, 26S proteasome degrades HLA-DRα and maintains immunoprivilege of MSCs. The exposure to hypoxia leads to inactivation of 26S proteasome and formation of immunoproteasome in MSCs, which is associated with upregulation and activation of HLA-DRα, and as a result MSCs become immunogenic. Furthermore, inhibition of immunoproteasome formation in hypoxic MSCs preserves the immunoprivilege. Therefore, hypoxia induced shift in the phenotype of proteasome from 26S toward immunoproteasome triggers loss of immunoprivilege of allogeneic MSCs and rejection. In our ongoing studies we are investigating if preventing the formation of immunoproteasome would prevent rejection of allogeneic MSCs in the ischemic heart and improve survival of transplanted cells. The outcome of these studies may provide molecular targets to plan interventions to preserve immunoprivilege of allogeneic MSCs in the ischemic heart and improve benefits of allogeneic MSCs for cardiac repair.
Strategic plan for integrated care of patients with kidney failure
Authors: David C.H. Harris, Simon J. Davies, Fredric O. Finkelstein, Vivekanand Jha, Aminu K. Bello, Mark Brown, Fergus J. Caskey, Jo-Ann Donner, Adrian Liew, Elmi Muller, Saraladevi Naicker, Philip J. O’Connell, Roberto Pecoits Filho, Tushar Vachharajani, Ali K. Abu Alfa, Gloria Ashuntantang, Edwina Brown, Brett Cullis, Gavin Dreyer, Felicia U. Eke, Guillermo Garcia Garcia, Bak Leong Goh, Brenda Hemmelgarn, Fan Fan Hou, Arpana Iyengar, David W. Johnson, Nathan W. Levin, Valerie A. Luyckx, Dominique E. Martin, Mignon I. McCulloch, Yewondwossesn Tadesse Mengistu, Mohammed Rafique Moosa, Rachael L. Morton, Abdou Niang, Gregorio T. Obrador, Ikechi G. Okpechi, Shahrzad Ossareh, Kamal D. Shah, Laura Sola, Charles Swanepoel, Irma Tchokhonelidze, Marcello Tonelli, Michele Trask, Rumeyza Turan Kazancioglu, Ahmed Twahir, Robert Walker, Anthony J.O. Were, Chih-Wei Yang, Karen Yeates, Elena Zakharova, Carlos Zuniga
Journal: Kidney International (2020)
Successful Outcomes of Children Simultaneously Diagnosed with Acute Myeloid Leukemia and Covid-19: The Role of a Mild Chemotherapeutic Induction Regimen
Authors: Mecneide Mendes Lins, Juliana Teixeira Costa, Alayde Vieira Wanderley, Adriana Seber, Cinthya Rocha, Luciana Nunes Silva, Laudreisa da Costa Pantoja, Gustavo Zamperlini, Valentino Conter, Raul Ribeiro
Journal: Blood (2020)
Thomas Kenneth Hardy
Authors: June Cooper, William Roberts
Journal: BMJ (2020)

In 1962 Thomas Kenneth Hardy (“Ken”) was appointed consultant anaesthetist at Caernarfon and Anglesey General Hospital in Bangor, north Wales. With an interest in pain management he soon set up the first chronic pain clinic in Wales. He was elected to the presidency of the British Pain Society, and during his three year leadership he established close links with other groups concerned …
Abstract 12988: Symptoms of Daytime Sleepiness Predict Inflammation and Ambulatory Blood Pressure in Sleep Apnea
Authors: Victoria Pak, Brittany Butts, Vicki Hertzberg, Nancy Collop, Arshed A Quyyumi, Ann Rogers, Sandra B Dunbar
Journal: Circulation (2019)

Introduction: Sleepiness and cardiovascular disease share common mechanistic pathways; thus, the biological factors that place one at risk for sleepiness may also predict cardiovascular disease ris...
Establishing a Comprehensive Database for Patients with Sickle Cell Disease in the State of Nebraska, the First Step of Improving Their Care
Authors: Omar Abughanimeh, Mahammed Khan Suheb, Steven Ebers, Julie Eclov, Robin High, Alex Nester, Aleh Bobr, Scott A Koepsell, James Harper, Krishna Gundabolu, Laxmi Narayana Buddharaju
Journal: Blood (2020)
First Results of an Open Label Phase II Study to Evaluate the Efficacy and Safety of Inotuzumab Ozogamicin for Induction Therapy Followed By a Conventional Chemotherapy Based Consolidation and Maintenance Therapy in Patients Aged 56 Years and Older with Acute Lymphoblastic Leukemia (INITIAL-1 trial)
Authors: Matthias Stelljes, Simon Raffel, Ralph Wäsch, Sebastian Scholl, Mustafa Kondakci, Andreas Rank, Mathias Haenel, Sonja Martin, Katjana Schwab, Julian Knaden, Klaus Wethmar, Tim Sauer, Wolfgang E. Berdel, Georg Lenz, Martin Dugas, Monika Brüggemann, Nicola Goekbuget, Nael Alakel
Journal: Blood (2020)
Abstract 381: Mcur1 is a Potential Target to Modulate Cardiac Contractility and Alleviate Cardiac Function During Heart Failure
Authors: Rajika Roy, Santhanam Shanmughapriya, Xueqian Zhang, Jianliang Song, Dhanendra Tomar, Sarah M. Schumacher, Erhe Gao, Hong Wang, Joseph Y. Cheung, Walter J. Koch, Sudarsan Rajan
Journal: Circulation Research (2020)

Cardiac contractility is regulated by the intracellular Ca 2+ concentration fluxes which are actively regulated by multiple channels and transporters. Ca 2+ uptake into the mitochondrial matrix is precisely controlled by the highly Ca 2+ selective channel, Mitochondrial Calcium Uniporter (MCU). Earlier studies on the cardiac-specific acute MCU knockout and a transgenic dominant-negative MCU mice have demonstrated that mitochondrial Ca 2+ ( m Ca 2+ ) signaling is necessary for cardiac ‘‘fight-or-flight’’ contractile response, however, the role of m Ca 2+ buffering to shape global cytosolic Ca 2+ levels and affect E-C coupling, particularly the Ca 2+ transient, on a beat-to-beat basis still remains to be solved. Our earlier studies have demonstrated that loss of MCU Regulator 1 (MCUR1) in cardiomyocytes results in the impaired m Ca 2+ uptake. We have now employed the cardiac-specific MCUR1 knockout mouse to dissect the precise role of MCU in regulating cytosolic Ca 2+ transients associated with excitation-contraction (E-C) coupling and cardiac function. Results from our studies including the in vivo analyses of cardiac physiology during normal and pressure-overloaded mouse models and in vitro experiments including single-cell cardiac contractility, calcium transients, and electrophysiology measurements demonstrate that MCUR1/MCU regulated m Ca 2+ buffering in cardiomyocytes, although insignificant under basal condition, becomes critical in stress induced conditions and actively participates in regulating the c Ca 2+ transients. Also, the ablation of MCUR1 in cardiomyocytes during stress conditions prevents m Ca 2+ overload and subsequent mROS overproduction. Our data indicate that MCUR1 ablation offers protection against pressure-overload cardiac hypertrophy. In summary, our results provide critical insights into the mechanisms by which the MCU channel contributes in regulating the contractile function of the cardiomyocytes and the role of m Ca 2+ in the development and progression of heart failure.
Early Reconstitution of CD6+ T Cells after Hematopoietic Cell Transplantation Identifies a Suitable Target for Acute Graft Versus Host Disease Treatment Using Anti-CD6 Monoclonal Antibody Itolizumab
Authors: Benedetta Rambaldi, Haesook T. Kim, Carol Reynolds, Sharmila Chamling Rai, Takeru Asano, Yohei Arihara, Mahasweta Gooptu, John Koreth, Corey Cutler, Sarah Nikiforow, Vincent T. Ho, Joseph H. Antin, Rizwan Romee, Robert J. Soiffer, Jeanette Ampudia, Cherie Tracy Ng, Stephen Connelly, Jerome Ritz
Journal: Blood (2020)
Genomic and Transcriptomic Profiling Reveals Distinct Subsets Associated with Outcomes in Mantle Cell Lymphoma
Authors: Yuting Yan, Shuhua Yi, Meiling Jin, Yi Wang, Ying Yu, Wang Jun, Dehui Zou, Tingyu Wang, Zhen Yu, Lanting Liu, Rui Cui, Wei Liu, Ryu Lv, Weiwei Sui, Wenyang Huang, Xiong Wenjie, Huijun Wang, Qi Sun, Mu Hao, Jianxiang Wang, Cheng Tao, Lugui Qiu, Lili Wang
Journal: Blood (2020)
SP0089 Cell-based technologies in joint repair
Authors: F Luyten
Journal: Annals of the Rheumatic Diseases (2001)

<h3></h3> Tissue engineering is a field of Biomedicine that is rapidly growing, and is critically driven by scientific advances in the areas of developmental and cell biology, material sciences and biochemistry/polymer chemistry. Regeneration of skeletal tissues, including joint surface repair, skin repair, and treatment of CNS disorders are among the most promising areas, and are closest to immediate novel clinical applications. Validation and appropriate regulation of these new biological treatments are critical. Autologous chondrocyte transplantation (ACT) is a promising approach for joint surface defect repair. The procedure involves autologous chondrocyte cell expansion, known to result in phenotypic de-differentiation. This may be associated with a reduction of cartilage forming ability <i>in vivo</i>, raising the need for proper quality controls for expanded chondrocyte populations. We have linked an <i>in vivo</i> cartilage-forming assay to molecular markers. This set of molecular markers can represent a quality control for chondrocyte expansion and transplantation, and a tool for developing procedures aimed at preserving/restoring the phenotypic stability of expanded chondrocytes. However, it is has still to be established if the ACT procedure is the first line treatment for articular cartilage defects. Apart from the phenotypic instability, there are other disadvantages associated with this procedure. One of them is the cartilage biopsy needed to obtain chondrocytes. Therefore, we have set out to identify precursor cell populations capable of contributing to joint tissue repair. Our data indicate that besides bone marrow stromal cells, periosteal- and synovium-derived fibroblast-like cells (FLCs) are potential progenitors for joint repair. Both human periosteal- and synovium-derived FLCs can be obtained and expanded reproducibly and consistently, independent of the age of the donor. These cell populations are phenotypically stable over at least 10–15 passages. In addition, they are and maintain a multilineage potential, i.e. they are chondrogenic, osteogenic, myogenic and adipogenic grown under appropriate culture conditions. We have also linked these precursor cell populations to specific markers. These cell-based technologies provide important tools to optimise the repair and engineering of joints and joint associated tissues.
Case 34-2020: A 74-Year-Old Man with Chronic Kidney Disease
Authors: Frank B. Cortazar, Eugene P. Rhee, Sumit Gupta, Rahul Sakhuja, John H. Stone, Robert B. Colvin
Journal: New England Journal of Medicine (2020)

A 74-year-old man presented for evaluation of his chronic kidney disease before a planned transcatheter aortic-valve replacement. Pancreatitis had been diagnosed 25 years earlier, and enlargement of the lacrimal and salivary glands had occurred. Pathological specimens, imaging studies, and cardiology studies were reviewed. A diagnostic test was performed.
Strategies in the delivery of Cas9 ribonucleoprotein for CRISPR/Cas9 genome editing
Authors: Song Zhang, Jiangtao Shen, Dali Li, Yiyun Cheng
Journal: Theranostics (2020)

CRISPR/Cas9 genome editing has gained rapidly increasing attentions in recent years, however, the translation of this biotechnology into therapy has been hindered by efficient delivery of CRISPR/Cas9 materials into target cells. Direct delivery of CRISPR/Cas9 system as a ribonucleoprotein (RNP) complex consisting of Cas9 protein and single guide RNA (sgRNA) has emerged as a powerful and widespread method for genome editing due to its advantages of transient genome editing and reduced off-target effects. In this review, we summarized the current Cas9 RNP delivery systems including physical approaches and synthetic carriers. The mechanisms and beneficial roles of these strategies in intracellular Cas9 RNP delivery were reviewed. Examples in the development of stimuli-responsive and targeted carriers for RNP delivery are highlighted. Finally, the challenges of current Cas9 RNP delivery systems and perspectives in rational design of next generation materials for this promising field will be discussed.
Neither earlier nor late tocilizumab improved outcomes in the intensive care unit patients with COVID-19 in a retrospective cohort study
Authors: Sergey Moiseev, Sergey Avdeev, Ekaterina Tao, Michail Brovko, Nikolay Bulanov, Anastasiia Zykova, Larisa Akulkina, Irina Smirnova, Victor Fomin
Journal: Annals of the Rheumatic Diseases (2020)

Tocilizumab (TCZ), a recombinant monoclonal antibody against the interleukin (IL)-6 receptor, has been proposed as a potential therapy for severe SARS-CoV-2 pneumonia based on observational studies.1 Recently, a strategy involving a course of high-dose glucocorticoids, followed by TCZ if needed (in 43% of patients), was shown to improve mortality in patients with rapid respiratory deterioration plus elevation of at least two out of three biomarkers (C reactive protein (CRP), ferritin and/or D-dimer).2 Nevertheless, a short-term use of TCZ is not free from serious adverse events, and the efficacy data, although promising, are preliminary.3

The timing of anti-inflammatory treatments in relation to the stage of disease seems to be important in patients with COVID-19.4 Therefore, the objective of our retrospective study was to assess the efficacy of earlier and late intravenous TCZ, that is, prior to and after initiation of mechanical ventilation, respectively, in reducing mortality in a cohort of patients with severe COVID-19 pneumonia who required support in intensive care unit (ICU).

In March 2020, the Russian Ministry of Health set up a Federal Center at the Sechenov University (Moscow) to provide virtual support for the ICU physicians caring for patients with COVID-19.5 All local COVID-19 hospitals were proposed to submit medical records of critically ill patients via secure network to the Federal Center giving urgent advice on the critical care management. For this study, we selected consecutive ICU patients whom TCZ administration was recommended given the presence of bilateral …
Fanconi Anemia Gene Associated Germline Predisposition in Aplastic Anemia and Hematologic Malignancies
Authors: Daijing Nie, Fang Wang, Jing Zhang, Xvxin Li, Lili Liu, Wei Zhang, Panxiang Cao, Xue Chen, Yang Zhang, Jiaqi Chen, Xiaosu Zhou, Qisheng Wu, Hongxing Liu
Journal: Blood (2020)
Abstract 285: High Throughput Profiling of Gsk3α Regulated Fibroblast Kinome Reveals Raf as a Mediator of Fibrosis in Failing Heart
Authors: Prachi Umbarkar, Sultan Tousif, Anand P Singh, Joshua C Anderson, Qinkun Zhang, Hind Lal
Journal: Circulation Research (2020)

Background: Heart failure is the leading cause of mortality, morbidity, and healthcare expenditures worldwide. Numerous studies have implicated Glycogen Synthase Kinase-3 (GSK-3) as a promising therapeutic target for cardiovascular diseases. GSK-3 isoforms appear to play overlapping, unique, and even opposing functions in the heart. Recently our group has identified cardiac fibroblast (CF) GSK3β as a negative regulator of fibrotic remodeling in the ischemic heart. However, the role of CF-GSK3α in cardiac pathophysiology is unknown. Methods and Results: GSK3α was deleted specifically from cardiac fibroblasts or myofibroblasts with tamoxifen-inducible TCF21- or periostin- promoter-driven Cre recombinase. At 2 months of age, WT and KO mice were subjected to cardiac injury, and heart functions were monitored by serial echocardiography. Histological analysis and morphometric studies were performed at 8 weeks post-injury. In both settings, GSK3α deletion restricted fibrotic remodeling and improved cardiac function. To investigate underlying mechanisms, we examined the effect of GSK3α deletion on myofibroblast transformation and pro-fibrotic TGFβ1-SMAD3 signaling in vitro . WT and KO mouse embryonic fibroblasts (MEFs) were treated with TGFβ1. Indeed, a significant reduction in cell migration, collagen gel contraction, and α-SMA expression in TGFβ1 treated KO MEFs confirmed that GSK3α is required for myofibroblast transformation. Surprisingly, GSK3α deletion had no effect on SMAD3 activation, indicating the pro-fibrotic role of GSK3α is SMAD3 independent. At 4 weeks post-injury, total proteins were isolated from CFs of WT and KO animals, and kinome profiling was performed by utilizing PamStation®12 high throughput microarray platform. The upstream kinase analysis identified the downregulation of RAF family kinase activity in GSK3α-KO-CFs. Moreover, mapping of significantly altered kinases against literature annotated interactions generated ERK-centric networks. These findings are consistent with previous studies that implicated ERK in fibrotic diseases across multiple organs. Conclusion: CF-GSK3α plays a causal role in the cardiac pathophysiology that could be therapeutically targeted for future clinical applications.
The Predictive Value of Programmed Death Ligand 1 in Patients with Metastatic Renal Cell Carcinoma Treated with Immune-checkpoint Inhibitors: A Systematic Review and Meta-analysis
Authors: Keiichiro Mori, Mohammad Abufaraj, Hadi Mostafaei, Fahad Quhal, Harun Fajkovic, Mesut Remzi, Pierre I. Karakiewicz, Shin Egawa, Manuela Schmidinger, Shahrokh F. Shariat, Kilian M. Gust
Journal: European Urology (2020)

Immune-checkpoint inhibitors (ICIs) are a mainstay treatment of metastatic renal cell carcinoma (mRCC). As not all patients benefit from ICIs, a biomarker-driven clinical decision-making strategy is desirable.To assess the predictive value of programmed death ligand 1 (PD-L1) in mRCC patients treated with ICIs.Multiple databases were searched for articles published up to April 2020 according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. Studies comparing objective response rate (ORR), complete response rate (CRR), progressive disease rate (PDR), or progression-free survival (PFS) based on tumor PD-L1 status in mRCC patients were eligible.Six studies matched our eligibility criteria. Treatment with ICIs was associated with significantly higher ORRs and CRRs, and lower PDRs in patients with PD-L1-positive tumors than in those with PD-L1-negative status (odds ratio [OR] 1.84, 95% confidence interval [CI] 1.48-2.28; OR 3.11, 95% CI 2.04-4.75; and OR 0.43, 95% CI 0.31-0.60, respectively). ICI treatment was associated with significantly better PFS in PD-L1-positive patients than in sunitinib-treated patients (hazard ratio 0.65, 95% CI 0.57-0.74), whereas this was not found in patients with PD-L1-negative tumors. Compared with sunitinib, ICI combination therapy improved ORRs and PFS significantly in PD-L1-positive patients of all examined ICIs. Nivolumab plus ipilimumab had the highest likelihood of providing the highest ORR and longest PFS in PD-L1-positive patients.PD-L1 positivity of the tumor is associated with improved ORRs and prolonged PFS in mRCC patients receiving ICI treatment and thus helps identify mRCC patients most likely to benefit from ICI treatment.The use of an immune-checkpoint inhibitor for the treatment of metastatic renal cell carcinoma (mRCC) improved oncological outcomes, and the status of programmed death ligand 1 could contribute to guiding patients and clinicians when determining personalized treatment strategies for mRCC.
Feasibility and Prognostic Value of Vasodilator Stress Perfusion CMR in Patients With Atrial Fibrillation
Authors: Théo Pezel, Francesca Sanguineti, Marine Kinnel, Valentin Landon, Solenn Toupin, Thierry Unterseeh, Yves Louvard, Stéphane Champagne, Marie Claude Morice, Thomas Hovasse, Philippe Garot, Jérôme Garot
Journal: JACC. Cardiovascular imaging (2020)