tbuckley/cabot-search huggingface dataset:
Reply to Riuko Ohashi, Arndt Hartmann, Holger Moch, and Guido Martignoni’s Letter to the Editor re: Svetlana Avulova, John C. Cheville, Christine M. Lohse, et al. Grading of Chromophobe Renal Cell Carcinoma: Evidence for a Four-tiered Classification Incorporating Coagulative Tumor Necrosis. Eur Urol 2021;79:225–31: Two-, Three-, or Four-tiered Grading of Chromophobe Renal Cancer: That’s the Question!
Authors: Svetlana Avulova, John C. Cheville, Christine M. Lohse, R. Houston Thompson, Aaron M. Potretzke
Journal: European Urology (2021)
Effect of infusion set replacement intervals on catheter-related bloodstream infections (RSVP): a randomised, controlled, equivalence (central venous access device)–non-inferiority (peripheral arterial catheter) trial
Authors: Claire M Rickard, Nicole M Marsh, Emily N Larsen, Matthew R McGrail, Nicholas Graves, Naomi Runnegar, Joan Webster, Amanda Corley, David McMillan, John R Gowardman, Debbie A Long, John F Fraser, Fenella J Gill, Jeanine Young, Marghie Murgo, Evan Alexandrou, Md Abu Choudhury, Raymond J Chan, Nicole C Gavin, Azlina Daud, Annamaria Palermo, Adrian Regli, E Geoffrey Playford
Journal: The Lancet (2021)
CircPTPRA blocks the recognition of RNA N6-methyladenosine through interacting with IGF2BP1 to suppress bladder cancer progression
Authors: Fei Xie, Chao Huang, Feng Liu, Hui Zhang, Xingyuan Xiao, Jiayin Sun, Xiaoping Zhang, Guosong Jiang
Journal: Molecular Cancer (2021)

Circular RNAs (circRNAs) have been found to have significant impacts on bladder cancer (BC) progression through various mechanisms. In this study, we aimed to identify novel circRNAs that regulate the function of IGF2BP1, a key m6A reader, and explore the regulatory mechanisms and clinical significances in BC.Firstly, the clinical role of IGF2BP1 in BC was studied. Then, RNA immunoprecipitation sequencing (RIP-seq) analysis was performed to identify the circRNAs interacted with IGF2BP1 in BC cells. The overall biological roles of IGF2BP1 and the candidate circPTPRA were investigated in both BC cell lines and animal xenograft studies. Subsequently, we evaluated the regulation effects of circPTPRA on IGF2BP1 and screened out its target genes through RNA sequencing. Finally, we explored the underlying molecular mechanisms that circPTPRA might act as a blocker in recognition of m6A.We demonstrated that IGF2BP1 was predominantly binded with circPTPRA in the cytoplasm in BC cells. Ectopic expression of circPTPRA abolished the promotion of cell proliferation, migration and invasion of BC cells induced by IGF2BP1. Importantly, circPTPRA downregulated IGF2BP1-regulation of MYC and FSCN1 expression via interacting with IGF2BP1. Moreover, the recognition of m6A-modified RNAs mediated by IGF2BP1 was partly disturbed by circPTPRA through its interaction with KH domains of IGF2BP1.This study identifies exonic circular circPTPRA as a new tumor suppressor that inhibits cancer progression through endogenous blocking the recognition of IGF2BP1 to m6A-modified RNAs, indicating that circPTPRA may serve as an exploitable therapeutic target for patients with BC.
Gaining Efficiency in Clinical Trials With Cardiac Biomarkers
Authors: James L Januzzi, John M Canty, Saumya Das, Christopher R DeFilippi, Gary A Gintant, David E Gutstein, Allan Jaffe, Emily P Kaushik, Christopher Leptak, Cyrus Mehta, Ileana Pina, Thomas J Povsic, Curtis Rambaran, Rhonda F Rhyne, Maribel Salas, Victor C Shi, Jacob A Udell, Ellis F Unger, Tanja S Zabka, Jonathan H Seltzer
Journal: Journal of the American College of Cardiology (2021)
A novel microRNA-based prognostic model outperforms standard prognostic models in patients with acetaminophen-induced acute liver failure
Authors: Oliver D. Tavabie, Constantine J. Karvellas, Siamak Salehi, Jaime L. Speiser, Christopher F. Rose, Krishna Menon, Andreas Prachalias, Michael A. Heneghan, Kosh Agarwal, William M. Lee, Mark J.W. McPhail, Varuna R. Aluvihare, W.M. Lee, Anne M. Larson, Iris Liou, Oren Fix, Michael Schilsky, Timothy McCashland, J. Eileen Hay, Natalie Murray, A. Obaid S. Shaikh, Andres Blei, Daniel Ganger, Atif Zaman, Steven H.B. Han, Robert Fontana, Brendan McGuire, Raymond T. Chung, Alastair Smith, Robert Brown, Jeffrey Crippin, Edwin Harrison, Adrian Reuben, Santiago Munoz, Rajender Reddy, R. Todd Stravitz, Lorenzo Rossaro, Raj Satyanarayana, Tarek Hassanein, Constantine J. Karvellas, Jodi Olson, Ram Subramanian, James Hanje, Bilal Hameed, Ezmina Lalani, Carla Pezzia, Corron Sanders, Nahid Attar, Linda S. Hynan, Valerie Durkalski, Wenle Zhao, Jaime Speiser, Catherine Dillon, Holly Battenhouse, Michelle Gottfried
Journal: Journal of Hepatology (2021)
Asexuality Associated with Marked Genomic Expansion of Tandemly Repeated rRNA and Histone Genes
Authors: Kyle E McElroy, Stefan Müller, Dunja K Lamatsch, Laura Bankers, Peter D Fields, Joseph R Jalinsky, Joel Sharbrough, Jeffrey L Boore, John M Logsdon, Maurine Neiman
Journal: Molecular Biology and Evolution (2021)

How does asexual reproduction influence genome evolution? Although is it clear that genomic structural variation is common and important in natural populations, we know very little about how one of the most fundamental of eukaryotic traits-mode of genomic inheritance-influences genome structure. We address this question with the New Zealand freshwater snail Potamopyrgus antipodarum, which features multiple separately derived obligately asexual lineages that coexist and compete with otherwise similar sexual lineages. We used whole-genome sequencing reads from a diverse set of sexual and asexual individuals to analyze genomic abundance of a critically important gene family, rDNA (the genes encoding rRNAs), that is notable for dynamic and variable copy number. Our genomic survey of rDNA in P. antipodarum revealed two striking results. First, the core histone and 5S rRNA genes occur between tandem copies of the 18S-5.8S-28S gene cluster, a unique architecture for these crucial gene families. Second, asexual P. antipodarum harbor dramatically more rDNA-histone copies than sexuals, which we validated through molecular and cytogenetic analysis. The repeated expansion of this genomic region in asexual P. antipodarum lineages following distinct transitions to asexuality represents a dramatic genome structural change associated with asexual reproduction-with potential functional consequences related to the loss of sexual reproduction.
Abstract 211: Delayed Cell Death in CA1 Region in a Cardiac Arrest Rat Model: Continuing After 2 Weeks of Survival?
Authors: Sandra Högler, Ursula Teubenbacher, Wolfgang Weihs, Fritz Sterz, Ingrid A M Magnet, Florian Ettl, Alexandra-Maria Warenits, Andreas Schober, Christoph Testori, Michael Holzer, Daniel Grassman, Michael Wagner, Petra Kodajova, Andreas Janata
Journal: Circulation (2014)

Background: Evolution of histological lesions in selectively vulnerable brain regions in animal models of cardiac arrest (CA)give evidence of potential therapeutic windows. Delayed cell death is of special interest in this regard. Methods: In male Sprague-Dawley rats (350g) ventricular fibrillation (VF) CA was induced for 6 min followed by chest compressions, ventilation and drugs for 2 min. To achieve return of spontaneous circulation animals were defibrillated every 2 min. Animals were sacrificed after one week (n=5) or two weeks (n=7) of survival and compared to four sham animals. Brains were fixed in formalin, embedded in paraffin wax and cut into 3 μm thick coronary sections for histological examination. Viable neurons with nucleolus were counted in Hematoxylin-Eosin (HE)-stained sections in a 250 μm sector of the medial CA1 region. FluoroJade B staining was applied to count dying neurons in the same sector. Results: In HE-staining sham animals had 31±4 viable neurons. In one week survivors 11±9 viable neurons (p=0.003) and in two week survivors 7±7 viable neurons (p=0.001 vs sham, p=0.49 vs one week survivors) were counted. Furthermore, a lot of degenerated hypereosinophilic neurons were present in HE-staining in both CA-groups. FluoroJade B-staining was negative in sham animals. In one week survivors 29±8 dying neurons (p=0.006) and in two week survivors 33±13 dying neurons (p= 0.016 vs sham, p=0.343 vs one week survivors) were detectable. Conclusions: Consistent damage in the medial CA1 region was present after 6 min VFCA in both survival time groups. Lesions seemed to be constant, with no significant differences between time points. Contrary to expectations, FluoroJade B-staining was still positive after two weeks of survival, suggesting that delayed cell death might go on for a longer time period than assumed so far.
Effective killing of CML cells by PEITC is associated with rapid increase of cellular ROS, depletion of glutathione and BCR-ABL degradation
Authors: Hui Zhang, Dunyaporn Trachootham, Weiqin Lu, Jennifer Carew, Francis Giles, Michael Keating, Ralph Arlinghaus, Peng Huang
Journal: Cancer Research (2008)

3315  Chronic myelogenous leukemia (CML) is a myeloproliferative disorder that represents approximately 15-20% of all adult leukemia. The development of CML is clearly linked to the constitutively active tyrosine kinase of the chimeric protein BCR-ABL, which is encoded by the Bcr-Abl fusion gene due to chromosome 9/22 translocation or other aberrant cytogenetic events. Several recent studies and our findings suggested that the CML oncoprotein BCR-ABL could initiate cellular redox imbalance and promote persistent cellular oxidative stress. Cell adaptation to this redox alteration may promote CML cell survival and the development of this disease. Thus disrupting cellular redox system in CML cells is a possible strategy to kill the leukemia cells. Here we showed that β-phenylethyl isothiocyanate (PEITC), a natural compound found in edible vegetables, is effective in killing cultured human BCR-ABL positive CML cells by causing severe ROS stress and glutathione depletion. Importantly, we showed that CML cells harboring T315I-mutantation insensitive to the Bcr-Abl-targeted drug Gleevec remained sensitive to PEITC. The killing ability of PEITC was confirmed using CML cell lines and primary leukemia cells isolated from CML patients harboring T315I-mutant BCR-ABL. Treatment of CML cells expressing wild-type or T315I-mutant BCR-ABL with 10 μM PEITC resulted in a rapid increase of reactive oxygen species (ROS) stress, a severe depletion of cellular glutathione (GSH), and a redox-mediated degradation of the BCR-ABL protein, leading to massive cell death. Incubation with the GSH precursor antioxidant NAC attenuated the PEITC-induced oxidative stress in CML cells, and prevented the degradation of BCR-ABL, caspase-3 activation, and cell death. We further showed that the PEITC-induced degradation of BCR-ABL was mediated partially by caspase-3 and the proteasome pathway. Our results suggest that PEITC is a promising compound capable of killing both Gleevec-sensitive and -resistant CML cells through a ROS-mediated mechanism.
ARRY-520, a KSP inhibitor with efficacy and pharmacodynamic activity in animal models of solid tumors
Authors: Richard Woessner, Chris Corrette, Shelley Allen, Jeremy Hans, Qian Zhao, Tom Aicher, Joe Lyssikatos, John Robinson, Greg Poch, Laura Hayter, April Cox, Patrice Lee, Jim Winkler, Kevin Koch, Eli Wallace
Journal: Cancer Research (2007)

1433  Kinesins are eukaryotic microtubule-associated motor proteins. One of these, kinesin spindle protein (KSP) is a mitotic-specific kinesin that plays a key role in spindle pole separation and production of the bipolar spindle, as well as centrosome separation and maturation. As KSP is expressed predominately in proliferating cells and is absent from postmitotic neurons, inhibition of KSP has the potential to provide the antitumor activity of a mitotic inhibitor while avoiding peripheral neuropathy. ARRY-520 is a member of a series of KSP inhibitors discovered and optimized by structure-based design. It is a potent inhibitor of human KSP (IC50 6 nM) and a potent inducer of cellular phosphorylation of histone H3 (pHH3, a pharmacodynamic marker for accumulation of cells in mitosis), with in vitro antiproliferative IC50s ranging from subnanomolar to single digit nanomolar across a variety of human and rodent tumor cell lines. We report here the characterization of the in vivo efficacy of this compound. At its maximally tolerated dose (MTD) in mice of 25 - 30 mg/kg IP on a q4dx3 schedule, ARRY-520 caused tumor regressions, with some complete responses and cures, in several subcutaneous mouse xenograft models: HT-29 (colon), HCT-116 (colon), A2780 (ovarian), HL-60 (acute promyelocytic leukemia) and K-562 (chronic myelogenous leukemia). In the HT-29, HCT-116 and A2780 models, the antitumor efficacy of ARRY-520 was greater than that of paclitaxel. ARRY-520 had modest efficacy against subcutaneous HCT-15 xenografts (resistant to paclitaxel due to overexpression of p-glycoprotein), but the efficacy was greater than that of paclitaxel. Efficacy was greater than that of vincristine in the K562 model. ARRY-520 also had a potent pharmacodynamic effect in vivo. After a single IP dose of the compound at its MTD in nude mice bearing subcutaneous HT-29 xenografts, tumor pHH3 remained elevated for 4 days, indicating that the pharmacodynamic effect of the drug could be maintained for the duration of the dosing interval on the q4dx3 schedule. Quantitation of monopolar spindles in tumor sections from xenograft studies also demonstrated the duration of the pharmacodynamic effect. The molecule possess desirable drug-like properties, including high aqueous solubility (> 4 mg/ml at physiological pH), low CYP inhibition (> 25uM for 3A4, 2C9, 1A2, 2D6, and 2C19), and pharmacokinetics favorable for an IV-infused targeted chemotherapeutic. Owing to this combination of excellent in vivo efficacy and good properties, ARRY-520 has been selected for clinical development.
Diagnostic accuracy and clinical impact of [18F]FET PET in childhood CNS tumors
Authors: Lisbeth Marner, Michael Lundemann, Astrid Sehested, Karsten Nysom, Lise Borgwardt, René Mathiasen, Peder S Wehner, Otto M Henriksen, Carsten Thomsen, Jane Skjøth-Rasmussen, Helle Broholm, Olga Østrup, Julie L Forman, Liselotte Højgaard, Ian Law
Journal: Neuro-Oncology (2021)

Abstract Background Central nervous system (CNS) tumors cause the highest death rates among childhood cancers, and survivors frequently have severe late effects. Magnetic resonance imaging (MRI) is the imaging modality of choice, but its specificity can be challenged by treatment-induced signal changes. In adults, O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET) PET can assist in interpreting MRI findings. We assessed the clinical impact and diagnostic accuracy of adding [18F]FET PET to MRI in children with CNS tumors. Methods A total of 169 [18F]FET PET scans were performed in 97 prospectively and consecutively included patients with known or suspected childhood CNS tumors. Scans were performed at primary diagnosis, before or after treatment, or at relapse. Results Adding [18F]FET PET to MRI impacted clinical management in 8% [95% confidence interval (CI): 4%-13%] of all scans (n = 151) and in 33% [CI: 17%-53%] of scans deemed clinically indicated due to difficult decision making on MRI alone (n = 30). Using pathology or follow-up as reference standard, the addition of [18F]FET PET increased specificity (1.00 [0.82-1.00] vs 0.48 [0.30-0.70], P = .0001) and accuracy (0.91 [CI: 0.87-0.96] vs 0.81 [CI: 0.75-0.89], P = .04) in 83 treated lesions and accuracy in 58 untreated lesions (0.96 [CI: 0.91-1.00] vs 0.90 [CI: 0.82-0.92], P &amp;lt; .001). Further, in a subset of patients (n = 15) [18F]FET uptake correlated positively with genomic proliferation index. Conclusions The addition of [18F]FET PET to MRI helped discriminate tumor from non-tumor lesions in the largest consecutive cohort of pediatric CNS tumor patients presented to date.
Colchicine acts selectively in the liver to induce hepatokines that inhibit myeloid cell activation
Authors: Jui-Hsia Weng, Peter David Koch, Harding H. Luan, Ho-Chou Tu, Kenichi Shimada, Iris Ngan, Richard Ventura, Ruomu Jiang, Timothy J. Mitchison
Journal: Nature Metabolism (2021)
Increased FDG Uptake of the Pectoral Girdle and Serratus Anterior Due to Wallpaper Stripping on PET/CT—Exquisite Demonstration of the Biomechanics
Authors: Ayah Adel Nawwar, Monique Vekeria, Julie Searle, Rajiv Singh, Iain Douglas Lyburn
Journal: Clinical Nuclear Medicine (2021)

Abstract According to published guidelines and routine procedures, patients are instructed to avoid strenuous exercise for 6 to 24 hours before FDG imaging, avoiding unfavorable muscular uptake. A 40-year-old man with esophageal carcinoma underwent FDG PET/CT for response assessment. Intense uptake was noted in the muscles of the right upper limb and chest. The patient stated he had avoided exercise before scanning. On further questioning, he was found to be a professional painter and decorator and had been working stripping wallpaper. Marked skeletal FDG uptake occurs in subjects who have strenuously exerted themselves before or after the injection of FDG.
International Society of Nephrology Global Kidney Health Atlas: structures, organization, and services for the management of kidney failure in Newly Independent States and Russia
Authors: Elena Zakharova, Abduzhappar Gaipov, Aminu K. Bello, David W. Johnson, Vivekanand Jha, David C.H. Harris, Adeera Levin, Syed Saad, Maryam Khan, Deenaz Zaidi, Mohamed A. Osman, Feng Ye, Meaghan Lunney, Marcello Tonelli, Ikechi G. Okpechi, Alexander Zemchenkov, Irma Tchokhonelidze
Journal: Kidney International Supplements (2021)
Identification of X-chromosomal genes that drive sex differences in embryonic stem cells through a hierarchical CRISPR screening approach
Authors: Oriana Genolet, Anna A. Monaco, Ilona Dunkel, Michael Boettcher, Edda G. Schulz
Journal: Genome biology (2021)

Abstract Background X-chromosomal genes contribute to sex differences, in particular during early development, when both X chromosomes are active in females. Double X-dosage shifts female pluripotent cells towards the naive stem cell state by increasing pluripotency factor expression, inhibiting the differentiation-promoting MAP kinase (MAPK) signaling pathway, and delaying differentiation. Results To identify the genetic basis of these sex differences, we use a two-step CRISPR screening approach to comprehensively identify X-linked genes that cause the female pluripotency phenotype in murine embryonic stem cells. A primary chromosome-wide CRISPR knockout screen and three secondary screens assaying for different aspects of the female pluripotency phenotype allow us to uncover multiple genes that act in concert and to disentangle their relative roles. Among them, we identify Dusp9 and Klhl13 as two central players. While Dusp9 mainly affects MAPK pathway intermediates, Klhl13 promotes pluripotency factor expression and delays differentiation, with both factors jointly repressing MAPK target gene expression. Conclusions Here, we elucidate the mechanisms that drive sex-induced differences in pluripotent cells and our approach serves as a blueprint to discover the genetic basis of the phenotypic consequences of other chromosomal effects.
Ensuring tight control in patients with rheumatoid arthritis treated with targeted therapies during the COVID-19 pandemic using a telehealth strategy
Authors: Francesca Ingegnoli, Gilberto Cincinelli, Angela Flavia Luppino, Ennio Giulio Favalli, Annalisa Orenti, Patrizia Boracchi, Roberto Caporali
Journal: Annals of the Rheumatic Diseases (2021)

COVID-19 pandemic in its early months has deeply influenced rheumatic patients’ follow-up in terms of treatment adherence, disease control achieved with treat-to-target and tight-control strategies. Nationwide mitigation strategies such as confinement, travel restrictions and inadequate access to routine visits catalysed the rapid switch to remote rheumatologic consultations as an attempt to partially compensate for the decline of in-person outpatient visits.

This observational retrospective study was conducted to establish if the hybrid of in-person and telephone tight-control approach activated by our rheumatology unit in Milan (Italy) during the first lockdown (LD) period has been effective in maintaining remission in patients with rheumatoid arthritis (RA) treated with targeted therapies and to identify potential factors associated with its maintenance.

Data were extracted from a longitudinal observational registry (Eethics Committee 138_1999) including consecutive adult patients with RA treated with biologic or targeted synthetic drugs. During the first pandemic wave, before the visit, rheumatologists provided virtual care handled by telephone to assess the clinical status and to guarantee the absence of current contraindications to therapy. After tele counselling, based on the care required, patients …
On the Increased Event Rate of Urinary Tract Infection and Pneumonia in CKD Patients Treated with Roxadustat for Anemia
Authors: Theodoros Eleftheriadis, Georgios Pissas, Vassilios Liakopoulos, Ioannis Stefanidis
Journal: Journal of the American Society of Nephrology (2021)

Oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors have recently been added to the nephrologist's armament against renal anemia. Many studies confirmed the efficacy and the relatively safe profile of this new class of drugs. The recently published results from a randomized phase 3 trial about roxadustat for treating anemia in patients with CKD, not on dialysis, confirmed its efficacy and safety. However, in the same study, the event rate of urinary tract infection and pneumonia appeared higher for roxadustat than the placebo group. According to the authors, there is no clear biologic mechanism for this observation.1 Interestingly, randomized phase 3 trials, with a smaller sample size and a shorter duration, for treating anemia in patients on chronic dialysis with roxadustat detected a higher incidence of upper respiratory infection in the roxadustat group than in the epoetin alfa or darbepoetin alfa group.2,3 Oral HIF prolyl hydroxylase inhibitors affect erythropoietin production and iron metabolism by increasing HIF-2α and HIF-1α, respectively. However, HIFs are expressed in any cell type and transcribe too many genes. Experimental data support that roxadustat might increase certain infections by affecting the adaptive immune response through HIF-1α upregulation. Upon T-cell activation, HIF-1α is upregulated even in the absence of anoxia and affects cell metabolism, proliferation, and differentiation toward various effector or regulatory phenotypes.4 In the human mixed-lymphocyte reaction, an established experimental model of alloimmunity, roxadustat increased HIF-1α and HIF-2α levels in CD4+ T cells, decreased their proliferation, and induced apoptosis. In parallel, roxadustat facilitated CD4+ T-cell differentiation toward a T helper 2 (Th2) cell phenotype instead of a Th1 phenotype, and into a regulatory T cell phenotype instead of a Th17 phenotype. Finally, roxadustat suppressed humoral alloimmunity, as assessed by alloantibody production.5 Thus, in our opinion, the increased incidence of certain infections in the patients treated with roxadustat might be the result of its effect on the adaptive immune response. The pleiotropic effects and possible side effects of HIF prolyl hydroxylase inhibitors should be evaluated further. Disclosures V. Liakopoulos reports receiving research funding from Baxter and Genesis, and serving as a member of the World Kidney Day Steering Committee. All remaining authors have nothing to disclose. Funding None.
RISK PREDICTORS FOR MYOCARDIAL INJURY IN SEVERE COVID-19
Authors: Jorge H.P. Nascimento, Luiza V. Amaral, Carolina M. Cavalcanti, Andrea H. Neves, Rafael L. Costa, Luiz F.N. Simvoulidis, Liszt P. Oliveira, Eduardo C.F. Silva, Max R.F. Ramos, Glaucia Maria Moraes De Oliveira
Journal: Journal of the American College of Cardiology (2021)