tbuckley/cabot-search huggingface dataset:
MTH1 Inhibitor TH588 Disturbs Mitotic Progression and Induces Mitosis-Dependent Accumulation of Genomic 8-oxodG
Authors: Sean G. Rudd, Helge Gad, Kumar Sanjiv, Nuno Amaral, Anna Hagenkort, Petra Groth, Cecilia E. Ström, Oliver Mortusewicz, Ulrika Warpman Berglund, Thomas Helleday
Journal: Cancer Research (2020)

Reactive oxygen species (ROS) oxidize nucleotide triphosphate pools (e.g., 8-oxodGTP), which may kill cells if incorporated into DNA. Whether cancers avoid poisoning from oxidized nucleotides by preventing incorporation via the oxidized purine diphosphatase MTH1 remains under debate. Also, little is known about DNA polymerases incorporating oxidized nucleotides in cells or how oxidized nucleotides in DNA become toxic. Here we show that replacement of one of the main DNA replicases in human cells, DNA polymerase delta (Pol δ), with an error-prone variant allows increased 8-oxodG accumulation into DNA following treatment with TH588, a dual MTH1 inhibitor and microtubule targeting agent. The resulting elevated genomic 8-oxodG correlated with increased cytotoxicity of TH588. Interestingly, no substantial perturbation of replication fork progression was observed, but rather mitotic progression was impaired and mitotic DNA synthesis triggered. Reducing mitotic arrest by reversin treatment prevented accumulation of genomic 8-oxodG and reduced cytotoxicity of TH588, in line with the notion that mitotic arrest is required for ROS buildup and oxidation of the nucleotide pool. Furthermore, delayed mitosis and increased mitotic cell death was observed following TH588 treatment in cells expressing the error-prone but not wild-type Pol δ variant, which is not observed following treatments with antimitotic agents. Collectively, these results link accumulation of genomic oxidized nucleotides with disturbed mitotic progression. SIGNIFICANCE: These findings uncover a novel link between accumulation of genomic 8-oxodG and perturbed mitotic progression in cancer cells, which can be exploited therapeutically using MTH1 inhibitors.See related commentary by Alnajjar and Sweasy, p. 3459.
An Auristatin nanoconjugate targeting CXCR4+ leukemic cells blocks acute myeloid leukemia dissemination
Authors: Victor Pallarès, Ugutz Unzueta, Aïda Falgàs, Laura Sánchez-García, Naroa Serna, Alberto Gallardo, Gordon A. Morris, Lorena Alba-Castellón, Patricia Álamo, Jorge Sierra, Antonio Villaverde, Esther Vázquez, Isolda Casanova, Ramon Mangues
Journal: Journal of Hematology & Oncology (2020)

Abstract Background Current acute myeloid leukemia (AML) therapy fails to eliminate quiescent leukemic blasts in the bone marrow, leading to about 50% of patient relapse by increasing AML burden in the bone marrow, blood, and extramedullar sites. We developed a protein-based nanoparticle conjugated to the potent antimitotic agent Auristatin E that selectively targets AML blasts because of their CXCR4 receptor overexpression (CXCR4+) as compared to normal cells. The therapeutic rationale is based on the involvement of CXCR4 overexpression in leukemic blast homing and quiescence in the bone marrow, and the association of these leukemic stem cells with minimal residual disease, dissemination, chemotherapy resistance, and lower patient survival. Methods Monomethyl Auristatin E (MMAE) was conjugated with the CXCR4 targeted protein nanoparticle T22-GFP-H6 produced in E. coli . Nanoconjugate internalization and in vitro cell viability assays were performed in CXCR4+ AML cell lines to analyze the specific antineoplastic activity through the CXCR4 receptor. In addition, a disseminated AML animal model was used to evaluate the anticancer effect of T22-GFP-H6-Auristatin in immunosuppressed NSG mice ( n = 10/group). U of Mann-Whitney test was used to consider if differences were significant between groups. Results T22-GFP-H6-Auristatin was capable to internalize and exert antineoplastic effects through the CXCR4 receptor in THP-1 and SKM-1 CXCR4+ AML cell lines. In addition, repeated administration of the T22-GFP-H6-Auristatin nanoconjugate (9 doses daily) achieves a potent antineoplastic activity by internalizing specifically in the leukemic cells (luminescent THP-1) to selectively eliminate them. This leads to reduced involvement of leukemic cells in the bone marrow, peripheral blood, liver, and spleen, while avoiding toxicity in normal tissues in a luminescent disseminated AML mouse model. Conclusions A novel nanoconjugate for targeted drug delivery of Auristatin reduces significantly the acute myeloid leukemic cell burden in the bone marrow and blood and blocks its dissemination to extramedullar organs in a CXCR4+ AML model. This selective drug delivery approach validates CXCR4+ AML cells as a target for clinical therapy, not only promising to improve the control of leukemic dissemination but also dramatically reducing the severe toxicity of classical AML therapy.
Minimal clinically important differences in average, best, worst and current intensity and unpleasantness of chronic breathlessness
Authors: Magnus Ekström, Miriam J. Johnson, Chao Huang, David C. Currow
Journal: European Respiratory Journal (2020)

Background Chronic breathlessness has devastating consequences. The minimal clinically important difference (MCID) for current intensity has been estimated as 9 mm on a 100-mm visual analogue scale (VAS). We aimed to determine MCIDs for commonly used dimensions and recall periods: the current unpleasantness and current, average, best and worst intensity of the past 24 h for chronic breathlessness. Methods This was a secondary analysis of a randomised controlled trial of morphine versus placebo over 7 days in people with chronic breathlessness from severe disease. The breathlessness scores were self-reported using a diary each evening on 100-mm VAS. The MCID for improvement in each score was estimated using anchor-based and distribution-based methods. Results 283 participants (mean age 74.2 years; 63% male; 58% COPD; 87.0% modified Medical Research Council (mMRC) score 3–4) were included. Anchor-based MCIDs for breathlessness scores ranged from −13.9 mm to −9.5 mm. The MCIDs were similar when using different anchors and across all participants, and participants with more severe breathlessness (mMRC 3–4). Distribution-based effect sizes were classed as small (−4.7−6.3 mm), moderate (−9.4−12.5 mm) and large (−15.0−20.0 mm) effect. Sample sizes for trials using the different scores were proposed. MCIDs of absolute change were more stable than using relative change from baseline. Conclusion An improvement of ∼10 mm on a 100-mm VAS is likely to be clinically meaningful across commonly used measures of chronic breathlessness (current intensity, unpleasantness, and average, best and worst intensity over the past 24 h) to evaluate clinical benefit and effects in therapeutic trials.
Pembrolizumab for Treatment of a Patient With Multiple Cutaneous Squamous Cell Carcinomas and Recessive Dystrophic Epidermolysis Bullosa
Authors: Alfredo Piccerillo, Maya El Hachem, Rita De Vito, Erika Valentina De Luca, Ketty Peris
Journal: JAMA Dermatology (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal
HDAC inhibitors elicit metabolic reprogramming by targeting super-enhancers in glioblastoma models
Authors: Trang Thi Thu Nguyen, Yiru Zhang, Enyuan Shang, Chang Shu, Consuelo Torrini, Junfei Zhao, Elena Bianchetti, Angeliki Mela, Nelson Humala, Aayushi Mahajan, Arif O. Harmanci, Zhengdeng Lei, Mark Maienschein-Cline, Catarina M. Quinzii, Mike-Andrew Westhoff, Georg Karpel-Massler, Jeffrey N. Bruce, Peter Canoll, Markus D. Siegelin
Journal: Journal of Clinical Investigation (2020)

The Warburg effect is a tumor-related phenomenon that could potentially be targeted therapeutically. Here, we showed that glioblastoma (GBM) cultures and patients' tumors harbored super-enhancers in several genes related to the Warburg effect. By conducting a transcriptome analysis followed by ChIP-Seq coupled with a comprehensive metabolite analysis in GBM models, we found that FDA-approved global (panobinostat, vorinostat) and selective (romidepsin) histone deacetylase (HDAC) inhibitors elicited metabolic reprogramming in concert with disruption of several Warburg effect–related super-enhancers. Extracellular flux and carbon-tracing analyses revealed that HDAC inhibitors blunted glycolysis in a c-Myc–dependent manner and lowered ATP levels. This resulted in the engagement of oxidative phosphorylation (OXPHOS) driven by elevated fatty acid oxidation (FAO), rendering GBM cells dependent on these pathways. Mechanistically, interference with HDAC1/-2 elicited a suppression of c-Myc protein levels and a concomitant increase in 2 transcriptional drivers of oxidative metabolism, PGC1α and PPARD, suggesting an inverse relationship. Rescue and ChIP experiments indicated that c-Myc bound to the promoter regions of PGC1α and PPARD to counteract their upregulation driven by HDAC1/-2 inhibition. Finally, we demonstrated that combination treatment with HDAC and FAO inhibitors extended animal survival in patient-derived xenograft model systems in vivo more potently than single treatments in the absence of toxicity.
Multi-atlas image registration of clinical data with automated quality assessment using ventricle segmentation
Authors: Florian Dubost, Marleen de Bruijne, Marco Nardin, Adrian V. Dalca, Kathleen L. Donahue, Anne-Katrin Giese, Mark R. Etherton, Ona Wu, Marius de Groot, Wiro Niessen, Meike Vernooij, Natalia S. Rost, Markus D. Schirmer
Journal: Medical Image Analysis (2020)
Is there a future for hydroxychloroquine/chloroquine in prevention of SARS-CoV-2 infection (COVID-19)?
Authors: Sergey Moiseev, Sergey Avdeev, Michail Brovko, Pavel Novikov, Victor Fomin
Journal: Annals of the Rheumatic Diseases (2020)

In a recent article, Spinelli et al discussed a potential role of antimalarials in prevention of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and suggest that, waiting for supportive data from clinical trials, the scientific community is moving towards pre-emptive use of chloroquine (CQ) and hydroxychloroquine (HCQ).1

During pandemic of COVID-19, physicians face an imperative to use the drugs with unproven clinical efficacy and at best only moderate activity against SARS-CoV-2 (CQ and HCQ among them) in an attempt to save lives of patients with severe viral pneumonia complicated by acute respiratory distress syndrome. Several reports from China showed that both CQ and HCQ can block viral replication in vitro,2 3 whereas a small non-randomised trial from Gautret et al found HCQ to have a promising efficacy in enhancing viral clearance.4 These preliminary data resulted in a widespread use of antimalarials to treat COVID-19 and prompted US President Donald Trump to tout HCQ as ‘one of the biggest game-changers in the history of medicine’. However, recent evidence suggests that it might be …
Diagnosis of ventilator-associated pneumonia in critically ill adult patients—a systematic review and meta-analysis
Authors: Shannon M. Fernando, Alexandre Tran, Wei Cheng, Michael Klompas, Kwadwo Kyeremanteng, Sangeeta Mehta, Shane W. English, John Muscedere, Deborah J. Cook, Antoni Torres, Otavio T. Ranzani, Alison E. Fox-Robichaud, Waleed Alhazzani, Laveena Munshi, Gordon H. Guyatt, Bram Rochwerg
Journal: Intensive Care Medicine (2020)
Phase II Study of Ensituximab, a Novel Chimeric Monoclonal Antibody, in Adults with Unresectable, Metastatic Colorectal Cancer
Authors: Richard D. Kim, Nilofer S. Azad, Michael A. Morse, Elizabeth Poplin, Amit Mahipal, Benjamin Tan, Sharon A. Mavroukakis, Massimo Fantini, Kwong Y. Tsang, Anjum Zaki, Jose Torrealba, Philip M. Arlen, Muhammad S. Beg
Journal: Clinical Cancer Research (2020)

Patients with metastatic colorectal cancer refractory to chemotherapy have limited treatment options. Ensituximab (NEO-102) is a novel chimeric mAb targeting a variant of MUC5AC with specificity to colorectal cancer.Single-arm, phase II trial assessed the efficacy and safety of ensituximab in patients with advanced, refractory cancer who expressed MUC5AC antigen in tumor tissue. Ensituximab was administered intravenously every 2 weeks with 3 mg/kg as recommended phase II dose (RP2D). A minimum sample size of 43 patients was required on the basis of the assumption that ensituximab would improve median overall survival (OS) by 7 months using a one-sided significance level of 10% and 80% power. Written informed consent was obtained from all patients.Sixty-three patients with advanced, refractory colorectal cancer were enrolled and 53 subjects were treated in phase II arm. Median age was 58 years and 46% of the patients were female. Among 57 evaluable patients, median OS was 6.8 months. No responses were observed, and stable disease was achieved in 21% of the patients. The most common treatment-related adverse events (AE) at RP2D included fatigue (38%), anemia (30%), nausea (15%), vomiting (11%), increased bilirubin (9%), constipation (8%), decreased appetite (6%), and diarrhea (6%). Serious AEs at least possibly related to ensituximab occurred in 4 patients and included anemia, nausea, increased bilirubin, and hypoxia. No patients discontinued treatment due to drug-related AEs.Ensituximab was well tolerated and demonstrated modest antitumor activity in patients with heavily pretreated refractory colorectal cancer.
Additional Value of Dynamic Contrast-enhanced Sequences in Multiparametric Prostate Magnetic Resonance Imaging: Data from the PROMIS Study
Authors: Ahmed El-Shater Bosaily, Elena Frangou, Hashim U. Ahmed, Mark Emberton, Shonit Punwani, Richard Kaplan, Louise C. Brown, Alex Freeman, Charles Jameson, Richard Hindley, Delia Peppercorn, Andrew Thrower, Mathias Winkler, Tara Barwick, Victoria Stewart, Nick Burns-Cox, Paul Burn, Maneesh Ghei, Jeevan Kumaradevan, Raj Prasad, Janice Ash-Miles, Iqbal Shergill, Sanjay Agarwal, Derek Rosario, Ferekh Salim, Simon Bott, Hywel Evans, Alastair Henderson, Sukanya Ghosh, Tim Dudderidge, J. Smart, Ken Tung, Alexander Kirkham
Journal: European Urology (2020)
Neighborhood Screening in Communities Throughout the Nation for Children with Elevated Blood Lead Levels
Authors: Dudley G. Anderson, John L. Clark
Journal: Environmental Health Perspectives (1974)

From the spring of 1971 to September 1973, neighborhood surveys were conducted in 58 communities throughout the nation to determine whether children with confirmed elevated blood lead levels could be identified. Another purpose of these screenings was to assist communities in identifying children with elevated blood lead levels and thereby demonstrate to community officials that such children do exist in communities screened. The children screened were not a random sample. In those communities where the initial elevated blood levels were confirmed all but seven had one or more children requiring followup and/or treatment. Of those children screened, black children had an elevated rate about three times as great as nonblack children. With few exceptions, the homes in the neighborhoods had at least one interior surface with sufficient quantities of lead paint to be dangerous if the paint were ingested.
Attenuation of Murine Collagen‐Induced Arthritis by Targeting <scp>CD</scp>6
Authors: Yan Li, Jeffrey H. Ruth, Stephanie M. Rasmussen, Kalana S. Athukorala, Daniel P. Weber, M. Asif Amin, Phillip L. Campbell, Nora G. Singer, David A. Fox, Feng Lin
Journal: Arthritis & Rheumatology (2020)

Objective CD 6 is an important regulator of T cell function that interacts with the ligands CD 166 and CD 318. To further clarify the significance of CD 6 in rheumatoid arthritis ( RA ), we examined the effects of targeting CD 6 in the mouse model of collagen‐induced arthritis ( CIA ), using CD 6‐knockout ( CD 6‐ KO ) mice and CD 6‐humanized mice that express human CD 6 in lieu of mouse CD 6 on their T cells. Methods We immunized wild‐type ( WT ) and CD 6 gene– KO mice with a collagen emulsion to induce CIA . For treatment studies using CD 6‐humanized mice, mice were immunized similarly and a mouse anti‐human CD 6 IgG ( UMCD 6) or control IgG was injected on days 7, 14, and 21. Joint tissues were evaluated for tissue damage, leukocyte infiltration, and local inflammatory cytokine production. Collagen‐specific Th1, Th9, and Th17 responses and serum levels of collagen‐specific IgG subclasses were also evaluated in WT and CD 6‐ KO mice with CIA . Results The absence of CD 6 reduced 1) collagen‐specific Th9 and Th17, but not Th1 responses, 2) the levels of many proinflammatory joint cytokines, and 3) serum levels of collagen‐reactive total IgG and IgG1, but not IgG2a and IgG3. Joint homogenate hemoglobin content was significantly reduced in CD 6‐ KO mice with CIA compared to WT mice with CIA ( P &lt; 0.05) (reduced angiogenesis). Moreover, treating CD 6‐humanized mice with mouse anti‐human CD 6 monoclonal antibody was similarly effective in reducing joint inflammation in CIA . Conclusion Taken together, these data suggest that interaction of CD 6 with its ligands is important for the perpetuation of CIA and other inflammatory arthritides that are T cell driven.
Annals Graphic Medicine - Facing Transitional Care in Still Disease
Authors: Adèle Charransol, Alexandre Belot, Sophie Georgin-Lavialle
Journal: Annals of Internal Medicine (2020)

Web Exclusives21 April 2020Annals Graphic Medicine - Facing Transitional Care in Still DiseaseFREEAdèle Charransol, Alexandre Belot, MD, PhD, and Sophie Georgin-Lavialle, MD, PhDAdèle CharransolParis, France (A.C.)Search for more papers by this author, Alexandre Belot, MD, PhDUniversity of Lyon and Mère-Enfant Hospital, Lyon, France (A.B.)Search for more papers by this author, and Sophie Georgin-Lavialle, MD, PhDSorbonne University, Tenon Hospital, and Assistance Publique–Hôpitaux de Paris, Paris, France (S.G.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G19-0039 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: Paris, France (A.C.)University of Lyon and Mère-Enfant Hospital, Lyon, France (A.B.)Sorbonne University, Tenon Hospital, and Assistance Publique–Hôpitaux de Paris, Paris, France (S.G.)Image Information: The image depicts a patient who developed systemic-onset juvenile idiopathic arthritis, including polyarthritis, evanescent rash, and a life-threatening pericardial effusion, at age 15, requiring drainage. Steroids resulted in transient weight increase, with subsequent successful transition to anti–interleukin-1 therapy. When she began her art studies in Paris at age 18, her care was transferred to an internal medicine practice. She did not initially express her feelings or speak about her disease, but she spontaneously created this drawing illustrating how she has been changed during the past few years. Despite the positive response to therapies, this illustration highlights the importance of body representation during adolescence and suggests that art can be useful for young patients as a way to express their emotions during transitional care.Disclosures: The authors have disclosed no conflicts of interest. The forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G19-0039.Corresponding Author: Sophie Georgin-Lavialle, MD, PhD (e-mail, s.georgin.[email protected]com). PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 21 April 2020Volume 172, Issue 8Page: W95-W96KeywordsConflicts of interestDisclosureEmotionsHealth careInformation technologyJuvenile idiopathic arthritisPericardial diseasesRashesSteroidsSystemic diseases ePublished: 21 April 2020 Issue Published: 21 April 2020 Copyright & PermissionsCopyright © 2020 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Masks and Coronavirus Disease 2019 (COVID-19)
Authors: Angel N. Desai, David M. Aronoff
Journal: JAMA (2020)

Lisa A. Pompeii, PhD; Colleen S. Kraft, MD, MSc; Erik A. Brownsword, MPP; Morgan A. Lane, MPH; Elisa Benavides, MPH; Janelle Rios, MPH, PhD; Lewis J. Radonovich Jr, MD
Chinese expert consensus on diagnosis and treatment of coagulation dysfunction in COVID-19
Authors: Jing-Chun Song, Gang Wang, Wei Zhang, Yang Zhang, Wei-Qin Li, Zhou Zhou
Journal: Military Medical Research (2020)

Since December 2019, a novel type of coronavirus disease (COVID-19) in Wuhan led to an outbreak throughout China and the rest of the world. To date, there have been more than 1,260,000 COVID-19 patients, with a mortality rate of approximately 5.44%. Studies have shown that coagulation dysfunction is a major cause of death in patients with severe COVID-19. Therefore, the People's Liberation Army Professional Committee of Critical Care Medicine and Chinese Society on Thrombosis and Hemostasis grouped experts from the frontline of the Wuhan epidemic to come together and develop an expert consensus on diagnosis and treatment of coagulation dysfunction associated with a severe COVID-19 infection. This consensus includes an overview of COVID-19-related coagulation dysfunction, tests for coagulation, anticoagulation therapy, replacement therapy, supportive therapy and prevention. The consensus produced 18 recommendations which are being used to guide clinical work.