tbuckley/cabot-search huggingface dataset:
Pernicious anaemia: switch to oral B12 supplementation to reduce risk of covid-19 transmission
Authors: Amrit Takhar
Journal: BMJ (2020)

We present a 75-year-old man who was admitted to our hospital due to 4 months of general deterioration, gait disturbance and cognition impairment which appeared very close to the start of levetiracetam (LEV) as a new antiepileptic drug. Brain CT shows central and less peripheral atrophy of brain, and diagnosis of normal pressure hydrocephalus was raised; however, removal of 30 cc of cerebrospinal fluid (CSF) by lumbar puncture in order to amend walking did not lead to gait improvement. After excluding metabolic, vascular, infection, inflammatory and other reasons explaining his status. Thinking that may be any correlation between LEV added in the last months and his clinical condition, we stopped LEV. Several days after that, there is marked improvement in his general sensation, alertness and cognitive status and there is marked improvement in walking balance to the point of being able to walk without the use of walker or cane or help from other person. Certain cognitive impairment and gait difficulties are not known as side effects of LEV treatment.
Phase I Trial of First-in-Class ATR Inhibitor M6620 (VX-970) as Monotherapy or in Combination With Carboplatin in Patients With Advanced Solid Tumors
Authors: Timothy A. Yap, Brent O’Carrigan, Marina S. Penney, Joline S. Lim, Jessica S. Brown, Maria J. de Miguel Luken, Nina Tunariu, Raquel Perez-Lopez, Daniel Nava Rodrigues, Ruth Riisnaes, Ines Figueiredo, Suzanne Carreira, Brian Hare, Katherine McDermott, Saira Khalique, Chris T. Williamson, Rachael Natrajan, Stephen J. Pettitt, Christopher J. Lord, Udai Banerji, John Pollard, Juanita Lopez, Johann S. de Bono
Journal: Journal of Clinical Oncology (2020)

PURPOSE Preclinical studies demonstrated that ATR inhibition can exploit synthetic lethality (eg, in cancer cells with impaired compensatory DNA damage responses through ATM loss) as monotherapy and combined with DNA-damaging drugs such as carboplatin. PATIENTS AND METHODS This phase I trial assessed the ATR inhibitor M6620 (VX-970) as monotherapy (once or twice weekly) and combined with carboplatin (carboplatin on day 1 and M6620 on days 2 and 9 in 21-day cycles). Primary objectives were safety, tolerability, and maximum tolerated dose; secondary objectives included pharmacokinetics and antitumor activity; exploratory objectives included pharmacodynamics in timed paired tumor biopsies. RESULTS Forty patients were enrolled; 17 received M6620 monotherapy, which was safe and well tolerated. The recommended phase II dose (RP2D) for once- or twice-weekly administration was 240 mg/m 2 . A patient with metastatic colorectal cancer harboring molecular aberrations, including ATM loss and an ARID1A mutation, achieved RECISTv1.1 complete response and maintained this response, with a progression-free survival of 29 months at last assessment. Twenty-three patients received M6620 with carboplatin, with mechanism-based hematologic toxicities at higher doses, requiring dose delays and reductions. The RP2D for combination therapy was M6620 90 mg/m 2 with carboplatin AUC5. A patient with advanced germline BRCA1 ovarian cancer achieved RECISTv1.1 partial response and Gynecologic Cancer Intergroup CA125 response despite being platinum refractory and PARP inhibitor resistant. An additional 15 patients had RECISTv1.1 stable disease as best response. Pharmacokinetics were dose proportional and exceeded preclinical efficacious levels. Pharmacodynamic studies demonstrated substantial inhibition of phosphorylation of CHK1, the downstream ATR substrate. CONCLUSION To our knowledge, this report is the first of an ATR inhibitor as monotherapy and combined with carboplatin. M6620 was well tolerated, with target engagement and preliminary antitumor responses observed.
Risk for Nephrogenic Systemic Fibrosis After Exposure to Newer Gadolinium Agents
Authors: Joseph Lunyera, Dinushika Mohottige, Anastasia-Stefania Alexopoulos, Hilary Campbell, C. Blake Cameron, Nicole Sagalla, Timothy J. Amrhein, Matthew J. Crowley, Jessica R. Dietch, Adelaide M. Gordon, Andrzej S. Kosinski, Sarah Cantrell, John W. Williams, Jennifer M. Gierisch, Belinda Ear, Karen M. Goldstein
Journal: Annals of Internal Medicine (2020)

The risk for nephrogenic systemic fibrosis (NSF) after exposure to newer versus older gadolinium-based contrast agents (GBCAs) remains unclear.To synthesize evidence about NSF risk with newer versus older GBCAs across the spectrum of kidney function.MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science for English-language references from inception to 5 March 2020.Randomized controlled trials, cohort studies, and case-control studies that assessed NSF occurrence after GBCA exposure.Data were abstracted by 1 investigator and verified by a second. Investigator pairs assessed risk of bias by using validated tools.Of 32 included studies, 20 allowed for assessment of NSF risk after exposure to newer GBCAs and 12 (11 cohort studies and 1 case-control study) allowed for comparison of NSF risk between newer and older GBCAs. Among 83 291 patients exposed to newer GBCAs, no NSF cases developed (exact 95% CI, 0.0001 to 0.0258 case). Among the 12 studies (n = 118 844) that allowed risk comparison between newer and older GBCAs, 37 NSF cases developed after exposure to older GBCAs (exact CI, 0.0001 to 0.0523 case) and 4 occurred (3 confounded) after exposure to newer GBCAs (exact CI, 0.0018 to 0.0204 case). Data were scant for patients with acute kidney injury or those at risk for chronic kidney disease.Study heterogeneity prevented meta-analysis. Risk of bias was high in most studies because of inadequate exposure and outcome ascertainment.Although NSF occurrence after exposure to newer GBCAs is very rare, the relatively scarce data among patients with acute kidney injury and those with risk factors for chronic kidney disease limit conclusions about safety in these populations.U.S. Department of Veterans Affairs. (PROSPERO: CRD42019135783).
Combination therapy of BCR-ABL-positive B cell acute lymphoblastic leukemia by tyrosine kinase inhibitor dasatinib and c-JUN N-terminal kinase inhibition
Authors: Xinhua Xiao, Ping Liu, Donghe Li, Zhizhou Xia, Peihong Wang, Xiuli Zhang, Mingzhu Liu, Lujian Liao, Bo Jiao, Ruibao Ren
Journal: Journal of Hematology & Oncology (2020)

Abstract Background The Philadelphia chromosome (Ph), which leads to the creation and expression of the fusion gene product BCR-ABL, underlines the pathogenesis of chronic myelogenous leukemia (CML) and a fraction of adult and pediatric acute B-lymphoblastic leukemia (B-ALL). The BCR-ABL tyrosine kinase inhibitors (TKIs) have shown a remarkable clinical activity in patients with CML, but their efficacy in treating Ph + B-ALL is limited. Identifying additional therapeutic targets is important for the effective treatment of Ph + B-ALL. Methods Activation of the JNK signaling pathway in human and mouse BCR-ABL + B-ALL cells with or without dasatinib treatment was analyzed by Western blotting. JNK was inhibited either by RNA interference or chemical inhibitors, such as JNK-IN-8. The effect of JNK inhibition with or without BCR-ABL TKI dasatinib on BCR-ABL + B-ALL cells was analyzed by the CellTiter-Glo® Luminescent Cell Viability Assay. The in vivo effects of JNK-IN-8 and dasatinib alone or in combination were tested using a BCR-ABL induced B-ALL mouse model. Results We found that the c-JUN N-terminal kinase (JNK) signaling pathway is abnormally activated in both human and mouse BCR-ABL + B-ALL cells, but the BCR-ABL TKI does not inhibit JNK activation in these cells. Inhibition of JNK, either by RNAi-mediated downregulation or by JNK inhibitors, could significantly reduce viability of Ph + B-ALL cells. JNK inhibition by RNAi-mediated downregulation or JNK inhibitors also showed a synergistic effect with the BCR-ABL TKI, dasatinib, in killing Ph + B-ALL cells in vitro. Furthermore, a potent JNK inhibitor, JNK-IN-8, in combination with dasatinib markedly improved the survival of mice with BCR-ABL induced B-ALL, as compared to the treatment with dasatinib alone. Conclusions Our findings indicate that simultaneously targeting both BCR-ABL and JNK kinase might serve as a promising therapeutic strategy for Ph + B-ALL.
Self-Measured Blood Pressure Monitoring at Home: A Joint Policy Statement From the American Heart Association and American Medical Association
Authors: Daichi Shimbo, Nancy T. Artinian, Jan N. Basile, Lawrence R. Krakoff, Karen L. Margolis, Michael K. Rakotz, Gregory Wozniak
Journal: Circulation (2020)

The diagnosis and management of hypertension, a common cardiovascular risk factor among the general population, have been based primarily on the measurement of blood pressure (BP) in the office. BP may differ considerably when measured in the office and when measured outside of the office setting, and higher out-of-office BP is associated with increased cardiovascular risk independent of office BP. Self-measured BP monitoring, the measurement of BP by an individual outside of the office at home, is a validated approach for out-of-office BP measurement. Several national and international hypertension guidelines endorse self-measured BP monitoring. Indications include the diagnosis of white-coat hypertension and masked hypertension and the identification of white-coat effect and masked uncontrolled hypertension. Other indications include confirming the diagnosis of resistant hypertension and detecting morning hypertension. Validated self-measured BP monitoring devices that use the oscillometric method are preferred, and a standardized BP measurement and monitoring protocol should be followed. Evidence from meta-analyses of randomized trials indicates that self-measured BP monitoring is associated with a reduction in BP and improved BP control, and the benefits of self-measured BP monitoring are greatest when done along with cointerventions. The addition of self-measured BP monitoring to office BP monitoring is cost-effective compared with office BP monitoring alone or usual care among individuals with high office BP. The use of self-measured BP monitoring is commonly reported by both individuals and providers. Therefore, self-measured BP monitoring has high potential for improving the diagnosis and management of hypertension in the United States. Randomized controlled trials examining the impact of self-measured BP monitoring on cardiovascular outcomes are needed. To adequately address barriers to the implementation of self-measured BP monitoring, financial investment is needed in the following areas: improving education and training of individuals and providers, building health information technology capacity, incorporating self-measured BP readings into clinical performance measures, supporting cointerventions, and enhancing reimbursement.
Paroxysmal Nocturnal Hemoglobinuria Clones in Children with Acquired Aplastic Anemia: A Multicentric Study
Authors: Fabio Stefano Timeus, Nicoletta Crescenzio, Alessandra Doria, Luiselda Foglia, Sara Pagliano, Anna Lorenzati, Paola Quarello, Valentina Decimi, Johanna Svhan, Franco Locatelli, Antonio Ruggiero, Baldassarre Martire, Marta Pillon, Aldo Misuraca, Daniela Longoni, Carlo Dufour, Ugo Ramenghi, Paola Saracco
Journal: Blood (2012)
Diagnostic accuracy of the FebriDx host response point-of-care test in patients hospitalised with suspected COVID-19
Authors: Tristan W. Clark, Nathan J Brendish, Stephen Poole, Vasanth V. Naidu, Christopher Mansbridge, Nicholas Norton, Helen Wheeler, Laura Presland, Sean Ewings
Journal: Journal of Infection (2020)

IntroductionManagement of the COVID-19 pandemic is hampered by long delays associated with centralised laboratory PCR testing. In hospitals this leads to poor patient flow and nosocomial transmission and so rapid, accurate diagnostic tests are urgently required. The FebriDx is a point-of-care test that detects an antiviral host response protein in finger prick blood within 10 min, but its accuracy for the identification of COVID-19 is unknown.MethodsWe performed a real-world diagnostic accuracy study of FebriDx in hospitalised patients during the first wave of the pandemic. Measures of diagnostic accuracy were calculated based on FebriDx results compared to the reference standard of SARS-CoV-2 PCR on combined nose and throat swabs. A multivariable predictive model including FebriDx, age, sex, and clinical characteristics was developed and underwent internal validation.ResultsFebriDx was performed on 251 patients and gave a valid result in 248. 118 of 248 (48%) were PCR positive for COVID-19. FebriDx results were available after 10 min compared with 1.7 (1.6 to 2.1) hours with point-of-care PCR testing and 23.4 (17.2 to 31.1) hours with laboratory PCR testing. Sensitivity of FebriDx for the identification of COVID-19 was 93% (110/118; 95% CI 87 to 97%) and specificity was 86% (112/130; 95%CI 79 to 92%). Positive and negative likelihood ratios were 6.73 (95%CI 4.37 to 10.37) and 0.08 (95%CI 0.04 to 0.15) respectively. In the multivariate model age, sex and other clinical features did not contribute significantly to the effect of the FebriDx result in distinguishing patients with and without COVID-19.ConclusionsDuring the first wave of the pandemic, FebriDx had high accuracy for the identification of COVID-19 in hospitalised adults and could be deployed as a front door triage tool.Trial registrationISRCTN14966673
Astrocyte-microglia interaction drives evolving neuromyelitis optica lesion
Authors: Tingjun Chen, Vanda A. Lennon, Yong U. Liu, Dale B. Bosco, Yujiao Li, Min-Hee Yi, Jia Zhu, Shihui Wei, Long-Jun Wu
Journal: Journal of Clinical Investigation (2020)

Neuromyelitis optica (NMO) is a severe inflammatory autoimmune CNS disorder triggered by binding of an IgG autoantibody to the aquaporin 4 (AQP4) water channel on astrocytes. Activation of cytolytic complement has been implicated as the major effector of tissue destruction that secondarily involves myelin. We investigated early precytolytic events in the evolving pathophysiology of NMO in mice by continuously infusing IgG (NMO patient serum–derived or AQP4-specific mouse monoclonal), without exogenous complement, into the spinal subarachnoid space. Motor impairment and sublytic NMO-compatible immunopathology were IgG dose dependent, AQP4 dependent, and, unexpectedly, microglia dependent. In vivo spinal cord imaging revealed a striking physical interaction between microglia and astrocytes that required signaling from astrocytes by the C3a fragment of their upregulated complement C3 protein. Astrocytes remained viable but lost AQP4. Previously unappreciated crosstalk between astrocytes and microglia involving early-activated CNS-intrinsic complement components and microglial C3a receptor signaling appears to be a critical driver of the precytolytic phase in the evolving NMO lesion, including initial motor impairment. Our results indicate that microglia merit consideration as a potential target for NMO therapeutic intervention.
Pharmacokinetic Profiles Determine Optimal Combination Treatment Schedules in Computational Models of Drug Resistance
Authors: Itziar Irurzun-Arana, Thomas O. McDonald, Iñaki F. Trocóniz, Franziska Michor
Journal: Cancer Research (2020)

Identification of optimal schedules for combination drug administration relies on accurately estimating the correct pharmacokinetics, pharmacodynamics, and drug interaction effects. Misspecification of pharmacokinetics can lead to wrongly predicted timing or order of treatments, leading to schedules recommended on the basis of incorrect assumptions about absorption and elimination of a drug and its effect on tumor growth. Here, we developed a computational modeling platform and software package for combination treatment strategies with flexible pharmacokinetic profiles and multidrug interaction curves that are estimated from data. The software can be used to compare prespecified schedules on the basis of the number of resistant cells where drug interactions and pharmacokinetic curves can be estimated from user-provided data or models. We applied our approach to publicly available
Role of the anatomic site in the association of HLA class I antigen expression level in metastases with clinical response to ipilimumab therapy in patients with melanoma
Authors: Andrea Ladányi, Eszter Papp, Anita Mohos, Tímea Balatoni, Gabriella Liszkay, Judit Oláh, Anita Varga, Zsuzsanna Lengyel, Gabriella Emri, Soldano Ferrone
Journal: Journal for ImmunoTherapy of Cancer (2020)

The clinical response to immune checkpoint inhibitors (ICIs) in only part of the treated patients, in conjunction with the potentially serious side effects associated with this type of therapy, has emphasized the need to identify biomarkers to select patients who may benefit from ICI treatment. The aim of our study was to test human leukocyte antigen (HLA) class I and II expression in melanoma metastases as potential biomarkers of response to ipilimumab and survival in patients with metastatic melanoma, since these molecules play a crucial role in the interactions of malignant cells with host's immune system.
Comparison Between ESC and Duke Criteria for the Diagnosis of Prosthetic Valve Infective Endocarditis
Authors: Mary Philip, Laetitia Tessonier, Julien Mancini, Jean-Luc Mainardi, Marie-Paule Fernandez-Gerlinger, David Lussato, David Attias, Serge Cammilleri, Pierre Weinmann, Albert Hagege, Florent Arregle, Hélène Martel, Leopold Oliver, Laurence Camoin, Anne Claire Casalta, Jean Paul Casalta, Frédérique Gouriet, Alberto Riberi, Hubert Lepidi, Didier Raoult, Michel Drancourt, Gilbert Habib
Journal: JACC. Cardiovascular imaging (2020)
Animal Models of Atrial Fibrillation
Authors: Dominik Schüttler, Aneesh Bapat, Stefan Kääb, Kichang Lee, Philipp Tomsits, Sebastian Clauss, William J. Hucker
Journal: Circulation Research (2020)

Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in humans and is a significant source of morbidity and mortality. Despite its prevalence, our mechanistic understanding is incomplete, the therapeutic options have limited efficacy, and are often fraught with risks. A better biological understanding of AF is needed to spearhead novel therapeutic avenues. Although "natural" AF is nearly nonexistent in most species, animal models have contributed significantly to our understanding of AF and some therapeutic options. However, the impediments of animal models are also apparent and stem largely from the differences in basic physiology as well as the complexities underlying human AF; these preclude the creation of a "perfect" animal model and have obviated the translation of animal findings. Herein, we review the vast array of AF models available, spanning the mouse heart (weighing 1/1000th of a human heart) to the horse heart (10× heavier than the human heart). We attempt to highlight the features of each model that bring value to our understanding of AF but also the shortcomings and pitfalls. Finally, we borrowed the concept of a SWOT analysis from the business community (which stands for strengths, weaknesses, opportunities, and threats) and applied this introspective type of analysis to animal models for AF. We identify unmet needs and stress that is in the context of rapidly advancing technologies, these present opportunities for the future use of animal models.
Abstract B65: Precompetitive collaboration on liquid biopsy for early cancer assessment
Authors: Lynn Sorbara, David Wong, Carter Bob, Richard Cote, Hakho Lee, Nickolas Papadopoulos, Abhijit Patel, Sudhir Srivastava
Journal: Clinical Cancer Research (2020)

Abstract Precompetitive collaboration is a term used when competitors share early stages of research and development that are beneficial to all stakeholders. This Public-Private Partnership Consortium supports research to advance technologies and use these technologies for early cancer detection, to distinguish benign disease from cancer, and to distinguish aggressive from nonaggressive cancer. Combining the complementary expertise of both academics and industry may increase the likelihood of developing a viable diagnostic assay. In the era of personalized medicine, it is desirable to have noninvasive or minimally invasive methods to determine and follow longitudinally the molecular composition and characterization of a patient’s tumor, which will help gain a broader understanding of the disease. Liquid biopsy (CTC, ctDNA, extracellular vesicles, etc.) can be used to molecularly characterize the tumor and monitor genetic changes over time using repeat sampling of biofluids. The current technologies have shown great potential in diagnosis, predicting response to therapy, and monitoring relapse; however, the biologic and analytical challenges have rendered their usefulness for early detection/screening more difficult to establish. To address these challenges, the NCI developed this cooperative agreement program to support the work of six teams. Each team consists of a group of experts that include oncologists, bioinformaticians, researchers, and at least one industry partner. The current teams are developing a variety of unique assays/technologies that range from capture enhancements, microscope integration, nanoplasmonics, to specialized machine learning algorithms and bioinformatic analyses. Ovarian, breast, lung, and brain cancers are the model systems being studied, and there are at least two teams focused on each cancer type. The Consortium conducts work with the assistance of two working subgroups, Study Design and Biorepository, in conjunction with NCI staff. To monitor progress, there are yearly face-to-face Steering Committee meetings and monthly conference calls/Webex meetings. Progress in the first year of funding has been noteworthy. One of the teams has already achieved Clinical Laboratory Improvement Amendments (CLIA) and College of American Pathologists Certification, while another team has an insurance reimbursable extracellular vesicles test for risk assessment for prostate cancer. Citation Format: Lynn Sorbara, David Wong, Carter Bob, Richard Cote, Hakho Lee, Nickolas Papadopoulos, Abhijit Patel, Sudhir Srivastava. Precompetitive collaboration on liquid biopsy for early cancer assessment [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr B65.