tbuckley/cabot-search huggingface dataset:
A Man in His 40s With Exertional Dyspnea and T-Wave Inversions on Electrocardiography
Authors: Abdalla Elagha, Khaled Mandour
Journal: JAMA Cardiology (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 Cardiology 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 Cardiology journal
A phase <scp>II</scp> trial evaluating the efficacy of <scp>high‐dose</scp> Radioiodinated Tositumomab ( <scp>Anti‐CD20</scp> ) antibody, etoposide and cyclophosphamide followed by autologous transplantation, for <scp>high‐risk</scp> relapsed or refractory <scp>non‐hodgkin</scp> lymphoma
Authors: Victor A. Chow, Joseph G. Rajendran, Darrell R. Fisher, Frederick R. Appelbaum, Ryan D. Cassaday, Paul S. Martin, Leona A. Holmberg, Theodore A. Gooley, Philip A. Stevenson, John M. Pagel, Damian J. Green, Oliver W. Press, Ajay K. Gopal
Journal: American Journal of Hematology (2020)

Radiation is the most effective treatment for localized lymphoma, but treatment of multifocal disease is limited by toxicity. Radioimmunotherapy (RIT) delivers tumoricidal radiation to multifocal sites, further augmenting response by dose-escalation. This phase II trial evaluated high-dose RIT and chemotherapy prior to autologous stem-cell transplant (ASCT) for high-risk, relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (NHL). The primary endpoint was progression free survival (PFS). Secondary endpoints were overall survival (OS), toxicity, and tolerability. Patients age < 60 years with R/R NHL expressing CD20 were eligible. Mantle cell lymphoma (MCL) patients could proceed to transplant in first remission. Patients received I-131-tositumomab delivered at ≤25Gy to critical normal organs, followed by etoposide, cyclophosphamide and ASCT. A group of 107 patients were treated including aggressive lymphoma (N = 29), indolent lymphoma (N = 45), and MCL (N = 33). After a median follow-up of 10.1 years, the 10-year PFS for the aggressive, indolent, and MCL groups were 62%, 64%, 43% respectively. The 10-year OS for the aggressive, indolent, and MCL groups were 61%, 71%, 48% respectively. Toxicities were similar to standard conditioning regimens and non-relapse mortality at 100 days was 2.8%. Late myeloid malignancies were seen in 6% of patients. High-dose I-131-tositumomab, etoposide and cyclophosphamide followed by ASCT appeared feasible, safe, and effective in treating NHL, with estimated PFS at 10-years of 43%-64%. In light of novel cellular therapies for R/R NHL, high-dose RIT-containing regimens yield comparable efficacy and safety and could be prospectively compared.
Biochemical Correlates of Cardiac Hypertrophy
Authors: TADASHI KOIDE, MURRAY RABINOWITZ
Journal: Circulation Research (1969)

Cardiac hypertrophy was produced in rats by banding the ascending aorta. Increases in heart weight and RNA content occurred within 48 hours, indicating that hypertrophy develops rapidly. The total RNA content and the specific radioactivity of RNA labeled with 3 H-uridine were determined. The rate of RNA synthesis was estimated from these data and from the specific radioactivity of the myocardial uridine nucleotide pool. The rate of RNA synthesis in hearts of banded animals averaged four times greater than controls on the second postoperative day and about two to three times greater on the fourth to fifth postoperative days. An expansion of the myocardial uridine nucleotide pool was observed in banded rats, but the size of the myocardial adenosine nucleotide pool was not changed. No changesin base composition of 28S, 18S, or 4S RNA were observed following cardiac hypertrophy.
Principles of RNA processing from analysis of enhanced CLIP maps for 150 RNA binding proteins
Authors: Eric L. Van Nostrand, Gabriel A. Pratt, Brian A. Yee, Emily C. Wheeler, Steven M. Blue, Jasmine Mueller, Samuel S. Park, Keri E. Garcia, Chelsea Gelboin-Burkhart, Thai B. Nguyen, Ines Rabano, Rebecca Stanton, Balaji Sundararaman, Ruth Wang, Xiang-Dong Fu, Brenton R. Graveley, Gene W. Yeo
Journal: Genome biology (2020)

A critical step in uncovering rules of RNA processing is to study the in vivo regulatory networks of RNA binding proteins (RBPs). Crosslinking and immunoprecipitation (CLIP) methods enable mapping RBP targets transcriptome-wide, but methodological differences present challenges to large-scale analysis across datasets. The development of enhanced CLIP (eCLIP) enabled the mapping of targets for 150 RBPs in K562 and HepG2, creating a unique resource of RBP interactomes profiled with a standardized methodology in the same cell types.
Defining tumor resistance to PD-1 pathway blockade: recommendations from the first meeting of the SITC Immunotherapy Resistance Taskforce
Authors: Harriet M. Kluger, Hussein A. Tawbi, Maria L. Ascierto, Michaela Bowden, Margaret K. Callahan, Edward Cha, Helen X. Chen, Charles G. Drake, David M. Feltquate, Robert L. Ferris, James L. Gulley, Shilpa Gupta, Rachel W. Humphrey, Theresa M. LaVallee, Dung T. Le, Vanessa M. Hubbard-Lucey, Vassiliki A. Papadimitrakopoulou, Michael A. Postow, Eric H. Rubin, Elad Sharon, Janis M. Taube, Suzanne L. Topalian, Roberta Zappasodi, Mario Sznol, Ryan J. Sullivan
Journal: Journal for ImmunoTherapy of Cancer (2020)

As the field of cancer immunotherapy continues to advance at a fast pace, treatment approaches and drug development are evolving rapidly to maximize patient benefit. New agents are commonly evaluated for activity in patients who had previously received a programmed death receptor 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitor as standard of care or in an investigational study. However, because of the kinetics and patterns of response to PD-1/PD-L1 blockade, and the lack of consistency in the clinical definitions of resistance to therapy, the design of clinical trials of new agents and interpretation of results remains an important challenge. To address this unmet need, the Society for Immunotherapy of Cancer convened a multistakeholder taskforce-consisting of experts in cancer immunotherapy from academia, industry, and government-to generate consensus clinical definitions for resistance to PD-(L)1 inhibitors in three distinct scenarios: primary resistance, secondary resistance, and progression after treatment discontinuation. The taskforce generated consensus on several key issues such as the timeframes that delineate each type of resistance, the necessity for confirmatory scans, and identified caveats for each specific resistance classification. The goal of this effort is to provide guidance for clinical trial design and to support analyses of emerging molecular and cellular data surrounding mechanisms of resistance.
Proportion of Patients in Phase I Oncology Trials Receiving Treatments That Are Ultimately Approved
Authors: Sean X Zhang, Dean Fergusson, Jonathan Kimmelman
Journal: JNCI Journal of the National Cancer Institute (2020)

Phase I oncology trials are often regarded as a therapeutic option for patients. However, such claims have relied on surrogate measures of benefit, such as objective response.Using a systematic search of publications, we assessed the therapeutic value of phase I cancer trial participation by determining the probability that patients will receive active doses of treatments that eventually receive FDA approval or a National Comprehensive Cancer Network (NCCN) guideline recommendation for their indication. ClinicalTrials.gov, PubMed, American Society of Clinical Oncology reports, NCCN guidelines, and Drugs@FDA were searched between May 1, 2018, and July 31, 2018. All statistical tests were 2-sided.A total of 1000 phase I oncology trials initiated between 2005 and 2010 and enrolling 32 582 patients were randomly sampled from 3229 eligible trials on ClinicalTrials.gov. A total of 386 (1.2%) patients received a treatment that was approved by the US Food and Drug Administration for their malignancy at a dose delivered in the trial; including NCCN guideline recommendations, the number and proportion are 1168 (3.6%). Meta-regression showed a statistically significantly greater proportion of patients receiving a drug that was ultimately FDA approved in biomarker trials (rate ratio = 4.49, 95% confidence interval [CI] = 1.53 to 13.23; P = .006) and single-indication trials (rate ratio = 3.32, 95% CI = 1.21 to 9.15; P = .02); proportions were statistically significantly lower for combination vs monotherapy trials (rate ratio = 0.09, 95% CI = 0.01 to 0.68; P = .02).One in 83 patients in phase I cancer trials received a treatment that was approved for their indication at the doses received. Given published estimates of serious adverse event rates of 10%-19%, this represents low therapeutic value for phase I trial participation.
Age Differences in the Neural Correlates of Anxiety Disorders: An fMRI Study of Response to Learned Threat
Authors: Andrea L. Gold, Rany Abend, Jennifer C. Britton, Brigid Behrens, Madeline Farber, Emily Ronkin, Gang Chen, Ellen Leibenluft, Daniel S. Pine
Journal: American Journal of Psychiatry (2020)

Objective: Although both pediatric and adult patients with anxiety disorders exhibit similar neural responding to threats, age-related differences have been found in some functional MRI (fMRI) studies. To reconcile disparate findings, the authors compared brain function in youths and adults with and without anxiety disorders while rating fear and memory of ambiguous threats. Methods: Two hundred medication-free individuals ages 8–50 were assessed, including 93 participants with an anxiety disorder. Participants underwent discriminative threat conditioning and extinction in the clinic. Approximately 3 weeks later, they completed an fMRI paradigm involving extinction recall, in which they rated their levels of fear evoked by, and their explicit memory for, morph stimuli with varying degrees of similarity to the extinguished threat cues. Results: Age moderated two sets of anxiety disorder findings. First, as age increased, healthy subjects compared with participants with anxiety disorders exhibited greater amygdala-ventromedial prefrontal cortex (vmPFC) connectivity when processing threat-related cues. Second, age moderated diagnostic differences in activation in ways that varied with attention and brain regions. When rating fear, activation in the vmPFC differed between the anxiety and healthy groups at relatively older ages. In contrast, when rating memory for task stimuli, activation in the inferior temporal cortex differed between the anxiety and healthy groups at relatively younger ages. Conclusions: In contrast to previous studies that demonstrated age-related similarities in the biological correlates of anxiety disorders, this study identified age differences. These findings may reflect this study’s focus on relatively late-maturing psychological processes, particularly the appraisal and explicit memory of ambiguous threat, and inform neurodevelopmental perspectives on anxiety.
Safety and Feasibility of PARP1/2 Imaging with 18F-PARPi in Patients with Head and Neck Cancer
Authors: Heiko Schöder, Paula Demétrio De Souza França, Reiko Nakajima, Eva Burnazi, Sheryl Roberts, Christian Brand, Milan Grkovski, Audrey Mauguen, Mark P. Dunphy, Ronald A. Ghossein, Serge K. Lyashchenko, Jason S. Lewis, Joseph A. O'Donoghue, Ian Ganly, Snehal G. Patel, Nancy Y. Lee, Thomas Reiner
Journal: Clinical Cancer Research (2020)

Abstract Purpose: We performed a first-in-human clinical trial. The aim of this study was to determine safety and feasibility of PET imaging with 18F-PARPi in patients with head and neck cancer. Patients and Methods: Eleven patients with newly diagnosed or recurrent oral and oropharyngeal cancer were injected with 18F-PARPi (331 ± 42 MBq), and dynamic PET/CT imaging was performed between 0 and 25 minutes postinjection. Static PET/CT scans were obtained at 30, 60, and 120 minutes postinjection. Blood samples for tracer concentration and metabolite analysis were collected. Blood pressure, ECG, oxygen levels, clinical chemistry, and complete blood count were obtained before and after tracer administration. Results: 18F-PARPi was well-tolerated by all patients without any safety concerns. Of the 11 patients included in the analysis, 18F-PARPi had focal uptake in all primary lesions (n = 10, SUVmax = 2.8 ± 1.2) and all 18F-FDG–positive lymph nodes (n = 34). 18F-PARPi uptake was seen in 18F-FDG–negative lymph nodes of 3 patients (n = 6). Focal uptake of tracer in primary and metastatic lesions was corroborated by CT alone or in combination with 18F-FDG. The overall effective dose with 18F-PARPi PET was 3.9 mSv – 5.2 mSv, contrast was high [SUVmax(lesion)/SUVmax(trapezius muscle) = 4.5] and less variable than 18F-FDG when compared with the genioglossus muscle (1.3 vs. 6.0, P = 0.001). Conclusions: Imaging of head and neck cancer with 18F-PARPi is feasible and safe. 18F-PARPi detects primary and metastatic lesions, and retention in tumors is longer than in healthy tissues.
Severity of eczema linked to ability to carry out daily work
Authors: L. Andersen, M.E. Nyeland, F. Nyberg
Journal: British Journal of Dermatology (2020)

Atopic dermatitis (also known as AD or eczema) is a common skin disease which is seen in all countries. It is most common in childhood, and we do not know exactly how common it is in adults. This study reports on a postal survey of adults with AD in France, Germany, the UK, and the USA. The investigators were from the pharmaceutical companies, Leo and Astra Zeneca. Participants completed two surveys, one of which concerned the severity of their skin condition, and the other which recorded any impairment in their ability to carry out work (their employment). Both used questionnaires that had been successfully tested and correctly used previously. 1098 respondents were found to have moderate to severe forms of eczema. The study found that if they had reduced work capacity (i.e. were less able to work) this was directly related to the severity of the AD. For instance, for overall work impairment due to AD, respondents with mild AD reported a mean of 2.4 hours per week of potential work productivity lost, respondents with moderate AD 9.6 hours and respondents with severe AD 19.0 hours. The overall impairment in the capacity of those affected to carry out their daily activities was different in different countries; for instance, in those participants with moderate AD the reduction was 26.7% for all participants, 34.0% for those living in Europe, and 15.2% for those in the USA. The difference was thought to be due to differences in access to social and economic support in different countries. The investigation confirms that moderate or severe atopic dermatitis can have a significant and detrimental effect on the ability of adults with the disease to carry out their normal employment. This is a summary of the study: Increasing severity of atopic dermatitis is associated with a negative impact on work productivity among adults with atopic dermatitis in France, Germany, the U.K. and the U.S.A.
The Early Change in Pa<sub>CO<sub>2</sub></sub>after Extracorporeal Membrane Oxygenation Initiation Is Associated with Neurological Complications
Authors: Yiorgos Alexandros Cavayas, Laveena Munshi, Lorenzo del Sorbo, Eddy Fan
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Large decreases in PaCO2 that occur when initiating extracorporeal membrane oxygenation (ECMO) in patients with respiratory failure may cause cerebral vasoconstriction and compromise brain tissue perfusion.Objectives: To determine if the magnitude of PaCO2 correction upon ECMO initiation is associated with an increased incidence of neurological complications in patients with respiratory failure.Methods: We conducted a multicenter, international, retrospective cohort study using the Extracorporeal Life Support Organization Registry, including adults with respiratory failure receiving ECMO via any mode between 2012 and 2017. The relative change in PaCO2 in the first 24 hours was calculated as (24-h post-ECMO PaCO2 − pre-ECMO PaCO2)/pre-ECMO PaCO2. The primary outcome was the occurrence of neurological complications, defined as seizures, ischemic stroke, intracranial hemorrhage, or brain death.Measurements and Main Results: We included 11,972 patients, 88% of whom were supported with venovenous ECMO. The median relative change in PaCO2 was −31% (interquartile range, −46% to −12%). Neurological complications were uncommon overall (6.9%), with a low incidence of seizures (1.1%), ischemic stroke (1.9%), intracranial hemorrhage (3.5%), and brain death (1.6%). Patients with a large relative decrease in PaCO2 (>50%) had an increased incidence of neurological complications compared with those with a smaller decrease (9.8% vs. 6.4%; P < 0.001). A large relative decrease in PaCO2 was independently associated with neurological complications after controlling for previously described risk factors (odds ratio, 1.7; 95% confidence interval, 1.3 to 2.3; P < 0.001).Conclusions: In patients receiving ECMO for respiratory failure, a large relative decrease in PaCO2 in the first 24 hours after ECMO initiation is independently associated with an increased incidence of neurological complications.
CRISPRi-based radiation modifier screen identifies long non-coding RNA therapeutic targets in glioma
Authors: S. John Liu, Martina Malatesta, Brian V. Lien, Parna Saha, Shivani S. Thombare, Sung Jun Hong, Leslie Pedraza, Mark Koontz, Kyounghee Seo, Max A. Horlbeck, Daniel He, Harjus S. Birk, Miten Jain, Hugh E. Olsen, Mark Akeson, Jonathan S. Weissman, Michelle Monje, Nalin Gupta, David R. Raleigh, Erik M. Ullian, Daniel A. Lim
Journal: Genome biology (2020)

Abstract Background Long non-coding RNAs (lncRNAs) exhibit highly cell type-specific expression and function, making this class of transcript attractive for targeted cancer therapy. However, the vast majority of lncRNAs have not been tested as potential therapeutic targets, particularly in the context of currently used cancer treatments. Malignant glioma is rapidly fatal, and ionizing radiation is part of the current standard-of-care used to slow tumor growth in both adult and pediatric patients. Results We use CRISPR interference (CRISPRi) to screen 5689 lncRNA loci in human glioblastoma (GBM) cells, identifying 467 hits that modify cell growth in the presence of clinically relevant doses of fractionated radiation. Thirty-three of these lncRNA hits sensitize cells to radiation, and based on their expression in adult and pediatric gliomas, nine of these hits are prioritized as lncRNA Glioma Radiation Sensitizers ( lncGRS ). Knockdown of lncGRS-1 , a primate-conserved, nuclear-enriched lncRNA, inhibits the growth and proliferation of primary adult and pediatric glioma cells, but not the viability of normal brain cells. Using human brain organoids comprised of mature neural cell types as a three-dimensional tissue substrate to model the invasive growth of glioma, we find that antisense oligonucleotides targeting lncGRS-1 selectively decrease tumor growth and sensitize glioma cells to radiation therapy. Conclusions These studies identify lncGRS-1 as a glioma-specific therapeutic target and establish a generalizable approach to rapidly identify novel therapeutic targets in the vast non-coding genome to enhance radiation therapy.
Tubule-Specific Mst1/2 Deficiency Induces CKD via YAP and Non-YAP Mechanisms
Authors: Chunhua Xu, Li Wang, Yu Zhang, Wenling Li, Jinhong Li, Yang Wang, Chenling Meng, Jinzhong Qin, Zhi-Hua Zheng, Hui-Yao Lan, Kingston King-Lun Mak, Yu Huang, Yin Xia
Journal: Journal of the American Society of Nephrology (2020)

The serine/threonine kinases MST1 and MST2 are core components of the Hippo pathway, which has been found to be critically involved in embryonic kidney development. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are the pathway's main effectors. However, the biologic functions of the Hippo/YAP pathway in adult kidneys are not well understood, and the functional role of MST1 and MST2 in the kidney has not been studied.We used immunohistochemistry to examine expression in mouse kidneys of MST1 and MST2, homologs of Hippo in Drosophila. We generated mice with tubule-specific double knockout of Mst1 and Mst2 or triple knockout of Mst1, Mst2, and Yap. PCR array and mouse inner medullary collecting duct cells were used to identify the primary target of Mst1/Mst2 deficiency.MST1 and MST2 were predominantly expressed in the tubular epithelial cells of adult kidneys. Deletion of Mst1/Mst2 in renal tubules increased activity of YAP but not TAZ. The kidneys of mutant mice showed progressive inflammation, tubular and glomerular damage, fibrosis, and functional impairment; these phenotypes were largely rescued by deletion of Yap in renal tubules. TNF-α expression was induced via both YAP-dependent and YAP-independent mechanisms, and TNF-α and YAP amplified the signaling activities of each other in the tubules of kidneys with double knockout of Mst1/Mst2.Our findings show that tubular Mst1/Mst2 deficiency leads to CKD through both the YAP and non-YAP pathways and that tubular YAP activation induces renal fibrosis. The pathogenesis seems to involve the reciprocal stimulation of TNF-α and YAP signaling activities.
Postingestive Modulation of Food Seeking Depends on Vagus-Mediated Dopamine Neuron Activity
Authors: Ana B. Fernandes, Joaquim Alves da Silva, Joana Almeida, Guohong Cui, Charles R. Gerfen, Rui M. Costa, Albino J. Oliveira-Maia
Journal: Neuron (2020)

Postingestive nutrient sensing can induce food preferences. However, much less is known about the ability of postingestive signals to modulate food-seeking behaviors. Here we report a causal connection between postingestive sucrose sensing and vagus-mediated dopamine neuron activity in the ventral tegmental area (VTA), supporting food seeking. The activity of VTA dopamine neurons increases significantly after administration of intragastric sucrose, and deletion of the NMDA receptor in these neurons, which affects bursting and plasticity, abolishes lever pressing for postingestive sucrose delivery. Furthermore, lesions of the hepatic branch of the vagus nerve significantly impair postingestive-dependent VTA dopamine neuron activity and food seeking, whereas optogenetic stimulation of left vagus nerve neurons significantly increases VTA dopamine neuron activity. These data establish a necessary role of vagus-mediated dopamine neuron activity in postingestive-dependent food seeking, which is independent of taste signaling.
Inside the heart of COVID-19
Authors: Rui Adão, Tomasz J Guzik
Journal: Cardiovascular Research (2020)

No abstract. Commentary on ‘Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China’, by D. Wang et al., JAMA 2020; doi:10.1001/jama.2020.1585.