tbuckley/cabot-search huggingface dataset:
A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence
Authors: Vineet D Menachery, Boyd L Yount, Kari Debbink, Sudhakar Agnihothram, Lisa E Gralinski, Jessica A Plante, Rachel L Graham, Trevor Scobey, Xing-Yi Ge, Eric F Donaldson, Scott H Randell, Antonio Lanzavecchia, Wayne A Marasco, Zhengli-Li Shi, Ralph S Baric
Journal: Nature Medicine (2015)

The emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome (MERS)-CoV underscores the threat of cross-species transmission events leading to outbreaks in humans. Here we examine the disease potential of a SARS-like virus, SHC014-CoV, which is currently circulating in Chinese horseshoe bat populations. Using the SARS-CoV reverse genetics system, we generated and characterized a chimeric virus expressing the spike of bat coronavirus SHC014 in a mouse-adapted SARS-CoV backbone. The results indicate that group 2b viruses encoding the SHC014 spike in a wild-type backbone can efficiently use multiple orthologs of the SARS receptor human angiotensin converting enzyme II (ACE2), replicate efficiently in primary human airway cells and achieve in vitro titers equivalent to epidemic strains of SARS-CoV. Additionally, in vivo experiments demonstrate replication of the chimeric virus in mouse lung with notable pathogenesis. Evaluation of available SARS-based immune-therapeutic and prophylactic modalities revealed poor efficacy; both monoclonal antibody and vaccine approaches failed to neutralize and protect from infection with CoVs using the novel spike protein. On the basis of these findings, we synthetically re-derived an infectious full-length SHC014 recombinant virus and demonstrate robust viral replication both in vitro and in vivo. Our work suggests a potential risk of SARS-CoV re-emergence from viruses currently circulating in bat populations.
The Broad Approach of a Structural Intervention Study and the Lack of Effect Detection
Authors: William J. Woods, Lance M. Pollack, Diane Binson
Journal: JAMA Pediatrics (2015)

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 Pediatrics 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 Pediatrics journal
Occurrence and Recurrence of Attempted Suicide Among People With Epilepsy
Authors: Dale C. Hesdorffer, Lianna Ishihara, David J. Webb, Lakshmi Mynepalli, Nicholas W. Galwey, W. Allen Hauser
Journal: JAMA Psychiatry (2015)

People with epilepsy have a 5-fold increased risk of suicide. Less is known about attempted suicide and whether psychiatric disorders and antiepileptic drugs modify the risk of attempted suicide.To estimate the magnitude of the association between attempted suicide and epilepsy by comparing a first suicide attempt and a second suicide attempt (hereafter referred to as a recurrent suicide attempt) among people before they received a diagnosis of epilepsy (case patients) with a first suicide attempt and a recurrent suicide attempt among people without epilepsy (control patients), and to evaluate the effect of comorbid psychiatric disorders and the exclusion of antiepileptic drug prescriptions on this association.Population-based retrospective cohort study in the United Kingdom of case patients with incident epilepsy and control patients without a history of epilepsy in a general practice setting using Clinical Practice Research Datalink. The case patients with incident epilepsy were identified between 1987 and 2013 and were 10 to 60 years of age. The control patients for each case patient were 4 randomly selected people who did not receive a diagnosis of epilepsy before the case patient's epilepsy was diagnosed (the index date), matched by year of birth, sex, and general practice for a control to case ratio of 4 to 1.Hazard ratio for incident and recurrent suicide attempts among case patients with epilepsy compared with control patients without.For 14,059 case patients (median age, 36 years [range, 10-60 years]) who later had an onset of epilepsy vs 56,184 control patients (median age, 36 years [range, 10-60 years]), the risk was increased 2.9-fold (95% CI, 2.5- to 3.4-fold) for a first suicide attempt during the time period before the case patients received a diagnosis of epilepsy. For 278 case patients (median age, 37 years [range, 10-61 years]) who later had an onset of epilepsy vs 434 control patients (median age, 35 years [range, 11-61 years]), the risk was increased 1.8-fold (95% CI, 1.3- to 2.5-fold) for a recurrent suicide attempt up to and including the day that epilepsy was diagnosed. Exclusion of antiepileptic drugs prescribed before the index date did not meaningfully alter the findings, nor did separate analyses of patients with and patients without diagnosed psychiatric disorders.Suicide attempts and recurrent suicide attempts are associated with epilepsy even before epilepsy manifests, suggesting a common underlying biology. Our findings indicate that both incident and recurrent suicide attempts are associated with incident epilepsy in the absence of antiepileptic drugs and in the absence of diagnosed psychiatric disorders, further strengthening the evidence for a common underlying etiology with an as-yet-unknown mechanism.
Disruption of<i>in vivo</i>Chronic Lymphocytic Leukemia Tumor–Microenvironment Interactions by Ibrutinib – Findings from an Investigator-Initiated Phase II Study
Authors: Carsten U. Niemann, Sarah E.M. Herman, Irina Maric, Julio Gomez-Rodriguez, Angelique Biancotto, Betty Y. Chang, Sabrina Martyr, Maryalice Stetler-Stevenson, Constance M. Yuan, Katherine R. Calvo, Raul C. Braylan, Janet Valdez, Yuh Shan Lee, Deanna H. Wong, Jade Jones, Clare Sun, Gerald E. Marti, Mohammed Z.H. Farooqui, Adrian Wiestner
Journal: Clinical Cancer Research (2015)

Chronic lymphocytic leukemia (CLL) cells depend on microenvironmental interactions for proliferation and survival that are at least partially mediated through B-cell receptor (BCR) signaling. Ibrutinib, a Bruton tyrosine kinase inhibitor, disrupts BCR signaling and leads to the egress of tumor cells from the microenvironment. Although the on-target effects on CLL cells are well defined, the impact on the microenvironment is less well studied. We therefore sought to characterize the in vivo effects of ibrutinib on the tumor microenvironment.Patients received single-agent ibrutinib on an investigator-initiated phase II trial. Serial blood and tissue samples were collected pretreatment and during treatment. Changes in cytokine levels, cellular subsets, and microenvironmental interactions were assessed.Serum levels of key chemokines and inflammatory cytokines decreased significantly in patients on ibrutinib. Furthermore, ibrutinib treatment decreased circulating tumor cells and overall T-cell numbers. Most notably, a reduced frequency of the Th17 subset of CD4(+)T cells was observed concurrent with reduced expression of activation markers and PD-1 on T cells. Consistent with direct inhibition of T cells, ibrutinib inhibited Th17 differentiation of murine CD4(+)T cells in vitro Finally, in the bone marrow microenvironment, we found that ibrutinib disaggregated the interactions of macrophages and CLL cells, inhibited secretion of CXCL13, and decreased the chemoattraction of CLL cells.In conjunction with inhibition of BCR signaling, these changes in the tumor microenvironment likely contribute to the antitumor activity of ibrutinib and may impact the efficacy of immunotherapeutic strategies in patients with CLL. See related commentary by Bachireddy and Wu, p. 1547.
Occult hemorrhage in children with severe ITP
Authors: Adolfo Flores, George R. Buchanan
Journal: American Journal of Hematology (2015)

Little is known about the frequency and significance of clinically unapparent or occult hemorrhage in ITP. Therefore, we prospectively explored the sites and frequency of occult bleeding in children with severe ITP at diagnosis or upon symptomatic relapse in a prospective, single-institution cohort study of patients ≤ 18 years of age and a platelet count ≤ 10,000/mm(3) . Data collected included bleeding severity assessment, urinalysis, fecal occult blood testing, and non-contrast brain MRI. Stool and urine samples were tested within 7 days of diagnosis or symptomatic relapse. Three months after diagnosis or relapse a noncontrast brain MRI evaluated hemosiderin deposits resulting from prior localized hemorrhage. Fifty-two ITP patients were enrolled with a mean platelet count of 4,000/mm(3) . A significant occurrence of occult hemorrhage was identified in the urine (27%) compared with clinically overt hematuria (0.91%, P < 0.0005). CNS microbleeding in the superficial cortex of the left frontal lobe was identified in one child with occult bleeding in the urinary tract. There was no relationship between occult hemorrhage and bleeding manifestations on physical examination. Occult hemorrhage was not a harbinger of subsequent bleeding. Our findings suggest that occult hemorrhage occurs with greater frequency than overt bleeding in children with severe ITP. CNS microbleeding is a potential risk in this patient population. Assessment of brain microbleeds and microscopic hematuria in this patient population require additional study.
PWE-260 Elderly patients undergoing laparoscopic resection for colorectal cancer have better survival than patients undergoing open surgery
Authors: A Askari, S Nachiappan, A Currie, A Bottle, T Athanasiou, O Faiz
Journal: Gut (2015)

<h3>Introduction</h3> Elderly patients are at increased risk of death following surgery for colorectal cancer, even in the elective setting. This national study aims to examine the relationship between patient selection for laparoscopic resection and survival in an elderly cohort. <h3>Method</h3> Elderly patients (80 years and over) undergoing elective colorectal cancer resection between the years 2001–2011 were identified from the Hospital Episode Statistics (HES) database. Mortality data from Office for National Statistics (ONS) were obtained. Survival analyses using multivariable cox proportional hazard regression were carried. Confounding variables such as gender, medical comorbidity, type of operation and chemotherapy were adjusted for. <h3>Results</h3> In the time period, 5,398 elderly patients underwent elective colorectal cancer resection, of which 1,479 patients (27.4%) underwent laparoscopic resection. The mean 5-year survival in the open group was 41.0 months (95% CI 40.3–41.7) in the open group compared with 52.3 months (95% CI 51.2–53.3) in the laparoscopic group (p &lt; 0.001). Multivariable cox hazard regression, demonstrated laparoscopic resection to have a 61% survival benefit over open surgery in elderly patients (HR 0.39, CI 0.33–0.45, p &lt; 0.001). This survival benefit persisted, even when adjusting for immediate (90-day) post-operative mortality (HR 0.40, CI 0.32–0.44, p &lt; 0.001). <h3>Conclusion</h3> Laparoscopic resections for colorectal cancer confer a survival advantage beyond the immediate post operative period in elderly patients. Offering this high-risk patient group elective laparoscopic resections in experienced units could help deliver better outcomes. <h3>Disclosure of interest</h3> None Declared.
Symptom Monitoring With Patient-Reported Outcomes During Routine Cancer Treatment: A Randomized Controlled Trial
Authors: Ethan Basch, Allison M. Deal, Mark G. Kris, Howard I. Scher, Clifford A. Hudis, Paul Sabbatini, Lauren Rogak, Antonia V. Bennett, Amylou C. Dueck, Thomas M. Atkinson, Joanne F. Chou, Dorothy Dulko, Laura Sit, Allison Barz, Paul Novotny, Michael Fruscione, Jeff A. Sloan, Deborah Schrag
Journal: Journal of Clinical Oncology (2015)

Purpose There is growing interest to enhance symptom monitoring during routine cancer care using patient-reported outcomes, but evidence of impact on clinical outcomes is limited. Methods We randomly assigned patients receiving routine outpatient chemotherapy for advanced solid tumors at Memorial Sloan Kettering Cancer Center to report 12 common symptoms via tablet computers or to receive usual care consisting of symptom monitoring at the discretion of clinicians. Those with home computers received weekly e-mail prompts to report between visits. Treating physicians received symptom printouts at visits, and nurses received e-mail alerts when participants reported severe or worsening symptoms. The primary outcome was change in health-related quality of life (HRQL) at 6 months compared with baseline, measured by the EuroQol EQ-5D Index. Secondary endpoints included emergency room (ER) visits, hospitalizations, and survival. Results Among 766 patients allocated, HRQL improved among more participants in the intervention group than usual care (34% v 18%) and worsened among fewer (38% v 53%; P < .001). Overall, mean HRQL declined by less in the intervention group than usual care (1.4- v 7.1-point drop; P < .001). Patients receiving intervention were less frequently admitted to the ER (34% v 41%; P = .02) or hospitalized (45% v 49%; P = .08) and remained on chemotherapy longer (mean, 8.2 v 6.3 months; P = .002). Although 75% of the intervention group was alive at 1 year, 69% with usual care survived the year (P = .05), with differences also seen in quality-adjusted survival (mean of 8.7 v. 8.0 months; P = .004). Benefits were greater for participants lacking prior computer experience. Most patients receiving intervention (63%) reported severe symptoms during the study. Nurses frequently initiated clinical actions in response to e-mail alerts. Conclusion Clinical benefits were associated with symptom self-reporting during cancer care.
The SELECT study: A multicenter phase II trial of adjuvant erlotinib in resected epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC).
Authors: Joel W. Neal, Nathan A. Pennell, Ramaswamy Govindan, Michael Lanuti, Rachel Pam Greenerger Rosovsky, Rebecca Suk Heist, Alice Tsang Shaw, Jennifer S. Temel, Alona Muzikansky, Pasi A. Janne, Thomas James Lynch, Christopher G. Azzoli, Lecia V. Sequist
Journal: Journal of Clinical Oncology (2012)

7010 Background: Cancers with activating EGFR mutations are exquisitely sensitive to EGFR tyrosine kinase inhibitors (TKIs) and retrospective data suggests adjuvant TKIs may improve outcomes in EGFR mutants. This prospective trial investigates the safety and efficacy of adjuvant erlotinib in EGFR mutation-positive NSCLC. Methods: Patients (pts) with surgically resected stage IA-IIIA NSCLC harboring activating EGFR mutations were treated with 150 mg/day of erlotinib for 2 years (y) after completion of any standard adjuvant chemotherapy and/or radiotherapy. The trial was designed to enroll 36 patients, and powered to demonstrate a primary endpoint of 2 y disease free survival (DFS) exceeding 85%, which would suggest improvement over the historically expected 70% 2 y DFS in early stage EGFR-mutant NSCLC (J Thorac Oncol 6:569). Results: Thirty-six pts were enrolled at five sites between 1/08 and 11/09; 53% stage I; 19% stage II; 28% stage IIIA. Toxicities were typical of erlotinib; no grade 4 or 5 events or pneumonitis occurred. 8 pts (22%) required one dose reduction to 100 mg/day and 5 (14%) two reductions to 50 mg/day for grade 3 or persistent grade 2 toxicities. 11 pts discontinued before 2 full years (&lt;1 month (mo) [4], 1-12 mo [2] and 12-23 mo [5]) for toxicities [6], patient preference [3], prostate cancer [1] and recurrence [1]. After a median follow-up of 2.5 y, the 2 y DFS from enrollment is 94% (95% CI 80%, 99%). 10 patients have recurred, 1 during erlotinib treatment and the others after stopping erlotinib (interval before recurrence 2 mo [1], 6-12 mo [4], &gt;12 mo [4]). Genotyping on repeat biopsies from seven of the recurrent cases is underway, as is assessment of response to subsequent erlotinib therapy. Two pts have died of recurrence: one at 1.5 y who stopped erlotinib after 1 mo for toxicity, and one at 2 y who progressed while on erlotinib. Conclusions: This is the first prospective study to report the efficacy of adjuvant erlotinib in NSCLC pts with EGFR mutations. This approach is feasible and yields excellent 2y DFS compared to historical genotype-matched controls. This trial was subsequently expanded to 100 pts to permit subgroup analysis by stage.
Fully Magnetically Levitated Left Ventricular Assist System for Treating Advanced HF
Authors: Ivan Netuka, Poornima Sood, Yuriy Pya, Daniel Zimpfer, Thomas Krabatsch, Jens Garbade, Vivek Rao, Michiel Morshuis, Silvana Marasco, Friedhelm Beyersdorf, Laura Damme, Jan D. Schmitto
Journal: Journal of the American College of Cardiology (2015)

The HeartMate 3 left ventricular assist system (LVAS) is intended to provide long-term support to patients with advanced heart failure. The centrifugal flow pump is designed for enhanced hemocompatibility by incorporating a magnetically levitated rotor with wide blood-flow paths and an artificial pulse.The aim of this single-arm, prospective, multicenter study was to evaluate the performance and safety of this LVAS.The primary endpoint was 6-month survival compared with INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support)-derived performance goal. Patients were adults with ejection fraction ≤ 25%, cardiac index ≤ 2.2 l/min/m(2) without inotropes or were inotrope-dependent on optimal medical management, or listed for transplant.Fifty patients were enrolled at 10 centers. The indications for LVAS support were bridge to transplantation (54%) or destination therapy (46%). At 6 months, 88% of patients continued on support, 4% received transplants, and 8% died. Thirty-day mortality was 2% and 6-month survival 92%, which exceeded the 88% performance goal. Support with the fully magnetically levitated LVAS significantly reduced mortality risk by 66% compared with the Seattle Heart Failure Model-predicted survival of 78% (p = 0.0093). Key adverse events included reoperation for bleeding (14%), driveline infection (10%), gastrointestinal bleeding (8%), and debilitating stroke (modified Rankin Score > 3) (8%). There were no pump exchanges, pump malfunctions, pump thrombosis, or hemolysis events. New York Heart Association classification, 6-min walk test, and quality-of-life scores showed progressive and sustained improvement.The results show that the fully magnetically levitated centrifugal-flow chronic LVAS is safe, with high 30-day and 6-month survival rates, a favorable adverse event profile, and improved quality of life and functional status. (HeartMate 3™ CE Mark Clinical Investigation Plan [HM3 CE Mark]; NCT02170363).
Spontaneous production of interleukin-6 by Ki-1-positive large-cell anaplastic lymphoma with extensive bone destruction [letter]
Authors: K Agematsu, S Takeuchi, M Ichikawa, A Yabuhara, Y Uehara, H Kawai, Y Miyagawa, K Ishii, T Katsuyama, T Nakahata
Journal: Blood (1991)
Recurrent Fusions in <i>MYB</i> and <i>MYBL1</i> Define a Common, Transcription Factor–Driven Oncogenic Pathway in Salivary Gland Adenoid Cystic Carcinoma
Authors: Kathryn J. Brayer, Candace A. Frerich, Huining Kang, Scott A. Ness
Journal: Cancer Discovery (2015)

Abstract Adenoid cystic carcinoma (ACC), the second most common malignancy of salivary glands, is a rare tumor with a bleak prognosis for which therapeutic targets are unavailable. We used RNA sequencing (RNA-seq) to analyze low-quality RNA from archival, formaldehyde-fixed, paraffin-embedded samples. In addition to detecting the most common ACC translocation, t(6;9) fusing the MYB proto-oncogene to NFIB, we also detected previously unknown t(8;9) and t(8;14) translocations fusing the MYBL1 gene to the NFIB and RAD51B genes, respectively. RNA-seq provided information about gene fusions, alternative RNA splicing, and gene expression signatures. Interestingly, tumors with MYB and MYBL1 translocations displayed similar gene expression profiles, and the combined MYB and MYBL1 expression correlated with outcome, suggesting that the related MYB proteins are interchangeable oncogenic drivers in ACC. Our results provide important details about the biology of ACC and illustrate how archival tissue samples can be used for detailed molecular analyses of rare tumors. Significance: Using RNA-seq to perform whole-transcriptome analysis of archival ACC tumor samples, we identified novel, recurrent gene fusions, detected alternative RNA splicing, and established gene expression signatures that provide detailed information about the biology of ACC tumors. Cancer Discov; 6(2); 176–87. ©2015 AACR. See related commentary by Gonda and Ramsay, p. 125. This article is highlighted in the In This Issue feature, p. 109
Bias-Corrected Targeted Next-Generation Sequencing for Rapid, Multiplexed Detection of Actionable Alterations in Cell-Free DNA from Advanced Lung Cancer Patients
Authors: Cloud P. Paweletz, Adrian G. Sacher, Chris K. Raymond, Ryan S. Alden, Allison O'Connell, Stacy L. Mach, Yanan Kuang, Leena Gandhi, Paul Kirschmeier, Jessie M. English, Lee P. Lim, Pasi A. Jänne, Geoffrey R. Oxnard
Journal: Clinical Cancer Research (2015)

Tumor genotyping is a powerful tool for guiding non-small cell lung cancer (NSCLC) care; however, comprehensive tumor genotyping can be logistically cumbersome. To facilitate genotyping, we developed a next-generation sequencing (NGS) assay using a desktop sequencer to detect actionable mutations and rearrangements in cell-free plasma DNA (cfDNA).An NGS panel was developed targeting 11 driver oncogenes found in NSCLC. Targeted NGS was performed using a novel methodology that maximizes on-target reads, and minimizes artifact, and was validated on DNA dilutions derived from cell lines. Plasma NGS was then blindly performed on 48 patients with advanced, progressive NSCLC and a known tumor genotype, and explored in two patients with incomplete tumor genotyping.NGS could identify mutations present in DNA dilutions at ≥ 0.4% allelic frequency with 100% sensitivity/specificity. Plasma NGS detected a broad range of driver and resistance mutations, including ALK, ROS1, and RET rearrangements, HER2 insertions, and MET amplification, with 100% specificity. Sensitivity was 77% across 62 known driver and resistance mutations from the 48 cases; in 29 cases with common EGFR and KRAS mutations, sensitivity was similar to droplet digital PCR. In two cases with incomplete tumor genotyping, plasma NGS rapidly identified a novel EGFR exon 19 deletion and a missed case of MET amplification.Blinded to tumor genotype, this plasma NGS approach detected a broad range of targetable genomic alterations in NSCLC with no false positives including complex mutations like rearrangements and unexpected resistance mutations such as EGFR C797S. Through use of widely available vacutainers and a desktop sequencing platform, this assay has the potential to be implemented broadly for patient care and translational research.
Targeting megakaryocytic-induced fibrosis in myeloproliferative neoplasms by AURKA inhibition
Authors: Qiang Jeremy Wen, Qiong Yang, Benjamin Goldenson, Sébastien Malinge, Terra Lasho, Rebekka K Schneider, Lawrence J Breyfogle, Rachael Schultz, Laure Gilles, Priya Koppikar, Omar Abdel-Wahab, Animesh Pardanani, Brady Stein, Sandeep Gurbuxani, Ann Mullally, Ross L Levine, Ayalew Tefferi, John D Crispino
Journal: Nature Medicine (2015)