tbuckley/cabot-search huggingface dataset:
Survival of patients with metastatic HER2 positive gastroesophageal cancer treated with second-line chemotherapy plus trastuzumab or ramucirumab after progression on frontline chemotherapy plus trastuzumab.
Authors: Justin Moser, Benjamin Solomon, Christopher Duane Nevala-Plagemann, Glynn Weldon Gilcrease, Jonathan R. Whisenant, Ignacio Garrido-Laguna
Journal: Journal of Clinical Oncology (2019)

69 Background: Optimal second line treatment for patients with metastatic HER2 positive gastroesophageal cancer (Her2GE) is unknown. A retrospective study has suggested continuation of chemotherapy with trastuzumab (CT), as compared to chemotherapy alone, may improve outcomes. However, CT has never been compared to the current standard second-line treatment of chemotherapy plus ramucirumab (CR). Methods: The Flatiron Health EHR-derived database, a nationally representative database comprising patient-level structured and unstructured data, curated via technology-enabled abstraction, was reviewed for patients with metastatic Her2GE who received CT in the first line setting, followed by either second line CT or CR. Survival from second line therapy (SST) and time to next therapy or death (TTNTD) were compared using Kaplan-Meier curves and Log-Rank analysis. Demographics between treatment groups were compared using standard T tests and chi-squared analysis. Results: 135 patients were identified, of whom 34 received second-line CR and 101 received CT. Median SST for patients treated with CT was 10.2 months (m) [interquartile range (IQR) 5.1-20.8] and 6.8 m (IQR 3.2-20.2) for those treated with CR, p = 0.39. Median TTNTD for patients treated with CT versus CR was 4.9 m (IQR 2.8-9.8) and 4.8 m (IQR 2.3-7.5), respectively (p = 0.53). There was no difference between patients who received CT or CR in regards to average age (63 vs. 62, p = 0.72), average duration of first-line therapy (7.8 m vs. 9.1 m, p = 0.36), or percentage of patients with ECOG &gt; 1 (15% vs. 22%, p = 0.50). Patients who received CT were more likely to receive a multiagent chemotherapy backbone (76% vs. 3%, p ≤ 0.001). Conclusions: This data suggest a non-significant trend towards increased SST for patients treated with second line CT versus CR. Further studies are needed to clarify optimal second-line treatment for this patient population.
Changes in food spending among food allergic families following the COVID-19 pandemic
Authors: Michael Golding, Catherine Lemoine-Courcelles, Elissa Abrams, Moshe Ben-Shoshan, Edmond Chan, Derek Chu, Jennifer Gerdts, Harold Kim, Elinor Simons, Julia Upton, Jennifer Protudjer
Journal: Journal of Allergy and Clinical Immunology (2021)

Efforts to combat the spread of COVID-19 have disrupted food supply chains and shifted consumption patterns leading to increased food prices and shortages of some products. It is hypothesized that these changes may disproportionately affect food allergic families given their restricted diet. Between 1 May and 30 June 2020, 205 families completed an online questionnaire that assessed food spending before and after the outbreak of COVID-19. Of these families, 171 had at least one member with a physician-diagnosed food allergy, while 34 families reported no food allergic members. Logistic regression analyses were used to assess changes in food spending among food allergic and non-food allergic families. Pandemic duration and the prevalence of COVID-19 in each participant's province were included as covariates. Relative to families without a food allergic member, food allergic families were 2.37 times more likely to report increased spending on food following the outbreak of COVID-19 (95%CI=1.08, 5.21, p=.03). An analysis of these families revealed that monthly spending on food increased by an average of 23% (e.g., $191.28 CAD, SD=31.13) following the pandemic. Moreover, results indicated that among food allergic families, increased spending on food was associated with a lack of food availability (OR=2.63; 95%CI=1.28, 5.41, p=.01). Results from the current study suggest that food allergic families are particularly affected by changes in the price and availability of food that have followed the COVID-19 pandemic. Policy makers should consider this increased burden when developing policies aimed at lessening the financial impact of COVID-19 on families.
Eradication success for non-tuberculous mycobacteria in children with cystic fibrosis
Authors: Dominic A. Hughes, Idan Bokobza, Siobhán B. Carr
Journal: European Respiratory Journal (2021)

<b>Non-tuberculous mycobacteria pulmonary disease affects cystic fibrosis lung health and increasingly affects children. This study reports treatment outcomes from a large CF centre, with eradication rates exceeding 60% for <i>M. abscessus</i> complex infection.</b>https://bit.ly/2L8TdFM
Exploratory biomarkers in the HGF/SF:c-Met axis: preclinical and clinical results
Authors: Angela Coxon, Karen Rex, Jan Sun, Jodi Moriguchi, Jennifer Malella, Mark Ma, Abraham Anderson, Yun Lan, Michael Gordon, Lia Gore, Christopher Sweeney, Lucy Yan, Darrin Beaupre, Kelly Oliner, Teresa Burgess
Journal: Cancer Research (2008)

2804  Introduction: Hepatocyte growth factor (HGF - also known as Scatter Factor (SF)) and its receptor, c-Met, have been implicated in the progression of several types of cancers. AMG 102 is a fully human monoclonal antibody to HGF that is currently in phase 2 clinical trials as a cancer therapeutic. We have previously shown that this antibody can significantly inhibit the growth of HGF-dependent tumor models, including the U-87 MG model of glioblastoma. Here we examined exploratory biomarkers that might be useful pharmacodynamic or patient enrichment markers for HGF/SF:c-Met therapies in the clinic.  Methods: In preclinical experiments, CD-1 nude mice were injected with 5x106 U-87 MG human glioblastoma cells. When tumors reached an average volume of 475 mm3, mice were treated with a single dose of AMG 102 ranging from 3- 300 µg IP. On days 3 and 7 after treatment initiation, plasma was harvested and levels of total human HGF, soluble human c-Met and CD44v6 (a c-Met associated protein) were quantified by ELISA. Plasma samples from patients enrolled in the AMG 102 FIH trial were also examined. Total HGF and soluble c-Met levels were determined in plasma from patients in sequential dose cohorts (4-6 pts/cohort) that had been treated with AMG 102 at 0.5, 1, 3, 5, 10, or 20 mg/kg.  Results: Tumor-derived, human HGF levels in the plasma of mice treated with isotype control antibody correlated with tumor volume (133 to 399 pg/mL). As previously shown, treatment with AMG 102 led to a dose-dependent reduction in tumor volume. However, despite the reduction in tumor mass, AMG 102 treatment also resulted in a dose-dependent increase in total HGF levels, (up to 1300 and 5476 pg/mL on day 3 and day 7 post treatment, respectively). In contrast, soluble human c-Met and CD44v6 levels correlated with tumor size, regardless of treatment. In all patients, we observed a similar dose-dependent increase in the levels of plasma HGF upon treatment with AMG 102. In the high-dose cohorts HGF reached a plateau by day 8. Pharmacokinetic measurements of AMG 102 suggest that even at the highest levels of plasma HGF measured, AMG 102 is in great excess. Soluble c-Met levels did not change with AMG 102 treatment.  Conclusions: Targeting the HGF/SF:c-Met axis is a promising oncology therapeutic strategy. We have shown that treatment of tumor bearing mice or cancer patients with AMG 102 gives rise to a dose-dependent increase in circulating HGF levels. This suggests that monitoring HGF levels during treatment may serve as a biomarker for inhibition of the HGF/SF:c-Met pathway, in addition to its potential utility as a patient enrichment marker.
Abstract PO048: Inhibition of P300 histone acetyltransferase activity rescues invasive phenotypes of ARID1A-deficient endometrial epithelium
Authors: Mike R. Wilson, Jake J. Reske, Ronald L. Chandler
Journal: Clinical Cancer Research (2021)

Abstract Invasion is a hallmark feature of endometrial pathologies, including myometrial invasion of endometrial cancer and invasion of distal sites during endometriosis. Mutations in the chromatin remodeling protein ARID1A have been observed at high rates in endometrial cancer and endometriosis. ARID1A loss, in combination with phosphoinositide 3-kinase (PI3K) pathway activation, has been shown to induce invasion phenotypes in the endometrial epithelium. Using bioinformatic approaches, we identified histone acetyltransferase (HAT) protein P300 as potential co-regulator of ARID1A-deficient gene expression programs. Knockdown of P300 prevented invasive phenotypes in a genetically engineered mouse model and human endometrial epithelial cells through induction of apoptosis, indicating a synthetic-lethal relationship between ARID1A and P300 in the endometrial epithelium. Using the novel HAT inhibitor, A-485, we identified P300 HAT activity as the mechanism by which P300 promotes invasive phenotypes. A-485 treatment rescued invasion in vitro at concentrations which had no effect on cell viability in adherent culture, but induced anoikis in suspension culture. Using an RNA-seq approach, we identified cell adhesion and migration pathways as being regulated by ARID1A knockdown and P300 co-knockdown or A-485 co-treatment. Among genes in these pathways, we identified SERPINE1 as an essential component of P300-dependent invasive processes. SERPINE1 is overexpressed following ARID1A loss in mouse and human models, and SERPINE1 knockdown rescued invasive phenotypes following ARID1A loss. By chromatin immunoprecipitation, we identified a role for P300-dependent acetylation of histone 3 lysine 27 (H3K27ac) at the SERPINE1 super-enhancer. The novel P300 bromodomain inhibitor CCS1477 also rescues invasion and SERPINE1 expression following ARID1A loss, suggesting a role for bromodomain inhibition as a modulator of P300 H3K27ac deposition. These studies suggest the therapeutic utility of P300 inhibition to induce anoikis in mutant endometrium which has detached from the basement membrane, thereby preventing invasion. Citation Format: Mike R. Wilson, Jake J. Reske, Ronald L. Chandler. Inhibition of P300 histone acetyltransferase activity rescues invasive phenotypes of ARID1A-deficient endometrial epithelium [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO048.
Primary Hepatic Squamous Cell Carcinoma With High Microsatellite Instability Shows Good Response to Programmed Cell Death 1 Inhibitor as Adjuvant Therapy
Authors: Ke Wang, Cai De Lu, Jian Nan Sun, Chun Nian Wang, Guo Gao, Yang Ke Hu, Hui Zhi Zhang, Ding Zhang, Sheng Dong Wu
Journal: Hepatology (2021)
Central Nervous System Complications of Erdheim-Chester Disease
Authors: Nuh Filizoglu, Salih Ozguven, Tunc Ones, Halil Turgut Turoglu, Tanju Yusuf Erdil
Journal: Clinical Nuclear Medicine (2021)

Erdheim-Chester disease is an uncommon non-Langerhans cell histiocytosis. The diagnosis depends on imaging and histological criteria. The most common presentation is the multiple bone lesions with involvement of at least 1 more organ. We present the FDG PET/CT findings of a 19-year-old man who presented with central nervous system symptoms such as progressive polyuria, polydipsia, gait disturbances, and eye pain and was later diagnosed with Erdheim-Chester disease.
Abstract 117: Poly (i:c) Attenuates Myocardial I/R Injury via Glycolytic Dependent Yap Activation and by Suppression of MiR-143
Authors: Yuanping Hu, Xiaohui Wang, Tuanzhu Ha, John Kalbfleisch, Race Kao, David Williams, Chuanfu Li
Journal: Circulation Research (2016)

Glycolytic metabolism plays a critical role in ischemia/reperfusion (I/R) injury. The Yes associated protein (YAP) is a core effector of the Hippo pathway that regulates cell proliferation and apoptosis. We observed that poly (I:C) enhanced glycolysis and Yap activation in neonatal cardiomyocytes. This study investigated whether poly (I:C) will attenuate myocardial I/R injury via a glycolytic dependent mechanism. Mice (n=6/group) were treated with poly (I:C) (10 μg/25g body weight) one h before the hearts were subjected to ischemia (45 min) followed by reperfusion (24 h). Sham surgery served as sham control. Poly (I:C) treatment significantly reduced infarct size by 35% and enhanced EF% by 20.5% and FS% by 24.9% compared with I/R group. The expression of miR-143 was markedly reduced and Yap levels were significantly increased in poly (I:C) treated hearts. In vitro data show that poly (I:C) treatment enhanced extracellular acidification rate (ECAR) and lactate production in HL-1 cardiomyocytes. In vivo inhibition of hexokinase 2 abolished poly (I:C)-induced cardioprotection. To determine the role of miR-143 in regulation of glycolysis, we transfected HL-1 cardiomyocytes with anti-miR-143 mimics before the cells were subjected to hypoxia/reoxygenation. We observed that anti-miR-143 significantly enhanced cell viability, reduced LDH release, and increased hexokinase 2 levels and extracellular acidification rate (ECAR). To determine whether suppression of miR-143 will induce protection against myocardial I/R injury, we loaded anti-miR-143 on exosomes (Exo-antimiR-143) by transection of bone marrow stromal cells with anti-miR-143 mimics. MiR-control mimics served as control (Exo-miR-control). Exo-miR-143 was delivered into the myocardium through the right carotid artery immediately before the hearts (n=6/group) were subjected to I/R. We observed that delivery of Exo-antimiR-143 significantly enhanced EF% by 20.5% and FS% by 26.4% and decreased infarct size by 42.2%, when compared with untreated I/R group. Delivery of Exo-miR-control did not alter I/R-induced cardiac dysfunction and infarct size. We conclude that poly (I:C) attenuates myocardial I/R injury via glycolytic dependent YAP mechanism and suppression of miR-143 expression.
Does Point-Of-Care SARS-CoV-2 Antibody Testing Have Similar Sensitivity and Specificity To High Complexity Serology?
Authors: Kelly O'Shea, Charles Schuler, Jesse Chen, Carmen Gherasim, Donald Giacherio, James Baldwin, James Baker
Journal: Journal of Allergy and Clinical Immunology (2021)

Point-of-care (POC) antibody screening for SARS-CoV-2 infection has yielded varied results. We analyzed two POC antibody testing devices to study whether these are comparable to ELISA testing done in a high complexity CLIA facility employed as a standard. We enrolled 146 individuals, with 41 individuals having had a history of positive PCR for COVID-19. After informed consent, we obtained serum and at the same time performed a finger stick for whole blood. Autobio and MEDsan rapid IgG/IgM tests that use SARS-CoV-2 spike protein to detect antibody were performed with serum and compared to Roche's SARS-CoV-2 immunoassay, which uses nucleocapsid protein to detect antibody. The Autobio test was also evaluated using whole blood obtained by finger stick. Serum testing using the Autobio kit versus the Roche immunoassay (used as the standard for comparison) revealed a sensitivity of 93.2% and a specificity of 96.1%; whole blood testing using the Autobio kit vs. the Roche immunoassay revealed a sensitivity of 90.5% and a specificity of 97.9%. Whole blood compared to serum testing using the Autobio POC kit revealed a sensitivity of 90.7% and a specificity of 99.0%. Serum testing using the MEDsan kit vs. the Roche immunoassay revealed a sensitivity of 100% and a specificity of 96.1%. Despite using different antigens, both the POC devices showed comparable results to the high complexity ELISA. POC testing for antibodies to SARS-CoV-2 is easier, requires fewer resources than high-complexity lab testing and provides rapid results regarding individual antibody status to SARS-CoV-2. However, the specific test characteristics for each kit must be rigorously evaluated, as they vary substantially.
Chest radiography or computed tomography for COVID-19 pneumonia? Comparative study in a simulated triage setting
Authors: Nicola Sverzellati, Christopher J. Ryerson, Gianluca Milanese, Elisabetta A. Renzoni, Annalisa Volpi, Paolo Spagnolo, Francesco Bonella, Ivan Comelli, Paola Affanni, Licia Veronesi, Carmelinda Manna, Andrea Ciuni, Carlotta Sartorio, Giulia Tringali, Mario Silva, Emanuele Michieletti, Davide Colombi, Athol U. Wells
Journal: European Respiratory Journal (2021)

Introduction For the management of patients referred to respiratory triage during the early stages of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) pandemic, either chest radiography or computed tomography (CT) were used as first-line diagnostic tools. The aim of this study was to compare the impact on the triage, diagnosis and prognosis of patients with suspected COVID-19 when clinical decisions are derived from reconstructed chest radiography or from CT. Methods We reconstructed chest radiographs from high-resolution CT (HRCT) scans. Five clinical observers independently reviewed clinical charts of 300 subjects with suspected COVID-19 pneumonia, integrated with either a reconstructed chest radiography or HRCT report in two consecutive blinded and randomised sessions: clinical decisions were recorded for each session. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and prognostic value were compared between reconstructed chest radiography and HRCT. The best radiological integration was also examined to develop an optimised respiratory triage algorithm. Results Interobserver agreement was fair (Kendall's W =0.365, p&lt;0.001) by the reconstructed chest radiography-based protocol and good (Kendall's W =0.654, p&lt;0.001) by the CT-based protocol. NPV assisted by reconstructed chest radiography (31.4%) was lower than that of HRCT (77.9%). In case of indeterminate or typical radiological appearance for COVID-19 pneumonia, extent of disease on reconstructed chest radiography or HRCT were the only two imaging variables that were similarly linked to mortality by adjusted multivariable models Conclusions The present findings suggest that clinical triage is safely assisted by chest radiography. An integrated algorithm using first-line chest radiography and contingent use of HRCT can help optimise management and prognostication of COVID-19.
Right Ventricular Functional Abnormalities in Arrhythmogenic Cardiomyopathy
Authors: Feddo P. Kirkels, Øyvind H. Lie, Maarten J. Cramer, Monica Chivulescu, Christine Rootwelt-Norberg, Folkert W. Asselbergs, Arco J. Teske, Kristina H. Haugaa
Journal: JACC. Cardiovascular imaging (2021)

This study aimed to perform an external validation of the value of right ventricular (RV) deformation patterns and RV mechanical dispersion in patients with arrhythmogenic cardiomyopathy (AC). Secondly, this study assessed the association of these parameters with life-threatening ventricular arrhythmia (VA).Subtle RV dysfunction assessed by echocardiographic deformation imaging is valuable in AC diagnosis and risk prediction. Two different methods have emerged, the RV deformation pattern recognition and RV mechanical dispersion, but these have neither been externally validated nor compared.We analyzed AC probands and mutation-positive family members, matched from 2 large European referral centers. We performed speckle tracking echocardiography, whereby we classified the subtricuspid deformation patterns from normal to abnormal and assessed RV mechanical dispersion from 6 segments. We defined VA as sustained ventricular tachycardia, appropriate implantable cardioverter-defibrillator therapy, or aborted cardiac arrest.We included 160 subjects, 80 from each center (43% proband, 55% women, age 41 ± 17 years). VA had occurred in 47 (29%) subjects. In both cohorts, patients with a history of VA showed abnormal deformation patterns (96% and 100%) and had greater RV mechanical dispersion (53 ± 30 ms vs. 30 ± 21 ms; p < 0.001 for the total cohort). Both parameters were independently associated to VA (adjusted odds ratio: 2.71 [95% confidence interval: 1.47 to 5.00] per class step-up, and 1.26 [95% confidence interval: 1.07 to 1.49]/10 ms, respectively). The association with VA significantly improved when adding RV mechanical dispersion to pattern recognition (net reclassification improvement 0.42; p = 0.02 and integrated diagnostic improvement 0.06; p = 0.01).We externally validated 2 RV dysfunction parameters in AC. Adding RV mechanical dispersion to RV deformation patterns significantly improved the association with life-threatening VA, indicating incremental value.
Efficacy of Lanadelumab in Hereditary Angioedema Patients With and Without Prior Use of Long-Term Prophylaxis: Final Results From the HELP Open-Label Extension Study
Authors: Kim Paes, Jonathan Bernstein, Hilary Longhurst, Emel Aygoren-Pursun, Hong Ren, Timothy Craig
Journal: Journal of Allergy and Clinical Immunology (2021)
The Antibiotic Dosage of Fastest Resistance Evolution: Gene Amplifications Underpinning the Inverted-U
Authors: Carlos Reding, Pablo Catalán, Gunther Jansen, Tobias Bergmiller, Emily Wood, Phillip Rosenstiel, Hinrich Schulenburg, Ivana Gudelj, Robert Beardmore
Journal: Molecular Biology and Evolution (2021)

Abstract To determine the dosage at which antibiotic resistance evolution is most rapid, we treated Escherichia coli in vitro, deploying the antibiotic erythromycin at dosages ranging from zero to high. Adaptation was fastest just below erythromycin’s minimal inhibitory concentration (MIC) and genotype-phenotype correlations determined from whole genome sequencing revealed the molecular basis: simultaneous selection for copy number variation in three resistance mechanisms which exhibited an “inverted-U” pattern of dose-dependence, as did several insertion sequences and an integron. Many genes did not conform to this pattern, however, reflecting changes in selection as dose increased: putative media adaptation polymorphisms at zero antibiotic dosage gave way to drug target (ribosomal RNA operon) amplification at mid dosages whereas prophage-mediated drug efflux amplifications dominated at the highest dosages. All treatments exhibited E. coli increases in the copy number of efflux operons acrAB and emrE at rates that correlated with increases in population density. For strains where the inverted-U was no longer observed following the genetic manipulation of acrAB, it could be recovered by prolonging the antibiotic treatment at subMIC dosages.
Carob-Fruit-Enriched Meat Ameliorates Non-Alcoholic Steatohepatitis In Late–Stage T2DM Rats
Authors: A. Macho-González, A. Garcimartín, M.E. López-Oliva, R. García-Fernández, M. Hernández-Martín, R. Redondo-Castillejo, A. Parfenova, A. Bocanegra, S. Bastida, J. Benedí, F.J. Sánchez-Muniz
Journal: Metabolism (2021)
Progress “painfully slow” on air quality and other environmental issues, inquiry concludes
Authors: Gareth Iacobucci
Journal: BMJ (2021)

The UK government is failing to deliver on its 2011 promise to improve the natural environment “within a generation” and must do more to tackle critical issues like air and water quality, a parliamentary inquiry has concluded.

The Public Accounts Committee said in a report1 that the complexity of environmental issues “is not a good enough excuse” for serious delays in tackling them, where progress has been “painfully slow.” The committee noted that the government’s 25 Year Environment Plan, published in 2018, once again claimed to set …