tbuckley/cabot-search huggingface dataset:
Abstract 4093: Synergy of CTL tumor cytotoxicity with myxoma oncolytic virotherapy
Authors: Meixuan Chen, Ana L. Matos, Padhmavathy Yuvaraj, Laura Belmont, Grant McFadden, Karen S. Anderson
Journal: Cancer Research (2019)

Abstract Background: Checkpoint blockade (CKB) are in clinical trials in breast cancer, but responses may be limited by the low tumor micro-immune profile and somatic mutation burden. Oncolytic viruses may function by activating the immune microenvironment, and improve clinical responses when combined with CKB against cancers like melanoma. In this study, we evaluate the synergy of cytotoxic T lymphocytes (CTLs) combined with oncolytic myxoma virus in an in vitro model of human breast cancer. Method: BMLF1-CTLs were generated from human HLA-A*02 PBMCs, which were stimulated with antigen presenting cells pulsed with the EBV BMLF1 HLA-A*02 peptide (GLCTLVAML). MCF-7 was engineered to express the full-length BMLF1 gene from EBV. To assess the impact of myxoma virus infection on CTL cytotoxicity, target MCF-7 cells (+/- BMLF1) were co-cultured with BMLF1-CTLs (E:T ratio=5:1) and myxoma virus vMyx-M135KO-GFP (vMyx135KO), at multiplicity of infection (MOI) ranges from 0.1 to 10 ffu/cell, in vitro for 48 hours. Cytotoxicity was measured by flow cytometry with propidium iodide (PI). Cell surface expression of MHC class I and class II were measured by flow cytometry. Statistical comparisons were performed using an unpaired t-test and variation among and between groups was calculated using ANOVA. Statistical significance was defined as p&amp;lt;0.05. Results: At the highest MOI (10 ffu/cell), cell surface MHC class I expression on MDA-MB-231 was decreased 38-fold (p&amp;lt;0.01), compared to untreated control. MCF-7 was more sensitive to MHC class I downregulation (MOI 1 ffu/cell, 37.3-fold reduction, p&amp;lt;0.002). No significant change of cell surface expression of MHC class II was detected in either breast cancer cell lines at any MOI. In MCF-7-BMLF1- cells, baseline cytotoxicity remained low in both CTL and vMyx135KO (MOI=0.1 ffu/cell) only treatments (14% vs. 10%). With antigen expression (MCF-7-BMLF1+), CTL cytotoxicity increase to 21% (p=0.02). At a MOI of 0.1 ffu/cell, vMyx135KO viral infection further sensitized cells to CTL cytotoxicity (21% vs. 36%, p&amp;lt;0.001) Conclusions: Oncolytic myxoma virus infection can decrease the MHC class I expression in human breast cancer cell lines, but only at high multiplicities of infection. At low level of virus, myxoma virus infection can enhance CTL cytotoxcity of breast cancer cell line. Citation Format: Meixuan Chen, Ana L. Matos, Padhmavathy Yuvaraj, Laura Belmont, Grant McFadden, Karen S. Anderson. Synergy of CTL tumor cytotoxicity with myxoma oncolytic virotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4093.
Vemurafenib acts as an aryl hydrocarbon receptor antagonist: Implications for inflammatory cutaneous adverse events
Authors: Heike C. Hawerkamp, Andreas Kislat, Peter A. Gerber, Marius Pollet, Katharina M. Rolfes, Anatoly A. Soshilov, Michael S. Denison, Afaque A. Momin, Stefan T. Arold, Angeliki Datsi, Stephan A. Braun, Péter Oláh, Mario E. Lacouture, Jean Krutmann, Thomas Haarmann‐Stemmann, Bernhard Homey, Stephan Meller
Journal: Allergy (2019)

In recent years, the BRAF inhibitor vemurafenib has been successfully established in the therapy of advanced melanoma. Despite its superior efficacy, the use of vemurafenib is limited by frequent inflammatory cutaneous adverse events that affect patients' quality of life and may lead to dose reduction or even cessation of anti-tumor therapy. To date, the molecular and cellular mechanisms of vemurafenib-induced rashes have remained largely elusive.In this study, we deployed immunohistochemistry, RT-qPCR, flow cytometry, lymphocyte activation tests, and different cell-free protein-interaction assays.We here demonstrate that vemurafenib inhibits the downstream signaling of the canonical pathway of aryl hydrocarbon receptor (AhR) in vitro, thereby inducing the expression of proinflammatory cytokines (eg, TNF) and chemokines (eg, CCL5). In line with these results, we observed an impaired expression of AhR-regulated genes (eg, CYP1A1) and an upregulation of the corresponding proinflammatory genes in vivo. Moreover, results of lymphocyte activation tests showed the absence of drug-specific T cells in respective patients.Taken together, we obtained no hint of an underlying sensitization against vemurafenib but found evidence suggesting that vemurafenib enhances proinflammatory responses by inhibition of canonical AhR signaling. Our findings contribute to our understanding of the central role of the AhR in skin inflammation and may point toward a potential role for topical AhR agonists in supportive cancer care.
Abstract 4756: Activation of AURKA contributes to TKI resistance in EGFR-mutant non-small lung cancer
Authors: Meng-Hsuan Lee, Shiao-Ya Hong, Yu-Rung Kao, Cheng-Wen Wu
Journal: Cancer Research (2019)

Abstract The epithelial growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been widely used to treat EGFR-mutant non-small cell lung cancer (NSCLC) in clinics. Several generations of TKI were invented to overcome the unfavorable response and acquired resistance after long-term usage of EGFR TKI. Several mechanisms of acquired resistance have been reported. The well-studied resistant mechanism results from EGFR secondary mutations including T790M and C797S, which are involved in the resistance to first and third generation TKI, respectively. Other mechanisms aside from secondary mutation on EGFR including Her2 and MET amplification or epithelial mesenchymal transition (EMT) also distribute to TKI resistance. However, the resistant mechanisms which are independent to these alterations have not been completely identified yet. Here, we generated resistant cells selected by three different generations of TKI and analyzed their gene expression profiles. We discovered that many signal pathways, especially involved in cell cycle regulation, are commonly upregulated in three TKI-resistant cell lines. Aurora kinase A (AURKA) was the upstream kinase of those pathways; however, neither RNA level nor protein level of AURKA was significant changed. Interestingly, we found that phosphorylation of Aurora A at Thr288 in its catalytic domain is higher in TKI resistant cells. This reveals the possibilities that AURKA activation plays a role in the occurrence of TKI-resistance and that TKI-resistant NSCLC patients have a better response rate to AURKA inhibitor treatments. Citation Format: Meng-Hsuan Lee, Shiao-Ya Hong, Yu-Rung Kao, Cheng-Wen Wu. Activation of AURKA contributes to TKI resistance in EGFR-mutant non-small lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4756.
Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson’s Disease
Authors: Sangjune Kim, Seung-Hwan Kwon, Tae-In Kam, Nikhil Panicker, Senthilkumar S. Karuppagounder, Saebom Lee, Jun Hee Lee, Wonjoong Richard Kim, Minjee Kook, Catherine A. Foss, Chentian Shen, Hojae Lee, Subhash Kulkarni, Pankaj J. Pasricha, Gabsang Lee, Martin G. Pomper, Valina L. Dawson, Ted M. Dawson, Han Seok Ko
Journal: Neuron (2019)
Regorafenib combined with irinotecan as second-line treatment in patients with metastatic gastro-oesophageal adenocarcinomas: A randomized phase 2 trial (PRODIGE 58 – UCGI 35 – REGIRI)
Authors: E. Samalin, A. Turpin, F. Khemissa, A. Zaanan, M. Benabdelghani, H. Senellart, M. Gilabert, L. Evesque, L. Dahan, D. Sefrioui, O. Bouché, C. De la Fouchardière, A. Hennequin, L. Monard, S. Gourgou, A. Lopez
Journal: Annals of Oncology (2019)
What Is Safe Sedation in the ICU?
Authors: Douglas B. Coursin, Yoanna Skrobik
Journal: New England Journal of Medicine (2019)

For decades, the comfort and safety of patients who are undergoing mechanical ventilation in the intensive care unit (ICU) entailed deep sedation, the nearly ubiquitous administration of opiates, and the liberal use of neuromuscular blockade. Concomitant with rising demands on ICU resources and expenditures, clinical studies started evaluating whether sedation truly mitigated patients' acute discomfort and subsequent unpleasant recall of critical illness or prevented inadvertent extubation or catheter removal. The development of reliable, psychometrically valid, ICU-based sedation scales1,2 made it possible to establish that deeper sedation correlates with prolonged mechanical ventilation.3 A seminal investigation determined that interrupting and lightening pharmacologic . . .
Automatic Measurement of Kidney and Liver Volumes from MR Images of Patients Affected by Autosomal Dominant Polycystic Kidney Disease
Authors: Maatje D.A. van Gastel, Marie E. Edwards, Vicente E. Torres, Bradley J. Erickson, Ron T. Gansevoort, Timothy L. Kline
Journal: Journal of the American Society of Nephrology (2019)

The formation and growth of cysts in kidneys, and often liver, in autosomal dominant polycystic kidney disease (ADPKD) cause progressive increases in total kidney volume (TKV) and liver volume (TLV). Laborious and time-consuming manual tracing of kidneys and liver is the current gold standard. We developed a fully automated segmentation method for TKV and TLV measurement that uses a deep learning network optimized to perform semantic segmentation of kidneys and liver.We used 80% of a set of 440 abdominal magnetic resonance images (T2-weighted HASTE coronal sequences) from patients with ADPKD to train the network and the remaining 20% for validation. Both kidneys and liver were also segmented manually. To evaluate the method's performance, we used an additional test set of images from 100 patients, 45 of whom were also involved in longitudinal analyses.TKV and TLV measured by the automated approach correlated highly with manually traced TKV and TLV (intraclass correlation coefficients, 0.998 and 0.996, respectively), with low bias and high precision (<0.1%±2.7% for TKV and -1.6%±3.1% for TLV); this was comparable with inter-reader variability of manual tracing (<0.1%±3.5% for TKV and -1.5%±4.8% for TLV). For longitudinal analysis, bias and precision were <0.1%±3.2% for TKV and 1.4%±2.9% for TLV growth.These findings demonstrate a fully automated segmentation method that measures TKV, TLV, and changes in these parameters as accurately as manual tracing. This technique may facilitate future studies in which automated and reproducible TKV and TLV measurements are needed to assess disease severity, disease progression, and treatment response.
Preliminary results of earlier steroid use with axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory large B-cell lymphoma (R/R LBCL).
Authors: Max S. Topp, Tom van Meerten, Martin Wermke, Elly J. Lugtenburg, Monique C. Minnema, Kevin W. Song, Catherine Thieblemont, Yizhou Jiang, Vicki Plaks, Anne Kerber, Marie Jose Kersten
Journal: Journal of Clinical Oncology (2019)

7558 Background: Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved in the EU and US for patients (pts) with R/R LBCL with ≥ 2 prior systemic therapies. In the 2-y follow-up of ZUMA-1, the objective response rate (ORR) was 83% with a complete response (CR) rate of 58%. Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events (NE) occurred in 11% and 32% of pts, respectively; 26% of pts received steroids, and 43% received tocilizumab (Locke et al. Lancet Oncol. 2019). A safety expansion cohort was added to evaluate the effect of earlier steroid use on the rates of these adverse events (AEs). Methods: Eligible pts with R/R LBCL were leukapheresed and received conditioning chemotherapy followed by a target dose of 2 × 10 6 anti-CD19 CAR T cells/kg. Pts in this cohort received early steroid intervention starting at Grade 1 NE and at Grade 1 CRS when no improvement was observed after 3 days of supportive care. The primary endpoint for this cohort was incidence and severity of CRS and NE. Results: As of 9/14/2018, 21 of 40 planned pts received axi-cel with a minimum follow-up of 1 mo (median, 2.6 mo). The median age was 63 y (range, 36 – 73), 67% were male, 81% had disease stage III-IV, 76% were R/R to ≥ second-line therapy, and 10% had relapsed post-autologous stem cell transplantation. Seventy-six percent of pts received steroids and 81% received tocilizumab. Most pts (81%) had Grade ≥ 3 AEs, most commonly neutrophil count decreased (33%), anemia (29%), and pyrexia (24%). Grade ≥ 3 NE occurred in 10% of pts; the most common symptoms were somnolence (10%) and confusional state (10%). Grade 1 and 2 NE occurred in 38% and 5% of pts, respectively. No pt had Grade ≥ 3 CRS; 33% of pts had Grade 1 CRS and 67% had Grade 2. There were no deaths due to AEs; 1 pt died due to disease progression. The ORR per investigator assessment was 76% with 48% of pts achieving a CR. Pharmacokinetic data will be presented. Conclusions: Early use of steroids may help in managing severe CRS and NE by potentially reducing their incidence in pts treated with CAR T cell therapy without affecting response rates. Optimizing AE management may help to further improve the benefit:risk profile of CAR T cell therapy. Clinical trial information: NCT02348216.
Gastric malignancy presenting after elective Roux-en-Y gastric bypass for treatment of morbid obesity.
Authors: Peter N Nau, Ozanan Meireles
Journal: Journal of Clinical Oncology (2013)

e12559 Background: Obesity has become a significant public health problem in westernized societies. Medical attempts at weight loss are fraught with failures and recidivism. Bariatiric surgery provides for reliable and durable weight loss. The rate of gastrointestinal pathology in this population is significantly higher than in the non-obese. Gastric malignancy following Roux-en-Y gastric bypass (RYGB) is an uncommon presentation. Symptoms occur late secondary to the properties of the RYGB complicating a curative approach. Methods: A retrospective review of the Massachusetts General Hospital bariatric surgical history and PubMed literature search were performed. Data points recorded include the patient age and risk factors for cancer, use of preoperative screening, presenting symptoms, and outcomes of gastric malignancy following RYGB. Statistical analysis was performed using SPSS 20.0. Results: Including the one case treated at Massachusetts General Hospital, that are 11 reported cases of gastric malignancies following RYGB in the literature. The average patient age was 53 years. In four cases preoperative risk factors for gastric cancer were identified. No reports identified pre-bypass evaluation of the stomach. Seventy percent of the cases involved malignancies arising from the gastric remnant. The median time between operation and presentation was 8 years (range 1 – 26). The most common chief complaint was pain (70%). Additional symptoms included nausea and vomiting (50%), and dysphagia (30%). At the time of diagnosis 4 patients had advanced disease rendering surgical resection impossible. Conclusions: Surgical management of obesity provides for durable weight loss and improvement in obesity-associated medical comorbidities. This population is at a higher risk for harboring asymptomatic gastrointestinal pathology. There are 11 cases of gastric malignancies following RYGB in the literature. In four cases the diagnosis of advanced cancer dictated palliative measures only. Diagnosis of this disease is complicated by its subtle presentation and the inability to access the remnant stomach. Given this, it is reasonable to screen all patients prior to exclusion of the gastric remnant.
Abstract P205: Quality of Reporting and Methods of Systematic Reviews and Meta-analysis Addressing High-intensity Interval Training Efficacy on Cardiorespiratory Fitness: A Meta-Epidemiological Study
Authors: Lucas Helal, Cintia E Botton, Marlos R Domingues, Daniel Umpierre
Journal: Circulation (2018)

Introduction: The efficacy of high-intensity interval training (HIIT) for cardiorespiratory fitness (VO 2 max) has been increasingly investigated in different populations, resulting in efforts to summarize intervention effects through generation of systematic reviews and meta-analysis (SRMAs). Despite of many available SRMAs, the quality of methods and reporting of these syntheses is still unknown. Thus, we aimed to quantify it by a meta-epidemiological design, in order to cover all eligible SRMAs. Hypothesis: We hypothesized that SRMAs would have low quality of reporting and methodology, based on previous findings on overall biomedical literature. Methods: We searched four electronic databases, grey-literature, and hand-searched relevant SRMAs. Eligibility criteria were any SRMA having HIIT/SIT on VO2max as one of addressed meta-analysis from individual studies including apparently healthy subjects as well as patients with cerebrovascular (stroke) or cardiovascular (CVD) diseases (coronary artery disease, heart failure, heart attack, and peripheral artery disease). No restriction was made regarding publication status or language. Eligibility assessment and data extraction were done in duplicate and discordances were solved by consensus. We used 14 items adapted from PRISMA and AMSTAR tools to assess methodological, quantitative and reporting practices in SRMAs. This SR is registered (CRD42017067269) and all documentation and raw data are available at https://github.com/lhelal/srma-hiit.git and osf.io/6xzyf. This abstract is the first report regarding our final analysis. Results: From 141 retrieved titles, 47 duplicates were excluded and 94 full-texts were assessed, resulting in 13 eligible SRMAs. Of these, 7 SRMAs were on CVD and 6 on apparently healthy patients. Median AMSTAR score was 4/11 (median ± IQR, 4 ± 2). Regarding reporting, none of the SRMAs reported registry (0%), 39% (5/13) self-reported as in accordance to PRISMA, 8/13 (62%) reported disclosure status, 46% (6/13) reported full eligibility and extraction process and 100% (13/13) referred to a comparator group. For methodology, database median number was 4 (4 ± 5), where 92% (12/13) restricted to English and 61.5% (8/13) restricted to publication status on their primary study eligibility criteria. Moreover, 69% (9/13) had a comparator group, 31% (4/13) provided full-search strategy that allows replication and 62% (8/13) analyzed primary study risk of bias. Conclusions: Only a low to modest proportion of SRMAs followed practices to provide adequate literature coverage, methodological transparency and assessment of potential biases. Since such syntheses are useful to decision making regarding exercise interventions, increased adherence to approaches that enhance methodological and reporting quality is warranted from authors and journal editors.
Exhaled volatile organic compounds in adult asthma: a systematic review
Authors: Adnan Azim, Clair Barber, Paddy Dennison, John Riley, Peter Howarth
Journal: European Respiratory Journal (2019)

The search for biomarkers that can guide precision medicine in asthma, particularly those that can be translated to the clinic, has seen recent interest in exhaled volatile organic compounds (VOCs). Given the number of studies reporting “breathomics” findings and its growing integration in clinical trials, we performed a systematic review of the literature to summarise current evidence and understanding of breathomics technology in asthma. A PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)-oriented systematic search was performed (CRD42017084145) of MEDLINE, Embase and the Cochrane databases to search for any reports that assessed exhaled VOCs in adult asthma patients, using the following terms (asthma AND (volatile organic compounds AND exhaled) OR breathomics). Two authors independently determined the eligibility of 2957 unique records, of which 66 underwent full-text review. Data extraction and risk of bias assessment was performed on the 22 studies deemed to fulfil the search criteria. The studies are described in terms of methodology and the evidence narratively summarised under the following clinical headings: diagnostics, phenotyping, treatment stratification, treatment monitoring and exacerbation prediction/assessment. Our review found that most studies were designed to assess diagnostic potential rather than focus on underlying biology or treatable traits. Results are generally limited by a lack of methodological standardisation and external validation and by insufficiently powered studies, but there is consistency across the literature that exhaled VOCs are sensitive to underlying inflammation. Modern studies are applying robust breath analysis workflows to large multi-centre study designs, which should unlock the full potential of measurement of exhaled volatile organic compounds in airways diseases such as asthma.
Abstract 16493: Is it Possible to Achieve High Quality CPR by Mass Training? A Randomized Manikin Study
Authors: Enrico Contri, Enrico Baldi, Stefano Cornara, Dario Fina, Beatrice Zelaschi, Michela Tonani, Ferdinando Fichtner, Alberto Somaschini
Journal: Circulation (2015)

Introduction: ILCOR 2010 Guidelines stressed the importance of high-quality CPR to improve cardiac arrest survival. However, it is crucial to train the largest number of people. Mass Training could achieve both this goals, but there is a lack of data about its efficacy. Hypothesis: The aim of our randomized controlled manikin study was to assess the quality of chest compressions after Mass Training in comparison to standard BLS training. Methods: We randomly divided 200 CPR-untrained lay people in two groups with an allocation ratio 1:1. Group 1 was trained with a standard BLS course (1-h theory and 4-h practice) on a classic BLS manikin with an instructor:attendee:manikin ratio of 1:5:1. Group 2 was trained with a Mass Training course (30-mins theory and 45-mins practice) on a low-budget inflatable manikin with an instructor:attendee:manikin ratio of 1:15:15. At the end of both courses we recorded 1-min compression-only CPR for every participant using a skill evaluator manikin. We measured: percentage of adequate compression depth (target 5 cm) (Cdepth%), compressions per minute (Cmin), percentage of correctly released compressions (target 0 cm) (Crel%) and percentage of correct hand position (Cpos%). Results: Anthropometric variables did not significantly differ between the two groups. There was no significant difference (calculated with Mann-Whitney test) between group 1 and group 2 regarding Cdepth% (80.7% (95%CI, 51.9-95.2) vs 78% (95%CI, 57.9-90.6), p=0.733) and Cpos% (100% (95%CI, 100-100) vs 100% (95%CI, 100-100, p=0.418), whilst there was a significant difference in Crel% (96% (95%CI, 92-96) vs 70.5% (95%CI, 57.7-86.3), p&lt;0.001) and in Cmin (120 (95%CI, 117-122) vs 116 (95%CI, 114-120), p=0.037). Conclusions: Mass Training achieves the goal of increasing the amount of people trained in high-quality CPR: percentage of compression with correct depth and with correct hand position are similar to classic BLS Training, moreover Mass Training attendees reached the target of compressions per minute more often than the others probably because of the continuous use of a personal manikin. Nevertheless correctly released compressions were better in group 1: this could be due to the fact that the manikin used in this course has a better pressure feedback.