tbuckley/cabot-search huggingface dataset:
Identifying Cardiac Amyloid in Aortic Stenosis
Authors: Paul R. Scully, Kush P. Patel, Bunny Saberwal, Ernst Klotz, João B. Augusto, George D. Thornton, Rebecca K. Hughes, Charlotte Manisty, Guy Lloyd, James D. Newton, Nikant Sabharwal, Andrew Kelion, Simon Kennon, Muhiddin Ozkor, Michael Mullen, Neil Hartman, João L. Cavalcante, Leon J. Menezes, Philip N. Hawkins, Thomas A. Treibel, James C. Moon, Francesca Pugliese
Journal: JACC. Cardiovascular imaging (2020)

The purpose of this study was to validate computed tomography measured ECV (ECVCT) as part of routine evaluation for the detection of cardiac amyloid in patients with aortic stenosis (AS)-amyloid. AS-amyloid affects 1 in 7 elderly patients referred for transcatheter aortic valve replacement (TAVR). Bone scintigraphy with exclusion of a plasma cell dyscrasia can diagnose transthyretin-related cardiac amyloid noninvasively, for which novel treatments are emerging. Amyloid interstitial expansion increases the myocardial extracellular volume (ECV). Patients with severe AS underwent bone scintigraphy (Perugini grade 0, negative; Perugini grades 1 to 3, increasingly positive) and routine TAVR evaluation CT imaging with ECVCT using 3- and 5-min post-contrast acquisitions. Twenty non-AS control patients also had ECVCT performed using the 5-min post-contrast acquisition. A total of 109 patients (43% male; mean age 86 ± 5 years) with severe AS and 20 control subjects were recruited. Sixteen (15%) had AS-amyloid on bone scintigraphy (grade 1, n = 5; grade 2, n = 11). ECVCT was 32 ± 3%, 34 ± 4%, and 43 ± 6% in Perugini grades 0, 1, and 2, respectively (p < 0.001 for trend) with control subjects lower than lone AS (28 ± 2%; p < 0.001). ECVCT accuracy for AS-amyloid detection versus lone AS was 0.87 (0.95 for 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid Perugini grade 2 only), outperforming conventional electrocardiogram and echocardiography parameters. One composite parameter, the voltage/mass ratio, had utility (similar AUC of 0.87 for any cardiac amyloid detection), although in one-third of patients, this could not be calculated due to bundle branch block or ventricular paced rhythm. ECVCT during routine CT TAVR evaluation can reliably detect AS-amyloid, and the measured ECVCT tracks the degree of infiltration. Another measure of interstitial expansion, the voltage/mass ratio, also performed well.
Bone marrow–derived myeloid progenitors as driver mutation carriers in high- and low-risk Langerhans cell histiocytosis
Authors: Yanling Xiao, Astrid G. S. van Halteren, Xin Lei, Jelske Borst, Eline Steenwijk, Tom de Wit, Joanna Grabowska, Rhianne Voogd, Paul Kemps, Jennifer Picarsic, Cor van den Bos, Jannie Borst
Journal: Blood (2020)
Macrophage-derived exosomes attenuate fibrosis in airway epithelial cells through delivery of antifibrotic miR-142-3p
Authors: Julien Guiot, Maureen Cambier, Amandine Boeckx, Monique Henket, Olivier Nivelles, Fanny Gester, Edouard Louis, Michel Malaise, Franck Dequiedt, Renaud Louis, Ingrid Struman, Makon-Sébastien Njock
Journal: Thorax (2020)

Introduction Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease of unknown aetiology and cure. Recent studies have reported a dysregulation of exosomal microRNAs (miRs) in the IPF context. However, the impact of IPF-related exosomal miRs on the progression of pulmonary fibrosis is unknown. Methods Two independent cohorts were enrolled at the ambulatory care polyclinic of Liège University. Exosomes from sputum were obtained from 19 patients with IPF and 23 healthy subjects (HSs) (cohort 1), and the ones from plasma derived from 14 patients with IPF and 14 HSs (cohort 2). Exosomal miR expression was performed by quantitative reverse transcription–PCR. The functional role of exosomal miRs was assessed in vitro by transfecting miR mimics in human alveolar epithelial cells and lung fibroblasts. Results Exosomal miR analysis showed that miR-142-3p was significantly upregulated in sputum and plasma of patients with IPF (8.06-fold, p&lt;0.0001; 1.64 fold, p=0.008, respectively). Correlation analysis revealed a positive association between exosomal miR-142-3p and the percentage of macrophages from sputum of patients with IPF (r=0.576, p=0.012), suggesting macrophage origin of exosomal miR-142-3p upregulation. The overexpression of miR-142-3p in alveolar epithelial cells and lung fibroblasts was able to reduce the expression of transforming growth factor β receptor 1 (TGFβ-R1) and profibrotic genes. Furthermore, exosomes isolated from macrophages present antifibrotic properties due in part to the repression of TGFβ-R1 by miR-142-3p transfer in target cells. Discussion Our results suggest that macrophage-derived exosomes may fight against pulmonary fibrosis progression via the delivery of antifibrotic miR-142–3 p to alveolar epithelial cells and lung fibroblasts.
PD-1 does not mark tumor-infiltrating CD8+ T cell dysfunction in human gastric cancer
Authors: Yang Shen, Yongsheng Teng, Yipin Lv, Yongliang Zhao, Yuan Qiu, Weisan Chen, Lina Wang, Ying Wang, Fangyuan Mao, Ping Cheng, Daiyuan Ma, Yuan Zhuang, Quanming Zou, Liusheng Peng
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Overexpression of programmed cell death protein 1 (PD-1) is linked to CD8+ T cell dysfunction and contributes to tumor immune escape. However, the prevalence and functional regulations of PD-1 expression on CD8+ T cells in human gastric cancer (GC) remain largely unknown. Methods Flow cytometry was performed to analyze the level, phenotype, functional and clinical relevance of PD-1+CD8+ T cells in GC patients. Peripheral blood CD8+ T cells were purified and subsequently exposed to culture supernatants from digested primary GC tumor tissues (TSN) in vitro for PD-1 expression and functional assays. Tumor responses to adoptively transferred TSN-stimulated CD8+ T cells or to the TSN-stimulated CD8+ T cell transfer combined with an anti-PD-1 antibody injection were measured in an in vivo xenograft mouse model. Results GC patients’ tumors showed a significantly increased PD-1+CD8+ T cell infiltration. However, these GC-infiltrating PD-1+CD8+ T cells showed equivalent function to their PD-1−CD8+ counterparts and they did not predict tumor progression. High level of transforming growth factor-β1 (TGF-β1) in tumors was positively correlated with PD-1+CD8+ T cell infiltration, and in vitro GC-derived TGF-β1 induced PD-1 expression on CD8+ T cells via Smad3 signaling, whereas Smad2 signaling was involved in GC-derived TGF-β1-mediated CD8+ T cell dysfunction. Furthermore, GC-derived TGF-β1-mediated CD8+ T cell dysfunction contributed to tumor growth in vivo that could not be attenuated by PD-1 blockade. Conclusions Our data highlight that GC-derived TGF-β1 promotes PD-1 independent CD8+ T cell dysfunction. Therefore, restoring CD8+ T cell function by a combinational PD-1 and TGF-β1 blockade might benefit future GC immunotherapy.
AB0682 FUNCTIONAL IMPAIRMENT IN PATIENTS WITH AXIAL SPONDYLOARTHROPATHY IN A GERMAN COHORT: WORSE OUTCOMES AND WORSE QUALITY OF LIFE FOR FEMALE PATIENTS
Authors: N. Frede, S. Hiestand, S. Finzel, R. Voll, J. Thiel, N. Venhoff
Journal: Annals of the Rheumatic Diseases (2020)

Background: Axial spondyloarthritis (AxSpA) may lead to significant structural damage resulting in marked impairment and disability. Historically, AxSpA has been thought to have a distinct male predominance regarding both, occurrence but also disease severity. However, it has recently been shown in international cohorts that women with AxSpA may have in fact an increased disease burden and worse outcome than their male counterparts. Objectives: The aim of this project was to analyse functional capacity in a German cohort of AxSpA patients and identify associated factors by comparing demographic data, clinical characteristics, disease activity and treatments. Methods: Analysis of a German University Hospital outpatient clinic cohort of 150 AxSpA patients. Questionnaire-based screening tools were used to assess disease activity, functional impairment and quality of life (BASDAI, FFbH, WHOQOL-BREF). Female and male patients were compared by independent samples two-tailed T tests for continuous variables as well as chi-squared test for categorical variables. Results: A German cohort of 150 AxSpA patients with 89 male and 61 female patients (mean age 49.3 years for males, 48.5 for females, p=0.77) was analyzed for functional capacity. Female patients had a significantly higher functional impairment in everyday life compared to males (p=0.013). After adjusting for age, linear regression showed female sex still to be significantly associated with functional impairment. Female patients rated their satisfaction with health as well as their physical and mental health-related quality of life significantly lower than male patients (p=0.015, respectively p=0.003 and p=0.002). There were no significant differences in disease duration, diagnostic delay or family history between male and female patients (p=0.731, p=0.971 and p=0.776). Women had a slightly higher disease activity (BASDAI 4.08 vs. 3.36), although just not statistically significant in our cohort (p=0.056). Female patients had more peripheral joint involvement (52.5% vs. 34.8%, p=0.032), as well as more enthesitis (31.1% vs. 16.9%, p=0.04), whereas there were no differences concerning eye involvement (p=0.51). Female patients were less likely to be HLA B27 positive (65.6 vs. 80.7%, p=0.04). and were less likely to be on anti-TNF treatment (p=0.032, respectively p=0.042). Conclusion: Also in our cohort female patients had a higher burden of disease as well as a worse patient reported outcome with worse quality of life and more self-reported functional impairment in everyday life. These data underline the importance of raising awareness for sex differences in disease presentation and suggest that female patients might require different treatment to achieve improved outcomes. Disclosure of Interests: None declared
End-of-Treatment CT and Serial FDG-PET Imaging to Assess Residual Disease in Primary Mediastinal B-Cell Lymphoma
Authors: Christopher Melani, Ranjana H. Advani, Mark Roschewski, Kelsey M. Walters, Clara C. Chen, Lucia Barrato, Mark A. Ahlman, Milos D. Miljkovic, Seth M. Steinberg, Margaret Shovlin, Kieron Dunleavy, Stefania Pittaluga, Elaine S. Jaffe, Wyndham H. Wilson
Journal: Blood (2017)
Abstract 14055: (Pro)renin Receptor Blockade Ameliorates Renal Dysfunction-Associated Heart Failure by Suppressing Cardiac Fibrosis but Not by Interfering Autophagy
Authors: Akihiro Yoshida, Hiromitsu Kanamori, Genki Naruse, Shingo Minatoguchi, Hisaaki Komaki, Shinya Baba, Junko Naito, Yuka Hayakawa, Masamitsu Iwasa, Yoshihisa Yamada, Atsushi Mikami, Masanori Kawasaki, Kazuhiko Nishigaki, Shinya Minatoguchi
Journal: Circulation (2017)

Chronic kidney disease (CKD) is a major cardiovascular risk factor because of elevated tissue renin-angiotensin system (RAS) activity in the heart. The (pro)renin receptor ((P)RR), recently identif...
Abstract 5477: The Double Helix Model of High Density Lipoprotein
Authors: Zhiping Wu, Valentin Gogonea, Xavier Lee, A Wagner Matthew, Xin-Min Li, Roland P May, Joseph (Giuseppe) Zaccai, Joseph DiDonato, Stanley L Hazen
Journal: Circulation (2008)

High-density lipoprotein (HDL), the carrier of “good” cholesterol, has remained resistant to structural interrogation by traditional high-resolution approaches. Using an integrative multimodal appr...
Recanalization of a complete colorectal anastomotic stenosis: an application of the Hot AXIOS stent
Authors: Jérôme Winkler, Charles Peyret, Marine Barraud-Blanc, Pablo Sage, Olivier Comiti, Laurent Heyries, Philippe Grandval
Journal: Endoscopy (2020)

A 43-year-old woman underwent emergency surgery for a neoplastic colonic perforation. A sigmoidectomy with colorectal anastomosis protected by an ileostomy was performed. Pathological findings showed a well differentiated pt4N1aM0 adenocarcinoma. FOLFOX adjuvant chemotherapy was given. At endoscopy, 3 months later, a complete anastomotic stenosis was detected ([Fig. 1]). After discussion with the surgical team, it was decided to proceed with endoscopic management using a lumen-apposing metal stent (LAMS), as described in previous cases[1] [2].
Molecular Classification of the PORTEC-3 Trial for High-Risk Endometrial Cancer: Impact on Prognosis and Benefit From Adjuvant Therapy
Authors: Alicia León-Castillo, Stephanie M. de Boer, Melanie E. Powell, Linda R. Mileshkin, Helen J. Mackay, Alexandra Leary, Hans W. Nijman, Naveena Singh, Pamela M. Pollock, Paul Bessette, Anthony Fyles, Christine Haie-Meder, Vincent T. H. B. M. Smit, Richard J. Edmondson, Hein Putter, Henry C. Kitchener, Emma J. Crosbie, Marco de Bruyn, Remi A. Nout, Nanda Horeweg, Carien L. Creutzberg, Tjalling Bosse
Journal: Journal of Clinical Oncology (2020)

The randomized Adjuvant Chemoradiotherapy Versus Radiotherapy Alone in Women With High-Risk Endometrial Cancer (PORTEC-3) trial investigated the benefit of combined adjuvant chemotherapy and radiotherapy (CTRT) versus radiotherapy alone (RT) for women with high-risk endometrial cancer (EC). Because The Cancer Genome Atlas defined an EC molecular classification with strong prognostic value, we investigated prognosis and impact of chemotherapy for each molecular subgroup using tissue samples from PORTEC-3 trial participants.Paraffin-embedded tissues of 423 consenting patients were collected. Immunohistochemistry for p53 and mismatch repair (MMR) proteins, and DNA sequencing for POLE exonuclease domain were done to classify tumors as p53 abnormal (p53abn), POLE-ultramutated (POLEmut), MMR-deficient (MMRd), or no specific molecular profile (NSMP). The primary end point was recurrence-free survival (RFS). Kaplan-Meier method, log-rank test, and Cox model were used for analysis.Molecular analysis was successful in 410 high-risk EC (97%), identifying the 4 subgroups: p53abn EC (n = 93; 23%), POLEmut (n = 51; 12%), MMRd (n = 137; 33%), and NSMP (n = 129; 32%). Five-year RFS was 48% for patients with p53abn EC, 98% for POLEmut EC, 72% for MMRd EC, and 74% for NSMP EC (P < .001). The 5-year RFS with CTRT versus RT for p53abn EC was 59% versus 36% (P = .019); 100% versus 97% for patients with POLEmut EC (P = .637); 68% versus 76% (P = .428) for MMRd EC; and 80% versus 68% (P = .243) for NSMP EC.Molecular classification has strong prognostic value in high-risk EC, with significantly improved RFS with adjuvant CTRT for p53abn tumors, regardless of histologic type. Patients with POLEmut EC had an excellent RFS in both trial arms. EC molecular classification should be incorporated in the risk stratification of these patients as well as in future trials to target specific subgroups of patients.
Optimizing the anti-tumor efficacy of protein-drug conjugates by engineering the molecular size and half-life
Authors: Fabian Brandl, Sarah Busslinger, Uwe Zangemeister-Wittke, Andreas Plückthun
Journal: Journal of Controlled Release (2020)

Despite some approvals of antibody-drug conjugates for cancer therapy, their clinical success rate is unsatisfactory because of very small therapeutic windows, influenced by on-target and off-target toxicities of conjugate and liberated toxin. Additional formats with systematically investigated molecular parameters must therefore be explored to increase their therapeutic window. Here we focused on the effective molecular weight. To generate conjugates with exactly defined drug loads and tunable pharmacokinetics, we used Designed Ankyrin Repeat Proteins (DARPins), fused to unstructured polypeptides of different lengths, to produce proteins with any desired half-life, to identify those with the best efficacy. We generated an EpCAM-targeting DARPin-MMAF conjugate, fused to PAS or XTEN of different lengths, and a matched series of controls of a non-binding DARPin to account for the enhanced permeability and retention (EPR) effect, covering half-lives of minutes to 20.6 h in mice. All conjugates were produced at high purity, and demonstrated high specificity and cytotoxicity in human tumor cell cultures, with IC50 values in the low nM range, independent of the polypeptide type and length. Due to their more facile purification, the PASylated conjugates were tested in nude mice bearing HT29 tumor xenografts. Independent of their size, all PASylated conjugates were very well tolerated after repeated systemic administration of 300 nmol/kg. We found that the conjugates with intermediate size and half-life showed the strongest anti-tumor effects, and deduced that this effect is a compromise of serum half-life and diffusion within the tumor, as on-rates and affinities are essentially identical, with extravasation playing only a very minor role.
Abstract B20: Characterization of tumor mutational landscape in smokers and nonsmokers with urothelial carcinoma
Authors: Aleksandra Walasek, Nima Almassi, Min Yuen Teo, Samuel Funt, Nikolaus Schultz, Guido Dalbagni, Wenhu Hu, Hikmat Al-Ahmadie, Dean F Bajorin, Jonathan E Rosenberg, Gopakumar Iyer, Bernard H. Bochner, David B. Solit, Eugene J. Pietzak
Journal: Clinical Cancer Research (2020)

Abstract Introduction and Objectives: Smoking is a major risk factor for development of bladder cancer. It has been previously shown that smoking-related and non-smoking-related cancers have characteristic mutational signatures. Hypothesizing that somatic alterations differ between smokers and nonsmokers with urothelial carcinoma, we used next-generation sequencing to evaluate for differences in genomic alterations between these two groups of patients. Methods: We identified in our prospectively maintained institutional database all patients with urothelial carcinoma whose tumors underwent next-generation sequencing using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay. A panel of genes previously reported by The Cancer Genome Atlas (TCGA) as being commonly mutated in bladder cancer was chosen for analysis. Results: A total of 1,044 samples from 968 patients were included in the analysis. Seven hundred eighty-five (85%) of the samples represented bladder tumors and 259 (25%) of the samples represented tumors of the upper tract. Patients with smoking history comprised 66% of the cohort. The most frequently altered genes in active or former smokers and never smokers were TERT promoter (55% and 60%), TP53 (43% and 41%), KDM6A (30% and 26%), and FGFR3 (27% and 26%). Conclusions: Mutational profiling of urothelial tumors in this large cohort of patients showed high incidence of genomic alterations consistent with prior studies. The frequency of alterations in these genes was similar between smokers and nonsmokers. To further understand smoking-related mutational process, we are examining mutational signatures and differences in genomic alterations as a function of smoking intensity exposure. Citation Format: Aleksandra Walasek, Nima Almassi, Min Yuen Teo, Samuel Funt, Nikolaus Schultz, Guido Dalbagni, Wenhu Hu, Hikmat Al-Ahmadie, Dean F Bajorin, Jonathan E Rosenberg, Gopakumar Iyer, Bernard H. Bochner, David B. Solit, Eugene J. Pietzak. Characterization of tumor mutational landscape in smokers and nonsmokers with urothelial carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr B20.
Abstract A22: YAP1 knockout in vitro models of medulloblastoma showed improved response to sonidegib
Authors: Gustavo Alencastro Veiga Cruzeiro, Taciani de Almeida Magalhães, Graziella de Sousa Ribeiro, Pablo Ferreira das Chagas, Ricardo Bonfim Silva, Sampurna Chatterje, Carlos Alberto Scrideli, Luiz Gonzaga Tone
Journal: Cancer Research (2020)

Abstract Background: Medulloblastoma (MB) is the most common malignant brain tumor in childhood. Despite improvement in current treatment, children still suffer from long-term sequelae resulting from standard care therapy. World Health Organization considers MB as 4 distinct entities: SHH, WNT, Group 3, and Group 4. The most aggressive variant of SHH MB is the bearer of TP53 mutation and it is resistant to standard chemo/radiation therapy. Therefore, novel treatments modalities are urgently needed. In this study we aimed to evaluate the biologic relevance of YAP1 in SHH MB human cell lines bearers of TP53 mutation and its potential as a new therapeutic target. Methods: We generated YAP1 CRISPR/CAS9 knockout single-cell clones of human cell lines DAOY and UW228 assigned as “MB SHH-like” and bearers of TP53 mutation. We picked sonidegib as a standard-care chemotherapy for in vitro SHH MB model and assessed the apoptosis/necrosis using Annexin V/Propidium-Iodide staining to identify positive cells through flow cytometry. Proliferation and colony formation were assessed by cell counting Kit 8 proliferation assay and GIEMSA staining, respectively. Additionally, we used verteporfin, a YAP1 inhibitor, and evaluated its effect on cell proliferation. Findings: Using single-cell cloning, we successfully generated DAOY and UW228 cell lines with depleted YAP1 protein. YAP1 knockout cell lines DAOY and UW228 showed improved response to sonidegib regarding i) decrease in proliferation (p&amp;lt;0.05), ii) apoptosis induction (p&amp;lt;0.01), and iii) colony formation abrogation (p&amp;lt;0.001). In order to step towards translation, we tested verteporfin (YAP1 inhibitor) and found that this compound successfully reduced proliferation in both cell lines (p&amp;lt;0.05). Conclusion: Although YAP1 depletion showed association with better response to sonidegib, a smoothened inhibitor, more experiments are needed to evaluate if the in vitro findings might shed new light on a potential synergistic combination between sonidegib and verteporfin and provide a good rationale for targeted therapy. Citation Format: Gustavo Alencastro Veiga Cruzeiro, Taciani de Almeida Magalhães, Graziella de Sousa Ribeiro, Pablo Ferreira das Chagas, Ricardo Bonfim Silva, Sampurna Chatterje, Carlos Alberto Scrideli, Luiz Gonzaga Tone. YAP1 knockout in vitro models of medulloblastoma showed improved response to sonidegib [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A22.
Myocardial Native T1 Predicts Load-Independent Left Ventricular Chamber Stiffness In Patients With HFpEF
Authors: Taku Omori, Shiro Nakamori, Naoki Fujimoto, Masaki Ishida, Kakuya Kitagawa, Yasutaka Ichikawa, Naoto Kumagai, Tairo Kurita, Kyoko Imanaka-Yoshida, Michiaki Hiroe, Hajime Sakuma, Masaaki Ito, Kaoru Dohi
Journal: JACC. Cardiovascular imaging (2020)
Perioperative Stroke Risk Reduction in Patients With Patent Foramen Ovale
Authors: Nidhi Rohatgi, Nathaniel R. Smilowitz, Maarten G. Lansberg
Journal: JAMA Neurology (2020)

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