tbuckley/cabot-search huggingface dataset:
<i>RSPO2</i> gene rearrangement: a powerful driver of β-catenin activation in liver tumours
Authors: Thomas Longerich, Volker Endris, Olaf Neumann, Eugen Rempel, Martina Kirchner, Zahra Abadi, Sebastian Uhrig, Mark Kriegsmann, Karl Heinz Weiss, Kai Breuhahn, Arianeb Mehrabi, Tim Frederik Weber, Ludwig Wilkens, Beate K Straub, Andreas Rosenwald, Falko Schulze, Benedikt Brors, Stefan Froehling, Rossella Pellegrino, Jan Budczies, Peter Schirmacher, Albrecht Stenzinger
Journal: Gut (2019)

Objective We aimed at the identification of genetic alterations that may functionally substitute for CTNNB1 mutation in ß-catenin-activated hepatocellular adenomas (HCAs) and hepatocellular carcinoma (HCC). Design Large cohorts of HCA (n=185) and HCC (n=468) were classified using immunohistochemistry. The mutational status of the CTNNB1 gene was determined in ß-catenin-activated HCA (b-HCA) and HCC with at least moderate nuclear CTNNB1 accumulation. Ultra-deep sequencing was used to characterise CTNNB1 wild-type and ß-catenin-activated HCA and HCC. Expression profiling of HCA subtypes was performed. Results A roof plate-specific spondin 2 (RSPO2) gene rearrangement resulting from a 46.4 kb microdeletion on chromosome 8q23.1 was detected as a new morphomolecular driver of β-catenin-activated HCA. RSPO2 fusion positive HCA displayed upregulation of RSPO2 protein, nuclear accumulation of β-catenin and transcriptional activation of β-catenin-target genes indicating activation of Wingless-Type MMTV Integration Site Family (WNT) signalling. Architectural and cytological atypia as well as interstitial invasion indicated malignant transformation in one of the RSPO2 rearranged b-HCAs. The RSPO2 gene rearrangement was also observed in three β-catenin-activated HCCs developing in context of chronic liver disease. Mutations of the human telomerase reverse transcriptase promoter—known to drive malignant transformation of CTNNB1 -mutated HCA—seem to be dispensable for RSPO2 rearranged HCA and HCC. Conclusion The RSPO2 gene rearrangement leads to oncogenic activation of the WNT signalling pathway in HCA and HCC, represents an alternative mechanism for the development of b-HCA and may drive malignant transformation without additional TERT promoter mutation.
Spliced XBP1 Rescues Renal Interstitial Inflammation Due to Loss of Sec63 in Collecting Ducts
Authors: Yasunobu Ishikawa, Sorin Fedeles, Arnaud Marlier, Chao Zhang, Anna-Rachel Gallagher, Ann-Hwee Lee, Stefan Somlo
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement CKD of various etiologies manifests with declining kidney function in the setting of progressive interstitial inflammation, with increased myofibroblasts and collagen deposition. In this study, the authors developed a novel genetic model, demonstrating that impairment of protein homeostatic mechanisms in the endoplasmic reticulum of collecting duct cells is sufficient to produce interstitial inflammation, fibrosis, and impaired kidney function. In this model, genes encoding both Sec63, a resident protein in the endoplasmic reticulum membrane, and Xbp1, a transcription factor that is central to the unfolded protein response, were inactivated in the collecting ducts of neonatal mice. The result was progressive macrophage and myofibroblast expansion within 5 weeks and significant progressive kidney dysfunction thereafter. The Sec63-Xbp1 collecting duct knockout mouse offers a novel genetic model for studying chronic tubulointerstitial kidney injury. Background SEC63 encodes a resident protein in the endoplasmic reticulum membrane that, when mutated, causes human autosomal dominant polycystic liver disease. Selective inactivation of Sec63 in all distal nephron segments in embryonic mouse kidney results in polycystin-1–mediated polycystic kidney disease (PKD). It also activates the Ire1 α -Xbp1 branch of the unfolded protein response, producing Xbp1s, the active transcription factor promoting expression of specific genes to alleviate endoplasmic reticulum stress. Simultaneous inactivation of Xbp1 and Sec63 worsens PKD in this model. Methods We explored the renal effects of postnatal inactivation of Sec63 alone or with concomitant inactivation of Xbp1 or Ire1α , specifically in the collecting ducts of neonatal mice. Results The later onset of inactivation of Sec63 restricted to the collecting duct does not result in overt activation of the Ire1 α -Xbp1 pathway or cause polycystin-1–dependent PKD. Inactivating Sec63 along with either Xbp1 or Ire1α in this model causes interstitial inflammation and associated fibrosis with decline in kidney function over several months. Re-expression of XBP1s in vivo completely rescues the chronic kidney injury observed after inactivation of Sec63 with either Xbp1 or Ire1α . Conclusions In the absence of Sec63 , basal levels of Xbp1s activity in collecting ducts is both necessary and sufficient to maintain proteostasis (protein homeostasis) and protect against inflammation, myofibroblast activation, and kidney functional decline. The Sec63-Xbp1 double knockout mouse offers a novel genetic model of chronic tubulointerstitial kidney injury, using collecting duct proteostasis defects as a platform for discovery of signals that may underlie CKD of disparate etiologies.
Novel Third-Generation EGFR Tyrosine Kinase Inhibitors and Strategies to Overcome Therapeutic Resistance in Lung Cancer
Authors: Ayesha Murtuza, Ajaz Bulbul, John Paul Shen, Parissa Keshavarzian, Brian D. Woodward, Fernando J. Lopez-Diaz, Scott M. Lippman, Hatim Husain
Journal: Cancer Research (2019)

EGFR-activating mutations are observed in approximately 15% to 20% of patients with non-small cell lung cancer. Tyrosine kinase inhibitors have provided an illustrative example of the successes in targeting oncogene addiction in cancer and the role of tumor-specific adaptations conferring therapeutic resistance. The compound osimertinib is a third-generation tyrosine kinase inhibitor, which was granted full FDA approval in March 2017 based on targeting EGFR T790M resistance. The compound has received additional FDA approval as first-line therapy with improvement in progression-free survival by suppressing the activating mutation and preventing the rise of the dominant resistance clone. Drug development has been breathtaking in this space with other third-generation compounds at various stages of development: rociletinib (CO-1686), olmutinib (HM61713), nazartinib (EGF816), naquotinib (ASP8273), mavelertinib (PF-0647775), and AC0010. However, therapeutic resistance after the administration of third-generation inhibitors is complex and not fully understood, with significant intertumoral and intratumoral heterogeneity. Repeat tissue and plasma analyses on therapy have revealed insights into multiple mechanisms of resistance, including novel second site EGFR mutations, activated bypass pathways such as MET amplification, HER2 amplification, RAS mutations, BRAF mutations, PIK3CA mutations, and novel fusion events. Strategies to understand and predict patterns of mutagenesis are still in their infancy; however, technologies to understand synthetically lethal dependencies and track cancer evolution through therapy are being explored. The expansion of combinatorial therapies is a direction forward targeting minimal residual disease and bypass pathways early based on projected resistance.
Abstract 11553: The CHA2DS2-VASc Score and the Risk of Ischemic Stroke by Atrial Fibrillation Status: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: M Chadi Alraies, Faye L Norby, Elsayed Z Soliman, Alvaro Alonso, Lin Y Chen
Journal: Circulation (2015)

Background: CHA2DS2-VASc score has been shown to be predictive of risk of ischemic stroke (IS) in persons without atrial fibrillation (AF). These observations raise the question whether it is AF per se or the associated vascular risk factors that elevate the risk of IS. Hypothesis: AF elevates the risk of IS over and above vascular risk factors in the CHA2DS2-VASc score and as the CHA2DS2-VASc score increases, AF plays a more important role in determining the risk of stroke. Methods: Using the ARIC study_a biracial, community-based prospective cohort study we compared (a) the model discrimination of the CHA2DS2-VASc score for IS in participants with vs. without AF, and (b) the risk of IS by CHA2DS2-VASc score among participants with vs. without AF. We included 1395 participants with AF who were matched to 4060 participants without AF based on age, race, and CHA2DS2-VASc score (mean age, 62 years; 57% women; 22% blacks). Participants with prevalent IS or anticoagulant use at baseline were excluded. AF was ascertained from hospitalization discharge codes and study ECGs. IS was physician-adjudicated. Results: Median follow-up was 14.7 years and 288 (5.3%) participants developed IS. The C-statistic of the CHA2DS2-VASc score for IS was not significantly different in participants with vs. without AF (Table). The incidence rate difference of IS increases with increasing CHA2DS2-VASc score in participants with vs. without AF (Table, p for interaction between AF and CHA2DS2-VASc score &lt;0.0001). Conclusion: Model discrimination of the CHA2DS2-VASc score for IS in individuals with AF is comparable to those without AF. However, with increasing score, the incidence rate of IS in individuals with AF increases to a greater extent than in those without AF. These findings suggest that as the CHA2DS2-VASc score increases, the disorganized rhythm of AF or other AF-related factor (e.g., left atrial dysfunction or enlargement) plays an even greater role to elevate the risk of IS.
Abstract IA07: Engineering T cells for the immunotherapy for pediatric solid tumors
Authors: Stephen Gottschalk, Chris DeRenzo, Meena Hegde, Melinda Mata, Phoung Nguyen, Giedre Krenciute, Nabil Ahmed
Journal: Cancer Research (2018)

Abstract Engineering T cells for the immunotherapy for pediatric solid tumorsImmunotherapy with genetically modified T cells holds the promise to improve outcome for pediatric cancer patients who currently cannot be cured. In addition, T-cell therapy has the potential to reduce treatment-related complication for all patients. Cell therapy with T cells, genetically modified to express chimeric antigen receptors (CARs), had dramatic success for pediatric patients with recurrent/refractory CD19-positive acute lymphoblastic leukemia (ALL), resulting in the recent FDA approval of CD19-CAR T cells for recurrent/refractory ALL. In contrast, CAR T-cell therapies thus far have been less successful for pediatric solid tumors. In my talk, I will review current challenges of CAR T-cell therapies for solid tumors, highlighting our clinical studies targeting HER2 (Ahmed et al., JCO 2015 and JAMA Oncol 2017). In addition, I will review genetic engineering approaches that are being developed to improve the efficacy of CAR T cells for pediatric solid tumors. Citation Format: Stephen Gottschalk, Chris DeRenzo, Meena Hegde, Melinda Mata, Phoung Nguyen, Giedre Krenciute, Nabil Ahmed. Engineering T cells for the immunotherapy for pediatric solid tumors [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr IA07.
Development and first validation of a patient-reported experience measure in chronic obstructive pulmonary disease (PREM-C9)
Authors: Matthew Hodson, C Michael Roberts, Sharon Andrew, Laura Graham, Paul W Jones, Janelle Yorke
Journal: Thorax (2019)

We developed a chronic obstructive pulmonary disease (COPD) patient-reported experience measure (PREM-C9). 174 patients with COPD (86 [49%] with a confirmed diagnosis and 88 [51%] with a self-reported diagnosis of COPD) completed a 38-item list, COPD Assessment Test (CAT) and Hospital Anxiety and Depression Scale (HADS). Hierarchical and Rasch analysis produced a 9-item list (PREM-C9). It demonstrated fit to the Rasch model (χ² p=0.33) and correlated moderately with CAT (r=0.42), HAD-anxiety (r=0.30) and HAD-depression (r=0.41) (p&lt;0.05). A substudy confirmed its ability to detect change prepulmonary and postpulmonary rehabilitation. The PREM-C9 is a simple, valid measure of experience of patients living with COPD, validated in this study population with mild to very severe disease; it may be a useful measure in research and clinical audits.
Abstract A37: Self-seeding resulting from tumor-tumor IL-6 signaling protects lungs from osteosarcoma metastasis
Authors: Amanda J. Saraf, Helene Le Pommellet, Amy Gross, Sarah Winget, Ryan D. Roberts
Journal: Cancer Research (2018)

Abstract Metastatic osteosarcoma (OS) remains a fatal disease with overall survival less than 20%. The factors that drive metastasis remain poorly understood. Many have speculated on the biology that might drive development of metastasis after resection of a primary tumor. Our work suggests that OS tumors exhibit a high degree of self-seeding—“metastasis” of cancer cells back to the site of the primary tumor—and that circulating cells recolonize the primary tumor site preferentially over other sites. Removal of the primary tumor in orthotopic mouse models of OS triggers a redirection of circulating tumor cells toward colonization of alternative tissues, such as the lung. Mice that undergo amputation experience increased metastasis to the lungs relative to mice that continue to bear an orthotopic tumor. Our work demonstrates the involvement of IL-6 in the process of OS self-seeding. We show that osteosarcoma cells not only produce IL-6, but demonstrate directional migration and invasion in response to an IL6 gradient. Primary tumors engineered to lose the ability to produce IL6 demonstrate impairment of self-seeding and therefore become less able to “protect” from the development of lung metastasis. These results suggest that IL-6 is a primary mediator of tumor-tumor interactions that drive self-seeding in a process that might be amenable to therapeutic manipulation for the prevention of OS lung metastasis. Citation Format: Amanda J. Saraf, Helene Le Pommellet, Amy Gross, Sarah Winget, Ryan D. Roberts. Self-seeding resulting from tumor-tumor IL-6 signaling protects lungs from osteosarcoma metastasis [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A37.
Transfusion Therapy in a Multi-Ethnic Sickle Cell Population Real-World Practice. a Preliminary Data Analysis of Multicentre Survey
Authors: Giovanna Graziadei, Laura Sainati, Pietro Bonomo, Donatella Venturelli, Nicoletta Masera, Maddalena Casale, Aurora Vassanelli, Gianluca Lodi, Frédéric B Piel, Vincenzo Voi, Lucia De Franceschi, Paolo Rigano, Alessandra Quota, Lucia Dora Notarangelo, Giovanna Russo, Rosamaria Rosso, Massimo Allò, Domenico D'Ascola, Elena Facchini, Silvia Macchi, Francesco Arcioni, Alberto Piperno, Federico Bonetti, Giovanni Palazzi, Maria Grazia Bisconte, Antonella Sau, Roberto Lisi, Fiorina Giona, Saveria Campisi, Gloria Colarusso, Paola Giordano, Gianluca Boscariol, Sarah Marktel, Aldo Filosa, Raffaella Origa, Mauro Murgia, Paola Maroni, Barbara Gianesin, Luca Badalamenti, Gian Luca Forni
Journal: Blood (2018)
Drying technology strategies for colon-targeted oral delivery of biopharmaceuticals
Authors: Panna Vass, Balázs Démuth, Edit Hirsch, Brigitta Nagy, Sune K. Andersen, Tamás Vigh, Geert Verreck, István Csontos, Zsombor K. Nagy, György Marosi
Journal: Journal of Controlled Release (2019)
The European Alpha-1 Research Collaboration (EARCO): a new ERS Clinical Research Collaboration to promote research in alpha-1 antitrypsin deficiency
Authors: Marc Miravitlles, Joanna Chorostowska-Wynimko, Ilaria Ferrarotti, Noel G. McElvaney, Karen O'Hara, Jan Stolk, Robert A. Stockley, Alice Turner, Marion Wilkens, Timm Greulich
Journal: European Respiratory Journal (2019)

Alpha-1 antitrypsin deficiency (AATD) is a common but under-recognised genetic condition that affects approximately 1 in 2000 to 1 in 5000 individuals and predisposes to early-onset emphysema and liver disease [1]. Alpha-1 antitrypsin (AAT) is mainly produced in the liver, and its main function is to protect the lung against proteolytic damage, especially from neutrophil elastase [2]. To date, more than 100 variant alleles of the AAT gene ( SERPINA1 ) have been described, but the Z allele is the most prevalent and responsible for severe AATD leading to lung and liver disease [3]. The European Alpha-1 Research Collaboration (EARCO) will promote international research in alpha-1 antitrypsin deficiency <http://ow.ly/DWwg30nwCj4> We want to acknowledge the support from Elise Heuvelin and Cèline Genton (European Respiratory Society, Lausanne, Switzerland) in the logistics and organisation of EARCO.
Myelodysplasia, Leukemia, Lymphoid Malignancies, and Other Cancers in Patients with Severe Chronic Neutropenia
Authors: David C Dale, Audrey Anna Bolyard, Blanche P. Alter, Mary Ann Bonilla, James Connelly, Daniel C. Link, Peter E. Newburger, Philip S. Rosenberg, Akiko Shimamura, Kelly J. Walkovich
Journal: Blood (2018)
Abstract 11426: Factors Precipitating Hospital Admissions for Heart Failure in Women: Insights From the Gulf CARE Registry
Authors: Amar M Salam, Kadhim Sulaiman, Jassim Al-Suwaidi, Khalid AlHabib, Wael Almahmeed, Alawi Alsheikh-Ali, Prashanth Panduranga, Husam AlFaleh, Abdelfatah Elasfar, Ahmed Al-Motarreb, Nooshin Bazargani, Mustafa Ridha, Bassam Bulbanat, Mohammed Al-Jarallah, Haitham Amin, Nidal Asaad, Awad Al-Qahtani, Rajvir Singh, Magdi Yacoub
Journal: Circulation (2014)

OBJECTIVES: Although factors precipitating hospital admissions for heart Failure (HF) have been identified in overall cohorts of HF registries, however. It remains unknown whether these factors are different in women and if there is gender variations in these factors. The aim of the current study was to identify factors precipitating HF hospitalizations peculiar to women and to compare them to those for men using a large multinational multicenter registry from the Middle-East. METHODS: From February 2012 to November 2013, consecutive patients hospitalized with HF were enrolled from 47 hospitals in 7 Middle East countries. Identifiable factors contributing to HF hospitalization were captured at admission and included myocardial ischemia, arrhythmia, nonadherence to medications or diet, salt retaining drugs, anemia, community acquired infections, hypertension, and worsening renal function. Patients were divided into 2 groups according to gender and the 2 groups were compared. RESULTS: During the study perio...
Associations of Monounsaturated Fatty Acids From Plant and Animal Sources With Total and Cause-Specific Mortality in Two US Prospective Cohort Studies
Authors: Marta Guasch-Ferré, Geng Zong, Walter C. Willett, Peter L. Zock, Anne J. Wanders, Frank B. Hu, Qi Sun
Journal: Circulation Research (2019)

Dietary monounsaturated fatty acids (MUFAs) can come from both plant and animal sources with divergent nutrient profiles that may potentially obscure the associations of total MUFAs with chronic diseases.
A Neutrophil Timer Coordinates Immune Defense and Vascular Protection
Authors: José M. Adrover, Carlos del Fresno, Georgiana Crainiciuc, Maria Isabel Cuartero, María Casanova-Acebes, Linnea A. Weiss, Hector Huerga-Encabo, Carlos Silvestre-Roig, Jan Rossaint, Itziar Cossío, Ana V. Lechuga-Vieco, Jaime García-Prieto, Mónica Gómez-Parrizas, Juan A. Quintana, Ivan Ballesteros, Sandra Martin-Salamanca, Alejandra Aroca-Crevillen, Shu Zhen Chong, Maximilien Evrard, Karl Balabanian, Jorge López, Kiril Bidzhekov, Françoise Bachelerie, Francisco Abad-Santos, Cecilia Muñoz-Calleja, Alexander Zarbock, Oliver Soehnlein, Christian Weber, Lai Guan Ng, Cristina Lopez-Rodriguez, David Sancho, María A. Moro, Borja Ibáñez, Andrés Hidalgo
Journal: Immunity (2019)
Abstract 12827: Detection of Spontaneous Pulse Using Acceleration Signals Acquired From CPR Feedback Sensor in Porcine Model of Cardiac Arrest
Authors: Liang Wei, Tao Yu, Peng Gao, Weilun Quan, Yongqin Li
Journal: Circulation (2016)

Background: Reliable detection of return of spontaneous circulation (ROSC) without long interruptions of chest compressions is part of high-quality cardiopulmonary resuscitation (CPR) and routinely done by checking pulsation of carotid or femoral arteries. The purpose of the current study was to investigate whether acceleration signals acquired from a CPR feedback sensor can be used to distinguish perfusing rhythm from pulseless electrical activity (PEA) in a porcine model of cardiac arrest. Methods: The experimental data were collected from 50 male adult pigs with prolonged cardiac arrest and CPR. ECG, arterial blood pressure and acceleration signals were synchronously recorded at a sample rate of 300 Hz. The acceleration signal (ACC) was acquired from an accelerometer-based CPR sensor that was placed on the surface of the animal’s chest over the heart. During chest compression pauses 3-second segments of signals were extracted. ROSC was defined as systolic arterial pressure (SAP) &gt;60 mmHg and pulse pressure (PP) &gt;10 mmHg in the presence of an organized rhythm. ACC was pre-processed using a narrow band-pass filter with the center frequency from 0.5 to 7.5Hz. Cross-correlation function was calculated between ECG and filtered ACC to obtain the peak correlation coefficient (CCp). Area under the receiver operating characteristic curve (AUC) was used to evaluate the ability of CCp to detect ROSC. Results: A total of 216 segments were obtained with 63 in perfusing rhythm and 153 in PEA. The filtered ACC tracings (ACC’) in perfusing rhythm showed periodic oscillations synchronized with R waves, but no periodic oscillations were observed for PEA. Compared with PEA, heart rate (159.0±50.7 vs. 86.0±44.9 bpm, p &lt;0.01), SAP (143.3±38.3 vs. 18.9±13.3 mmHg, p &lt;0.01), pulse pressure (42.3±14.5 vs. 5.6±8.3 mmHg, p &lt;0.01) and CCp (0.443±0.171 vs. 0.096±0.085, p &lt;0.01) were significantly higher for perfusing rhythm. The AUC was 0.95 when CCp was used to differentiate ROSC from PEA. Using a cut-off threshold of 0.244, the sensitivity and specificity were 90.5% respectively. Conclusions: In this animal model, the acceleration signals acquired from a CPR feedback sensor can be used to distinguish perfusing rhythm from PEA.
Port-wine stains on the neck respond better to a pulsed dye laser than lesions on the face: An intrapatient comparison study with histopathology
Authors: Wenxin Yu, Jiafang Zhu, Yifei Gu, Yijie Chen, Yue Han, Ying Shang, Hui Chen, Yunbo Jin, Xi Yang, Lei Chang, Gang Ma, Xiaoxi Lin
Journal: Journal of the American Academy of Dermatology (2019)