tbuckley/cabot-search huggingface dataset:
Integrated molecular analysis of adult sonic hedgehog (SHH)-activated medulloblastomas reveals two clinically relevant tumor subsets with VEGFA as potent prognostic indicator
Authors: Andrey Korshunov, Konstantin Okonechnikov, Damian Stichel, Marina Ryzhova, Daniel Schrimpf, Felix Sahm, Philipp Sievers, Oksana Absalyamova, Olga Zheludkova, Andrey Golanov, David T W Jones, Stefan M Pfister, Andreas von Deimling, Marcel Kool
Journal: Neuro-Oncology (2021)

Abstract Background Up to now, adult medulloblastoma (MB) patients are treated according to the protocols elaborated for pediatric MB although these tumors are different in terms of clinical outcomes and biology. Approximately 70% of adult MB disclose a sonic hedgehog (SHH) molecular signature in contrast to about 30% in pediatric cohorts. In addition, adult SHH-MB (aSHH-MB) are clinically heterogeneous but there is consensus neither on their optimal treatment nor on risk stratification. Thus, the identification of clinically relevant molecular subsets of aSHH-MB and identification of potential treatment targets remains inconclusive. Methods We analyzed 96 samples of institutionally diagnosed aSHH-MB through genome-wide DNA methylation profiling, targeted DNA sequencing, and RNA sequencing to identify molecular subcategories of these tumors and assess their prognostic significance. Results We defined two aSHH-MB numerically comparable epigenetic subsets with clinical and molecular variability. The subset “aSHH-MBI” (46%/48%) was associated with PTCH1/SMO (54%/46%) mutations, “neuronal” transcriptional signatures, and favorable outcomes after combined radio-chemotherapy (5-year PFS = 80% and OS = 92%). The clinically unfavorable “aSHH-MBII” subset (50%/52%; 5-year PFS = 24% and OS = 45%) disclosed GLI2 amplifications (8%), loss of 10q (22%), and gene expression signatures associated with angiogenesis and embryonal development. aSHH-MBII tumors revealed strong and ubiquitous expression of VEGFA both at transcript and protein levels that was correlated with unfavorable outcome. Conclusions (1) The histologically uniform aSHH-MB cohort exhibits clear molecular heterogeneity separating these tumors into two molecular subsets (aSHH-MBI and aSHH-MBII), which are associated with different cytogenetics, mutational landscapes, gene expression signatures, and clinical course. (2) VEGFA appears to be a promising biomarker to predict clinical course, which needs further prospective validation as its potential role in the pathogenesis of this subset.
Genomic landscape of MDS/CMML associated with systemic inflammatory and autoimmune disease
Authors: Lin-Pierre Zhao, Maxime Boy, Célia Azoulay, Emmanuelle Clappier, Marie Sébert, Ludivine Amable, Jihene Klibi, Kamel Benlagha, Marion Espéli, Karl Balabanian, Claude Preudhomme, Alice Marceau-Renaut, Lina Benajiba, Raphaël Itzykson, Arsène Mekinian, Olivier Fain, Antoine Toubert, Pierre Fenaux, Nicolas Dulphy, Lionel Adès
Journal: Leukemia (2021)
Metabolic signature might be an option to identify patients with early CP
Authors: Bálint Erőss, Andrea Szentesi, Peter Hegyi
Journal: Gut (2021)

Metabolites are biomarkers measured in blood, urine, stool and tissue samples, determined by several factors, most importantly by the gut microbiota and changes in the metabolism from underlying diseases. Theoretically, specific diseases lead to changes in both factors that result in specific metabolomic profiles characterising these disorders. In recent years, metabolomic profiling for the diagnosis and the prognostic assessment of GI diseases has been an emerging and new tool; there are examples of metabolomics in diagnosing and assessing chronic GI disorders such as cancers, IBD and cirrhosis.1–6

The recent studies on metabolomics have assessed its potential roles in gastroenterology patients' care, but it is not yet part of the daily routine.

In Gut , Adam et al report a very important study, which aimed to assess metabolomics' diagnostic potential in chronic pancreatitis (CP).7 Patients with unequivocally diagnosed CP had been identified by a set of criteria, including radiological changes and severely abnormal pancreatic function tests.8–10 Their metabolomic profiles were compared against three control groups, the …
Mortality Among Minority Populations with Systemic Lupus Erythematosus, Including Asian and Hispanic/Latino Persons — California, 2007–2017
Authors: Milena A. Gianfrancesco, Maria Dall’Era, Louise B. Murphy, Charles G. Helmick, Jing Li, Stephanie Rush, Laura Trupin, Jinoos Yazdany
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with manifestations that vary widely in severity. Although minority populations are at higher risk for SLE and have more severe outcomes (1), population-based estimates of mortality by race and ethnicity are often lacking, particularly for Asian and Hispanic/Latino persons. Among 812 patients in the California Lupus Surveillance Project (CLSP) during 2007-2009 (2,3), who were matched to the 2007-2017 National Death Index (NDI), 16.6% had died by 2017. This proportion included persons of White (14.4%), Black (25%), Asian (15.3%), and Hispanic/Latino (15.5%) race/ethnicity. Standardized mortality ratios (SMRs) of observed-to-expected deaths among persons with SLE within each racial/ethnic group were 2.3, 2.0, 3.8, and 3.9, respectively. These findings provide the first population-based estimates of mortality among Asian and Hispanic/Latino persons with SLE. Coordination of robust care models between primary care providers and rheumatologists could ensure that persons with SLE receive a timely diagnosis and appropriate treatments that might help address SLE-associated mortality.
Abstract PS2-43: Innovating a magnetic experience on wirral peninsula in the United Kingdom- our experience with magseed localisation of impalpable breast tumours and axillary node for therapeutic surgery and staging
Authors: Tahera Arif, Mohammed Shameem Absar, Jonathan Michael Lund
Journal: Cancer Research (2021)

Abstract INTRODUCTION Magseed is a novel localization technology in which a tiny seed is inserted to accurately mark the site of breast tumour. These can be detected intra-operatively by sentimag localization system. These can be implanted days prior to surgery and do not require use of radioactive material. It aids localization of impalpable breast lesions improving margin clearance rates. METHODS A study was undertaken of 50 patients undergoing Magseed localization of non-palpable breast lesions in rural and urban areas of Wirral Peninsula in the UK. Data including age, mode of localization (Stereo-guided/ Ultrasound guided), presentation (Symptomatic/Screen detected), and time to surgery after localization, size and weight of specimen, histology and re-excision rates was collected between June 2019 and November 2019. RESULTS A total of 50 patients had 52 Magseed inserted. n=14 were symptomatic, n=35 were screen detected and n=1 was an incidental finding on surveillance mammogram for a B3 lesion. All 50 patients had therapeutic surgery. 30 seeds were inserted on the right and 22 were inserted on the left (two were bilateral). 44 seeds were inserted under Ultrasound guidance and the rest were targeted under stereo guidance (n=8).Deployment of 2 Magseed resulted in malposition requiring wire localization. Mean age of subjects was 59.76 (range 31-81) years. Mean time to surgery after Magseed insertion was 8.04 (range 1-27) days. Mean weight of the specimen was 48.57(range 10-264) gm. Mean size of the lesions was 20.32 (range 8-65) mm. Redo surgery for margin clearance was performed bringing the re-excision rate to 15.38% (n=8). CONCLUSION We conclude that Magseed localization of breast tumours is a safe and reliable technique in terms of accuracy, localization and clearance of margins without any radiation concerns. Our re-excision rate for margin clearance is comparable to the national average. The only caveat we observed was localization of impalpable lesions prior to surgery in bulky breasts where we had to utilize wire guided localization on the day of surgery. Large scale data are lacking to compare Magseed localization with other localization techniques for non-palpable breast lesions. Citation Format: Tahera Arif, Mohammed Shameem Absar, Jonathan Michael Lund. Innovating a magnetic experience on wirral peninsula in the United Kingdom- our experience with magseed localisation of impalpable breast tumours and axillary node for therapeutic surgery and staging [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS2-43.
Abstract PD1-08: Oral paclitaxel and encequidar (oPac+E) versus IV paclitaxel (IVPac) in the treatment of metastatic breast cancer (mBC) patients (study KX-ORAX-001): Progression free survival (PFS) and overall survival (OS) updates
Authors: G Umanzor, H S Rugo, F J Barrios, R H Vasallo, M A Chivalan, S Bejarano, J R Ramirez, L Fein, R D Kowalyszyn, D L Cutler, D Kramer, J Goldfinch, H Wang, T Moore, R MF Kwan
Journal: Cancer Research (2021)

Abstract Background: IVPac is widely used to treat patients with breast cancer. oPac+E is oral paclitaxel in combination with Encequidar, an oral, minimally absorbed, specific p-glycoprotein inhibitor that enables the absorption of oral paclitaxel. Results of the phase III trial, KX-ORAX-001, were presented at SABCS, 2019, Abstract # GS6-01. At the time of the database lock for the final analysis of the primary endpoint of confirmed tumor response rate, analyses of PFS and OS were performed. The confirmed tumor response rate was significantly higher in the oPac+E group vs IVPac (35.8% vs 23.4%, p=0.011 ITT, population). The median overall survival was 27.7 months vs 16.7 months, respectively favoring oPac. An update of the duration of response, PFS and OS data comprising an additional 14 months follow-up will be presented. At the time of the update it is projected that approximately 60% of subjects will have had a survival event. Methods: Study KX-ORAX-001 was a phase III, randomized, international study in women with mBC for whom treatment with IVPac was recommended. Eligible patients were randomized 2:1 to receive oPac+E or IVPac. Patients continued treatment until discontinuation due to progressive disease or toxicity. oPac 205 mg/m2 was given once daily for 3 days weekly. E 12.9 mg was given 1 hour before each dose of oPac. IVPac 175 mg/m2 was infused over 3 hours every 3 weeks. The primary endpoint was efficacy defined as tumor response confirmed by BICR at two consecutive evaluations. Key secondary endpoints included PFS, OS. Safety was monitored throughout the study. Results: A total of 402 mBC patients were randomized (oPac+E 265: IVPac 137) and represent the ITT population of which 399 subjects were dosed. Updated data for duration of response, PFS and OS for the ITT and prespecified mITT populations will be presented. (NCT 02594371) Citation Format: G Umanzor, H S Rugo, F J Barrios, R H Vasallo, M A Chivalan, S Bejarano, J R Ramirez, L Fein, R D Kowalyszyn, D L Cutler, D Kramer, J Goldfinch, H Wang, T Moore, R MF Kwan. Oral paclitaxel and encequidar (oPac+E) versus IV paclitaxel (IVPac) in the treatment of metastatic breast cancer (mBC) patients (study KX-ORAX-001): Progression free survival (PFS) and overall survival (OS) updates [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD1-08.
Development and validation of a prediction model for 30-day mortality in hospitalised patients with COVID-19: the COVID-19 SEIMC score
Authors: Juan Berenguer, Alberto M Borobia, Pablo Ryan, Jesús Rodríguez-Baño, Jose M Bellón, Inmaculada Jarrín, Jordi Carratalà, Jerónimo Pachón, Antonio J Carcas, María Yllescas, José R Arribas
Journal: Thorax (2021)

Objective To develop and validate a prediction model of mortality in patients with COVID-19 attending hospital emergency rooms. Design Multivariable prognostic prediction model. Setting 127 Spanish hospitals. Participants Derivation (DC) and external validation (VC) cohorts were obtained from multicentre and single-centre databases, including 4035 and 2126 patients with confirmed COVID-19, respectively. Interventions Prognostic variables were identified using multivariable logistic regression. Main outcome measures 30-day mortality. Results Patients’ characteristics in the DC and VC were median age 70 and 61 years, male sex 61.0% and 47.9%, median time from onset of symptoms to admission 5 and 8 days, and 30-day mortality 26.6% and 15.5%, respectively. Age, low age-adjusted saturation of oxygen, neutrophil-to-lymphocyte ratio, estimated glomerular filtration rate by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, dyspnoea and sex were the strongest predictors of mortality. Calibration and discrimination were satisfactory with an area under the receiver operating characteristic curve with a 95% CI for prediction of 30-day mortality of 0.822 (0.806–0.837) in the DC and 0.845 (0.819–0.870) in the VC. A simplified score system ranging from 0 to 30 to predict 30-day mortality was also developed. The risk was considered to be low with 0–2 points (0%–2.1%), moderate with 3–5 (4.7%–6.3%), high with 6–8 (10.6%–19.5%) and very high with 9–30 (27.7%–100%). Conclusions A simple prediction score, based on readily available clinical and laboratory data, provides a useful tool to predict 30-day mortality probability with a high degree of accuracy among hospitalised patients with COVID-19.
Abstract SP057: Mechanisms Controlling Expression of the Breast Cancer Genomic DNA Deaminase APOBEC3B
Authors: R Harris
Journal: Cancer Research (2021)

Abstract Introduction: APOBEC3B (A3B)-catalyzed DNA cytosine deamination contributes to the overall mutational landscape in primary and metastatic breast cancer. While low in normal tissues, A3B expression and activity are elevated in many primary tumors and increase further in metastases. Prior studies have implicated the RB/E2F signaling pathway in A3B overexpression in breast cancer but a detailed molecular mechanism has yet to be described. Methods: A combination of genetic, biochemical, proteomic, and bioinformatic approaches were used to investigate whether dysregulation of the RB/E2F signaling pathway is a molecular trigger for A3B overexpression in breast cancer. Results: First, an A3B promoter-driven luciferase reporter was used to demonstrate functional repression by one of five predicted E2F binding sites. Disruption of this single E2F site both phenocopied and prevented further induction by BK polyomavirus T antigen, which was known from prior studies to induce A3B expression. Second, targeted disruption of the endogenous E2F binding site caused strong A3B upregulation and confirmed the importance of this cis-regulatory element. Third, proteomics experiments showed that members of the DREAM and PRC1.6 complexes are able to bind to wildtype but not to mutant E2F promoter sequences. Additional biochemical, genetic, and cell biological studies implicated both the E2F4/DREAM complex and E2F6/PRC1.6 complex in endogenous A3B repression. Last, bioinformatic analyses of breast cancer data sets showed A3B overexpression and higher levels of APOBEC signature mutations in tumors with coordinately overexpressed E2F target genes. Conclusions: These studies combine to demonstrate that A3B expression is suppressed in normal cells by repressive E2F complexes and that disruption of this regulatory network triggers overexpression in breast cancer and provides fuel for tumor evolution. These studies raise the possibility that overexpression of an E2F gene set in breast tumors may be a biomarker for APOBEC mutability. Citation Format: R Harris. Mechanisms Controlling Expression of the Breast Cancer Genomic DNA Deaminase APOBEC3B [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SP057.
Decentralisation, integration, and task-shifting in hepatitis C virus infection testing and treatment: a global systematic review and meta-analysis
Authors: Ena Oru, Adam Trickey, Rohan Shirali, Steve Kanters, Philippa Easterbrook
Journal: The Lancet Global Health (2021)

Increasing access to hepatitis C virus (HCV) care and treatment will require simplified service delivery models. We aimed to evaluate the effects of decentralisation and integration of testing, care, and treatment with harm-reduction and other services, and task-shifting to non-specialists on outcomes across the HCV care continuum.
Integrated vaccination and physical distancing interventions to prevent future COVID-19 waves in Chinese cities
Authors: Bo Huang, Jionghua Wang, Jixuan Cai, Shiqi Yao, Paul Kay Sheung Chan, Tony Hong-wing Tam, Ying-Yi Hong, Corrine W. Ruktanonchai, Alessandra Carioli, Jessica R. Floyd, Nick W. Ruktanonchai, Weizhong Yang, Zhongjie Li, Andrew J. Tatem, Shengjie Lai
Journal: Nature Human Behaviour (2021)

The coronavirus disease 2019 (COVID-19) pandemic has posed substantial challenges to the formulation of preventive interventions, particularly since the effects of physical distancing measures and upcoming vaccines on reducing susceptible social contacts and eventually halting transmission remain unclear. Here, using anonymized mobile geolocation data in China, we devise a mobility-associated social contact index to quantify the impact of both physical distancing and vaccination measures in a unified way. Building on this index, our epidemiological model reveals that vaccination combined with physical distancing can contain resurgences without relying on stay-at-home restrictions, whereas a gradual vaccination process alone cannot achieve this. Further, for cities with medium population density, vaccination can reduce the duration of physical distancing by 36% to 78%, whereas for cities with high population density, infection numbers can be well-controlled through moderate physical distancing. These findings improve our understanding of the joint effects of vaccination and physical distancing with respect to a city's population density and social contact patterns.
LACC1 deficiency links juvenile arthritis with autophagy and metabolism in macrophages
Authors: Ommar Omarjee, Anne-Laure Mathieu, Gaëlle Quiniou, Marion Moreews, Michelle Ainouze, Cécile Frachette, Isabelle Melki, Cécile Dumaine, Mathieu Gerfaud-Valentin, Agnès Duquesne, Tilmann Kallinich, Eda Tahir Turanli, Christophe Malcus, Sébastien Viel, Rémi Pescarmona, Sophie Georgin-Lavialle, Yvan Jamilloux, Jean-Paul Larbre, Guillaume Sarrabay, Flora Magnotti, Gillian I. Rice, Francoise Bleicher, Jonathan Reboulet, Samir Merabet, Thomas Henry, Yanick J. Crow, Mathias Faure, Thierry Walzer, Alexandre Belot
Journal: The Journal of Experimental Medicine (2020)

Juvenile idiopathic arthritis is the most common chronic rheumatic disease in children, and its etiology remains poorly understood. Here, we explored four families with early-onset arthritis carrying homozygous loss-of-expression mutations in LACC1. To understand the link between LACC1 and inflammation, we performed a functional study of LACC1 in human immune cells. We showed that LACC1 was primarily expressed in macrophages upon mTOR signaling. We found that LACC1 deficiency had no obvious impact on inflammasome activation, type I interferon response, or NF-κB regulation. Using bimolecular fluorescence complementation and biochemical assays, we showed that autophagy-inducing proteins, RACK1 and AMPK, interacted with LACC1. Autophagy blockade in macrophages was associated with LACC1 cleavage and degradation. Moreover, LACC1 deficiency reduced autophagy flux in primary macrophages. This was associated with a defect in the accumulation of lipid droplets and mitochondrial respiration, suggesting that LACC1-dependent autophagy fuels macrophage bioenergetics metabolism. Altogether, LACC1 deficiency defines a novel form of genetically inherited juvenile arthritis associated with impaired autophagy in macrophages.
COPD discharge bundle and pulmonary rehabilitation referral and uptake following hospitalisation for acute exacerbation of COPD
Authors: Ruth E Barker, Samantha SC Kon, Stuart F Clarke, Jenni Wenneberg, Claire M Nolan, Suhani Patel, Jessica A Walsh, Oliver Polgar, Matthew Maddocks, Morag Farquhar, Nicholas S Hopkinson, Derek Bell, Jadwiga A Wedzicha, William D-C. Man
Journal: Thorax (2021)

Pulmonary rehabilitation (PR) following hospitalisations for acute exacerbation of COPD (AECOPD) is associated with improved exercise capacity and quality of life, and reduced readmissions. However, referral for, and uptake of, post-hospitalisation PR are low. In this prospective cohort study of 291 consecutive hospitalisations for AECOPD, COPD discharge bundles delivered by PR practitioners compared with non-PR practitioners were associated with increased PR referral (60% vs 12%, p&lt;0.001; adjusted OR: 14.46, 95% CI: 5.28 to 39.57) and uptake (40% vs 32%, p=0.001; adjusted OR: 8.60, 95% CI: 2.51 to 29.50). Closer integration between hospital and PR services may increase post-hospitalisation PR referral and uptake.
Endoscopic submucosal dissection of a laterally spreading tumor involving a colonic diverticulum using the counter-traction technique
Authors: Thomas Lambin, Jérémie Jacques, Jérôme Rivory, Florian Rostain, Timothée Wallenhorst, Mathieu Pioche
Journal: Endoscopy (2021)

Endoscopic submucosal dissection (ESD) is the technique of choice for the resection of superficial colorectal lesions larger than 20 mm [1], but the procedure can be technically challenging in some situations. If a lesion involves a diverticulum, there is fear of a higher risk of perforation due to the lack of muscle layer. However, ESD has recently been described as safe and effective in this particular case [2]. Use of a clip and rubber band (counter-traction technique [3]) can help to achieve a satisfying resection with higher technical comfort. This technique has been proved to be effective and safe for resection of neoplastic lesions involving the appendiceal orifice [4]. However, few data are available for lesions involving a diverticulum [5].
Suramin and prostate cancer: where do we go from here?
Authors: J W Clark, B A Chabner
Journal: Journal of Clinical Oncology (1995)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1995.13.9.2155 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 7666073 Suramin and prostate cancer: where do we go from here? J W ClarkxJ W ClarkSearch for articles by this author , B A ChabnerxB A ChabnerSearch for articles by this author https://doi.org/10.1200/JCO.1995.13.9.2155 First Page PDF © 1995 by American Society of Clinical Oncology
Abstract 14824: Creg1 is Required for Proper Myocardial Compaction
Authors: Russell J Pepe, Yanmei Qi, Jie Liu, Pranav Sathuvalli, Billie Fyfe-Kirschner, He Wang, Leonard Y Lee, Shaohua Li
Journal: Circulation (2019)

Introduction: Cellular repressor of E1A-stimulated genes 1 (CREG1) is an evolutionarily conserved glycoprotein of 220 amino acids. It is localized in the endosomal-lysosomal system. In cultured cel...
SARS-CoV-2 variants and convalescent plasma: reality, fallacies, and opportunities
Authors: Arturo Casadevall, Jeffrey P. Henderson, Michael J. Joyner, Liise-anne Pirofski
Journal: Journal of Clinical Investigation (2021)

In recent months genomic characterization of pandemic SARS-CoV-2 isolates identified viral variants that are less susceptible to neutralization by convalescent plasma (CP), vaccine-elicited plasma/sera, or SARS-CoV-2 monoclonal antibodies than earlier SARS-CoV-2 strains. In this Viewpoint, Casadevall et al. argue against the causal association made in some press articles between the emergence of SARS-CoV-2 variants and convalescent plasma use.