tbuckley/cabot-search huggingface dataset:
Atypical 3q26/MECOM rearrangements genocopy inv(3)/t(3;3) in acute myeloid leukemia
Authors: Sophie Ottema, Roger Mulet-Lazaro, H. Berna Beverloo, Claudia Erpelinck, Stanley van Herk, Robert van der Helm, Marije Havermans, Tim Grob, Peter J. M. Valk, Eric Bindels, Torsten Haferlach, Claudia Haferlach, Leonie Smeenk, Ruud Delwel
Journal: Blood (2020)
Lymph node staging in esophageal/junctional tumors after chemoradiotherapy: should we change strategy?
Authors: Gianenrico Rizzatti, Mihai Rimbaș, Alberto Larghi
Journal: Endoscopy (2020)

See also: Endoscopic ultrasound and fine-needle aspiration for the detection of residual nodal disease after neoadjuvant chemoradiotherapy for esophageal cancerEndoscopy 2020; 52(03): 186-192DOI: 10.1055/a-1065-1759 See also: Reply to Rizzatti et al.Endoscopy 2020; 52(04): 317-317DOI: 10.1055/a-1114-2608
Beta cell-specific CD8+ T cells maintain stem cell memory-associated epigenetic programs during type 1 diabetes
Authors: Hossam A. Abdelsamed, Caitlin C. Zebley, Hai Nguyen, Rachel L. Rutishauser, Yiping Fan, Hazem E. Ghoneim, Jeremy Chase Crawford, Francesca Alfei, Shanta Alli, Susan Pereira Ribeiro, Ashley H. Castellaw, Maureen A. McGargill, Hongjian Jin, Shannon K. Boi, Cate Speake, Elisavet Serti, Laurence A. Turka, Michael E. Busch, Mars Stone, Steven G. Deeks, Rafick-Pierre Sekaly, Dietmar Zehn, Eddie A. James, Gerald T. Nepom, Ben Youngblood
Journal: Nature Immunology (2020)
Abstract #2356: p53 nuclear accumulation and CRM1 down-regulation in lung lesions of a bitransgenic mouse lung tumor model
Authors: Lixia Chen, Joseph Moore, Changxia Shao, Everardo Cobos, Mark Miller, Weimin Gao
Journal: Cancer Research (2009)

p53, a tumor suppressor gene, plays an essential role in tumorigenesis. Chromosomal region maintenance 1 (CRM1) has been suggested to export p53 protein from the nucleus to the cytoplasm. Our recent in vitro cell study has shown p53 protein was up-regulated and accumulated in the nucleus after lung-specific carcinogen exposure resulting from CRM1 down-regulation. Phospho-p53 expression has also been shown to be up-regulated in our bitransgenic mouse lung tumor model, generated from the human Ki-rasG12C allele in a doxycycline (DOX)-inducible lung-specific manner. Curcumin, a chemopreventive agent, has been unexpectedly shown to cause lung tumor promotion of DOX-induced lung lesions through enhancing reactive oxygen species formation. Our objectives in the present study are to further evaluate the p53 subcellular localization and CRM1 expression level using this specific lung tumor model. The mice were treated with either olive oil (vehicle-treated control), DOX alone (500 \#956;g/ml), or co-treated with DOX (500 \#956;g/ml) and curcumin (4000 ppm) for 9 months. Semi-quantitative immunohistochemistry was performed to analyze the protein expression. p53 was stained in both nucleus and cytoplasm from lung epithelial cells. It was characterized to 3 staining patterns in the cell, including nucleus predominant (N>C), nucleus and cytoplasm (N=C), and cytoplasm predominant (N C p53 staining (46±7%), followed by lung lesions of mice co-treated with DOX and curcumin (31±12%), and controls (17±4%), suggesting that expression of the mutant Ki-rasG12C transgene increased p53 accumulation in the nucleus; co-treatment with curcumin partially reversed this effect. The CRM1 staining intensities (H scores, Mean±SE) in epithelial cells from control group, lung lesions of mice treated with DOX, and lung lesions of mice co-treated with DOX and curcumin, were 90.2±16.8, 0±0, and 46.8±21.0, respectively. CRM1 expression was dramatically inhibited in lung lesions of mice treated with DOX compared to controls (P=0.001), and could be partially reversed after curcumin treatment (P=0.028, DOX vs DOX+curcumin). In summary, the results from this study demonstrated that p53 accumulated in nucleus in lung lesions of mice expressing the mutant Ki-rasG12C transgene as a result of down-regulation of CRM1. Furthermore, these alterations could be partially reversed by curcumin treatment. These findings confirm both our in vitro cell study and in vivo animal study, suggesting that p53 subcellular localization resulting from CRM1 alterations might play an important role in lung tumorigenesis, and the curcumin-mediated decrease in nuclear p53 may be one mechanism by which curcumin enhances lung tumor progression in this mouse model.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2356.
Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19
Authors: Muthiah Vaduganathan, Orly Vardeny, Thomas Michel, John J.V. McMurray, Marc A. Pfeffer, Scott D. Solomon
Journal: New England Journal of Medicine (2020)

RAAS Inhibitors in Patients with Covid-19 The effects of renin–angiotensin–aldosterone system blockers on angiotensin-converting enzyme 2 levels and activity in humans are uncertain. The authors hy...
Clinical and CT features of early stage patients with COVID-19: a retrospective analysis of imported cases in Shanghai, China
Authors: Shuyi Yang, Yuxin Shi, Hongzhou Lu, Jianqing Xu, Feng Li, Zhiping Qian, Yebin Jiang, Xinyan Hua, Xueting Ding, Fengxiang Song, Jie Shen, Yang Lu, Fei Shan, Zhiyong Zhang
Journal: European Respiratory Journal (2020)

<b>COVID-19 emerged in Wuhan, China, and threatens public health. The clinical and CT features of early stage patients have not previously been characterised. This study aimed to explore the early stage clinical and CT signs.</b>http://bit.ly/38Tbq08
Abstract 416: Four Score Remains Effective Prognostic Tool in Cardiac Arrest After Eliminating Respiratory Component
Authors: Jonathan Duskin, Stephanie Liang, Katie Dam, William Spears, Kushak Suchdev, David M Greer
Journal: Circulation (2019)

Introduction: The FOUR (Full Outline of UnResponsiveness) score was developed as a more effective alternative to the Glasgow Coma Scale for prognostication of critically-ill neurology patients. Current research on the FOUR score in cardiac arrest is limited, but suggests that it may be useful. Given that whether or not a patient over-breathes the ventilator can often be confounded by the set respiratory rate, hypocarbia, and other factors, we evaluated the FOUR score with and without the respiratory component (FOUR-). Methods: We retrospectively studied 83 cardiac arrest patients treated at an urban hospital from 2011-2018 from the Multimodal outcome characterization in comatose cardiac arrest (MOCHA) registry. FOUR and FOUR- score within first 24 hours (day 1) and 72-96 hours (day 4) after arrest were evaluated for ability to predict in-hospital mortality and survival to discharge. Results: Day 1 FOUR score &lt; 4 had 78% (67%-87%) sensitivity and 57% (29%-82%) specificity, while FOUR- score &lt; 4 had 84% (73%-92%) sensitivity and 50% (23%-77%) specificity for predicting in-hospital mortality. Day 4 FOUR and FOUR- scores &lt; 4 had higher specificities (both 94% [71%-100%]) but lower sensitivities (63% [45%-79%] and 69% [51%-83%], respectively) for mortality than day 1. With outcome changed to survival to discharge, day 1 FOUR score &gt; 8 had 29% (8%-58%) sensitivity and 97% (90%-100%) specificity, while FOUR- &gt; 8 had 21% (5%-51%) sensitivity and 100% (95%-100%) specificity. Day 4 FOUR and FOUR- scores &gt; 8 had lower specificities (89% [73%-97%] and 91% [77%-98%], respectively), but higher sensitivities (53% [28%-77%]) and 47% [23%-72%], respectively) than day 1. There were no differences in mortality between FOUR and FOUR- &lt; 4 on day 1 (p=0.89) or 4 (p=0.95), and no differences in survival between FOUR and FOUR- &gt; 8 on day 1 (p=0.26) or 4 (p=0.85). Conclusions: Both the FOUR and FOUR- scores had high specificity for mortality and survival, which is important given that incorrectly predicting a bad outcome could lead to premature withdrawal of life support. The absence of a significant difference between the FOUR and FOUR- and the stronger prognostic ability of the FOUR- suggest that the respiratory component may not provide additional prognostic utility in cardiac arrest.
The IKKβ‐USP30‐ACLY Axis Controls Lipogenesis and Tumorigenesis
Authors: Li Gu, Yahui Zhu, Xi Lin, Bingjun Lu, Xinyi Zhou, Feng Zhou, Qiu Zhao, Edward V. Prochownik, Youjun Li
Journal: Hepatology (2020)

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death that develops as a consequence of obesity, cirrhosis, and chronic hepatitis. However, the pathways along which these changes occur remain incompletely understood.In this study, we show that the deubiquitinase USP30 is abundant in HCCs that arise in mice maintained on high-fat diets. IKKβ phosphorylated and stabilized USP30, which promoted USP30 to deubiquitinate ATP citrate lyase (ACLY) and fatty acid synthase (FASN). IKKβ also directly phosphorylated ACLY and facilitated the interaction between USP30 and ACLY and the latter's deubiquitination. In HCCs arising in DEN/CCl4 -treated mice, USP30 deletion attenuated lipogenesis, inflammation, and tumorigenesis regardless of diet. The combination of ACLY inhibitor and programmed death ligand 1 antibody largely suppressed chemical-induced hepatocarcinogenesis. The IKKβ-USP30-ACLY axis was also found to be up-regulated in human HCCs.This study identifies an IKKβ-USP30-ACLY axis that plays an essential and wide-spread role in tumor metabolism and may be a potential therapeutic target in HCC.
Gut bacteria affect the tumoral immune milieu: distorting the efficacy of immunotherapy or not？
Authors: Pu Xiaoyu, Ge Chao, Dong Lihua, Chang Pengyu
Journal: Gut Microbes (2020)

Immunotherapy using immune-checkpoint inhibitors is revolutionizing oncotherapy. However, the application of immunotherapy may be restricted because of the lack of proper biomarkers in a portion of cancer patients. Recently, emerging evidence has revealed that gut commensal bacteria can impact the therapeutic efficacy of immune-checkpoint inhibitors in several cancer models. In addition, testing the composition of gut bacteria provides context for prediction of the efficacy and toxicity of immunotherapy. In this review, we discuss the impacts of gut commensal bacteria on the tumoral immune milieu, highlighting some typical bacteria and their associations with immunotherapy.
Microbiota-Derived Metabolites Suppress Arthritis by Amplifying Aryl-Hydrocarbon Receptor Activation in Regulatory B Cells
Authors: Elizabeth C. Rosser, Christopher J.M. Piper, Diana E. Matei, Paul A. Blair, André F. Rendeiro, Michael Orford, Dagmar G. Alber, Thomas Krausgruber, Diego Catalan, Nigel Klein, Jessica J. Manson, Ignat Drozdov, Christoph Bock, Lucy R. Wedderburn, Simon Eaton, Claudia Mauri
Journal: Cell Metabolism (2020)

The differentiation of IL-10-producing regulatory B cells (Bregs) in response to gut-microbiota-derived signals supports the maintenance of tolerance. However, whether microbiota-derived metabolites can modulate Breg suppressive function remains unknown. Here, we demonstrate that rheumatoid arthritis (RA) patients and arthritic mice have a reduction in microbial-derived short-chain fatty acids (SCFAs) compared to healthy controls and that in mice, supplementation with the SCFA butyrate reduces arthritis severity. Butyrate supplementation suppresses arthritis in a Breg-dependent manner by increasing the level of the serotonin-derived metabolite 5-Hydroxyindole-3-acetic acid (5-HIAA), which activates the aryl-hydrocarbon receptor (AhR), a newly discovered transcriptional marker for Breg function. Thus, butyrate supplementation via AhR activation controls a molecular program that supports Breg function while inhibiting germinal center (GC) B cell and plasmablast differentiation. Our study demonstrates that butyrate supplementation may serve as a viable therapy for the amelioration of systemic autoimmune disorders.
Selective inhibition of TGFβ1 activation overcomes primary resistance to checkpoint blockade therapy by altering tumor immune landscape
Authors: Constance J. Martin, Abhishek Datta, Christopher Littlefield, Ashish Kalra, Christopher Chapron, Stefan Wawersik, Kevin B. Dagbay, Christopher T. Brueckner, Anastasia Nikiforov, Francis T. Danehy, Frederick C. Streich, Christopher Boston, Allison Simpson, Justin W. Jackson, Susan Lin, Nicole Danek, Ryan R. Faucette, Pichai Raman, Allan D. Capili, Alan Buckler, Gregory J. Carven, Thomas Schürpf
Journal: Science Translational Medicine (2020)

Inhibiting a specific isoform of TGFβ augments the effectiveness of checkpoint blockade therapy in cancer treatment.
Positive airway pressure in obesity hypoventilation syndrome: is it worth it?
Authors: Amanda Piper, Jean Louis Pépin, Nicholas Hart
Journal: Thorax (2020)

Over the past decade, increasing attention has been paid to the evaluation and management of obesity hypoventilation syndrome (OHS).1 This disorder is characterised by daytime hypercapnia and three main phenotypes of sleep disordered breathing, including severe obstructive sleep apnoea (OSA), combined OSA and OHS and isolated OHS.2 Rising rates of global obesity along with a greater awareness of the significant health and social costs of this disorder have been driving factors fuelling interest in how best to manage those with OHS. Although the cornerstone of treatment has been to address sleep breathing abnormalities using positive airway pressure (PAP) therapy, the mode of therapy which optimises outcomes in the most cost-effective manner has been less clear.3–6

In many centres, OHS has become a major indication for home ventilation, with most individuals prescribed bilevel therapy.7 However, OHS can present as chronic respiratory failure as a consequence of OSA, OSA and OHS or lone OHS, with the OSA and OSA-OHS phenotypes accounting for more than 90% of individuals diagnosed with OHS, 70% of whom will have apnoea-hypopnea indices>30 events/hour.4 Although continuous single level PAP therapy (CPAP) does not directly provide inspiratory assistance to increase tidal volumes, correction of upper airway obstruction in conjunction with increased resting lung volumes, resetting of the respiratory centres, reduced WOB and prevention of expiratory flow limitation8 can improve gas exchange, alleviate symptoms and improve quality of life. Several medium-term randomised studies3 5 6 and one long term randomised trial9 comparing CPAP to bilevel therapy have failed to find significant differences between these therapies in terms of resolving waking chronic respiratory failure, improving quality of life, therapy adherence, …
Combined immunotherapy with nivolumab and ipilimumab with and without local therapy in patients with melanoma brain metastasis: a DeCOG* study in 380 patients
Authors: Teresa Amaral, Felix Kiecker, Sarah Schaefer, Henner Stege, Katharina Kaehler, Patrick Terheyden, Anja Gesierich, Ralf Gutzmer, Sebastian Haferkamp, Jochen Uttikal, Carola Berking, David Rafei-Shamsabadi, Lydia Reinhardt, Friedegund Meier, Ante Karoglan, Christian Posch, Thilo Gambichler, Claudia Pfoehler, Kai Thoms, Julia Tietze, Dirk Debus, Rudolf Herbst, Steffen Emmert, Carmen Loquai, Jessica C Hassel, Frank Meiss, Thomas Tueting, Vanessa Heinrich, Thomas Eigentler, Claus Garbe, Lisa Zimmer
Journal: Journal for ImmunoTherapy of Cancer (2020)

Nivolumab combined with ipilimumab have shown activity in melanoma brain metastasis (MBM). However, in most of the clinical trials investigating immunotherapy in this subgroup, patients with symptomatic MBM and/or prior local brain radiotherapy were excluded. We studied the efficacy of nivolumab plus ipilimumab alone or in combination with local therapies regardless of treatment line in patients with asymptomatic and symptomatic MBM.Patients with MBM treated with nivolumab plus ipilimumab in 23 German Skin Cancer Centers between April 2015 and October 2018 were investigated. Overall survival (OS) was evaluated by Kaplan-Meier estimator and univariate and multivariate Cox proportional hazard analyses were performed to determine prognostic factors associated with OS.Three hundred and eighty patients were included in this study and 31% had symptomatic MBM (60/193 with data available) at the time of start nivolumab plus ipilimumab. The median follow-up was 18 months and the 2 years and 3 years OS rates were 41% and 30%, respectively. We identified the following independently significant prognostic factors for OS: elevated serum lactate dehydrogenase and protein S100B levels, number of MBM and Eastern Cooperative Oncology Group performance status. In these patients treated with checkpoint inhibition first-line or later, in the subgroup of patients with BRAFV600-mutated melanoma we found no differences in terms of OS when receiving first-line either BRAF and MEK inhibitors or nivolumab plus ipilimumab (p=0.085). In BRAF wild-type patients treated with nivolumab plus ipilimumab in first-line or later there was also no difference in OS (p=0.996). Local therapy with stereotactic radiosurgery or surgery led to an improvement in OS compared with not receiving local therapy (p=0.009), regardless of the timepoint of the local therapy. Receiving combined immunotherapy for MBM in first-line or at a later time point made no difference in terms of OS in this study population (p=0.119).Immunotherapy with nivolumab plus ipilimumab, particularly in combination with stereotactic radiosurgery or surgery improves OS in asymptomatic and symptomatic MBM.
Ticagrelor With or Without Aspirin After Complex PCI
Authors: George Dangas, Usman Baber, Samin Sharma, Gennaro Giustino, Shamir Mehta, David J. Cohen, Dominick J. Angiolillo, Samantha Sartori, Rishi Chandiramani, Carlo Briguori, Dariusz Dudek, Javier Escaned, Kurt Huber, Timothy Collier, Ran Kornowski, Vijay Kunadian, Upendra Kaul, Keith Oldroyd, Gennaro Sardella, Richard Shlofmitz, Bernhard Witzenbichler, Han Ya-Ling, Stuart Pocock, C. Michael Gibson, Roxana Mehran
Journal: Journal of the American College of Cardiology (2020)
Abstract P3-05-08: Sortilin-related receptor regulates receptor tyrosine kinase traffic and signaling
Authors: Hussein Al Akhrass, James Conway, Mark Barok, Olav Andersen, Johanna Ivaska
Journal: Cancer Research (2020)

Abstract Understanding the mechanisms of resistance to targeted therapies is a major challenge in epidermal growth factor receptor 2 (ERBB2)-amplified breast cancer and acquired resistance to ERBB2 inhibition is a common feature of recurrent tumors. In such a setting, the activation of intracellular oncogenic signaling pathways, through alternative growth factor receptors, adds a layer of complexity to therapeutic options. Our aim is to scrutinize the intracellular retrograde transport of ERBB-family receptors and to assess whether the key sorting proteins involved within this pathway represent a potential vulnerability in ERBB2-amplified breast cancer. Sortilin-related receptor (SorLA; SORL1) is a vacuolar protein sorting 10 (VPS10)-domain receptor well characterized for its role in Alzheimer’s and metabolic diseases. In a previous study, we demonstrated a previously unknown role of SorLA in cancer. SorLA increases ERBB2 stability by stimulating its recycling from endosomes back to the plasma membrane thus sustaining ERBB2 oncogenic signaling in vitro. In an orthotopic xenograft model, SorLA silencing inhibits tumor growth adding translational relevance for SorLA targeting in breast cancer. Here we investigate possible crosstalk inputs from other growth factor receptors, and we evaluate the potential of SorLA inhibition as a unique strategy to halt the progression of ERBB2-amplified tumors. Citation Format: Hussein Al Akhrass, James Conway, Mark Barok, Olav Andersen, Johanna Ivaska. Sortilin-related receptor regulates receptor tyrosine kinase traffic and signaling [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-05-08.
Glutathione Restricts Serine Metabolism to Preserve Regulatory T Cell Function
Authors: Henry Kurniawan, Davide G. Franchina, Luana Guerra, Lynn Bonetti, Leticia Soriano - Baguet, Melanie Grusdat, Lisa Schlicker, Oliver Hunewald, Catherine Dostert, Myriam P. Merz, Carole Binsfeld, Gordon S. Duncan, Sophie Farinelle, Yannic Nonnenmacher, Jillian Haight, Dennis Das Gupta, Anouk Ewen, Rabia Taskesen, Rashi Halder, Ying Chen, Christian Jäger, Markus Ollert, Paul Wilmes, Vasilis Vasiliou, Isaac S. Harris, Christiane B. Knobbe-Thomsen, Jonathan D. Turner, Tak W. Mak, Michael Lohoff, Johannes Meiser, Karsten Hiller, Dirk Brenner
Journal: Cell Metabolism (2020)
177Lu-DOTATOC Peptide Receptor Radionuclide Therapy in a Patient With Neuroendocrine Breast Carcinoma and Breast Invasive Ductal Carcinoma
Authors: Qingxing Liu, Jingjing Zhang, Harshad R. Kulkarni, Richard P. Baum
Journal: Clinical Nuclear Medicine (2020)

Abstract Radiolabeled somatostatin analogs for somatostatin receptor (SSTR)–targeted imaging and peptide receptor radionuclide therapy (PRRT) have demonstrated remarkable success in the management of SSTR-expressing neuroendocrine neoplasms. Primary neuroendocrine breast carcinoma is rare. Heterogeneous SSTR overexpression has also been documented in breast cancer, in both human breast cancer specimens and clinical studies. We report here a case of a 69-year-old woman who had both breast invasive ductal carcinoma and primary large-cell neuroendocrine breast carcinoma (Ki-67 proliferation index of 20%), with disseminated bone and lymph node metastases, demonstrating exceptional tracer uptake on 68 Ga-DOTATOC PET/CT, and remarkably partial remission after 177 Lu-DOTATOC PRRT.
Modeling Human Cytomegalovirus-Induced Microcephaly in Human iPSC-Derived Brain Organoids
Authors: Guoqiang Sun, Flavia Chiuppesi, Xianwei Chen, Cheng Wang, E Tian, Jenny Nguyen, Mindy Kha, Daniel Trinh, Hannah Zhang, Maria C. Marchetto, Hongjun Song, Guo-Li Ming, Fred H. Gage, Don J. Diamond, Felix Wussow, Yanhong Shi
Journal: Cell Reports Medicine (2020)

Although congenital infection by human cytomegalovirus (HCMV) is well recognized as a leading cause of neurodevelopmental defects, HCMV neuropathogenesis remains poorly understood. A major challenge for investigating HCMV-induced abnormal brain development is the strict CMV species specificity, which prevents the use of animal models to directly study brain defects caused by HCMV. We show that infection of human-induced pluripotent-stem-cell-derived brain organoids by a "clinical-like" HCMV strain results in reduced brain organoid growth, impaired formation of cortical layers, and abnormal calcium signaling and neural network activity. Moreover, we show that the impeded brain organoid development caused by HCMV can be prevented by neutralizing antibodies (NAbs) that recognize the HCMV pentamer complex. These results demonstrate in a three-dimensional cellular biosystem that HCMV can impair the development and function of the human brain and provide insights into the potential capacity of NAbs to mitigate brain defects resulted from HCMV infection.