tbuckley/cabot-search huggingface dataset:
Paradoxical Low-Flow, Low-Gradient Aortic Stenosis: Adding New Pieces to the Puzzle⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Philippe Pibarot, Jean G. Dumesnil
Journal: Journal of the American College of Cardiology (2011)
Bacterial O-GlcNAcase genes abundance decreases in ulcerative colitis patients and its administration ameliorates colitis in mice
Authors: Xiaolong He, Jie Gao, Liang Peng, Tongtong Hu, Yu Wan, Meijuan Zhou, Peilin Zhen, Hong Cao
Journal: Gut (2020)

Objective O-linked N-acetylglucosaminylation (O-GlcNAcylation), controlled by O-GlcNAcase (OGA) and O-GlcNAc transferase (OGT), is an important post-translational modification of eukaryotic proteins and plays an essential role in regulating gut inflammation. Gut microbiota encode various enzymes involved in O-GlcNAcylation. However, the characteristics, abundance and function of these enzymes are unknown. Design We first investigated the structure and taxonomic distribution of bacterial OGAs and OGTs. Then, we performed metagenomic analysis to explore the OGA genes abundance in health samples and different diseases. Finally, we employed in vitro and in vivo experiments to determine the effects and mechanisms of bacterial OGAs to hydrolyse O-GlcNAcylated proteins in host cells and suppress inflammatory response in the gut. Results We found OGAs, instead of OGTs, are enriched in Bacteroidetes and Firmicutes , the major bacterial divisions in the human gut. Most bacterial OGAs are secreted enzymes with the same conserved catalytic domain as human OGAs. A pooled analysis on 1999 metagenomic samples encompassed six diseases revealed that bacterial OGA genes were conserved in healthy human gut with high abundance, and reduced exclusively in ulcerative colitis. In vitro studies showed that bacterial OGAs could hydrolyse O-GlcNAcylated proteins in host cells, including O-GlcNAcylated NF-κB-p65 subunit, which is important for activating NF-κB signalling. In vivo studies demonstrated that gut bacteria-derived OGAs could protect mice from chemically induced colonic inflammation through hydrolysing O-GlcNAcylated proteins. Conclusion Our results reveal a previously unrecognised enzymatic activity by which gut microbiota influence intestinal physiology and highlight bacterial OGAs as a promising therapeutic strategy in colonic inflammation.
Abstract 12288: Circulating Arterial Microrna Profiles Identify Variant Angina Among Patients Presenting Chest Pain
Authors: Chan Soon Park, Inho Kim, Gyu Chul Oh, Jung-Kyu Han, Han-Mo Yang, Kyung Woo Park, Hyun-Jai Cho, Hyun-Jae Kang, Bon-Kwon Koo, Woo-Young Chung, Seil Oh, Byung-Hee Oh, Hae-young Lee
Journal: Circulation (2017)

Introduction: Variant angina is difficult to be identified with patients presenting chest pain in real-world clinics. Hypothesis: With microRNA (miR), we aimed to classify the patients presenting t...
TAMI-18. SINGLE-CELL SEQUENCING AND GENETIC LABELING TO CHARACTERIZE HYPOXIC GBM CELLS IN THEIR MICROENVIRONMENT
Authors: Anirudh Sattiraju, Valerie Marallano, Aarthi Ramakrishnan, Concetta Brusco, Li Shen, Alexandre Wojcinski, Santosh Kesari, Roland H Friedel, Hongyan Zou
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM) recurrence, arising from treatment-resistant hypoxic cells, is a major contributor to patient mortality. We have engineered GBM cell lines with a novel genetic reporter system (“HRE-UnaG”), which sensitively labels hypoxic cells with green fluorescence. Using murine GL261 HRE-UnaG GBM cells in intracranial transplants in immunocompetent hosts, we detected hypoxic cells primarily around pseudopalisading structures. Here, we report our new results of single cell RNA-seq sequencing of intracranial GL261-HRE-dUnaG GBM tumors, which revealed in hypoxic UnaG+ GBM cells upregulation of more than 60 genes, including canonical hypoxia response genes such as Slc2a1, Bnip3, Ldha and Vegfa, and downregulation of a smaller number of genes, such as Rgcc, Cdc20 and Hist1h2ap, which regulate cell cycle progression. This novel GBM hypoxia signature was in TCGA patient samples mostly upregulated in recurrent GBM and associated with worse prognosis, especially within proneural and mesenchymal subtypes. Gene set enrichment analysis revealed that the GBM hypoxia signature was positively correlated with hypoxia, glycolysis, TNFα and MTORC1 signaling, and negatively correlated with oxidative phosphorylation, Myc and DNA repair pathways. Subclustering revealed four distinct subpopulations of hypoxic GBM cells, which were distinguished by differential expression of pathway genes for proliferation, angiogenesis, stress response, and type I/II interferon signaling. Intercellular communication between hypoxic GBM cells and the stromal cells were predicted using NicheNET package. To spatio-temporally label in future studies hypoxic GBM cells and their progeny, we have engineered GBM cells with an inducible, hypoxia-sensitive lineage-tracing reporter (HRE-Cre; floxed-tdTomato). In combination with the HRE-UnaG hypoxia reporter, we will be able to reveal the role of “hypoxia memory” in GBM expansion and recurrence after treatment. Identifying key markers of hypoxic cells in respect to treatment resistance and relapse will lead to improvements in GBM detection and new options for therapeutic treatments.
EXTH-46. ARTIFICIAL INTELLIGENCE-BASED IDENTIFICATION OF COMBINED VANDETANIB AND EVEROLIMUS IN THE TREATMENT OF ACVR1-MUTANT DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Diana Carvalho, Peter Richardson, Nagore Gene Olaciregui, Reda Stankunaite, Cinzia Emilia Lavarino, Valeria Molinari, Elizabeth Corley, Ruth Ruddle, Adam Donovan, Akos Pal, Florence I Raynaud, John P Overington, Anne Phelan, Dave Sheppard, Andrew Mackinnon, Michael Hubank, Ofelia Cruz, Andres Morales La Madrid, Sabine Mueller, Angel Montero Carcaboso, Fernando Carceller, Chris Jones
Journal: Neuro-Oncology (2020)

Abstract Somatic mutations in ACVR1, encoding the serine/threonine kinase ALK2 receptor, are found in a quarter of children with the currently incurable brain tumour diffuse intrinsic pontine glioma (DIPG). Treatment of ACVR1-mutant DIPG patient-derived models with multiple inhibitor chemotypes leads to a reduction in cell viability in vitro and extended survival in orthotopic xenografts in vivo, though there are currently no specific ACVR1 inhibitors licensed for DIPG. Using an Artificial Intelligence-based platform to search for approved compounds which could be used to treat ACVR1-mutant DIPG, the combination of vandetanib and everolimus was identified as a possible therapeutic approach. Vandetanib, an approved inhibitor of VEGFR/RET/EGFR, was found to target ACVR1 (Kd=150nM) and reduce DIPG cell viability in vitro, but has been trialed in DIPG patients with limited success, in part due to an inability to cross the blood-brain-barrier. In addition to mTOR, everolimus inhibits both ABCG2 (BCRP) and ABCB1 (P-gp) transporter, and was synergistic in DIPG cells when combined with vandetanib in vitro. This combination is well-tolerated in vivo, and significantly extended survival and reduced tumour burden in an orthotopic ACVR1-mutant patient-derived DIPG xenograft model. Based on these preclinical data, three patients with ACVR1-mutant DIPG were treated with vandetanib and everolimus. These cases may inform on the dosing and the toxicity profile of this combination for future clinical studies. This bench-to-bedside approach represents a rapidly translatable therapeutic strategy in children with ACVR1 mutant DIPG.
Markers of disease activity in COPD: an 8-year mortality study in the ECLIPSE cohort
Authors: Bartolome Celli, Nicholas Locantore, Julie C. Yates, Per Bakke, Peter M.A. Calverley, Courtney Crim, Harvey O. Coxson, David A. Lomas, William MacNee, Bruce E. Miller, Hana Mullerova, Stephen I. Rennard, Edwin K. Silverman, Emiel Wouters, Ruth Tal-Singer, Alvar Agusti, Jørgen Vestbo
Journal: European Respiratory Journal (2020)

Rationale There are no validated measures of disease activity in COPD. Since “active” disease is expected to have worse outcomes ( e.g. mortality), we explored potential markers of disease activity in patients enrolled in the ECLIPSE cohort in relation to 8-year all-cause mortality. Methods We investigated 1) how changes in relevant clinical variables over time (1 or 3 years) relate to 8-year mortality; 2) whether these variables inter-relate; and 3) if any clinical, imaging and/or biological marker measured cross-sectionally at baseline relates to any activity component. Results Results showed that 1) after 1 year, hospitalisation for COPD, exacerbation frequency, worsening of body mass index, airflow obstruction, dyspnoea and exercise (BODE) index or health status (St George's Respiratory Questionnaire (SGRQ)) and persistence of systemic inflammation were significantly associated with 8-year mortality; 2) at 3 years, the same markers, plus forced expiratory volume in 1 s (FEV 1 ) decline and to a lesser degree computed tomography (CT) emphysema, showed association, thus qualifying as markers of disease activity; 3) changes in FEV 1 , inflammatory cytokines and CT emphysema were not inter-related, while the multidimensional indices (BODE and SGRQ) showed modest correlations; and 4) changes in these markers could not be predicted by any baseline cross-sectional measure. Conclusions In COPD, 1- and 3-year changes in exacerbation frequency, systemic inflammation, BODE and SGRQ scores and FEV 1 decline are independent markers of disease activity associated with 8-year all-cause mortality. These disease activity markers are generally independent and not predictable from baseline measurements.
Covid-19: Sweden considers tougher restrictions as ICU beds near capacity
Authors: Marta Paterlini
Journal: BMJ (2020)

Health officials in Sweden have warned that intensive care units (ICUs) in and around Stockholm are under severe pressure and close to capacity for the first time during the pandemic.Although the city's hospitals could increase the number of beds allocated to ICUs, there are insufficient specialist staff to support them, said Björn Eriksson, director of Region Stockholm Healthcare. He toldThe BMJ, "So far, we have been one step ahead of the virus by continuously opening more care places so that they're available when the need arises.Now, healthcare staff are so hard pressed and the margins are so tight that on 10 December I formally asked the National Board of Health and Welfare for more specialised staff."One option being considered is "borrowing" trained staff from private care providers, he said.The Swedish government changed its approach to the pandemic last month when it introduced tougher restrictions on social interactions after cases started to rise. 1 The soft approach the government had adopted, based on recommendations and voluntary behaviour of citizens, has shifted as cases of infection with SARS-CoV-2 have continued to surge along with hospitalisations and deaths.This week Prime Minister Stefan Löfven announced that the ban on gatherings of more than eight people would extend to the Christmas holidays, while secondary schools have been told to switch to distance learning for the rest of the term.The government has also asked the parliament to grant it more authority to implement new measures such as closing shopping malls and gyms.On 10 December, Sweden reported a daily record of 10 464 cases, bringing its overall total of confirmed infections to 320 098.There have been 7514 deaths to date, 2836 of them in the capital and its environs.There are 1989 people with covid-19 in Sweden's hospitals with 258 in ICUs, 78% of the country's capacity.Stockholm and the surrounding region are particularly hard hit and have seen cases soar to 756 per 100 000 inhabitants in the past 14 days, much higher than neighbouring Scandinavian countries.By comparison, cases per 100 000 are 434 in Denmark, 116 in Finland, and 97 in Norway.Johan Styrud, chairman of the Stockholm Medical Association and chief physician at Danderyd Hospital, one of Stockholm's main facilities, told The BMJ that he would like to see stricter adherence to government guidelines to help relieve pressure on the healthcare system.However, Karin Tegmark Wisell of the Public Health Agency, which manages pandemics in Sweden, claimed at the weekly press conference on 10 December that data show that Swedes were adhering to recommendations and are moving around the country less. 1
The One-Stop Shop Offering Both Coronary Anatomy and Myocardial Perfusion: May Well Be Opening Soon, Around the Corner⁎⁎Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
Authors: William Wijns
Journal: JACC. Cardiovascular imaging (2012)
Natriuretic Effect of Two Weeks of Dapagliflozin Treatment in Patients With Type 2 Diabetes and Preserved Kidney Function During Standardized Sodium Intake: Results of the DAPASALT Trial
Authors: Rosalie A. Scholtes, Marcel H.A. Muskiet, Michiel J.B. van Baar, Anne C. Hesp, Peter J. Greasley, Cecilia Karlsson, Ann Hammarstedt, Niki Arya, Daniël H. van Raalte, Hiddo J.L. Heerspink
Journal: Diabetes Care (2020)

OBJECTIVE Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk for heart failure hospitalization potentially by inducing sodium excretion, osmotic diuresis, and plasma volume contraction. Few studies have investigated this hypothesis, but none have assessed cumulative sodium excretion with SGLT2 inhibition during standardized sodium intake in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS The DAPASALT trial was a mechanistic, nonrandomized, open-label study in patients with type 2 diabetes with preserved kidney function on a controlled standardized sodium diet (150 mmol/day). It evaluated the effects of dapagliflozin on sodium excretion, 24-h blood pressure, and extracellular, intracellular, and plasma volumes at the start of treatment (ST) (days 2–4), end of treatment (ET) (days 12–14), and follow-up (FU) (days 15–18). RESULTS Fourteen patients were included in the efficacy analysis. Mean (SD) baseline sodium excretion (150 [32] mmol/24-h) did not significantly change during treatment (change at ST: −7.0 mmol/24-h [95% CI −22.4, 8.4]; change at ET: 2.1 mmol/24-h [−28.8, 33.0]). Mean baseline 24-h systolic blood pressure was 128 (10) mmHg and significantly reduced at ST (−6.1 mmHg [−9.1, −3.1]; P &amp;lt; 0.001) and ET (−7.2 mmHg [−10.0, −4.3]; P &amp;lt; 0.001). Dapagliflozin did not significantly alter plasma volume or intracellular volume, while extracellular volume changed at ST (−0.7 L [−1.3, −0.1]; P = 0.02). As expected, 24-h urinary glucose excretion significantly increased during dapagliflozin treatment and reversed during FU. CONCLUSIONS During standardized sodium intake, dapagliflozin reduced blood pressure without clear changes in urinary sodium excretion, suggesting that factors other than natriuresis and volume changes may contribute to the blood pressure–lowering effects.
Microbial adaptation to the healthy and inflamed gut environments
Authors: Yijie Guo, Sho Kitamoto, Nobuhiko Kamada
Journal: Gut Microbes (2020)

There are 100 trillion diverse bacterial residents in the mammalian gut. Commensal bacterial species/strains cooperate and compete with each other to establish a well-balanced community, crucial for the maintenance of host health. Pathogenic bacteria hijack cooperative mechanisms or use strategies to evade competitive mechanisms to establish infection. Moreover, pathogenic bacteria cause marked environmental changes in the gut, such as the induction of inflammation, which fosters the selective growth of pathogens. In this review, we summarize the latest findings concerning the mechanisms by which commensal bacterial species/strains colonize the gut through cooperative or competitive behaviors. We also review the mechanisms by which pathogenic bacteria adapt to the inflamed gut and thrive at the expense of commensal bacteria. The understanding of bacterial adaptation to the healthy and the inflamed gut may provide new bacteria-targeted therapeutic approaches that selectively promote the expansion of beneficial commensal bacteria or limit the growth of pathogenic bacteria.
MBRS-21. CLINICAL AGGRESSIVENESS OF TP53-WILD TYPE SONIC HEDGEHOG MEDULLOBLASTOMA WITH MYCN AMPLIFICATION
Authors: Yuichi Mitani, Kohei Fukuoka, Yuko Matsushita, Yuko Hibiya, Satoko Honda, Makiko Mori, Yuki Arakawa, Koichi Ichimura, Masao Kobayashi, Yutaka Tanami, Atsuko Nakazawa, Jun Kurihara, Katsuyoshi Koh
Journal: Neuro-Oncology (2020)

Abstract Clinical implication of MYCN amplification in sonic hedgehog (SHH) medulloblastoma may still be controversial due to the frequent co-occurrence with TP53 mutation, which is one of the poorest prognostic factors among the subgroup. We described two cases of TP53-wild type SHH medulloblastoma with MYCN amplification, showing dismal clinical course with rapid disseminated relapse just after the end of treatment. CASE 1: A 7-year-old boy developed a non-metastatic cerebellar tumor. Pathology of the tumor was consistent with classic medulloblastoma. The patient received treatment that involved reduced-dose (18 Gy) craniospinal irradiation (CSI), local irradiation, and chemotherapy. However, sudden respiratory arrest developed due to massive intracranial disseminated relapse 9 months after the initial surgery. CASE 2: A 6-year-old boy presented a large mass in his 4th ventricle without dissemination. He diagnosed with large cell/anaplastic medulloblastoma and underwent radiation therapy (24 Gy of CSI and local irradiation) and chemotherapy, followed by high-dose chemotherapy. However, dissemination through neuroaxis occurred 9 months after the diagnosis. Methylation data of the cases was entered into a recently published classifier and both tumors were classified as “medulloblastoma, subclass SHH A (children and adult)”. Copy number analysis demonstrated MYCN amplification in both cases. TP53 mutation analysis from exon 2 to 10 indicated wild type in one case. Additionally, p53 immunochemistry in both cases also indicated wild type. The cases remind us of the clinical aggressiveness of SHH medulloblastoma with MYCN amplification, even if there is no TP53 mutation. The tumor should still be treated with the most intensified treatment.
CBIO-24. KINETOCHORE MISREGULATION IN GLIOBLASTOMA AND OTHER CANCERS
Authors: Jake Herman, Jun Zhu, Jennifer DeLuca, Patrick Paddison
Journal: Neuro-Oncology (2020)

Abstract Aneuploidy is a hallmark of most late stage cancers and contributes to tumor cell evolution, invasiveness, therapy resistance, and recurrence. A major cause of aneuploidy is lagging anaphase chromosomes that have merotelic kinetochore (KT) attachments in mitosis. In this scenario, a KT (i.e., the proteinaceous structure assembled onto centromeres in mitosis) is bound to microtubules (MTs) emanating from both spindle poles, causing chromosome mis-segregation. “Background” chromosome missegregation likely contributes to the initiation of multiple cancers, including glioblastoma (GBM), where chr 7 gain and chr 10 loss are early events. However, we have found that in GBM and transformed cells activation of the RAS signaling pathway significantly increases lagging anaphase chromosomes, and, as a result, aneuploidy and tumor heterogeneity. However, the underlying mechanism of RAS-induced chromosome instability has remained elusive. Here we present one possible cause: MAPK-driven KT stress. The hallmarks of KT stress include chronic KT-MT attachment instability in mitosis, dramatic changes in KT morphology, and increases in merotelic KT attachments and chromosome segregation errors. KT stress is lethal to cancer cells. However, stressed cells survive by relying on BUB1B/BubR1 activity to strengthen KT-MT attachments. We first observed KT stress in GBM patient isolates, where ~60–70% display its hallmarks. We subsequently found that RAS or MEK activity is sufficient to induce KT stress in both CNS and non-CNS derived cell types. We propose that KT stress is caused by aberrant mitotic RAS/MAPK activity, which likely targets one or more KT proteins resulting in KT-MT attachment defects and chromosome instability. In addition, Dr. Jun Zhu’s lab has also created a computational classifier that can identify KT stressed cells and tumors based on the expression of 838 genes associated with KT stress, which can be also used to identify orthogonal therapeutic sensitivities. We will present these findings as well at this meeting.
CTNI-55. PREDICTIVE FACTORS FOR HIGH GRADE TRANSFORMATION IN BENIGN MENINGIOMAS
Authors: Jeong Hoon Kim, Hee Jun Yoo
Journal: Neuro-Oncology (2020)

Abstract OBJECT Meningiomas are generally slow-growing, benign tumors, most of which are classified as WHO Grade I. Rarely, benign meningiomas may recur after surgery with transformation into WHO Grade II atypical meningiomas. As atypical meningiomas are different from benign meningiomas in terms of clinical course, and prognosis, predicting the transformation is important for patient management. The purpose of the study was to investigate the radiological and pathological factors that predict the risk of tumor progression from benign to atypical meningioma. METHOD All patients treated with recurrent meningiomas in whom the tumor showed histopathologically confirmed high grade transformation between 2001 and 2017 were included. To evaluate the predictors for transformation, patients’ medical records for previous benign meningioma before transformation were collected. Each patient was matched with 4 age and sex-matched controls treated with benign meningioma, and were analyzed. RESULTS Fourteen patients with high grade transformation were included. The median time interval of transformation was 63 months (range of 19 – 132). Multivariate analysis indicated that increased mitotic index (OR, 10.409, 95% CI, 1.297–83.549, p=0.027) was significant predictive factor of transformation. And prominent peritumoral edema (OR, 33.822, 95% CI, 0.935–223.688, p=0.054) showed relative risk for transformation. CONCLUSION Increased mitotic index and prominent peritumoral edema may be predictors for high grade transformation of benign meningiomas. Although these tumors do not meet the criteria for atypical meningioma, they may be required more attentive observation and management than other benign meningiomas.