tbuckley/cabot-search huggingface dataset:
Mitochondrial metabolism as a potential therapeutic target in myeloid leukaemia
Authors: Lucie de Beauchamp, Ekaterini Himonas, G. Vignir Helgason
Journal: Leukemia (2021)

Abstract While the understanding of the genomic aberrations that underpin chronic and acute myeloid leukaemia (CML and AML) has allowed the development of therapies for these diseases, limitations remain. These become apparent when looking at the frequency of treatment resistance leading to disease relapse in leukaemia patients. Key questions regarding the fundamental biology of the leukaemic cells, such as their metabolic dependencies, are still unresolved. Even though a majority of leukaemic cells are killed during initial treatment, persistent leukaemic stem cells (LSCs) and therapy-resistant cells are still not eradicated with current treatments, due to various mechanisms that may contribute to therapy resistance, including cellular metabolic adaptations. In fact, recent studies have shown that LSCs and treatment-resistant cells are dependent on mitochondrial metabolism, hence rendering them sensitive to inhibition of mitochondrial oxidative phosphorylation (OXPHOS). As a result, rewired energy metabolism in leukaemic cells is now considered an attractive therapeutic target and the significance of this process is increasingly being recognised in various haematological malignancies. Therefore, identifying and targeting aberrant metabolism in drug-resistant leukaemic cells is an imperative and a relevant strategy for the development of new therapeutic options in leukaemia. In this review, we present a detailed overview of the most recent studies that present experimental evidence on how leukaemic cells can metabolically rewire, more specifically the importance of OXPHOS in LSCs and treatment-resistant cells, and the current drugs available to target this process. We highlight that uncovering specific energy metabolism dependencies will guide the identification of new and more targeted therapeutic strategies for myeloid leukaemia.
A deep-learning-based workflow to deal with the defocusing problem in high-throughput experiments
Authors: Yunfan Xue, Honglin Qian, Xu Li, Jing Wang, Kefeng Ren, Jian Ji
Journal: Bioactive Materials (2021)

The increasing throughput of experiments in biomaterials research makes automatic techniques more and more necessary. Among all the characterization methods, microscopy makes fundamental contributions to biomaterials science where precisely focused images are the basis of related research. Although automatic focusing has been widely applied in all kinds of microscopes, defocused images can still be acquired now and then due to factors including background noises of materials and mechanical errors. Herein, we present a deep-learning-based method for the automatic sorting and reconstruction of defocused cell images. First, the defocusing problem is illustrated on a high-throughput cell microarray. Then, a comprehensive dataset of phase-contrast images captured from varied conditions containing multiple cell types, magnifications, and substrate materials is prepared to establish and test our method. We obtain high accuracy of over 0.993 on the dataset using a simple network architecture that requires less than half of the training time compared with the classical ResNetV2 architecture. Moreover, the subcellular-level reconstruction of heavily defocused cell images is achieved with another architecture. The applicability of the established workflow in practice is finally demonstrated on the high-throughput cell microarray. The intelligent workflow does not require a priori knowledge of focusing algorithms, possessing widespread application value in cell experiments concerning high-throughput or time-lapse imaging.
Adenosine-to-inosine editing of endogenous Z-form RNA by the deaminase ADAR1 prevents spontaneous MAVS-dependent type I interferon responses
Authors: Qiannan Tang, Rachel E. Rigby, George R. Young, Astrid Korning Hvidt, Tanja Davis, Tiong Kit Tan, Anne Bridgeman, Alain R. Townsend, George Kassiotis, Jan Rehwinkel
Journal: Immunity (2021)

Nucleic acids are powerful triggers of innate immunity and can adopt the Z-conformation, an unusual left-handed double helix. Here, we studied the biological function(s) of Z-RNA recognition by the adenosine deaminase ADAR1, mutations in which cause Aicardi-Goutières syndrome. Adar1mZα/mZα mice, bearing two point mutations in the Z-nucleic acid binding (Zα) domain that abolish Z-RNA binding, displayed spontaneous induction of type I interferons (IFNs) in multiple organs, including in the lung, where both stromal and hematopoietic cells showed IFN-stimulated gene (ISG) induction. Lung neutrophils expressed ISGs induced by the transcription factor IRF3, indicating an initiating role for neutrophils in this IFN response. The IFN response in Adar1mZα/mZα mice required the adaptor MAVS, implicating cytosolic RNA sensing. Adenosine-to-inosine changes were enriched in transposable elements and revealed a specific requirement of ADAR1's Zα domain in editing of a subset of RNAs. Thus, endogenous RNAs in Z-conformation have immunostimulatory potential curtailed by ADAR1, with relevance to autoinflammatory disease in humans.
P04.15 Radiomics features in prediction of pseudo-progression and response to hypofractionated stereotactic radiotherapy and anti-PDL1 Durvalumab combination in recurrent glioblastoma from STERIMGLI phase I trial
Authors: G Glemarec, D Pouessel, A Mervoyer, D Larrieu-Ciron, B Carrabou, M Robert, J Frenel, M Mounier, E Cohen-Jonathan Moyal, S Ken
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Due to the risk of pseudo-progression, evaluating the response of such combined treatment with anti-PDL1 immunotherapy and hypofractionated stereotactic radiotherapy (hFSRT) in patients with recurrent glioblastoma (GBM) is difficult even with iRANO criteria. We aim to analyze multi-modal MRI radiomic features in recurrent GBM patients included in the phase I STERIMGLI (NCT02866747) clinical trial. MATERIAL AND METHODS In phase I trial STERIMGLI, six patients received hFSRT 24 Gy in 3 fractions of 8 Gy prescribed to the 80% covering isodose in combination with Durvalumab IV 1500mg the same day following the third fraction of radiation then every 4 weeks for a maximum of 12 months. All patients underwent multi-modal MRI acquisitions. Contrast-enhancement on post-gadolinium T1 MRI (Gd-T1) and hyper-T2 signal on FLAIR MRI were manually segmented as volume-of-interest (VOIs) from baseline at week 0 (W0) and every eight weeks until weeks sixteen (W16). For patient 05, segmentation was performed until progression (W40). First order radiomics were extracted and normalized from these longitudinal VOIs in a total of 42 MRI: volume (in cm3), mean and median intensity, entropy, skewness and kurtosis were computed for each VOI. In total 504 (2 x 42 x 6) features were extracted. RESULTS Two patients underwent pseudoprogression (patients 04 and 05). All patients but one (patient 05) presented an early relapse with an increase of FLAIR and Gd-T1 volumes and respective entropies from the first evaluation without decrease during follow up (until W16). Patient 05 presented a Dose Limiting Toxicities and had the longest time to progression after Durvalumab and hFSRT. Contrary to the other patients, his FLAIR radiomics features presented a decrease of volume, intensity and entropy between W0 and W16 then, interestingly an increase between W24 and W40, date of progression. Moreover, patient 05 presented the lowest tumor volume and the lowest Gd-T1entropy. The intensity of the Gd-T1 followed the same trend as the hyper intense signal on the FLAIR in all patients, in particular for patient 05. CONCLUSION In our study, entropy and tumor volume for both FLAIR and Gd-T1, and FLAIR intensity seems to be the most interesting parameters to access the response of combined treatment. FLAIR signal may be more specific to the tumor microenvironment. First order radiomics allowed us to follow tumor heterogeneity and identify the patient with the longest time to progression.
An altered sputum macrophage transcriptome contributes to the neutrophilic asthma endotype
Authors: Michael Fricker, Ling Qin, Stephany Sánchez‐Ovando, Jodie L. Simpson, Katherine J. Baines, Carlos Riveros, Hayley A. Scott, Lisa G. Wood, Peter AB. Wark, Nazanin Z. Kermani, Kian Fan Chung, Peter G. Gibson
Journal: Allergy (2021)

Neutrophilic asthma (NA) is a clinically important asthma phenotype, the cellular and molecular basis of which is not completely understood. Airway macrophages are long-lived immune cells that exert important homeostatic and inflammatory functions which are dysregulated in asthma. Unique transcriptomic programmes reflect varied macrophage phenotypes in vitro. We aimed to determine whether airway macrophages are transcriptomically altered in NA.We performed RNASeq analysis on flow cytometry-isolated sputum macrophages comparing NA (n = 7) and non-neutrophilic asthma (NNA, n = 13). qPCR validation of RNASeq results was performed (NA n = 13, NNA n = 23). Pathway analysis (PANTHER, STRING) of differentially expressed genes (DEGs) was performed. Gene set variation analysis (GSVA) was used to test for enrichment of NA macrophage transcriptomic signatures in whole sputum microarray (cohort 1 - controls n = 16, NA n = 29, NNA n = 37; cohort 2 U-BIOPRED - controls n = 16, NA n = 47, NNA n = 57).Flow cytometry-sorting significantly enriched sputum macrophages (99.4% post-sort, 44.9% pre-sort, p < .05). RNASeq analysis confirmed macrophage purity and identified DEGs in NA macrophages. Selected DEGs (SLAMF7, DYSF, GPR183, CSF3, PI3, CCR7, all p < .05 NA vs. NNA) were confirmed by qPCR. Pathway analysis of NA macrophage DEGs was consistent with responses to bacteria, contribution to neutrophil recruitment and increased expression of phagocytosis and efferocytosis factors. GSVA demonstrated neutrophilic macrophage gene signatures were significantly enriched in whole sputum microarray in NA vs. NNA and controls in both cohorts.We demonstrate a pathophysiologically relevant sputum macrophage transcriptomic programme in NA. The finding that there is transcriptional activation of inflammatory programmes in cell types other than neutrophils supports the concept of NA as a specific endotype.
Association of Hospital Public Quality Reporting With Electronic Health Record Medication Safety Performance
Authors: A. Jay Holmgren, David W. Bates
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Despite billions spent in public investment, electronic health records (EHRs) have not delivered on the promise of large quality and safety improvement. Simultaneously, there is debate on whether public quality reporting is a useful tool to incentivize quality improvement. <h3>Objective</h3> To evaluate whether publicly reported feedback was associated with hospital improvement in an evaluation of medication-related clinical decision support (CDS) safety performance. <h3>Design, Settings, and Participants</h3> This nonrandomized controlled trial included US hospitals that participated in the Computerized Provider Order Entry (CPOE) Evaluation Tool in the Leapfrog Hospital Survey, a national quality reporting program that evaluates safety performance of hospital CDS using simulated orders and patients, in 2017 to 2018. A sharp regression discontinuity design was used to identify the association of receiving negative feedback with hospital performance improvement in the subsequent year. Data were analyzed from January through September 2020. <h3>Exposures</h3> Publicly reported quality feedback. <h3>Main Outcomes and Measures</h3> The main outcome was improvement from 2017 to 2018 on the Leapfrog CPOE Evaluation Tool, using regression discontinuity model estimates of the association of receiving negative publicly reported feedback with quality improvement. <h3>Results</h3> A total of 1183 hospitals were included, with a mean (SD) CPOE score of 59.3% (16.3%) at baseline. Hospitals receiving negative feedback improved 8.44 (95% CI, 0.09 to 16.80) percentage points more in the subsequent year compared with hospitals that received positive feedback on the same evaluation. This change was driven by differences in improvement in basic CDS capabilities (β = 8.71 [95%CI, 1.67 to 18.73]) rather than advanced CDS (β = 6.15 [95% CI, −9.11 to 26.83]). <h3>Conclusions and Relevance</h3> In this nonrandomized controlled trial, publicly reported feedback was associated with quality improvement, suggesting targeted measurement and reporting of process quality may be an effective policy lever to encourage improvement in specific areas. Clinical decision support represents an important tool in ensuring patient safety and decreasing adverse drug events, especially for complex patients and those with multiple chronic conditions who often receive several different drugs during an episode of care.
P14.24 Estimating survival outcomes in elderly (70+ years) patients with primary glioblastoma
Authors: M J Zorman, P Webb, M Nixon, S Sravanam, S Honeyman, M Nandhabalan, V Apostolopoulos, R Stacey, C Hobbs, P Plaha
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Elderly patients with glioblastoma are perceived to face a poor prognosis, with perceptions around older age and a relative lack of randomized data raising a concern about their undertreatment. The EANO guidelines recommend &amp;gt;70-year-old patients with good performance status to undergo maximal safe resection followed by hypofractionated (40 Gy in 15 fractions, i.e. RT40/15) radiotherapy with or without concurrent and adjuvant Temozolomide (TMZ), depending on MGMT promoter methylation. This study evaluated the relative survival impact of biological, histological, surgical and oncological factors and aimed to devise a scoring system to estimate the survival of elderly glioblastoma patients, with an aim to more accurately guide treatment in this cohort. METHODS The records of 169 elderly (≥70 years) patients with a new diagnosis of IDH-wild type glioblastoma were retrospectively examined for gender, age, WHO performance status (PS), comorbidities, MGMT methylation, surgical intervention and chemoradiation regime. The adjusted survival impact of these factors was determined using Cox proportional hazards model and used to devise a two-stage scoring system to estimate survival of patients at the stage of surgical (Elderly Glioblastoma Surgical Score, EGSS) and oncological management (Elderly Glioblastoma Oncological Score, EGOS). RESULTS The overall median survival (MS) of the cohort was 28.8 weeks. Subtotal resection (MS=27.7 weeks, 95%CI 24.1–31.6 weeks, HR=0.58) and gross-total resection (MS=77.8 weeks, 95%CI 67.0–88.6 weeks, HR=0.36) were associated with significant overall survival benefit compared to biopsy alone (MS=18.2 weeks, 95%CI 15.7–20.7 weeks, HR=5.23), p&amp;lt;0.05. Hypofractionated radiation with Temozolomide (RT40/15+TMZ, MS=60.9 weeks, 95%CI 49.9–71.8 weeks, HR=0.13) was non-inferior to the Stupp protocol (RT60/30+TMZ, MS=50.6 weeks, 95%CI 32.4–66.7 weeks, HR=0.11), p=0.72. Negative prognosticators included age above 75 years, biopsy alone and no chemoradiotherapy. Subgroup analysis revealed that MGMT unmethylated 70–75 year old patients who received the Stupp protocol had significantly improved overall survival (MS=57.6 weeks, 95%CI 27.7–88.1 weeks) compared to standard of care RT40/15 alone (MS=29.7 weeks, 95%CI 7.1–51.6 weeks), p=0.002. EGSS and EGOS scores estimated survival with 65% and 73% accuracy, respectively. CONCLUSION When appropriate and safe, a subgroup of elderly glioblastoma patients may benefit from more aggressive surgical and oncological management. The proposed EGSS and EGOS scores takes into account important prognostic factors to help guide which patients should receive such treatment.
AdipoAtlas: A reference lipidome for human white adipose tissue
Authors: Mike Lange, Georgia Angelidou, Zhixu Ni, Angela Criscuolo, Jürgen Schiller, Matthias Blüher, Maria Fedorova
Journal: Cell Reports Medicine (2021)

Obesity, characterized by expansion and metabolic dysregulation of white adipose tissue (WAT), has reached pandemic proportions and acts as a primer for a wide range of metabolic disorders. Remodeling of WAT lipidome in obesity and associated comorbidities can explain disease etiology and provide valuable diagnostic and prognostic markers. To support understanding of WAT lipidome remodeling at the molecular level, we provide in-depth lipidomics profiling of human subcutaneous and visceral WAT of lean and obese individuals. We generate a human WAT reference lipidome by performing tissue-tailored preanalytical and analytical workflows, which allow accurate identification and semi-absolute quantification of 1,636 and 737 lipid molecular species, respectively. Deep lipidomic profiling allows identification of main lipid (sub)classes undergoing depot-/phenotype-specific remodeling. Previously unanticipated diversity of WAT ceramides is now uncovered. AdipoAtlas reference lipidome serves as a data-rich resource for the development of WAT-specific high-throughput methods and as a scaffold for systems medicine data integration.
Abstract 11645: Upregulation of Cardiac Beta3-Adrenergic Receptor-Activated Inducible Nitric Oxide Synthase Promotes Cardiac Aging: Role of Oxidant Stress
Authors: Heng-Jie Cheng, Peng Zhou, Qun Shao, Dalane W Kitzman, Stephen B Kritchevsky, David C Sane, William C Little, Che Ping Cheng
Journal: Circulation (2012)

Background. Cardiac aging (CA) is accompanied by oxidative stress and cardiac dysfunction; the link between the two is unclear. Although β3-adrenergic receptor (AR)-mediated nitric oxide synthase (...
P14.14 Adjuvant treatment versus initial observation in newly diagnosed WHO grade II and grade III oligodendroglioma: real-life data from two academic, tertiary care centers in Austria
Authors: M J Mair, A Leibetseder, A Wöhrer, G Widhalm, K Dieckmann, M Aichholzer, S Weis, T von Oertzen, J Pichler, M Preusser, A S Berghoff
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Oligodendrogliomas are rare, slow-growing brain tumors with a survival prognosis of &amp;gt;10 years. Although adjuvant radio-chemotherapy has been shown to prolong survival, aggressive treatment comes at the cost of increased toxicity. Systematic data on the optimal timing of adjuvant treatment in oligodendroglioma are lacking. MATERIAL AND METHODS Patients treated for a newly diagnosed IDH-mutated, 1p/19q-codeleted oligodendroglioma (WHO grades II/III) in 2000 - 2018 at the Medical University of Vienna or the Kepler University Hospital Linz (Austria) were included in this retrospective study. Adjuvant treatment was defined as radiotherapy (RT), chemotherapy (CHT) or radio-chemotherapy (R-CHT) within 6 months after resection in the absence of progression. “Wait and see” was defined as regular follow up with magnetic resonance imaging and treatment at progression. RESULTS 185 patients were identified, comprising 123/185 (66.5%) WHO grade II and 62/185 (33.5%) WHO grade III oligodendrogliomas. Median age at diagnosis was 42 years (range: 20–82). Gross total resection (GTR) could be achieved in 77/178 (42.3%) evaluable patients. Adjuvant treatment was applied in 63/185 (38.2%) patients, of whom 43/63 (68.3%) underwent R-CHT, 9/63 (14.3%) CHT only and 11/63 (17.5%) RT only. 43/52 (82.7%) received temozolomide-based treatment, 1/52 (1.9%) procarbazine, lomustine and vincristine (PCV), 1/52 dacarbazine/fotemustine and in 7/52 (13.5%) patients, no data on used regimens was available. Adjuvant treatment was more frequently applied in WHO grade 3 tumors (p&amp;lt;0.001), while there was no association of adjuvant treatment with extent of resection (p=0.24). Patients after GTR who underwent adjuvant therapy presented with longer progression-free survival (PFS) compared to patients initially managed with observation (median: 150 months, 95%CI: 100 - not reached (n.r.) vs. median: 101 months, 95%CI: 73.2–115; p=0.053). In non-GTR tumors, patients with adjuvant therapy presented with a significantly longer median PFS of 107.5 months (95%CI: 62.8-n.r.) as compared to patients initially managed with observation (45.3 months, 95%CI: 41.2–78.8; p=0.025). CONCLUSION The application of adjuvant therapy was associated with favorable PFS in patients who underwent resection of newly diagnosed oligodendroglioma in this retrospective study. Prospective clinical trials should investigate the risks and benefits of adjuvant treatment versus initial observation in patients with oligodendroglioma.
Hematologic parameters in asymptomatic patients with active covid-19 infection
Authors: M. Ababou, S. Jennane, M. Mahtat, H. E. Maaroufi, A. Terfay, O. Mourafiq, N. Messaoudi, B. Chaguar, K. Doghmi
Journal: HemaSphere (2021)

Background: In December 2019, coronavirus disease 2019 (COVID-19) was first found in Wuhan, China caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is currently a pandemic infection reported all around the world. It was previously highlighted that laboratory medicine plays an essential role in the early detection, diagnosis and management of many diseases. Complete blood count is the most available, efficient and economic examination. We compared the data of complete blood count betwen COVID19 pateints and a conrol group. Aims: This study aims to retrospect and analyze the complete blood count of asymptomatic patients with active COVID-19 infection diagnosed by polymerase chain reaction (PCR) in order to obtain possible indirect key indicators of active disease in asymptomatic patients. Methods: Sidi Yahya El Gharb Hospital is a field Hospital for asymptomatic patients diagnosed with COVID-19 infection mainly during contact cases screening. Confirmed cases were based on polymerase chain reaction (PCR) nucleic acid testing for SARS-CoV-2 infection. We collected patients from June 20 to July 13, 2020, all of them were isolated and treated according to a national regiment. Patients received hydroxychloroquine 200 mg three times daily for 07 days and azithromycin 500mg once daily for three days. We compared the data of complete blood count, the neutrophil lymphocyte ratio (NLR), the mastocyte lymphocyte ration (MLR) and the platelet lymphocyte ratio (PLR) of our patients with a data of a control group from the Hematologic Laboratory in the Military Hospital Mohammed V of Rabat. The analysis of the data was done using the JAMOVI 1.6.8 statistical programs. Results: COVID-19 infection was confirmed in 220 patients, no one was febrile. Comparisons made with a control group including 220. The sex ratio was 0,23 vs 0,44. The median values of Leucocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils, hemoglobin, platelet, the neutrophil lymphocyte ratio (NLR), the mastocyte lymphocyte ration (MLR) and the platelet lymphocyte ratio (PLR) between the COVID-19 group and the control one was as following: 7110[5495- 8683] vs 6500[5375-8000], 3200[2165-4400]vs 3700[2775-2500], 2800[2257-3305]vs 2000[1600-2500], 615[460-780] vs500[400-700], 140[70-230]vs 100[100-200], 50[40-72] vs 0[0-100], 13,1[12,2-13,9] vs 13,2[12,3-14,1], 282500[224000-353250]vs234000[196000- 297750],1,12[0,765-1,69] vs1,42[1,19-2,19], 0,207[0,152-0,277] vs0,212[0,211-0,316] and 103[79-126]vs105[97,9-156].Comparisons made between the two groups revealed a significant difference regarding neutrophils, lymphocyts, basophils, NLR, MLR and PLR (p < 0.05). Summary/Conclusion: Neutrophil, lymphocyts, basophils, NLR, MLR and PLR can be used to predict n COVID-19 infection in asymptomatic patients.
Association of Disease-Modifying Treatment and Anti-CD20 Infusion Timing With Humoral Response to 2 SARS-CoV-2 Vaccines in Patients With Multiple Sclerosis
Authors: Giulio Disanto, Rosaria Sacco, Enos Bernasconi, Gladys Martinetti, Franco Keller, Claudio Gobbi, Chiara Zecca
Journal: JAMA Neurology (2021)

Humoral and T-Cell Response to SARS-CoV-2 Vaccination in Patients With Multiple Sclerosis Treated With Ocrelizumab