tbuckley/cabot-search huggingface dataset:
Coordinated eco-leadership can unite clinicians towards net zero
Authors: Jess Davies, Sophia Grobler
Journal: BMJ (2021)

Sherman and colleagues provide practical and realistic ways in which clinicians can shape healthcare’s progress to net zero.1 We agree that health professionals are well positioned agents of change and that coordinated and collaborative approaches are necessary. TRA2SH (trainee led research and audit in anaesthesia for sustainable healthcare) is an Australasian sustainability network.

TRA2SH’s Operation Clean Up is an example of how clinicians can act collectively in …
Abstract 11719: Short Term Moderate Intensity Exercise in an Aged Cohort Reversed Early Findings of Diastolic Dysfunction and Was Associated With Changes in the Serum Metabolome: A Randomized Clinical Trial
Authors: Jie Jun Wong, Jien sze Ho, Louis L Teo, Hai Ning Wee, Kee Voon Chua, Jianhong Ching, Fei Gao, Swee Yaw Tan, Ru San Tan, Jean Paul Kovalik, Angela S Koh
Journal: Circulation (2021)

Introduction: We previously reported changes in the serum metabolome associated with sub-clinical diastolic dysfunction in an aged cohort. In this trial, we subjected subjects with mild diastolic dysfunction to exercise intervention and evaluated effects on cardiovascular function and serum metabolome. Methods: Thirty (83% females) middle-aged adults (53±4 years) with early diastolic dysfunction were randomly assigned to either 12 weeks of moderate intensity exercise training (n=15) or control (n=15). Central hemodynamics and echocardiography were performed pre- and post- intervention, with serum sampling for metabolomic analyses.(E/A (ratio of peak velocity flow in early diastole E (m/s) to peak velocity flow in late diastole by atrial contraction A (m/s). Results: 29 adults completed once-weekly (for 12 weeks) aerobic exercise and muscle strength training for sixty minutes each in a laboratory (n=14 in intervention group, one drop-out) with n=15 controls.E/A increased by magnitude (ratio of post to pre intervention timepoints) of 1.059±0.29 in intervention (p&lt;0.0001) and decreased by 0.969±0.225 (p&lt;0.0001) in control groups. After 12 weeks, central pulse wave velocity) was lower in the intervention compared to control group (7.416±0.789 vs 8.117±0.642, m/s, p=0.032). There were significant accumulations of a medium chain acylcarnitine C12:2-OH/C10:2-DC, alanine and arginine (fold-change 1.825 vs 0.9376, p=0.023; 1.1733 vs 0.95344, p=0.035; 1.1379 vs 0.9501, p=0.041 respectively), with reductions in long-chain acylcarnitine C20:2-OH/C18:2-DC (fold-change 0.7136 vs 1.741, p=0.011), among intervention compared to controls. Conclusions: Our novel pilot data demonstrated reversal of mild diastolic dysfunction after exercise intervention, associated with cellular fuel oxidation and amino acid pathways. We highlight a role for exercise strategies and central carbon metabolism in treating ageing-associated cardiovascular disease.
Supervillin: a membrane skeleton protein at podosomes and invadopodia
Authors: Jessica Crowley, Elizabeth Luna
Journal: Cancer Research (2007)

1349  Cells interact with the extracellular matrix (ECM) through specialized adhesion sites, including focal adhesions and podosomes, and through formation of invadopodia. Podosomes are dynamic, F-actin rich adhesion structures associated with Src family kinases; invadopodia are F-actin rich protrusions associated with matrix degradation. Supervillin (SV) is a myosin II- and F-actin-binding peripheral membrane protein that co-purifies with matrix metalloproteinase MT6-MMP/MMP-25 as a component of the neutrophil membrane skeleton (Nebl et al., 2002). SV also transactivates the androgen receptor (Ting et al., 2002) and negatively regulates cell-substrate adhesion in cultured cells (Takizawa et al., 2006). Five-fold overexpression of EGFP-SV in COS7 cells decreases the numbers and extent of stress fibers with a concomitant increase in F-actin punctae. Consistent with the possibility that these structures are a type of podosome, endogenous SV localizes to apical surfaces of the F-actin cores of podosomes generated by constitutively active Src. Like classical podosomes (Evans et al., 2003), F-actin punctae induced by EGFP-SV are highly dynamic, exhibiting fusion and fission by time-lapse microscopy. Unlike podosomes but like invadopodia precursors (Yamaguchi et al., 2005), EGFP-SV punctae also move laterally. Besides F-actin, SV punctae contain cortactin, a key invadopodial component, but are devoid of focal adhesion kinase (FAK) and vinculin, proteins present in podosomes but absent from invadopodia (Bowden et al., 2006, Artym et al., 2006). Hence, EGFP-SV punctae resemble invadopodia precursors. Furthermore, EGFP-SV induces the redistribution of cortactin from the cell periphery to internal regions of the cell, including SV punctae. Colocalization of EGFP-SV with constitutively active Arf6 at PIP2-rich membrane vesicles and tubules, structures implicated in invadopodia function (Hashimoto et al., 2004), suggests a role in trafficking. EGFP-SV and endogenous SV localize with invadopodia at regions of matrix degradation in MDA-MB-231 cells. RNAi-mediated knockdowns of SV are underway to determine whether SV is necessary for invadopodia formation and/or function. Taken together, our results suggest that supervillin is a component of Src-induced podosomes and invadopodia, and the F-actin punctae formed by EGFP-SV have characteristics of pre-invadopodial complexes. The emerging model is that SV and associated proteins modulate invadopodial assembly either at the plasma membrane and/or through directed intracellular trafficking. Supported by NIH grant GM33048.
NCOG-37. THE UTILITY OF NEUROPSYCHOLOGICAL SCREENING IN MULTIDISCIPLINARY CLINICS FOR PEDIATRIC NEURO-ONCOLOGY POPULATIONS
Authors: Jonathan Mietchen, Alanna Kessler-Jones, Shawn Damodharan, Diane Puccetti
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND The purpose of this project was to examine the utility of neuropsychological screening in multidisciplinary clinics for pediatric neuro-oncology populations and determine whether a brief evaluation can adequately screen children for cognitive dysfunction or psychiatric comorbidities. METHODS Children underwent neuropsychological screening as part of their multidisciplinary clinic visit. This screening evaluation consisted of clinical interview, neuropsychological testing, and the completion of emotional/behavioral checklists. Our neuropsychological test battery included the Kaufman Brief Intelligence Test-Second Edition (KBIT-2) and the NIH Toolbox Fluid Cognition Composite (consisting of 6 subtests). RESULTS Over a six-month period 40 children and adolescents with CNS tumors and/or NF1 were seen in our neuropsychology screening clinic. Females made up 37.5% of the sample. The average age was 11.1 years (range=5-25 years). The average time to complete neuropsychological testing was 56.8 minutes. On average, children in this sample met criteria for 1.8 neuropsychological diagnoses with an average of 1.2 new diagnoses that had not been given prior to their neuropsychological screening. The most common new diagnoses were major or mild neurocognitive disorder (mild=27.5%, major=20%), anxiety (27.5%), ADHD (15%), mood disorder (12.5%), and intellectual disability (10%). On average, these children performed lower than expectation on neurocognitive tests, including intellectual functioning (KBIT-2 Verbal IQ=93.1; KBIT-2 Nonverbal IQ=88.7; KBIT-2 Total IQ=90.1), attention (NIH Flanker T-Score=44.1), working memory (NIH Working Memory T-Score=42.9), processing speed (NIH Processing Speed T-Score=39.9), cognitive flexibility (NIH Card Sort T-Score=43.4), memory (NIH Picture Memory T-Score=44.5), and fluid cognition (NIH Fluid Cognition Composite T-Score=38.7). Behavioral health recommendations were needed for 72.5% of this sample. Educational recommendations were needed for 62.5%. CONCLUSIONS Brief neuropsychological screening completed as part of multidisciplinary clinics for pediatric neuro-oncology patients was efficient and useful in identifying neuropsychological diagnoses in children.
PATH-17. POSSIBLE ASSOCIATION BETWEEN OLIGODENDROGLIAL HISTOLOGICAL FEATURES OF IDHMUT/CODEL LOWER GRADE GLIOMAS AND PATIENT'S FAVORABLE PROGNOSIS, BUT NOT IN IDHMUT/NONCODEL AND IDH-WILDTYPE TUMORS
Authors: Eriel Pareira, Makoto Shibuya, Kentaro Ohara, Yu Nakagawa, Tokunori Kanazawa, Dai Kamamoto, Yasutaka Kato, Eriko Aimono, Kazunari Yoshida, Hiroshi Nishihara, Hikaru Sasaki
Journal: Neuro-Oncology (2021)

Abstract Comprehensive diagnostic using histological and molecular characteristics began to be implemented in WHO 2016 but the relevance of oligodendroglial histological features to patients’ prognoses is still controversial. To elucidate the connection between oligodroglial histology and patient’s prognoses we analyzed 93 LrGGs resected for about 2 decades were reassessed for histological features based on WHO2007 with special interest to pure oligodendroglial diagnosis (namely, oligodendroglioma or anaplastic oligodendroglioma) and presence of classic for oligodendroglioma (CFO) features. Those histological features, patients’ OS, and tumor chromosomal/genetic characteristics were correlated each other in each of the 3 IDH-1p/19q based molecular groups. The reassessed morphology-based diagnosis was shown to be most strict for astrocytic, but loosened for oligodendroglial tumors as compared with the original institutional diagnoses and WHO2016. The pure oligodendroglial diagnosis by reassessment was associated with longer OS in IDHmut/codel group, but not in IDHmut/noncodel and IDH-wildtype groups. The presence of CFO was not associated with patients’ OS in any molecular groups. Gain of 8q was associated with the oligodendroglial diagnosis in IDHmut/noncodel group. Neither the oligodendroglial diagnosis nor CFO was predictive for the methylation status of the MGMT gene in any of the 3 molecular groups. NGS of the IDHmut/codel tumors suggested that mutations in the FUBP1 and CIC genes might be associated with poor prognosis. The oligodendroglial histological feature is not independently predictive for either patients’ prognosis or chemotherapeutic response in LrGGs, except the oligodendroglial diagnosis in IDHmut/codel tumors.
Severe acute respiratory syndrome coronavirus 2 causes lung inflammation and injury
Authors: Le-Le Wang, Jia-Wei Yang, Jin-Fu Xu
Journal: Clinical Microbiology and Infection (2021)

BackgroundAs of 14 October 2021, coronavirus disease 2019 (COVID-19) has affected more than 246 million individuals and caused more than 4.9 million deaths worldwide. COVID-19 has caused significant damage to the health, economy and lives of people worldwide. Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is not as lethal as SARS coronavirus or Middle East respiratory syndrome coronavirus, its high transmissibility has had disastrous consequences for public health and health-care systems worldwide given the lack of effective treatment at present.ObjectivesTo clarify the mechanisms by which SARS-CoV-2 caused lung inflammation and injury, from the molecular mechanism to lung damage and tissue repair, from research to clinical practice, and then presented clinical requirements.SourcesReferences for this review were identified through searches '(COVID-19 [Title]) OR (SARS-CoV-2 [Title])' on PubMed, and focused on the pathological damage and clinical practice of COVID-19.ContentWe comprehensively reviewed the process of lung inflammation and injury during SARS-CoV-2 infection, including pyroptosis of alveolar epithelial cells, cytokine storm and thrombotic inflammatory mechanisms.ImplicationsThis review describes SARS-CoV-2 in comparison to SARS and explores why most people have mild inflammatory responses, even asymptomatic infections, and only a few develop severe disease. It suggests that future therapeutic strategies may be targeted antiviral therapy, the pathogenic pathways in the lung inflammatory response, and enhancing repair and regeneration in lung injury.
Abstract 10090: Cost-Effectiveness of Management for Hospitalized Patients; Gender Difference Between Female and Male Cardiologists
Authors: Atsuko Nakayama, Satoshi Kodera, Hiroyuki Morita, Norifumi Takeda, Issei Komuro
Journal: Circulation (2021)

Introduction: The cost and/or cost-effectiveness for inpatient management according to the gender of attending physicians remain to be elucidated. Hypothesis: The treatment by female cardiologists may be cost-effective. Methods: The hospitalization costs were extracted from the Diagnosis Procedure Combination (DPC) -based payment system. Using the dataset of 7,457 hospitalized patients with cardiovascular diseases in our hospital from 2012 to 2018, we compared the actual cost of inpatient management by female cardiologists with that by male cardiologists. Next, we estimated the cost-effectiveness of inpatient management according to the gender of attending cardiologists. Results: The cost of initial hospitalization per patient was similar between the patients treated by a female middle-grade cardiologist and those treated by a male middle-grade cardiologist ($17,527 ± 14,158, vs. $17,358 ± 15,183, P=0.69). As an analysis on cost-effectiveness, the incremental cost of hospitalization managed by male middle-grade cardiologists was $67 per patient as compared with that by female middle-grade cardiologists. Concordantly, the evaluation on incremental cost-effectiveness ratio per quality-adjusted life year gained showed that the inpatient management by female cardiologists was dominant over that by male cardiologists (less cost and better effect). Conclusions: Inpatient management by female cardiologists was more cost-effective as compared with that by male cardiologists. Physicians’ gender might have a considerable effect on the medical economics.
Abstract 122: Pharmacological Inhibition Of Macrophage Infiltration Prevents Myxomatous Valve Degeneration In Marfan Syndrome
Authors: Na Xu, Katherine E Yutzey
Journal: Circulation Research (2021)

Introduction: Myxomatous valve degeneration (MVD) is the most common cause of mitral regurgitation, characterized by valve leaflet thickening and progressive valve degeneration, leading to impaired cardiac function and heart failure. Currently, there is no medical therapy for the treatment of MVD. MVD in a mouse model of Marfan syndrome (MFS) is characterized leaflet thickening and increased macrophage infiltration, which are reduced with loss of C-C chemokine receptor type 2 (CCR2). However, the specific contributions of macrophages to pathological extracellular matrix (ECM) remodeling and underlying mechanisms are unknown. Hypothesis: Inhibition of macrophage infiltration by a CCR2 inhibitor blocks ECM abnormalities and MVD progression in mitral valves of MFS mice by suppressing the response to cytokine/chemokines. Methods: Mice with the mutation of Fibrillin 1 (Fbn1 C1039G/+ ) recapitulate histopathological features of MFS. Here, we tested the efficacy of a selective CCR2 antagonist RS504393 in the valves of MFS mice in the initiation (1-month-old) and the progression (2-month-old) of MVD, respectively. MFS mice were intraperitoneally injected with RS504393 at 2 mg/kg/d for 30 days. Histological evaluation and immunofluorescence for macrophages and ECM were performed. RNAseq was performed in mitral valves from 2-month old Fbn1 C1039G/+ mice with CCR2 knockout (CCR2 RFP/RFP ). Results: MFS valves revealed ECM abnormalities characterized by collagen fragmentation and proteoglycan accumulation. RS504393 treatment reduced infiltrating macrophages (MHCII+, CCR2+) in myxomatous valves. Remarkably, RS504393 was protective against both the initiation and the progression of MVD, detected by decreased mitral valve thickness and prevention of pathological ECM remodeling in MFS mice. RNAseq data confirmed increased leukocyte activation involved in immune response and abnormal extracellular matrix remodeling in MFS valves. CCR2 deficiency blocked macrophage infiltration and inhibited the response to cytokines in Fbn1 C1039G/+ valves. Conclusions: Our results show that macrophage infiltration is critical for progressive MVD. Moreover, CCR2 inhibition ameliorates MVD progression by preventing immune response. Thus, the CCR2 inhibitor RS504393 is a potential pharmacological candidate to treat MVD in MFS.
RADT-24. SYNTHETIC TREATMENT OF CENTRAL NERVOUS SYSTEM EWING/PRIMITIVE NEUROECTODERMAL TUMOR (EWING/PNET): A CASE REPORT
Authors: yanying Yang, Changguo Shan, Weiping Hong, Linbo Cai
Journal: Neuro-Oncology (2021)

Abstract Ewing/PNET is a rare tumor of the central nervous system. After the standard treatment, there’re still 86.7% of patients had recurrence and no standard treatment after recurrence. Here we report a case of Ewing/PNET with a good survival after synthetic treatment to provide evidence for future clinical strategies. A 23-year-old male underwent resection of the left frontal tumor on April 28, 2017, the pathological diagnosis was Ewing/PNET. He received whole brain radiotherapy 36Gy in 18 fractions, and tumor bed boost to 56Gy in 28 fractions, with 3 courses of Nedaplatin adjuvant chemotherapy. The tumor recured 23 months after the surgery. The patient underwent the second resection, followed by 4 courses of ADM+VCR+CTX/IE chemotherapy. However, 27 months after the first surgery, the tumor evaluation progressive resection of recurrent tumors in the anterior cranial base-ethmoid sinus. During the chemotherapy, MRI showed that tumor still increased. There was a mass in the root of the forehead and nose. After the third recurrence, the patient received re-radiotherapy (50Gy in 25 fractions) 29 months later after the first RT. The tumor was significantly reduced after radiotherapy. Physical examination showed that the sense of smell continued to weaken, the visual acuity was the same as before. 8 courses of VIT (Irinotecan, vincristine, temozolomide) were followed by second RT, tumor was assessed every 2 courses. 44 months after the first surgery, he suffered a third recurrence in spina cord. And then he received rescue RT (20Gy in 10 fractions) in the recurrent tumor. The tumor was reduced after local radiotherapy. He was undergoing follow-up till May 2021, And the OS is 49 months. In conclusion, the incidence of this disease is low, especially in adults. However, the prognosis is poor. Early detection, early operation, combined with radiotherapy and chemotherapy are promising to improve the efficacy of Ewing/PNET.
CBIO-13. THOC1 DRIVES GBM AGGRESSION THROUGH MODULATION OF R-LOOPS AND GENOMIC STABILITY
Authors: Shreya Budhiraja, Shivani Baisiwala, Khizar Nandoliya, Li Chen, Crismita Dmello, Ella Perrault, Cheol Park, Andrew Zolp, Gabriel Dara, Adam Sonabend, Atique Ahmed
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma (GBM) is the most aggressive and common type of adult malignant brain tumor, with a median survival of only 21 months. To identify which genes drive its highly aggressive phenotype, we performed a genome-wide CRISPR-Cas9 knockout screen. Results showed substantial enrichment of ~160 novel essential oncogenic driver genes and pathways, including a previously unstudied gene THOC1—involved in RNA processing—that showed significant elevations in expression at RNA and protein levels (p&amp;lt; 0.05) in GBM, as well as a significant survival benefit in patient datasets when downregulated (p&amp;lt; 0.05). Knocking out THOC1 resulted in cell death in multiple GBM patient-derived xenograft (PDX) lines and extended survival compared to the controls (p&amp;lt; 0.01) in vivo. Overexpression of THOC1 in neural stem cells resulted in transformation to a cancerous phenotype, as evidenced by sphere formation in a soft agar assay (p&amp;lt; 0.01) and in vivo tumor engraftment assays. Further investigation of THOC1 through immunoprecipitation in neural stem cells and multiple GBM lines showed significant interaction in GBM with histone deacetylase complex SIN3A, involved in recruiting major histone deacetylases in order to close the DNA and prevent the accumulation of R-loops, RNA:DNA hybrids that pose a threat to genomic stability. Additional investigation revealed that THOC1-knockdowns in vitro induced R-loop formation and DNA damage, while THOC1-overexpression in vitro resulted in an untenable decrease in R-loops and DNA damage, suggesting that the THOC1-SIN3A axis is elevated in GBM in order to prevent the accumulation of genotoxic R-loops. Additionally, histone deacetylase activity was shown to be elevated in THOC1-overexpression conditions and reduced in THOC1-knockdown conditions, confirming that the THOC1-SIN3A axis functions to prevent R-loop accumulation through the epigenetic regulation. In summary, our whole-genome CRISPR-Cas9 knockout screen has identified a promising therapeutic target for GBM—a disease desperately in need of therapeutic innovations.
Abstract 10268: Establishment of a Hypoimmunogenic Human Induced Pluripotent Stem Cell Line Which Allows <i>in Vivo</i> Tracing of Ventricular Cardiomyocytes
Authors: Lina Ottele, Paul Heinrich, Harald Lahm, Elda Dzilic, Stefanie Doppler, Ruediger Lange, Markus Krane, Martina Dressen
Journal: Circulation (2021)

Introduction: In recent years, human induced pluripotent stem cells (hiPSCs) have emerged as a promising source for cardiac cell therapy. However, immune rejection and insufficient methods for cell fate tracing compromise the assessment of graft efficiency and survival. Hence, we sought to establish a hiPSC line for regenerative therapies which combines hypoimmunogenic and in vivo traceable features. Methods: A hiPSC line was modified using CRISPR/Cas9 technology to first insert a tdTomato reporter into the MLC2v gene and in a second step to replace exons 2 and 3 of the B2M gene with a neomycin resistance cassette, designated B2M-KO. MHC-I surface expression was evaluated by flow cytometry analysis. The immune response of cytotoxic CD8+ T cells and natural killer (NK) cells against the B2M-KO and wild-type hiPSCs was evaluated with a lactate dehydrogenase-based cytotoxicity assay. Immunocytochemistry and qRT-PCR expression analyses were performed to study the cardiomyogenic capacity of B2M-KO hiPSCs during directed cardiac differentiation. Results: The homozygous disruption of the B2M gene was confirmed by qRT-PCR and flow cytometry. However, mRNA expression of essential cardiac transcription factors ( NKX2.5, TBX5 ) and important structural genes ( MLC2a, MLC2v ) during cardiac differentiation was not affected. By contrast, CD8+ T cell-mediated cytotoxicity against B2M -deficient hiPSCs was dramatically reduced compared to wild-type hiPSCs (p&lt;0.002) while NK cell-dependent lysis remained unaffected. The tdTomato fluorescence in differentiating B2M -deficient hiPSCs was generally detectable around day 20 of the directed cardiac differentiation protocol and increased over time. These cells concomitantly also showed expression of MLC2v . Finally, immunocytochemistry confirmed expression of MLC2a, MLC2v and α-ACTININ similar to unedited cells after 30 days of cardiac differentiation. Conclusions: Genetic manipulation of MHC-I surface expression is an efficient strategy to reduce T cell-mediated immune rejection, yet unable to decrease NK cell-mediated cytotoxicity. The generated B2M-KO hiPSC line exhibits hypoimmunogenic properties and allows post-transplantational in vivo tracking of ventricular cardiomyocytes.