tbuckley/cabot-search huggingface dataset:
EXTH-70. ESTABLISHMENT OF INTRAVENTRICULAR SHH INHIBITION AS A THERAPEUTIC OPTION IN YOUNG PATIENTS WITH MEDULLOBLASTOMA
Authors: Catena Kresbach, Melanie Schoof, Tara Leven, Lea Holst, Timur Yorgan, Antonina Wrzeszcz, Stefan Rutkowski, Ulrich Schüller
Journal: Neuro-Oncology (2021)

Abstract Medulloblastoma is the most common malignant brain tumor in children. The embryonal tumor arises in the posterior fossa and disseminates via the cerebrospinal fluid. Medulloblastoma divides in four molecular subgroups, one of which is characterized by mutations in the sonic-hedgehog (SHH) -pathway. SHH inhibition provides an elegant way of targeted therapy. The small molecule Vismodegib allosterically inhibits Smoothened (SMO), an upstream activator of SHH. Unfortunately, Vismodegib has shown to cause irreversible premature epiphyseal growth plate fusions in preclinical studies and clinical trials, preventing its systemic application in children (Kimura et al. 2008; Robinson et al. 2017). We established an intraventricular therapy with Vismodegib, combining the benefits of targeted drug delivery and minimizing systemic side effects. In a mouse model for SHH medulloblastoma, we compare intraventricular, oral and placebo treatment regarding effects on survival, tumor biology, and bone morphology. Math1-cre::Ptch1 Fl/Fl mice show a homozygous loss of PTCH1 in Math1-positive cells, resulting in SHH-pathway overactivation and development of SHH medulloblastomas. At postnatal day 11-13, Math1-cre::Ptch1 Fl/Fl mice were randomized in four treatment arms: group A (n= 9) received placebo intrathecally, B (n= 9) received Vismodegib 200 mg/kd/d orally, C (n= 19) received Vismodegib 0.2 mg/kg/d intrathecally, and D (n= 8) received Vismodegib 1.6 mg/kg/d intrathecally. Kaplan-Meier survival analysis showed a significant survival benefit for 1.6 mg/kg/d intraventricular Vismodegib compared to placebo (p= 0.012). Bone histology and X-ray analysis of intraventricular treated mice showed intact femoral and tibial growth plates, in contrast to orally treated mice that developed skeletal malformations. Further analyses such as DNA sequencing, gene expression analysis, and histological evaluation are ongoing and will add to the picture of the anti-tumor effects of intraventricular SHH-inhibition. Based on the preliminary experimental results, we conclude that intrathecal application of a SMO-inhibitor might evolve as a promising new way of targeted treatment of SHH medulloblastomas.
A Clinical Study of 15 Acute Leukemia Patients with Plasmacytoid Dendritic Cells Expansion
Authors: Ya-Lan Zhou, Yan Wei, Xiaohong Liu, Jing Wang, Jinsong Jia, Hong-Xia Shi, Ying-Jun Chang, Xiao-Su Zhao, Yan-Rong Liu, Guo-Rui Ruan, Xiao-Jun Huang, Hao Jiang
Journal: Blood (2021)
Using a Human Liver Tissue Equivalent (hLTE) Platform to Define the Functional Impact of Liver-Directed AAV Gene Therapy
Authors: Ritu M Ramamurthy, Wen Ting Zheng, Sunil George, Meimei Wan, Yu Zhou, Baisong Lu, Colin E Bishop, Anthony Atala, Christopher D Porada, M. Graca Almeida-Porada
Journal: Blood (2021)
Abstract 10690: Prevalence of Electronic Cigarette Use and Its Determinants in Us Persons of Hispanic Heritage: The Hispanic Community Health Study / Study of Latinos (HCHS/SOL)
Authors: Ayana K April-Sanders, Martha L Daviglus, Un Jung Lee, Krista Perreira, Amber Pirzada, Frank Bandiera, Aida L Giachello, Thanhhuyen T Vu, Carlos J Rodriguez
Journal: Circulation (2021)

Introduction: Popularity and use of electronic nicotine delivery systems (ENDS or e-cigarettes), have increased tremendously in the United States (US). Yet, data in a representative sample of US Hispanics/Latinos is limited. We determined the prevalence and correlates of ENDS use from the national Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Methods: Cross-sectional data collected between the years 2015–2017 were analyzed to assess ENDS use (ever (current: use ≤ past 30 days; former: use &gt; past 30 days) and never) among 11,623 adults aged 23+ years. Weighted prevalence estimates were reported and age-adjusted logistic regression models were used to examine associations between sociodemographic, lifestyle/behavioral, and clinical exposures with ENDS use (vs. nonsmokers and cigarette-only smokers, separately). Results: Mean age 47 years ± 0.3 and 52% women. The weighted prevalence of current and former ENDS use was 2.0% and 10.4%, respectively. Over 67% of current ENDS users reported dual-cigarette use. Current ENDS use prevalence estimates ranged from 1.1% in Hispanics/Latinos of South American background to 2.1% in Hispanics/Latinos of Mexican and Puerto Rican background. In logistic regression models, compared with nonsmokers, increased odds of current ENDS use was associated with males (OR=4.90, p&lt;0.001), higher education (OR=2.03, p&lt;0.05), English language preference (OR=7.59, p&lt;0.001), Puerto Rican background (OR=2.09, p&lt;0.05), a high level of physical activity (OR=4.02, p&lt;0.001), and history of alcohol use (OR=15.93, p&lt;0.001). Older age (≥45 years) (OR=0.30, p&lt;0.001), foreign-born participants (OR=0.12, p&lt;0.001), and those with obesity (OR=0.60, p&lt;0.05) and type 2 diabetes (OR=0.46, p&lt;0.001) had lower odds of current ENDS use. These trends were generally similar when cigarette-only smokers were the reference group. Having ever used ENDS was associated with prevalent coronary artery disease. Conclusions: Our study suggest that Hispanic/Latino individuals who are young adults, male, US-born, or have high acculturation are more likely to report current ENDS use.
Abstract 13234: Impact of Sex on Outcomes After Cardiac Surgery: A Systematic Review and Meta-Analysis
Authors: Lauren K Dixon, Ettorino Di Tommaso, Arnaldo Dimagli, Shubhra Sinha, Manraj Sandhu, gianni angelini, Benedetto Umberto
Journal: Circulation (2021)

Introduction: Despite advances in cardiac surgery, there is evidence from observational studies which suggests that females have poorer post-operative outcomes than males. This study is the first to review sex related outcomes following both coronary artery bypass graft (CABG) and valve surgery with or without combined CABG. Hypothesis: Females have worse outcomes following cardiac surgery than males. Methods: We identified 30 primary research articles reporting either short-term mortality (in-hospital/30 day), long-term mortality, post-operative stroke, sternal wound infection and post-operative myocardial infarction (MI) in both sexes following CABG and valve surgery with or without combined CABG Reported adjusted odds/hazard ratio were pooled using an inverse variance model. Results: Females were at higher risk of short-term mortality (odds ratio (OR) 1.40; 95% confidence interval (CI) 1.32-1.49; I 2 =79%) and post-operative stroke (OR 1.2; CI 1.07-1.34; I 2 =90%) when compared to males. There was no increased risk in long-term mortality (OR 1.04; 95% CI: 0.93-1.16; I 2 =82%), post-operative MI (OR 1.22; 95%CI: 0.89-1.67; I 2 =60%) or deep sternal wound infection (OR 0.92; 95%CI: 0.65-1.03, I 2 =87%). No evidence of publication bias or small study effect was found. Conclusions: Females are at a greater risk of short-term mortality and post-operative stroke than males following CABG and valve surgery with or without combined CABG. However long-term mortality is equivalent in both sexes.
Abstract 12911: Outcomes of Transcatheter Aortic Valve Replacement at Teaching versus Non Teaching Hospitals in the United States
Authors: James Brown, Edgar Aranda-Michel, Derek Serna-Gallegos, Hemal Gada, Dustin Kliner, Catalin Toma, Saurabh Sanon, Yisi Wang, Ibrahim A Sultan
Journal: Circulation (2021)

Introduction: Transcatheter aortic valve replacement (TAVR) has become widely available across the United States; however, national trends have not been evaluated by hospital teaching status. Hypothesis: There will be no differences in outcomes between teaching hospitals (TH) versus non teaching hospitals. Methods: This was an observational study of patients undergoing TAVR from 2012-2017, utilizing the Nationwide Readmissions Database with appropriate trend weights to generate national estimates. Codes from the International Classification of Diseases were used to identify patients with a primary procedure code for TAVR. TAVRs were stratified by hospital teaching status, while in-hospital mortality, complications, costs, and 30- and 90-day readmissions were compared between the groups. Results: During the study’s timeframe, 123,557 patients underwent TAVR, of which 90% occurred at a TH. The number of TAVRs increased by 744% from 2012 to 2017 (Cochrane-Armitage test, p&lt;0.001), with a larger increase for non-TH. Median age [IQR] was 82.0 [76.0-87.0] and 46.2% were women. Patients undergoing TAVR at a teaching hospital were more likely to have diabetes, dyslipidemia, hypertension, coronary artery disease, congestive heart failure, peripheral vascular disease, and cerebrovascular disease. In-hospital mortality was higher for patients undergoing TAVR at a TH (2.6% vs. 2.2%, p&lt;0.001). After TAVR, there was more stroke (1.5% vs. 0.9%), acute kidney injury (14.6% vs. 11.3%), and myocardial infarction (4.2% vs. 2.8%) in the TH group. TAVR at a TH was associated with higher total cost of care during their index admission (47.9 [37.5-61.9] vs. 44.3 [34.7-58.7] x $1000) and longer length of hospital stay (4.0 [2.0-7.0] vs. 3.0 [2.0-6.0] days). Moreover, patients undergoing TAVR at a TH were more likely to have been discharged to an intermediate care facility or home health care (50.0% vs. 40.9%). 30-day readmissions were higher for the TH group (18.7% vs. 18.0%), while 90-day readmissions were similar across each group (28.4% for the entire cohort). Conclusions: While patients undergoing TAVR at a teaching hospital had more comorbidities, they also had higher in-hospital mortality, more postoperative complications, and greater healthcare costs.
Post-acute COVID-19 syndrome: a new tsunami requiring a universal case definition
Authors: Gema M. Lledó, Jacobo Sellares, Carlos Brotons, Mireia Sans, Juana Díez Antón, Julià Blanco, Quique Bassat, Adelaida Sarukhan, José M. Miró, Silvia de Sanjosé, Silvia de Sanjosé, Josep M. Miró, Quique Bassat, Magda Campins, Robert Guerri, Carles Brotóns, Juana Díez, Julià Blanco, Mireia Sans, Adelaida Sarukhan, Antoni Plasència, Josep M. Antó
Journal: Clinical Microbiology and Infection (2021)
Antiretroviral therapy timing impacts latent tuberculosis infection reactivation in a Mycobacterium tuberculosis/SIV coinfection model
Authors: Riti Sharan, Shashank R. Ganatra, Allison N. Bucsan, Journey Cole, Dhiraj K. Singh, Xavier Alvarez, Maya Gough, Cynthia Alvarez, Alyssa Blakley, Justin Ferdin, Rajesh Thippeshappa, Bindu Singh, Ruby Escobedo, Vinay Shivanna, Edward J. Dick, Shannan Hall-Ursone, Shabaana A. Khader, Smriti Mehra, Jyothi Rengarajan, Deepak Kaushal
Journal: Journal of Clinical Investigation (2021)

Studies using the nonhuman primate model of Mycobacterium tuberculosis/simian immunodeficiency virus coinfection have revealed protective CD4+ T cell–independent immune responses that suppress latent tuberculosis infection (LTBI) reactivation. In particular, chronic immune activation rather than the mere depletion of CD4+ T cells correlates with reactivation due to SIV coinfection. Here, we administered combinatorial antiretroviral therapy (cART) 2 weeks after SIV coinfection to study whether restoration of CD4+ T cell immunity occurred more broadly, and whether this prevented reactivation of LTBI compared to cART initiated 4 weeks after SIV. Earlier initiation of cART enhanced survival, led to better control of viral replication, and reduced immune activation in the periphery and lung vasculature, thereby reducing the rate of SIV-induced reactivation. We observed robust CD8+ T effector memory responses and significantly reduced macrophage turnover in the lung tissue. However, skewed CD4+ T effector memory responses persisted and new TB lesions formed after SIV coinfection. Thus, reactivation of LTBI is governed by very early events of SIV infection. Timing of cART is critical in mitigating chronic immune activation. The potential novelty of these findings mainly relates to the development of a robust animal model of human M. tuberculosis/HIV coinfection that allows the testing of underlying mechanisms.
BIOM-01. MTH1 EXPRESSION IS UPREGULATED IN BRAIN METASTASES OF MALIGNANT MELANOMA
Authors: Marco Timmer, Marco Timmer, Saskia Kuhl, Roland Goldbrunner
Journal: Neuro-Oncology (2021)

Abstract MuT Homolog1 (MTH1) is an enzyme involved in DNA repair in normal cells and is often up-regulated in cancer cells. The enzyme catalyses the hydrolysis of oxidised dNTPs, to prevent their incorporation into DNA or RNA, resulting in mutations or cell damage/death. Cancer cells can have a high concentration of ROS, due to defective redox regulation. This results in the damage of DNA and oxidises free dNTPS, which in turn leads to mutations in DNA replication or cell death. The quantification of MTH1 expression was done by Western Blot analysis. 16 tumours were obtained during neurosurgery, 8 metastatic and 8 recurrent tumours of the same patient, and immediately frozen using liquid nitrogen. The proteins were extracted using RIPA lysis buffer. Western Blot was performed and detection followed via peroxidase linked secondary antibodies. MTH1 expression was shown to be up-regulated in brain metastases (1,442+/-0,6374) versus normal brain tissue (0,4133+/-0,277). However, in the recurrent tumour of the brain metastases, MTH1 was not expressed in a significantly higher amount compared the control tissue and less than in the brain metastases (0,6941+/-0,4146). The high expression of MTH1 in cerebral metastases presents a therapeutic target for MTH1-inhibitors, provided these are able to cross the blood brain barrier. Comparison to the primary melanoma tumour would be useful in showing significant differences of the metastases. Lower levels of MTH1 in recurrent brain metastases may suggest dedifferentiation from the original metastases. It may present a target for specific treatment of brain metastases of melanoma.
Abstract 11237: Expression of Mitochondrial, Contractile, and Calcium Regulatory Proteins is Altered in Patients with Atrial Fibrillation
Authors: Julie H Rennison, Catherine C Cantlay, Ling Li, Cheryl R Lin, Beth S Lovano, Laurie Castel, Paul J Cantlay, A M Gillinov, Christine S Moravec, Belinda B Willard, Jonathan D Smith, Mina K Chung, John Barnard, David R Van Wagoner
Journal: Circulation (2021)

Introduction: Atrial fibrillation (AF) increases energy demand for contractile and electrical activity. Changes in left atrial (LA) protein expression of AF patients are poorly characterized. Hypothesis: Mitochondrial protein expression in patients with AF is altered in an attempt to meet increased energy demand. Methods: LA appendage tissue was obtained from 198 patients undergoing Maze surgery. At the time of surgery, 80 were in sinus rhythm (SR) (50 paroxysmal AF, 30 persistent AF) and 118 in AF (65 persistent AF, 53 permanent AF). Protein content was assessed by mass spectrometry and 2539 proteins were identified. Results: In AF compared to SR, 257 proteins were differentially expressed (q&lt;0.05); 44 of 62 mitochondrial proteins detected (MitoCarta 3.0) were increased. KEGG pathway analysis revealed Oxidative Phosphorylation was increased (p=1.01E-3) in AF, including 17 subunits of the electron transport chain (A). The Hypertrophic Cardiomyopathy pathway was decreased (p=1.01E-03). Expression of ryanodine receptor, and troponin and tropomyosin subunits decreased, but tropomyosin 4 and myosin heavy chain 9 and 10 increased (B), providing evidence of changes in myofibrillar and calcium regulatory proteins in AF. Among 39 putative AF risk genes detectable at the protein level, 8 were altered in AF (C). The Tricarboxylic Acid Cycle KEGG pathway was decreased (p=2.55E-3) in patients with permanent compared to persistent AF, with no significant changes in other cellular pathways or protein expression of putative AF risk genes. Conclusions: In one of the largest proteomic datasets in human LA to date, we find that expression of proteins in metabolic, myofibrillar, and calcium regulation pathways is altered in patients with AF. Additional metabolic changes were detected with progression to permanent AF. These data identify proteins that are altered in patients with AF providing insight into cellular pathways that may be targeted for AF prevention and therapy.
Abstract 13322: Development of the Preclinical Science Integration and Translation (PRESCIANT) Method and Application to the Apolipoprotein E Knockout Mouse Atherosclerosis Model
Authors: Megan M Shuey, Rachel R Xiang, Mary Moss, Brigett V Carvajal, Yihua Wang, Nicholas Camarda, Daniel Fabbri, Protiva Rahman, Jacob Ramsey, Alec Stepanian, Paola Sebastiani, Quinn Wells, Joshua A Beckman, Iris Z Jaffe
Journal: Circulation (2021)

Introduction: Animal models of human diseases are used extensively to interrogate molecular mechanisms in a reductionist fashion. We tested whether aggregation and integration of preclinical data can identify new causative pathways that faithfully model human disease mechanisms. We have termed this novel technique, the Preclinical Science Integration and Translation (PRESCIANT) method. Methods and Results: Data were extracted from 716 manuscripts in the journal Arteriosclerosis, Thrombosis, and Vascular Biology from 1995-2019 using the apolipoprotein E knockout mouse (ApoE-KO) to study atherosclerosis. We identified 360 unique studies in which genes were experimentally perturbed in ApoE-KO mice to impact atherosclerotic plaque size and/or composition. Impacts of the interventions on plaque size, inflammation, and lipid content were analyzed using Ingenuity Pathway Analysis. The top upstream regulatory network (sc-58125, a COX2 inhibitor) linked 37.2% (134) of the genes implicated in atherosclerosis into a single network. Further, Ingenuity Pathway Analysis identified TREM1 signaling, LXR/RXR activation, and renin-angiotensin signaling as the top 3 pathways associated with changes in atherosclerosis parameters. Specifically, early atherogenesis genes were enriched with pathways associated with inflammatory cell migration and infiltration (including TREM1) whereas late atherosclerosis genes were associated with cell metabolism and survival (including LXR/RXR activation). These two pathways were interrogated in a clinical cohort of 88,660 patients by testing for association between genetically predicted expression of the human homologs of mouse pathway genes and a composite phenotype composed of 27 human atherosclerosis diagnoses. There was a significant enrichment (p&lt;0.01 for both pathways) in the number of human homologs associated with atherosclerosis, including 12 (57.2%) genes in the TREM1 pathway and 15 (53.6%) in the LXR/RXR pathway. Conclusion: PRESCIANT can successfully leverage decades of animal investigations to translate results from large-volume singular preclinical studies to make novel causal inferences into human disease.
FLGS-03. Fluorescein sodium-guided biopsy or resection in patients with contrast enhancing brainstem lesion in MRI
Authors: Fuhua Lin, Zhenghe Chen, Xiangheng Zhang, Yonggao Mou
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND It is challenging to resect or just biopsy the lesions in the brainstem, due to the essential function of the surfaces and limited space. Neuro-navigation is not always reliable and stereotatic biopsy is infrequently inconclusive due to small or inadequate samples. We want to share our experiences in the application of fluorescein sodium in surgery on patients with brainstem lesion which is contrast enhancing in MRI. METHODS Between January 2017 and June 2021, 5 patients with brainstem lesion underwent fluorescein sodium-guided surgery in neurosurgery department of Sun Yat-sen University Cancer Center. After injection of low dose of sodium fluorescein (3 mg/kg), the lesions with strong fluorescence staining were identified as the target area for biopsy or resection. RESULTS 5 consecutive patients (aged 6–47 years) with brainstem lesions prospectively underwent fluorescein sodium-guided surgery. The lesions were located in pontine in 3 patients and in the medulla in 2 patients. Gross total resection was achieved in 2 patients, and partial resection in the other 3 patients. In all patients, a pathological diagnosis was obtained (4 gliomas and 1 metastasis from non-small cell lung carcinoma) without severe complications, including mild facial or abduct nerve palsy in 3 patients. And all the specimens with strong fluorescence staining sent for pathology were proved to be tumorous. CONCLUSION Fluorescein sodium-guided technique was helpful to locate the lesion in brainstem which was contrast-enhanced in MRI. It was effective and safe to figure out an ideal trajectory to avoid damage of the crucial structures and improve the diagnostic rate.
BIOM-09. MYO-INOSITOL LEVELS ON MR SPECTROSCOPY CAN PREDICT FAILURE OF ANTI-ANGIOGENIC TREATMENT IN RECURRENT GLIOBLASTOMA
Authors: Mohamed El-Abtah, Michael Wenke, Pratik Talati, Melanie Fu, Daniel Kim, Akila Weerasekera, Julian He, Anna Vaynrub, Mark Vangel, Otto Rapalino, Ovidiu Andronesi, Isabel Arrillaga-Romany, Deborah Forst, Yi-Fen Yen, Bruce Rosen, Tracy Batchelor, Ramon Gonzalez, Jorg Dietrich, Elizabeth Gerstner, Eva-Maria Ratai
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Recurrent glioblastoma (rGBM) patients are often treated with anti-angiogenic agents such as bevacizumab (BEV). Despite therapeutic promise, conventional MR methods fail to determine which patients may not benefit. PURPOSE: The purpose of this study was to utilize magnetic resonance spectroscopic imaging (MRSI) with intermediate and short echo time to generate corrected Myo-inositol normalized by contralateral creatine (mI/c-Cr) in patients with rGBM treated with BEV and investigate whether it can predict survivorship prior to BEV initiation (baseline) and at 1-day, 4-weeks, and 8-weeks thereafter. METHODS We conducted a prospective, longitudinal study and evaluated spectroscopic data of myo-inositol (mI), a glial marker and osmoregulator within the brain, normalized to contralateral-creatine (mI/c-Cr) in the intratumoral, contralateral normal appearing white matter, and peritumoral volumes of rGBM patients. Area under the ROC curve (AUC) was calculated for all volumes at baseline, 1-day, 4-weeks, and 8-weeks after treatment to determine mI/c-Cr’s ability to predict survivorship. RESULTS 21 participants (62 ± 12 years, 15 men) were evaluated. Lower mI/c-Cr in the tumor prior to and during BEV treatment predicted poor survivorship, with ROC analyses illustrating an AUC of 0.75 at baseline, 0.87 at 1-day, and 1 at 8 weeks. Lower levels of mI/c-Cr were also observed in the contralateral and the peritumoral volumes for shorter-term survivors. In the contralateral volume, lower mI/Cr was predictive of shorter-term survival at baseline and all other timepoints. Within the peritumoral volume, lower mI/c-Cr was predictive of shorter-term survival at baseline (AUC=0.80), 1-day (AUC=0.93), and 4-weeks (AUC=0.68). CONCLUSIONS Lower levels of mI/c-Cr within intratumoral, contralateral, and peritumoral volumes were predictive of poor survivorship and anti-angiogenic treatment failure as early as one month before BEV treatment. Acquiring MRSI alongside conventional MR imaging modalities can convey critical information regarding tumor microenvironment that informs management of patients with rGBM.