tbuckley/cabot-search huggingface dataset:
The cut-off value of transient elastography to the value of hepatic venous pressure gradient in alcoholic cirrhosis
Authors: Se Ri Ryu, Jeong-Ju Yoo, Seong Hee Kang, Soung Won Jeong, Moon Young Kim, Young Kyu Cho, Young Chang, Sang Gyune Kim, Jae Young Jang, Young Seok Kim, Soon Koo Baik, Yong Jae Kim, Su Yeon Park, Baigal Baymbajav
Journal: Clinical and Molecular Hepatology (2020)

Background/Aims: The hepatic venous pressure gradient (HVPG) reflects portal hypertension, but its measurement is invasive. Transient elastography (TE) is a noninvasive method for evaluating liver stiffness (LS). We investigated the correlation between the value of LS, LS to platelet ratio (LPR), LS-spleen diameter-to-platelet ratio score (LSPS) and HVPG according to the etiology of cirrhosis, especially focused on alcoholic cirrhosis.Methods: Between January 2008 and March 2017, 556 patients who underwent HVPG and TE were consecutively enrolled. We evaluated LS, LPR, and LSPS according to the etiology of cirrhosis and analyzed their correlations with HVPG.Results: The LS value was higher in patients with alcoholic cirrhosis than viral cirrhosis based on the HVPG (43.5 vs. 32.0 kPa, P&lt;0.001). There were no significant differences in the LPR or LSPS between alcoholic and viral cirrhosis groups, and the areas under the curves for the LPR and LSPS in subgroups according to HVPG levels were not superior to that for LS. In alcoholic cirrhosis, the LS cutoff value for predicting an HVPG ≥10 mmHg was 32.2 kPa with positive predictive value (PPV) of 94.5% and 36.6 kPa for HVPG ≥12 mmHg with PPV of 91.0%.Conclusions: The LS cutoff value should be determined separately for patients with alcoholic and viral cirrhosis. In alcoholic cirrhosis, the LS cutoff values were 32.2 and 36.6 kPa for predicting an HVPG ≥10 and ≥12 mmHg, respectively. However, there were no significant differences in the LPR or LSPS between alcoholic and viral cirrhosis groups.
MBRS-19. SYNERGISM OF HDAC AND PARP INHIBITORS IN MYC-DRIVEN GROUP 3 MEDULLOBLASTOMA CELLS
Authors: Johanna Vollmer, Jonas Ecker, Thomas Hielscher, Gintvile Valinciute, Sina Oppermann, Heike Peterziel, Ina Oehme, Olaf Witt, Till Milde
Journal: Neuro-Oncology (2020)

Abstract Patients with MYC-driven Group 3 medulloblastoma (MB) show particularly poor outcome. It was previously shown that MYC-driven MBs are highly sensitive to class I histone deacetylase inhibition (HDACi). We studied the molecular effects of the class I HDACi entinostat in MYC-driven MB cells to identify potentially synergistic drug combinations, prioritizing drug clinical availability to enable clinical translation. Gene expression profiles of the MYC-amplified group 3 MB cell line HD-MB03 treated with entinostat were analyzed using bioinformatic approaches, identifying 29 altered biomechanisms. Overlay with a translational drug library of n=76 compounds resulted in 44 compounds targeting 9 biomechanisms. Filtering for publications supporting each drug′s role in MYC-driven entities, or functional interaction with HDACs, without publication of this combination in MBs, resulted in 5 compounds (olaparib, idasanutlin, ribociclib, selinexor, vinblastine). Synergism testing identified olaparib as the drug with the strongest synergism. Validation of the combination olaparib and entinostat by p.H2AX and PI staining as well as trypan blue exclusion showed increased double strand breaks (DSBs), increased cell death, loss of viability and cell numbers. Selectivity of MYC-amplified MB cells was shown by comparison to MYC-non amplified cell lines, which showed higher IC50s, and reacted with cell cycle arrest as opposed to cell death to the combination treatment. The role of HDACis in DNA damage repair was confirmed by increased DSBs when entinostat was added to the combination of olaparib with doxorubicin. Our study identified olaparib as a potential combination partner with entinostat for the treatment of MYC-driven Group 3 MB.
Intravital imaging of interactions between iNKT and kupffer cells to clear free lipids during steatohepatitis
Authors: Haitao Wang, Longjun Li, Yinling Li, Yue Li, Yeqin Sha, Shuang Wen, Qiang You, Lixin Liu, Meiqing Shi, Hong Zhou
Journal: Theranostics (2020)

Rationale: Invariant natural killer T (iNKT) cells and Kupffer cells represent major hepatic populations of innate immune cells. However, their roles in steatohepatitis remain poorly understood. To elucidate their functions in steatohepatitis development, real-time, in vivo analysis is necessary to understand the pathophysiological events in the dynamic interactions between them during diet-induced steatohepatitis. Methods: We used a steatohepatitis animal model induced by a methionine-choline-deficient (MCD) diet. Multi-photon confocal live imaging and conventional experimental techniques were employed to investigate the hepatic pathological microenvironment of iNKT and Kupffer cells, interactions between them, and the biological effects of these interactions in steatohepatitis. Results: We found that iNKT cells were recruited and aggregated into small clusters and interacted dynamically with Kupffer cells in the early stage of steatohepatitis. Most significantly, the iNKT cells in the cluster cleared free lipids released by necrotic hepatocytes and presented a non-classical activation state with high IFN-γ expression. Furthermore, the Kupffer cells in the cell cluster were polarized to type M1. The transcriptome sequencing of iNKT cells showed upregulation of genes related to phagocytosis and lipid processing. Adoptive transfer of iNKT cells to Jα18-/- mice showed that iNKT and Kupffer cell clusters were essential for balancing the liver and peripheral lipid levels and inhibiting liver fibrosis development. Conclusions: Our study identified an essential role for dynamic interactions between iNKT cells and Kupffer cells in promoting lipid phagocytosis and clearance by iNKT cells during early liver steatohepatitis. Therefore, modulating iNKT cells is a potential therapeutic strategy for early steatohepatitis.
EXTH-47. PRECISION IMMUNOTHERAPY VACCINES FOR GLIOBLASTOMA USING CANCER IMMUNOGENOMICS AND SELECTIVE GENE ENRICHMENT STRATEGY
Authors: Vrunda Trivedi, Changlin Yang, Oleg Yegorov, Kyle Dyson, Duane Mitchell
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Development of successful immunotherapy targeting antigens in Glioblastoma (GBM) remains a challenge owing to the heterogeneous nature of GBM and the low mutation burden. It is therefore important to identify multiple tumor antigens that can be targeted simultaneously. Our goal is to develop a personalized RNA vaccination approach that employs the use of cancer immunogenomics in identifying tumor immunogenic epitopes and target enrichment strategies that allow for targeting only the tumor specific antigens. APPROACH RNAseq and WES was performed for murine GBM tumors KR158 and GL261. Using our Open Reading Frame Antigen Network (O.R.A.N.) algorithm, we identified neoantigens and tumor-associated antigens (TAAs) which includes cancer testis and developmental antigens that are aberrantly over-expressed in the KR158 and GL261 tumors. The genes identified as harboring the target epitopes were subjected to a gene enrichment strategy which included hybridization, capture and amplification of our identified genes from a pool of total tumor cDNA. The precision RNA libraries generated from the enriched cDNA samples were then validated for enrichment of target genes using RNAseq. RESULTS We predicted 12 neoantigens and 15 TAAs as immunogenic targets for the KR158 tumor and 192 neoantigens and 37 TAAs for GL261. Pre-capture and amplification, the 27 KR158 tumor genes constituted only 1.14% of the total tumor cDNA pool, however, we were able to enrich the selected genes to up to 95% of the cDNA pool. The IVT RNA library generated from the enriched cDNA templates also consisted of a 90–95% majority of the predicted tumor-specific genes and only 5–10% of the genes were background. CONCLUSION We have demonstrated the ability to generate tumor antigen specific personalized RNA libraries for murine GBM tumors. RNA vaccines targeting specifically and simultaneously numerous tumor antigens, will pave way for the future of immunotherapy vaccines without the induction of intolerable autoimmunity.
SWK-04. A MOBILE AUGMENTED REALITY APP FOR SURGICAL PREPARATION FOR CHILDREN WITH BRAIN TUMORS
Authors: Sharon Granville, Jessica Spat-Lemus, Blakely Rice, Allison Pzena, Phil Stieg, Jeffrey Greenfield, Mark Souweidane
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Children with brain tumors experience significant anxiety secondary to diagnosis and interventions such as surgical management. Preoperative anxiety is known to adversely affect operative outcomes and overall quality of life. Programs that utilize “child-friendly” approaches have been shown to ease anxiety, decrease analgesic requirements, shorten hospital stay, and contribute toward better outcomes. Implementation of these programs is limited due to time, cost, and staffing constraints as well as sociodemographic factors (i.e., language barriers). Therefore, an effective and cost-efficient method could be advantageous. We sought to develop a universally available APP that can assist with these goals and address the current barriers. METHODS In conjunction with a philanthropic resource (Brain Tumor Foundation, New York, NY, USA) a developer was tasked with creating an App for children with brain tumors. The developer integrated published clinical research, multi-specialty input, and patient and family testimonials for possible integration into the tool. RESULTS A mobile App was developed that is modifiable for patient-specific features (age, language, and ethnicity). Initial evaluations of the prototype by healthcare providers, appropriately aged children, and their parents have demonstrated positive engagement, appeal, and ease of use. CONCLUSIONS The mobile App provides a rapid, affordable, and modifiable platform for assisting children with brain tumors cope with their diagnosis and intervention options. Validation with measurable outcomes is planned. The App is currently being evaluated for purposes of psycho-social clinical research tool.
ATRT-07. HIGH-DOSE CHEMOTHERAPY AND AUTOLOGOUS STEM CELL TRANSPLANTATION FOR AN ADULT PRESENTATION OF THE ATYPICAL TERATOID-RHABDOID TUMOR (ATRT)
Authors: Maciej Mrugala, Aditya Raghunathan, Jose Leis
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND ATRT is a rare primary CNS tumor occurring predominantly in children with the peak age of onset at less than 3 years old. Adult presentations are exceedingly rare, associated with poor prognosis and no standard therapies exist. METHODS Case presentation. RESULTS 61 y old woman presented with headaches, sinus pressure, and cognitive decline. She was found to have a pineal tumor causing obstructive hydrocephalus. The patient underwent gross total resection of the tumor with pathology reported as ATRT. Her CNS staging, including CSF, was negative. She subsequently received radiotherapy to the resection bed. There was no consensus on what should be the next step in her therapy given lack of data in adults. Ultimately, we adopted a pediatric regimen and treated the patient with a combination of high-dose chemotherapy with cisplatin, cyclophosphamide, and vincristine followed by autologous stem cell transplantation (ASCT). This regimen called for up to 4 cycles of chemotherapy with ASCT and we had collected enough cells to complete 3 cycles. The patient completed 2 cycles of therapy with moderate toxicity. Her CNS imaging remained stable with no evidence of recurrence 14-months from the original diagnosis. CONCLUSIONS ATRT continues to be an exceedingly rare diagnosis in adults. No standard therapies exist and treatment decisions are challenging given lack of data and lack of prospective clinical trials. Pediatric regimens can frequently be adopted for adults although high-dose chemotherapy with ASCT can be challenging. Our case exemplifies the feasibility of treating ATRT in an adult in the most aggressive fashion.
Diabetic Foot Care Before and During the COVID-19 Epidemic: What Really Matters?
Authors: Vilma Urbančič-Rovan
Journal: Diabetes Care (2020)

The coronavirus disease 2019 (COVID-19) epidemic reached Europe at the beginning of the year 2020. It posed an enormous toll on people and the economy and had a significant impact on health care systems. Health care delivery had to be modified in order to fulfill the increased demands due to the epidemic and to prevent infection spread.

The first case in Slovenia (2,095,861 inhabitants) was confirmed on 4 March 2020. The COVID-19 epidemic was officially declared on 12 March. All preventative medical activities, including those of foot clinics (foot screening and perfusion pressure measurement) were suspended by a decree of the government and fully resumed only after 15 May 2020. The outpatient foot clinic at University Medical Centre Ljubljana has been running daily without limitations since then (with two full-time and one part-time nurse and one doctor, a consultant diabetologist), in spite of the strong second wave that began in mid-August.

During the lockdown period, the clinic remained open for all foot ulcer patients without signs or symptoms of COVID-19 who have not been in contact with COVID-19 patients. Strict measures to limit …
Upstream/Downstream: Glycoprotein IIb/IIIa in Non–ST-Segment Elevation Myocardial Infarction⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Ori Ben-Yehuda
Journal: Journal of the American College of Cardiology (2006)
TBIO-18. ESTABLISHING A PIPELINE FOR INDIVIDUALIZED TREATMENT OPTIONS FOR PEDIATRIC BRAIN CANCER
Authors: Luna Djirackor, Skarphedinn Halldorsson, Cecilie Sandberg, Philipp Euskirchen, Erlend Skaga, Evgeny Kulesskiy, Krister Wennerberg, Iver Langmoen, Einar Vik-Mo
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Despite being able to characterize pediatric brain tumors such as medulloblastoma and high-grade gliomas using detailed molecular analysis tools, this knowledge hasn’t been translated to better treatment methods. In this project, we aim to create a biobank of pediatric brain tumors (PBTs), characterize samples using next generation molecular diagnostics and identify patient specific drug-treatment options using high-throughput drug screening (HTDS). METHODS To establish tumor spheres from biopsies, we mechanically dissociated the tissue and digested it in trypsin. The cells isolated were cultured in serum free DMEM medium. Immunocytochemistry analysis was done to compare the spheres and original tumor. After the second passage, DNA was extracted and subjected to low-pass whole genome nanopore sequencing. HTDS with a library of FDA/EMA-approved anticancer drugs and investigational compounds was also performed. RESULTS We’ve established tumor sphere cultures that grew to passage two and onwards from five juvenile pilocytic astrocytomas, two gangliogliomas and two midline gliomas. The spheres expressed markers of stem cells (Nestin), neurons (β3-tubulin) and glial (GFAP), similar to the original tumor. Copy number profiling and methylation-based classification of the spheres showed the same alterations and classification as the biopsy. HTDS revealed significant differences in drug sensitivity including patient-specific vulnerabilities to anticancer drugs. CONCLUSION We’ve created a protocol to generate tumor spheres from PBTs. We are also building a biobank comprising high and low grade PBTs. Our tumor spheres maintain the characteristics of the original tumor and can be used for further downstream analysis including drug screening.
CamGFR v2: A New Model for Estimating the Glomerular Filtration Rate from Standardized or Non-standardized Creatinine in Patients with Cancer
Authors: Edward H. Williams, Thomas R. Flint, Claire M. Connell, Daniel Giglio, Hassal Lee, Taehoon Ha, Eva Gablenz, Nicholas J. Bird, James M.J. Weaver, Harry Potts, Cameron T. Whitley, Michael A. Bookman, Andy G. Lynch, Hannah V. Meyer, Simon Tavaré, Tobias Janowitz
Journal: Clinical Cancer Research (2020)

Management of patients with cancer, specifically carboplatin dosing, requires accurate knowledge of glomerular filtration rate (GFR). Direct measurement of GFR is resource limited. Available models for estimated GFR (eGFR) are optimized for patients without cancer and either isotope dilution mass spectrometry (IDMS)- or non-IDMS-standardized creatinine measurements. We present an eGFR model for patients with cancer compatible with both creatinine measurement methods.
Association of Serum Bile Acids Profile and Pathway Dysregulation With the Risk of Developing Diabetes Among Normoglycemic Chinese Adults: Findings From the 4C Study
Authors: Jieli Lu, Shuangyuan Wang, Mian Li, Zhengnan Gao, Yu Xu, Xinjie Zhao, Chunyan Hu, Yi Zhang, Ruixin Liu, Ruying Hu, Lixin Shi, Ruizhi Zheng, Rui Du, Qing Su, Jiqiu Wang, Yuhong Chen, Xuefeng Yu, Li Yan, Tiange Wang, Zhiyun Zhao, Xiaolin Wang, Qi Li, Guijun Qin, Qin Wan, Gang Chen, Min Xu, Meng Dai, Di Zhang, Xulei Tang, Guixia Wang, Feixia Shen, Zuojie Luo, Yingfen Qin, Li Chen, Yanan Huo, Qiang Li, Zhen Ye, Yinfei Zhang, Chao Liu, Youmin Wang, Shengli Wu, Tao Yang, Huacong Deng, Donghui Li, Shenghan Lai, Yiming Mu, Lulu Chen, Jiajun Zhao, Guowang Xu, Guang Ning, Yufang Bi, Weiqing Wang
Journal: Diabetes Care (2020)

OBJECTIVE Comprehensive assessment of serum bile acids (BAs) aberrations before diabetes onset remains inconclusive. We examined the association of serum BA profile and coregulation with the risk of developing type 2 diabetes mellitus (T2DM) among normoglycemic Chinese adults. RESEARCH DESIGN AND METHODS We tested 23 serum BA species in subjects with incident diabetes (n = 1,707) and control subjects (n = 1,707) matched by propensity score (including age, sex, BMI, and fasting glucose) from the China Cardiometabolic Disease and Cancer Cohort (4C) Study, which was composed of 54,807 normoglycemic Chinese adults with a median follow-up of 3.03 years. Multivariable-adjusted odds ratios (ORs) for associations of BAs with T2DM were estimated using conditional logistic regression. RESULTS In multivariable-adjusted logistic regression analysis, per SD increment of unconjugated primary and secondary BAs were inversely associated with incident diabetes, with an OR (95% CI) of 0.89 (0.83–0.96) for cholic acid, 0.90 (0.84–0.97) for chenodeoxycholic acid, and 0.90 (0.83–0.96) for deoxycholic acid (P &amp;lt; 0.05 and false discovery rate &amp;lt;0.05). On the other hand, conjugated primary BAs (glycocholic acid, taurocholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, and sulfated glycochenodeoxycholic acid) and secondary BA (tauroursodeoxycholic acid) were positively related with incident diabetes, with ORs ranging from 1.11 to 1.19 (95% CIs ranging between 1.05 and 1.28). In a fully adjusted model additionally adjusted for liver enzymes, HDL cholesterol, diet, 2-h postload glucose, HOMA-insulin resistance, and waist circumference, the risk estimates were similar. Differential correlation network analysis revealed that perturbations in intraclass (i.e., primary and secondary) and interclass (i.e., unconjugated and conjugated) BA coregulation preexisted before diabetes onset. CONCLUSIONS These findings reveal novel changes in BAs exist before incident T2DM and support a potential role of BA metabolism in the pathogenesis of diabetes.
EPCT-01. PHASE I STUDY OF DAY101 (TAK580) IN CHILDREN AND YOUNG ADULTS WITH RADIOGRAPHICALLY RECURRENT OR PROGRESSIVE LOW-GRADE GLIOMA (LGG)
Authors: Karen Wright, Emily Krzykwa, Lianne Greenspan, Susan Chi, Kee Kiat Yeo, Sabine Mueller, Michael Prados, Daphne Haas-Kogan
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND We report a phase I study examining pharmacokinetics, safety and recommended dosage of the type 2 RAF inhibitor DAY101 in children/young adults with radiographically recurrent/progressive LGGs harboring MAPK pathway alterations. METHODS Applying a 3 + 3 design, patients &amp;lt; 18 years of age with radiographically recurrent/progressive LGG received oral DAY101 weekly for 4-week cycles up to a maximum of 2 years, if deriving clinical benefit. The starting DAY101 dosage was 280 mg/m2. Dose limiting toxicities were determined after one cycle. RESULTS We treated nine eligible patients at 280, 350, and 420 mg/m2. Eight patients had KIAA1549:BRAF fusions. One patient with NF1 did not have a biopsy. There were no DLTs. Weekly administration of DAY101 in children resulted in dose-proportional increases in Cmax and AUC similar to that described in adults. A 2.2-fold mg/kg exposure difference was observed with respect to weight-based dosing and suggested a correlation to best radiographic RANO responses of 2 complete responses, 2 partial responses, 3 stable disease, and 2 progressive disease (independently-reviewed). Median time to response was 10.5 weeks (range: 8–32 weeks). CONCLUSION The phase 1A data provide initial pharmacokinetic parameters to describe oral weekly dosing of DAY101 in pediatric patients with radiographically recurrent/progressive LGG. Plasma exposures of DAY101 achieved in adults can be reached in pediatric patients. Oral weekly DAY101 is well-tolerated and possesses anti-tumor activity. The amended protocol will explore additional dose levels and the potential for differential dosing to achieve similar responses across a variety of BSAs.
Peer Review and the Quest for Technical Excellence in Surgery—A Lesson in Self-awareness
Authors: John C. Alverdy
Journal: JAMA Surgery (2020)

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