tbuckley/cabot-search huggingface dataset:
EPID-05. TREATMENT PATTERNS OF GLIOMAS: AN EPIDEMIOLOGICAL STUDY
Authors: Mohammad Hamza Bajwa, Noor Imran, Mashal Shah, Erum Baig, Altaf Ali Laghari, Saad Bin-Anis, Naveed Zaman Akhunzada, Jaleed Gilani, Noyan Jawed, Usman Khalid, Namra Qadeer, Areeb Lutfi, Izza Tahir, Rameen Bajwa, Huzaifa Rashid, Haleema Sadia, Kinzah Ghazi, Mishal Gillani, Pakistan Brain Tumor Consortium, Sameen Siddiqi, Syed Ather Enam
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Gliomas are the most common malignant brain tumors of the central nervous system in adults. Specialized treatment modalities have improved morbidity and mortality within high-income countries. In lower- and middle-income countries (LMICs), the overall mortality rate is still seen to be alarmingly high. As there is a shortage of statistical data available regarding the epidemiology of these tumors and their management within the country, the objective of this study is to define the landscape of treatment patterns and current epidemiological data regarding gliomas in Pakistan. METHODS As part of the Pakistan Brain Tumor Epidemiology Study (PBTES), data was collected from major neurosurgical centers across the country, consisting of 35 hospitals in all 4 provinces. Our retrospective study looked at patients who underwent surgical procedures for gliomas in 2019, where a surgical pathology was available. The data was collated and analyzed using appropriate statistical methods. RESULTS 791 patients with gliomas were identified (61.8 % in public sector hospitals, 39.1% in private sector). The most common histopathological subtypes were glioblastoma (33.5%), followed by astrocytoma (18.8%) and oligodendroglioma (11.9%). Gender distribution was skewed towards men (65%). The most commonly performed initial surgical procedure was gross total resection (50% in public hospitals, 41% in private hospitals). Private institution hospitals performed surgical biopsies as the first surgical procedure (23%) more often than public hospitals (9%). Regarding adjuvant treatments, only 26% of patients were given chemotherapy, and there was no data regarding 53% of patients. Similarly, only 15% of patients received radiation therapy, and there was no data for 60% of patients. CONCLUSIONS Our study was able to identify the gaps in glioma management within Pakistan, particularly with regards to chemoradiotherapy. Identifying these unmet needs is the first step in developing comprehensive care for glioma patients.
Abstract 11946: Comparison of Unsupervised Learning Approaches Applied to Electronic Health Record Traits in Heart Failure
Authors: Nosheen Reza, William P Bone, Pankhuri Singhal, Yifan Yang, Anurag Verma, Ashwin C Murthy, Srinivas Denduluri, Srinath Adusumalli, Marylyn Ritchie, Thomas P Cappola
Journal: Circulation (2021)

Introduction: Unsupervised machine learning (UML) applied to high dimensional data has been used to discover cardiovascular disease subtypes; however, the reproducibility of subtypes identified by different algorithms has not been explored. We compared the ability of several promising UML and clustering algorithms to identify heart failure (HF) subtypes using high dimensional electronic health record (EHR) data. Methods: Using the Penn Medicine EHR, we identified all patients who had &gt; 2 instances of ICD-10-CM HF diagnosis. We extracted 1272 EHR-based features (vital signs, demographics, echocardiographic measurements, laboratories, comorbidities) from time of HF diagnosis and limited the cohort based on data completeness (n=8569). We selected the following methods based on prior success in simulation studies and used them to identify HF subtypes: Similarity Network Fusion (SNF), Locally Linear Embedding (LLE), Modified LLE, Uniform Manifold Approximation and Projection (UMAP), and Principal Component Analysis (PCA) followed by several clustering algorithms including K-means, Density-based spatial clustering of applications with noise (DBSCAN), and Spectral Clustering. K groups 2-12 were evaluated. Clustering performance was assessed by silhouette score and visual separation. Results: Model visualizations are shown in the Figure. Highest silhouette score achieved for each model varied widely from 0.02-0.62; optimal cluster number ranged from 2-4 across models. Normalization and standardization of continuous data did not significantly alter silhouette scores or optimal cluster number. Conclusions: HF subtypes identified through UML applied to EHR data may vary substantially depending on the algorithms used. Benchmarking strategies to evaluate reproducibility of UML in the EHR are needed to ensure valid HF patient stratification and phenotypic refinement.
Abstract 11956: Wharton Jelly Mesenchymal Stem Cell-Derived Extracellular Vesicles Improves Cardiac Performance Following Myocardial Injury
Authors: Rosemeire M Kanashiro-takeuchi, Michael Bellio, Lauro Takeuchi, Shathiyah Kulandavelu, Yee-Shuan Lee, Wayne Balkan, Joshua M Hare, Aisha Khan
Journal: Circulation (2021)

Introduction: Mesenchymal Stem Cells (MSC)-derived extracellular vesicles (EVs) are being considered as a therapeutic option for treatment of myocardial infarction (MI). We hypothesize that systemic delivery of Wharton’s Jelly (WJ)-MSC-EVs following injury will improve cardiac function and reduce scar size. Methods: C57Bl/6J male mice were subjected to MI by permanent ligation of the left anterior coronary artery. One-week post-MI, mice were randomized into placebo (PL)- and EV-treated groups. WJ-MSC-EVs isolated from healthy full-term human umbilical cords were injected into the jugular vein once a week for 6 weeks beginning at week 1 post-MI (n=14/group). Cardiac function was assessed using echocardiography before and after treatment, cardiac performance was assessed using pressure-volume loops, and Masson’s trichrome staining was used to assess myocardial infarct size. Results: Echocardiographic evaluation showed an increase in ejection fraction (EF, 21.9 ± 2.3% vs. 11.8 ± 1.4%) and cardiac output (CO, 15.2 ± 1.2 μl/min vs. 8.70 ± 1.0 μl/min) in the EV treated group compared to PL (p&lt;0.05). Similarly, hemodynamic performance was improved indicating cardiac benefits of EVs. As depicted in Fig 1A-F, EV group showed improvement by an increase in the stroke work (SW), CO, EF and ventricular arterial coupling (Ea/Ees), while end-diastolic pressure-volume relationship (EDPVR) was reduced (*p&lt;0.05, ***p&lt;0.0001). EV treatment significantly reduced scar size (Fig 1G). Conclusions: Systemic delivery of EVs improved cardiac performance and reduced scar size following establishment of MI. Accordingly, WJ-MSC-EVs represent a potential therapeutic approach to attenuate impairment of cardiac function and scar size.
Changing the Course of an Orphan Disease
Authors: Manuela Schmidinger
Journal: New England Journal of Medicine (2021)

Patients with von Hippel–Lindau (VHL) disease, a rare autosomal dominant inherited disease,1 have a shorter life expectancy than the general population.2,3 A prospective analysis involving 128 patients in Italy showed that mortality among persons in the VHL population who were between 25 and 64 years of age was significantly higher than that in the general population (P=0.0001).3 The development of clear-cell renal cell carcinoma is usually a late event in the course of VHL disease (at a mean of 34 to 61.8 years of age).3,4 However, extrarenal manifestations of the disease typically occur earlier and are associated with substantial morbidity . . .
B-PRISM (Precision Intervention Smoldering Myeloma): A Phase II Trial of Combination of Daratumumab, Bortezomib, Lenalidomide and Dexamethasone in High-Risk Smoldering Multiple Myeloma
Authors: Omar Nadeem, Robert A. Redd, Julia Prescott, Amada Metivier, Kelsey Tague, Veronica Romines, Meredith Bertoni, Alexandra Savell, Rebekah Medina, Alexandra Distaso, Houry Leblebjian, Clifton C. Mo, Jacob P. Laubach, Adam S. Sperling, Paul G. Richardson, Irene M. Ghobrial
Journal: Blood (2021)
Abstract 11800: Inhibition of Pyruvate Dehydrogenase Kinase Does Not Improve Cardiac Abnormalities in a Mouse Model of Human Barth Syndrome
Authors: Amanda A Greenwell, Christina T Saed, Keshav Gopal, Seyed Amirhossein Tabatabaei Dakhili, Jennifer Kruger, Farah Eaton, Gary D Lopaschuk, Gavin Y Oudit, John R Ussher
Journal: Circulation (2021)

Introduction/Hypothesis: Heart failure presents as the leading cause of infant mortality in individuals with the rare genetic disease, Barth Syndrome (BTHS). The causative mutation underlying the BTHS phenotype has been mapped to the tafazzin ( TAZ) g ene, which encodes for a phospholipid transacylase critical for the remodelling of the mitochondrial phospholipid, cardiolipin. Perturbations in myocardial energy metabolism may contribute to the development and progression of cardiomyopathy in BTHS. Given that cardiac glucose oxidation is impaired in a mouse model of human BTHS, we hypothesized that pharmacological enhancement of glucose oxidation through dichloroacetate (DCA) treatment could mitigate BTHS-related cardiac dysfunction. Methods: DCA was added to the drinking water (84 mM) of 6-week-old mice with experimental BTHS (doxycycline-inducible Taz knockdown (TazKD) mice) for 6-weeks. In vivo cardiac function was assessed via ultrasound echocardiography prior to and following the DCA treatment period. Hearts were extracted from TazKD mice and their wild-type (WT) littermates for protein expression profiling and enzyme activity assessment at the end of the treatment protocol. Results: Prior to treatment at 4-5 weeks of age, TazKD mice exhibited hypertrophic cardiomyopathy as demonstrated by an increase in the ratio between left ventricular (LV) anterior and posterior wall thickness during diastole in relation to lean body mass (0.042±0.003 vs 0.062±0.008 mm/g; 0.049±0.002 vs 0.069±0.005 mm/g). TazKD mice also exhibited impaired LV systolic and diastolic volumes. Treatment with DCA decreased inhibitory phosphorylation of pyruvate dehydrogenase, the rate-limiting enzyme of glucose oxidation, and trended to increase its activity ( p =0.19) in ventricular extracts from TazKD mice compared to their WT littermates, thus suggestive of increased myocardial glucose oxidation. However, despite a potential improvement of cardiac energy metabolism, treatment with DCA did not improve cardiac structural and functional parameters in TazKD mice. Conclusions: Our findings suggest that optimization of cardiac glucose oxidation may not be a feasible strategy for alleviating BTHS-associated cardiomyopathy.
CTIM-19. TEM-GBM: A PHASE I-IIA DOSE-ESCALATION STUDY DELIVERING IFN-Α WITHIN GLIOBLASTOMA MULTIFORME TUMOR MICROENVIRONMENT BY GENETICALLY MODIFIED TIE-2 EXPRESSING MONOCYTES
Authors: Gaetano Finocchiaro, Bernhard Gentner, Eoli Marica, Farina Francesca, Alessia Capotondo, Valeria Ferla, Matteo Carrabba, Valeria Cuccarini, Francesco Di Meco, Federico Legnani, Bianca Pollo, Marco Saini, Paolo Ferroli, Roberto Pallini, Giorgio D'Alessandris, Monica Patanè, Rosina Paterra, Mariagrazia Garramone, Gabriele Antonarelli, Matteo Naldini, Matteo Barcella, Valentina Brambilla, Tiziana Magnani, Stefania Mazzoleni, Zahid Bashir, Alessandro Olivi, Mariagrazia Bruzzone, Carlo Russo, Luigi Naldini, Fabio Ciceri
Journal: Neuro-Oncology (2021)

Abstract Temferon is an ex vivo gene therapy consisting of autologous HSPCs genetically modified to deliver IFN-α2 within the tumor microenvironment (TME) by Tie-2 expressing macrophages. TEM-GBM is an open-label, Phase I/IIa dose-escalation study evaluating safety and efficacy of Temferon in up to 21 newly diagnosed GBM patients with unmethylated MGMT. Autologous HSPCs are transduced with a LVV encoding for IFN-a2 gene. As of 30th April 2021, 18 patients have been enrolled; 13 received Temferon (D+0) with follow-up of 8 – 662 days. After conditioning and Temferon infusion, a rapid engraftment and hematological recovery occurred, with median neutrophil and platelet engraftment at D+13 and D+12, respectively. No dose limiting toxicities were reported. Temferon-derived cells were found within 14 days post treatment and persisted albeit at lower levels in the long-term. Five deaths occurred: one at +478, three at +322, +340 and +402 days due to PD, and the fourth at +60 due to complications following the conditioning regimen. Eight patients had PD (-12 to +239). SAEs include respiratory tract infections, pulmonary embolism, CMV and C.Diff infections, febrile neutropenia, hemiparesis, seizure, brain abscess, worsening of performance status and respiratory failure compatible with ASCT, concomitant medications and PD. Four patients underwent second surgery. Recurrent tumors had gene-marked cells present and increased expression of ISGs compared to diagnosis, indicative of local IFNa release by TEMs. In one patient, a stable lesion had a higher proportion of T cells and TEMs within the myeloid infiltrate and an increased IFN-response signature than in a progressing lesion. Characterization of T-cell immune repertoire suggests the expansion of tumor-associated clones. TME characterization by scRNA and TCR sequencing is ongoing. Interim results show that Temferon is well tolerated, with no dose limiting toxicities identified to date and provide initial evidence of potential immune system activation within the TME.
DDRE-30. CELL-PENETRATING PEPTIDE ANTAGONIST OF CCAAT/ENHANCER BINDING PROTEIN ß DISPLAYS POTENT ANTI-GLIOBLASTOMA ACTIVITY
Authors: Jim Rotolo, Lila Ghamsari, Ricardo Ramierez, Mark Koester, Siok Leong, Erin Gallagher, Emad Darvishi, Gene Merutka, Barry Kappel
Journal: Neuro-Oncology (2021)

Abstract CCAAT/Enhancer Binding Protein Beta (C/EBPß) is a transcription factor overexpressed in glioblastoma (GBM). Mechanistically, C/EBPß is a master regulator of mesenchymal transition in GBM, and its increased expression correlates with mesenchymal differentiation and predicts poor clinical outcome. C/EBPß activity requires dimerization with co-factors such as CREB/ATF family members via leucine zipper interactions. ST101 is a novel peptide antagonist of C/EBPß currently being evaluated in a Phase 1/2 clinical study in patients with advanced unresectable and metastatic solid tumors. ST101 binds to the C/EBPß leucine zipper, thereby preventing dimer formation and inhibiting its transcriptional activity, resulting in selective tumor cell cytotoxicity. Here, we describe ST101 non-clinical anti-tumor activity against GBM. In vitro studies in T98G and U251 cells demonstrate ST101 dose-dependent impact of cell viability (EC50 of 2.2 and 1.2 μM, respectively), accompanied by significant impact on C/EBPß-mediated gene expression as determined by qPCR analysis. In contrast, normal human mononuclear and epithelial cells were not sensitive to ST101 (EC50 &amp;gt; 80 μM). In vivo, ST101 displayed significant anti-tumor activity in a U251 GBM subcutaneous xenograft model, resulting in 81.4% tumor growth inhibition (TGI) vs. control and undetectable tumors in 50% of animals. Following ST101 exposure tumors displayed reduced BIRC3 and ID2 gene expression, and significantly increased cleaved caspase 3 immunostaining indicative of cell death induction. In U251 tumors, subtherapeutic ST101 (&amp;lt; 5% TGI) in combination with temozolomide (&amp;lt; 5% TGI) resulted in 52.8% TGI, significantly greater than either single-agent alone. Similarly, in a temozolomide-refractory T98G GBM subcutaneous xenograft model, ST101 (41.6% TGI) in combination with TMZ (&amp;lt; 5% TGI) resulted in significant anti-GBM response (72.4% TGI). These data emphasize the potential of ST101 as a potent peptide therapeutic for GBM.
Abstract 11840: Serum Apolipoprotein E Levels Predict Residual Cardiovascular Risk in Patients With Chronic Coronary Syndrome Undergoing First Percutaneous Coronary Intervention and On-Statin Treatment
Authors: Tatsuya Fukase, Tomotaka Dohi, ryota nishio, Mitsuhiro Takeuchi, Norihito Takahashi, Yuichi Chikata, Hirohisa Endo, Shinichiro Doi, Hiroki Nishiyama, Iwao Okai, Hiroshi Iwata, Shinya Okazaki, Kikuo Isoda, Katsumi MIYAUCHI, Hiroyuki Daida, Tohru Minamino
Journal: Circulation (2021)

Background: Little is known about the long-term impact of apolipoprotein E (apoE) on residual cardiovascular risk in the patients with chronic coronary syndrome (CCS) receiving statin treatment. Methods: A total of 1109 consecutive patients (mean age, 67±10 years; 83% men) with CCS who underwent their first intervention between 2000 and 2016 were included in this study. All patients had achieved LDL-C &lt;100 mg/dL on statin treatment, as target value recommended by the guidelines at that time, and were divided into two groups based on median serum apoE value. We evaluated the incidence of major adverse cardiovascular events (MACEs), including cardiovascular death, non-fatal acute coronary syndrome, and target vessel revascularization. Results: A total of 552 and 557 patients were categorized to the higher, and lower apoE groups, respectively. There were significant relationships between apoE levels and total cholesterol levels, triglyceride levels, high-density lipoprotein cholesterol levels and estimated remnant cholesterol except for LDL-C levels. During the median follow-up period of 5.1 years, 195 patients (17.6%) developed MACEs. Kaplan-Meier analysis revealed that the cumulative incidence of MACEs in the higher apoE group was significantly higher than in the lower apoE group (29.5% vs.23.8% log-rank test, p =0.019). On multivariable Cox hazard analysis, serum apoE level (1-mg/dL increase) (hazard ratio 1.15; 95% confidence interval 1.03-1.29, p =0.013) was a most strongly independent predictor of MACEs. Furthermore, after adjustment for various confounders including TG, HDL-C, LDL-C, and traditional cardiovascular risk factors, the higher apoE group was significantly associated with an increased risk of MACEs compared with the lower apoE group (p =0.008). Conclusions: Serum ApoE level could be a strong predictor and residual cardiovascular risk in patients with CCS on long-term, even if controlled LDL-C levels with statin treatment.
DDRE-07. TARGETING TUMOR HYPOXIA AND MITOCHONDRIAL METABOLISM WITH ANTI-PARASITIC DRUGS AS AN APPROACH TO IMPROVE THE RADIOSENSITIVITY OF DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Faiqa Mudassar, Cecilia Chang, Prunella Ing, Kristina Cook, Geraldine O'Neill, Han Shen, Eric Hau
Journal: Neuro-Oncology (2021)

Abstract Diffuse intrinsic pontine glioma (DIPG) is an incurable pediatric brain tumor with a median survival of 12 months. Current management is limited to radiotherapy; however, the tumor recurs secondary to radioresistance. Tumor hypoxia appears to be one of the major contributors to radioresistance of DIPG, as oxygenation is critical to successful radiotherapy treatment. Therefore, strategies to alleviate hypoxia could enhance the effectiveness of radiotherapy and result in improved survival outcomes of patients with DIPG. Recent approaches to target tumor hypoxia are predicated on inhibiting mitochondrial respiration of the tumors to decrease oxygen consumption rate (OCR) and increase oxygenation. Here, we aimed to identify a safe but potent mitochondrial inhibitor that could decrease OCR and hypoxia, and improve the radiosensitivity of DIPG. A subset of anti-parasitic drugs (atovaquone, ivermectin, quinacrine, mefloquine and proguanil) which are known mitochondrial inhibitors were studied against a panel of patient-derived DIPG cell lines. We assessed their antiproliferative effects, OCR inhibition and radiosensitising efficacy using cell proliferation, extracellular flux and colony formation assays. Among the five tested drug candidates, atovaquone was found to be the most potent OCR inhibitor with minimal antiproliferative effects on DIPG cultures. It also decreased hypoxia in 3-dimensional DIPG neurospheres, reduced the expression of hypoxia-inducible factor-1α and improved the radiosensitivity of neurospheres of DIPG. Its anti-mitochondrial role was further confirmed by inhibition of various mitochondrial parameters and increase in reactive oxygen species. Overall, these results provide promising in vitro evidence of atovaquone as a hypoxia modifier and radiosensitiser in DIPG and pave a way for rapid translation to in vivo studies.
Abstract 13229: Statins Improve Endothelial Function via Suppression of Epigenetics Driven-EndMT
Authors: Chun Liu, Ian Y Chen, Yu Liu, Mengcheng Shen, Mo Ameen, Nazish Sayed, Joseph C Wu
Journal: Circulation (2021)

Introduction and Hypothesis: Statins, a class of HMG-CoA reductase inhibitors that repress the mevalonate pathway, have been increasingly recognized to reduce cardiovascular risks in a pleiotropic manner independent of their lipid-lowering effects. Yet, the precise molecular mechanisms underlying their cardiovascular protection effects remain elusive. As an unlimited alternate source of human primary cells, we sought to use human induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) to tackle this question. Methods: We treated iPSC-ECs with or without statins in both baseline and prodiabetic conditions, and evaluated their biological functions specifically at the transcriptional and epigenetic levels using an array of state-of-the-art technologies, such as transcriptome profiling, ChIP-seq, ATAC-seq, and CRISPR interference (CRISPRi). Results: We observed that, compared to vehicles, statins significantly improved endothelial functions in both baseline and prodiabetic conditions in iPSC-ECs. Mechanistically, statins could reduce chromatin accessibility at TEAD elements and ultimately at endothelial-to-mesenchymal transition (EndMT)-regulating genes in a yes-associated protein (YAP)-dependent manner. Interestingly, inhibition of geranylgeranyltransferase I (GGTase I), a mevalonate pathway intermediate, was able to block YAP nuclear translocation and thereby YAP activity by suppressing RhoA signaling. Based on these observations, we further confirmed that inhibition of any component of the GGTase-RhoA-YAP/TEAD signaling axis using either genetic or pharmacological approaches was effective to rescue EndMT-associated endothelial dysfunction, especially under prodiabetic conditions. Conclusions: Taken together, our study identifies a novel protective role of statins in endothelial dysfunction by epigenetically repressing EndMT, and proposes that GGTase, RhoA, and YAP inhibitors may be tested as potential therapeutic candidates in addition to statins to prevent or treat endothelial dysfunction-associated cardiovascular diseases.