tbuckley/cabot-search huggingface dataset:
Abstract 24037: ZMYND8 Regulates the Hypoxic Response in Cardiomyocytes
Authors: Kathryn J Schunke, Chad B Walton, Ralph V Shohet
Journal: Circulation (2017)

Introduction: The Zmynd8 gene contains a variety of recognized motifs including a bromodomain and PHD finger, which are implicated in cooperative binding to acetylated nucleosomes. It was recently identified as a key regulator of cancer progression and transcriptional repression by directing modification of histone methylation in the enhancer regions of genes. Mutations and dysregulation of Zmynd8 have been found in multiple cancer types, however its role in the cardiac myocardium is unexplored. Hypoxia-inducible factor 1α (HIF-1α) upregulation and stabilization is a common feature of both cancer and myocardial ischemia, promoting cellular functions such as proliferation, glucose metabolism and angiogenesis. Therefore, we investigated the role of Zmynd8 in the pathophysiology of cardiac ischemia in a model of HIF-1 activation. Hypothesis: Zmynd8 modulates the HIF-1 response in ischemic heart disease by inhibiting enhancer activity of HIF-1 target genes. Methods &amp; Results: We expressed an inducible cardiac-specific, oxygen-stable form of HIF-1α in a mixed strain of mice that genetically express increased Zmynd8 (Z+). Compared to HIF-induced wild-type (WT) mice, these mice did not exhibit the expected HIF-1 phenotype of increased heart weight to body weight (6.4±0.3 vs. 4.8±0.2 vs. 5.1±0.3 mg/g, WT vs. Z+ vs. uninduced; p&lt;0.05) with reduced ventricular function and associated chamber dilation. Semi-quantitative qPCR analysis of HL-1 and H9C2 cardiac cell lines transfected with CMV-expression plasmids for Zmynd8 and oxygen-stable HIF-1α resulted in striking reduction of multiple HIF-1 target genes such as PDK1 (45% reduction) compared to the HIF-1α plasmid alone. RNAi mediated knockdown of Zmynd8 alleviated this negative regulation (65% increase). Bioinformatic analysis of human Zmynd8 and HIF-1α ChIP-seq data indicates that Zmynd8 binds to the enhancer of 78% of HIF-1 regulated genes. This further supports our observation that Zmynd8 modulates HIF-1 activity in the heart. Conclusion: We have discovered a new regulator of HIF-1 action that modifies the hypoxic response, likely through chromatin remodeling. We suggest that this new form of regulation can modify the pathophysiology of ischemia and potentially provide new targets for therapy.
EXTH-50. NOVEL IODINE NANOPARTICLES (INPs) FOR RADIATION ENHANCEMENT OF BRAIN TUMORS
Authors: Henry Smilowitz, James Hainfeld, Sharif Ridwan, Rahul Panchal
Journal: Neuro-Oncology (2018)

Nanoprobes Inc. in collaboration with the Smilowitz lab pioneered the use of non-toxic 15nm gold nanoparticles (AuNPs) to enhance radiation therapy (RT) of advanced murine EMT-6 mammary tumors growing subcutaneously (Hainfeld et al., 2004) and advanced gliomas growing in the brains of mice (Hainfeld et al., 2013). Because of skin discoloration and clearance concerns, second generation INPs were developed by Nanoprobes, Inc. These 20nm non-toxic particles (blood half-life 40 hrs) passively and selectively leak into brain tumors after IV injection. Tumor accumulations, determined by MIcroCT, were seen throughout the tumors, were macroscopically heterogeneous and achieved clinically relevant levels. Liver INP clearance was 50% over 6-months. Fluorescence microscopy showed INPs localized to the region of the brain containing the advanced glioma. Confocal microscopy (63X) revealed INPs largely associated with the tumor endothelium and the surface of tumor cells with some evidence of tumor cell internalization. Using advanced U87 tumors growing in the brains of athymic nude mice, IV injection of 3.5 and 7g/kg INP twenty-four hours prior to single-dose 15Gy RT (RT100KeV X-Ray source) provided median life extensions of ~2 and 2.4-fold, respectively. Tumors followed by bioluminescence showed an initial slowing of the tumors followed by a slower rate of increase after the administration of INPs. Median life extension was also seen in the context of fractionated RT (2x10Gy). Importantly, INP-enhanced RT synergistically increased the efficacy of DOXIL chemotherapy administered at 15mg/kg given in six IV doses over two weeks. Canine safety studies and clinical trials in dogs with gliomas are warranted prior to human translation.
CSIG-18. MODELING TEMOZOLOMIDE RESISTANCE WITH GLIOBLASTOMA PATIENT DERIVED XENOGRAFTS
Authors: C David James, Atique Ahmed, Adam Sonabend, Craig Horbinski, Roger Stupp
Journal: Neuro-Oncology (2018)

We have conducted experiments with intracranial patient-derived xenograft (PDX) models of glioblastoma (GBM) in which PDX recurrence, following the administration of radiotherapy (RT) and temozolomide (TMZ) to animal subjects, is monitored by bioluminescence imaging. Recurrent tumors were resected from brain then sequentially propagated as subcutaneous xenografts through three successive mouse hosts that received no treatment during tumor propagation. Subcutaneous tumor from the third mouse host was used for establishing intracranial tumors in a new series of mice that received the same treatments as in the initial experiment, in order to assess whether recurrent, treated tumors respond differently to the same treatments used in treating corresponding therapy naïve tumors. We observed no indication of tumor recurring from one cycle of RT + TMZ treatment as displaying resistance to the same treatments used in treating corresponding therapy naïve tumor. However, recurrent tumor that was subjected to two additional cycles of TMZ treatment, prior to resection from brain and subcutaneous propagation through 3 successive mice (107 days total subcutaneous propagation while receiving no treatment), displayed TMZ resistance when tested for response to the same treatments as corresponding naïve tumor. Median TMZ treatment survivals for mice intracranially engrafted with naïve, RT + 1 cycle TMZ treated, and RT + 3 cycles TMZ treated tumor cells were 80, 74, and 42 days, respectively, and survival results yielded log-rank p-values <0.001 for naïve and RT + 1 cycle TMZ comparisons against mice with RT + 3 cycle TMZ treated intracranial tumor. These results suggest that GBM PDX with stable TMZ resistance can be developed in vivo by repetitive, cyclical administration of TMZ to mice with intracranial tumor. Results from the multidimensional analysis of such PDX should yield useful information for testing therapeutic hypotheses aimed at improving treatment outcomes for patients with recurrent GBM.
Pharmacokinetic (PK) phase I study to determine tolerability of single escalated doses of 90Yttrium (90Y) antiferritin antibody administrated in patients with refractory or relapsed Hodgkin’s lymphoma
Authors: Keyvan Rezai, Olivier Madar, Sophie Weill, Didier Decaudin, Jean Kadouche, Veronique Edeline, Alain Pecking, Francois Lokiec
Journal: Cancer Research (2008)

4896   Background:  Radioimmunotherapy (RIT) appears to be an innovative approach for treatment of refractory or relapsed Hodgkin’s lymphoma. A  90 Y antiferritin antibody was developed, since it presents the dual benefit of specific recognition of the tumor region and selective irradiation of the tumor cells. This study was conducted to determine the Maximum Tolerated Dose (MTD), plasma PK parameters and excretion profile of  90 Y polyclonal rabbit antibody against human ferritin in patients with refractory or relapsed Hodgkin’s lymphoma.  Study Design :  This is an open label, multi-center, PK phase I, one armed RIT dose escalation study.  Methods: RIT regimen consisted in a diagnostic  111 Indium ( 111 In) labeled antibody injection at day 1, to confirm tumor targeting, followed 7 days later, by increasing therapeutic doses of  90 Y labeled antibody injection. For each dose level, safety was evaluated weekly from the day of first study administration to week 11. The radiolabelling procedure was performed with Ferritarg kits (MatBiopharma Evry France) followed by determination of radiochemical purity (RCP) by Instant thin-layer chromatography, silica gel (ITLC-SG). The RCP must be >95%. Serial plasma and urine samples were collected at 0 (before  90 Y infusion) up to 96 hr post dose. Sample radioactivity was measured by liquid scintillation counting. PK parameters were estimated from plasma radioactivity concentration-time data using a bi-compartmental method.  Results:  7 patients (4 males and 3 females) were enrolled at 3 dose levels. Patients received sequentially, 7.5 MBq/kg (2 patients), 11 MBq/kg (2 patients) and 15 MBq/kg (3 patients) of  90 Y antiferritin antibody single dose IV injection. The RCP ranges were 95.6%-98.5% and 97.3%-99.4% for  111 In and  90 Y labeled antibodies respectively. AUC 0-∞  expressed as total radioactivity, of  90 Y spread between 2.15 to 217 µg.h/mL for the three dose level groups. Radioactivity total body clearance ranged from 14.8 to 93.6 mL/h, expressing a high interpatient variability. The mean radioactive terminal half-life was 55 ± 19 h.  Conclusions:  Radiolabelling procedure permitted a low variable RCP, always higher than the 95% limit.  The MTD was not reached at the highest dose level used. Higher dose levels, by increments of 2 MBq/kg will be explored until the MTD is reached.  The PK parameters are best described by a bi-compartmental model with a high interindividual variability, and are consistent with those obtained in previous studies. Nonradioactive antibody will be assessed to estimate PK parameters. A dosimetric study with  111 In is ongoing to best describe distribution and elimination of anti ferritin antibody.
IMMU-52. TUMOR TREATING FIELDS (TTFIELDS) INDUCE IMMUNOGENIC CELL DEATH RESULTING IN ENHANCED ANTITUMOR EFFICACY WHEN COMBINED WITH ANTI-PD-1 THERAPY
Authors: Tali Voloshin, Shiri Davidi, Yaara Porat, Anna Shteingauz, Mijal Munster, Noa Kaynan, Moshe Giladi, Eilon Kirson, Uri Weinberg, Yoram Plati
Journal: Neuro-Oncology (2018)

Tumor Treating Fields (TTFields) are an effective anti-neoplastic treatment modality delivered via noninvasive application of low intensity (1–3V/cm), intermediate frequency (100–300kHz), alternating electric fields. TTFields are employed as a regional treatment modality using insulated transducer arrays applied to the skin, with the intent to kill tumor cells and reduce local recurrence. This therapy is approved for the treatment of patients with glioblastoma. Previous investigations have shown that TTFields disrupt microtubules and septin filaments, both of which govern key processes in mitosis. The outcomes of mitosis under TTFields application include abnormal chromosome segregation, which trigger different forms of cell death. In this study we evaluated whether TTFields-induced cell death can be immunogenic. We demonstrate that cancer cells that die during TTFields application exhibit endoplasmic reticulum (ER) stress leading to calreticulin translocation to the cell surface and release of damage-associated molecular patterns including the chromatin-binding protein HMGB1 and adenosine triphosphate. Further, we show that TTFields-treated cells promote phagocytosis by dendritic cells (DCs) and maturation of DCs under co-culture conditions. In vivo, the combined treatment of lung tumor-bearing mice with TTFields in combination with the immune checkpoint inhibitor anti-PD-1, significantly improved therapeutic efficacy compared to the control group or TTFields and anti-PD-1 alone. Significant increase in the number of tumor infiltrating immune cells was observed in the TTFields plus anti-PD-1 group. These infiltrating cells, specifically macrophages and DCs, demonstrated upregulation of surface PD-L1 expression. Correspondingly, cytotoxic T-cells isolated from these tumors have shown higher levels of IFN-γ production relative to untreated mice. Collectively, our results suggest that TTFields application induces both ER stress and autophagy, resulting in immunogenic cell death. Combining TTFields with anti-PD-1 may therefore achieve tumor control by further enhancing antitumor immunity.
ACTR-39. TWO-YEAR RESULTS OF THE INTELLANCE 2/EORTC TRIAL 1410 RANDOMIZED PHASE II STUDY ON DEPATUX–M ALONE, DEPATUX-M COMBINED WITH TEMOZOLOMIDE (TMZ) AND EITHER TMZ OR LOMUSTINE IN RECURRENT EGFR AMPLIFIED GLIOBLASTOMA (NCT02343406
Authors: Martin van den Bent, Pim French, Marica Eoli, Juan Sepulveda, Annemiek Walenkamp, Jean-Sebastian Frenel, Enrico Franceschi, Paul Clement, Michael Weller, Iris de Heer, Jim Looman, Jyotirmoy Dey, Scott Krause, Hao Xiong, Peter Ansell, Sarah Nuyens, Joana Brilhante, Maarten Spruyt, Thierry Gorlia, Vassilis Golfinopoulos
Journal: Neuro-Oncology (2018)

Depatux-M is an antibody-drug-conjugate consisting of an antibody (ABT-806) specific to the activated conformation of EGFR bound to the toxin monomethylauristatin-F. In the primary analysis on EORTC 1410 we reported a trend (p = 0.06) towards improved overall survival (OS) in patients with EGFR-amplified (amp) recurrent glioblastoma treated with Depatux-M in combination with temozolomide. Eligible were patients with centrally confirmed EGFRamp glioblastoma at 1st recurrence after temozolomide chemo-irradiation. Patients were randomized to either a) Depatux-M 1.0 mg/kg every 2 weeks intravenously, or b) the same treatment combined with temozolomide 150–200 mg/m2 day 1–5 every 4 weeks, or c) either lomustine or temozolomide (TMZ/LOM) depending on the time of relapse. Primary endpoint was OS. Pharmacokinetic sampling was part of the study design, all samples were used to calculate the Depatux-M average concentration during course 1 (CavgC1). The level of EGFRamp was re-analysed using next generation sequencing. In February 2018, an updated OS comparison performed after 220 observed deaths of Depatux-M in combination with TMZ versus TMZ/LOM using log-rank test and cox models stratified by stratification factors at randomization showed a HR of 0.68 (95%CI [0.48, 0.95]; p = 0.024) and 1-year OS rates of 40% versus 28%. In multivariate analysis CavgC1 was a significant predictor for OS (HR 0.96, 95% CI [0.93, 0.98], p = 0.0013). In Depatux-M treated patients, EGFR status (high vs low level amplification) did not correlate with OS. At the meeting the follow-up from Aug 2018 will be presented, obtained more than 24 months after the end of accrual. CONCLUSION: This updated OS analysis of Depatux-M in combination with temozolomide confirmed the OS improvement in EGFRamp recurrent glioblastoma. In Depatux-M treated patients, higher drug levels during course 1 were associated with improved OS, but high levels of EGFR amplification at first diagnosis were not.
Abstract 18638: Combination Therapy With Adipose Tissue-derived Regenerative Cells and Ppar Gamma Agonist Enhance the Regenerative Capacity in the Failing Heart With Ischemic Cardiomyopathy Through the Activated M2-polarized Macrophage
Authors: Daisuke Mori, Shigeru Miyagawa, Shin Yajima, Takayoshi Ueno, Koichi Toda, Yoshiki Sawa
Journal: Circulation (2017)

Background: The efficacy of cell transplantation has been reported to be modest for heart failure and adjuvant drug combined with cell therapy may be one of options to improve the effectiveness in ...
RTHP-39. SINGLE ARM, MULTI-CENTRIC PHASE II CLINICAL STUDY NAMED “BORON NEUTRON CAPTURE THERAPY AND TEMOZOLOMIDE IN TREATING PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME”
Authors: Shin-Ichi Miyatake, Shinji Kawabata, Toshihiko Kuroiwa, Yoshinori Sakurai, Koji Ono
Journal: Neuro-Oncology (2018)

We have applied tumor-selective particle radiation boron neutron capture therapy (BNCT) to malignant brain tumors. Here we introduce the single arm, multi-centric phase II clinical study named “BNCT and Temozolomide in Treating Patients with Newly Diagnosed Glioblastoma Multiforme” (OSAKA-TRIBRAIN0902, NCT00974987). MATERIALS AND Nine neurosurgical institutes and a neuclear reactor were involved in this trial. From September 2009 to January 2014, 32 newly diagnosed GBMs were enrolled. Primary end point was overall survival 2 years (OS2yr) and the results were compared with Stupp’s ones published in NEJM 2005. The secondary endpoints were local control rate and incidence of brain radiation necrosis. We applied BNCT with 2 boron compounds, BSH and BPA simultaneously. Limiting factor for BNCT was setted for the maximum normal brain dose as 13 Gy-Eq. BNCT was followed by conventional XRT with three layers gradient of 8, 16, 24 Gy as opposing portal fashion from brain surface to the bottom of tumor clinical target volume. This was aimed to compensate BNCT’s heterogeneity and shortage of deep tumor absorbed dose and decrease the possibility of brain radiation necrosis (BRN). The patients were administered with TMZ as Stupp’s regimen as long as possible. At the initial plan, patients’ registration was scheduled as 45 cases, however we had to finish patients accrual as 32 cases due to the disastrous earthquake in Japan. OS2yr of this clinical trial adjusted by Kaplan-Meyer analysis was 45.5% (29.9 - 59.9, as confidence interval), which is superior to historical control, Stupp’s published OS2yr 27.3% (p=0.012). Local control was achieved in 64.3% (35.1–87.2) and cumulative incidence of BRN was 7/28 cases (25%). DISCUSSIONS: In this study, BNCT followed by XRT/TMZ exceeded the results of standard treatment (XRT/TMZ) in OS with acceptable BRN incidence and excellent local tumor control.
NIMG-60. AUTOMATIC DETECTION OF HIGH AMINO ACID UPTAKE REGIONS IN GLIOBLASTOMA FROM MULTI-MODAL MRI: A FULL 3D U-NET STUDY OF DEEPLY LEARNED PET DATA
Authors: Jeong-Won Jeong, Min-Hee Lee, Flora John, Natasha Robinette, Alit Amit-Yousif, Geoffrey Barger, Keval Shah, Sandeep Mittal, Csaba Juhasz
Journal: Neuro-Oncology (2018)

Previous studies reported that high amino acid uptake by alpha-[C-11]-methyl-L-tryptophan (AMT)-PET can accurately detect glioblastoma cell infiltration both in enhancing and non-enhancing tumor portions. Thus, AMT uptake is a strong and independent imaging marker of the metabolically active tumor region. However, amino acid PET is not widely available for clinical usage. Here we introduce a novel end-to-end deep learning framework to detect the high tryptophan uptake glioblastoma regions using clinical multi-modal MRI. Contrast-enhanced T1, non-contrast T2/FLAIR MR images, apparent diffusion coefficient maps from diffusion weighted imaging, and AMT-PET images were analyzed in 12 patients with glioblastoma (mean age: 57 years). Multi-modal images were spatially co-registered and resampled at the same resolution (1mmx1mmx1mm). A binary mask of the metabolically active tumor was obtained as the ground truth from AMT-PET by applying a previously established threshold of 1.65 tumor/normal cortex ratio. A 3D U-net (Ronneberger et al., 2015; https://arxiv.org/pdf/1505.04597.pdf) was implemented to learn input: multi-modal MRI and output: ground truth using Google TensorFlow library with 4 layers of the encoding and decoding paths. Dice similarity coefficient (DSC) was used as a measure of detectability and also a loss function that was back-propagated through the U-net. Data augmentation was performed to generate 1200 study data by applying random affine transformation to the original data of 12 patients (70%/30% for training/validation set). After 1200 iterations, all DSC values reached 0.98/0.96 in the training/validation set. At the voxel level, the resulting model led to 0.87 ± 0.05 sensitivity, 0.99 ± 0.0 specificity, 0.86 ± 0.06 positive predictive value and 0.99 ± 0.0 negative predictive value. CONCLUSIONS: This study translates the advanced deep learning technique to clinical practice where AMT-PET is currently unavailable. Systematic investigation of the proposed U-net may improve presurgical evaluation in glioblastoma by supplementing conventional multi-modal MRI to approximate glioblastoma volume with high amino acid uptake.
Abstract P121: Racial and Ethnic Differences in Ideal Cardiovascular Health and Perception About Weight Among Females With High Education, Income, and Bmi in the US, 2011-2012
Authors: Anshul Saxena, Lara Arias, Tanuja Rajan, Tian Tian, Gulmeena Khan, Emir Veledar
Journal: Circulation (2018)

Introduction: Higher education and income can modify behavioral risk factors for lifetime cardiovascular disease (CVD) risk. The aim of this study was to observe ethnic differences in the CV health, as measured by inadequate cardiovascular health index (CVHI) category, among a cohort of females with high family income, education, and BMI. We also examined differences in perception about self-reported weight and attitudes toward weight loss and exercise. Methods: Adult non-pregnant females aged 20 years or older from the 2011-2012 NHANES were included in the study. Participants were at least college educated, had a poverty to income ratio of 350% or above, and BMI (≥ 30). Weighted regression was adjusted for demographics, PHQ-9 score, perception about weight, if participant tried to lose weight last year, and history of CVD, angina, or heart attack. Results: The sample represented 2,990,456 eligible females in the US. About 13.2% Hispanic perceived their weight to be about right as compared to 10% Black, and 3.3% White. About 89% Hispanics tried to lose weight in past year compared to 71% White and Black. Weighted regression showed that Hispanic (β: -2.47, 95% CI: -4.44, -0.50) and Black (β: -0.74, 95% CI: -1.93, 0.45) had low CVHI score as compared to White. Higher PHQ9 score (β: -0.12, p &gt; 0.05) and those who did not try to lose weight (β: -1.55, p &lt; 0.01) were associated with lower, and those with positive attitude towards their weight were associated with higher CVHI score (β: 0.38, p &gt; 0.05). Our study suggests huge variations in these characteristics by country of birth and citizenship with corroborated ambiguity in definitions. Conclusion: Previous research is inconclusive about existence of Hispanic paradox in cardiovascular health domain. Our study suggests that Hispanic ethnicity was a significant predictor of negative CVHI, when socioeconomic status (SES) was high among all obese females. There was higher prevalence of history of weight management and low CVHI score among Hispanic females; Hispanic females belonging to higher SES may be at a higher risk for CVD related adverse events. In our study, effect of education and income diminished and SES was not associated with participant’s willingness to lose weight despite being obese. Health disparities expressed as differences in CVHI exist despite high education and family income.