tbuckley/cabot-search huggingface dataset:
Abstract #3774: Activation of PRDM1 in mantle cell lymphoma
Authors: Shruti Desai, Michelle Maurin, Matthew Smith, Sophie Dessureault, Jianguo Tao, Eduardo Sotomayor, Kenneth Wright
Journal: Cancer Research (2009)

Mantle Cell Lymphoma (MCL) is a Non-Hodgkin\#8217;s B cell Lymphoma, involving the cells from the mantle zone that surrounds the germinal center (GC). It is an aggressive form of lymphoma with poor prognosis and short disease free survival. Current treatment regimes are ineffective and novel therapeutic approaches are needed. Bortezomib, a proteasome inhibitor, has been approved for the treatment of refractory MCL, although its downstream effectors are poorly understood. The PRDM1 gene encodes the transcriptional repressor protein PRDI-BF1 (BLIMP-1), a key regulator of B cell terminal differentiation into antibody secreting plasma cells. PRDM1 acts as a molecular switch to silence genes required for the B cell phenotype although only a limited number of direct targets of PRDM1 are known. The focus of this study is to identify potential roles of PRDM1 in MCL and in the response to Bortezomib. Freshly isolated MCL patients\#8217; cells were cultured in the presence of stromal conditioned media and exposed to increasing doses of Bortezomib. PRDM1 mRNA and protein expression was induced in a time and dose dependent manner. Apoptosis as detected by PARP cleavage paralleled the activation of PRDM1. Analysis of the MCL cell lines Mino and Jeko-1 revealed a similar induction of PRDM1 and apoptosis in response to 5nM Bortezomib. Ectopic expression of PRDM1 in the MCL cell lines directly induced apoptosis in the absence of Bortezomib. Knock-down of PRDM1 by an siRNA prevented PRDM1 protein expression in presence of Bortezomib. The specific absence of PRDM1 resulted in a significant inhibition of Bortezomib mediated apoptosis. These results suggest a role for PRDM1 in the apoptotic response of MCL to Bortezomib. In order to determine the molecular mechanism of PRDM1 in MCL, the ability of PRDM1 to bind and silence its target genes was analyzed. Chromatin immunoprecipitation (ChIP) utilizing PRDM1 antibodies followed by real-time PCR analysis demonstrated that the PRDM1 protein induced by Bortezomib was recruited to the known target gene CIITA as well the novel target PCNA. PRDM1 binding was associated with increases in the epigenetic silencing mark of histone H3 lysine 9 dimethylation. This is consistent with known ability of PRDM1 to recruit the H3K9 methyltransferase G9a. Furthermore ChIP analysis of RNA polymerase binding revealed a loss of polymerase corresponding to the silencing of the target genes. These studies show that activation of functional PRDM1 in MCL is required for the maximal apoptotic effect of Bortezomib. Importantly this suggests that characterizing the activity of PRDM1 will be critical to understand the mechanism of Bortezomib in MCL.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3774.
TMOD-34. IMPROVED TREATMENT OF MELANOMA BRAIN METASTASIS USING A SYNTHETIC PEPTIDE
Authors: Synnove Aasen, Heidi Espedal, Christopher Florian Holte, Olivier Keunen, Tine Veronika Karlsen, Olav Tenstad, Zaynah Maherally, Hrvoje Miletic, Anne Vaag Eikeland, Habib Baghirov, Rolf Bjerkvig, Dag Erlend Olberg, Gobinda Sarkar, Robert Jenkins, Frits Thorsen
Journal: Neuro-Oncology (2018)

Individuals with brain metastasis usually await a poor prognosis. Even with the ongoing development of novel targeted therapies, a major impediment in the treatment of brain metastasis is delivering of drugs across the blood-brain/tumor barrier. Different strategies to accomplish temporary opening of the heterogenous blood-brain barrier have been described. Here, we report on a synthetic peptide, K16ApoE, which is able to open the blood-brain barrier for improved drug-delivery in a non-permanent manner. We carried out extensive dynamic contrast enhanced magnetic resonance imaging experiments to study the ability of the peptide to open the blood-brain barrier in healthy mice. We further performed dynamic positron emission/computer tomography, with F18-labeled albumin and IgG to validate an open blood-brain barrier after co-injecting with K16ApoE. Further, we studied the effects of the peptide on cells and tissue in vitro and in vivo. The biodistribution of the peptide was studied in healthy mice by labeling I-125 to the imidazole ring of histidine in K16ApoE and tracking the peptide in plasma and tissue. We also conducted a treatment study on BRAFV600Emutant brain metastases, where the treatment groups received K16ApoE before a BRAF inhibitor was administered, BRAF inhibitor only, K16ApoE only or vehicle. We found a peptide-induced therapeutic window at approximately 30 minutes using dynamic contrast enhanced magnetic resonance imaging. The dynamic positron emission/computer tomography showed cerebral uptake of albumin (∼67 kDa) and IgG (∼150 kDa) in healthy mice with a presumed intact blood-brain barrier. Further, we identified lysis of cells treated with K16ApoE in addition to in part endocytosis-mediated peptide uptake. In vitro blood-brain barrier modeling demonstrated endothelial and astrocyte cell layer regrowth within approximately three and 15 hours, respectively, after treatment with the peptide. We observed a significant treatment effect of co-injecting the peptide with a BRAF inhibitor on BRAF mutated brain metastases.
QOLP-23. PALLIATIVE CARE AND END OF LIFE HEALTHCARE UTILIZATION IN PATIENTS WITH INCURABLE PRIMARY MALIGNANT BRAIN TUMORS
Authors: Sunil Bhatt, Areej El-Jawahri, Ryan Nipp, Tracy Batchelor, Jennifer Temel, Deborah Forst
Journal: Neuro-Oncology (2018)

Patients with primary malignant brain tumors (PMBT) experience high symptom burden and mortality. However, their healthcare utilization at the end of life, including palliative care utilization, has not been well studied. We conducted a single-center, retrospective analysis of deceased patients diagnosed with PMBT between 1/1/12 and 8/31/15. We assessed healthcare utilization including hospitalizations, palliative care usage and hospice enrollment. We identified 200 patients with incurable PMBT within the above timeframe. The majority of patients (86.0%, 171/200) had a diagnosis of glioblastoma. Most patients were white (185/200, 93.0%), non-Hispanic (189/200, 95.5%), and male (117/200, 59.0%). Median survival was 13.8 months. When excluding hospitalizations for planned procedures or chemotherapy, the median number of hospitalizations was 2 (range 0–9). In the last 30 days of life, 61/200 patients (30.5%) were hospitalized. Notably, only 63/200 (31.5%) patients ever received a palliative care consultation. The majority of these patients (39/63, 61.9%) were seen by palliative care only as inpatients. Of those seen by palliative care, only 19/63 (30.2%) had their first contact in the outpatient setting. The median time from first palliative care consultation to death was 53 days (range 0–981) and from first inpatient consultation to death was 32 days (range 0–354). Most patients were enrolled in hospice prior to death (154/200, 77.0%), with a median length of stay in hospice of 25 days (range 0–405). The majority of patients (112/200, 56.0%) died at home, 6.5% (13/200) died in the hospital, while 29.5% (59/200) died in a skilled nursing or hospice facility. CONCLUSIONS: Despite the known poor prognosis in patients with PMBT, palliative care is used infrequently, late in the disease course and typically initiated only in the inpatient setting. As such, there is a need to develop and study interventions to ensure timely outpatient palliative care referral in this population.
High performance capillary electrophoresis (HPCE) as a powerful tool to study overall genomic changes in DNA methylation, CpG islands, repeat sequences, histone acetylation and histone methylation in cancer
Authors: Mario F. Fraga, Esteban Ballestar, Ana Villar-Garea, Manel Esteller
Journal: Cancer Research (2004)

4992  The abnormal functioning of the epigenetic machinery is one of the most important molecular mechanisms involved in human cancer. Classically, the most studied epigenetic alterations are those occurring at the promoter region of CpG islands of tumor suppressor genes that, may became hypermethylated at the DNA and hypoacetylated and hypermethylated at the tail of the surrounding histones. Both processes are associated with gene silencing and they are one of the causes of the transcriptional repression of tumor suppressor genes in cancer. With the aim of simplifying and unifying the methods currently used to analyze global epigenetic variations at the genomic DNA and histones (mainly based on HPLC and Western Blot techniques), we present here an integrated methodology based on high performance capillary electrophoresis (HPCE). HPCE allows the quantification of the overall levels of genomic DNA methylation using a minimal amount of starting material. We have gone a step further and, coupling the HPCE technology with enzymatic digestions and chromatographic DNA separation, we are also able to determine global DNA methylation levels in fractions of the genome such as CpG islands or particular repeat sequences. Using this approach we have studied the different effects induced by knocking-out the DNA methyltransferases. Finally, HPCE showed to be a versatile tool to determine changes of histone modifications (the “histone code”). We have optimized the method to determine the acetylation and methylation content of histones H3 and H4. We have used this technology to analysis tumor tissues versus normal counterparts and in vitro models with defects in histone deacetylase, histones acetyltransferases and histone methyltransferases. Finally, the described HPCE method were also successfully exploited not only in monitoring the effect of DNA demethylating drugs and inhibitors of histone deacetylases in cancer cell lines, but also demonstrated its value to detect the biological effect of these antitumoral drugs in the blood, opening a new avenue for the follow-up of clinical trials using these pharmacological agents.
TMIC-29. REPROGRAMMING BONE MARROW OF TUMOR-BEARING HOSTS FOR GLIOMA IMMUNOTHERAPY
Authors: Tyler Wildes, Bayli DiVita, Adam Grippin, Kyle Dyson, Catherine Flores, Duane Mitchell
Journal: Neuro-Oncology (2018)

We recently demonstrated that hematopoietic stem and progenitor cell (HSC) transfer during adoptive T cell immunotherapy (ACT) for malignant brain tumors facilitates extended survival and long-term cures. HSCs migrated to tumors and used T cell-released IFN-g to differentiate into dendritic cells (DCs). In those studies, we transferred syngeneic HSCs from naïve hosts that were not endemic to the tumor-bearing hosts, unlike the clinical paradigm of autologous transfers. In peripheral cancers, HSCs of tumor-bearing hosts (TB HSCs) possess considerable immunosuppressive potential. We therefore evaluated the immunologic function of HSCs from naïve and tumor-bearing hosts to determine if malignant gliomas affect the immune-potentiating function of HSCs. We used treatment-resistant intracranial gliomas KR158B and GL261 to generate TB HSCs that were isolated from the bone marrow. We then performed in vitro HSC culture experiments alone and with activated T cell supernatants to study HSC differentiation by flow cytometry. Intravenous transfers were used to study HSC differentiation in brain tumors as well as survival benefit during ACT. Culturing naïve or TB HSCs led to differentiation into 30% or 60% myeloid-derived suppressor cells (MDSCs; CD11b+Ly-6G/6C+), respectively. However, when cultured in activated T cell supernatants containing IFN-g, both HSC types differentiated into 30% MDSCs and 80% MHCII+ antigen-presenting cells. We then determined that TB HSCs express more IFN-gR than naïve HSCs including 40% more IFN-gR1 and 90% more IFN-gR2 on DC progenitors. In vivo, ACT rescued intratumoral TB HSC differentiation, prolonged median survival, and led to long-term cures. While gliomas exert an immunosuppressive pressure on TB HSCs, ACT can reprogram TB HSC differentiation into functional antigen-presenting cells. A phase I trial evaluating the impact of HSC transfer on adoptive immunotherapy in pediatric high-grade gliomas is underway at our center (ACTION; clinicaltrials.gov NCT03334305).
Use of High-Sensitivity Cardiac Troponin for the Exclusion of Inducible Myocardial Ischemia
Authors: Muhammad Hammadah, Jeong Hwan Kim, Ayman Samman Tahhan, Bryan Kindya, Chang Liu, Yi-An Ko, Ibhar Al Mheid, Kobina Wilmot, Ronnie Ramadan, Ayman Alkhoder, Fahad Choudhary, Mohamad Mazen Gafeer, Naser Abdelhadi, Pratik Pimple, Pratik Sandesara, Bruno B. Lima, Amit J. Shah, Laura Ward, Michael Kutner, J. Douglas Bremner, David S. Sheps, Paolo Raggi, Laurence S. Sperling, Viola Vaccarino, Arshed A. Quyyumi
Journal: Annals of Internal Medicine (2018)

Background: Many patients with coronary artery disease (CAD) are routinely referred for surveillance stress testing despite recommendations against it. Objective: To determine whether low levels of resting high-sensitivity cardiac troponin I (hs-cTnI) can identify persons without inducible myocardial ischemia. Design: Observational study. Setting: A university-affiliated hospital network. Patients: Persons with stable CAD: 589 in the derivation group and 118 in the validation cohort. Measurements: Presence of inducible myocardial ischemia was determined by myocardial perfusion imaging with technetium-99m single-photon emission computed tomography during either treadmill or pharmacologic stress testing. Resting plasma hs-cTnI was measured within 1 week of the stress test, and the negative predictive value (NPV) for inducible ischemia was calculated. The derivation cohort was followed for 3 years for incident cardiovascular death and myocardial infarction. Results: In the derivation cohort, 10 of 101 patients with an hs-cTnI level below 2.5 pg/mL had inducible myocardial ischemia (NPV, 90% [95% CI, 83% to 95%]) and 3 of 101 had inducible ischemia involving at least 10% of the myocardium (NPV, 97% [CI, 92% to 99%]). In the validation cohort, 4 of 32 patients with an hs-cTnI level below 2.5 pg/mL had inducible ischemia (NPV, 88% [CI, 71% to 96%]) and 2 of 32 had ischemia of 10% or greater (NPV, 94% [CI, 79% to 99%]). After a median follow-up of 3 years in the derivation cohort, no adverse events occurred in patients with an hs-cTnI level below 2.5 pg/mL, compared with 33 (7%) cardiovascular deaths or incident myocardial infarctions among those with an hs-cTnI level of 2.5 pg/mL or greater. Limitation: The data may not be applicable to a population without known CAD or to persons with unstable angina, and the modest sample sizes warrant further validation in a larger cohort. Conclusion: Very low hs-cTnI levels may be useful in excluding inducible myocardial ischemia in patients with stable CAD. Primary Funding Source: National Institutes of Health.
TMOD-25. MODELING IDH1-MUTATED GLIOMAS: GENERATION, CHARACTERIZATION AND THERAPEUTIC SENSITIVITIES OF SEVEN PATIENT-DERIVED IDH1-MUTANT GLIOMA CELL LINES
Authors: Cassandra Verheul, Trisha Kers, Mariëlle Van Der Kaaij, Tessa Pierson, Ya Gao, Clemens Dirven, Eduard Struys, Gajja Salomons, Sieger Leenstra, Pim French, Martine Lamfers
Journal: Neuro-Oncology (2018)

In spite of significant attention IDH mutations have attracted in glioma research, in vitro model systems with endogenous IDH mutations remain scarce. Development of these models is crucial not only for unraveling the molecular mechanisms that contribute to this disease entity, but especially for the development of new therapeutic interventions. Fresh glioma tissue was obtained directly from the operating theater, dissociated and cultured under serum-free conditions. The presence of IDH mutations was verified at multiple passages using Sanger sequencing. D2-HG levels were measured through mass spectrometry. Cell proliferation was assessed through cell counting, cell viability was measured with an ATP-based viability assay. Drug screens were carried out with an FDA-approved Oncology Drugs Set from the NIH and multiple IDH mutant-specific inhibitors. Over 800 consecutive low grade and high grade glioma samples were processed for cell culture. From seven tumors one or more successful IDH mutant cell cultures were established that maintain the mutation in culture for at least five passages. All cultures were derived from astrocytic tumors. From one patient both the primary grade II astrocytoma and recurrent grade IV glioblastoma formed successful IDH-mutant cell lines. IDH-mutant specific inhibitors showed modest effects on cell viability, indicating limited dependence on D2-HG for growth. Drug screening revealed a subset of compounds that decrease viability at clinically-feasible drug concentrations which warrant further investigation. Whole exome sequencing in parallel with matched fresh-frozen tumor tissue, as well as RNA sequencing analyses are underway. We established a set of cell cultures derived from seven IDH mutant gliomas and characterized these on both genetic and transcriptional levels, and investigated drug sensitivity and D2-HG dependence. This unique set can be utilized to investigate novel therapeutic strategies.
MNGI-02. SUBCENTIMETER MENINGIOMAS – IS IT OKAY TO IGNORE?
Authors: Carlen Yuen, Laura Castillo-Saavedra, Andrew Wilmington, Matthew Walker, David Kamson
Journal: Neuro-Oncology (2018)

Meningiomas are among the most common incidental neuroimaging findings. Although most are indolent, a subgroup of meningiomas will eventually warrant clinical intervention. While larger diameters (e.g. ≥2.5cm) predict more aggressive behavior, there is a paucity of data regarding how much surveillance smaller meningiomas require if any. PURPOSE: To assess radiographic features of subcentimeter meningiomas that may predict future progression. We included asymptomatic treatment naïve patients with subcentimeter probable meningiomas who had ≥6 months of MRI follow-up. Progression was defined as reaching the 1cm threshold or becoming symptomatic. Imaging characteristics such as presence of calcification, perilesional edema, T2-weighted intensity were assessed in relationship to tendency to progress via log-rank. Thirty-nine patients (mean age 62y, 34F) were identified, who had a total follow-up of 251 years. Twenty-four patients (60%) remained subcentimeter by the end of follow-up. Median time to reach 1cm was 3.0 years for the remaining 15 patients. Only 2 enlarged to 1.5cm, a 69-year-old female who reached this size after 4.5 years and a plateaud on subsequent scans. The other was a 71-year-old male whose tumor doubled about every 3 years, leading to resection after 7 years at 33mm. He harbored a grade 2 meningioma. None of the patients became symptomatic during the follow-up period. None of the patient’s lesions had peritumoral edema. T2W intensity did not predict progression. In contrast, only 1 patient with a calcified meningioma reached 1cm. Calcification predicted slower progression (12.1 vs 6.8 years, log-rank p=0.03). Our data corroborates that most subcentimeter meningiomas grow extremely slowly. A single scan confirming calcification in the tumor may further support this growth pattern. However, repeated imaging seems necessary to identify exponential growth pattern, which is associated with higher grade meningiomas that can still present in this population.
NIMG-07. DEEP LEARNING DETECTS DIFFERENCES IN THE MRIs OF MALE AND FEMALE GLIOMAS
Authors: Kyle Singleton, Joseph Mitchell, Sara Ranjbar, Konstantinos Kamnitsas, Scott Whitmire, Kamala Clark-Swanson, Cassandra Rickertsen, Joshua Rubin, Ben Glocker, Leland Hu, Kristin Swanson
Journal: Neuro-Oncology (2018)

While a growing body of research on the intrinsic biological differences between male and female tumors and their environments continues to evolve, few deep learning techniques have been trained with a sex-specific focus. To investigate the influence of sex differences on automated tumor segmentation, a set of Male and Female 3D deep convolutional neural networks were trained and evaluated (MaleDNN and FemaleDNN). A balanced data set was obtained from our brain tumor database of 518 cases with known sex, pretreatment T1GD and FLAIR MRI, and at least one brain tumor segmentation. Cases were split by sex to create training cohorts of 200 male and female cases to train the MaleDNN and FemaleDNN. A set of 59 unseen test cases for each sex were reserved for evaluation. Both networks were used to segment tumor volumes from male and female test cases. Whole-tumor Dice coefficients (1=perfect overlap, 0=no overlap) were calculated by comparing network segmentations against segmentations from trained measurers. The MaleDNN had higher overall performance on all cases (Dice male=0.8416; female=0.7800) compared to the FemaleDNN (Dice male=0.8269, female=0.7639). The difference in performance between networks was significant for male tumors (p=0.0466), but not female tumors (p=0.1872). Both networks performed better on male tumors. Average dice scores were significantly lower for the MaleDNN (Dice decrease=0.0616, p=0.0273) and FemaleDNN (Dice decrease=0.629, p=0.0422) when evaluating female tumors. DISCUSSION: It was anticipated that the MaleDNN and FemaleDNN would have highest performance on test cases from the same sex. However, the FemaleDNN performed better on males than females and the MaleDNN had comparable performance for female tumors. The significant differences between these sex-specific deep neural networks indicate that male and female gliomas differ on imaging and that female tumors are more difficult to segment at initial presentation.
Abstract 10300: Crosstalk Between GATA4 and Mitochondria During Cardiomyocyte Differentiation Upon Exposure to Tyrosine Kinase Inhibitors
Authors: Qing Liu, Haodi Wu, Mingtao Zhao, Chao Jiang, Anil M Narasimha, Kevin Van Bortle, Baoqing Zhao, Joseph C Wu, Michael P Snyder
Journal: Circulation (2018)

Introduction: Tyrosine kinase inhibitors (TKIs) are known to induce cardiotoxicity and mitochondrial dysfunction. TKIs can cross the placenta, posing high risks for congenital heart defects. Mitoch...