tbuckley/cabot-search huggingface dataset:
GENE-24. DNA METHYLATION SIGNATURES DETECTED IN A SERUM-BASED LIQUID BIOPSY DISTINGUISH FUNCTIONAL AND INVASIVENESS FEATURES IN PITUITARY ADENOMAS
Authors: Michael Wells, Thais Sarraf Sabedot, Karam Asmaro, Maritza Mosella, Tathiane Malta, Kevin Nelson, James Snyder, Ana deCarvalho, Abir Mukherjee, Arti Bahn, Adam Robin, Mark Rosenblum, Tom Mikkelsen, Laila Poisson, Ian Lee, Tobias Walbert, Steven Kalkanis, Jack Rock, Houtan Noushmehr, Dhananjay Chitale, Anavaleria Castro
Journal: Neuro-Oncology (2019)

Abstract Pituitary tumors are the second most common CNS neoplasia (~15%). Despite mostly benign and slow-growing, they may be nonfunctioning and invade surrounding structures resulting in significant comorbidities. Currently, classification of PT according to their risk for aggressiveness is mainly based on invasiveness detected by imaging methods and histopathological features which requires surgically resected tumor. Being able to detect molecular markers associated with tumor subtypes and behavior pre-surgically using minimally invasive approaches (blood draw) is desirable in these tumors and may help to address current diagnostic and therapeutic challenges. In tissue specimens, distinct DNA methylation patterns distinguish PT according to their functional status but their role in invasiveness is still unclear. We hypothesized that profiling cell-free DNA (cfDNA) released by PT into the bloodstream allow the identification of epigenetic markers associated with relevant clinicopathological features. Genome-wide methylome profile of paired serum cfDNA (EPIC array) and tissue from 13 patients with pituitary macroadenomas (9 males; median age: 62; 9 Nonfunctioning/4 functioning, 6 invasive/7 noninvasive) and 3 controls serum (patients with epilepsy). Unsupervised analysis of the serum methylome from patients harboring PT was distinct from controls and other diseases (hypopituitarism, glioma and colorectal cancer) and supervised analysis (Wilcoxon Rank-sum Test) identified significant differentially methylated probes (DMP) that segregated PT from control serum specimens. Nonfunctioning and invasive-specific DMPs identified in the serum also defined functional, and less prominently invasive status, in the tissue of an independent cohort of PT. This is the first study to show the feasibility to profile the serum methylome from patients with PT using cfDNA. In addition, we identified unique methylation signatures that distinguished PT according to functional and invasiveness subtypes. These results underpin the potential role of methylation profile and liquid biopsy as a noninvasive approach to assess clinically relevant molecular features in the serum of patients harboring PT.
A Phase I Study of IMGN632, a Novel CD123-Targeting Antibody-Drug Conjugate, in Patients with Relapsed/Refractory Acute Myeloid Leukemia, Blastic Plasmacytoid Dendritic Cell Neoplasm, and Other CD123-Positive Hematologic Malignancies
Authors: Naval G. Daver, Pau Montesinos, Daniel J. DeAngelo, Eunice S. Wang, Nikolaos Papadantonakis, Eric Deconinck, Harry P. Erba, Naveen Pemmaraju, Andrew A. Lane, David A. Rizzieri, Kendra L. Sweet, Giovanni Martinelli, Corrado Tarella, Elisabetta Todisco, Marina Y Konopleva, Callum M. Sloss, Kerry Culm-Merdek, Jiuzhou Wang, Kara E. Malcolm, Patrick A. Zweidler-McKay, Hagop M. Kantarjian
Journal: Blood (2019)
Selinexor-Containing Regimens for the Treatment of Patients with Multiple Myeloma Refractory to Chimeric Antigen Receptor T-Cell (CAR-T) Therapy
Authors: Ajai Chari, Dan T. Vogl, Sundar Jagannath, Jagoda K. Jasielec, Andrew DeCastro, TJ Unger, Jatin Shah, Andrzej Jakubowiak
Journal: Blood (2019)
Tandem CAR T Cells Targeting CD19 and CD22 Is a Safe and Highly Efficacious Treatment for Relapse/ Refractory ALL Patients
Authors: Xiaowen Tang, Liqing Kang, Wei Qi, Wei Cui, Haiping Dai, Zheng Li, Jia Yin, Changju Qu, Ting Xu, Xiaming Zhu, Lei Yu, Depei Wu
Journal: Blood (2019)
Abstract MP99: Cerebral Small Vessel Disease and the Epigenetic Clock: The Atherosclerosis Risk in Communities Study
Authors: Abhay Raina, Xiaoping Zhao, Jan Bressler, Rebecca F Gottesman, Megan L Grove, Weihua Guan, James S Pankow, Eric Boerwinkle, Thomas H Mosley, Myriam Fornage
Journal: Circulation (2016)

Cerebral small vessel disease (SVD) is one of the most common degenerative vessel disorders of the aging brain. White matter hyperintensities (WMH) on magnetic resonance imaging (MRI) are viewed as typical markers of SVD and are associated with an increased risk of stroke, dementia, and death. Advancing age is the strongest predictor of WMH prevalence and severity. Recent studies have developed a novel biomarker of aging, termed “epigenetic clock”, based on DNA methylation levels at specific sites across the genome, which are strongly correlated with chronological age. The deviation of the DNA methylation (DNAm)-predicted age from the chronological age, defined as “age acceleration”, is used as an index of an individual’s rate of aging. Here, we estimated blood DNAm age in African-Americans from the Atherosclerosis Risk in Communities (ARIC) study using two methodologies, and examined the cross-sectional association between WMH on MRI and measures of accelerated epigenetic aging. We hypothesized that DNAm age acceleration, defined as the residual value from the regression of the predicted DNAm age onto chronological age, is associated with greater WMH burden independently of chronological age and other known risk factors, including sex, body mass index, systolic blood pressure, hypertension, diabetes, and current smoking. DNA methylation was measured using the Illumina HM450 array on genomic DNA extracted from blood samples of African-American participants of the ARIC study. We estimated DNAm age using two published algorithms in 713 individuals aged 51-73 with both DNAm and brain MRI data. Linear regression models were used to estimate the association of the natural log-transformed WMH burden with each measure of age acceleration adjusting for covariates. Age acceleration was significantly associated with WMH burden and results were similar for both estimates of DNAm age. Each unit increase in WMH burden (on the log scale) was associated with a 1.2 and 1.3 year increase in DNAm age after accounting for chronological age and other known risk factors (P=0.01 and 0.004). Further adjustment for blood cell composition did not meaningfully change these results. In this population-based study of middle-aged to older African-American adults, we report evidence of an association between accelerated epigenetic aging of blood and increased WMH burden, independent of known risk factors, including chronologic age. Additional studies are ongoing to clarify whether DNAm age is simply a marker of the rate of aging or reflects biological mechanisms implicated in the aging of the cerebral white matter.
PATH-65. MOLECULAR SIGNATURE OF FAT1 RELATED MOLECULES IN GLIOMAS IN THE CONTEXT OF THE WHO 2016 CLASSIFICATION
Authors: Kunzang Chosdol, Manvi Arora, Nargis Malik, Prerana Jha, Jyotsna Singh, Ashish Suri, Subrata Sinha, Vaishali Suri
Journal: Neuro-Oncology (2019)

Abstract Glioblastoma (GBM, WHO grade-IV) being the most malignant and aggressive form of glioma remains a major clinical challenge, with an overall 5-year survival rate of only 9.8%. Till recently, glioma diagnosis and grading were solely dependent on the phenotypic and histological features. However, with the advancement in the understanding of the molecular biology of glioma several molecules have been identified. The importance of these molecular/genotypic features of the tumor became evident by the inclusion of these molecular features by World Health Organization (WHO) in 2016 in glioma sub-grouping. Our lab is focused on studying the role of FAT1 gene (human ortholog of Drosophila tumor suppressor gene, fat) in glioma biology and aggressiveness. We observed FAT1 gene to have an oncogenic role in glioma where it has been found to upregulate migration/invasion, inflammatory microenvironment of the tumors, HIF1α expression/activity in the tumor-cells under severe hypoxia and in regulating EMT/stemness properties of GBM-cells under hypoxia. Here, we have characterized the molecular relationship between FAT1 related molecules and known- molecular markers of glioma with the hope of identifying glioma subgroup with a molecular signature of clinical significance by (i) analyzing the expression correlation of FAT1 and FAT1 regulated pro-inflammatroy molecules like COX2, IL1b and IL6 with the known- molecular markers of glioma like p53, IDH1, MGMT, EGFR, TERT in low-grade (grade-II) and high-grade (grade-III/IV) gliomas (n=50) by real-time PCR, sequencing, immunohistochemistry and in-silico analysis of TCGA-GBM-data (ii) Analyzed the regulatory role of FAT1 on the above known markers by siRNA mediated knockdown of FAT1 in in-vitro cell-culture system and (iii) further analyzed the identified molecular signature for their correlation with the patients prognosis/survival in the follow up patients. We observed a novel molecular signature with significant correlation with patients’ clinical outcome. Therapeutic targetting of FAT1 may benefit patients with high FAT1 expressing tumors.
GENE-44. BRD4 DELETION LEADS TO CEREBELLAR DEFICITS AND ATAXIA
Authors: Nagi Ayad
Journal: Neuro-Oncology (2019)

Abstract Cerebellar neuronal progenitors undergo a series of divisions before irreversibly exiting the cell cycle and differentiating into neurons. Dysfunction of this process underlies many neurological diseases including ataxia and the most common pediatric brain tumor, medulloblastoma. To better define the pathways controlling the most abundant neuronal cells in the mammalian cerebellum, cerebellar granule cell progenitors (GCPs), we performed RNA-sequencing of GCPs exiting the cell cycle. Time-series modeling of GCP cell cycle exit identified downregulation of activity of the epigenetic reader protein Brd4. Brd4 binding to the Gli1 locus is controlled by Casein Kinase 1δ (CK1 δ-dependent phosphorylation during GCP proliferation, and decreases during GCP cell cycle exit. Importantly, conditional deletion of Brd4 in vivo in the developing cerebellum induces cerebellar morphological deficits and ataxia. These studies define an essential role for Brd4 in cerebellar granule cell neurogenesis and are critical for designing clinical trials utilizing Brd4 inhibitors in neurological indications.
Impact of Serum Immunoglobulin Subsets and Levels on Chronic Lymphocytic Leukemia Natural History: A Retrospective Multicentric Italian Experience
Authors: Luca Laurenti, Andrea Corbingi, Idanna Innocenti, Annamaria Tomasso, Raffaella Pasquale, Andrea Visentin, Marzia Varettoni, Francesco Autore, Francesca Morelli, Livio Trentin, Gianluigi Reda
Journal: Blood (2019)
TMIC-09. MULTIMODAL VISIBLE LIGHT OPTICAL COHERENCE MICROSCOPY AND FLUORESCENCE IMAGING OF GLIOBLASTOMA REGIONAL SAMPLES
Authors: Johanna Gesperger, Antonia Lichtenegger, Thomas Roetzer, Georg Widhalm, Barbara Kiesel, Adelheid Woehrer, Bernhard Baumann
Journal: Neuro-Oncology (2019)

Abstract Optical coherence tomography (OCT) is an imaging modality based on the inherent backscattering of light within different tissue types. OCT was introduced in the early 1990s and has since become a standard diagnostic tool in ophthalmology. Images can be acquired non-destructively, in real time and three dimensions at micrometer resolution. Only recently, OCT has been increasingly recognized in other fields such as neuroimaging. Here we present a multimodal imaging approach using a custom-built visible light optical coherence microscope (OCM) combined with a fluorescence imaging mode for the evaluation of different tumor compartments in glioblastoma (GB) samples retrieved during 5-aminolevulinic acid (5-ALA) fluorescence-guided surgery. 18 biopsies of ten GB patients were imaged using the visible light OCM system, providing the three-dimensional morphologic structure of the tissue on a cellular level (axial resolution in brain tissue 0.88 µm, penetration depth 100 µm). Attenuation coefficients, i.e., indicators for light penetration and scattering, were calculated for each sample. Tumor-specific contrast enhanced by 5-ALA was evaluated in co-registered images from the fluorescence channel. Samples were ultimately processed for histopathologic work-up and compared to OCM findings. Three different groups of biopsies could be defined based on quantitative 5-ALA fluorescence [normalized between 0 and 1], attenuation [mm-1] and histological H&amp;E stainings: tumor core (n=8; fluorescence [median ± standard deviation]=0.72±0.13, attenuation [median ± standard deviation]=3.9±0.66), infiltration zone (n=6; fluorescence=0.5±0.19, attenuation=4.4±0.5), and adjacent brain parenchyma (n=4; fluorescence=0.3±0.12, attenuation=5.0±0.79). Concurrent increase in fluorescence intensity and cell density was significantly associated with tissue malignancy (tumor core: 3849±1028 nuclei/mm²; brain parenchyma: 1364±236 nuclei/mm². p=0.024). Furthermore, a negative correlation between fluorescence and attenuation coefficient was detected (r=0.51, p=0.032). Aforementioned results suggest that this multimodal imaging setup is a promising approach for non-destructively investigating the three-dimensional morphologic structure at microscopic resolution whilst at the same time leveraging tumor-specific contrast through 5-ALA fluorescence.
Glutamylation of deubiquitinase BAP1 controls self-renewal of hematopoietic stem cells and hematopoiesis
Authors: Zhen Xiong, Pengyan Xia, Xiaoxiao Zhu, Jingjing Geng, Shuo Wang, Buqing Ye, Xiwen Qin, Yuan Qu, Luyun He, Dongdong Fan, Ying Du, Yong Tian, Zusen Fan
Journal: The Journal of Experimental Medicine (2019)

All hematopoietic lineages are derived from a limited pool of hematopoietic stem cells (HSCs). Although the mechanisms underlying HSC self-renewal have been extensively studied, little is known about the role of protein glutamylation and deglutamylation in hematopoiesis. Here, we show that carboxypeptidase CCP3 is most highly expressed in BM cells among CCP members. CCP3 deficiency impairs HSC self-renewal and hematopoiesis. Deubiquitinase BAP1 is a substrate for CCP3 in HSCs. BAP1 is glutamylated at Glu651 by TTLL5 and TTLL7, and BAP1-E651A mutation abrogates BAP1 glutamylation. BAP1 glutamylation accelerates its ubiquitination to trigger its degradation. CCP3 can remove glutamylation of BAP1 to promote its stability, which enhances Hoxa1 expression, leading to HSC self-renewal. Bap1E651A mice produce higher numbers of LT-HSCs and peripheral blood cells. Moreover, TTLL5 and TTLL7 deficiencies sustain BAP1 stability to promote HSC self-renewal and hematopoiesis. Therefore, glutamylation and deglutamylation of BAP1 modulate HSC self-renewal and hematopoiesis.
Burkitt’s Lymphoma Involving Multiple Hormone-Producing Organs on FDG PET/CT
Authors: Zhe Wen, Hongming Zhuang
Journal: Clinical Nuclear Medicine (2019)

Abstract Lymphoma involving many different organs can be occasionally observed. However, lymphoma involvement of multiple hormone-producing organs is rare. In this report, we described our FDG PET/CT findings in a 21-year-old man whose Burkitt's lymphoma involved not only lymph nodes, the spleen, the brain, and the bones, but also 4 organs in the endocrine system, including the thyroid, right adrenal, the pancreas, and the right testicle.
Wound Closure with Adhesive Tape
Authors: C. P. Monty, M. J. Tsapogas
Journal: BMJ (1963)

MEDCA JOUM"{A Scheme was launched on the whole country.without preliminary trials.Let us give the Area Health Board a trial.Keeping up with the Joneses may be distasteful or difficult for some, but if the exercise is for the good of the pro- fession as a whole, and the Health Service, it may be worth the endeavour.-I am, etc., G. MuRRAY JoNEs.Caerphilly.
HIV RNA, CD4+ Percentage, and Risk of Hepatocellular Carcinoma by Cirrhosis Status
Authors: Jessie Torgersen, Michael J Kallan, Dena M Carbonari, Lesley S Park, Rajni L Mehta, Kathryn D’Addeo, Janet P Tate, Joseph K Lim, Matthew Bidwell Goetz, Maria C Rodriguez-Barradas, Cynthia L Gibert, Norbert Bräu, Sheldon T Brown, Jason A Roy, Tamar H Taddei, Amy C Justice, Vincent Lo Re
Journal: JNCI Journal of the National Cancer Institute (2019)

Despite increasing incidence of hepatocellular carcinoma (HCC) among HIV-infected patients, it remains unclear if HIV-related factors contribute to development of HCC. We examined if higher or prolonged HIV viremia and lower CD4+ cell percentage were associated with HCC.We conducted a cohort study of HIV-infected individuals who had HIV RNA, CD4+, and CD8+ cell counts and percentages assessed in the Veterans Aging Cohort Study (1999-2015). HCC was ascertained using Veterans Health Administration cancer registries and electronic records. Cox regression was used to determine hazard ratios (HR, 95% confidence interval [CI]) of HCC associated with higher current HIV RNA, longer duration of detectable HIV viremia (≥500 copies/mL), and current CD4+ cell percentage less than 14%, adjusting for traditional HCC risk factors. Analyses were stratified by previously validated diagnoses of cirrhosis prior to start of follow-up.Among 35 659 HIV-infected patients, 302 (0.8%) developed HCC over 281 441 person-years (incidence rate = 107.3 per 100 000 person-years). Among patients without baseline cirrhosis, higher HIV RNA (HR = 1.25, 95% CI = 1.12 to 1.40, per 1.0 log10 copies/mL) and 12 or more months of detectable HIV (HR = 1.47, 95% CI = 1.02 to 2.11) were independently associated with higher risk of HCC. CD4+ percentage less than 14% was not associated with HCC in any model. Hepatitis C coinfection was a statistically significant predictor of HCC regardless of baseline cirrhosis status.Among HIV-infected patients without baseline cirrhosis, higher HIV RNA and longer duration of HIV viremia increased risk of HCC, independent of traditional HCC risk factors. This is the strongest evidence to date that HIV viremia contributes to risk of HCC in this group.
Evaluation of the Oral SYK Inhibitor Fostamatinib in Patients after Allogeneic Transplantation for Chronic Graft-Versus-Host Disease
Authors: William C. McManigle, Rachel A. DiCioccio, Sarah Anand, Zhiguo Li, Jonathan C Poe, Krista R. Nichols, Amy N. Suthers, Wei Jia, Kelly Corbet, Megan Covington, Julia Lloyd-Cowden, Richard D. Lopez, Gwynn D. Long, Mitchell E. Horwitz, Cristina Gasparetto, Anthony D. Sung, Nelson J. Chao, David A. Rizzieri, Stefanie Sarantopoulos
Journal: Blood (2019)
Retrospective Study of Incidence and Survival for Patients with Hematologic Malignancies Residing at the U.S./Mexico Border
Authors: Alfonso Enrique Bencomo, Andres J Rubio, Mayra Alejandra Gonzalez, Idaly Maria Olivas, Joshua Lara, Kiran Ghimire, Osvaldo Padilla, Angelica Padilla, Nawar Hakim, Attilio Orazi, Javier Corral, Alexander Philipovskiy, Sumit Gaur, Anna M. Eiring
Journal: Blood (2019)
TMIC-44. IL-1 ANTAGONIST ANAKINRA INHIBITS GLIOBLASTOMA PROLIFERATION BY ANTAGONIZING THE PROINFLAMMATORY MICROENVIRONMENT
Authors: David Effinger, Max Hübner, Tingting Wu, Niklas Thon, Friedrich-Wilhelm Kreth, Simone Kreth
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION The recombinant IL-1 receptor antagonist anakinra prevents binding of IL-1 to its receptor and blocks IL-1β-mediated proinflammatory signaling. It is currently used in the treatment of autoinflammatory diseases. As inflammation is a major driver of malignancy, we hypothesized that anakinra – by ameliorating the inflammatory tumor environment – might be capable to mitigate glioblastoma (GBM) progression. METHODS T98G GBM cells were cultivated with PBMC, separated by cell culture inserts with or without anakinra and incubated 48h in 5% O2 mimicking the GBM microenvironment. T-cells were obtained by magnetic bead isolation. mRNA expression levels were measured by quantitative Real-Time-PCR (qRT-PCR). Cytokine production was assessed by ELISA. Cell proliferation was analyzed by flow cytometric quantification of Ki-67 protein expression. Anakinra has been provided by Swedish Orphan Biovitrum AB (Sweden). Results are presented as mean±SEM, p-Values were calculated using Student’s t-test. RESULTS After administration of anakinra, mRNA expression levels of the inflammatory and proangiogenic genes IL-1β, COX-2, CCL2 and IL-8 were reduced in T98G (-64%±19.1%, -56.2%±21.3%, -87.1%±28.8%, -91.7%±27.2%, n=7, p&lt; 0.05). Surprisingly, no changes of these targets were detectable in PBMC. However, in T-cells, anakinra induced mRNA expression of Th2 transcription factor GATA3 and the antiinflammatory cytokines IL-4 and IL-10 (+6,7%±4,6%, +36,1%±22,9%, +69,1%32,8%, n=10, p&lt; 0.05). The expression of the protumorigenic genes IL-22, IL-17 as well as IFNγ was dramatically repressed (-63.2%±21.9%, -88.1%±21.7%, -85.6%±45.2%, n=10, p&lt; 0.05), protein secretion of IL-22 and IFNγ was strongly blocked (-36.3%±9.1%, -13.9%±0.5%, n=6, p&lt; 0.05). Importantly, treatment with anakinra markedly attenuated GBM cell proliferation (-20.1%±5%, n=4, p&lt; 0.05). CONCLUSION Anakinra indeed puts the brake on proinflammatory signaling pathways in GBM cells and simultaneously promotes a shift towards an anti-inflammatory T-cell phenotype. As a result, GBM proliferation is diminished. Hence, administration of anakinra might be an interesting and novel therapeutic approach to reduce Glioblastoma aggressiveness.
Long-term Risk of Recurrence in Surgically Treated Renal Cell Carcinoma: A Post Hoc Analysis of the Eastern Cooperative Oncology Group—American College of Radiology Imaging Network E2805 Trial Cohort
Authors: Marcus L. Jamil, Jacob Keeley, Akshay Sood, Deepansh Dalela, Sohrab Arora, James O. Peabody, Quoc-Dien Trinh, Mani Menon, Craig G. Rogers, Firas Abdollah
Journal: European Urology (2019)
Efficacy and Safety of Ibrutinib Use in Patients with Chronic Lymphocytic Leukemia in Real World Experiences: Results of a Prospective Multicenter Study
Authors: Anil Tombak, Funda Pepedil Tanrikulu, Salih Sertac Durusoy, Emel Gurkan, Emin Kaya, Elif G Umit, Irfan Yavasoglu, Özgür Mehtap, Burak Deveci, Mehmet Ali Ozcan, Hatice Terzi, Mufide Okay, Nilgun Sayinalp, Mehmet Yilmaz, Vahap Okan, Alperen Kizikli, Omer Ozcan, Güven Çetin, Sinan Demircioglu, Ismet Aydogdu, Guray Saydam, Eren arslan Davulcu, Gul Ilhan, Mehmet Ali Ucar, Gulsum Ozet, Seval Akpinar, Burhan Turgut, Ilhami Berber, Erdal Kurtoglu, Mehmet Sönmez, Derya Selim Batur, Rahsan Yildirim, Vildan Ozkocaman, Ahmet Kursat Gunes, Birsen Sahip, Sehmus Ertop, Meltem Akay, Abdulkadir Basturk, Mehmet Hilmi Dogu, Aydan Akdeniz, Ali Unal, Ahmet Seyhanli, Burhan Ferhanoglu
Journal: Blood (2019)