tbuckley/cabot-search huggingface dataset:
TMIC-21. TARGETING INVADOPODIA TO BLOCK IONIZING RADIATION-INDUCED GLIOBLASTOMA CELL INVASION
Authors: Lisa Decotret, Kevin Bennewith
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Glioblastoma multiforme (GBM) is a highly heterogeneous and aggressive brain tumour that is considered incurable. The majority of GBM patients have a median survival of 15 months despite undergoing extensive treatment. The principal reason for poor outcome is a high rate of recurrence, often due to the tumours cells escaping therapy by infiltrating into the surrounding healthy brain tissue. Previous work from our lab suggests tumour cells that survive radiation therapy (RT) exhibit a more aggressively metastatic phenotype. We hypothesize that RT may increase GBM cell invasion by promoting the activity of invadopodia. Invadopodia are protrusions of the plasma membrane that secrete matrix metalloproteinases to degrade surrounding tissue. Further understanding of the mechanisms by which RT regulates invadopodial biology may lead to new therapeutic strategies to slow or halt the invasion of GBM cells and extend the lives of patients. RESULTS Three human GBM cell lines were exposed to 0, 2, or 5 Gy of ionizing radiation (IR) prior to quantification of cell viability by clonogenic survival assays. Invasion was investigated using a Transwell Matrigel Invasion Assay 48 hours post-IR. Exposure to 2 Gy IR increased invasion of LN229 and U87-MG cells but not LN18 cells. These data suggest that clinically relevant levels of radiation (2 Gy) increases the invasiveness of a subset of GBM cells in vitro. We are currently analyzing proteomic changes in LN229, U87-MG, and LN18 cells post-IR to identify novel drivers of IR-induced GBM cell invasion. Future work will involve genetically or pharmacologically inhibiting the proteins identified via mass spectrometry to determine their role in therapy induced invadopodia-mediated GBM cell invasion. SIGNIFICANCE: Recent evidence suggests tumour cells that survive RT exhibit a more aggressive phenotype. Identifying novel therapeutic targets to limit IR-induced GBM invasion may help to increasing the efficacy of current brain cancer therapy.
Loss of Heterozygosity of FLT3-ITD Is Common in Acute Myeloid Leukemia and May be a More Consistent Prognostic Marker Than FLT3-ITD Allele Frequency
Authors: Eric A. Severson, Ethan S. Sokol, Russell Madison, Daniel Duncan, Amanda Hemmerich, Claire Edgerly, Richard Huang, Nicholas Britt, Jo-Anne Vergilio, Julia A Elvin, Prasanth Reddy, Pratheesh Sathyan, Brian Alexander, Jeffrey S. Ross, Siraj M Ali, Shakti H. Ramkissoon
Journal: Blood (2019)
RDNA-03. AUTOPHAGY AS A NOVEL THERAPEUTIC TARGET IN MUTANT IDH1 GLIOMAS
Authors: Felipe Nunez, Maria Garcia-Fabiani, Padma Kadiyala, Hanna Hong, Andrea Comba, Costas Lyssiotis, Shi-Yuan Cheng, Pedro Lowenstein, Maria Castro
Journal: Neuro-Oncology (2019)

Abstract Mutated Isocitrate dehydrogenase 1 (IDH1R132H; mIDH1) is found in 50% of all adult gliomas and in 80% of lower-grade gliomas. IDH1R132H promotes 2-hydroxyglutarate production which inhibits histone and DNA demethylases, inducing epigenetic reprogramming of the tumor transcriptome. We recently demonstrated that epigenetic reprogramming enhances DNA-damage response and confers radioresistance in mIDH1 glioma, harboring p53 and ATRX loss. Furthermore, several studies indicate that IDH1R132H triggers cellular metabolism reprogramming. In this study, RNA-seq data revealed that mIDH1 glioma neurospheres (mIDH1-NS) have downregulated gene ontologies related to mitochondrial metabolism. Analysis of mitochondrial and glycolytic activity, using a Seahorse Analyzer, showed that mIDH1-NS have decreased levels of oxygen consumption and extracellular acidification rates, characteristic of quiescent state. Nevertheless, mIDH1 glioma cells can grow and generate tumors, suggesting that they might maintain self-renewal via autophagy. To investigate this hypothesis, we studied autophagy in wild-type and mIDH1 glioma cells analyzing LC3 conversion, p62 expression, and ULK1 protein phosphorylation. Mouse and human mIDH1 glioma cells exhibited increased expression of pULK1-S555, enhanced conversion of LC3I to LC3II, and decreased expression of p62, indicating that mIDH1 cells have an augmented autophagy. Also, key proteins involved in autophagy, including MST4 and UVRAG, are upregulated in mIDH1-NS. We also studied autophagy flux using LC3-mCherry-GFP reporter to identify LC3 recruitment at the autophagosome membranes and the autolysosome activity. Our results showed that mIDH1 cells have increased LC3 recruitment and enhanced autolysosome activity. Interestingly, autophagy has been related with glioma radioresistance. In our study, mouse and human mIDH1 glioma cells are sensitive to autophagy inhibition. In addition, autophagy inhibition restored radiosensitivity in mouse and human mIDH1 glioma cells, and in our mIDH1 glioma model, enhancing median survival compared with radiation alone. In conclusion, our results indicate that mIDH1 glioma cells maintain self-renewal via activation of autophagy, which represents a novel therapeutic target.
NIMG-41. RAPID AND ACCURATE CREATION OF PATIENT-SPECIFIC COMPUTATIONAL MODELS FOR GBM PATIENTS RECEIVING OPTUNE THERAPY WITH CONVENTIONAL IMAGING (T1w/PD)
Authors: Cornelia Wenger, Hadas Sara Hershkovich, Catherine Tempel-Brami, Moshe Giladi, Ze’ev Bomzon
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND For understanding the electric field distributions in glioblastoma (GBM) patients receiving OptuneTM therapy computational head models are employed. Accurate and fast model creation is of high importance to patient-specific treatment planning for improving efficacy, i.e., for maximizing intensity delivered to the tumor which depends on the tissues’ electric properties (EPs). Traditional model creation relies on time-consuming tissue segmentation and troublesome binary categorization of distinct tumor areas for assigning homogenous EPs. Here, we present a feasibility study of a new approach for fast model creation that uses individually created, heterogeneous EP maps from conventional MRIs. METHODS In a previous animal study we adapted water-content based electrical properties tomography (wEPT) for creating electrical conductivity (σ) maps at 200 kHz, the operating frequency of OptuneTM therapy. This adapted wEPT approach uses a T1w and a PD image to map the tissues’ water-content (WC) with a simple function. Subsequently the σ map is calculated as a function of WC based on Maxwell’s mixture theory. Three patients of the EF-14 trial were selected for calculating WC and σ maps. One patient was chosen to create a computational head model for simulating OptuneTM treatment. RESULTS The wEPT-estimated values of WC and σ in the healthy brain are accurate, homogenous and consistent among patients. Contrary, wEPT-estimates of WC and σ in tumor tissues are very heterogeneous and variable between patients. The patient-specific model with wEPT reveals more detailed current pathways during OptuneTM therapy. CONCLUSIONS The results emphasize the need for individual head model creation, since binary segmentation masks with pre-defined σ values are not recommended for the heterogeneous and variable tumor. The presented approach holds great promise for rapid creation of patient-specific computational models because only conventional MRIs are needed. However, this method needs to be validated and further established with analyzing more patients.
Low Serum Albumin Level Predicts the Risk of Azacitidine Early Discontinuation in MDS, CMML and 20-30% AML Patients- Results from the Polaza, the Retrospective Study of the Polish Adult Leukemia Group
Authors: Krzysztof Madry, Karol Lis, Andrzej Tukiendorf, Pawel Szwedyk, Katarzyna Kapelko-Słowik, Edyta Subocz, Janusz Halka, Aleksandra Golos, Wioletta Makowska, Anna Masternak, Anna Kopinska, Magdalena Czemerska, Sara Zawadzka-Leska, Patrycja Rusicka, Joanna Drozd-Sokolowska, Wiater Elżbieta, Hołojda Jadwiga, Bartłomiej Pogłódek, Piotr Centkowski, Anna Waszczuk-Gajda, Rafal Machowicz, Grzegorz W Basak, Jadwiga Dwilewicz-Trojaczek
Journal: Blood (2019)
Ancient Adaptive Lateral Gene Transfers in the Symbiotic Opalina–Blastocystis Stramenopile Lineage
Authors: Naoji Yubuki, Luis Javier Galindo, Guillaume Reboul, Purificación López-García, Matthew W Brown, Nicolas Pollet, David Moreira
Journal: Molecular Biology and Evolution (2019)

Lateral gene transfer is a very common process in bacterial and archaeal evolution, playing an important role in the adaptation to new environments. In eukaryotes, its role and frequency remain highly debated, although recent research supports that gene transfer from bacteria to diverse eukaryotes may be much more common than previously appreciated. However, most of this research focused on animals and the true phylogenetic and functional impact of bacterial genes in less-studied microbial eukaryotic groups remains largely unknown. Here, we have analyzed transcriptome data from the deep-branching stramenopile Opalinidae, common members of frog gut microbiomes, and distantly related to the well-known genus Blastocystis. Phylogenetic analyses suggest the early acquisition of several bacterial genes in a common ancestor of both lineages. Those lateral gene transfers most likely facilitated the adaptation of the free-living ancestor of the Opalinidae-Blastocystis symbiotic group to new niches in the oxygen-depleted animal gut environment.
Nicotinamide and Blood Sugar
Authors: S. Karani
Journal: BMJ (1947)

emergencies is seldom in the patient's best interest, and an obstetric emergency service should consist primarily of an ambulance equipped as an efficient resuscitation unit with unlimited blood at its disposal.The obstetrician can thus ensure that he is not forced by circumstances to perform opera- tions at home that would have a wider margin of safety in hospital.-Iam, etc., Birmingham.W. G. MILLS. Child-bearing and TuberculosisSIR,-Child-bearing and tuberculosis is still a subject which arouses strong feelings.We are grateful to your correspondents for their interest in our work and for some very appreciative remarks.We have endeavoured to make an objective judgment on this difficult subject, but we hope our figures are a sufficient basis for an opinion.It cannot be denied that the tuberculous disease in some patients becomes worse in association with pregnancy.This is a habit of tuberculous disease in nonpregnant women too, and in our experience equally common in both groups.We too wish to emphasize the importance of the environment of the tuberculous woman who has borne a child.Efficient
A heat-stable microparticle platform for oral micronutrient delivery
Authors: Aaron C. Anselmo, Xian Xu, Simone Buerkli, Yingying Zeng, Wen Tang, Kevin J. McHugh, Adam M. Behrens, Evan Rosenberg, Aranda R. Duan, James L. Sugarman, Jia Zhuang, Joe Collins, Xueguang Lu, Tyler Graf, Stephany Y. Tzeng, Sviatlana Rose, Sarah Acolatse, Thanh D. Nguyen, Xiao Le, Ana Sofia Guerra, Lisa E. Freed, Shelley B. Weinstock, Christopher B. Sears, Boris Nikolic, Lowell Wood, Philip A. Welkhoff, James D. Oxley, Diego Moretti, Michael B. Zimmermann, Robert Langer, Ana Jaklenec
Journal: Science Translational Medicine (2019)

Micronutrient deficiencies affect up to 2 billion people and are the leading cause of cognitive and physical disorders in the developing world. Food fortification is effective in treating micronutrient deficiencies; however, its global implementation has been limited by technical challenges in maintaining micronutrient stability during cooking and storage. We hypothesized that polymer-based encapsulation could address this and facilitate micronutrient absorption. We identified poly(butylmethacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methylmethacrylate) (1:2:1) (BMC) as a material with proven safety, offering stability in boiling water, rapid dissolution in gastric acid, and the ability to encapsulate distinct micronutrients. We encapsulated 11 micronutrients (iron; iodine; zinc; and vitamins A, B2, niacin, biotin, folic acid, B12, C, and D) and co-encapsulated up to 4 micronutrients. Encapsulation improved micronutrient stability against heat, light, moisture, and oxidation. Rodent studies confirmed rapid micronutrient release in the stomach and intestinal absorption. Bioavailability of iron from microparticles, compared to free iron, was lower in an initial human study. An organotypic human intestinal model revealed that increased iron loading and decreased polymer content would improve absorption. Using process development approaches capable of kilogram-scale synthesis, we increased iron loading more than 30-fold. Scaled batches tested in a follow-up human study exhibited up to 89% relative iron bioavailability compared to free iron. Collectively, these studies describe a broad approach for clinical translation of a heat-stable ingestible micronutrient delivery platform with the potential to improve micronutrient deficiency in the developing world. These approaches could potentially be applied toward clinical translation of other materials, such as natural polymers, for encapsulation and oral delivery of micronutrients.
Type I IFN Sensing by cDCs and CD4+ T Cell Help Are Both Requisite for Cross-Priming of AAV Capsid-Specific CD8+ T Cells
Authors: Jamie L. Shirley, Geoffrey D. Keeler, Alexandra Sherman, Irene Zolotukhin, David M. Markusic, Brad E. Hoffman, Laurence M. Morel, Mark A. Wallet, Cox Terhorst, Roland W. Herzog
Journal: Molecular Therapy (2019)

Adeno-associated virus (AAV) vectors are widely used in clinical gene therapy to correct genetic disease by in vivo gene transfer. Although the vectors are useful, in part because of their limited immunogenicity, immune responses directed at vector components have complicated applications in humans. These include, for instance, innate immune sensing of vector components by plasmacytoid dendritic cells (pDCs), which sense the vector DNA genome via Toll-like receptor 9. Adaptive immune responses employ antigen presentation by conventional dendritic cells (cDCs), which leads to cross-priming of capsid-specific CD8+ T cells. In this study, we sought to determine the mechanisms that promote licensing of cDCs, which is requisite for CD8+ T cell activation. Blockage of type 1 interferon (T1 IFN) signaling by monoclonal antibody therapy prevented cross-priming. Furthermore, experiments in cell-type-restricted knockout mice showed a specific requirement for the receptor for T1 IFN (IFNaR) in cDCs. In contrast, natural killer (NK) cells are not needed, indicating a direct rather than indirect effect of T1 IFN on cDCs. In addition, co-stimulation by CD4+ T cells via CD40-CD40L was required for cross-priming, and blockage of co-stimulation but not of T1 IFN additionally reduced antibody formation against capsid. These mechanistic insights inform the development of targeted immune interventions. Adeno-associated virus (AAV) vectors are widely used in clinical gene therapy to correct genetic disease by in vivo gene transfer. Although the vectors are useful, in part because of their limited immunogenicity, immune responses directed at vector components have complicated applications in humans. These include, for instance, innate immune sensing of vector components by plasmacytoid dendritic cells (pDCs), which sense the vector DNA genome via Toll-like receptor 9. Adaptive immune responses employ antigen presentation by conventional dendritic cells (cDCs), which leads to cross-priming of capsid-specific CD8+ T cells. In this study, we sought to determine the mechanisms that promote licensing of cDCs, which is requisite for CD8+ T cell activation. Blockage of type 1 interferon (T1 IFN) signaling by monoclonal antibody therapy prevented cross-priming. Furthermore, experiments in cell-type-restricted knockout mice showed a specific requirement for the receptor for T1 IFN (IFNaR) in cDCs. In contrast, natural killer (NK) cells are not needed, indicating a direct rather than indirect effect of T1 IFN on cDCs. In addition, co-stimulation by CD4+ T cells via CD40-CD40L was required for cross-priming, and blockage of co-stimulation but not of T1 IFN additionally reduced antibody formation against capsid. These mechanistic insights inform the development of targeted immune interventions.
RARE-46. MULTIMODAL TREATMENT OF TWO PATIENTS WITH DISSEMINATED JUVENILE PILOCYTIC ASTROCYTOMA
Authors: David Gass, Scott Wait, Chad Jacobsen
Journal: Neuro-Oncology (2019)

Abstract Juvenile Pilocytic Astrocytoma (JPA) is characterized by an indolent course with excellent survival if gross total resection is achieved. However, a rare subset of these low-grade neoplasms will disseminate. We present two patients with disseminated JPA and review the multimodal treatment approach required to manage this disease. CLINICAL IMPORTANCE: Disseminated JPA is a low-grade tumor with a chronic relapsing course. Radiation has previously been successful, however, the significant treatment volume needed for disease control is toxic in young children. Approaches using repeated surgical resections and multiple chemotherapy regiments to postpone time to radiation is becoming a standard approach. CLINICAL OUTCOME: Our first patient is a 7-year-old girl who had four progressions in her primary third ventricular mass in the last 2 years. Her disseminated disease has been stable throughout treatment. Initially, she underwent subtotal resection of third ventricular mass, which showed JPA, with negative BRAF v600e and negative BRAF fusion. After observation, she had her first progression and was treated with vincristine and carboplatin. Three months later she had her second progression and then treated with six cycles of selumetinib. Next, she received weekly vinblastine prior to her fourth progression. She then underwent gross total resection of her primary mass and has disease stability for five months. Our second patient is a 13-year-old male who had two progressions in last seven years. After initial subtotal resection, he had local progression and had a second resection of cerebellar mass. After four years of stability, the mass disseminated to his thoracolumbar spine. He underwent resection of spinal tumor which showed positive BRAF fusion and then treated with carboplatin and vincristine. He is showing mild response to treatment after 6 months of chemotherapy. CONCLUSION: We demonstrate that with using multimodal treatment with surgery and chemotherapy regiments, radiation for young children can be postponed.
Delay of Regulatory T Cell Reconstitution in Elderly Patients Increases the Frequency of Chronic Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Fumihito Tajima, Koji Adachi, Takaya Nishio, Toshio Kawatani, Junji Suzumiya
Journal: Blood (2019)
Extramedullary Relapses after Allogeneic Stem Cell Transplant (allo-SCT) in Adult Patients with Acute Lymphoblastic Leukemia (ALL)
Authors: Hiroaki Shimizu, Takuma Ishizaki, Nahoko Hatsumi, Satoru Takada, Akihiko Yokohama, Takayuki Saitoh, Toru Sakura, Hiroshi Handa
Journal: Blood (2019)
Comprehensive Analysis of Genotype and Prior Exposures in Therapy-Related Myeloid Neoplasms (t-MNs)
Authors: Veronica A Guerra, Yan Yuanqing, Joanne Hsu, Feng Wang, Mansour Alfayez, Kiyomi Morita, Xingzhi Song, Courtney D. DiNardo, Marina Y Konopleva, Gautam M. Borthakur, Guillermo Montalban Bravo, Jianhua Zhang, Latasha Little, Curtis Gumbs, Hagop M. Kantarjian, Guillermo Garcia-Manero, Andrew Futreal, Koichi Takahashi
Journal: Blood (2019)
Increase of tissue factor expression on the surface of peripheral monocytes of patients with chronic spontaneous urticaria
Authors: Ryo Saito, Yuhki Yanase, Akiko Kamegashira, Shunsuke Takahagi, Akio Tanaka, Kazue Uchida, Tomoko Kawaguchi, Michihiro Hide
Journal: Allergy (2019)

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Tuberculosis in the Family
Authors: F. J. Bentley
Journal: BMJ (1949)

B 365 which so often mark the beginning of active trouble raise first the blood sugar and subsequently the C.S.F.sugar level,' and should the latter alone be estimated an apparently normal read- ing may be obtained.But this correlated with a blood-sugar reading taken at the same time will give a ratio below the lower limits of normality should tuberculous meningitis be present.The level of C.S.F.chlorides is dependent on that of blood chlorides and is not, to my mind, of much diagnostic signifi- cance.If vomiting is a marked symptom, then they will both be lowered in the early stages, but I had several cases in which they approximated to normal even in the terminal stages of the disease.My results were published in detail in 1939.2In view of the number of letters which appear in these columns drawing the attention of more recent workers to already published results which they have apparently overlooked, might I put in a plea that more use should be made of the Quarterly Cumiulative Index Medicuis ?-I am, etc.,
Abstract 11982: Impact of Coronary Artery Disease Severity on Risk of Cardiovascular Events in Type 2 Diabetes Patients: A Swedish Nationwide Observational Study
Authors: Daniel Lindholm, David Erlinge, Lars Pål Hasvold, Bodil Svennblad, Johan Bodegard, Karolina A Sundell, Marcus Thuresson, Tomas Jernberg, Magnus Janzon
Journal: Circulation (2018)

Introduction: The impact of coronary artery disease (CAD) severity on short term risk of cardiovascular (CV) events in type 2 diabetes (T2D) patients is not well known. Hypothesis: In a nationwide ...
Joint American Academy of Dermatology–National Psoriasis Foundation guidelines of care for the management and treatment of psoriasis in pediatric patients
Authors: Alan Menter, Kelly M. Cordoro, Dawn M.R. Davis, Daniela Kroshinsky, Amy S. Paller, April W. Armstrong, Cody Connor, Boni E. Elewski, Joel M. Gelfand, Kenneth B. Gordon, Alice B. Gottlieb, Daniel H. Kaplan, Arthur Kavanaugh, Matthew Kiselica, Dario Kivelevitch, Neil J. Korman, Mark Lebwohl, Craig L. Leonardi, Jason Lichten, Henry W. Lim, Nehal N. Mehta, Sylvia L. Parra, Arun L. Pathy, Elizabeth A. Farley Prater, Reena N. Rupani, Michael Siegel, Benjamin Stoff, Bruce E. Strober, Emily B. Wong, Jashin J. Wu, Vidhya Hariharan, Craig A. Elmets
Journal: Journal of the American Academy of Dermatology (2019)
Comparing Gradings of Immune Effector Cells Toxicities: Application of Astct Consensus Grading System and Implications for Clinical Management
Authors: Martina Pennisi, Tania Jain, Elena Mead, Bianca Santomasso, Mari Lynne Silverberg, Yakup Batlevi, Roni Shouval, Molly A. Maloy, Sean M. Devlin, Connie Lee Batlevi, Renier J. Brentjens, Parastoo B. Dahi, Claudia Diamonte, Jessica Flynn, Sergio A Giralt, Elizabeth Halton, Maria Lia Palomba, Miriam Sanchez-Escamilla, Craig S. Sauter, Michael Scordo, Gunjan L. Shah, Jae H. Park, Miguel-Angel Perales
Journal: Blood (2019)
Potential Factors That Impact Lenalidomide/R-CHOP Efficacy in Previously Untreated Diffuse Large B-Cell Lymphoma in the ROBUST and ECOG-ACRIN 1412 Studies
Authors: Grzegorz Nowakowski, Annalisa Chiappella, Fangxin Hong, Randy D. Gascoyne, David W. Scott, William R. Macon, Rebecca L. King, Jennifer E. Amengual, Richard F. Little, John P. Leonard, Jonathan W. Friedberg, Lale Kostakoglu, Wojciech Jurczak, Kazuhito Yamamoto, Myron Czuczman, Jacqueline Russo, Krista Hudak, Jingshan Zhang, Steve Wade, Thomas E. Witzig, Brad S. Kahl, Umberto Vitolo
Journal: Blood (2019)
Efficacy and Safety of Apatinib in Relapsed or Refractory Diffuse Large B Cell Lymphoma: An Open-Label, Single-Arm, Prospective Study
Authors: Xinran Ma, Ling Li, Lei Zhang, Xin Li, Xiaorui Fu, Xinhua Wang, Jingjing Wu, Xudong Zhang, Xiaoyan Feng, Zhiyuan Zhou, Yu Chang, Zhaoming Li, Ken H. Young, Mingzhi Zhang
Journal: Blood (2019)