tbuckley/cabot-search huggingface dataset:
Abstract 63: Evaluation Of The Immune Dynamics Of Kawasaki Disease :For Opting Timing for Vaccination
Authors: kayoko Kobayashi, Shohei Ogata, Manabu Takanashi, Takashi Honda, Yoshihito Ogihara, Katunori Minoura, Masahiro Ishii
Journal: Circulation (2015)

Background: We investigated immune function in Kawasaki diseas(KD)patints during the acute phase , 1 month aftr onset , 6 months after onset and 9 months after onset. Methods: All patients treated with 2g/kg of Intravenous immunoglobulin (single IVIG) or 4g/kg of IVIG(additional IVIG). We enrolled 18 KD patients(age,4 to 90 months).IgG,IgM,IgA,IgD,B-cell surface immunoglobulin(Sm-Ig),CD3,CD4,CD8,CD20,CD56 were measured using flow cytometry;the lymphocyte transformation test(LTT)was also performed.In addition,migration of IVIG antibodies was assessed,and measles,rubella,mumps,and chickenpox antibodies were investigated using enzyme immunoassay(EIA). Results: IgG at 1 month after KD onset was significantly higher than before IVIG treatment. In addition, the number of the lymphocytes at 1 month after KD onset was higher than before IVIG treatment.. The valus for Sm-Ig IgM,Sm-Ig IgD,Sm-Ig κ,and Sm-Ig λ before IVIG treatment was higher than those at 1 month after KD onset. In addition, The valus for CD8 before IVIG treatment was higher than those at 1 month after KD onset. The values for CD3,CD4 before IVIG treatment was lower then those at 1 month after KD onset. The values for CD8 was higher at 1 month after KD onset. The levels of measles,rubella,mumps,and chickenpox antibodies were positive at 1 month after single IVIG treatment and these antibodies were negative at 6 months after single IVIG treatment. The levels of measles,rubella,mumps,and chickenpox antibodies were positive at 1 month after additional IVIG treatment. These antibodies were still positive in some of patient at 6 month after additional IVIG treatment,but negative at 9 months after additional IVIG treatment. Conclusions: Abnormal immune function at KD onset may improve at 1month after KD. onset.We can vaccinate children at least 2 month after KD onset. However it is recommended that live vaccines be deferred for at least 6 months following treatment with single IVIG ,and 9 months following treatment with additional IVIG.
INNV-03. EFFICACY AND LONG-TERM OUTCOMES IN THE MANAGEMENT OF LARGE BRAIN METASTASIS (≥ 4 CM3) USING 2-STAGED STEREOTACTIC RADIOSURGERY (2-SSRS): AN INTERNATIONAL STUDY
Authors: Yusuke Hori, Shoji Yomo, Wei Wei, Josue Avecillas-Chasin, Gene Barnett, John Suh, Samuel Chao, Erin Murphy, Alireza Mohammadi, Lilyana Angelov
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Stereotactic radiosurgery (SRS) for brain metastases results in time-to-local failure (TTLF) that significantly correlates with target volume and prescription dose. For large brain metastases (LBM), defined as ≥ 4 cm3, SRS monotherapy can result in &amp;lt; 40% local control (LC) rates. To overcome the TTLF limitations in the management of LBM, 2-staged SRS (2-SSRS) has demonstrated 6-month LC rates of 85–90%. This international multi-institutional study represents the largest series of patients with LBM managed with 2-SSRS. METHODS 181 patients with 218 LBM treated with 2-SSRS were retrospectively reviewed. Local failure (LF) was defined as ≥ 71.5% volumetric increase (equivalent to ≥ 20% increase in maximum diameter; RECIST criteria) from smallest volume date. Kaplan-Meier and log-rank tests were used to estimate and compare overall survival (OS) and TTLF; multivariable analysis was performed using Cox regression model. RESULTS Median age was 63 years (range: 29‒88), male sex was 50.3% with 34.8% of patients having non-small cell lung cancer. Median follow-up was 13.8 months (range:1.1‒49.4) and median OS was 14.6 months (95%CI: 12.6‒17.0). Median TTLF was 27.9 months (95%CI: 17.9‒NA) with a cumulative 6, 12 and 24-month LC of 91%, 81% and 71%, respectively. Using multivariable analysis, older age (≥ 65 years old; HR 1.58, 95%CI 1.06‒2.35, p=0.02) and larger total volume of concurrent small lesions (&amp;gt; 3 cm3; HR 2.05, 95%CI 1.25‒3.39, p=0.005) negatively impacted OS while younger age (&amp;lt; 65 years old; HR 2.60, 95%CI 1.26‒5.34, p=0.01) and RPA Class 3 (HR 3.10, 95%CI 1.26‒7.65, p=0.01) decreased TTLF. The number of concurrent LBM treated and total volume of the LBM were not significant factors. CONCLUSIONS This large multi-institutional dataset demonstrates excellent efficacy and long-term control of LBMs treated with 2-SSRS, which is independent of number or total volume of concurrent LBM.
NCOG-30. ADJUVANT VERSUS SALVAGE MANAGEMENT FOR IDH-MUTANT LOW GRADE GLIOMA
Authors: Martin Tom, Deborah Park, Surabhi Tewari, Wei Wei, Samuel Chao, Jennifer Yu, John Suh, Manmeet Ahluwalia, David Peereboom, Glen Stevens, Jaleh Fallah, Richard Prayson, Gene Barnett, Lilyana Angelov, Alireza Mohammadi, Erin Murphy
Journal: Neuro-Oncology (2020)

Abstract PURPOSE Timing of postoperative treatment in low-grade glioma (LGG) remains controversial. We sought to evaluate outcomes between adjuvant versus salvage management among patients with IDH-mutant molecularly-defined LGG. METHODS We analyzed a single-institutional database of adults diagnosed with LGG (grade II) with an IDH-mutation and either 1p19q-codeletion (oligodendroglioma) or 1p19q-intact (astrocytoma). Cox multivariable analysis (MVA) accounting for age, sex, and extent-of-resection, was used to compare adjuvant versus salvage approaches on overall survival (OS), progression free survival (PFS), next-intervention free survival (NIFS, defined as intervention subsequent to either adjuvant or salvage treatment), and malignant-transformation free survival (MTFS). Adjuvant treatment was defined as immediate postoperative treatment with radiotherapy (RT) and/or temozolomide (TMZ) prior to progression. Salvage management was defined as postoperative observation followed by surgery or RT and/or TMZ at progression. RESULTS Of 162 patients with oligodendroglioma, median follow-up was 8.5 years (range, 0.03-25.7). Adjuvant treatment was given to 97 (59.9%) patients, with 65 (40.1%) undergoing a salvage approach. On MVA, adjuvant treatment was not associated with OS, PFS, NIFS, or MTFS (p &amp;gt; 0.05 each). Among 82 patients with astrocytoma, median follow-up was 6.1 years (range, 0.5–25.7), and adjuvant treatment was administered to 41 (50.0%) patients, while 41 (50.0%) received salvage management. On MVA, adjuvant treatment was associated with improved PFS (HR 0.42, 95% CI 0.24-0.73, p &amp;lt; 0.001) and NIFS (HR 0.35, 95% CI 0.18–0.65, p &amp;lt; 0.001), but was not associated with OS or MTFS (p &amp;gt; 0.05 each). CONCLUSIONS Among grade II, IDH-mutant oligodendrogliomas, initial postoperative observation followed by salvage treatment at progression may be appropriate, as immediate adjuvant therapy was not associated improved outcomes. However, a more individualized postoperative management approach is required for grade II, IDH-mutant astrocytomas, as adjuvant treatment was associated with improved PFS and NIFS, but not OS. Further validation and prospective studies are required.
DDRE-08. POTENTIAL THERAPEUTIC EFFECTS OF ETOMOXIR IN COMBINATION WITH TEMOZOLOMIDE AGAINST HUMAN GLIOBLASTOMA TUMORSPHERES
Authors: Eui Hyun Kim, Jin-Kyoung Shim, Jungseong Park, Jieun Seon, Hyun Sil Kim, Ju Hyung Moon, Jong Hee Chang, Jong In Yook, Seok-Gu Kang
Journal: Neuro-Oncology (2020)

Abstract PURPOSE Glioblastoma (GBM) is the most common and lethal brain tumor with the median survival between 10 and 14 months. Since current treatments including surgical resection, radiation and chemotherapy fail to cure GBM, a new strategy to maximize the efficacy is needed. Here, etomoxir, an inhibitor of fatty acid oxidation, has been combined with temozolomide, a standard treatment for GBM, to examine its anti-tumor effects. Etomoxir has shown anti-cancer effects against human bladder, prostate cancers as well as GBM. We hypothesize that etomoxir inhibits fatty acid metabolism in cancer cell to suppress tumor progression while temozolomide causes cancer cell death. METHOD Four kinds of human GBM tumorspheres (TSs) were treated with temozolomide or etomoxir alone, or in combination with each other. Therapeutic effects of two drugs were evaluated by measuring cell viability, apoptosis, neurosphere formation, 3D-invasion using collagen/matrigel matrix, and LC/MS analysis of energy metabolism. Protein and mRNA expression profiles after drug treatment were evaluated by western blotting and RNA-sequencing. RESULTS Combination treatment of temozolomide and etomoxir significantly inhibited the cell viability, stemness, and invasiveness in GBM TSs. Expression levels of stemness-, invasiveness-associated markers were also decreased by the combined treatment. The combined treatment also significantly inhibited ATP production in TCA cycle. CONCLUSIONS Our findings suggest that combined treatment of etomoxir and TMZ may be therapeutically effective in the treatment GBM
EXTH-67. PHARMACOLOGIC INHIBITION OF LYSINE SPECIFIC DEMETHYLASE-1 (LSD1) AS AN ADJUVANT IMMUNE-SENSITIZATION STRATEGY IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Cavan Bailey, Tiara Collier, Verlene Henry, Michelle Monje, Javad Nazarian, Dean Lee, Linghua Wang, Vidya Gopalakrishnan, Oren Becher, Joya Chandra
Journal: Neuro-Oncology (2020)

Abstract Diffuse midline gliomas (DMG), including brainstem DIPG (diffuse intrinsic pontine glioma), are incurable pediatric brain tumors. Mutations in the H3 histone tail (H3.1/3.3-K27M) are a feature of DIPG, highlighting epigenetic aberrations in these tumors. Lysine specific demethylase-1 (LSD1), is an enzyme that acts upon mono and di-methylated histone H3K4/K9, and pharmacological inhibitors of its enzymatic and scaffolding domains are clinically viable. Patient-derived DIPG cell lines, orthotopic mouse models, and pediatric high-grade glioma (pHGG) datasets were used to evaluate effects of LSD1 inhibitors on cytotoxicity and immune gene expression. Because an unique immune signature was sen with enzymatic LSD1 inhibitors in DIPG cells in vitro, immune cell cytotoxicity was assessed in DIPG cells pre-treated with LSD1 inhibitors and informatics platforms were used to determine immune infiltration of pHGG. Selective cytotoxicity and an immunogenic gene expression signature was established in DIPG cell lines and in brainstem tumor-bearing mice using clinically-relevant LSD1 inhibitors. Pediatric HGG patient sequencing data demonstrated survival benefit using this LSD1-dependent gene expression signature. On-target binding of catalytic LSD1 inhibitors was confirmed in DIPG and pre-treatment of DIPG with these inhibitors increased lysis by natural killer (NK) cells. CIBERSORT analysis of patient data confirmed NK infiltration is beneficial to patient survival while CD8 T-cells are negatively prognostic. Catalytic LSD1 inhibitors are non-perturbing to NK cells while scaffolding LSD1 inhibitors are toxic to NK cells and do not induce the gene expression signature in DIPG cells. Treatment of orthotopic xenograft bearing DIPG mouse models with catalytic LSD1 inhibitors and NK cells showed a significant reduction in tumor burden. In summary, we find that LSD1 inhibition using catalytic inhibitors is both selectively cytotoxic and promotes a functional immune gene expression signature that is associated with NK cell killing, representing a therapeutic opportunity for pHGG.
Correlation of matrix‐related airway remodeling and bradykinin B1 receptor expression with fixed airflow obstruction in severe asthma
Authors: Francesca Bertolini, Vitina Carriero, Michela Bullone, Andrea Elio Sprio, Ilaria Defilippi, Valentina Sorbello, Federica Gani, Antonino Di Stefano, Fabio Luigi Massimo Ricciardolo
Journal: Allergy (2020)

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
The histone deacetylase inhibitor PCI-24781 impairs calcium influx and inhibits proliferation and metastasis in breast cancer
Authors: Tianshu Yang, Pei Wang, Xin Yin, Jingyao Zhang, Miaomiao Huo, Jie Gao, Gen Li, Xu Teng, Hefen Yu, Wei Huang, Yan Wang
Journal: Theranostics (2020)

Histone deacetylases (HDACs) are involved in key cellular processes and have been implicated in cancer. As such, compounds that target HDACs or drugs that target epigenetic markers may be potential candidates for cancer therapy. This study was therefore aimed to identify a potential epidrug with low toxicity and high efficiency as anti-tumor agents. Methods: We first screened an epigenetic small molecule inhibitor library to screen for an epidrug for breast cancer. The candidate was identified as PCI-24781 and was characterized for half maximal inhibitory concentration (IC50), for specificity to breast cancer cells, and for effects on carcinogenesis and metastatic properties of breast cancer cell lines in vitro. A series of in silico and in vitro analyses were further performed of PCI-24781 to identify and understand its target. Results: Screening of an epigenetic inhibitor library in MDA-MB-231 cells, a malignant cancer cell line, showed that PCI-24781 is a potential anti-tumor drug specific to breast cancer. Ca2+ related pathways were identified as a potential target of PCI-24781. Further analyses showed that PCI-24781 inhibited Gαq-PLCβ3-mediated calcium signaling by activating the expression of regulator of G-protein signaling 2 (RGS2) to reduce cell proliferation, metastasis, and differentiation, resulting in cell death in breast cancer. In addition, RGS2 depletion reversed anti-tumor effect and inhibition of calcium influx induced by PCI-24781 treatment in breast cancer cells. Conclusions: We have demonstrated that PCI-24781 is an effective anti-tumor therapeutic agent that targets calcium signaling by activating RGS2. This study also provides a novel perspective into the use of HDAC inhibitors for cancer therapy.
TAMI-08. A TALE OF TWO TELOMERE MAINTENANCE MECHANISMS: TERT EXPRESSION AND THE ALT PATHWAY INDUCE UNIQUE MRS-DETECTABLE METABOLIC REPROGRAMMING IN LOW-GRADE GLIOMAS
Authors: Pavithra Viswanath, Georgios Batsios, Anne Marie Gillespie, Hema Artee Luchman, Joseph Costello, Russell Pieper, Sabrina Ronen
Journal: Neuro-Oncology (2020)

Abstract Telomeres are nucleoprotein structures at chromosomal ends that shorten with cell division and constitute a natural barrier to proliferation. In order to proliferate indefinitely, all tumors require a telomere maintenance mechanism (TMM). Telomerase reverse transcriptase (TERT) expression is the TMM in most tumors, including low-grade oligodendrogliomas (LGOGs). In contrast, low-grade astrocytomas (LGAs) use the alternative lengthening of telomeres (ALT) pathway as their TMM. As molecular hallmarks of tumor proliferation, TMMs are attractive tumor biomarkers and therapeutic targets. Non-invasive imaging of TMM status will, therefore, allow assessment of tumor proliferation and treatment response. However, translational methods of imaging TMM status are lacking. Here, we show that TERT expression and the ALT pathway are associated with unique magnetic resonance spectroscopy (MRS)-detectable metabolic reprogramming in LGOGs and LGAs respectively. In genetically-engineered and patient-derived LGOG models, TERT expression is linked to elevated 1H-MRS-detectable NAD(P)/H, glutathione, aspartate and AXP. In contrast, the ALT pathway in LGAs is associated with higher α-ketoglutarate, glutamate, alanine and AXP. Importantly, elevated flux of hyperpolarized [1-13C]-alanine to pyruvate, which depends on α-ketoglutarate, is a non-invasive in vivo imaging biomarker of the ALT pathway in LGAs while elevated flux of hyperpolarized [1-13C]-alanine to lactate, which depends on NADH, is an imaging biomarker of TERT expression in LGOGs. Mechanistically, the ALT pathway in LGAs is linked to higher glutaminase (GLS), a key enzyme for α-ketoglutarate biosynthesis while TERT expression in LGOGs is associated with elevated nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme for NADH biosynthesis. Notably, TERT expression and the ALT pathway are linked to MRS-detectable metabolic reprogramming in LGOG and LGA patient biopsies, emphasizing the clinical validity of our observations. Collectively, we have identified unique metabolic signatures of TMM status that integrate critical oncogenic information with noninvasive imaging modalities that can improve diagnosis and treatment response monitoring for LGOG and LGA patients.
Silencing PCBP2 normalizes desmoplastic stroma and improves the antitumor activity of chemotherapy in pancreatic cancer
Authors: Yuanke Li, Zhen Zhao, Chien-Yu Lin, Yanli Liu, Kevin F Staveley-OCarroll, Guangfu Li, Kun Cheng
Journal: Theranostics (2020)

Rationale: Dense desmoplastic stroma is a fundamental characteristic of pancreatic ductal adenocarcinoma (PDAC) and comprises up to 80% of the tumor mass. Type I collagen is the major component of the extracellular matrix (ECM), which acts as a barrier to impede the delivery of drugs into the tumor microenvironment. While the strategy to deplete PDAC stroma has failed in clinical trials, normalization of the stroma to allow chemotherapy to kill the tumor cells in the "nest" could be a promising strategy for PDAC therapy. We hypothesize that silencing the poly(rC)-binding protein 2 (αCP2, encoded by the PCBP2 gene) leads to the destabilization and normalization of type I collagen in the PDAC stroma. Methods: We develop a micro-flow mixing method to fabricate a peptide-based core-stabilized PCBP2 siRNA nanocomplex to reverse the accumulation of type I collagen in PDAC tumor stroma. Various in vitro studies were performed to evaluate the silencing activity, cellular uptake, serum stability, and tumor penetration of the PCBP2 siRNA nanocomplex. We also investigated the penetration of small molecules in stroma-rich pancreatic cancer spheroids after the treatment with the PCBP2 siRNA nanocomplex. The anti-tumor activity of the PCBP2 siRNA nanocomplex and its combination with gemcitabine was evaluated in an orthotopic stroma-rich pancreatic cancer mouse model. Results: Silencing the PCBP2 gene using siRNA reverses the accumulation of type I collagen in human pancreatic stellate cells (PSCs) and mouse NIH 3T3 fibroblast cells. The siRNA nanocomplex significantly reduces ECM production and enhances drug penetration through desmoplastic tumor stroma. The combination of gemcitabine with the PCBP2 siRNA nanocomplex markedly suppresses the tumor progression in a desmoplastic PDAC orthotopic mouse model. Conclusion: This approach provides a new therapeutic avenue to improve the antitumor efficacy of PDAC therapies by normalizing tumor stroma using the PCBP2 siRNA nanocomplex.
MUC4 expression at the apical surfaces of endothelial cells: A new contributor to the cell surface properties of blood vessels
Authors: Jin Zhang, George Theodore, Mohammad Yasin, Coralie A. Carothers-Carraway, Kermit L. Carraway
Journal: Cancer Research (2004)

4943  MUC4 is a heterodimeric membrane mucin, composed of a mucin subunit ASGP-1 and a transmembrane subunit ASGP-2, which has been implicated in the protection of epithelial cell surfaces. Surprisingly, development and characterization of a new monoclonal antibody, called 1G8, against ASGP-2 demonstrated by immunohistochemistry the presence of MUC4 at the luminal surfaces of blood vessels of both normal tissues and tumors. Immunofluorescence and immunohistochemistry of airway tissues using three different antibodies showed the expression of similar levels of MUC4 in both epithelial and endothelial cells. This expression of MUC4 in endothelial cells was confirmed by immunoblotting with 1G8 in human umbilical vein endothelial cells (HUVECs), human iliac artery endothelial cells and human microvascular endothelial cells. MUC4 could be observed on HUVECs grown on either plastic or Matrigel. In the latter the endothelial cells form cords, and the MUC4 co-localizes with the endothelial marker von Willebrand factor III. Finally, MUC4 expression in the three types of endothelial cell lines was confirmed by reverse transcription-polymerase chain reaction. These results provide, to our knowledge, the first demonstration of a member of the MUC gene family and membrane mucin in blood vessels. As a luminal surface component the MUC4 is situated to contribute to the non-adhesive luminal surface and to act as an intrinsic protection and survival factor, as proposed for epithelia.
IMMU-35. TRANSCRIPTIONALLY DEFINED IMMUNE CONTEXTURE IN HUMAN GLIOMAS AT SINGLE-CELL RESOLUTION
Authors: Pravesh Gupta, Minghao Dang, Krishna Bojja, Tuan Tran M, Huma Shehwana, Carlos Kamiya-Matsuoka, Jianzhuo Li, Cynthia Kassab, Martina Ott, Joy Gumin, Atul Maheshwari, John de Groot, Frederick Lang, Veerakumar Balasubramaniyan, Nicholas Navin, Amy Heimberger, Linghua Wang, Krishna Bhat
Journal: Neuro-Oncology (2020)

Abstract The brain tumor immune microenvironment (TIME) continuously evolves during glioma progression and a comprehensive understanding of the glioma-centric immune cell repertoire beyond a priori cell types and/or states is uncharted. Consequently, we performed single-cell RNA-sequencing on ~123,000 tumor-derived immune cells from 17-pathologically stratified, IDH (isocitrate dehydrogenase)-differential primary, recurrent human gliomas, and non-glioma brains. Our analysis delineated predominant 34-myeloid cell clusters (~75%) over 28-lymphoid cell clusters (~25%) reflecting enormous heterogeneity within and across gliomas. The glioma immune diversity spanned functionally imprinted phagocytic, antigen-presenting, hypoxia, angiogenesis and, tumoricidal myeloid to classical cytotoxic lymphoid subpopulations. Specifically, IDH-mutant gliomas were enriched for brain-resident microglial subpopulations in contrast to enhanced bone barrow-derived infiltrates in IDH-wild type, especially in a recurrent setting. Microglia attrition in IDH-wild type -primary and -recurrent gliomas were concomitant with invading monocyte-derived cells with semblance to dendritic cell and macrophage/microglia like transcriptomic features. Additionally, microglial functional diversification was noted with disease severity and mostly converged to inflammatory states in IDH-wild type recurrent gliomas. Beyond dendritic cells, multiple antigen-presenting cellular states expanded with glioma severity especially in IDH-wild type primary and recurrent- gliomas. Furthermore, we noted differential microglia and dendritic cell inherent antigen presentation axis viz, osteopontin, and classical HLAs in IDH subtypes and, glioma-wide non-PD1 checkpoints associations in T cells like Galectin9 and Tim-3. As a general utility, our immune cell deconvolution approach with single-cell-matched bulk RNA sequencing data faithfully resolved 58-cell states which provides glioma specific immune reference for digital cytometry application to genomics datasets. Resultantly, we identified prognosticator immune cell-signatures from TCGA cohorts as one of many potential immune responsiveness applications of the curated signatures for basic and translational immune-genomics efforts. Thus, we not only provide an unprecedented insight of glioma TIME but also present an immune data resource that can be exploited to guide pragmatic glioma immunotherapy designs.
Is Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography Imaging Cost-effective in Prostate Cancer: An Analysis Informed by the proPSMA Trial
Authors: Rafael E. de Feria Cardet, Michael S. Hofman, Tatiana Segard, Jackie Yim, Scott Williams, Roslyn J. Francis, Mark Frydenberg, Nathan Lawrentschuk, Declan G. Murphy, Richard De Abreu Lourenco
Journal: European Urology (2020)