tbuckley/cabot-search huggingface dataset:
Abstract 12923: The Sustained Benefit of Short Term Treatment With Colchicine After Acute Myocardial Infarction
Authors: Koichiro Fujisue, Seigo Sugiyama, Koichi Sugamura, Hirofumi Kurokawa, Junichi Matsubara, Yasuhiro Izumiya, Koichi Kaikita, Seiji Hokimoto, Hisao Ogawa
Journal: Circulation (2016)

Background: In acute myocardial infarction (MI), acute inflammation and NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome are involved in cardiac damage, remodeling, and developing heart failure (HF). Several studies have reported that colchicine attenuated the infarct size and inflammation in MI. However, the sustained benefit of colchicine administration after MI on survival and cardiac function is unknown. We hypothesized that short-term treatment with colchicine could inhibit the cardiac inflammation and NLRP3 inflammasome, and improve survival and cardiac function during recovery phase of MI. Methods: Mice were induced MI by permanent ligation of the left anterior descending coronary artery. Mice randomly received 0.1 mg/kg/day colchicine or saline (control) orally from one hour to 7 days after MI. Results: Colchicine significantly improved survival rate compared with control at 4 weeks after MI (colchicine, n=48: 89.6% vs. vehicle, n=51: 70.6%, P&lt;0.01). Colchicine significantly improved left ventricular end-diastolic diameter (5.0±0.2 vs. 5.6±0.2 mm, P&lt;0.05) and ejection fraction (41.5±2.1 vs. 23.8±3.1%, P&lt;0.001) assessed by echocardiogram, and HF-development as pulmonary edema assessed by lung weight at 4 weeks after MI (P&lt;0.05). Histological analysis revealed that colchicine significantly inhibited the infiltration of Gr-1-positive granulocytes and Iba-1-positive macrophages in the infarct area at 24 hours after MI, and significantly improved left ventricular scar expansion at 1 week after MI. In the infarcted myocardium at 24 hours after MI, colchicine significantly attenuated the MI-induced myeloperoxydase activity and the mRNA expression of tissue necrosis factor-α, interleukin-1ß, monocyte chemoattractant protein-1, macrophage inflammatory protein-2, NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain, and pro-caspase-1 compared with control. Conclusions: Short-term treatment with colchicine successfully attenuated the infiltration of inflammatory cells, cytokines, and NLRP3 inflammasome in the infarcted myocardium, leading to improvement of adverse cardiac remodeling, cardiac function, HF-development, and survival.
Influence of Surgical Procedures and General Anesthesia on Child Development Before Primary School Entry Among Matched Sibling Pairs
Authors: James D. O’Leary, Magdalena Janus, Eric Duku, Duminda N. Wijeysundera, Teresa To, Ping Li, Jason T. Maynes, David Faraoni, Mark W. Crawford
Journal: JAMA Pediatrics (2018)

Substantial preclinical evidence suggests that the developing brain is susceptible to injury from anesthetic drugs. Findings from clinical studies of the neurotoxic effects of anesthesia are mixed, but these effects can be influenced by unmeasured confounding from biological and environmental risk and protective factors on child development.To examine the association between surgical procedures that require general anesthesia before primary school entry and child development in biological siblings.This retrospective sibling-matched cohort study included sibling pairs aged 5 to 6 years with the same birth mother who had Early Development Instrument (EDI) data completed. The EDI is a population-based measure of child development that assesses children's readiness to learn in 5 major domains (physical health and well-being, social knowledge and competence, emotional health and maturity, language and cognitive development, and communication skills and general knowledge). All eligible children in public and Catholic schools in Ontario, Canada, from 2004 through 2012 were included. Data were analyzed from December 13, 2017, through July 27, 2018.Surgical procedures that require general anesthesia from the date of birth to EDI completion.Early developmental vulnerability, defined as any major domain of the EDI in the lowest 10th percentile of the Ontario population.Of the 187 226 eligible children for whom the EDI was completed, a total of 10 897 sibling pairs (21 794 children; 53.8% female; mean [SD] age, 5.7 [0.3] years) were subsequently identified, including 2346 with only 1 child exposed to surgery. No significant differences were found between exposed and unexposed children in early developmental vulnerability (697 of 3080 [22.6%] vs 3739 of 18 714 [20.0%]; adjusted odds ratio [aOR], 1.03; 95% CI, 0.98-1.14; P = .58) or for each of the 5 major EDI domains (aOR for language and cognitive development, 0.96 [95% CI, 0.80-1.14]; aOR for physical health and well-being, 1.09 [95% CI, 0.96-1.24]; aOR for social knowledge and competence, 0.98 [95% CI, 0.84-1.14]; aOR for emotional health and maturity, 0.98 [95% CI, 0.84-1.14]; and aOR for communication skills and general knowledge, 0.90 [95% CI, 0.77-1.05]), after adjusting for confounding factors (age at EDI completion, sex, mother's age at birth, and eldest sibling status).In this provincial cohort study, children who had surgical procedures that require general anesthesia before primary school entry were not found to be at increased risk of adverse child development outcomes compared with their biological siblings who did not have surgery. These findings further support that anesthesia exposure in early childhood is not associated with detectable adverse child development outcomes.
RTHP-03. TIMING OF RADIATION THERAPY AFTER SURGICAL RESECTION OF INTRACRANIAL NON-SMALL CELL LUNG CANCER METASTASES: A RETROSPECTIVE ANALYSIS IN 28 PATIENTS
Authors: Sophie Peeters, John Sheppard, Giyarpuram Prashant, Carlito Lagman, Cheng Chen, Vera Ong, Methma Udawatta, Thien Nguyen, Bilwaj Gaonkar, Tania Kaprealian, William Yong, Stephen Tenn, Percy Lee, Isaac Yang
Journal: Neuro-Oncology (2018)

The current treatment of brain metastases from the lung involves surgical resection of symptomatic lesions followed by adjuvant radiation therapy (ART) with no evidence-based guideline describing the ideal time from surgery to ART in this patient population. Our objective was to evaluate optimal post-operative timing of adjuvant RT with respect to survival outcomes. We retrospectively identified 28 patients with pathologically confirmed primary non-small cell lung cancer and intracranial metastases who underwent a single craniotomy for resection with adjuvant RT between 2001 and 2016. Patient demographics, treatment details, and clinical outcomes were noted. Median surgery-to-radiation interval (SRI) was 31 days. We categorized patients into expedited RT (defined as SRI < 6 weeks, n=20) or delayed RT (SRI 3 6 weeks, n=8). Patients receiving Delayed RT did not differ from patients receiving Expedited RT in demographics, pre-operative metastatic burden, post-operative functional status, or adjuvant RT modality. Fifteen patients (54%) were living at last follow-up (median follow-up 8.2 months, mean 20.3 months). Across all patients, expected overall survival (OS) was 21.4 post-operative months and progression-free survival (PFS) was 13.2 months. OS was significantly shorter after Delayed RT compared to Expedited RT (7.0 vs. 28.3 months, P = 0.011). PFS was 15.0 months with Expedited RT and 3.2 months with Delayed RT (P = 0.39). Our results suggest that delayed adjuvant RT with SRI 3 6 weeks is associated with a shorter expected survival of up to 21 post-operative months. However, our study is limited by its retrospective nature, limited sample size, and limited follow-up. Refined studies are needed to more conclusively delineate optimal timing of adjuvant RT after surgical resection of intracranial lung cancer metastases, ideally involving well-powered randomized trials.
CBMT-39. METABOLIC PROFILING OF HUMAN GLIOMAS ASSESSED WITH NMR
Authors: Seung-Ho Yang, Jung Eun Lee
Journal: Neuro-Oncology (2018)

Little is known about the underlying metabolic alterations of gliomas. The objective of this study was to analyze metabolomic profiles of gliomas diagnosed according to revised WHO classification to demonstrate metabolic signatures beyond isocitrate dehydrogenase (IDH) 1/2 mutation. 1H-NMR spectroscopy of tumor extracts was performed to analyze brain tumor metabolism. We detected 46 metabolites including 2-hydroxyglutarate from human brain tumors. Metabolic profiles obtained were analyzed using multivariate analysis and MetaboAnalyst 3.0, a pathway analysis tool. We found that 2-hydroxglutarate, glutamine, and O-phophocholine had top-ranked VIP scores in metabolic pathway analyses of glioma. Major metabolism pathways perturbed in glioma included alanine/aspartate/glutamate metabolism, glycine/serine/threonine metabolism, pyruvate metabolism, taurine/hypotaurine metabolism, and D-Glutamine/D-glutamate metabolism. MetaboAnalyst 3.0 generated three unique clusters of gliomas. Concentration of 4-aminobutyrate was the highest in cluster 1 while concentrations of acetate and O-phosphocholine were the highest in cluster 2. Other metabolites had higher concentrations in cluster 2 compared to those in cluster 1 or cluster 3. Concentrations of isoleucine and phenylalanine were lower in those with high-grade gliomas than in those with low-grade gliomas. Gliomas could be reclassified according to their metabolomics features. Metabolic cluster approach may lead to development of metabolic anti-glioma therapy.
Edward John James Davies
Authors: Iwan Roberts
Journal: BMJ (2018)

Edward John James Davies (“Eddie”) was a GP in Cerrigydrudion, near Corwen in north Wales. A man of distinction and humility, he served his community faithfully for 37 years (from 1950 to 1987).

He grew up in the slate mining community of Tanygrisiau near Blaenau Ffestiniog. Eddie met Sybil when he was working at the Stanley Hospital in Liverpool; they married two years later and were together …
IMMU-73. GLIOMA IN SITU VACCINATION WITH COWPEA MOSAIC VIRUS NANOPARTICLES
Authors: Amber Kerstetter-Fogle, Sourabh Shukla, Veronique Beiss, Peggy Harris, Andrew Sloan, Nicole Steinmetz
Journal: Neuro-Oncology (2018)

Glioblastoma multiforme is the most malignant brain cancer affecting adults. Despite recent advancements, the current prognosis is dismal with median survival of 12 months post diagnosis even with multi-modal therapy. Cancer immunotherapy has made significant advances in treatment of multiple cancer types and is a promising avenue for development for glioma treatment. However, the highly immunosuppressive tumor microenvironment remains a challenge. The tumor microenvironment induces tolerance, exhaustion or death of T effector cells, protecting the tumor from most immune effector cells. Here we have utilized a 30 nm-sized virus like particle (VLP) derived from the plant virus Cowpea mosaic virus (CPMV) as an immunotherapy. The VLP is applied intratumorally as an in situ vaccine, modulating the tumor microenvironment and stimulating anti-tumor immunity. The VLPs are ingested by innate immune cells driving a cascade of immunological events, which leads to activation of the adaptive immune system and cancer cell death. We have demonstrated that weekly VLP treatment of immunocompetent mice with a high tumor burden of GL261 cells creates a localized inflammatory response that kills tumor cells. MRI imaging demonstrates GL261 tumor bearing mice have increased edema and swelling indicative of immune infiltration after treatment. Histological analysis with markers for immune cells support this finding. The ensuing immune response was also characterized using flow cytometry analysis on brain and spleen tissues and using ELISAs to determine cytokines milieu following the treatment.
PDTM-42. TARGETED INHIBITION OF BET BROMODOMAIN AND JMJD3 PROTEINS FOR THE TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Hiroaki Katagi, Ali Zhang, Gavin T. Blyth, Frank D. Eckerdt, Patrick A. Ozark, Lihua Zou, Xingyao He, Kathryn E. Loughlin, Takahiro Sasaki, Craig Horbinski, Rishi R. Lulla, Amanda M. Saratsis, Stewart Goldman, C David James, Ali Shilatifard, Rintaro Hashizume
Journal: Neuro-Oncology (2018)

Recent discovery of somatic histone gene mutations, resulting in replacement of lysine 27 by methionine (K27M) in the encoded histone H3.3 proteins, in diffuse intrinsic pontine glioma (DIPG) has dramatically improved our understanding of disease pathogenesis, and stimulated the development of novel therapeutic approaches targeting epigenetic regulators for disease treatment. K27M mutant DIPG shows a dramatic reduction in global methylation at K27 residues. We have shown that the JMJD3 demethylase inhibitor, GSKJ4, acted to restore K27 methylation in DIPG cells, while demonstrating potent anti-tumor activity, in vitro and in vivo. In addition to H3K27 methylation, H3K27 can also be acetylated (K27ac), which requires bromo- and extra-terminal domain (BET) protein activity. Increase level of H3K27 acetylation and bromodomain proteins in K27M-containing nucleosomes suggests that inhibitor of BET bromodomain protein 4 (BRD4), JQ1, could be useful for the treatment of K27M DIPG. Our aim is to investigate the hypothesis that the combined JQ1 + GSKJ4 have greater anti-tumor activity in vitro and in vivo than either monotherapy and reduce the likelihood of drug resistance. The level of H3K27 methylation and acetylation in DIPG cells with treated JQ1 + GSKJ4 were studied by western blotting. JQ1 + GSKJ4 increased H3K27 methylation and reduced K27acetylation in DIPG cells. MTS assay showed that combination treatment of JQ1 + GSKJ4 significantly increased growth inhibition, compared with either therapy alone. Colony formation assay showed that combination treatment of JQ1 + GSKJ4 significantly reduced the number of colonies. Boyden chamber assay showed that combination treatment of JQ1 + GSKJ4 significantly reduced cell invasion. Annexin V assay showed that combination treatment of JQ1 + GSKJ4 significantly promoted cell apoptosis. In vivo response to monotherapy and combination of JQ1 + GSKJ4 will be measured by bioluminescence imaging and animal survival studies in our human DIPG xenograft model.
Abstract 18781: Elevated Trimethylamine-n-oxide Levels May Contributes to Progression of Cerebral Small Vessel Diseases in Poststroke Patients via Blood Brain Barrier Disruption
Authors: Yuan Liu, Yining Huang
Journal: Circulation (2015)

Introduction: High level of serum gut micro-devrived metabolite trimethylamine-N-oxide(TMAO) have recently been association with cardiovascular disease(CVD) and chronic kidney disease(CKD) risk. Hypothesis: Here, we aim to test the hypothesis that whether TMAO play a direct contributory role in progression of cerebral small disesase. Methods: First, we examined the plasma TMAO level in both subjects with and without cerebral small vessel diseases by liquid chromatography with on-line mass spectrometry (LC/MS) analysis. Further, SD rat were raised with either normal chow diet or normal chow diet supplemented with additional high amounts of TMAO. Animals were killed 14 weeks later and brains were preserved. Paraffin-embedded brain sections were stained using hematoxylin and eosin (HE), anti-claudin5 antibody and anti-ZO1 anti body. Results: It is reveals that TMAO level among cerebral small vessel disease is higher than that in normal control subjects. Results also shown that blood brain barrier was disrupted in high TMAO raised group and expression of tight juction proteins decreased. Sample size should be expanded in our following work. What’s more, cell model of blood brain barrier should be established to demonstrated the molecular mechanism of effect of TMAO. Conclusions: In conclusion, our study indicates that high serum level of TMAO is association with progression of cerebral small vessel diseases in poststroke patients and raised with diet supplemented with additional high amounts of TMAO lead to blood brain barrier disruption in vivo.
CSIG-39. HIV-1 ENVELOPE PROTEIN GP120 PROMOTES ACTIVATION OF PROTEIN SYNTHESIS IN GLIOMAS THROUGH THE ERK AND AKT SIGNALING
Authors: Gabriel Valentin-Guillama, Yuriy Kucheryavykh, Lilia Kucheryavykh
Journal: Neuro-Oncology (2018)

Patients infected with human immunodeficiency virus (HIV-1) are more prone to developing cancers, including glioblastomas (GBMs). The median survival for GBM patients with HIV is significantly shorter than for HIV-negative GBM patients, despite the fact that they receive the same treatments. This difference indicates that HIV infection is associated with more aggressive tumor behavior and with treatment resistance. Earlier we demonstrated that gp120, a main glycoprotein in the HIV shell, stimulates glycolysis and protein synthesis in glioma cells. The purpose of this study was to evaluate the underlying gp120 dependent signaling mechanism in glioma cell. Using MAPK kinase antibody array and western blot assays we have identified the activation of MAP kinase and Akt/mTOR pathways in U87, A172, and primary glioma cells treated with gp120 (100 ng/ml) for 5 consequent days. Specifically, up regulation of pMEK1/2(Ser217/221), pERK(Thr202/Tyr224), pP90RSK(Thr359), pmTOR(S2448), pAkt(pS473), and pGSK3b(pS9) have been identified. These data coincide with previously obtained results showing that glioma cells treated with gp120 exhibit higher protein synthesis and proliferation rates compared to un-treated glioma cells. The use of pharmacological inhibitors of PI3K/Akt and ERK signaling reversed the stimulatory effect of gp120 on global protein synthesis, as revealed by flow cytometry analysis. Overall, we demonstrated that gp120 triggers activation of ERK and Akt signaling in glioma cells, resulting in increased protein synthesis and cell growth. This research was made possible by NIH grant number 1SC1GM122691 and Puerto Rico Science, Technology, and Research Trust grant 2016-00157.
Identification of cooperating oncogenes and tumor suppressor genes in p53+/- mouse osteosarcomas
Authors: Ou Ma, Weiwen Cai, Tsz-Kwong Man, Ching Lau, Lawrence Donehower
Journal: Cancer Research (2007)

2154  We are investigating the cooperating functional mutations in p53-related osteosarcomagenesis, in an effort to discover new oncogenes or tumor suppressor genes. p53 is important in maintenance of genomic stability. Loss of p53 function is important, but not sufficient for tumorigenesis, as additional cooperating mutations are required. Our lab has generated p53 knockout mice and we found that osteosarcomas are the most frequent tumor type in the heterozygous knockout mice (p53+/-). In this study, 41 osteosarcomas from p53+/- mice have been analyzed by BAC Array Comparative Genomic Hybridization and six regions of frequent chromosomal copy number gain or loss were found. One of the frequent copy number gains was on chromosome 9, on which reside ten Matrix Metalloproteinase (MMP) genes and the Baculoviral IAP Repeat-Containing 2 and 3 (Birc2 and Birc3) genes. This region has also been shown to be amplified in human pancreatic and oral squamous cell carcinomas. The MMPs are a family of endopeptidases involved in matrix remodeling, and have been implicated in both early and late stages of tumorigenesis. Of the MMP genes in this region, MMP13 was of particular interest because it is specifically expressed in osteoblasts. Real-time PCR and immunohistochemistry both revealed that MMP13 is highly overexpressed in all mouse p53+/- osteosarcomas (but not in p53+/- rhabdomyosarcomas or normal osteoblasts). Moreover, gene expression microarray profiling of 147 human osteosarcomas showed consistent high expression levels of MMP13. This expression pattern is unique to MMP13, as other MMPs in this amplicon do not have the same overexpression pattern. Stable osteosarcoma cell lines expressing MMP13 shRNA were constructed by lentivirus transduction. By allograft study, we found that the tumors formed by MMP13-knockdown osteosarcoma cells had significantly reduced growth rate compared to the tumors formed by control lines. This suggested that MMP13 contributes to the development or progression of osteosarcomas. Birc2 and Birc3 are anti-apoptotic proteins and have been indicated as oncogenes in a liver cancer model. Their expression was also examined, and found to be universally overexpressed in both human and mouse osteosarcomas. Future studies will attempt to understand the mechanistic and synergistic roles of MMP13, Birc2 and Birc3 in p53-related osteosarcomagenesis, and their potential as targets for osteosarcoma diagnosis and treatment.
Medications With Depression as an Adverse Effect
Authors: Bruno Agustini, Michael Berk
Journal: JAMA (2018)

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