tbuckley/cabot-search huggingface dataset:
Abstract 18995: Statins in Familial Hypercholesterolemia - Effects on Coronary Artery Disease and All-cause Mortality
Authors: Joost Besseling, Gerard K Hovingh, John J Kastelein, Barbara A Hutten
Journal: Circulation (2015)

Introduction: Heterozygous familial hypercholesterolemia (heFH) is characterized by high levels of low-density lipoprotein cholesterol (LDL-C) and increased risk for premature coronary artery disease (CAD) and death. Reduction of CAD and mortality by statins has not been properly quantified in heFH. The aim of the current study is to determine the effect of statins on CAD and mortality in heFH. Methods: All adult heFH patients identified by the Dutch FH screening program between 1994 and 2014 and registered in the PHARMO Database Network were eligible. Of these patients we obtained hospital, pharmacy (in- and outpatient), and mortality records in the period between 1995 and 2015. The effect of statins (time-varying) on CAD and all-cause mortality was determined using a Cox proportional hazard model, while correcting for the use of other lipid-lowering therapy, thrombocyte aggregation inhibitors, antihypertensive and antidiabetic medication (all time-varying). Furthermore, we used inverse probability for treatment weighting (IPTW) to account for differences between statin-treated and untreated patients regarding history of CAD before follow-up, age at start of follow-up and age of screening, as well as body mass index, LDL-C and triglycerides. Results: Of the 25,479 identified heFH patients, 11,021 gave informed consent to obtain their medical records, of whom 2,447 could be retrieved. We excluded 766 patients younger than 18. The remaining 1,681 heFH patients comprised our study population and these had very similar characteristics as compared to the 23,798 excluded FH patients, e.g. mean (SD) LDL-C levels were 214 (74) vs. 203 (77) mg/dL. Among 1,151 statin users, there were 133 CAD events and 15 deaths during 10,115 statin treated person-years, compared to 17 CAD events and 9 deaths during 4,965 person-years in 530 never statin users (combined rate: 14.6 vs. 5.2, respectively, p&lt;0.001). After applying IPTW to account for indication bias and correcting for use of other medications, the hazard ratio of statin use for CAD and all-cause mortality was 0.61 (0.40 - 0.93). Conclusions: In heFH patients, statins lower the risk for CAD and mortality by 39%.
PATH-56. CHEK2 MUTATION IN HIGH-RISK MEDULLOBLASTOMA
Authors: Nidhi Shah, Andrew Walter
Journal: Neuro-Oncology (2018)

Childhood cancer remains the leading cause of non-accidental death in children, with brain and central nervous system malignancies comprising about 18% of new diagnoses each year. Combination therapy, including surgery, chemotherapy and radiation therapy in standard-risk medulloblastoma has led to cure rates of 80% or better. The 20% of tumors that do not respond to traditional therapies, or relapse early, could be due to activation of tumor predisposition genes. CHEK2 is cell cycle checkpoint kinase 2, a tumor suppressor gene associated with increased risk of malignancies, most commonly breast and prostate cancer. Here we discuss a case of medulloblastoma, with evidence of germline and tumor CHEK2 mutation. This 4 year-old child was initially treated with surgery, achieving gross total resection, chemotherapy, tandem stem cell rescue, as well as local radiation therapy to posterior fossa. One year after completion of therapy, she relapsed with disease outside of the radiation field. Next generation sequencing of the whole genome performed on tumor tissue resulted in CHEK2 T367 mutation in the absence of TP53 mutation, or other mutations of known tumor suppressor genes. TP53 mutation is a cancer predisposition syndrome, associated with Li Fraumeni syndrome. CHEK2 mutation has been associated with worse progression-free survival in cases of non-Hodgkin’s lymphoma. Thus far, there have been no reported primary brain and central nervous system malignancies associated with CHEK2 mutation. This finding of CHEK2 mutation in medulloblastoma further supports the need for next generation sequencing on high-risk tumor types to predict response to therapy and overall prognosis.
EXTH-77. PARP INHIBITION STRIKINGLY ENHANCES CHEMOTHERAPEUTIC EFFECT IN CHORDOMA
Authors: Xiaoyu Cao, Yanxin Lu, Yang Liu, Jinkyu Jung, Qixin Wu, Deric Park, Chunzhang Yang
Journal: Neuro-Oncology (2018)

Therapy for chordoma, a cancer of the axial skeleton, consists of surgery often followed by high-dose irradiation. There are no known effective medical therapies. Because at recurrence, surgery and irradiation options are often limited, there is a critical unmet need to develop effective medical therapeutic strategies. In the present study, we investigated three patient-derived chordoma cells for molecular mechanisms of underlying therapeutic resistance. In vitro high throughput chemical screening assay, as well as in vivo xenograft model, was used to identify novel chemo-sensitizers for chordoma cells. We found that chordoma cell lines recapitulate disease phenotype, highlighted with robust therapy resistance and lack of DNA damage accumulation. Mechanistically, PARP DNA repair pathway plays central roles in the chemotherapeutic resistance. High throughput chemical screening confirmed that PARP inhibitors remarkably enhanced genotoxicity in chordoma cells. Combining an FDA-approved inhibitor olaparib not only potentiates DNA damage accumulation, cell cycle arrest, apoptotic changes in vitro, but also strikingly suppressed chordoma xenograft expansion in vivo. We conclude that combining PARP inhibitor with genotoxic therapy could be an effective therapeutic approach for the clinical management of chordoma.
Endoscopic retrieval of a migrated pancreatic stent using a handmade catheter with a guidewire loop
Authors: Hideki Kamada, Hideki Kobara, Kiyoyuki Kobayashi, Keiichi Okano, Yasuyuki Suzuki, Kiyohito Kato, Tsutomu Masaki
Journal: Endoscopy (2018)

Endoscopic pancreatic stenting (EPS) is performed to relieve obstruction to pancreatic juice flow in patients with various pancreatic conditions [1]. Migration of plastic pancreatic stents is one complication of EPS and occurs at a rate of 5 % – 6 % [2]. The migrated stent should be removed because it may induce a severe pancreatic condition [3]. However, endoscopic removal is technically difficult owing to the small diameter, bending course, and strictures of the pancreatic duct [3] [4]. We describe an innovative technique for removing a migrated pancreatic stent.
GENE-03. WILD-TYPE Tp53 UNDERGOES A CELL TYPE-SPECIFIC INACTIVATION BY SIRT1 IN DE NOVO GLIOBLASTOMA
Authors: Li Li, Vamsidhara Vemireddy, Mohammad Goodarzi, Tomoyuki Mashimo, Tara Billman, Kimmo Hatanpaa, Bruce Mickey, Elizabeth Maher, Robert Bachoo, Sara Piccirillo
Journal: Neuro-Oncology (2018)

In contrast to most solid tumors, the majority (72%) of de novo glioblastoma (GBM) retain a wild-type Tp53 gene while undergoing loss of CDKN2A (INK4a/Arf locus). Remarkably, transcriptional and proteomic data suggest that Tp53 is abundantly expressed in de novo GBM; however, it appears not to confer any survival advantage. The possibility that wild-type Tp53-expressing cells do not contribute to tumor growth seems unlikely since Tp53 is even more expressed in a paired analysis of initial and recurrent GBM. Taken together, these observations raise the possibility that the canonical Tp53 signaling may be functionally inactive in de novo GBM. Using primary cultures of conditional murine CDKN2A/B neural stem cells (NSC) and astrocytes we found that wild-type Tp53 is abundantly expressed following sequential loss of p16, p15 and p19 in astrocytes but not NSC. Astrocytes that lack both INK4a/b/Arf andTp53 show no growth advantage over INK4a/b/Arf-/- alone. Stable overexpression of Tp53 impairs proliferation of INK4a/b/Arf-/- NSC but not astrocytes, raising the intriguing possibility that inactivation of Tp53 signaling is cell type-specific. Furthermore, using Nutlin our data suggests that the Tp53-MDM2 axis is functional only in NSC but not astrocytes. Analysis of post-translational modifications (PTM) of Tp53 protein in INK4a/b/Arf-/- astrocytes and NSC reveals that it is entirely unacetylated in the former but not in the latter. Similarly, Tp53 expressed in primary GBM cells and patient-derived xenografts is also unacetylated. Consistent with this PTM, we found that SIRT1 is highly expressed in INK4a/b/Arf-/- astrocytes and not NSC and that inhibition of SIRT1 restores Tp53 acetylation, reduces cell proliferation and tumor growth. Mechanistic studies suggest that SIRT1 inhibition restores expression of Tp53 target genes (p21, PUMA, BAX). Taken together, our results identify a previously unrecognized cell type-specific PTM that inactivates Tp53 and provide a rationale for SIRT1 inhibition to restore Tp53 function.
Abstract 1627: Molecular Substrates of Carotid Body Chemoreceptor Activation
Authors: Zhi-Yong Tan, Yongjun Lu, Carol A Whiteis, Mark W Chapleau, Francois M Abboud
Journal: Circulation (2008)

Carotid bodies are powerful regulators of sympathetic nerve activity in response to acidosis, hypoxia and hypercarbia. They are hypersensitive in heart failure and hypertension. The molecular determinants of their responsiveness and hypersensitivity are not fully understood. We recently reported that the acid sensitive channels ASICs and TASKs mediate early and late depolarizations, respectively, in isolated glomus cells ( Circ. Res. 2007 ; 101 : 1009 –19 ). In these studies we addressed two questions. The first is whether the enhanced carotid body hypersensitivity known to occur in spontaneously hypertensive rats (SHR) reflects enhanced activity of ASICs and TASKs. The results indicate that low pH ranging from 7.0 to 6.0 induced both an early rapid and a late sustained depolarization of glomus cells isolated from young (4 – 6 weeks) SHR and WKY rats, however the response was markedly enhanced in SHR. The values for rapid and sustained depolarization at pH 6.0 were 24.4 ± 3.7 and 39.2 ± 2.3 mV for SHR cells (n = 16), and 12.7 ± 2.3 and 29.5 ± 2.6 mV for WKY cells (n = 26), respectively. The ASIC blocker amiloride (200 μM) suppressed significantly the early depolarization to a level of 2.0 ± 1.2 mV (n = 7), but not the sustained depolarization which remained at 33.6 ± 3.6 mV (n = 7). mRNAs encoding ASIC1b and 3 and TASK1 and 3 were augmented by 150%, 75%, 100% and 20% respectively in carotid bodies of SHR compared to WKY. The second question is whether glomus cells are selectively responsive to low pH vs. oxygen deprivation with cyanide. In contrast to the response to low pH, that to cyanide (2 mM) was not enhanced in SHR (13.9 ± 2.5 mV; n = 7) compared to WKY (11.8 ± 3.3 mV; n = 7). Moreover in six WKY cells, three were as sensitive to cyanide (20.0 ± 3.9 mV) as they were to low pH (29.3 ± 4.6 mV) whereas three other cells that were very sensitive to low pH (29.2 ± 1.9 mV) had negligible responses to cyanide (4.2 ± 0.9 mV). We conclude: that in a genetic model of neurogenic hypertension (SHR), overexpression of acid sensitive ion channels (ASICs and TASKs) causes selective carotid body chemoreceptor hypersensitivity to low pH and may contribute to the development of hypertension; and that different glomus cell populations may be selectively sensitive to specific chemical stimuli (e.g. low pH vs. hypoxia).
IMMU-71. EVALUATING THE COMPATIBILITY OF TUMOR TREATING ELECTRIC FIELDS WITH KEY ANTI-TUMORAL T CELL FUNCTIONS
Authors: Gl Diamant, Hadar Simchony, Tamar Shiloach, Anat Globerson-Levin, Zelig Eshhar, Rachel Grossman, Zvi Ram, Ilan Volovitz
Journal: Neuro-Oncology (2018)

Combining Tumor Treating electrical Fields (TTFields) with immunotherapy is a rational approach due to their different mechanisms of action (MOA) and to TTFields’ ability to induce immunogenic cell death (ICD). Conversely, TTFields may interfere with immune functions critical for effective T cell responses. T cells from healthy donors’ peripheral blood or from viably dissociated glioblastoma samples were cultured under normal or TTFields conditions, with or without superantigen-stimulation. Eight-color flow cytometry was used to assess T cell responses by monitoring select pivotal antitumoral functions: proliferation (CFSE), IFNγ secretion, cytotoxic degranulation (CD107a), activation/exhaustion (PD1) and viability. Direct cytotoxicity was evaluated using chimeric antigen receptor (CAR) T cells. The viability of stimulated T cells that attempted to proliferate decreased under TTFields, in line with TTFields’ MOA. Small or no reductions in viability were found in activated T cells that did not attempt to proliferate and in unstimulated T cells. The functionality of stimulated peripheral-blood T cells and tumor-infiltrating T cells (TILs) under TTFields was unhindered: T cells exhibited comparable PD1 upregulation, IFNγ secretion and CD107a expression as controls. T cell polyfunctionality, associated with effective antitumoral responses, was retained under TTFields conditions. PD1-expressing TILs, a subset containing most of the tumor antigen-specific TILs, exhibited unaltered viability and functionality under TTFields. CAR T-cells, which utilize the same killing machinery as unmodified T cells, exhibited unaltered cytotoxic capability under TTFields. Gene expression analysis of GBM tissues obtained before and after patients’ treatment with chemoradiation or chemoradiation+TTFields, demonstrated, in TTFields treated patients, increases of transcripts associated with antitumoral responses (CD8, NKp46, GranzymeB, Perforin), and decreases in protumoral-associated myeloid-compartment transcripts (CD66b, CD163, HLADR) All antitumoral T cell functions examined, with the exception of proliferation, were unhindered by TTFields. Our findings warrant the further preclinical and clinical investigation into the combination of TTFields and immunotherapy.
The Combination of Atomoxetine and Oxybutynin Greatly Reduces Obstructive Sleep Apnea Severity. A Randomized, Placebo-controlled, Double-Blind Crossover Trial
Authors: Luigi Taranto-Montemurro, Ludovico Messineo, Scott A. Sands, Ali Azarbarzin, Melania Marques, Bradley A. Edwards, Danny J. Eckert, David P. White, Andrew Wellman
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Rationale: There is currently no effective pharmacological treatment for obstructive sleep apnea (OSA). Recent investigations indicate that drugs with noradrenergic and antimuscarinic effects improve genioglossus muscle activity and upper airway patency during sleep.Objectives: We aimed to determine the effects of the combination of a norepinephrine reuptake inhibitor (atomoxetine) and an antimuscarinic (oxybutynin) on OSA severity (apnea–hypopnea index [AHI]; primary outcome) and genioglossus responsiveness (secondary outcome) in people with OSA.Methods: A total of 20 people completed a randomized, placebo-controlled, double-blind, crossover trial comparing 1 night of 80 mg atomoxetine plus 5 mg oxybutynin (ato–oxy) to placebo administered before sleep. The AHI and genioglossus muscle responsiveness to negative esophageal pressure swings were measured via in-laboratory polysomnography. In a subgroup of nine patients, the AHI was also measured when the drugs were administered separately.Measurements and Main Results: The participants’ median (interquartile range) age was 53 (46–58) years and body mass index was 34.8 (30.0–40.2) kg/m2. ato–oxy lowered AHI by 63% (34–86%), from 28.5 (10.9–51.6) events/h to 7.5 (2.4–18.6) events/h (P < 0.001). Of the 15/20 patients with OSA on placebo (AHI > 10 events/hr), AHI was lowered by 74% (62–88%) (P < 0.001) and all 15 patients exhibited a ≥50% reduction. Genioglossus responsiveness increased approximately threefold, from 2.2 (1.1–4.7)%/cm H2O on placebo to 6.3 (3.0 to 18.3)%/cm H2O on ato–oxy (P < 0.001). Neither atomoxetine nor oxybutynin reduced the AHI when administered separately.Conclusions: A combination of noradrenergic and antimuscarinic agents administered orally before bedtime on 1 night greatly reduced OSA severity. These findings open new possibilities for the pharmacologic treatment of OSA.Clinical trial registered with www.clinicaltrials.gov (NCT02908529).
CBMT-38. ASSOCIATION OF miR-146aC&gt;G, miR-149C&gt;T, miR-196a2C&gt;T, AND miR-499A&gt;G POLYMORPHISMS WITH BRAIN TUMORS
Authors: Jaejoon Lim, Jung Oh Kim, NamKeun Kim, Kyunggi Cho
Journal: Neuro-Oncology (2018)

MicroRNAs (miRNAs) are short, noncoding RNAs that are implicated in tumorigenesis, functioning as both tumor suppressors and oncogenes. However, the clinical significance of miRNA expression profiles for brain tumors remains unclear. Therefore, we designed a study to investigate the association between microRNA genetic variants and brain tumor risk. We recruited 362 participants; 179 for the healthy subjects and 183 who were brain tumor patients confirmed as having gliomas, meningiomas, or schwannomas. This study investigated the single nucleotide polymorphisms miR-146aC>G, miR-149T>C, miR-196a2T>C, and miR-499A>G by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). We found that the dominant miR-149 and CC genotypes were significantly more frequent in patients with glioma. The odds ratios for the C-C-C-G, C-T-C-G, and G-C-T-G haplotypes (miR-146aC>G-miR-149T>C-miR-196a2T>C-miR-499A>G) were significantly increased in glioma, as was the odds ratio for the GCT haplotype of miR-146aC>G, miR-149T>C, and miR-196a2T>C and for the CCG haplotype of miR-149T>C, miR-196a2T>C, and miR-499A>G. In meningioma, the odds ratios were increased in the GTCG haplotype of miR-146aC>G, miR-149T>C, miR-196a2T>C, and miR-499A>G. The odds ratios were also increased in the GCG haplotype of miR-146aC>G, miR-196a2T>C, and miR-499A>G and CCG haplotype of miR-149T>C, miR-1962T>C, and miR-499A>G. The odds ratios for schwannoma were increased in the GCTG haplotype of miR-146aC>G, miR-149T>C, miR-196a2T>C, and miR-499A>G and the CCG haplotype of miR-149T>C, miR-196a2T>C, and miR-499A>G. In conclusion, our results suggested that the miR-149 polymorphism might be involved in the development of gliomas, and the CCG haplotype of miR-149T>C, miR-196a2T>C, and miR-499A>G showed increased odds ratios for all types of brain tumors in Koreans.
Abstract 12682: The Effect of Systolic Variation of Mitral Regurgitant Severity on Discordance Between Non-Invasive Imaging Modalities
Authors: Seth Uretsky, Konstantinos Koulogiannis, Leo Marcoff, John Brown, Edgar Argulian, Ashadevi Jagarlamudi, Hira Awan, Mark Rosenthal, Farooq Chaudhry, Linda Gillam, Steven D Wolff
Journal: Circulation (2015)

Introduction: Studies have shown a significant degree of discordance between echocardiography (Echo) and MRI in the quantification of mitral regurgitation (MR). A contributing factor to this discordance may be the systolic variation of MR severity. The ASE recommended quantitative parameters such as PISA and vena contracta rely on a single measurement during systole. These measurements can overestimate MR when MR severity varies during systole. We have previously developed a method to quantify the variation of MR during systole. Hypothesis: Greater systolic variation of MR severity is associated with discordance between MRI and Echo. Methods: This study included 94 pts (60 ± 14 yrs, male 60%) with MR. Echo was read per the ASE integrated method as mild, moderate or severe. Each MRI was read as mild, moderate, or severe based on calculated MR volume. Discordance was defined as the difference between the grades of MR (mild, moderate, or severe) by MRI and Echo. On MRI, systole was divided into thirds and the regurgitant rate was calculated for each third of systole as the difference between LV stroke volume and aortic outflow per unit time. The degree of systolic variation of MR severity was quantified by dividing the lowest regurgitant rate by the peak regurgitant rate, with higher numbers representing lower variation of MR severity during systole. Results: There was absolute agreement between echo and MRI in 38 pts, 1 grade difference in 41 pts, and a 2 grade difference in 15 pts. There was a trend of greater systolic variation of MR rate in pts with greater discordance between MRI and echo (figure). Pts with no discordance between echo and MRI had a significantly lower systolic variation of MR severity than those with 1 or 2 grades difference. Conclusions: Discordance between Echo and MRI in assessing MR severity was associated with greater systolic variation in MR severity. Thus, caution should be taken not to overestimate MR severity in patients with systolic variation of their MR.
EXTH-51. C18-CERAMIDE ANALOGUE DRUG OVERCOMES RESISTANCE TO TEMOZOLOMIDE IN GLIOBLASTOMA
Authors: Arabinda Das, Szulc Zdzislaw, David Cachia, Sunil J Patel, Besim Ogretmen
Journal: Neuro-Oncology (2018)

Glioblastoma (GB) is a WHO Grade IV brain tumor with very limited therapeutic option currently available. The DNA-alkylating agent temozolomide (TMZ) is currently the most effective chemotoxic drug for GB therapy but efficacy tends to be short-lasting with tumors eventually becoming resistant to treatment. Developing novel agents is therefore of paramount importance. Ceramide synthase 1 (CERS1) is the most highly expressed CERS in the central nervous system, and ceramide with an 18-carbon–containing fatty acid chain (C18-ceramide) plays important roles in signaling and sphingolipid development. However, the roles of CERS1 and C18-ceramide in glioma are largely unknown. Our results demonstrated C18 ceramide is down regulated in 70% of human GB tumor tissues as compared to non-tumor tissues, indicating that down-regulation of C18-ceramide synthesis might have a role glioma-genesis. These roles were examined by reconstitution of C18-ceramide in GB cells via addition of exogenous C18-ceramide analogue drug, or overexpression of CERS1, which has been shown to specifically induce the generation of C18-ceramide. Our results demonstrated that C18-ceramide reconstitution using pharmacologic or molecular tools induced cell death in human GB cells that exhibited resistance to TMZ, but had no effect on cell death induction in normal astrocytes. Thus, these data suggest that reconstitution of C18-ceramide signaling induces cell death in TMZ resistant GB.