tbuckley/cabot-search huggingface dataset:
Abstract 17063: The Effect of Clopidogrel Plus Aspirin versus Aspirin Only on Progression of Native Coronary Artery Disease 1 Year After CABG: Analysis From the CASCADE Randomized Trial
Authors: Dai Une, Talal Al-Atassi, Alexander Kulik, Pierre Voisine, Michel Le May, Marc Ruel
Journal: Circulation (2013)

Introduction: Clopidogrel improves patient outcomes after acute coronary syndrome and percutaneous coronary intervention. To this date, the effect of clopidogrel on native coronary artery disease (...
NCMP-13. BDNF ENHANCEMENT VIA AMPAKINES AS A POTENTIAL TREATMENT FOR CHEMOTHERAPY-RELATED COGNITIVE IMPAIRMENT
Authors: Naomi Lomeli, Diana Pearre, Kaijun Di, Daniela A. Bota
Journal: Neuro-Oncology (2018)

OBJECTIVES: Chemotherapy-related cognitive impairment (CRCI) is widely reported among cancer survivors. We focus on the neurocognitive impairments provoked by cisplatin, which is used for treatment of various malignancies including ovarian, testicular, head and neck cancers, and pediatric brain tumors. More than 30% of advanced ovarian cancer patients develop CRCI during and after cisplatin-based chemotherapy. We examined the role of brain-derived neurotrophic factor (BDNF) downregulation in cisplatin-induced CRCI, and whether pharmacological BDNF augmentation via ampakines can prevent cisplatin-induced neuronal damage. BDNF is broadly expressed in the hippocampus where it regulates dendritic spine integrity and neurogenesis, among other functions. We examined the effects of cisplatin on neurogenesis, neuronal morphology, BDNF levels, and cognition in rats. We also assessed the effects of cisplatin on dendritic spine density, BDNF mRNA levels, apoptosis, and the ability of ampakine CX1739 to mitigate cisplatin-induced neuronal damage in-vitro. Cisplatin reduced dendritic branching and spine density, and neurogenesis in the rat hippocampus. Chronic cisplatin treatment decreased hippocampal and serum BDNF levels, and impaired cognitive function in rats. In-vitro, ampakine administration upregulated BDNF levels, and mitigated cisplatin-induced dendritic damage in cultured hippocampal neurons. Concomitant administration of CX1739 with cisplatin did not affect cisplatins cytotoxic activity in two ovarian cancer cell lines. DISCUSSION: The cognitive deficits caused by cisplatin in rats result from the loss of excitatory synapses and dendritic spines that anchor them, neuronal apoptosis, as well as decrease in neurogenesis. Changes in BDNF levels are associated with cisplatin-induced CRCI. Importantly, CX1739 mitigated cisplatin-induced neurotoxicity and BDNF depletion in vitro. Next, we will examine whether CX1739 prevents cisplatin-induced cognitive deficits in rats. If so, we will plan a Phase I study to examine if ampakine administration to ovarian cancer patients receiving cisplatin is safe, and if it ameliorates the cognitive deficits described in this patient population.
NIMG-28. CONVENTIONAL AND ADVANCED IMAGING FINDINGS FOLLOWING INTRACAVITARY DELIVERY OF AUTOLOGOUS CHIMERIC ANTIGEN RECEPTOR T-CELL THERAPY IN RECURRENT GLIOBLASTOMA
Authors: Prativa Sahoo, Behnam Badie, Christine Brown, Jana Portnow, Ammar Chaudhry, Julie Kilpatrick, Russell Rockne
Journal: Neuro-Oncology (2018)

Chimeric antigen receptor (CAR) T-cell therapy is an emerging area of immunotherapy for treatment of recurrent glioblastoma (GBM). However, evaluating response to CAR T-cell therapy is a considerable challenge. Radiologic changes following CAR T-cell therapy may include inflammation, which may be misinterpreted as disease progression, resulting in premature termination of the treatment. The iRANO criteria provides a ‘limbo window’ of up to six months from the start of immunotherapy during which radiologic worsening is tolerated while continuing immunotherapy. However, the time frame for identifying tumor progression following CAR T-cell therapy in the recurrent setting has not yet been characterized. AIM: Here we report imaging findings from conventional and advanced MRI sequences along with 18-FDG-PET-CT, acquired before, during, and after intracavitary administration of autologous central memory derived IL13Rα2-targeted CAR T-cell therapy for recurrent glioblastoma. Imaging findings are reported from an ongoing dose-escalation study (NCT02208362) with maximum doses of 10x106 (dose schedule 1), 50x106 (dose schedule 2) and 100x106 (dose schedule 3) CAR T-cells. All patients underwent MRI scans on a 3T Siemens scanner prior to surgical debulking and CAR T-cell administration as well as at the end of each CAR T-cell treatment cycle, consisting of 3 CAR T-cell infusions into the resection cavity corresponding to time intervals of approximately 1 month. Conventional anatomic MRI included T1-weighted pre- and post-contrast, T2-spin echo, and T2-FLAIR sequences. Quantitative MRI included Dynamic Contrast Enhanced (DCE) Perfusion MRI and Diffusion Weighted Imaging (DWI). Additionally, patients underwent functional metabolic imaging with 18-FDG-PET-CT. Multiparametric imaging characteristics will be compared longitudinally before, during, and following CAR T-cell treatment and correlated to clinical progression. As of May 2018, 14 patients have been treated: dose 1 (n=3), dose 2 (n=3), dose 3 (n=8). Findings and analysis will be updated at the time of late-breaking abstract deadline.
TMIC-42. DEVELOPMENT OF NOVEL SPRAY-TYPE FLUORESCENT PROBES FOR BRAIN TUMORS
Authors: Yosuke Kitagawa, Shota Tanaka, Akira Ogasawara, Yugo Kuriki, Kyoko Yamamoto, Tsukasa Koike, Taijyun Hana, Satoshi Takahashi, Takahide Nejo, Masashi Nomura, Shunsaku Takayanagi, Mako Kamiya, Yasuteru Urano, Nobuhito Saito
Journal: Neuro-Oncology (2018)

PURPOSE: 5-Amino Levulinic Acid (5-ALA) is commonly used as an intraoperative aid in malignant glioma surgery, which has been proved to be effective for more radical tumor resection and better patient prognosis. However, there are some limitations in its use, such as false positivity, false negativity, and inability of re-administration. We aim to develop a novel fluorescent labeling system, which can be repeatedly administered by spray during surgery, using hydroxymethyl rhodamine green (HMRG) and 2 methyl siliconrhodamine (2MeSiR600) as host fluorescent nuclei originally designed at our university for cancer detection, complementing 5-ALA. Four groups of homogenized samples were prepared from frozen tissues which consisted of 10 peritumoral specimens, 5 glioblastomas, 5 astrocytomas, and 5 oligodendrogliomas. Probe screening was performed using the fluorescent probe library comprised of HMRG and 2MeSiR600 host fluorescent nuclei combined with various types of dipeptides. More than 720 kinds of fluorescent probes were applied to homogenized lysates. According to the fluorescence intensity measured over time after application, probes exhibiting strong focal fluorescent marks with large difference between peritumor and tumor tissues were selected as valid probes. The selected probes were then validated by the experiment using fresh specimens. RESULTS & DISCUSSION: The top probes were selected based upon the experiments using homogenized lysates as well as fresh specimens. They were validated prospectively with more surgical cases. With the combination of the two types of fluorescent host nuclei, glioblastoma can be identified in multi-color. Fluorescent probes with HMRG and 2MeSiR 600 host nuclei can be effective for intraoperative detection of glioma.
RDNA-07. IDH1-MUTANT GLIOBLASTOMA (GBM) CELLS FROM A PATIENT POST-TUMOR TREATING FIELDS (TTFIELDS) THERAPY ARE SENSITIVE TO TTFIELDS IN VITRO
Authors: Sharon Michelhaugh, Sam Kiousis, Neil Klinger, Sandeep Mittal
Journal: Neuro-Oncology (2018)

Tumor treating fields (TTFields) are FDA-approved for treatment of newly-diagnosed and recurrent GBM. TTFields extend progression-free survival and overall survival. Despite this advancement in patient outcome, many patients undergoing TTFields treatment ultimately progress with tumor recurrence. In this study, cell lines were generated from resected GBMs from two patients with secondary isocitrate dehydrogenase 1 (IDH1)-mutant glioblastoma. One patient received TTFields monotherapy for 1 year prior to resection, and one patient was TTFields-naïve. Cells were treated in vitro with TTFields followed by assessment of proliferative activity and cytotoxicity. Tumors were enzymatically and mechanically disrupted to generate single-cell suspensions for culturing. Cells grew in DMEM/F12 media with 10% fetal bovine serum and gentamicin. Prior to TTFields application, cells were plated on plastic coverslips (2 × 104cells/coverslip) and incubated overnight. Then, TTFields were applied at 200 kHz (field intensity ~1.6 V/cm) for 14 days. Proliferation and cytotoxicity were assessed with XTT assay (n=6/group) and lactate dehydrogenase (LDH) release assay (n=3/group), respectively. Groups were compared by one-tailed t-test. After 14 days, proliferation was reduced in TTFields-treated cells (mean± SD; 0.763 ± 0.075) compared to control cells (1.064 ± 0.014; p<0.002) in the cells from the TTFields-treated patient, with no significant difference between groups in the cells from the TTFields-naïve patient (treated 1.269 ± 0.064; control 1.184 ± 0.097). However, in both cell lines, in vitro TTFields increased LDH release. In cells from the TTFields naïve patient, LDH release increased (12.62 ± 0.96) compared to control (7.375 ± 0.98; p<0.002). In the TTFields-treated patient cells, LDH release was 3-fold greater than control (31.890 ± 16.7 vs. 9.001 ± 1.21; p<0.04). TTFields decreased proliferation and induced cytotoxicity in IDH1-mutant GBM cells in vitro. This is the first report of in vitro effects of TTFields on GBM cells with mutated IDH1.
EXTH-71. RADIATION-INDUCED TARGETED NANOPARTICLE-BASED GENE DELIVERY FOR BRAIN TUMORS
Authors: Gulsah Erel-Akbaba, Litia Carvalho, Tian Tian, Max ZInter, Pierre Obeid, Bakhos Tannous
Journal: Neuro-Oncology (2018)

Targeted therapy and programmed cell death ligand-1 blockade hold a great promise for the treatment of different aggressive tumor types, however little effect have been observed against gliomas probably due to inability of large antibodies in penetrating the brain. An effective glioma therapy requires a delivery system that reaches tumors in the central nervous system, with limited systemic effect. In this study, we developed an iRGD-based solid lipid nanoparticle (SLN) to deliver siRNAs against both EGFR and PD-L1 for combined targeted and immunotherapy against glioblastoma, the most aggressive type of brain tumors. Building on recent studies showing that radiation therapy alters tumors for enhanced nanotherapeutic delivery in tumor-associated macrophages-dependent fashion, we showed that low dose radiation primes an increase in targeted SLN uptake into the brain tumor region leading to enhanced downregulation of PD-L1 and EGFR. Bioluminescence imaging revealed that radiation therapy followed by systemic administration of targeted SLN lead to a significant decrease in glioblastoma growth, and prolonged mouse survival. This study combines radiation therapy to prime the tumor for nanoparticle uptake along with the targeting effect of iRGD conjugated nanoparticles to yield a straightforward but effective approach for combined targeted EGFR inhibition and immunotherapy against glioblastomas, which can be extended to other aggressive tumor types.
Long Noncoding RNA <i>LBCS</i> Inhibits Self-Renewal and Chemoresistance of Bladder Cancer Stem Cells through Epigenetic Silencing of SOX2
Authors: Xu Chen, Ruihui Xie, Peng Gu, Ming Huang, Jinli Han, Wen Dong, Weibin Xie, Bo Wang, Wang He, Guangzheng Zhong, Ziyue Chen, Jian Huang, Tianxin Lin
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Chemoresistance and tumor relapse are the leading cause of deaths in bladder cancer patients. Bladder cancer stem cells (BCSCs) have been reported to contribute to these pathologic properties. However, the molecular mechanisms underlying their self-renewal and chemoresistance remain largely unknown. In the current study, a novel lncRNA termed Low expressed in Bladder Cancer Stem cells (lnc-LBCS) has been identified and explored in BCSCs. Experimental Design: Firstly, we establish BCSCs model and explore the BCSCs-associated lncRNAs by transcriptome microarray. The expression and clinical features of lnc-LBCS are analyzed in three independent large-scale cohorts. The functional role and mechanism of lnc-LBCS are further investigated by gain- and loss-of-function assays in vitro and in vivo. Results: Lnc-LBCS is significantly downregulated in BCSCs and cancer tissues, and correlates with tumor grade, chemotherapy response, and prognosis. Moreover, lnc-LBCS markedly inhibits self-renewal, chemoresistance, and tumor initiation of BCSCs both in vitro and in vivo. Mechanistically, lnc-LBCS directly binds to heterogeneous nuclear ribonucleoprotein K (hnRNPK) and enhancer of zeste homolog 2 (EZH2), and serves as a scaffold to induce the formation of this complex to repress SRY-box 2 (SOX2) transcription via mediating histone H3 lysine 27 tri-methylation. SOX2 is essential for self-renewal and chemoresistance of BCSCs, and correlates with the clinical severity and prognosis of bladder cancer patients. Conclusions: As a novel regulator, lnc-LBCS plays an important tumor-suppressor role in BCSCs’ self-renewal and chemoresistance, contributing to weak tumorigenesis and enhanced chemosensitivity. The lnc-LBCS–hnRNPK–EZH2–SOX2 regulatory axis may represent a therapeutic target for clinical intervention in chemoresistant bladder cancer.
High rates of meticillin-resistant Staphylococcus aureus among asylum seekers and refugees admitted to Helsinki University Hospital, 2010 to 2017
Authors: Tuomas Aro, Anu Kantele
Journal: Eurosurveillance (2018)

Introduction Antimicrobial resistance is increasing rapidly in countries with low hygiene levels and poorly controlled antimicrobial use. The spread of resistant bacteria poses a threat to healthcare worldwide. Refugees and migrants from high-prevalence countries may add to a rise in multidrug-resistant (MDR) bacteria in low-prevalence countries. However, respective data are scarce. Methods We retrospectively collected microbiological and clinical data from asylum seekers and refugees treated at Helsinki University Hospital between January 2010 and August 2017. Results Of 447 asylum seekers and refugees (Iraq: 46.5%; Afghanistan: 10.3%; Syria: 9.6%, Somalia: 6.9%); 45.0% were colonised by MDR bacteria: 32.9% had extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE), 21.3% meticillin-resistant Staphylococcus aureus (MRSA), 0.7% carbapenemase-producing Enterobacteriaceae (CPE), 0.4% multiresistant Pseudomonas aeruginosa (MRPA), 0.4% multiresistant Acinetobacter baumannii (MRAB); no vancomycin-resistant Enterococcus (VRE) were found. Two or more MDR bacteria strains were recorded for 12.5% of patients. Multivariable analysis revealed geographical region and prior surgery outside Nordic countries as risk factors of MRSA colonisation. Young age (&lt; 6 years old), short time from arrival to first sample, and prior hospitalisation outside Nordic countries were risk factors of ESBL-PE colonisation. Conclusion We found MDR bacterial colonisation to be common among asylum seekers and refugees arriving from current conflict zones. In particular we found a high prevalence of MRSA. Refugees and migrants should, therefore, be included among risk populations requiring MDR screening and infection control measures at hospitals.
IMMU-62. LOW-GRADE GLIOMA EXCLUDE CD8 T CELLS, WHICH IS ACCOMPANIED BY LOW EXPRESSION OF CHEMO-ATTRACTANTS, NOT IMMUNOGENIC ANTIGENS
Authors: Bas Weenink, Kaspar Draaisma, Han Zi Ooi, Peter Sillevis Smitt, Reno Debets, Pim French
Journal: Neuro-Oncology (2018)

In multiple tumor types, prediction of response to immune therapies relate to the presence, distribution and activation state of tumor infiltrating lymphocytes (TILs). Little is known, however, about the immune contexture of TILs in gliomas. To this end, we assessed whether low and high-grade glioma (LGG and HGG) differ with respect to number, location and tumor reactivity of TILs; as well as expression of molecules involved in the trafficking and activation of T cells. TILs were collected from glioma samples and CD3 and CD8 T cells were quantified by flow cytometry (n=10) and immunofluorescence (n=35). Neo-antigen load and expression of Cancer Germline Antigens (CGAs) were assessed using whole exome sequencing and RNA-seq. TIL-derived DNA was sequenced and the variable domain of the TCRβ chain was classified according to IMGT nomenclature (n=5). QPCR was used to determine expression of T cell-related genes (n=20). T cell numbers were significantly lower in LGG. In HGG, CD8 T cells migrated into tumor tissue, whereas in LGG, they mainly remained in close vicinity to blood vessels. Although HGG had significantly more genetic changes, the number of neo-epitopes was only 2 in both tumor types. We also did not observe a difference in the expression of CGAs nor in dominant TCR-Vb gene usage. The low number and perivascular location of CD8 T cells in LGG was accompanied by a low expression of chemo-attractants CXCL9 and CXCL10, adhesion molecule ICAM1 and CD8 T cell effector molecule GZMK. LGG have lower numbers of TILs compared to HGG, potentially linked to decreased T cell extravasation and activation. We have found no evidence for distinct tumor reactivity of T cells in either tumor type. Our data argue that LGG would require sensitization to enhance numbers and trafficking of CD8 T cells prior to immune therapies, such as checkpoint inhibitors.
Consultant is struck off for billing NHS for hours he was already being paid for
Authors: Clare Dyer
Journal: BMJ (2018)

A consultant acute care physician who billed his NHS employer for extra work on “escalation wards” while also being paid for his regular contracted services has been struck off the UK medical register, after a medical practitioners tribunal found that his conduct amounted to “persistent dishonesty.”

Syed Ahmed told the hearing in Manchester that he had billed “in accordance with the common practice of his colleagues” at Stepping Hill Hospital in Stockport and did not think that he was doing anything wrong. But two business managers at the trust and three other consultants testified that such billing was not the norm.

Ahmed and other consultants at Stockport NHS Foundation Trust worked according to a job plan that required a …
A protective role for microRNA-688 in acute kidney injury
Authors: Nicholas Chun, Steven G. Coca, John Cijiang He
Journal: Journal of Clinical Investigation (2018)

Ischemia-reperfusion (I/R) sets off a devastating cascade of events, leading to cell death and possible organ failure. Treatments to limit I/R-associated damage are lacking, and the pathways that drive injury are poorly understood. In this issue of the JCI, Wei and colleagues identify microRNA-668 (miR-668) as a protective factor in acute kidney injury (AKI). miR-668 was shown to repress mitochondrial fission–associated protein MTP18, thereby inhibiting pathogenic mitochondrial fragmentation. In murine models of I/R-induced AKI, treatment with a miR-668 mimetic reduced mitochondrial fragmentation and improved renal function. Moreover, HIF-1α was shown to be required for miR-688 expression in response to I/R. Importantly, Wei et al. show miR-668 upregulation in a cohort of human patients with AKI. Together, these results identify a HIF-1α/miR-668/MTP18 axis that may have potential as a therapeutic target for AKI.
TMIC-21. THE POTENTIAL CONTRIBUTION OF PERICYTES TO GLIOBLASTOMA MULTIFORME TUMOUR MICRO-ENVIRONMENT IMMUNOSUPPRESSION VIA DAMPENED EXPRESSION OF ICAM-1, VCAM-1 AND MCP-1
Authors: Jena Macapagal, Thomas Park, Maximillian Joret, Justin Rustenhoven, Birger Dieriks, Richard Faull, Patrick Schweder, Mike Dragunow
Journal: Neuro-Oncology (2018)

Glioblastoma Multiforme (GBM) is the most aggressive, fatal, yet most common form of brain malignancy in adults. Despite advances in immune-based treatments for other modes of cancer, GBM remains a challenge due to its ability to dampen immune responses via mechanisms not yet fully understood. With a median survival time of only 15 months following diagnosis, there is a strong push to find new targets for therapy. An emerging aspect of GBM’s pathogenesis is the idea of the tumour’s immunosuppressive microenvironment which comprises a mixture of malignant tumour cells, stroma, blood vessels and infiltrating inflammatory cells. These cells can alter their phenotypes to express less pro-inflammatory and more anti-inflammatory mediators. Despite advances in understanding the contribution of these cells in establishing an anti-inflammatory microenvironment, the contribution of pericytes, an important neurovascular mural cell that forms the blood-brain barrier, has been inadequately studied. Therefore, we investigated the changes in immune responses between the non-neoplastic brain and GBM-derived pericytes isolated directly from the same patient’s tissues obtained during neurosurgery. Our results show that cellular responses to pro-inflammatory stimuli such as Interleukin 1 beta (IL-1ß) were dampened in GBM-derived pericytes when compared to pericytes isolated from non-neoplastic brain tissue from the same patient. More specifically, GBM-derived pericytes showed lower induction of pro-inflammatory molecules, Intracellular Adhesion Molecule 1 (ICAM-1), Vascular Cell Adhesion Molecule (VCAM-1), and Monocyte Chemoattractant Protein 1 (MCP-1) when compared to normal brain pericytes. Due to the involvement of these molecules in immune cell recruitment and infiltration, this decreased response may contribute to the maintenance of GBM microenvironment immunosuppression. This highlights potential targets for alleviating such immunosuppression, which could enhance the success of immunotherapy-based treatments for GBM.
Multidimensional Assessment of the Host Response in Mechanically Ventilated Patients with Suspected Pneumonia
Authors: James M. Walter, Ziyou Ren, Tyrone Yacoub, Paul A. Reyfman, Raj D. Shah, Hiam Abdala-Valencia, Kiwon Nam, Vince K. Morgan, Kishore R. Anekalla, Nikita Joshi, Alexandra C. McQuattie-Pimentel, Ching-I Chen, Monica Chi, SeungHye Han, Francisco J. Gonzalez-Gonzalez, Saul Soberanes, Raul P. Aillon, Satoshi Watanabe, Kinola J. N. Williams, Ziyan Lu, Joseph Paonessa, Peter Hountras, Madonna Breganio, Nicole Borkowski, Helen K. Donnelly, Jonathan P. Allen, Luis A. Amaral, Ankit Bharat, Alexander V. Misharin, Neda Bagheri, Alan R. Hauser, G. R. Scott Budinger, Richard G. Wunderink
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

The identification of informative elements of the host response to infection may improve the diagnosis and management of bacterial pneumonia.