tbuckley/cabot-search huggingface dataset:
CSIG-30. DEUBIQUITINATING ENZYME (USP5) COOPERATE WITH RNA BINDING PROTEIN (hnRNPA1) DURING GLIOMA PROGRESSION, BRING THERAPEUTIC INSIGHTS
Authors: Ajay Yadav
Journal: Neuro-Oncology (2018)

Glioma is a challenging disease with median survival less than a year. Disease reoccurrence where RNA binding proteins are potentially involved in modulating the whole cascade of event. Flexibility in alternative splicing variants formation are the major events, where key regulators (RBP’s) are under the control of deubiquitinating enzymes. Expression analysis of USP5 were evaluated in between Grade II and Grade IV Gliomas immunohistochemistry. USP5 expression were elevated in grade IV GBMs, whereas Grade II lacks its expression. USP5 expression were positively correlated with hnRNPA1(RBP). Western blotting experiments were performed in USP5 knock down glioma cell line shows downregulation of hnRNPA1. Similarly, interaction between USP5 and hnRNPA1 were performed, indicating a positive cooperation between USP5 and hnRNPA1. Ubiquitination and deubiquitination profiling of hnRNPA1 from grade to grade basis will help us in evaluating the disease outcome. Screening of drugs against USP5 activity along with expression studies of RNA binding proteins, would be a best strategy, to evaluate the therapeutic efficacy.
Abstract 17203: The Prognostic Value of Serum Potassium Levels in Patients With Heart Failure (HF) With Preserved Left Ventricular (LV) Ejection Fraction (HFpEF)
Authors: Taiki Nishihara, Takanori Tokitsu, Eiichiro Yamamoto, Masafumi Takae, Koichiro Fujisue, Daisuke Sueta, Yasuhiro Izumiya, Koichi Kaikita, Kenichi Tsujita
Journal: Circulation (2017)

Aims: Cellular potassium is important in cell-metabolism and -membrane excitability, and serum potassium (sK) levels are closely associated with the prognosis of chronic HF patients. However, its clinical significance in cardiovascular outcomes of HFpEF patients is not fully understood. Methods: We enrolled 512 consecutive HFpEF patients admitted to Kumamoto University Hospital between 2007 and 2013, and divided them into three groups according to sK levels (low-sK group; sK <4.0 mEq/L, mid-sK group; 4.0 ≤ sK <5.0 mEq/L, high-sK group; 5.0 mEq/L≤ sK). Results: Haemoglobin, serum sodium (sNa) and estimated glomerular filtration rate (eGFR) levels were lower and B-type natriuretic peptide, C-reactive protein, echo parameters (E/e’ and LV mass index), and usage of loop diuretics and aldosterone antagonists were higher in high-sK group compared to mid-sK group. By contrast, only sNa levels were higher in low-sK group compared to mid-sK group. Although there was no factor associated with low-sK, eGFR and usage...
Changes to Racial Disparities in Readmission Rates After Medicare’s Hospital Readmissions Reduction Program Within Safety-Net and Non–Safety-Net Hospitals
Authors: Krisda H. Chaiyachati, Mingyu Qi, Rachel M. Werner
Journal: JAMA Network Open (2018)

<h3>Importance</h3> Although readmission rates are declining under Medicare's Hospital Readmissions Reduction Program (HRRP), concerns remain that the HRRP will harm quality at safety-net hospitals because they are penalized more often. Disparities between white and black patients might widen because more black patients receive care at safety-net hospitals. Disparities may be particularly worse for clinical conditions not targeted by the HRRP because hospitals might reallocate resources toward targeted conditions (acute myocardial infarction, pneumonia, and heart failure) at the expense of nontargeted conditions. <h3>Objective</h3> To examine disparities in readmission rates between white and black patients discharged from safety-net or non–safety-net hospitals after the HRRP began, evaluating discharges for any clinical condition and the subsets of targeted and nontargeted conditions. <h3>Design, Setting, and Participants</h3> Cohort study conducting quasi-experimental analyses of patient hospital discharges for any clinical condition among fee-for-service Medicare beneficiaries from 2007 to 2015 after controlling for patient and hospital characteristics. Changes in disparities were measured within safety-net and non–safety-net hospitals after the HRRP penalties were enforced and compared with prior trends. These analyses were then stratified by targeted and nontargeted conditions. Analyses were conducted from October 1, 2017, through August 31, 2018. <h3>Main Outcomes and Measures</h3> Trends in 30-day readmission rates among white and black patients by quarter and differences in trends across periods. <h3>Results</h3> The study sample included 58 237 056 patient discharges (black patients, 9.8%; female, 57.7%; mean age [SD] age, 78.8 [7.9] years; nontargeted conditions, 50 372 806 [86.5%]). Within safety-net hospitals, disparities in readmission rates for all clinical conditions widened between black and white patients by 0.04 percentage point per quarter in the HRRP penalty period (95% CI, 0.01 to 0.07;<i>P</i> = .01). This widening was driven by nontargeted conditions (0.05 percentage point per quarter [95% CI, 0.01 to 0.08];<i>P</i> = .006), whereas disparities for the HRRP-targeted conditions did not change (with an increase of 0.01 percentage point per quarter [95% CI, −0.07 to 0.10];<i>P</i> = .74). Within non–safety-net hospitals, racial disparities remained stable in the HRRP penalty period across all conditions, whether the conditions were HRRP-targeted or nontargeted. <h3>Conclusions and Relevance</h3> Findings from this study suggest that disparities are widening within safety-net hospitals, specifically for non–HRRP-targeted conditions. Although increases in racial disparities for nontargeted conditions were modest, they represent 6 times more discharges in our cohort than targeted conditions.
TMIC-07. HYPOXIC MICROENVIRONMENT CONFERS SPECIFIC ALTERATIONS IN DNA METHYLATION PROFILES IN GLIOBLASTOMA
Authors: Sheila Mansouri, Carlos Velasquez, Shirin Karimi, Farshad Nassiri, Yasin Mamatjan, Olivia Singh, Julie Metcalf, Mira Li, Suganth Suppiah, Alireza Mansouri, Kenneth Aldape, Gelareh Zadeh
Journal: Neuro-Oncology (2018)

High cellularity and poorly organized tumour vasculature in high-grade gliomas leads to insufficient blood supply, hypoxic areas, and ultimately to the formation of necrosis. Thus, hypoxia is a hallmark of malignant glioma microenvironment and it is associated with aggressive tumor behavior such as growth, progression, and resistance to chemo-radiation. Current pathologic markers are insufficient to identify patients that may benefit from specific treatments. We therefore, hypothesized that underlying epigenetic alterations confer therapeutic resistance under hypoxic conditions. Twenty five GBM patients were consented and treated with pimonidazole (PIMO) 16–18 hours prior to surgery. Tumor sections were subjected to immunohistochemical analysis using antibodies against PIMO and other hypoxia markers such HIF1a and CAIX. Samples were subjected to laser capture microdissection followed by DNA isolation and DNA methylation profiling using the Illumina Human Methylation EPIC Array. Data was analyzed using minfi and conumee packages in Bioconductor, together with appropriate biostatistics tools. PIMO score was determined to range from 10–60% and positively correlated with other hypoxia markers such as CA IX and HIF1a (p4,000) were hypomethylated. Gene set enrichment analysis (GSEA) indicated that the majority of these CpGs are associated with genes involved in signalling cascades and oncogenic processes, including WNT and NOTCH. These were compared to DNA methylation profiles of glioma stem cells exposed to transient hypoxia and extensive overlap was found in proportion of hypomethylated CpG sites and cellular processes that were altered. These findings were correlated with complementary RNA expression data from RNA sequencing to establish the biological relevance of changes in DNA methylation profiles under hypoxia in GBM.
CSIG-34. PI3 KINASE PATHWAY ACTIVATION PROMOTES MALIGNANT PROGRESSION IN OLIGODENDROGLIAL TUMORS
Authors: Kensuke Tateishi, Taishi Nakamura, Alexandria Fink, Nina Lelic, Yuko Matsushita, Mara Koerner, Hidetoshi Murata, Koichi Ichimura, Tracy Batchelor, Tetsuya Yamamoto, Andrew Chi, John Iafrate, Hiroaki Wakimoto, Daniel Cahill
Journal: Neuro-Oncology (2018)

Oligodendroglioma (OD) is a subtype of adult diffuse glioma defined by IDH1/2 gene mutation and co-deletion of chromosomal arms 1p and 19q. Although prognosis in OD tumors is initially relatively favorable, the majority of OD develop outgrowth of a subclone that has undergone malignant transformation. Modeling the molecular mechanisms of this tumor progression is crucial to identify therapeutic targets for malignant disease. However, there are few available patient-derived OD xenograft models, which limit preclinical investigations. Here, we present novel patient derived anaplastic oligodendroglioma (AOD) xenograft models. In a panel of OD at different stages of disease, we harvested two distinct cell samples: those with and without PIK3CA mutation. From the tumor that subsequently rapidly progressed and had a PIK3CA mutation, we established a xenograft model that was lethal to the mouse and retained the PIK3CA mutation. In contrast, xenograft did not form from the other tumor that was clinically stable after resection and had wild-type PIK3CA. We confirmed AOD phenotype and the presence of IDH1 mutation and 1p/19q co-deletion in xenograft tissue, indicating successful capture of these signature OD genetic alterations. We also tested to see if PI3K/AKT/mTOR gene mutation could induce patient-derived OD xenograft formation. In our attempts to establish xenograft models, the presence of activating mutations in PI3K/AKT/mTOR pathway was consistently associated with successful xenograft establishment. OD/AOD tumors that did not form xenograft did not have mutation in the PI3K/AKT/mTOR pathway Importantly, we found progressive tumor cells that harbor mutant PIK3CA were vulnerable to alkylating agents and PIK/AKT/mTOR pathway inhibitors. These findings suggest there is a critical role of PI3K/AKT/mTOR pathway activation in driving progression and xenograft formation in oligodendroglial tumors. Our xenograft models will facilitate dissection of the mechanism of malignant transformation, contributing to the identification of optimal therapeutic strategies for patients with oligodendroglial tumors
NCOG-03. INDICATION OF AWAKE SURGERY FOR THE PATIENTS WITH GLIOBLASTOMA FROM THE VIEW POINT OF FUNCTIONAL INDEPENDENCE IN THE CHRONIC PHASE
Authors: Mitsutoshi Nakada, Riho Nakajima, Hirokazu Okita, Masashi Kinoshita
Journal: Neuro-Oncology (2018)

A growing number of studies demonstrated that awake surgery for lower-grade glioma results in both good functional and oncological outcome. However, indication of awake surgery for glioblastoma (GBM) has not been defined. Here, we intend to determine the indication of awake surgery for GBM based on the functional data at chronic phase. A total of 29 patients with GBM who underwent awake surgery between May 2012 and March 2018 were included (age: mean, 52.7; standard deviation [SD], 11.5). Additionally, 41 GBM patients (age, 65.4; SD, 11.4) who underwent surgery with general anesthesia (GA) were included as historical control. The Karnofsky Performance Status (KPS) of both groups were collected at pre- and postoperative 3 month (chronic phase). Moreover, to investigate factors relating to KPS score at chronic phase, multivariate analysis with following explanatory variables were performed: age, preoperative KPS score, genetic mutation, eloquent area, resected volume, laterality, and time of surgery. The rate of KPS score preservation was significantly higher in awake surgery group (72.4%) than that of GA group (51.2%, p=0.03). Factors that influence the KPS score at chronic phase were age and preoperative KPS score (p=0.014, p. CONCLUSIONS: Awake surgery for GBM patients is useful to preserve independence level at chronic phase. In the view of preservation of preoperative independence level, indication of awake surgery is KPS ≥ 90 and age ≤ 64.
CBMT-09. ESTABLISHMENT AND IN VITRO CHARACTERIZATION OF A SPORADIC PEDIATRIC ATYPICAL MENINGIOMA CELL LINE
Authors: Desmond Brown, Tatiana Kaptzan, Timothy Peterson, Mark Jentoft, David Daniels
Journal: Neuro-Oncology (2018)

Meningiomas represent ~30% of primary neoplasms in adults but only 0.4–4.6% in children. Due to the paucity of cases, relatively few studies have addressed pediatric meningiomas and there are insufficient cell lines to conduct in vitro studies. We have established and characterized a new cell line (PED-24) from a 12-year-old male who presented with headaches and subsequently underwent gross total resection of a sporadic, large left frontal meningioma, WHO grade 2. The tumor was focally positive for EMA and GFAP. Whole-exome sequencing of the patient was negative for NF-2. Compared to three high grade glioma lines (two H3K27M DIPG tumors and one adult GBM), PED-24 showed significantly increased growth kinetics as assessed by real-time live-cell analysis. The cells were also successfully cultured as neurospheres in neurobasal medium. Ultrastructural analysis with SEM and TEM demonstrated unique cellular morphology. Average cellular diameter was 3.2 ± 0.3 µm and the cells had a microvilli-covered smooth surface. There was a high burden of transport vesicles and an extensive network of endoplasmic reticulum with evidence of autophagy events. This line provides a resource for further exploration of pathogenic mechanisms involved in sporadic pediatric meningiomas. One novel avenue of interest is the potential presence of a stem-like subpopulation within sporadic pediatric atypical meningiomas.
IMMU-51. THE COMBINATION OF CCR2 ANTAGONIST AND PD-1 BLOCKADE PROLONGS SURVIVAL IN IMMUNE CHECKPOINT INHIBITOR RESISTANT GLIOMAS
Authors: Joseph Flores-Toro, Defang Luo, Adithya Gopinath, James Campbell, Israel Charo, Rajinder Singh, Thomas Schall, Jeffrey Harrison
Journal: Neuro-Oncology (2018)

Immuno-therapy directed at the PD-1/PD-L1 axis has produced significant treatment advances in various human cancers. Unfortunately, this progress has not extended to glioblastoma, with recent clinical trials failing to show efficacy of anti-PD-1 monotherapy in recurrent tumors. Commonly employed murine glioma models exhibit varied responsiveness to anti-PD-1 monotherapy, e.g. GL261 gliomas are sensitive while KR158 tumors are resistant. Previously, we reported that combining PD-1 blockade with either chemokine receptor CCR2 deficiency or a CCR2 antagonist improved survival over anti-PD-1 monotherapy in GL261 gliomas. This was associated with reduced numbers of MDSCs within tumors. The current study evaluated the combination of PD-1 blockade and a novel CCR2 antagonist in anti-PD-1 resistant gliomas. Determine if combination anti-PD-1/CCR2 antagonist therapy is an effective treatment in anti-PD-1 insensitive gliomas. Overall survival and immune cell characteristics were determined in KR158 and 005GSC gliomas established in either CCR2 deficient or wild type mice treated with CCR2 antagonist (CCX872) and/or PD-1 blockade. CCR2 deficiency unmasked an anti-PD-1 survival benefit in KR158 glioma-bearing mice. CCX872 increased median survival as a monotherapy in KR158 tumor-bearing animals, and significantly increased median and durable overall survival when combined with anti-PD-1. In 005GSC tumors, the combination of CCX872 and anti-PD-1 prolonged median survival time. Increases in overall CCR2+ cells and CD11b+/Ly6Chi myeloid derived suppressor cells (MDSC, known to be CCR2+) were evident in the bone marrow of CCR2-deficient mice. Additionally, these mice exhibited decreased MDSCs within established gliomas. The data demonstrate CCX872/anti-PD-1 synergize to increase survival in clinically relevant glioma models via reduced MDSC infiltration, resulting in a tumor microenvironment favorable for anti-PD-1 efficacy. The combination of CCX872 and anti-PD-1 is effective in clinically relevant murine glioma models, providing a basis on which to progress this novel combinatorial treatment toward early phase human trials.
Merkel Cells Activate Sensory Neural Pathways through Adrenergic Synapses
Authors: Benjamin U. Hoffman, Yoshichika Baba, Theanne N. Griffith, Eugene V. Mosharov, Seung-Hyun Woo, Daniel D. Roybal, Gerard Karsenty, Ardem Patapoutian, David Sulzer, Ellen A. Lumpkin
Journal: Neuron (2018)

Epithelial-neuronal signaling is essential for sensory encoding in touch, itch, and nociception; however, little is known about the release mechanisms and neurotransmitter receptors through which skin cells govern neuronal excitability. Merkel cells are mechanosensory epidermal cells that have long been proposed to activate neuronal afferents through chemical synaptic transmission. We employed a set of classical criteria for chemical neurotransmission as a framework to test this hypothesis. RNA sequencing of adult mouse Merkel cells demonstrated that they express presynaptic molecules and biosynthetic machinery for adrenergic transmission. Moreover, live-cell imaging directly demonstrated that Merkel cells mediate activity- and VMAT-dependent release of fluorescent catecholamine neurotransmitter analogs. Touch-evoked firing in Merkel-cell afferents was inhibited either by pre-synaptic silencing of SNARE-mediated vesicle release from Merkel cells or by neuronal deletion of β2-adrenergic receptors. Together, these results identify both pre- and postsynaptic mechanisms through which Merkel cells excite mechanosensory afferents to encode gentle touch.Video AbstracteyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiIyYjNjMDdjNWU5MjdhZDljNWYyMzg0ZTJjNjk1ZmQxNCIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjc3NzU4OTUwfQ.nLUTHym69Mv8-4M_XzF058JZU2a__6fyq0jQK_5SsTgSSHtK8NDRU9-_2DmS2q-EaasZB7L-0zEX-PrktDBaG81zjVRWO8OTzj_f3AtwHcYo1r5tL5AFiyHmWCL-ddsYsLJoO1Sn7AFI9lr66B1PFsc-WqatFFTo62iHTtl9rB04umXYqN0dflA2HJwGH6VWEJFGBc0xNDAXTi5a7b3ar3aNxOYVtPIfg8nPDOYTDz3C1jUKvybaUZ1LDM6aL6AOxKPdFXPTK-5DmALG-7smWiB2C-CAX7dQEypgQNjLtGkQX7VohLxPWD1E5tbpYgMd6grLR1DtZpPVKb0wJLABSg(mp4, (39.47 MB) Download video
PI-88, a novel heparanase inhibitor, as adjuvant therapy for hepatocellular carcinoma: A large randomized phase II clinical trial
Authors: Anand Gautam, Elizabeth Wilson, Pei-Jer Chen, Po-Huang Lee, Deng-Yn Lin, Cheng-Chung Wu, Long-Bin Jeng, Pin-Wen Lin, King-Tong Mok, Chun-Jen Liu, Wei-Chen Lee, Hong-Zen Yeh, Kuan-Lang Lai, Shi-Chung Chang
Journal: Cancer Research (2007)

2650  Background/Aims: PI-88 is a first in class mimetic of heparan sulfate (HS) which targets two biological processes critical to the growth and progression of solid tumours: angiogenesis and metastasis. It antagonises HS interaction with angiogenic growth factors and inhibits cleavage of HS by heparanase in the extracellular matrix. Approximately 17,500 doses of PI-88 have been administered to 427 subjects at a variety of dosing regimens in phase I and phase II clinical trials in multiple myeloma, hepatocellular carcinoma (HCC), lung cancer, metastatic melanoma and prostate cancer. Overall, PI-88 has been well tolerated with an acceptable safety profile and has shown early signs of benefit in patients. Despite high first-year recurrence rates, few treatment options exist for patients in the adjuvant HCC setting. This phase II trial represents a unique opportunity to assess anti-angiogenic compounds, such as PI-88, in a patient population with a low tumour burden and aims to evaluate the efficacy and safety of PI-88 in patients with HCC following curative hepatic resection.   Methods: The trial was a randomized, three-arm, open label study. Following curative HCC resection, eligible patients were randomized 1:1:1 to an untreated control arm, or to self-administer subcutaneously one of two dose levels of PI-88 (160 or 250 mg/day) for 4 consecutive days per week for 3 weeks followed by a 1 week observation period. Patients were treated for up to 9 treatment cycles (36 weeks), with a follow-up period of 12 weeks, to assess disease-free rate and time to first recurrence.  Results: The trial recruited 172 Asian patients at six centres in Taiwan. 169 patients were evaluable for efficacy (median age = 53; M:F = 134:35; HBV:HCV:HBV+HCV:NBNC = 115:29:9:16). 38 patients (22%) had a CLIP score ≥ 3; 39 patients (23%) showed vascular invasion and 95 patients (53%) presented with liver cirrhosis. Preliminary safety data indicates that PI-88 has been well tolerated in this study, particularly at 160 mg/day.  Conclusions: PI-88was well tolerated in this patient population and warrants further investigation. Preliminary disease-free survival and recurrence rates at 30 weeks will be presented.
PATH-59. THALAMIC GLIOMAS WITH H3 K27M MUTATION. A CASE SERIES AND LITERATURE REVIEW
Authors: Divya Mella, Rahul Abhyankar, Edward Pan
Journal: Neuro-Oncology (2018)

To report 3 cases of thalamic gliomas harboring H3 K27M mutation and review the available literature. Thalamic gliomas are rare tumors. They predominantly occur in children and young adults. The World Health Organization 2016 classification of brain tumors defines diffuse midline glioma H3 K27M-mutant as a new entity and includes diffuse intrinsic pontine glioma (DIPG) among gliomas in other midline locations such as thalamus and spinal cord. Previously published case series report an unfavorable outcome in patients harboring this mutation. Retrospective chart reviews were conducted for patients with thalamic gliomas harboring H3 K27M mutation at the University Of Texas Southwestern Medical Center. 3 patients with thalamic gliomas were identified.The patients consented to publication of their diagnostic studies. 2 were female and 1 was male. Age at diagnoses was 18, 21 and 24. All 3 patients presented with headaches secondary to increased intracranial pressure. Gadolinium enhanced brain magnetic resonance imaging in all 3 patients showed thalamic cysts with enhancing mural nodules. 2 out of 3 patients underwent extensive resection of the mass and one underwent a subtotal resection. Pathology demonstrated WHO Grade I pilocytic astrocytoma in 2 cases and high grade astrocytoma in the third. All 3 samples were positive for the H3 K27M mutation. Due to the presence of the H3 K27M mutation, all 3 patients were treated as WHO Grade IV Glioblastoma with chemoradiation and maintenance chemotherapy following resection despite 2 patients demonstrating a pilocytic astrocytoma for which complete resection is curative. In children and young adults, gliomas harboring the H3 K27M mutation are characterized by a midline location and unfavorable prognosis. These cases highlight the need to aggressively treat midline gliomas with H3 K27M mutation regardless of their histological appearance. New targeted therapeutic approaches are needed to treat these tumors.