tbuckley/cabot-search huggingface dataset:
RDNA-18. TP5, A PEPTIDE INHIBITOR OF ABERRANT AND HYPERACTIVE CDK5/p25: A NOVEL THERAPEUTIC APPROACH AGAINST GLIOBLASTOMA
Authors: Emeline Tabouret, Herui Wang, Niranjana Amin, Christophe Redon, Jinkyu Jung, Jing Cui, Qi Song, Limin Liu, Romain Appay, Anjali Vyas, Deric Park, Mark Gilbert, Harish Pant, Zhengping Zhuang
Journal: Neuro-Oncology (2018)

Increasing evidence suggests a role of increased expression of CDK5 in cancer progression. Here, we examined the efficacy of selective inhibition of CDK5 in glioblastoma, the most frequent and aggressive primary brain tumor in adults. TP5 is a small peptide developed by National Institutes of Health which selectively inhibits aberrant and hyperactive CDK5/p25 while preserving the physiological CDK5/p35 functions. This peptide was modified to facilitate passage through blood brain barrier. METHODS & We demonstrated that TP5 decreased the activity but not the expression of CDK5 and p35. TP5 alone, but not the scrambled peptide, impacted cell viability and colony formation of glioblastoma cell lines and increased early and late apoptosis. Analyzing the pH2A.X expression by Immunofluorescence and Western Blot, we observed that TP5 increased the DNA damage in a dose dependent manner. TP5 impaired the DNA repair by reducing the G2 phase and decreased the phosphorylation of ATM. Whereas CDK5 activity is increased by DNA-damaging agents such as temozolomide (TMZ) and irradiation (IR), we observed that the addition of TP5 to either TMZ or IR was synergistic on colony formation due to an accumulation of DNA damages. Concomitant use of TP5 and either TMZ or IR increased the pH2A.X foci number and expression, inhibited the G2 arrest induced by these therapies and the phosphorylation of ATM. TP5 alone (300 mg/kg every 2 days) decreased the tumor volume of orthotopic glioblastoma mouse-model in a safety and dose-escalation experiment (4 mice per group: control, scrambled peptide, 100mg/kg, 300mg/kg). The treatment was well tolerated as the mouse weights were stable during the treatment and no hematologic, renal, pancreatic or liver function toxicities were observed (blood test). CONCLUSIONS: TP5 is a promising therapy for glioblastoma patients alone or in association with temozolomide and radiotherapy targeting a unique aspect of tumor biology.
Evaluation of Lowering the <i>P</i> Value Threshold for Statistical Significance From .05 to .005 in Previously Published Randomized Clinical Trials in Major Medical Journals
Authors: Cole Wayant, Jared Scott, Matt Vassar
Journal: JAMA (2018)

This study evaluates primary end points in randomized clinical trials (RCTs) published in 3 major general medical journals to determine how changing the P value threshold for statistical significance from .05 to .005 could affect the interpretation of previously published RCTs.
TMOD-10. METABOLIC AND BLOOD-BRAIN BARRIER MARKERS FOR FLUORESCENCE-GUIDED SURGERY: SYSTEMATIC HIGH-RESOLUTION MICROSCOPY INVESTIGATION IN HUMAN RELEVANT EXPERIMENTAL GLIOMAS
Authors: Evgenii Belykh, Alessandro Carotenuto, Laeth George, Eric Miller, Debbie R Healey, Ernesto Luna-Melendez, Vadim A Byvaltsev, Michael Staren, Adrienne Scheck, Chad Quarles, Shwetal Mehta, Peter Nakaji, Mark Preul
Journal: Neuro-Oncology (2018)

Fluorescence guidance with 5-aminolevulinic acid(5-ALA) increases resection extent and may benefit surgical outcomes in high-grade gliomas. We investigated if a combination of various fluorescence guidance techniques can provide further advantage. We systematically assessed and compared the fluorescent patterns of 5-ALA-induced protoporphyrin IX (PpIX), fluorescein sodium(FNa) and indocyanine green(ICG) to identify GL261 gliomas in mice and RFP-U251 gliomas in rats. 5-ALA(5mg), FNa(5 mg/kg) and ICG(20mg/kg) were administered perioperatively. Fluorescence patterns were recorded with operative microscope, laser scanning confocal microscope, and confocal laser endomicroscope. Fluorescence was assessed quantitatively as a surface area of fluorescent positive tissue and qualitatively(false/true, positive/negative) as compared to HE-stained histology. FNa highlighted a larger surface area(18.0mm2) than white light(16.9mm2,p=0.016) or PpIX (16.0mm2,p=0.035). Both 5-ALA and FNa showed inhomogeneous staining patterns: multiple areas of equal staining, when PpIX was present and FNa was not, and vice versa. ICG was visible in 8/31 tumor samples, all immediately after injection. ICG did not reveal clear tumor margins, but stained non-tumor tissue and nearby vasculature. FNa signal was stronger (tumor to background ratio (TBR)1.93 ± 0.56) compared to 5-ALA(1.52 ± 0.31;p ICG highlighted tumor only within the first few minutes and stained mostly hypervascularized areas. Confocal and surgical imaging revealed inhomogeneous tumor border staining with PpIX/FNa. Simultaneous administration of 5-ALA and FNA may provide additional benefit. Neither ICG, 5-ALA or FNa worked perfectly, emphasizing the need for more specific markers for fluorescence-guided brain tumor resection.
Abstract 16663: Premature Ventricular Contractions and Incident Heart Failure: Identifying Risk Factors via Interaction Analyses
Authors: Vratika Agarwal, Eric Vittinghoff, Isaac R Whitman, Thomas A Dewland, Jonathan Dukes, Gregory M Marcus
Journal: Circulation (2015)

Introduction: Premature ventricular contraction (PVC)-induced cardiomyopathy is a potentially reversible cause of heart failure (HF). The association between PVCs and HF has been limited to case reports and small observational studies. Our objective was to leverage a large population-based database to examine interactions that might prove clinically useful in risk stratification. Methods: We included adult patients free of structural heart disease in the California Healthcare Cost and Utilization Project (HCUP) database from 2005-2009. After excluding patients with prevalent cardiomyopathy or heart failure, we identified patients with a diagnosis of PVCs. The primary outcome was incident systolic HF. Results: Among 16.8 million patients experiencing 48.1 million hospitalizations, 35,817 (0.2%) had a PVC diagnosis, and 198,818 (1.2%) developed systolic HF during study follow-up. After adjustment for age, sex, race, income &amp; known HF risk factors, PVCs were an independent predictor of systolic HF [Hazard Ratio (HR) 1.57, 95% CI 1.51-1.63, p-value&lt;0.001]. Interaction analyses revealed that relationship between PVCs and incident systolic HF was especially strong among younger patients and in those without coronary artery disease (CAD), hypertension (HTN), diabetes mellitus (DM) or atrial fibrillation (AF) [Table 1]. In patients &lt;65 years without HTN, DM, CAD or AF, a PVC diagnosis was associated with an over 6-fold increase in incident HF risk (HR 6.5, 95% CI 5.5-7.7, p&lt;0.001). Conclusion: Using a large population-based database, we found that a diagnosis of PVCs predicts incident systolic HF even after adjusting for conventional risk factors. This effect is most pronounced in younger patients, and those without HTN, DM, CAD or AF, suggesting that PVCs impart the greatest risk for heart failure when other cardiac comorbidities are absent.
TMIC-41. APOPTOTIC CELLS PROMOTE MALIGNANCY OF SURVIVING GLIOBLASTOMA CELLS BY INTERCELLULAR TRANSFER OF SPLICING FACTORS
Authors: Marat Pavlyukov, Soniya Bastola, Hai Yu, Victoria O Shender, Ksenia Anufrieva, Do-Hyun Nam, Ichiro Nakano
Journal: Neuro-Oncology (2018)

Because of the pressure of rapid expansion of tumor, intratumoral microenvironment becomes inevitably harsh, resulting in abundant apoptotic tumor cells intermingled with neighboring proliferating cells. Recent studies have suggested that signals from dying cells may play an important role in the progression of various types of malignancies including glioblastoma (GBM). Nonetheless, mechanisms involved in the transduction of signal between apoptotic and surviving tumor cells remains elusive. Our findings recently published in Cancer Cell journal revealed that glioblastoma cells can specifically secrete RNA and protein components of spliceosomes after the courses of chemo- and radiotherapy. Further experiments demonstrated that spliceosomal proteins are exported by apoptotic cancer cells within exosome-like extracellular vesicles (EVs). These EVs induce pre-mRNA splicing changes in recipient glioblastoma cells and promote proliferation, migration, therapy resistance and aggressive mesenchymal phenotype of glioblastoma patient-derived neurospheres both in vitro and in vivo. Mechanistically, we identified RBM11 as a representative splicing factor that is upregulated in tumors after therapy and shed in EVs upon induction of apoptosis. Once internalized in recipient cells, exogenous RBM11 switch splicing of MDM4 and CyclinD1 towards the expression of more oncogenic isoforms which is associated with worse patient prognosis. Taken together, our findings reveal a novel role of spliceosomal proteins in intercellular communication between apoptotic and surviving tumor cells. It is likely that this mechanism is applicable to cancer types beyond GBM. Clinically, our data may provide the rationale for the molecular targeting of RNA splicing events or specific splicing factors to attenuate the gain of post-therapeutic malignant changes in GBM.
Abstract 16681: Hepatic Nuclear Factor 4 Alpha is the Major Regulator of Alanine:Glyoxylate Aminotransferase 2 Expression - A Novel Link Between Diabetes and Impaired Metabolism of Nitric Oxide and Lipids
Authors: Alexey A Kolobov, Dmitry V Burdin, Anton V Demyanov, Alexey A Soshnev, Chad Brocker, Nikolay Samusik, Silke Brilloff, Jens Martens-Lobenhoffer, Theresa Reetz, Renke Maas, Stefanie M Bode-Böger, Frank Gonzalez, Norbert Weiss, Roman N Rodionov
Journal: Circulation (2014)

Background: Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is elevated in numerous diseases associated with impairment in nitric oxide (NO) production, includ...
RDNA-13. VALIDATION OF BEHAVIORAL ANALYSIS ACROSS AGE IN A MOUSE MODEL FOR FUTURE INVESTIGATION OF RADIATION-INDUCED HYPERSOMNOLENCE (RIH) IN PRIMARY BRAIN TUMOR (PBT) PATIENTS
Authors: Caitlin Figiel, Dorela Shuboni-Mulligan, Terri Armstrong, DeeDee Smart
Journal: Neuro-Oncology (2018)

Cranial radiation is part of standard PBT treatment with patient age recognized to impact response and toxicity. RIH is one of the most common toxicities. We have reported an association between circadian gene variants and RIH susceptibility. No rodent model for RIH has been validated. The purpose of this study is to evaluate the impact of age on activity and circadian behavior to inform our novel mouse model of RIH. Ethovision XT Software and Phenotyper cages wereused to continually video animal behavior and generate general activity data. Male young (6wk, n=3) or old (18mo, n=3) C57BL/6 mice were individually housed. Mice were monitored for 10 days under 12:12hr light:dark conditions. The data was examined for activity and circadian parameters. Older mice had lower total activity levels (-36%) than younger controls, with greatly decreased levels during the active period (-49%) but increased levels during the sleep period (49%). Actograms of general activity binned in 10 min intervals demonstrated a dramatic impact of age on circadian rhythms. Older mice displayed a dampened amplitude of activity rhythms (-36%; t= 4.1, p<0.01) and higher phase angle of entrainment (40.3 ± 25.8min) compared to younger mice (-1.11 ± 0min). Earlier activity onset in older animals increased the total activity period (alpha) by 7% (t=2.9, p<0.05). Both general activity and circadian data collected with Ethovision XT provided clear validation of the technique. CONCLUSIONS: Activity, sleep and circadian rhythms are impacted by irradiation in patients. A good behavioral model to observe these changes has not yet been developed in rodents. Here we demonstrate a reliable system to collect/ analyze both activity and circadian parameters. Our study demonstrates a clear difference in all parameters at age extremes for control animals, a factor that warrants inclusion in our RIH model designed to recapitulate the human experience.
Case 34-2018: A 58-Year-Old Woman with Paresthesia and Weakness of the Left Foot and Abdominal Wall
Authors: Haatem M. Reda, H. Benjamin Harvey, Nagagopal Venna, John A. Branda
Journal: New England Journal of Medicine (2018)

A 58-year-old woman from New England presented to the outpatient neurology clinic in early autumn with hypoesthesia of the trunk and abdomen, paresthesia of the hands, and weakness of the left foot and abdominal wall. A diagnostic test was performed.
Hancock pledges to invest in prevention to tackle “root causes” of ill health
Authors: Gareth Iacobucci
Journal: BMJ (2018)

England’s health secretary, Matt Hancock, has pledged to invest more in primary and community care services and in tackling the social determinants of health as part of a major policy focus on prevention.

Hancock has made prevention one of his early priorities for the NHS.1 In a speech2 to the International Association of National Public Health Institutes on 5 November, he announced a forthcoming government green paper to take forward plans to place greater emphasis on early intervention and self management to improve the nation’s health.

As well as diverting more investment …
THU0684 Prevalence of rheumatic diseases in adult population in spain. episer 2016 study
Authors: D. Seoane-Mato, C. Sánchez-Piedra, F. Díaz-González, S. Bustabad
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Prevalence of rheumatic diseases was first studied in Spain in 2000 EPISER 2000 study<sup>1</sup>). Sociodemographic and lifestyle changes during the last 16 years and their possible influence in prevalence figures justify a new study. <h3>Objectives</h3> To estimate the prevalence of rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), Sjögren syndrome, symptomatic osteoarthritis (knee, hip, hands, cervical and lumbar spine), fibromyalgia, gout and symptomatic osteoporotic fracture in adult population in Spain. <h3>Methods</h3> Population-based multicenter cross-sectional study, with the participation of 78 municipalities in the 17 Spanish autonomous communities. The reference population are adults aged 20 and above residing in Spain. All participants gave their informed consent. CATI system (Computer Assisted Telephone Interview) was used for initial data collection and screening questionnaire. Diagnostic suspicions and diagnosis referred by the participants were studied by rheumatologists in the referral hospital for the selected municipalities. Statistical analysis: the prevalence of the rheumatic diseases were calculated using estimators and their 95% confidence intervals. Weights were calculated in each of the sampling stages in accordance with the probability of selection. The distribution of population in Spain obtained from the National Statistics Institute was taken into account. <h3>Results</h3> 4916 subjects were included in the study. 4753 completed their participation. Prevalence of rheumatic diseases were the following: The negative predictive value (NPV) of the initial screening questionnaire was 93.8%. The lower NPV corresponded to knee osteoarthritis (95.1%). <h3>Conclusions</h3> Prevalence of RA, PsA, AS, gout and SLE seems to be higher than previously published in other European countries. <h3>Reference</h3> [1] Carmona L, Ballina J, Gabriel R, Laffon A. The burden of musculoskeletal diseases in the general population of Spain: results from a national survey. Ann Rheum Dis2001;60(11):1040–5. <h3>Acknowledgements</h3> This study was funded by Celgene, Gebro Pharma, MSD, Novartis, Hopira/Pfizer and Sanofi Genzyme. <h3>Disclosure of Interest</h3> None declared
Cytoreductive Nephrectomy: Assessing the Generalizability of the CARMENA Trial to Real-world National Cancer Data Base Cases
Authors: Sohrab Arora, Akshay Sood, Deepansh Dalela, Hoang J. Tang, Amit Patel, Jacob Keeley, Quoc-Dien Trinh, Craig G. Rogers, Mani Menon, Firas Abdollah
Journal: European Urology (2018)
EXTH-53. IN VIVO QUANTITATIVE ANALYSIS OF ONCOLYTIC VIRUS-TUMOR KINETICS
Authors: Hirotaka Ito, Hiroshi Nakashima, Eric McLaughlin, E Antonio Chiocca
Journal: Neuro-Oncology (2018)

Oncolytic virus (OV) immunotherapy is becoming a clinically feasible therapy for cancer, with one FDA-approved product and many more in the clinical trial pipeline. Yet, there are still gaps in mechanistic knowledge related to how much oncolysis and OV replication is needed to achieve efficacious cytotoxic T cell responses. We have developed a series of “tools” to understand the kinetics of OV replication and correlate with antitumor efficacy. These consist of an oncolytic HSV that expresses two luciferase isoforms (Rluc and Fluc) activated at immediate early or late stages of viral replication cycle and U87dEGFR cells expressing a secreted luciferase (Cluc). Cluc levels in serum significantly correlated with tumor volumes measured by MRI (r = 0.9653). U87dEGFR-Cluc tumors in the brains of athymic mice were treated with this oncolytic HSV. Temporal analyses of the OV and tumor luciferases clustered mice into those that responded to therapy as assayed by stable MRIs or did not (MRIs showing increasing tumor volumes). While there was no significant difference in maximum tumor infection level by OVs between responders vs. non-responders (p = 0.17), responders showed significantly higher levels of replication (p = 0.036), followed by significantly faster decrease in both OV and tumor-expressed luciferases (p < 0.0001). Non-responders exhibited enlarging areas of tumor necrosis measured by T2 weighted MRI (increased from 10.3 to 17.4mm3 on day12-16 compared to a decrease from 10.8 to 4.7mm3 in responders) which correlated with the signal intensity of OV-expressed Rluc and Fluc (r = 0.6807 and 0.5526, respectively). Histologically, responders showed an even biodistribution of OV in tumors with densely recruited Iba-1 positive cells while non-responders had uneven distribution sometimes with tumor hemorrhages (3/6 in non-responders, 0/2 in responders). These analyses can help us better understand the results of OV therapy from clinical trials.
CADD-55. LOW SERUM 25 (OH) VITAMIN D LEVEL IS ASSOCIATED WITH INCREASED RISK OF PRIMARY CNS MALIGNANCY: A RETROSPECTIVE COHORT STUDY IN A VETERAN POPULATION
Authors: Emmanuel Mantilla, Salwa Maalouf, Oni Olurinde, Vikas Singh
Journal: Neuro-Oncology (2018)

Vitamin D (VitD) deficiency has been reported to be associated with numerous malignancies, presumed to be secondary to its action through VitD receptor, immune and cell cycle regulation. To investigate the relationship between VitD (25-hydroxyvitamin D [25(OH) D]) levels and primary brain malignancy. We conducted a retrospective cohort study of veterans who received care through VHA from January 2000 to December 2015 and had their VitD levels measured at least once over the course of their care. Primary outcome measure was the incidence of primary brain malignancy in relation to VitD levels. Exclusion criteria included diagnoses of metastatic brain cancer, meningeal, spinal, face, neck and throat malignancies; VitD measurements in the months of November to February; exposure to ionizing radiation; and presence of genetic factors predisposing to brain tumors formation. Propensity score matching and survival analyses were conducted on the cohorts to determine and compare the incidence and hazard ratios for brain malignancy between two groups of subjects. Group 1: subjects with VitD levels higher than 20 ng/ml; and Group 2: subjects with VitD deficiency defined as ≤ 20ng/ml. Kaplan Meier curves were plotted to compare the time to events between the groups. After matching the two groups on several confounders (Age, Gender, BMI, Smoking Status, Alcohol Abuse, Race, Ethnicity), the incidence of primary brain malignancy was significantly higher in Group 2 (384/251,636; 154 per 100,000) in comparison with Group 1 (992/694,707; 143 per 100,000). VitD deficiency was associated with higher risk of primary brain malignancy (HR 1.129, CI [1.004 -1.269] p <0.05). Kaplan Meier analysis showed subjects with vitamin D had lower probability of survival free from primary brain malignancy that was statistically significant. Findings from this study suggests increased risk of primary brain malignancy in subjects with VitD deficiency.
ACTR-71. PHASE 1/2 STUDY OF DIANHYDROGALACTITOL (VAL-083) WITH RADIATION THERAPY IN PATIENTS WITH NEWLY DIAGNOSED, MGMT-UNMETHYLATED GLIOBLASTOMA
Authors: Zhong-ping Chen, Chengcheng Guo, Jeffrey Bacha, Anne Steino, John Langlands, Claire Kwan, Sarath Kanekal, Richard Schwartz, Lorena Lopez, Dennis Brown
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard-of-care includes surgery followed by chemo-radiation and temozolomide. An unmethylated promoter for O6-methylguanine-DNA-methyltransferase (MGMT) is a validated biomarker for temozolomide-resistance and is strongly correlated with poor outcomes. Unmethylated MGMT represents the majority of newly diagnosed GBM tumors. VAL-083 is a first-in-class bi-functional DNA-targeting agent that has shown activity against GBM in NCI-sponsored clinical trials both as single agent and in combination with radiotherapy. VAL-083 induces interstrand cross-links at N7-guanine, leading to DNA double-strand breaks and cell-death. VAL-083s unique mechanism-of-action circumvents MGMT-mediated chemoresistance, and it has demonstrated cytotoxicity in MGMT-unmethylated GBM cell-lines, cancer stem cells (CSCs) and in vivo models. Furthermore, VAL-083 acts as a radiosensitizer in GBM CSCs and non-CSCs. We completed a dose-escalation trial of VAL-083 in recurrent GBM, and a generally well-tolerated dosing regimen was selected for further clinical development. The present trial is an ongoing open-label, biomarker-driven, Phase 1/2 study to evaluate the tolerability and efficacy of VAL-083 in combination with radiotherapy in newly diagnosed MGMT-unmethylated GBM patients. A treatment regimen, consisting of a 6-week induction period of VAL-083 and concurrent radiation (2 Gy daily, 5 days/week) followed by up to 24 weeks of maintenance therapy with single-agent VAL-083, is being evaluated. The study is being conducted in two parts: 1) a dose-escalation part (20, 30, and 40mg/m2/day IV infusion on days 1,2,3 of a 21-day cycle) in up to 10 patients; 2) an expansion part in up to 20 additional patients at the determined well-tolerated dose. Tumor response will be assessed by MRI, according to RANO criteria. Efficacy endpoints include progression-free survival (PFS) and overall survival (OS). Additional endpoints include safety evaluations and pharmacokinetic assessments of plasma and CSF samples. Enrollment and safety data update will be provided at the meeting. Clinicaltrials.gov identifier: NCT03050736.