tbuckley/cabot-search huggingface dataset:
SP0167 Renal urate transporters (SUMMARY FOR CLINICIANS)
Authors: F. Perez Ruiz
Journal: Annals of the Rheumatic Diseases (2018)

<h3></h3> Gout was, and still is in some academic environments, a "metabolic" disease. The advent of allopurinol in the mid of the XXth century, the first xanthine-oxidase inhibitor, precluded that most subjects with "primary gout" were to suffer from overproduction of uric acid. No actual overproduction was neatly demonstrated and some empiric observations showed that "renal underexcretion" was working in most patients with gout. In 2002, Enomoto and coworkers characterised the first renal urate transporter, URAT1, encoded by SL22A12, showing that the human knockout for URAT1 was associated with familiar hypouricemia. A bunch of uric acid transporters have been characterised since then, polymorphisms of some of them being associated with variability in renal handling of urate. The function of ransporters is complex: PDZK1 (also known as NHERF3) is a scaffolding protein that binds to several urate transporters such as URAT1, OAT4, and NPT1. Therefore, PDZK1 plays a pivotal role in forming a urate-transporting multimolecular complex (also named "urate transportsome") in humans. Hyperuricemia is no more a metabolic disease: it is a "transportpathy". In addition, linkage of urate transporters to Na, P, and sugars may help understanding some comorbid conditions associated to hyperuricemia and gout, such as diabetes and hypertension. In addition to the previously referred, ABCG2 is a cassette binding protein expressed in the in the kidney and more importantly in the intestine, where is involved with active excretion. The discovery of ABCG2 helped to explain that apparent overproduction in some patients is a "renal overload" due to impaired intestinal excretion. A summarised knowledge on the urate transporters may be useful for clinicians implicated in the management of gout, as it may explain why XOIs efficacy does differ in patients with apparent overproduction, why allopurinol response may be blunted in some patients, how targeting transporters may be helpful for the development of new urate-lowering molecules, and how to explain efficacy and safety models for uricosurics and combination therapies. <h3>Disclosure of Interest</h3> F. Perez Ruiz Grant/research support from: Asociación de reumatologos de Cruces, Consultant for: Grünenthal, Menarini, Speakers bureau: Grünenthal, Menarini
ANGI-08. TARGETING THE RhoGEF BETA-PIX TO ENHANCE THE ACTIVITY OF BEVACIZUMAB IN GLIOBLASTOMA: A NANOPARTICLE MEDIATED GENE SILENCING APPROACH
Authors: Kate Connor, David Murray, Bo Lou, Kieron Sweeney, Monika Jarzabek, Ian Miller, Alice O’Farrell, Eduardo Ruiz-Hernandez, Garry Duffy, Alan Wolfe, Enrico Mastrobattista, Raymond Schiffelers, Wim Hennink, Marc Symons, Annette Byrne
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM), a highly invasive brain malignancy, remains an incurable disease. Angiogenesis, the formation of new vasculature, is a defining feature of this disease. Targeting GBM angiogenesis with Bevacizumab (Bev) is associated with improved progression free survival, but may also enhance tumour invasion into the surrounding parenchyma (Norden et al., 2008) and is not curative. Rho GTPases and their activators, guanine nucleotide exchange factors (GEFs), play central roles in the invasive process (4). Herein, we sought to identify and target GEFs of importance in mediating GBM invasion with a view to improving Bev response. We report a novel mechanism by which GBM tumours invade and proliferate via overexpression of the GEF beta-PIX gene which was shown to be increased at the invasive edge in 74% of GBM tumours assessed (n=19), compared with tumour core (Hoelzinger et al., 2005). We have further demonstrated that siRNA-mediated knockdown of beta-PIX in GBM patient-derived xenograft cell cultures and cell lines resulted in decreased cell invasion in 3D, cell proliferation and survival assays in vitro. An in vivo pilot study whereby beta-Pix knockdown was achieved using commercially available alphaV-beta3 integrin targeting nanoparticles (InVivoPlex Aparna Bio Corp), suggested that treatment with beta-PIX siRNA nanoparticles in combination with Bev could improve survival compared with Bev- alone in tumour-bearing animals. To further develop this strategy, we have recently designed and characterized a proprietary novel biodegradable, RGD-targeting and cholesterol-stabilized polyplex system for siRNA delivery in GBM. This novel nanoparticle system supports efficient gene silencing, and demonstrates a low toxicity profile in vitro and in vivo. We are currently performing advanced pre-clinical efficacy studies employing a clinically relevant GBM rodent resection model (Sweeney et al., 2014), to determine if nanoparticle mediated beta-PIX gene silencing will improve survival outcomes when combined with Bevacizumb and delivered in the adjuvant setting.
ATIM-21. UPDATED RESULTS OF A PHASE I TRIAL OF ANTI-LAG-3 OR ANTI-CD137 ALONE AND IN COMBINATION WITH ANTI-PD-1 IN PATIENTS WITH RECURRENT GBM
Authors: Michael Lim, Xiaobu Ye, L Burt Nabors, Anna Piotrowski, Manmeet Ahluwalia, Arati Desai, Tobias Walbert, Joy Fisher, Serena Desideri, Megan Sims, Patrick Wen, Stuart Grossman
Journal: Neuro-Oncology (2018)

Others and we have shown additional checkpoint molecules are expressed in GBM and preclinical studies have shown that combining anti-Lag-3 and anti-CD137 with anti-PD-1 can induce effective antitumor immune responses. The Adult Brain Tumor Consortium (ABTC) 1501 trial is a phase I, open label, multicenter, multi-arm dose-finding/safety study of anti-LAG-3 (BMS-986016) or anti-CD137 (BMS-663513) alone and in combination with anti-PD-1 in patients with first time recurrent GBM. The primary objective was to define MTD for the mono and combination treatments with a secondary objective of OS. Using a sequential allocation, we started with doses of 80mg for anti-LAG-3 and 8mg flat for anti-CD137. Anti-PD-1 was given at a flat dose of 240 mg in the combination treatment arms. Using a 3 + 3 design our target DLT rate was < 33%. To date 30 patients were enrolled into the trial with median age at 56, median KPS of 90. Median treatment cycle was 3 and 43% tumors were MGMT methylated. Recruitment of the monotherapy Anti-LAG-3 and anti-CD137 arms were completed. We observed no DLT at the highest dose for Anti-LAG-3 at 800mg and only one DLT (a grade 3 elevated serum ALT at end of cycle 2) with anti-CD137 at the top dose of anti-CD137 at 8mg flat. In addition, three out of 12 patients developed elevated ALT at end of cycle 2 that was considered possibly related to anti-CD137. Another two patients had grade 1 elevated ALTs. Six patients are currently enrolled into a combination cohort of Anti-LAG-3 at160mg +anti-PD-1with no observed DLT and the combination arm of anti-CD137 with anti-PD-1 is open to accrual. The safe monotherapy dose is 800mg for anti-LAG-3 and 8mg flat for anti-CD137. Both Anti-LAG-3 and anti-CD137 in combination with antiPD-1 cohorts and an intratumoral surgical anti-CD137 cohort are open for accrual.
Approaches to physical stimulation of metallic nanoparticles for glioblastoma treatment
Authors: Sophie Pinel, Noémie Thomas, Cédric Boura, Muriel Barberi-Heyob
Journal: Advanced Drug Delivery Reviews (2018)

Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor. Despite new knowledges on the genetic characteristics, conventional therapy for GBM, tumor resection followed by radiotherapy and chemotherapy using temozolomide is limited in efficacy due to high rate of recurrence. GBM is indeed one of the most complex and difficult cancer to treat mainly due to its highly invasive properties and the standard treatments are thus rarely curative. Major challenges in the treatment of GBM are the limitation of irreversible brain damage, the infiltrative part of the tumor which is the ultimate cause of recurrence, the difficulty of identifying tumor margins and disseminated tumor cells, and the transport across the blood-brain barrier in order to obtain a sufficient therapeutic effect for pharmalogical agents. Considering these limitations, this review explores the in vivo potential of metal-based nanoparticles for hyperthermia, radiotherapy and photodynamic therapy. This article describes and clearly outlines the recent in vivo advances using innovative therapeutic metallic nanoparticles such as iron oxide, silver, gadolinium and gold nanoparticles.
HOUT-23. ASSOCIATION BETWEEN TREATMENT FACILITY VOLUME AND MORTALITY IN PATIENTS WITH GLIOBLASTOMA (GBM): A LARGE NATIONAL ANALYSIS
Authors: Sonikpreet Aulakh, Michelle DeDeo, Joseph Free, Kyle Berdeguez, Steven Rosenfeld, Alfredo Quinones-Hinojosa, Asher Chanan-Khan, Sikander Ailawadhi
Journal: Neuro-Oncology (2018)

GBM is an aggressive and incurable primary malignancy of the brain, treated with surgical resection and chemo-radiotherapy, yet it has a dismal prognosis of 12–14 month overall survival (OS). Optimal outcomes require an experienced team providing multidisciplinary management. We explored the association of treatment facility volume and mortality in patients with GBM. We identified incident GBM (ICD-O-3 code: 9440/3) cases from the National Cancer Database (NCDB) (2004–2013) and utilized Cox-regression to determine the facility volume-outcome (volume=quartiles; Q) relationship, adjusting for year of diagnosis, demographic (sex, age, race, ethnicity), socio-economic (income, education, insurance type), geographic (area of residence, treatment facility location, travel distance) and co-morbidity factors (Charlson-Deyo score). There were 114,467 patients (median age 60 years, range: 18–90) with GBM treated at 1207 facilities of which, 54.8% were men. Median annual facility volume was 5 patients/year (range: 0.1–136.4). The top 14 (1.2%) facilities treated >60 patients/year (10%). Median overall survival (OS) was 15 months There were significant differences (all p<0.001) in patient characteristics by facility volume. Unadjusted median OS by facility volume (months) was Q1: 29.1, Q2: 32.9, Q3: 36.4, Q4: 48.2 (p<0.0001). Multivariate analysis showed facility volume to be independently associated with all-cause mortality (Reference Q4; Q3 HR: 1.30, 95% CI 1.28–1.33; Q2 HR: 1.36, 95% CI 1.36–1.43; Q1 HR: 1.58 95% CI 1.50–1.67). OS disparity by facility volume is persistent but not worsening in recent years (2010–2013 vs 2004–2005). In GBM, facility-volume independently affects OS of the patients. Attempts should be made to address modifiable factors and get patients access to high-volume centers earlier in the disease course.
RTHP-17. PATTERNS OF RE-IRRADIATION FOR RECURRENT GLIOMAS AND VALIDATION OF A PROGNOSTIC SCORE
Authors: Cathalijne Post, Miranda Kramer, Ernst Smid, Hiske van der Weide, Karin Kleynen, Mart Heesters, Joost Verhoeff
Journal: Neuro-Oncology (2018)

Re-irradiation is a generally accepted method for salvage treatment in patients with recurrent glioma. However, no standard radiation regimen has been defined. This study aims to compare the efficacy and safety of different treatment regimens and to independently externally validate a recently published reirradiation risk score. We retrospectively analyzed a cohort of patients with recurrent malignant glioma treated with salvage conventionally fractionated (CFRT), hypofractionated (HFRT) or stereotactic radiotherapy (SRT) between 2007 and 2017 at the University Medical Center in Utrecht and Groningen. Moreover, we validated the reirradiation risk score. Of the 121 patients included, 60 patients (50%) underwent CFRT, 22 (18%) HFRT and 39 (32%) SRT. The primary tumor was grade 2/3 in 52 patients and grade 4 in 69 patients with median Overall Survival (mOS) since first surgery of 113 [Interquartile range: 53.2–137] and 39.7 [24.6–64.9] months respectively (p< 0.01). Overall, mOS from the first day of re-irradiation was 9.7 months [6.5–14.6]. No significant difference in mOS was found between the treatment groups. In multivariate analysis, Karnofsky performance scale 70% (p< 0.01), re-irradiation for first recurrence (p= 0.02), longer time interval (p< 0.01) and smaller planning target volume (p< 0.05) were significant favorable prognostic factors. The reirradiation risk score was validated. In our series, mOS after reirradiation was sufficient to justify more use of this modality. Until a reliable treatment decision tool is developed based on larger retrospective research, the decision for re-irradiation schedule should remain personalized and based on a multidisciplinary evaluation of each patient.
Abstract 17746: Cardiomyocyte-Specific KLF5 Deletion Accelerates Diet-Induced Obesity via Cardiac FGF21
Authors: Christine J Pol, Nina M Pollak, Michael J Jurczak, Iordanes Karagiannides, Panagiotis Ntziachristos, Diego A Scerbo, Brett R Brown, Mesele C Valenti, Iannis Aifantis, Gerald I Shulman, Ira J Goldberg, Konstantinos Drosatos
Journal: Circulation (2017)

Previously, we showed that inhibition of Kruppel-like factor (KLF) 5 decreases cardiac fatty acid oxidation. As cardiac fatty acid metabolism has a significant effect in systemic lipid balance, we ...
Earl Bakken: founder of Medtronic
Authors: Bob Roehr
Journal: BMJ (2018)

Credit: Getty Images



The crackle of electricity that brought life to Boris Karloff as Frankenstein’s monster also animated the 8 year old Earl Bakken, who watched the film again and again in the dim glow of a depression era American movie theatre. “Through the power of his wildly flashing laboratory apparatus, the doctor restored life to the unliving,” he would later write in his 1999 autobiography One Man’s Full Life .

His fascination with electricity, fortuitous encounters, and business acumen would lead Bakken to create Medtronic, a leading manufacturer of medical devices with worldwide annual sales topping $30bn (£23bn; €26bn) today.

Scandinavians settled in the upper midwest of the US and Bakken came from Norwegian stock. He was born and raised near Minneapolis, an exemplar of hard work and “Minnesota nice,” polite and self effacing.

His parents encouraged the lad’s tinkering with all things electrical and mechanical. As a teen he created a kiss-o-metre, ostensibly to measure the emotional strength of a …
Bridge-to-surgery gallbladder drainage with a lumen-apposing metal stent in malignant distal biliary obstruction: a choice tailored for the surgeon
Authors: Dario Ligresti, Ilaria Tarantino, Michele Amata, Fabio Cipolletta, Salvatore Gruttadauria, Davide Cintorino, Mario Traina
Journal: Endoscopy (2018)

A 70-year-old woman with cholangitis was diagnosed with a distal biliary stricture at another institution. The patient was referred to our center for biliary decompression and further evaluation.
COMP-19. WATER-CONTENT BASED ELECTRIC PROPERTY TOMOGRAPHY (wEPT) FOR MODELLING DELIVERY OF TUMOR TREATING FIELDS TO THE BRAIN
Authors: Zeev Bomzon, Catherine Tempel-Brami, Hadas Hershkovich, Cornelia Wenger, Moshe Giladi
Journal: Neuro-Oncology (2018)

Understanding how Tumor Treating Fields (TTFields) distribute in the brain is important for optimizing delivery. The distribution depends on the electric properties (EPs) of the brain, which are heterogeneous. Therefore, there is a need for methods that map electric properties within tissue with high spatial resolution. Water content based EP tomography (wEPT) utilizes the ratio of two T1w to map tissue water content, and EPs. wEPT has been applied to map EPs at 128 MHz. This study examines the suitability of wEPT to map EPs in the brain at 100–1000 kHz (TTFields frequency range). MATERIALS AND A model connecting T1 images, Water content (WC) and EPs in the 100–1000 kHz range was created using tissue samples derived from bovine brains and aporcine CSF sample. For each sample, T1w images were acquired and WC and EPs measured. Curve fitting yielded models connecting Ir, WC and EPs. Next, wEPT was applied to map water content and EPs in tumor-bearing rat brains. EPs and WC were measured on 6 samples excised from each brain. The measured values were compared to the WC and EPs in the regions of the wEPT map corresponding to the sample. Water content estimated using wEPT agreed well with measurements on excised sample. A connection between EPs estimated with wEPT and the measured values was found. However, in some samples, especially samples excised from the tumors, large differences between wEPT-derived EP values and measurements existed. wEPT maps WC in healthy and tumor brain tissues However, the relationship between WC and EPs within this frequency range is not clear. Further work is required to refine this relationship enabling a robust non-invasive method for mapping electrical properties within the brain, and better strategies for optimizing TTFields treatment.
PDCT-09. PHASE 1/2 STUDY OF DSP-7888 IN PEDIATRIC PATIENTS WITH MALIGNANT GLIOMA
Authors: Hiroyuki Fujisaki, Yoshiko Hashii, Keita Terashima, Hiroaki Goto, Keizo Horibe, Kazuhiko Sugiyama, Akinobu Watanabe, Saori Sugimoto, Takaaki Yanagisawa, Atsushi Kikuta, Hiroshi Kawamoto, Naoya Hashimoto, Junichi Hara
Journal: Neuro-Oncology (2018)

DSP-7888 is an experimental cancer vaccine containing peptides that induce WT1-specific CTLs and helper T cells. A phase 1/2 study in pediatric patients (pts) with malignant glioma was conducted to evaluate the efficacy and safety. Diffuse intrinsic pontine glioma (DIPG), glioblastoma (GBM) and other high grade glioma (HGG) pts for whom standard therapy failed or who have no available standard therapies were eligible. Pts received five-times DSP-7888 3.5 mg/body via intradermal injection weekly followed by biweekly administration. Response was assessed with MRIs via modified RANO criteria. Recommended dose was determined based on the traditional 3 + 3 design. Four pts were enrolled in phase 1 dose finding part (3.5 mg/body). One patient was replaced due to primary disease progression and the three pts completed DLT evaluation and no DLTs were observed. Therefore, recommended dose was determined as 3.5 mg/body. In a whole study, 18 pts (11 DIPG, 5 GBM and 2 HGG) were enrolled. There was no dose-limiting or unexpected toxicity. Most common treatment related adverse events was controllable injection site reaction only. Disease control (CR+PR+SD) was observed in 7 of 18 pts, with 1 PR and 6 SD. Median OS from initial dose in DIPG exceeded 5 months. Three out of 5 GBM pts are on survival more than 11 months. WT1 specific CTLs induction were observed in several pts. CONCLUSIONS: DSP-7888 is well tolerated at 3.5 mg/body for pts with pediatric malignant glioma. Survival results in DIPG pts exceeded in comparison with historical controls. Moreover, some GBM pts shows encouraging sign of long survival.
Orbital Apex Syndrome in a Patient With Histiocytic Sarcoma
Authors: Ying Li, Weiping Sun, Yining Huang
Journal: JAMA Neurology (2018)

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Thoracoscopic and endoscopic cooperative surgery (TECS): a novel less invasive technique for resection of gastric tube cancer after esophagectomy
Authors: Yoshiki Tsujii, Makoto Yamasaki, Yoshito Hayashi, Koji Tanaka, Tomoki Makino, Yuichiro Doki, Tetsuo Takehara
Journal: Endoscopy (2018)

With recent improvements in the survival of patients after esophagectomy, the occurrence of secondary malignancies arising in the gastric tube has been increasing [1] [2]. However, resection of the reconstructed gastric tube with lymphadenectomy for gastric tube cancer (GTC) is an invasive procedure associated with high morbidity and mortality [3]. Local resection without lymphadenectomy may be reasonable in high risk patients. We have developed a novel thoracoscopic and endoscopic cooperative surgery (TECS) technique as a minimally invasive alternative.
Abstract 17361: Loss of Notch1 in the Secondary Heart Field Exacerbates Ascending Aortic Aneurysm and Causes Aortic Rupture in Marfan Syndrome Mice <i>(Best of Basic Science Abstract)</i>
Authors: Sara N Koenig, Patrick Rowland, Aaron J Trask, Brenda Lilly, Vidu Garg
Journal: Circulation (2015)

Ascending aortic aneurysm (AscAA) is a life-threatening disease that affects approximately 3.5 in 100,000 people per year, but the mechanisms of AscAA remain poorly understood. We previously reported that NOTCH1 mutations are associated with familial bicuspid aortic valve (BAV), and a subset of these individuals displayed BAV aortopathy. NOTCH1 is expressed in multiple cell lineages that contribute to the aorta, and we found dysregulation of activated NOTCH1 expression in aneurysmal tissue from Marfan syndrome and BAV patients in comparison to control tissue. To investigate the role of NOTCH1 in AscAA, Notch1 haploinsufficiency was introduced into the Marfan syndrome mouse ( Fbn1 C1039G/+ ), a well-described model of AscAA. Serial echocardiographic, gross and histological characterization of the Notch1 deficient Marfan syndrome mice ( Notch1 +/- ;Fbn C1039G/+ ) demonstrated an exacerbated AscAA phenotype when compared to Fbn1 C1039G/+ mice. The compound mutant mice had increased aortic root diameter by three months of age (diameter: Notch1 +/- ;Fbn C1039G/+ = 2.11±0.11mm and Fbn1 C1039G/+ = 1.86±0.05mm, p&lt;0.05) as well as a higher rate of dilation from 1-5 months of age (rate: Notch1 +/- ;Fbn C1039G/+ =0.24±0.06mm/month and Fbn1 C1039G/+ =0.09±0.03mm/month, p&lt;0.05). Notch1 +/- and wildtype littermate mice had normal aortic diameters. Furthermore, a small subset (4/66) of the compound mutant mice succumbed to ascending aortic rupture, which was not observed in the Fbn1 C1039G/+ mice (0/63). Although endothelial Notch1 is critical for cardiovascular development, mice with heterozygous loss of Notch1 in endothelial cells that harbor the Fbn1 C1039G mutation ( Notch1 flox/+ ;Tie2-Cre +/- ;Fbn1 C1039G/+ ) did not recapitulate the phenotype of the Notch1 +/- ;Fbn C1039G/+ mice. Surprisingly, the phenotype was recapitulated with heterozygous loss of Notch1 in the lineage of secondary heart field cells ( Notch1 flox/+ ;Mef2C-AHF-Cre +/- ;Fbn1 C1039G/+ ) but not smooth muscle myosin heavy chain-expressing cells ( Notch1 flox/+ ;Myh11-Cre +/- ;Fbn1 C1039G/+ ). Our findings support a novel role for Notch1 in the non-endothelial secondary heart field and suggest that this loss of Notch1 alters a developmental process that contributes to AscAA.