tbuckley/cabot-search huggingface dataset:
Genetic Rescue Reverses Microglial Activation in Preclinical Models of Retinitis Pigmentosa
Authors: Lijuan Zhang, Xuan Cui, Ruben Jauregui, Karen Sophia Park, Sally Justus, Yi-Ting Tsai, Jimmy K. Duong, Chun-Wei Hsu, Wen-Hsuan Wu, Christine L. Xu, Chyuan-Sheng Lin, Stephen H. Tsang
Journal: Molecular Therapy (2018)

Microglia cells (MGCs) play a key role in scavenging pathogens and phagocytosing cellular debris in the central nervous system and retina. Their activation, however, contributes to the progression of multiple degenerative diseases. Given the potential damage created by MGCs, it is important to better understand their mechanism of activation. Here, we explored the role of MGCs in the context of retinitis pigmentosa (RP) by using four independent preclinical mouse models. For therapeutic modeling, tamoxifen-inducible CreER was introduced to explore changes in MGCs when RP progression halted. The phenotypes of the MGCs were observed using live optical coherence tomography, live autofluorescence, and immunohistochemistry. We found that, regardless of genetic background, MGCs were activated in neurodegenerative conditions and migrated beyond the layers where they are typically found to the inner and outer segments, where degeneration was ongoing. Genetic rescue not only halted degeneration but also deactivated MGCs, regardless of whether the intervention occurred at the early, middle, or late stage of the disease. These findings suggest that halting long-term disease progression may be more successful by downregulating MGC activity while co-administering the therapeutic intervention. Microglia cells (MGCs) play a key role in scavenging pathogens and phagocytosing cellular debris in the central nervous system and retina. Their activation, however, contributes to the progression of multiple degenerative diseases. Given the potential damage created by MGCs, it is important to better understand their mechanism of activation. Here, we explored the role of MGCs in the context of retinitis pigmentosa (RP) by using four independent preclinical mouse models. For therapeutic modeling, tamoxifen-inducible CreER was introduced to explore changes in MGCs when RP progression halted. The phenotypes of the MGCs were observed using live optical coherence tomography, live autofluorescence, and immunohistochemistry. We found that, regardless of genetic background, MGCs were activated in neurodegenerative conditions and migrated beyond the layers where they are typically found to the inner and outer segments, where degeneration was ongoing. Genetic rescue not only halted degeneration but also deactivated MGCs, regardless of whether the intervention occurred at the early, middle, or late stage of the disease. These findings suggest that halting long-term disease progression may be more successful by downregulating MGC activity while co-administering the therapeutic intervention.
PTH-141 The long term use of botulinum toxin in patients with recurrent acute pancreatitis
Authors: J Sanders, L White, M Abu Hilal, Z Hamady, C Johnson, F Shek
Journal: Gut (2017)

Introduction  Patients with recurrent acute pancreatitis suffers from repeated attacks of acute pancreatitis. They are frequently admitted to hospital with abdominal pain. They undergo numerous investigations for the cause of the pancreatitis. Botulinum toxin has been used to treat patients with sphincter of oddi dysfunction 1  but as yet there are no long term data of the use of botulinum toxin in patients with recurrent acute pancreatitis.  Method  Data collection for this series of patients started in 2011. Patients were fully consented for a duodenoscopy and a botulinum toxin injection to the sphincter of oddi. Using a duodenoscope (Olympus TJF-260V) to identify the papilla of vater, 100 units of botulinum toxin is injected to the sphincter of oddi. Patients with pancreatic divisum were injected with 100units of botulinum toxin to both papillae respectively. Patients were given a pre and post (14 days after)-procedure quality of life questionnaire (QLQ-C30-PAN26- specific for pancreatic diseases) and patients were asked to fill in the questionnaires and post back to the department of Endoscopy. The quality of life score ranged from 1–4. Patients were reviewed in clinic post procedure and were offered a repeat procedure when appropriate.  Results  21 patients (12 female:9 male) with recurrent acute pancreatitis were treated with botulinum toxin injection to the sphincter of oddi. 2 patients were known to have pancreatic divisum. The rest did not have a known cause for their pancreatitis. The mean age were 35 (Range 21–75). The mean improvement in the quality of life score in a sample of 12 patients was 16.5 (range 6–36). The response rate was 57%. No complications were noted during this period of study.  Conclusion  This study demonstrates that long term use of Botulinum toxin in patients with recurrent acute pancreatitis is a safe and effective way to manage these patients. This treatment can also be the treatment of choice rather than the pancreatic sphincterotomy which carries high morbidity of post ERCP pancreatitis.  Reference  . Wehrmann T, Schmitt TH, Arndt A, Lembcke B, Caspary WF, Seifert H. Endoscopic injection of botulinum toxin in patients with recurrent acute pancreatitis due to pancreatic sphincter of Oddi dysfunction. Aliment Pharmacol Ther. 2000Nov;14(11):1469–77.  Disclosure of Interest  None Declared
Association of Glycemic Control and Cell Stress With Telomere Attrition in Type 1 Diabetes
Authors: Tine Tesovnik, Jernej Kovac, Tinka Hovnik, Klemen Dovc, Nataša Bratina, Tadej Battelino, Katarina Trebušak Podkrajšek
Journal: JAMA Pediatrics (2018)

Association of Glycemic Control and Cell Stress With Telomere Attrition in Type 1 DiabetesHyperglycemia and abnormal blood glucose levels induce oxidative stress, promote the development of microvascular and macrovascular complications, 1 and may increase telomere loss in patients with type 1 diabetes. 2,3 All studies of adults with type 1 diabetes, except one, report a shorter telomere length associated with age, duration of type 1 diabetes, and higher glycated hemoglobin A 1c (HbA 1c ) levels. 4 To expand these data in a pediatric population at the onset of type 1 diabetes by assessing the association between telomere length and age or HbA 1c level, 5 we conducted a retrospective longitudinal study evaluating the association of glycemic control and associated cell stress with telomere dynamics during a 7-year follow-up.
QOL-43. CEREBELLAR MUTISM, NEUROCOGNITIVE AND ACADEMIC OUTCOME IN A CONSECUTIVE SAMPLE OF PEDIATRIC CEREBELLAR TUMOR PATIENTS
Authors: Thomas Pletschko, Ulrike Leiss, Christina Feichtenberger, Martin Kalser, Doris Lamplmair, Ursula Kastner-Koller, Pia Deimann, Thomas Czech, Irene Slavc, Andreas Peyrl
Journal: Neuro-Oncology (2018)

The Cerebellar Mutism Syndrome (CMS) is a severe complication after resection of a pediatric cerebellar tumor. Incidence rates vary and sophisticated neurocognitive and academic outcome studies are still rare. CMS is characterized by entire absence of speech for a certain time period after surgery. However, during long-term follow-up other distinct neurocognitive deficits become apparent, which have the impact to severely influence everyday life and academic achievement. Hence, the aim of this study was to investigate the long-term impact of cerebellar tumor treatment with a special focus on CMS. Therefore we retrospectively analyzed a consecutive sample of n=105 pediatric cerebellar tumor patients, all treated at the Medical University of Vienna between 2001 and 2015. Most common histologies were pilocytic astrocytoma (45.7%), medulloblastoma (31.4%) and ependymoma (13.3%). Eight patients were diagnosed with CMS (incidence rate = 7.6%). All patients underwent a comprehensive standard-of-care neuropsychological test-battery. Median time between diagnosis and follow-up assessment was 4 years. All patients suffering from postoperative CMS needed a special form of academic/occupational support at the time of assessment, compared to only 33% in the total sample. Regarding neurocognitive functioning, CMS patients showed significantly lower results in certain cognitive domains (e.g. divided attention, information processing speed). In conclusion, patients with CMS turned out to be a high-risk-group regarding neurocognitive late-effects, which in turn affect academic achievement and the need for special support services. Moreover, the results indicate the need for deficit-specific neurocognitive therapy and counselling. for pediatric cerebellar tumor patients in order to overcome illness-related academic disadvantages.
MBCL-36. MOLECULAR STUDY IN PEDIATRIC MEDULLOBLASTOMA. VALIDATION OF GENETIC MARKERS IN A NATIONAL COHORT OF FORTY YEARS
Authors: Miguel Garcia-Ariza, Olaia Aurtenetxe, Idoia Martin-Guerrero, Laura Zaldumbide, Itziar Astigarraga, Anna Llort, Carlota Calvo, Tomas Acha, Eduardo Quiroga, Jose Miguel Couselo, Alvaro Lassaletta, Ofelia Cruz, Aurora Navajas
Journal: Neuro-Oncology (2018)

To retrospectively assess at national level whether the addition of molecular data to clinical/histopathological factors could have modified the initial risk factors for survival in children with medulloblastoma. A 40 years (1975-2015) retrospective study of 218 patients (0-18 years) from 24 national hospitals was performed. Histology and molecular review, including CTNNB1 gene mutations (RT-PCR) p53(immunohistochemistry) and MYCC/MYCN (FISH), was centralized. The patients were reclassified as standard (SR) or high-risk (HR) according to current knowledge. 187 cases had valid data. Median age 6.9 years (76% <10 years). Male 120 (64%). Chang staging T3 57% and M0 75%. Total resection 68% and tumor rest <1,5cm2 94%. Classical histology 67%. Nuclear B-catenin positive 5.5%. Tumor p53 positive 18%. MYCC and MYCN were positive in 8,4% and 4%, respectively. Clinical or biological risks were standard in 64% and 88%. Considering both clinical and biological factors, 56% of cases were classified as SR. Overall survival at 5-10 years were 57% and 50% respectively; 12 patients initially classified as SR were reclassified as HR adding biological markers. National centralization review was accomplished thanks to a high level of collaboration. Independent prognostic risk factors were size of the tumoral rest, metastasis, LCA histology and MYCC amplification. Worse overall survival was observed with the presence of tumoral rest or with disseminated disease. Adding molecular information, 6% of the standard risk patients upgraded their risk and could have obtained some benefit if treated as high risk.
A single-arm phase II trial of afatinib in pretreated patients with advanced NSCLC harboring a <i>HER2</i> mutation: The ETOP NICHE trial.
Authors: Egbert F. Smit, Solange Peters, Rafal Dziadziuszko, Urania Dafni, Juergen Wolf, Bartosz Wasąg, Wojciech Biernat, Stephen Finn, Rosita Kammler, Zoi Tsourti, Manuela Rabaglio-Poretti, Barbara Ursula Ruepp, Heidi Roschitzki-Voser, Rolf A. Stahel, Enriqueta Felip
Journal: Journal of Clinical Oncology (2017)

9070 Background: HER2mutations are identified in about 2% of lung adenocarcinomas and are critical for lung carcinogenesis. Afatinib is a selective and irreversible erbB family blocker with a manageable toxicity profile and promising results in small retrospective studies targeting HER2 in NSCLC. Methods: NICHE is a single-arm phase II trial exploring the potential of afatinib to control disease (complete or partial response or disease stabilization for ≥12 weeks) in pre-treated patients with advanced NSCLC harboring HER2 exon 20 mutations. Patients were treated with afatinib 40 mg/day p.o. until tumor progression or lack of tolerability. A Simon’s two stage phase II design was adopted, to explore whether afatinib can achieve a DCR of 75%, as opposed to a DCR of 50% under the current treatment options. For a 1-sided type I error of 10% and power of 80%, a total of 22 patients were needed. Results: As of 24 November 2016, 13 patients were recruited into the trial. Median age was 60 years, 69% female and 62% never smokers. The overall toxicity profile was in the expected range, with 5 patients experiencing serious adverse events (dyspnea, diarrhea, dehydration, epistaxis, pleural, pericardial and renal insufficiency). The median follow-up was 23 weeks (IQR 12 – 39). Three patients died and 10 were still on follow-up, among them five were still on treatment. Total of 7 patients (54%) achieved DC at 12-weeks, 3 patients had PD before and 3 at 12-weeks. The 12-week PFS was 51% (95% CI: 22 - 75) and the median PFS 13 weeks (95% CI 6 - NE). In the 1 st stage analysis of the Simon’s design, with 9 patients included, the stopping boundary was crossed. Therefore and upon recommendations of the ETOP IDMC, recruitment into the trial was stopped prematurely in December 2016. Treatment and follow-up of the enrolled patients continues as planned. Conclusions: Based on the interim results, afatinib did not show the expected potential to control disease in this patient population. However in the full analysis set with 13 patients, clear signs of activity were seen. A comprehensive biomolecular analysis of the tumors is currently ongoing in order to identify a subgroup of patients who might still derive benefit from afatinib treatment. Clinical trial information: NCT02369484.
NFM-08. SAFETY AND EFFICACY OF TRAMETINIB IN THE MANAGEMENT OF CHILDREN WITH RASOPATHIES
Authors: Abhishek Bavle, Farooq Choudhry, Theresa Gavula, Rikin Shah, Alejandro Ruiz-Elizalde, Ashley Taylor, Naina Gross, Jo Elle Peterson, Kar-Ming Fung, Rene McNall-Knapp
Journal: Neuro-Oncology (2018)

There is emerging evidence regarding the efficacy of agents targeting the MAPK pathway in children with RASopathies. We report our experience with the use of trametinib, a MEK inhibitor, in this population. Three patients with neurofibromatosis type 1 (NF-1) and plexiform neurofibromas refractory to imatinib, and 4 patients with low grade gliomas (LGGs) (3 NF-1; 1 encephalocraniocutaneous lipomatosis), with progression on multiple chemotherapy regimens (carboplatin/vincristine; vinblastine; bevacizumab/irinotecan) were treated with trametinib (median dose 1 mg/m2/day; 0.7 - 1.5 mg/m2/day) Tumor response was evaluated by MRI using RECIST (Response Evaluation Criteria in Solid Tumors) criteria. All patients with plexiform neurofibromas had stable disease (median follow-up 8 months), but reported improvement of vision, cosmesis and snoring respectively. Of 3 patients with optic pathway glioma, one had partial response, two had stable disease, and 1 of these patients had complete response of a cerebellar LGG (median follow-up 8 months). Two patients were taken off-therapy due to grade III adverse events, with bleeding scalp excoriations within 2 weeks, and pyogenic granulomas of multiple fingers and toes 5 months after treatment initiation, respectively. One patient needed 25% dose-reduction for grade II mouth sores. Six patients developed grade 1-2 maculopapular rash on the face, trunk or arms, with improvement using steroid and emollient ointments. MEK inhibitors can be effective in the treatment of multiply-progressive cranial and peripheral nerve tumors, in patients with RASopathies. Long-term follow-up in a larger study population is needed to determine the efficacy and adverse effects of these agents.
Metabolic Coordination of Physiological and Pathological Cardiac Remodeling
Authors: Andrew A. Gibb, Bradford G. Hill
Journal: Circulation Research (2018)

Metabolic pathways integrate to support tissue homeostasis and to prompt changes in cell phenotype. In particular, the heart consumes relatively large amounts of substrate not only to regenerate ATP for contraction but also to sustain biosynthetic reactions for replacement of cellular building blocks. Metabolic pathways also control intracellular redox state, and metabolic intermediates and end products provide signals that prompt changes in enzymatic activity and gene expression. Mounting evidence suggests that the changes in cardiac metabolism that occur during development, exercise, and pregnancy as well as with pathological stress (eg, myocardial infarction, pressure overload) are causative in cardiac remodeling. Metabolism-mediated changes in gene expression, metabolite signaling, and the channeling of glucose-derived carbon toward anabolic pathways seem critical for physiological growth of the heart, and metabolic inefficiency and loss of coordinated anabolic activity are emerging as proximal causes of pathological remodeling. This review integrates knowledge of different forms of cardiac remodeling to develop general models of how relationships between catabolic and anabolic glucose metabolism may fortify cardiac health or promote (mal)adaptive myocardial remodeling. Adoption of conceptual frameworks based in relational biology may enable further understanding of how metabolism regulates cardiac structure and function.
Noninvasive ventilation for respiratory failure: a note of caution in selected patients
Authors: Caroline Macharete, Lara Ventura, Olga Rubio, Ignacio Catalan, Silvia Cano, Josep-Maria Alcoverro, Carles Subira, Jaume Masclans, Gina Rognoni, Rafael Fernandez
Journal: Intensive Care Medicine (2018)
IMMU-19. LSD1 MODULATES NK CELL IMMUNOTHERAPY THROUGH AN ONCO-IMMUNOGENIC GENE SIGNATURE IN DIPG
Authors: Cavan Bailey, Megan Romero, Ruolan Han, Jeffrey Larson, Oren Becher, Dean Lee, Michelle Monje, Vidya Gopalakrishnan, Wafik Zaky, Joya Chandra
Journal: Neuro-Oncology (2018)
Loss of Response to Vedolizumab and Ability of Dose Intensification to Restore Response in Patients With Crohn’s Disease or Ulcerative Colitis: A Systematic Review and Meta-analysis
Authors: Laurent Peyrin-Biroulet, Silvio Danese, Marjorie Argollo, Lieven Pouillon, Spyros Peppas, Marien Gonzalez-Lorenzo, Theodore Lytras, Stefanos Bonovas
Journal: Clinical Gastroenterology and Hepatology (2018)
EAPH-02. TARGETING 6-THIO-dG-INDUCED G2/M ARREST TO ERADICATE BRAIN TUMOR CELL SURVIVORS
Authors: Satarupa Sengupta, Shiva Senthil Kumar, Kyungwoo Lee, Rachid Drissi
Journal: Neuro-Oncology (2018)

High-risk pediatric brain tumors are often incurable due to therapy-resistance and recurrence. Therefore, developing effective combination therapies is required to not only reduce tumor burden but also to prevent recurrence by eradicating tumor cell survivors. Recently, we validated a novel approach to treat therapy-resistant telomerase-positive brain tumors, including DIPG and high-risk medulloblastoma. This approach consists of the telomerase-mediated incorporation of 6-thio-dG, a substrate analog, into telomeres leading to telomere dysfunction and cell death. 6-thio-dG induced a rapid cell growth inhibition of primary brain tumor cells in vitro and delayed tumor growth in vivo. Moreover, 6-thio-dG crosses the blood-brain barrier and specifically targets tumor cells in an orthotopic mouse model of DIPG. Mechanistically, 6-thio-dG induced an initial G2/M arrest followed by apoptotic cell death of telomerase-positive cancer cells. Both ATM and ATR DNA damage response pathways were activated. Interestingly, the effect of 6-thio-dG was sustained for several days after drug removal. Finally, treatment of telomerase-negative fast growing cancer cells with 6-thio-dG firstly caused a prolonged G2/M arrest due to 6-thio-dG-induced genomic damage, then cells resumed growth several days after drug removal. Together, these data provide a window of opportunity to design a targeted therapy that includes 6-thio-dG combined with G2/M checkpoint inhibitors to treat both telomerase-positive and negative brain tumors. This strategy has the potential to eradicate 6-thio-dG cell survivors by leading to mitotic catastrophe and cell death. Results from this ongoing study will be presented and discussed.
DIPG-51. BLACKFYNN: A SECURE, CLOUD-BASED PLATFORM FOR SHARING AND ANALYZING RESEARCH READY DATA FOR PEDIATRIC CNS CANCERS
Authors: Courtney Johnson, Amanda Christini, Alex Felmeister, Chris Baglieri, Madhuri Kambhampati, Angela Waanders, Jennifer Mason, Roger Packer, Adam Resnick, Javad Nazarian
Journal: Neuro-Oncology (2018)

Sharing research ready data between multiple institutions and across different platforms is a lengthy and cumbersome process which can delay research and potentially negatively impact patient care. Despite the recent surge in generating the genomic and molecular profiles of CNS cancers, correlation of this data with clinical or radiographic data is yet to be streamlined. To address this, CBTTC has partnered with Blackfynn, to develop their HIPAA-compliant, cloud-based platform for integration of histopathology, clinical, molecular, and neuroimaging data. This collaboration provides research ready data that can be easily accessed by clinicians and researchers across different institutions. MR imaging, genomic, histological data from a cohort of CBTTC patients diagnosed with midline gliomas were used in a pilot trial. The Blackfynn platform was used to share and annotate MR imaging and histological staining across two academic institutions. Clinicians, basic researchers, and software engineers participated in the project with the goal of integrating a multi-disciplinary, cross-data integration platform. The Blackfynn platform successfully allowed sharing and annotation of neuroimages as well as histopathology slides pertaining to the CBTTC cohort. The neuroimaging on the platform is interactive and can be viewed in axial, coronal and sagittal planes. The pathology slides are also interactive and can be viewed up to 50x magnification. Annotations can be made on all of the multimodal data with the possibility of localizing MR images with the corresponding pathology slides. In conclusion, Blackfynn provides the research community research ready data that is easily uploaded and shared between different institutions.
Could Grape Seed Extract Be an Alternative Treatment in the Management of Hot Flashes?—Reply
Authors: Arjun Gupta, Navid Sadeghi, Ugis Gruntmanis
Journal: JAMA Oncology (2018)

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