tbuckley/cabot-search huggingface dataset:
IMMU-29. LAG-3 COMPENSATES TIM-3 DOWN-REGULATION IN A HUMAN GLIOBLASTOMA MODEL
Authors: Elizabeth Ogando-Rivas, Paul Castillo-Caro, Noah Jones, Anjelika Dechkovskaia, Changlin Yang, Duane Mitchell
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION There are a few alternatives treatments beside the standard care for glioblastomas, one of them is adoptive cell therapy; our group has shown promising preliminary results with a dendritic cell-based vaccine that has being tested in first-in-human clinical trials. Checkpoint inhibitors have also shown promising results in the cancer arena, but not for brain tumors. OBJECTIVE We have assessed whether combination of checkpoint inhibition and transferred cellular therapy may enhance anti-tumor killing of adoptive T-cell therapies to improve survival in GBM patients. METHODS PBMCs were isolated from CMV+ donors, in order to generate dendritic cells and pulsed them with CMVpp65-mRNA. DCs were co-culture with T-cells for 15-days. Five groups were made (Tim3 at 300 ug/ml, PD1, Tim3, PD1+Tim3 at 10 ug/ml and PD1+Tim3 at 3 ug/ml) and their respective isotype-control groups. IL2 was added at 100UI/ml every 3 days as well as the blockade. Phenotyping was performed on Day0 and Day15th. Restimulation was made with pp65-pepmixes and UPGL a glioblastoma cell-line created by our group. Supernatant from overnight restimulation was analyzed for 10-cytokines. RESULTS PD1/Tim3 condition (3ug/ml), Lag3 expression was increased in central memory T-cells (mean 19.13% vs 30.98% p=0.02). On EM T-cells, Lag3 expression increased (57.98% vs 75.83%; p=0.03); for control vs 10ug/ml from combination checkpoint treatment group. On EMRA T-cells, the results were similar, Lag3 was upregulated in response of low-doses of double checkpoint inhibitor combination (8% vs 21% p=0.002). At increased doses (Tim3 at 300ug/ml), secretion of IFN-□ was reduced in T-cells treated with Tim3 vs relevant control. Secretion of IL-12 in treated T-cells with PD1/Tim3 was significantly increased. IL-1□ secretion was significantly lower in the PD1/Tim3 (10ug/ml) treatment-group compared with control-group (p &amp;lt; 0.004). CONCLUSIONS We have identified a potential activation component and dependent pathway between Tim3 and Lag3, once Tim3 and PD1 are blockade.
Интенсивность системного протеолиза и эндотоксикоза в динамике лечения гепатопротекторами больных неалкогольным стеатогепатитом на фоне ожирения при коморбидности с хроническим обструктивным заболеванием легких
Authors: O.S. Khukhlina, O.Ye. Hrinyuk, O.D. Liakhovych
Journal: GASTROENTEROLOGY (2020)

Актуальность. Распространенность заболеваемости неалкогольным стеатогепатитом (НАСГ) и хронической обструктивной болезнью легких (ХОБЛ) приобретает глобальное значение среди населения экономически развитых стран мира с тенденцией роста и в Украине. Цель исследования: определение интенсивности системного протеолиза и эндогенной интоксикации до лечения и в динамике применения антраля у больных НАСГ на фоне ожирения и коморбидной ХОБЛ. Материалы и методы. 76 больных НАСГ на фоне ожирения I ст. и ХОБЛ 2–3 D прошли обследование и были распределены на 3 группы в зависимости от назначенного лечения. В первую группу — контрольную (К) — вошли 23 больных, получавших базисную терапию НАСГ (комплекс эссенциальных фосфолипидов 300 мг по 2 капсулы 3 раза в день) на протяжении 30 дней и базисную терапию ХОБЛ. 25 больных (группа 2 — основная, О1), кроме аналогичной терапии ХОБЛ, для лечения НАСГ вместо комплекса эссенциальных фосфолипидов получали антраль 200 мг 3 раза в день на протяжении 30 дней. Третья группа (основная, О2) — 28 больных, кроме аналогичной терапии ХОБЛ, для лечения НАСГ вместо комплекса эссенциальных фосфолипидов получали антраль 200 мг 3 раза в день и дополнительно поликозанол 20 мг после ужина в течение 30 дней. Группу сравнения составили 30 практически здоровых лиц. Результаты. Предложенная терапия антралем повлияла на уменьшение интенсивности лизиса азоальбумина, азоказеина и азокола у больных группы О2: на 30 день указанный показатель снизился соответственно в 1,3; 1,2 и 1,6 раза (р &lt; 0,05), у больных группы О1: на 30 день — соответственно в 1,2; 1,2 и 1,6 раза (р &lt; 0,05) по сравнению с данными до лечения. В группе К снижение происходило менее интенсивно (р &lt; 0,05): достоверно менялся только показатель азокола — снизился в 1,3 раза (р &lt; 0,05) при наличии достоверной разницы с показателями в группах О1 и О2 (р &lt; 0,05). Выводы. Назначение антраля на фоне базисной терапии в течение 30 дней привело к существенной коррекции протеиназo-ингибиторного гомеостаза у больных НАСГ с ожирением и ХОБЛ, сопровождалось достоверным снижением эндотоксикоза (р &lt; 0,05) и повреждающего действия системного протеолиза (р &lt; 0,05).
LGG-53. PNOC001 (NCT01734512): A PHASE II STUDY OF EVEROLIMUS FOR RECURRENT OR PROGRESSIVE PEDIATRIC LOW-GRADE GLIOMAS (pLGG)
Authors: Sabine Mueller, Mariam Aboian, Kellie Nazemi, Karen Gauvain, Janet Yoon, Jane Minturn, Sarah Leary, Mohamed S AbdelBaki, Stewart Goldman, Jennifer Elster, Adam Resnick, Annette M Molinaro, Joanna Phillips, Michael Prados, Daphne Haas-Kogan
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE To estimate the 6-month Progression Free Survival (PFS6) associated with everolimus for progressive/recurrent pLGGs and to determine if activated PI3K/Akt/mTOR pathway as measured by positive phosphorylated-ribosomal protein S6 (p-RPS6) status was associated with response. METHOD: Patients 3–21 years of age with recurrent or progressive pLGG were enrolled. Everolimus was administered orally at 5 mg/m2 daily. Tissue availability for molecular analysis was mandatory. Immunohistochemistry (IHC) for p-RPS6 was performed centrally. An adaptive Simon two-stage design was employed based on p-RPS6 status. Based on results of the first stage, enrollment in the second stage was either limited to pathway activated patients or open to all subjects. RESULTS From December 2012 to July 2019 a total of 65 subjects enrolled [median age 9 years (range 3–19); 43% female]. As of December 15, 2019 median number of treatment cycle is 8 (range 1–24); 7 patients remain on treatment. Toxicity profile is similar to published reports with rash and elevated lipid profiles as most common adverse events. PFS6 for the entire cohort is 63%; PFS6 is 64% for the activated and 61% for the non-activated patients. Central imaging review (n=52) revealed 1 partial response, 1 complete response, 33 stable disease, and 17 progressive disease at the end of study treatment. Initial molecular analysis identified BRAF alterations in 35/65 patients. CONCLUSION Everolimus is well tolerated and active in a subset of pLGGs. Ongoing analyses will assess predictive biomarkers of response and will be reported at the meeting.
Pharmacokinetics and Pharmacodynamics of Three Different Formulations of Insulin Aspart: A Randomized, Double-Blind, Crossover Study in Men With Type 1 Diabetes
Authors: Eva Svehlikova, Ines Mursic, Thomas Augustin, Christoph Magnes, David Gerring, Jan Jezek, Daniela Schwarzenbacher, Maria Ratzer, Michael Wolf, Sarah Howell, Leon Zakrzewski, Martina Urschitz, Bernd Tschapeller, Christina Gatschelhofer, Franz Feichtner, Fiona Lawrence, Thomas R. Pieber
Journal: Diabetes Care (2020)

OBJECTIVE To investigate the pharmacokinetic and pharmacodynamic properties and safety of a novel formulation of insulin aspart (AT247) versus two currently marketed insulin aspart formulations (NovoRapid [IAsp] and Fiasp [faster IAsp]). RESEARCH DESIGN AND METHODS This single-center, randomized, double-blind, three-period, crossover study was conducted in 19 men with type 1 diabetes, receiving single dosing of trial products (0.3 units/kg) in a random order on three visits. Pharmacokinetics and pharmacodynamics were assessed during a euglycemic clamp lasting up to 8 h. RESULTS Onset of insulin appearance was earlier for AT247 compared with IAsp (−12 min [95% CI −14; −8], P = 0.0004) and faster IAsp (−2 min [−5; −2], P = 0.0003). Onset of action was accelerated compared with IAsp (−23 min [−37; −15], P = 0.0004) and faster IAsp (−9 min [−11; −3], P = 0.0006). Within the first 60 min, a higher exposure was observed for AT247 compared with IAsp by the area under the curve (AUC) glucose infusion rate (GIR) from 0 to 60 min (AUCAsp0–60min: treatment ratio vs. IAsp 2.3 [1.9; 2.9] vs. faster IAsp 1.5 [1.3; 1.8]), which was underpinned by a greater early glucose-lowering effect (AUCGIR,0–60min: treatment ratio vs. IAsp 2.8 [2.0; 5.5] vs. faster IAsp 1.7 [1.3; 2.3]). Furthermore, an earlier offset of exposure was observed for AT247 compared with IAsp (−32 min [−58; −15], P = 0.0015) and faster IAsp (−27 min [−85; −15], P = 0.0017), while duration of the glucose-lowering effect, measured by time to late half-maximum effect, did not differ significantly. CONCLUSIONS AT247 exhibited an earlier insulin appearance, exposure, and offset, with corresponding enhanced early glucose-lowering effect compared with IAsp and faster IAsp. It therefore represents a promising candidate in the pursuit for second-generation prandial insulin analogs to improve postprandial glycemic control.
ラット肝臓中のポルフィリン濃度に対する2,2 ́,4,4 ́,5,5 ́-ヘキサクロロビフェニルおよび2,3,7,8-テトラクロロジベンゾ-p-ジオキシンの相乗作用
Authors: Van Birgelen A P J M, Fase K M, Van Der Kolk J, Poiger H, Brouwer A, Seinen W, Van Den Berg M
Journal: Environmental Health Perspectives (1996)
LINC-25. BRAF ABERRATIONS IN PEDIATRIC PILOCYTIC ASTROCYTOMAS (PCAs): PREVALENCE AND IMPACT ON CLINICAL OUTCOME
Authors: Subramaniam Ramanathan, Maya Prasad, Tushar Vora, Mamta Gurav, Ayushi Sahay, Arpita Sahu, Aliasgar Moiyadi, Prakash Shetty, Jayant Sastri Goda, Rahul Krishnatry, Tejpal Gupta, Sridhar Epari, Girish Chinnaswamy
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Increasing knowledge on pilocytic astrocytoma (PCA) biology now points towards an aberration in BRAF/MAPK/ERK pathway which has both diagnostic and therapeutic implications. This study was done to note the impact of BRAF aberrations on clinical outcome in childhood PCA. METHODS FFPE tissues of all childhood PCA diagnosed during 2011–2017 were evaluated for BRAFV600E mutation by Sanger sequencing and KIAA1549 fusion transcripts (16–9;15–9;16-11) by reverse transcriptase polymerase chain reaction. Children undergoing gross tumor resection received no adjuvant treatment. Unresectable tumors (only biopsy) and NF-1 associated PCAs, were treated if clinically indicated. Only patients with documented therapy details/followup were included for analysis. STUDY RESULTS Ninety-eight patients (median age-7.7yrs; boy:girl ratio-1.4) were included. Major sites were: Cerebellum-37(38%), 3rd Ventricle-26(27%), Cerebrum-15(15%). While BRAFV600E mutation was noted in 7/89(8%) specimens, BRAF-fusions were found in 34/85(40%). Following surgery/biopsy, 23(24%) and 21(22%) received adjuvant chemotherapy and radiotherapy respectively. The 1-year/3-year/5-year-EFS of the overall cohort was 90.7%/81.3%/67.4% respectively. Cerebellar tumors did better vis-à-vis other sites(5yr-EFS:74.3% v/s 66.4%;p=0.403). The 5yr-EFS of BRAF-fusion positive tumors (34), tumors without any BRAF aberration (40) and BRAFV600E mutant tumors (7) was 84.8%/ 69.6%/ 42.9% (p=0.215). CONCLUSIONS BRAF-fusion and BRAFV600E mutation were associated with good and poor outcomes respectively. Lack of statistical significance could be attributed to use of radiation as planned therapy in patients from earlier years. Data on BRAF aberrations in PCAs aids decision making regarding adjuvant therapy and choosing appropriate salvage-therapy especially in relapsed/refractory PCAs.
Metastatic Medulloblastoma
Authors: Sreedharan Thankarajan ArunRaj, Arunav Kumar, Haresh KP, Nikhil Mohan, Subhash Gupta, Madhavi Tripathi, Chandrasekhar Bal
Journal: Clinical Nuclear Medicine (2020)

Abstract We describe the utility of molecular imaging with 18 F-FDG and 68 Ga-DOTANOC PET for treatment response assessment in a case of metastatic medulloblastoma. 18 F-FDG and 68 Ga-DOTANOC PET/CT revealed extensive metastases to bone and bone marrow. Patient subsequently had an excellent response to systemic chemotherapy which was evidenced by resolution of tracer-avid skeletal lesions on both FDG and DOTANOC PET/CT.
HGG-16. EXOSOME-MEDIATED INTER-CLONAL INTERACTIONS IN PEDIATRIC GBM AND DIPG
Authors: Giulia Pericoli, Angela Galardi, Stefania Petrini, Ezio Giorda, Lucia Lisa Petrilli, Alessandro Paolini, Marta Colletti, Emmanuel De Billy, Luisa Pascucci, Hector Peinado, Will Court, Chris Jones, Andrea Carai, Angela Mastronuzzi, Andrea Masotti, Franco Locatelli, Angela Di Giannatale, Maria Vinci
Journal: Neuro-Oncology (2020)

Abstract Pediatric Glioblastoma (pGBM) and Diffuse Intrinsic Pontine Glioma (DIPG) are highly heterogeneous brain tumors which we demonstrated are comprised by distinct sub-clones interacting in a functional network. Exosomes are known to mediate the crosstalk between tumor and its microenvironment. Based on this, we aimed to investigate the role of exosomes in mediating pGBM and DIPG inter-clonal communication. By using optical barcoding for single cell-tracking, we generated two bulk multicolor patient derived-cell lines (one DIPG H3.3K27M and one pGBM histone WT) from which we obtained two and five single cell-derived clones respectively. The sub-clones demonstrated significantly phenotypic differences in terms of morphology, growth, adhesion, migration and invasion properties. In particular, co-culture experiments, with the two most different clones for both cell-lines, confirmed the cell-cell interaction key role in driving their more aggressive phenotype. Furthermore, we found that pGBM and DIPG sub-clones release exosomes which are actively and differentially up-taken by individual clones. Analysis of the exosomal microRNAs showed a different profile between the two selected clones in each cell-line. In particular, we found a pool of five upregulated microRNAs in 1C5 clone (DIPG cell-line) strongly associated to Wnt-signaling and PI3K-AKT pathway. Similarly, a pool of five upregulated microRNAs for 5E2 clone (pGBM cell-line) were found associated with focal adhesion and PI3K-AKT pathway. Our study may provide novel therapeutic strategies by interfering with the exosome-mediated inter-clonal communication in pGBM and DIPG.
IMG-01. DWI RATIO OF HISTOLOGICAL MOLECULAR SUBTYPES OF PAEDIATRIC MEDULLOBLASTOMAS
Authors: Phua Hwee Tang, Sharon Low, Enrica Tan, Kenneth Chang
Journal: Neuro-Oncology (2020)

Abstract AIM To evaluate if diffusion weighted imaging (DWI) ratio on MRI is able to distinguish between the histological molecular subtypes of paediatric medulloblastomas. MATERIALS AND METHODS From 2002 to 2017, 38 cases of medulloblastoma with preoperative MRI available had histological subtyping performed with NanoString nCounter technology. The medulloblastomas were classified into 4 subtypes. There were 3 Sonic Hedgehog (SHH), 9 Wingless (WNT), 12 Group 3 and 14 Group 4 subtypes. Single operator manually outlined solid non-haemorrhagic component of the tumour on DWI images with largest axial tumour cross sectional diameter, correlating with the other MRI images (T1 pre and post contrast, SWI/GRE, FLAIR) to identify areas of haemorrhage. The same operator also drew region of interest to identify normal cerebellar tissue on the same axial images on which the tumour was outlined. All MRI images were obtained from the department’s Radiological Information System Picture Archiving and Communicating System (RIS PACS). DWI ratio for each case was obtained by dividing the values obtained from tumour by normal cerebellar tissue seen on the same axial image. RESULTS DWI ratio of all medullloblastomas is 1.34 +/- 0.18. DWI ratio of SHH subtype is 1.43 +/- 0.07. DWI ratio of WNT subtype is 1.40 +/- 0.07. DWI ratio of Group 3 subtype is 1.31 +/- 0.25. DWI ratio of Group 4 subtype is 1.30 +/- 0.17. There is no significant statistical differences in the DWI ratio between the various subtypes. CONCLUSION DWI ratio of medulloblastoma is unable to distinguish between the 4 medulloblastoma subtypes.
EPID-16. INTEGRATION OF EHR AND CANCER REGISTRY DATA TO CONSTRUCT A PEDIATRIC NEURO-ONCOLOGY SURVIVORSHIP COHORT AND IMPROVE LONG-TERM FOLLOW-UP CARE
Authors: David Noyd, Claire Howell, Kevin Oeffinger, Daniel Landi, Kristin Schroeder
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Pediatric neuro-oncology (PNO) survivors suffer long-term physical and neurocognitive morbidity. Comprehensive care addressing late effects of brain tumors and treatment in these patients is important. Clinical guidelines offer a framework for evaluating late effects, yet lack of extended follow-up is a significant barrier. The electronic health record (EHR) allows novel and impactful opportunities to construct, maintain, and leverage survivorship cohorts for health care delivery and as a platform for research. METHODS This survivorship cohort includes all PNO cases ≤18-years-old reported to the state-mandated cancer registry by our institution. Data mining of the EHR for exposures, demographic, and clinical data identified patients with lack of extended follow-up (&amp;gt;1000 days since last visit). Explanatory variables included age, race/ethnicity, and language. Primary outcome included date of last clinic visit. RESULTS Between January 1, 2013 and December 31, 2018, there were 324 PNO patients reported to our institutional registry with ongoing analysis to identify the specific survivorship cohort. Thirty patients died with an overall mortality of 9.3%. Two-hundred-and-sixteen patients were seen in PNO clinic, of which 18.5%% (n=40) did not receive extended follow-up. Patients without extended follow-up were an average of 3.5 years older up (p&amp;lt;0.01); however, there was no significant difference in preferred language (p=0.97) or race/ethnicity (p=0.57). CONCLUSION Integration of EHR and cancer registry data represents a feasible, timely, and novel approach to construct a PNO survivorship cohort to identify and re-engage patients without extended follow-up. Future applications include analysis of exposures and complications during therapy on late effects outcomes.
H3K27 acetylation activated-COL6A1 promotes osteosarcoma lung metastasis by repressing STAT1 and activating pulmonary cancer-associated fibroblasts
Authors: Ying Zhang, Zhaoyong Liu, Xia Yang, Weiqing Lu, Yelong Chen, Youbin Lin, Jin Wang, Suxia Lin, Jing-Ping Yun
Journal: Theranostics (2020)

Background: Collagen type VI alpha 1 (COL6A1) has been found to be dysregulated in several human malignancies. However, the role of COL6A1 in osteosarcoma (OS) progression remains largely unclear. Here, we aimed to explore the clinical significance and biological involvement of COL6A1 in the OS cell migration and invasion. Material and Methods: We used immunohistochemistry, qRT-PCR and western blot to detect the expression of COL6A1 in 181 OS patient samples. Chromatin immunoprecipitation (ChIP) and PCR were carried out to verify the regulatory interaction of p300, c-Jun and COL6A1 promoter. The invasion and migration function of COL6A1 in OS was detected in vitro and in vivo. RNA sequence was performed to detect the downstream pathway of COL6A1, and then co-immunoprecipitation (co-IP), ubiquitination assays and rescue experiments were performed to determine the regulatory effect of COL6A1 and signal transducers and activators of transcription (STAT1). Exosomes derived from OS cell lines were assessed for the ability to promote cancer progression by co-cultured assay and exosomes tracing. Results: COL6A1 was commonly upregulated in OS tissues, especially in lung metastasis tissues, which was associated with a poor prognosis. c-Jun bound p300 increased the enrichment of H3K27ac at the promoter region of the COL6A1 gene, which resulted in the upregulation of COL6A1 in OS. Overexpression of COL6A1 promoted OS cell migration and invasion via interacting with SOCS5 to suppress STAT1 expression and activation in an ubiquitination and proteasomal degradation manner. Most interestingly, we found that exosomal COL6A1 derived from OS cells convert normal fibroblasts to cancer-associated fibroblasts (CAFs) by secreting pro-inflammatory cytokines, including IL-6 and IL-8. The activated CAFs could promote OS cell invasion and migration by mediating TGF-β/COL6A1 signaling pathway. Conclusion: Our data demonstrated that upregulation of COL6A1 activated by H3K27 acetylation promoted the cell migration and invasion by suppressing STAT1 pathway in OS cells. Moreover, COL6A1 can be packaged into OS cell-derived exosomes and activate CAFs to promote OS metastasis.
GCT-14. SECOND-LOOK SURGERY FOR INTRACRANIAL GERM CELL TUMORS
Authors: Hideki Ogiwara
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE The authors present their experiences of second-look surgery in patients with intracranial GCTs who showed less than complete response despite normalizing or decreasing tumor markers after chemotherapy. METHODS Retrospective review of 14 patients who underwent second-look surgery for an intracranial GCT was performed. RESULTS Of 40 consecutive patients with newly diagnosed intracranial GCTs treated between August 2003 and 2019, 14 patients (35%) underwent second-look surgery. The mean age was 9.2 years. The initial diagnoses were mixed germ cell tumor in 6, immature teratoma in 4, yolk sac tumor in 2, and germinoma 2. Second-look surgery was performed after 1–3 courses of chemotherapy. Magnetic resonance imaging (MRI) at the surgery demonstrated increasing residual tumor in 8 and stable residual tumor in 6. Tumor markers were normalized in 10 and nearly-normalized in 4. Gross total resection was achieved in 12 patients and near-total resection in 2. Histopatholgy at second-look surgery revealed mature teratoma in 6, immature teratoma in 3, fibrosis with atypical cells in 2, and fibrosis in 3. Eleven patients subsequently underwent additional chemo-radiation therapy according to the initial diagnosis. All patients are alive with no evidence of recurrence with a mean follow-up of 69 months. CONCLUSIONS Second-look surgery plays an important role in the treatment of intracranial GCTs. Surgery may be encouraged at a relatively early phase after chemotherapy when the residual tumor increases or does not change the size despite normalized or nearly-normalized tumor markers in order to achieve complete resection and improve the outcome.