tbuckley/cabot-search huggingface dataset:
EXTH-01. INHIBITION OF DNA-PKcs BY M3814 POTENTIATES EFFICACY OF IONIZING RADIATION IN PATIENT-DERIVED XENOGRAFTS OF MELANOMA BRAIN METASTASES
Authors: Jianxiong Ji, Emily Smith, Paige Sarkaria, Ann Mladek, Surabhi Talele, Katelyn Swanson, Afroz S Mohammad, Wenjuan Zhang, Lihong He, Zeng Hu, Yu Zhao, Jiajia Chen, Margaret A Connors, Kendra A Porath, Katrina K Bakken, Sonja Dragojevic, Brett L Carlson, Shiv K Gupta, Danielle M Burgenske, Gaspar J Kitange, William F Elmquist, Jann Sarkaria
Journal: Neuro-Oncology (2020)

Abstract Radio-resistance mechanisms limit the benefit of radiation therapy (RT) for melanoma brain metastases. A key pathway for radiation-induced DNA double-strand break repair is non-homologous end joining, which is critically mediated by DNA-dependent protein kinase (DNA-PKcs). Here we evaluated radio-sensitizing effects of M3814, a selective oral inhibitor of DNA-PKcs, in patient-derived xenografts (PDXs) of melanoma brain metastases. In a clonogenic survival assay, M3841 augmented RT-induced killing of M12 cells at concentrations of ≥300 nM, and a minimum of 16 h exposure with ~300 nM M3814 was required for effective sensitization. M3814 inhibited RT-induced (5 Gy) auto-phosphorylation of serine-2056 of DNA-PKcs in primary cultures of M12, M15 and M27 PDX lines. Interestingly, inhibition of RT-induced DNA-PKcs by M3814 coincided with increased KAP1 phosphorylation, a DNA damage signaling regulated via ATM. Persistent γH2AX foci were observed in 28% M12 cells at 24 hours after co-treatment with M3814 and RT as compared to 12% cells following RT alone. In vivo pharmacokinetic analysis after single oral dose of 20 mg/kg M3814, showed reasonably short half-life (~2.44 hours) and poor brain distribution in wild-type FBV mice (Kpuu, 0.027). Consistent with an efflux liability, brain distribution of M3814 in triple knockout mice for BCRP/MDR1A/B was ~11 fold higher (Kpuu, 0.215). Compared to normal brain, much higher M3814 concentrations were detected in intracranially implanted M12 tumors (~23 fold and ~20 fold) 2 and 6 hours after a single oral dose of 50mg/kg respectively. The relative exclusion of M3814 from normal brain as compared to brain metastases suggests that this drug may have a favorable toxicity profile when combined with radiation for treatment of melanoma brain metastases, and this hypothesis is being tested in ongoing efficacy studies.
EXTH-33. VALPROIC ACID ENHANCES THE ANTI-PROLIFERATIVE EFFECT OF TUMOR-TREATING FIELDS ON PATIENT-DERIVED GLIOSARCOMA CELLS IN VITRO
Authors: Sharon Michelhaugh, Sandeep Mittal
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Valproic acid (VPA) is an anti-epileptic drug often prescribed for glioma-associated seizures. VPA is also investigated as a potential anti-proliferative cancer treatment due to its histone deacetylase inhibitor activity. Tumor-treating fields (TTFields) are an FDA-approved therapy that reduce proliferation of tumor cells by interfering with microtubule formation during mitosis. In this study, we determined whether the combination of VPA with TTFields in comparison to each treatment alone would alter proliferation or cytotoxicity in patient-derived gliosarcoma cells. METHODS Gliosarcoma cells were grown in DMEM/F12 media with 10% fetal bovine serum and gentamicin. Prior to TTFields application and VPA incubation, cells were plated on plastic coverslips (1×104cells/coverslip) and incubated overnight. TTFields were applied to cells at 200 kHz optimal frequency (field intensity of ~1.6 V/cm) for 14 days and/or incubated with VPA at concentrations of 0, 0.25, 0.5, or 1mM. Proliferation was assessed by quantifying total RNA from each coverslip (n=3–4/group). Cytotoxicity was assessed by measuring lactate dehydrogenase (LDH) released into the media (n=8/group). Groups were compared by t-tests. RESULTS RNA yields from cells treated with only VPA were unchanged compared to control. TTFields treatment alone reduced RNA yield from 14.85±4.23 to 8.92±1.39 µg (mean± SD; P&amp;lt; 0.05). The addition of 1mM VPA to TTFields further reduced RNA yield to 5.48±1.5 µg (P&amp;lt; 0.03), although VPA alone had no effect. Additionally, 1mM VPA increased media LDH from 4.00±1.3 to 6.68±1.7 AU (mean± SD; P&amp;lt; 0.01), while TTFields alone also increased media LDH to 5.67±0.99 AU (P&amp;lt; 0.02). Media LDH levels due to combined TTFields and 1mM VPA treatment was 5.86±1.2 AU (not statistically different from either alone). CONCLUSIONS In patient-derived gliosarcoma cells, TTFields and VPA individually elicited modest cytotoxicity. However, TTFields plus VPA combination treatment reduced proliferation more than TTFields alone, though VPA treatment alone did not induce an anti-proliferative effect.
EXTH-11. PATIENT DERIVED INDUCED NEURAL STEM CELLS FOR TREATMENT OF GLIOBLASTOMA
Authors: Andrew Buckley, Shaye Hagler, Vivien Lettry, Juli Bago, Spencer Maingi, Simon Khagi, Matthew Ewend, C Ryan Miller, Shawn Hingtgen
Journal: Neuro-Oncology (2020)

Abstract Induced neural stem-cells (iNSCs) represent a new opportunity in the emerging field of cellular immunotherapy. Patient-derived iNSCs modified to produce anti-tumoral compounds could lead to less rejection and safer outcomes than an off-the-shelf therapy. In this study, we established fibroblast lines (PFs) from skin-biopsies of patients being treated for glioblastoma (GBM) and transdifferentiated those fibroblasts into iNSC lines that produce anti-tumor compounds. We designed a combination of genomic and functional testing to assess iNSC line efficacy. Functional testing revealed differences in rate of transdifferentiation, therapeutic agent production, and tumor-homing amongst cell lines all of which varied among patients. RNAseq profiles of individual cells lines revealed biomarker signatures that differed in tumor-homing-pathways. There was no observed neuronal differentiation in the iNSCs from the transcriptomic profiles, indicating stability after transdifferentiation amongst PFs. Anti-tumor activity of patient-derived iNSCs was measured in vivo by surgical-resection mouse models with invasive CD133+ GBM cells. Patient-derived iNSCs showed variable tumoricidal effectiveness; more highly effective iNSC cells lines reduced tumor burden and increased survival post-resection from 28 to 45 days, whereas less effective cells lines could increase post-resection survival with increased iNSC dosage. PF origination and transcriptomic profile accounted for the differences amongst the iNSC lines. Identification of differentially expressed genes could indicate the cellular pathways that are most important for guaranteeing high, anti-tumoral activity. Further, the cellular profile of the patient-derived fibroblast influences the resulting cellular profile of the iNSC; potentially, correlation of fibroblast gene expression profile could predict tumoricidal efficacy of derived iNSCs.
BIOM-55. DGKζ-TARGETED REGULATION OF MIR-34A IN THE PROLIFERATION AND TUMORIGENICITY OF HUMAN GLIOBLASTOMA
Authors: Wangxian Gu, Guoqing Wan, Yanjun Zheng, Xintong Yang, Peng Zhang, Changlian Lu, Xuefeng Gu
Journal: Neuro-Oncology (2020)

Abstract Diacylglycerol kinase (DGK) is a lipid kinase that catalyzes the phosphorylation of diacylglycerol (DAG) to produce phosphatidic acid (PA), which uses ATP as a phosphate donor. Diacylglycerol kinases ζ(DGKζ) is characterized as specific type IV due to its myristoylated alanine-rich C-kinase substrate (MARCKS), ankyrin, and PDZ binding domain. Similar to other DGKs, DGKζ is also reported to be abnormally expressed in human colorectal cancer cells, and it is indispensable for the proliferation of cancer cells. However, its implications in human glioblastoma (GBM) is largely unknown. Both the mRNA and protein levels of DGKζ were significantly higher in GBM tissues than in precancerous lesions. Knockdown of DGKζ inhibited GBM cell proliferation, cell cycle and promoted apoptosis of GBM cells. Moreover, down-regulation of DGKζ markedly reduced in vitro colony formation and in vivo tumorigenic capability. Furthermore, we confirmed that DGKζ was the downstream target of miR-34a. The expression level of DGKζ was negatively correlated with miR-34a in GBM tissues. Overexpression of DGKζ reversed the tumor suppressive roles of miR-34a in GBM cells. Taken together, DGKζ can act as a potential prognostic biomarker for GBM patients and promote the growth of GBM cells was regulated by miR-34a, and it may represent a promising therapeutic target for patients with GBM.
In type 2 diabetes, SGLT2 inhibitors were linked to diabetic ketoacidosis vs. DPP-4 inhibitors
Authors: Aris Liakos, Apostolos Tsapas, Eleni Bekiari
Journal: Annals of Internal Medicine (2020)

Douros A, Lix LM, Fralick M, et al. Sodium-glucose cotransporter-2 inhibitors and the risk for diabetic ketoacidosis: a multicenter cohort study. Ann Intern Med. 2020;173:417-25. 32716707.
EPID-06. DIAGNOSTIC INTERVAL TIME OF PEDIATRIC CNS TUMORS: A REPORT OF THE CANCER IN YOUNG PEOPLE IN CANADA (CYP-C) DATABASE
Authors: Mohammad AlNajjar, Divya Goel, Valerie Larouche, Craig Erker, Sylvia Cheng, Randy Barber, Douglas Strother, Lillian Sung, Lucie Lafay-Cousin
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION CNS tumors are the second most common neoplasm in children and have historically been associated with longer time to diagnosis. Data on the time-to-diagnosis for Canadian children with CNS tumors are limited and outdated. We aimed at evaluating the diagnostic interval time(DIT) for Canadian children, and identifying factors possibly associated with prolonged DIT. METHODS Using the CYP-C database, we analyzed data from children &amp;lt;15 years, diagnosed with CNS tumors between 2001–2015. DIT was defined as time in weeks, elapsed from the first contact with a healthcare provider to confirming diagnosis. We described DIT according to patient’s demographics, socioeconomic, geographic factors as well as tumor-related criteria. RESULTS Patients from all Canadian provinces, except Ontario, had available timepoints to calculate DIT. The cohort included 842 patients. Mean DIT for all patients was 11.7 weeks(median 1.4). Gliomas had the longest mean DIT and embryonal tumors had the shortest(14.6 and 3.6 weeks p&amp;lt;0.01). ATRT and medulloblastoma had a mean DIT of 1.3 and 4.3 weeks respectively. DIT for HGG was shorter than for LGG (6.4 versus 16.1 weeks, p&amp;lt;0.01). Metastatic disease, infratentorial tumors, or age £36 months had significantly shorter DIT (5.6 vs 12.4 vs 18.4, 7.4 vs 13.1 and 8.6). Sex, annual income(QAIPPE), and distance from tertiary center did not influence DIT. CONCLUSION The current diagnostic interval time for pediatric CNS tumors in Canada is 11.7 weeks(median 1.4weeks). These results only reflect the healthcare system’s contribution toward diagnosis confirmation, but not the patient interval before seeking medical attention.
PATH-31. ARTIFICIAL INTELLIGENCE IN GLIOMA PATHOLOGY IMAGE ANALYSIS FOR RISK PREDICTION
Authors: Pranathi Chunduru, Joanna Phillips, Annette Molinaro
Journal: Neuro-Oncology (2020)

Abstract Pathological evaluation of tumor tissue images stained with hematoxylin and eosin (H&amp;E) is pivotal in diagnosis and predictive of outcome, yet only a small fraction of the rich phenotypic information on the slide is currently used for clinical care. In this study, we developed a computational approach based on deep learning to predict overall survival within distinct molecular subtypes of glioma patients and to extract prognostic biomarkers from microscopic images of tissue biopsies. Whole-slide images from 766 unique patients [IDH: 336 IDH-wildtype, 364 IDH-mutant, 1p/19q: 142 1p/19q-codeleted, 620 1p/19q-non-codeleted] were obtained from The Cancer Genome Atlas (TCGA). Sub-images that were free of artifacts and that contained viable tumor with descriptive histologic characteristics were extracted, which were used for training and testing the deep neural-network. Our unified survival deep learning framework (SDL) uses a residual CNN network integrated with a traditional survival model to predict patient risk from digitized whole-slide images. We employed statistical sampling techniques and randomized transformation of images to address challenges in learning from histology images. Univariable and multivariable Cox proportional-hazards regression models were used to evaluate the significance of predicted patient risk with and without controlling for known prognostic factors. The integrated SDL framework showed substantial prognostic power achieving a median c-index of 0.79 [95 % CI 0.77 - 0.81]. In multivariable Cox regression analysis, SDL risk was significantly associated with overall survival (hazard ratio of 1.65, 95% CI 1.49-1.83, p &amp;lt; 0.001) after adjusting for age, grade, IDH status, ATRX status, 1p19q codeletion and CDKN2A/2B status. Only IDH-status and age were also significant in the multivariable model. Preliminary findings highlight the emerging role of AI in precision medicine and suggest the utility for computational analysis of tumor tissue images for objective and accurate prediction of outcome for glioma patients and also for risk stratification for targeted clinical therapy.
Brian D Hore
Authors: Ian Hore, Andrew Hore
Journal: BMJ (2020)

Brian D Hore was born on 21 September 1937 and died on 26 July 2020. The intervening 82 years were incredibly full. He directly gave hope, and successful treatment, to thousands of patients in Manchester with alcohol dependence. At the same time, he helped move care forward in the UK through the Medical Council on Alcohol, and across the globe through the International Council on Alcohol and Addiction. All the more impressive, he managed to do this over many years while going through the trials and tribulations, ups and downs, of supporting Manchester City Football Club.

Born in Wembley, north London, Brian was an only child, or “only hope,” as his mum, Gladys, would say. He flourished even though the onset of the second world war was just around the corner. When Brian was growing up, his father, Harold, was a laboratory scientist at St George’s Hospital, when it was based at Hyde Park Corner. Brian’s parents doted on him. …
The race for ACE: A simple answer to the controversial puzzle of angiotensin-converting enzyme (ACE) polymorphisms**Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily reflect the views of JACCor the American College of Cardiology.
Authors: Bernhard Schieffer, Helmut Drexler
Journal: Journal of the American College of Cardiology (2003)
Post-Transcriptional Genetic Silencing of<i>BCL11A</i>to Treat Sickle Cell Disease
Authors: Erica B. Esrick, Leslie E. Lehmann, Alessandra Biffi, Maureen Achebe, Christian Brendel, Marioara F. Ciuculescu, Heather Daley, Brenda MacKinnon, Emily Morris, Amy Federico, Daniela Abriss, Kari Boardman, Radia Khelladi, Kit Shaw, Helene Negre, Olivier Negre, Sarah Nikiforow, Jerome Ritz, Sung-Yun Pai, Wendy B. London, Colleen Dansereau, Matthew M. Heeney, Myriam Armant, John P Manis, David A. Williams
Journal: New England Journal of Medicine (2020)

Sickle cell disease is characterized by hemolytic anemia, pain, and progressive organ damage. A high level of erythrocyte fetal hemoglobin (HbF) comprising α- and γ-globins may ameliorate these manifestations by mitigating sickle hemoglobin polymerization and erythrocyte sickling.
MBCL-06. RISK STRATIFICATION IMPROVEMENT OF THE HIT2000 AND I-HIT-MED COHORTS USING MOLECULAR SUBTYPES I-VIII OF GROUP 3/4 MEDULLOBLASTOMAS
Authors: Martin Mynarek, Denise Obrecht, Martin Sill, Florian Selt, Katja von Hoff, David Jones, Dominic Sturm, B - Ole Juhnke, Jonas Ecker, Torsten Pietsch, Andreas von Deimling, Felix Sahm, Stefan M Pfister, Olaf Witt, Michael Ludwig Bockmayr, Ulrich Schüller, Stefan Rutkowski, Till Milde
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE Molecular subtypes of Group 3/4 medulloblastoma have been identified by unsupervised clustering methods in different studies. We hypothesized that risk stratification using these subtypes I-VIII improves outcome prediction. PATIENTS AND METHODS n=340 patients with Group 3 or Group 4 medulloblastoma defined by DNA methylation array profiling enrolled into the HIT2000 study and HIT-MED registries were subtyped by the Heidelberg Medulloblastoma Classifier. The discovery cohort consisted of n=162 previously published samples, the validation cohort of n=178 newly analyzed samples. RESULTS AND DISCUSSION: n=300/340 (88%) MBs could be assigned to one of the subtypes with confidence (score &amp;gt;0.8; Heidelberg Medulloblastoma classifier). Subtype II,III and V showed a poor PFS and OS and were classified as HR (discovery:5y-PFS 45%[95%-CI:33–62], 5y-OS 50%[37–67]; validation:5y-PFS 32%[20–50], 5y-OS 40%[27–61]). Subtypes I, IV, VI-VIII fared better (discovery:5y-PFS 67%[58–77], 5y_OS 84%[77–91]; Validation:5y-PFS 70%[58–83], 5y-OS 89%[81–99]). Survival prediction by subtype-based risk assessment was improved compared to Group 3 versus 4 differentiation in both cohorts in univariate and multivariable Cox regression models (PFS:Hazard ratio HR versus LR 2.474, p&amp;lt;0.001; Group 3 versus Group 4 1.842, p=0.003; adjustment for anaplasia, age and metastatic disease). Patients older than 4 with subtype IV tumors (mainly Group 3) treated with radiotherapy achieved a 100% PFS, while subtype V patients (mainly Group 4) had poor survival. CONCLUSION We showed that molecular subtypes I-VIII improved risk stratification of Group 3/4 medulloblastomas. Group 3 subtype IV MB treated with RT had very high cure rates.
In vivo therapeutic effects of affinity-improved-TCR engineered T-cells on HBV-related hepatocellular carcinoma
Authors: Qi Liu, Ye Tian, Yanyan Li, Wei Zhang, Wenxuan Cai, Yaju Liu, Yuefei Ren, Zhaoduan Liang, Peipei Zhou, Yajing Zhang, Yifeng Bao, Yi Li
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background In patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), virus-specific cytotoxic T lymphocytes (CTLs) fail to eliminate HCC cells expressing HBV antigens. As the expression of viral antigen in HBV-associated HCC may decrease to allow tumor to escape immune attacks, we hypothesized that an HBV surface antigen (HBsAg)-specific affinity-improved-T-cell receptor (TCR) will enable T cells to target HCC more effectively than corresponding wild-type-TCR. We also postulated that TCR promiscuity can be exploited to efficiently capture HBV variants that can hinder CTL-based therapeutics. Methods We applied flexi-panning to isolate affinity-improved TCRs binding to a variant antigen, the human leukocyte antigen (HLA)-A*02:01-restricted nonapeptide HBs 371-379 -ILSPFLPLL, from libraries constructed with a TCR cloned using the decapeptide HBs 370-379 -SIVSPFIPLL. The potency and safety of the affinity-improved-TCR engineered T-cells (Ai-TCR-T) were verified with potentially cross-reactive human and HBV-variant peptides, tumor and normal cells, and xenograft mouse models. Results Ai-TCR-T cells retained cognate HBV antigen specificity and recognized a wide range of HBV genotypic variants with improved sensitivity and cytotoxicity. Cell infusions produced complete elimination of HCC without recurrence in the xenograft mouse models. Elevated accumulation of CD8 + Ai-TCR-T cells in tumors correlated with tumor shrinkage. Conclusion The in vitro and in vivo studies demonstrated that HBsAg-specific Ai-TCR-T cells had safety profiles similar to those of their wild-type counterparts and significantly enhanced potency. This study presents an approach to develop new therapeutic strategies for HBV-related HCC.
Association Between Bone Mineral Density and Autoantibodies in Patients With Rheumatoid Arthritis
Authors: Josephine A. M. P. Amkreutz, Emma C. de Moel, Lisa Theander, Minna Willim, Lotte Heimans, Jan‐Åke Nilsson, Magnus K. Karlsson, Tom W. J. Huizinga, Kristina E. Åkesson, Lennart T. H. Jacobsson, Cornelia F. Allaart, Carl Turesson, Diane van der Woude
Journal: Arthritis & Rheumatology (2020)

Objective Autoantibodies, such as anti–citrullinated protein antibodies (ACPAs), have been described as inducing bone loss in rheumatoid arthritis (RA), which can also be reflected by bone mineral density (BMD). We therefore examined the association between osteoporosis and autoantibodies in two independent RA cohorts. Methods Dual x‐ray absorptiometry (DXA) of the lumbar spine and left hip was performed in 408 Dutch patients with early RA during 5 years of follow‐up and in 198 Swedish patients with early RA during 10 years of follow‐up. The longitudinal effect of ACPAs and other autoantibodies on several BMD measures was assessed using generalized estimating equations. Results In the Dutch cohort, significantly lower BMD at baseline was observed in ACPA‐positive patients compared to ACPA‐negative patients, with an estimated marginal mean BMD in the left hip of 0.92 g/cm 2 (95% confidence interval [95% CI] 0.91–0.93) versus 0.95 g/cm 2 (95% CI 0.93–0.97) ( P = 0.01). In line with this, significantly lower Z scores at baseline were noted in the ACPA‐positive group compared to the ACPA‐negative group (estimated marginal mean Z score in the left hip of 0.18 [95% CI 0.08–0.29] versus 0.48 [95% CI 0.33–0.63]) ( P &lt; 0.01). However, despite clear differences at baseline, ACPA positivity was not associated with greater decrease in absolute BMD or Z scores over time. Furthermore, there was no association between BMD and higher levels of ACPAs or other autoantibodies (rheumatoid factor and anti–carbamylated protein antibodies). In the Swedish cohort, ACPA‐positive patients tended to have a higher prevalence of osteopenia at baseline ( P = 0.04), but again, ACPA positivity was not associated with an increased prevalence of osteopenia or osteoporosis over time. Conclusion The presence of ACPAs is associated with significantly lower BMD at baseline, but not with greater BMD loss over time in treated RA patients. These results suggest that ACPAs alone do not appear to contribute to bone loss after disease onset when disease activity is well‐managed.