tbuckley/cabot-search huggingface dataset:
Abstract 2284: Semiautomated MRI segmentation workflow for glioblastoma treated by Tumor Treating Fields
Authors: Joshua J. Timmons, Ed Lok, Pyay San, Kevin Bui, Eric T. Wong
Journal: Cancer Research (2018)

Abstract Background: Tumor Treating Fields (TTFields) therapy is an approved modality of treatment for glioblastoma. Patient anatomy-based finite element analysis (FEA) has the potential to reveal not only how these fields affect tumor control but also how they can be optimized to improve efficacy. Historically, this has been achieved with manual segmentation by an expert familiar with intracranial neuroanatomic structures, but this method is time-consuming, financially costly, and highly variable between individuals. While the availability of tools for segmenting MRIs obviates some of these obstacles, creating FEA models requires manual adjustments, including removal of disconnected voxels, incorporation of unsegmented structures that may alter the electric field, and addition of 36 electrodes matching those of the transducers on the scalp. Existing approaches are also not scalable to a large number of patient MRI scans. Methods: Patient anatomy-based FEA models were created by segmenting MRI images—using the NewSegment algorithm from Statistical Paramedic Mapping 8 (SPM8)—into tissue “masks” using ScanIP from Simpleware (Exeter, UK). The electric properties of each tissue were applied to these masks in silico using COMSOL Multiphysics (Burlington, MA). The fidelity of the segmentations was compared using the Dice coefficient, and COMSOL generated electric field maps were compared for models with and without post-processing in ScanIP. Results: A semiautomated workflow was developed to prepare FEA models for TTFields with fully automated electrode placement. The workflow encompassed image preprocessing, co-registration, segmentation, post-processing and mesh generation in ScanIP. Modified extended tissue probability maps were used to segment cerebellum and orbits in addition to white matter, gray matter, cerebrospinal fluid, skull, and scalp. Further automated post-processing in ScanIP cleaned up disconnected voxels, smoothed surfaces, and layered the masks to prevent erroneous boundary conditions. The Dice coefficient was greater for the model with ScanIP post-processing, as compared to the segmentations resulting from SPM8 NewSegment alone. COMSOL-generated electric field maps also displayed differences when models were generated with post-processing in ScanIP compared to those without. Conclusions: These software and workflow may be used to accelerate the investigation of TTFields in patients by facilitating the creation of FEA models, like electric field maps, derived from patient MRI. Citation Format: Joshua J. Timmons, Ed Lok, Pyay San, Kevin Bui, Eric T. Wong. Semiautomated MRI segmentation workflow for glioblastoma treated by Tumor Treating Fields [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2284.
Abstract 5852: FGF2 confers resistance to novel BET inhibitors in metastatic uveal melanoma
Authors: Vivian Chua, Timothy Purwin, Connie Liao, Andrew Aplin
Journal: Cancer Research (2018)

Abstract Uveal melanoma (UM) is the most common intraocular malignancy in adults and frequently metastasizes to the liver. Metastatic UM responds poorly to chemotherapy, immunotherapy and MAPK pathway inhibitors; hence, there is an urgent unmet need for new treatment strategies. UM has a low mutational burden and progression is associated with abberrant transcriptional programs. Inhibition of epigenetic modulators involved in transcriptional regulation such as the bromodomain and extraterminal domain (BET) proteins, may be feasible for the treatment of UM. Pre-clinically, JQ1, a first generation BET inhibitor, has been shown to suppress UM growth. Additionally, a multi-site clinical trial is ongoing testing a novel BET inhibitor, PLX51107 (Plexxikon Inc) in metastatic UM patients. Since growth factors in the tumor microenvironment potentially contribute to intrinsic resistance and poor responses to therapies, we determined effects of growth factors on the efficacy of BET inhibitors in metastatic UM cells. We show that FGF2 provides resistance of UM cells to the growth inhibitory effects of BET inhibitors, JQ1, PLX51107 and the third generation inhibitor, PLX72853. FGF2 rescued BET inhibitor-induced apoptosis and cell cycle arrest, which was associated with reversal of the decreased expression of cell cycle regulators (cyclin D1, phospho-RB) and increased expression of pro-apoptotic markers (cleaved PARP, Bim). Importantly, FGF receptor (FGFR) inhibitors reversed FGF2-induced BET inhibitor resistance. As UM predominantly metastasizes to the liver, we investigated FGF2 production by hepatic stellate cells. We show that hepatic stellate cells secrete FGF2 and stellate cell conditioned medium protects metastatic UM cells against the growth inhibitory effects of BET inhibitors. Interestingly, BET inhibitor treatment of UM cells elevated FGFR protein expression and this finding is also shown in UM cell xenograft tumors and in patient tumor samples following PLX51107 treatment. These results indicate that the FGF2/FGFR pathway is activated to promote resistance to BET inhibition via the secretion of FGF2 in the tumor stroma and adaptive upregulation of FGFR expression in UM. In conclusion, our studies suggest that co-targeting of FGFR signaling and BET proteins may be required to maximize the responses of metastatic UM to BET inhibitors. Citation Format: Vivian Chua, Timothy Purwin, Connie Liao, Andrew Aplin. FGF2 confers resistance to novel BET inhibitors in metastatic uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5852.
Abstract 3079: Epstein Barr virus-encoded LMP1 reprograms glucose metabolism to enhance cell motility in nasopharyngeal epithelial cell
Authors: Jun Zhang, Weitao Lin, Chi Man Tsang, Teng Fei Liu, Wing Chong Tang, Yim Ling Yip, Wen Deng, Lin Jia, Sai Wah Tsao
Journal: Cancer Research (2018)

Abstract How oncogenic virus rewires glucose flux to regulate cell motility is not well-understood. Epstein-Barr virus (EBV) infection of preinvasive nasopharyngeal epithelium is believed to be an essential initiation event during nasopharyngeal carcinoma pathogenesis. Here we demonstrate that EBV-encoded LMP1 enhances glycolysis thereby accelerating cell mobility of nasopharyngeal epithelial (NPE) cells. Activation of IGF1/mTORC2/AKT/PDHE1α signaling which mediates Histone 3 acetylation is involved in cell motility in EBV-infected NPE cells. Blocking the glucose uptake by pharmacological inhibitors effectively suppress glycolysis as well as the cell motility, linking the glucose metabolism to cell movement. We further show that mTORC2/AKT mediated phosphorylation of pyruvate decarboxylase kinase 1 (PDHK1) and its substrate, pyruvate decarboxylase E1α (PDHE1α) component plays a significant role in cell motility. PDHE1α knockdown effectively blocks LMP1-induced cell motility while overexpression of its phosphomimetic mutant S293A but not S293D inhibits LMP1-induced cell motility, supporting the involvement of PDHE1α in enhanced cell motility is depended on Ser293 phosphorylation. Furthermore, PDHE1α translocation into nucleus enhances Histone 3 acetylation and its binding to the promoter region of snail to enhance cell motility. Finally, we find that LMP1 increases the mRNA expression and the secretion of the ligand IGF1, which promotes phosphorylation of IGF1R as the key regulator for LMP1-induced mTORC2/AKT activation. In summary, this study provides evidences of involvement of EBV infection in metabolic reprogramming of NPE cells to promote cell motility involving activation of mTORC2/AKT/PDHE1α. Acknowledgment: This project was supported by funding from the Research Grants Council, Hong Kong: General Research Fund (17120814, 17161116, 17111516, 171110315), Area of Excellence (AoE/M-06/08), Theme-Based Research Scheme (T12-401/13-R), Collaborative Research Fund (Project reference: C7027-16G); Health and Medical Research Fund of Hong Kong (12110782, 13120872, 04151726); and CRCG, University of Hong Kong, Hong Kong. Citation Format: Jun Zhang, Weitao Lin, Chi Man Tsang, Teng Fei Liu, Wing Chong Tang, Yim Ling Yip, Wen Deng, Lin Jia, Sai Wah Tsao. Epstein Barr virus-encoded LMP1 reprograms glucose metabolism to enhance cell motility in nasopharyngeal epithelial cell [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3079.
Abstract CT071: Continuous i.v. Crotoxin in advanced cancer: Intra-patient dose escalation
Authors: Marian Gil Delgado, Gougis Paul, Dorothy H. Bray, Francois M. DELGADO, Jean P. SPANO, Ahmed Idbaih, Paul F. Reid, Khadija Benlhassan, Cheikh Diaw, David Khayat
Journal: Cancer Research (2018)

Abstract Introduction: Crotoxin (CRTX), a potent neurotoxin from the venom of Crotalus durissus terrificus, rattlesnake, upon intramuscular administration has been shown to have broad anti-tumor activity accompanied with significant toxicity. Preclinical animal data suggested that in intra-patient dose escalation protocol the administration of high doses and efficacy can be achieved without toxicity. Methods: We followed the design of Medioni et al (Contemp. Clinical Trials Comm. 7, 2017: 186-168) in intra-patient dose escalation study to administer CRTX in heavily pre-treated patients (5 males and 1 female) with advanced solid tumors: 1 nasal squamous cell carcinoma, 2 glioblastomas, 1 endometrial adenocarcinoma, 1 NSCLC and 1 prostatic carcinoma. Lightweight RythmicTM pump capable of continuous delivery (no weekend breaks) allowed patients to stay at home. Over 35 days, CRTX dose escalation from 0.08 to 0.64 mg/m2/day was carried on Mondays, Wednesdays and Fridays, followed each time by 2h observation at the clinic. Dose limiting toxicity (DLT) and maximum tolerated dose (MTD) were defined as the inability of dose escalation twice due to toxicity and the dose at which no further dose escalation can be safely achieved for &amp;gt;33% of the pts in the study, respectively. Results: 2/6 patients developed possibly drug-related G1 diplopia and 1/6 pts increased ASAT/ALAT. One patient recruited with pre-existent diarrhoea syndrome with uncontrolled G2 hypomagnesaemia, G3 hypokalaemia and G2 anaemia, developed complete arrhythmia with asymptomatic atrial fibrillation that resolved with amiodarone. Patient was hospitalised for observation and the event was classified as a possible study drug-related SAE as well as related to the digestive syndrome and tubulopathy resulting from previous chemotherapy (nivolumab and platinum salts). Stable disease was observed in 2/6 patients. Conclusion: No DLT or MTD have been reached. CRTX dose escalation is safe but too slow, doses achieved too low and too late for advanced patients. In a new cohort, CRTX regimen will be continued starting from higher dose with faster dose escalation. Citation Format: Marian Gil Delgado, Gougis Paul, Dorothy H. Bray, Francois M. DELGADO, Jean P. SPANO, Ahmed Idbaih, Paul F. Reid, Khadija Benlhassan, Cheikh Diaw, David Khayat. Continuous i.v. Crotoxin in advanced cancer: Intra-patient dose escalation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT071.
Abstract 13144: MicroRNA Sequencing Highlights Regulatory Networks Upstream of Osteopontin and B-type Natriuretic Peptide in Acute Coronary Sydrome
Authors: Lydia C Kwee, Elizabeth Grass, Megan L Neely, Simon G Gregory, Joseph V Haas, Dennis A Laska, Mark Kowala, Laura F Michael, John R Wetterau, Kevin L Duffin, Matthew Roe, E. M Ohman, Keith A Fox, Harvey White, Paul Armstrong, Mark Y Chan, Svati H Shah
Journal: Circulation (2016)

Introduction: The genomic regulatory networks underlying the pathogenesis of acute coronary syndrome (ACS) are incompletely understood. As intermediate traits, circulating protein biomarkers report on underlying disease severity and are powerfully prognostic in ACS. We hypothesized that integration of dense microRNA (miRNA) profiling with measurement of biomarkers would highlight potential regulatory pathways. Methods: We studied 186 patients enrolled in the biomarker substudy of the TRILOGY clinical trial of ACS. MiRNA sequencing was performed on RNA extracted from whole blood, and seven known prognostic protein biomarkers were measured from plasma (N-terminal pro B-type natriuretic peptide [NT-proBNP], C-reactive protein, osteopontin [OPN], myeloperoxidase, growth differentiation factor 15, monocyte chemoattractant protein 1, and neopterin). MiRNAs were tested for association with these biomarkers using generalized linear models. Target genes putatively regulated by the associated miRNAs were examined using pathway analysis. Results: Fourteen miRNAs, including cardiac-related miRs 20b-5p and 320a,b and d, were associated with OPN levels (min. p=1.1x10 -4 ), and five miRNAs, including cardiac-related miRs 25-3p and 423-3p, were associated with NT-proBNP levels (min. p=3.4x10 -4 ); no other biomarkers showed significant associations. Sixty-three KEGG pathways were enriched in the target genes of either NT-proBNP- or OPN-associated miRNAs, with five pathways found in the top ten for both biomarkers: prion diseases, fatty acid biosynthesis, lysine degradation, protein processing in endoplasmic reticulum, and viral carcinogenesis. Conclusions: By integrating large-scale microRNA profiling with circulating biomarkers as intermediate traits, we identified associations of known cardiac-related and novel miRs with two prognostic biomarkers (OPN and NT-proBNP), and identified potential genomic regulatory networks underlying these biomarkers. We further identified novel non-cardiac genomic pathways associated with these biomarkers. These results may inform future studies delineating genomic pathways underlying ACS outcomes.
Abstract 3622: Identify prognostic biomarkers for colorectal cancer by human villi development model
Authors: Botao Zhang, Lin Feng, Ting Xiao, Shujun Cheng
Journal: Cancer Research (2018)

Abstract Background Tumorigenesis and embryogenesis have many similar biological characteristics, such as proliferation, invasion, metabolism and immunity. The development of villi is a physiological process, it will stop after the fetus is born. Trophoblast have been defined as "physiological metastasis" or "pseudo-malignant". However, tumorigenesis is a pathological process that will go on indefinitely. We hypothesize that if the interactions between gene and gene in tumors deviate from the interactions in villi, it is more likely to develop into malignant tumors and have worse prognosis. Methods We collected tissue samples including human chorionic villus samples at 6 to 10 weeks of gestation (n = 15) and leaf chorionic samples from postpartum placental tissue (n = 6), then extracted RNA and carried out RNA sequencing. We processed bioinformatics analysis in combination with multi-stage colorectal cancer (CRC) transcriptome data, including normal (n = 12), low-grade adenoma (n = 21), high-grade adenoma (n = 30), cancer (n = 25). Results We found that CRC progress and villi development involve many genes with similar biological behaviors, such as proliferation, immunity, metabolism and invasion, but the genes of the relevant biological behavior are different between CRC and villi. Then we filtered those genes, of which the interactions in CRC are far from that in villi. Twenty-four genes, such as CBL, COL1A1, ATP5C1, CDC42 etc were finally selected. Abnormal expression of the 24 genes was significantly associated with poor survival in six independent CRC cohorts (The Cancer Genome Atlas, P&amp;lt;0.001; GSE39084, P= 0.002; GSE14333, P&amp;lt;0.001; GSE17536, P=0.003; GSE39582, P&amp;lt;0.001; GSE29621, P=0.001). Conclusions Villi development is a reliable and strictly regulated model that can illuminate the trajectory of human cancer development. Our study indicated that the interactions between gene and gene in CRC development deviate from that in villi, the deviation interactions of gene may have some substantial impacts on CRC development and reveal novel prognostic biomarkers. Citation Format: Botao Zhang, Lin Feng, Ting Xiao, Shujun Cheng. Identify prognostic biomarkers for colorectal cancer by human villi development model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3622.
Oligosaccharyltransferase Inhibition Reduces Receptor Tyrosine Kinase Activation and Enhances Glioma Radiosensitivity
Authors: Marta Baro, Cecilia Lopez Sambrooks, Amanda Quijano, W. Mark Saltzman, Joseph Contessa
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Parallel signaling reduces the effects of receptor tyrosine kinase (RTK)–targeted therapies in glioma. We hypothesized that inhibition of protein N-linked glycosylation, an endoplasmic reticulum co- and posttranslational modification crucial for RTK maturation and activation, could provide a new therapeutic approach for glioma radiosensitization. Experimental Design: We investigated the effects of a small-molecule inhibitor of the oligosaccharyltransferase (NGI-1) on EGFR family receptors, MET, PDGFR, and FGFR1. The influence of glycosylation state on tumor cell radiosensitivity, chemotherapy-induced cell toxicity, DNA damage, and cell-cycle arrest were determined and correlated with glioma cell receptor expression profiles. The effects of NGI-1 on xenograft tumor growth were tested using a nanoparticle formulation validated by in vivo molecular imaging. A mechanistic role for RTK signaling was evaluated through the expression of a glycosylation-independent CD8-EGFR chimera. Results: NGI-1 reduced glycosylation, protein levels, and activation of most RTKs. NGI-1 also enhanced the radiosensitivity and cytotoxic effects of chemotherapy in those glioma cells with elevated ErbB family activation, but not in cells without high levels of RTK activation. NGI-1 radiosensitization was associated with increases in both DNA damage and G1 cell-cycle arrest. Combined treatment of glioma xenografts with fractionated radiotherapy and NGI-1 significantly reduced tumor growth compared with controls. Expression of the CD8-EGFR eliminated the effects of NGI-1 on G1 arrest, DNA damage, and cellular radiosensitivity, identifying RTK inhibition as the principal mechanism for the NGI-1 effect. Conclusions: This study suggests that oligosaccharyltransferase inhibition with NGI-1 is a novel approach to radiosensitize malignant gliomas with enhanced RTK signaling. See related commentary by Wahl and Lawrence, p. 455
The Search for Treatments for Veterans With Major Depression
Authors: Charles B. Nemeroff
Journal: JAMA Psychiatry (2018)

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Art of bringing NHS data to life
Authors: Rebecca Coombes
Journal: BMJ (2018)

The amount the NHS spends on supporting us as patients throughout our lives, from cradle to grave, is visualised in a massive and interactive art installation on show from next week at the BMA’s headquarters in London. 

The Long Run , a 9 m long series of marble runs, invites users to reflect on what the NHS provides for them in different parts of their …
Comparison of Longitudinal CA125 Algorithms as a First-Line Screen for Ovarian Cancer in the General Population
Authors: Oleg Blyuss, Matthew Burnell, Andy Ryan, Aleksandra Gentry-Maharaj, Inés P. Mariño, Jatinderpal Kalsi, Ranjit Manchanda, John F. Timms, Mahesh Parmar, Steven J. Skates, Ian Jacobs, Alexey Zaikin, Usha Menon
Journal: Clinical Cancer Research (2018)

Abstract Purpose: In the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), women in the multimodal (MMS) arm had a serum CA125 test (first-line), with those at increased risk, having repeat CA125/ultrasound (second-line test). CA125 was interpreted using the “Risk of Ovarian Cancer Algorithm” (ROCA). We report on performance of other serial algorithms and a single CA125 threshold as a first-line screen in the UKCTOCS dataset. Experimental Design: 50,083 post-menopausal women who attended 346,806 MMS screens were randomly split into training and validation sets, following stratification into cases (ovarian/tubal/peritoneal cancers) and controls. The two longitudinal algorithms, a new serial algorithm, method of mean trends (MMT) and the parametric empirical Bayes (PEB) were trained in the training set and tested in the blinded validation set and the performance characteristics, including that of a single CA125 threshold, were compared. Results: The area under receiver operator curve (AUC) was significantly higher (P = 0.01) for MMT (0.921) compared with CA125 single threshold (0.884). At a specificity of 89.5%, sensitivities for MMT [86.5%; 95% confidence interval (CI), 78.4–91.9] and PEB (88.5%; 95% CI, 80.6–93.4) were similar to that reported for ROCA (sensitivity 87.1%; specificity 87.6%; AUC 0.915) and significantly higher than the single CA125 threshold (73.1%; 95% CI, 63.6–80.8). Conclusions: These findings from the largest available serial CA125 dataset in the general population provide definitive evidence that longitudinal algorithms are significantly superior to simple cutoff values for ovarian cancer screening. Use of these newer algorithms requires incorporation into a multimodal strategy. The results highlight the importance of incorporating serial change in biomarker levels in cancer screening/early detection strategies. Clin Cancer Res; 24(19); 4726–33. ©2018 AACR.