tbuckley/cabot-search huggingface dataset:
Charting the Path Forward for Risk Prediction in Liver Transplant for Hepatocellular Carcinoma: International Validation of HALTHCC Among 4,089 Patients
Authors: Daniel J. Firl, Kazunari Sasaki, Vatche G. Agopian, Andre Gorgen, Shoko Kimura, Wethit Dumronggittigule, John C. McVey, Samuele Iesari, Gianluca Mennini, Alessandro Vitale, Armin Finkenstedt, Simona Onali, Maria Hoppe‐Lotichius, Giovanni Vennarecci, Tommaso M. Manzia, Daniele Nicolini, Alfonso W. Avolio, Salvatore Agnes, Marco Vivarelli, Giuseppe Tisone, Giuseppe M. Ettorre, Gerd Otto, Emmanuel Tsochatzis, Massimo Rossi, Andre Viveiros, Umberto Cillo, James F. Markmann, Toru Ikegami, Toshimi Kaido, Quirino Lai, Gonzalo Sapisochin, Jan Lerut, Federico N. Aucejo
Journal: Hepatology (2019)

Prognosticating outcomes in liver transplant (LT) for hepatocellular carcinoma (HCC) continues to challenge the field. Although Milan Criteria (MC) generalized the practice of LT for HCC and improved outcomes, its predictive character has degraded with increasing candidate and oncological heterogeneity. We sought to validate and recalibrate a previously developed, preoperatively calculated, continuous risk score, the Hazard Associated with Liver Transplantation for Hepatocellular Carcinoma (HALTHCC), in an international cohort. From 2002 to 2014, 4,089 patients (both MC in and out [25.2%]) across 16 centers in North America, Europe, and Asia were included. A continuous risk score using pre-LT levels of alpha-fetoprotein, Model for End-Stage Liver Disease Sodium score, and tumor burden score was recalibrated among a randomly selected cohort (n = 1,021) and validated in the remainder (n = 3,068). This study demonstrated significant heterogeneity by site and year, reflecting practice trends over the last decade. On explant pathology, both vascular invasion (VI) and poorly differentiated component (PDC) increased with increasing HALTHCC score. The lowest-risk patients (HALTHCC 0-5) had lower rates of VI and PDC than the highest-risk patients (HALTHCC > 35) (VI, 7.7%[ 1.2-14.2] vs. 70.6% [48.3-92.9] and PDC:4.6% [0.1%-9.8%] vs. 47.1% [22.6-71.5]; P < 0.0001 for both). This trend was robust to MC status. This international study was used to adjust the coefficients in the HALTHCC score. Before recalibration, HALTHCC had the greatest discriminatory ability for overall survival (OS; C-index = 0.61) compared to all previously reported scores. Following recalibration, the prognostic utility increased for both recurrence (C-index = 0.71) and OS (C-index = 0.63). Conclusion: This large international trial validated and refined the role for the continuous risk metric, HALTHCC, in establishing pre-LT risk among candidates with HCC worldwide. Prospective trials introducing HALTHCC into clinical practice are warranted.
Abstract 12826: Muscle Stretching Causes Membrane Excitation Without Activation of Stretch-Activated Channels in Intact Rat Trabeculae
Authors: Tsuyoshi Nagano, Masahito Miura, Naomi Murai, Natsu Narumi, Chiyohiko Shindoh
Journal: Circulation (2012)

Background: The occurrence of action potentials caused by cardiac muscle stretching has been termed as mechano-electric coupling (MEC). Stretch-activated channels (SACs) have been believed to play ...
Dissecting Prognostic From Predictive Utility: Circulating AR-V7 Biomarker Testing for Advanced Prostate Cancer
Authors: Adam Sharp, Nuria Porta, Maryou B.K. Lambros, Jonathan C. Welti, Alec Paschalis, Ganesh V. Raj, Stephen P. Plymate, Johann S. de Bono
Journal: Journal of Clinical Oncology (2019)
Abstract 4079: EVT801: a selective VEGFR3 inhibitor with the potential for combination with immune-checkpoint therapies, preclinical evidences and plans for first-in-human evaluation
Authors: Pierre Fons, Michael Esquerre, Michael Paillasse, Virgile Visentin, Frederique Dol, Jerome Meneyrol, Gaelle Badet, Eric Cogo, Lionel Vidaud, Antoine Alam, Isabelle Blanc, Francoise Bono, Joanna Lisztwan, Muriel Poublanc, Thomas Filleron, Ian Hunneyball, Jean-Pierre Delord, Mark Whittaker
Journal: Cancer Research (2019)

Abstract We have identified a highly selective VEGFR3 inhibitor drug candidate, which strongly inhibits angiogenesis without inducing hypoxia, reputed as one of the main causes of cancer-associated immunosuppression. Combination of EVT801 and Immune Checkpoint Therapy (ICT) could be synergistic as hypoxia-induced-immunosuppression should be avoided. We have demonstrated that EVT801 is a narrow spectrum inhibitor of the VEGFR3 tyrosine kinase with residual activity against VEGFR2 and TAK1 and with an activity on VEGFRs different from Fruquitinib and Lenvatinib. We then showed that EVT801 inhibited human endothelial cell proliferation in vitro and tumor angiogenesis on ex-vivo mouse ring aortic assay. EVT801 was active in vivo in the RIP1-Tag2 mouse model during the angiogenic switch. In comparison to sorafenib, EVT801 in 2 different tumors mouse model decreased tumor development without inducing increase of hypoxia which is in favor to a sustained blood vessel tumor normalization. In orthotopic 4T1 mammary carcinoma, we demonstrated that EVT801 in combination with PD1 mAb was significantly superior than single agent treatment and a decrease of lung metastasis spreading was observed. We observed that decrease of MDSCs in blood in response to EVT801 was correlated with decrease in tumor weight. By IHC analysis, we showed that treatment with EVT801 increases CD8+ T-cells infiltration inside the tumor. Taken together, these results indicated that EVT801 represents an innovative anti-angiogenic drug for cancer immunotherapy which may improve the frequency of response to ICT. Clinical trial design including patient stratification and biomarkers of activity has been proposed in order to be ready for first-in-human evaluation by mid-2019. Citation Format: Pierre Fons, Michael Esquerre, Michael Paillasse, Virgile Visentin, Frederique Dol, Jerome Meneyrol, Gaelle Badet, Eric Cogo, Lionel Vidaud, Antoine Alam, Isabelle Blanc, Francoise Bono, Joanna Lisztwan, Muriel Poublanc, Thomas Filleron, Ian Hunneyball, Jean-Pierre Delord, Mark Whittaker. EVT801: a selective VEGFR3 inhibitor with the potential for combination with immune-checkpoint therapies, preclinical evidences and plans for first-in-human evaluation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4079.
Neoadjuvant modified FOLFIRINOX or gemcitabine-nab paclitaxel followed by stereotactic body radiotherapy for patients with locally advanced pancreatic cancer
Authors: R. Paluri, U. Manne, G. Williams, B. Rose, M. Heslin, S. Reddy, K. Kyanam Kabir Baig, S. Vickers, A. Ali, O. Gbolahan, C. Smith, R. Jacob
Journal: Annals of Oncology (2019)
mTORC1-to-AMPK switching underlies β cell metabolic plasticity during maturation and diabetes
Authors: Rami Jaafar, Stella Tran, Ajit N. Shah, Gao Sun, Martin Valdearcos, Piero Marchetti, Matilde Masini, Avital Swisa, Simone Giacometti, Ernesto Bernal-Mizrachi, Aleksey Matveyenko, Matthias Hebrok, Yuval Dor, Guy A. Rutter, Suneil K. Koliwad, Anil Bhushan
Journal: Journal of Clinical Investigation (2019)

Pancreatic beta cells (β-cells) differentiate during fetal life, but only postnatally acquire the capacity for glucose-stimulated insulin secretion (GSIS). How this happens is not clear. In exploring what molecular mechanisms drive the maturation of β-cell function, we found that the control of cellular signaling in β-cells fundamentally switched from the nutrient sensor target of rapamycin (mTORC1) to the energy sensor 5'-adenosine monophosphate-activated protein kinase (AMPK), and that this was critical for functional maturation. Moreover, AMPK was activated by the dietary transition taking place during weaning, and this in turn inhibited mTORC1 activity to drive the adult β-cell phenotype. While forcing constitutive mTORC1 signaling in adult β-cells relegated them to a functionally immature phenotype with characteristic transcriptional and metabolic profiles, engineering the switch from mTORC1 to AMPK signaling was sufficient to promote β-cell mitochondrial biogenesis, a shift to oxidative metabolism, and functional maturation. We also found that type 2 diabetes, a condition marked by both mitochondrial degeneration and dysregulated GSIS, was associated with a remarkable reversion of the normal AMPK-dependent adult β-cell signature to a more neonatal one characterized by mTORC1 activation. Manipulating the way in which cellular nutrient signaling pathways regulate β-cell metabolism may thus offer new targets to improve β-cell function in diabetes.
Abstract 19831: Lipid Im- and Export Affects Macrophage Turnover in the Plaque
Authors: Ingo Hilgendorf, Carmen Haerdtner, Alina Jander, Jiadai Zou, Jan Kornemann, Christopher Starz, Katja Grotius, Bi-Lin Schmidt, Sebastian Lubojansky, Natalie Hoppe, Bianca Dufner, Johannes Rotta deto Loria, Constantin von zur Muehlen, Christoph Bode, Andreas Zirlik
Journal: Circulation (2017)

Background: Macrophages in atherosclerotic plaques utilize scavenger receptors for oxidized low-density lipoprotein (oxLDL) uptake, partly involving cosignal with toll-like receptors (TLR). On the ...
Abstract 2220: Benchmarking of somatic variant calling algorithms for detection of circulating tumor DNA
Authors: Preetida J. Bhetariya, Sabine Hellwig, David A. Nix, Gabor T. Marth, Mary P. Bronner, Hunter R. Underhill
Journal: Cancer Research (2019)

Abstract Purpose: Establishing a reliable bioinformatics variant calling workflow is crucial for untargeted searches of low-frequency variants in plasma circulating cell-free DNA (ccfDNA). We sought to benchmark the performance of nine variant calling algorithms on simulated data and cancer patient ccfDNA sequencing samples. Methods: A simulated tumor dataset was constructed by in-silico introduction of pathogenic variants (303 SNVs and 91 INDELs; VAF of 0.1-12%) into a healthy control sequencing sample (128 gene capture panel; 128kb; 4200X depth). An unspiked replicate served as a control. Tumor and control datasets were analyzed by nine somatic variant calling algorithms available in the public domain (Table 1). Sensitivity and specificity were calculated for each caller. Variant calling algorithms that proved most successful in synthetic data (Lofreq, Mutect) were applied to 24 EGFR-mutant lung cancer patient ccfDNA library samples captured and sequenced under conditions identical to the benchmarking data set. Droplet digital PCR (ddPCR) was used to independently determine the VAFs of two EGFR SNVs (T790M and L858R) and exon 19 deletions in all lung cancer libraries (detected range: 0.1-48.5%). Results: Table 1:Sensitivity (Sens.) and false discovery rate (FDR) as determined for 9 variant callers. For synthetic data, results are shown for 1.6% VAF (NC = no call)CallerSynthetic data (1.6% VAF)Lung cancer ccfDNASNVINDELSNVINDEL% Sens.% FDR% Sens.% FDR% Sens. &amp;lt;1% VAF% Sens. &amp;gt;1% VAF% Sens. &amp;lt;1% VAF% Sens. &amp;gt;1% VAFLofreq87.15.792.35.675.094.466.7100Mutect47.52.291.26.762.588.916.787.5Mutect235.63.296.71.1Strelka17.83.57.69.2FreebayesNCNCNCNCVarscanNCNCNCNCVardictNCNCNCNCLumpy13.986.17.792.1DellyNCNCNCNC Conclusion: Performance of variant callers differed greatly, with Lofreq providing the best sensitivity at low VAF. In cancer ccfDNA libraries Lofreq detected most but not all low-frequency variants, indicating that ccfDNA diagnostics require optimized variant calling workflows to improve detection of variants with a VAF &amp;lt;1%. Citation Format: Preetida J. Bhetariya, Sabine Hellwig, David A. Nix, Gabor T. Marth, Mary P. Bronner, Hunter R. Underhill. Benchmarking of somatic variant calling algorithms for detection of circulating tumor DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2220.
Effect of Aerobic and Resistance Exercise on Cardiac Adipose Tissues
Authors: Regitse Højgaard Christensen, Anne-Sophie Wedell-Neergaard, Louise Lang Lehrskov, Grit Elster Legaard, Emma Dorph, Monica Korsager Larsen, Natja Launbo, Sabrina Ravn Fagerlind, Sidsel Kofoed Seide, Stine Nymand, Maria Ball, Nicole Buchner Vinum, Camilla Nørfelt Dahl, Marie Henneberg, Mathias Ried-Larsen, Mikael Ploug Boesen, Robin Christensen, Kristian Karstoft, Rikke Krogh-Madsen, Jaya Birgitte Rosenmeier, Bente Klarlund Pedersen, Helga Ellingsgaard
Journal: JAMA Cardiology (2019)

Epicardial and pericardial adipose tissues are emerging as important risk factors for cardiovascular disease, and there is a growing interest in discovering strategies to reduce the accumulation of fat in these depots.To investigate whether a 12-week endurance or resistance training intervention regulates epicardial and pericardial adipose tissue mass.Secondary analysis of a randomized, assessor-blinded clinical trial initiated on August 2016 and completed April 2018. This single-center, community-based study included 50 physically inactive participants with abdominal obesity.Participants were randomized to a supervised high-intensity interval endurance training (3 times a week for 45 minutes), resistance training (3 times a week for 45 minutes), or no exercise (control group).Change in epicardial and pericardial adipose tissue mass assessed by magnetic resonance imaging, based on a prespecified secondary analysis plan including 3 of 5 parallel groups.Of 50 participants (mean [SD] age, 41 [14] years, 10 men [26%]; mean [SD] body mass index [calculated as weight in kilograms divided by height in meters squared], 32 [5]), 39 [78%] completed the study. Endurance training and resistance training reduced epicardial adipose tissue mass by 32% (95% CI, 10%-53%) and 24% (95% CI, 1%-46%), respectively, compared with the no exercise control group (56% [95% CI, 24%-88%]; P = .001 and 48% [95% CI, 15%-81%]; P < .001, respectively). While there was a nonsignificant reduction in pericardial adipose tissue mass after endurance training (11% [95% CI, -5% to 27%]; P = .17), resistance training significantly reduced pericardial adipose tissue mass by 31% (95% CI, 16%-47%; P < .001) when compared with the no exercise control group. Compared with the no exercise control group, there was an increase in left ventricular mass by endurance (20 g [95% CI, 11%-30%]; P < .001) and resistance training (18 g [95% CI, 8%-28%]; P < .001). Other cardiometabolic outcomes remained unchanged after the 12-week trial period.In individuals with abdominal obesity, both endurance and resistance training reduced epicardial adipose tissue mass, while only resistance training reduced pericardial adipose tissue mass. These data highlight the potential preventive importance of different exercise modalities as means to reduce cardiac fat in individuals with abdominal obesity.ClinicalTrials.gov identifier: NCT02901496.
Engineering switchable and programmable universal CARs for CAR T therapy
Authors: Delong Liu, Juanjuan Zhao, Yongping Song
Journal: Journal of Hematology & Oncology (2019)

A traditional chimeric antigen receptor (CAR) has a fixed design, and one type of CAR T cells can only target one antigen epitope. This rigid design limits clinical application and leads to exceptionally high manufacturing cost. New CARs are being engineered with a modular approach so that the antigen recognition domain is split from the signaling domain of a conventional CAR, hence the target antigen can be switched or re-directed more readily without the requirement of re-engineering the CAR T cells. This CAR system can therefore serve as a universal CAR (UniCAR). The UniCAR platform has a modular design that splits the conventional CAR to 2 separate components: (1) a signaling module that binds to a specific epitope on the switching molecule and (2) a switching module with an antigen-binding domain and a switching epitope specifically recognized by the signaling module. A variety of switchable CARs have been engineered. The switchable modular designs include the dimerizing platforms using leucine zippers and biotin-avidin system, and the neo-epitope tagging platform using FITC, 5B9, and PNE. The switch molecule serves as a synapse between the CAR T cells and the target tumor cells. The universal CAR platforms are highly versatile, are easily re-programmable, and therefore have a vast potential for broad application and may significantly lower the cost of CAR T cell therapy. However, the current modular design of the switching molecules relies on adding exogenous sequences/epitopes. These unnatural epitopes can potentially lead to new antigenicity which may lead to generation of blocking antibodies. Furthermore, the generation, preparation, and clinical applications of the switching modules per se may involve additional clinical trials and regulatory examination for safety and efficacy, since repeated administrations of these molecules/“drugs” are anticipated. Thus, these switching molecules and UniCAR CAR T cells may require separate clinical trials and invoke different regulatory processes. This whole field is medically appealing and could present new challenges in the development of novel immunotherapeutic agents.
Abstract 1328: Exploring the pharmacokinetic-pharmacodynamic relationships of AZD3229, a novel and selective inhibitor of cKIT, in a range of mouse xenograft models of gastrointestinal stromal tumors
Authors: Venkatesh Pilla Reddy, Aaron Smith, Michael Grondine, Rana Anjum, Rhys D. Jones
Journal: Cancer Research (2019)

Abstract cKIT belongs a family of transmembrane tyrosine kinase growth factor receptors and gain of function mutations result in constitutive c-KIT activation that provide an important pathogenic role in gastrointestinal stromal tumors (GIST). AZD3229 is a highly potent and selective oral best-in-class KIT inhibitor that is active against a wide spectrum of primary and secondary KIT mutations that are known to confer resistance to standard of care agents. AZD3229 demonstrates rapid, extensive and sustained inhibition of KIT signaling in preclinical xenograft models with KIT primary exon 11 del mutations and primary/secondary ATP-binding pocket mutations (GIST 430/654A and patient-derived xenograft (PDX) model of KIT V654A, HGiXF-106) and A-loop mutations (PDX model of KIT Y823D, HGiXF-105 and Ba/F3 KIT D816H). In these models, AZD3229 results in anti-tumour activity (tumour regressions ranging from -60% to -99 % TGI) when dosed orally up to 20 mg/kg BID. The objective of this PK-PD modeling work was to (1) establish the PK-PD-Efficacy relationship for AZD3229 across the four cell-lines and PDX mouse models tested; (2) to confirm the extent and duration of pKIT inhibition required for optimal efficacy, as defined by tumor regressions. Inhibition of KIT phosphorylation observed with AZD3229 shows a direct relationship to free mouse plasma concentration and an estimated in vivo EC90 was estimated for each model (Ba/F3 D816H = 20 nM; GIST 430/V654A= 43 nM; HGiX-106 = 76 nM; HGiX-105 = 4 nM). No change in the extent of inhibition of KIT phosphorylation was observed on repeat dosing. Optimal efficacy is observed when sustained inhibition of pKIT, &amp;gt;90% is achieved over the dosing interval. Conclusion: Exploring the in vivo activity and PK-PD relationship in multiple cell-line derived xenograft and PDX models harboring different mutations provides a benchmark from which to anchor human dose predictions that partly reflect the spectrum of responses likely to be seen in GIST patients. Citation Format: Venkatesh Pilla Reddy, Aaron Smith, Michael Grondine, Rana Anjum, Rhys D. Jones. Exploring the pharmacokinetic-pharmacodynamic relationships of AZD3229, a novel and selective inhibitor of cKIT, in a range of mouse xenograft models of gastrointestinal stromal tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1328.
Abstract CT055: Microdose induced oxaliplatin-DNA adducts as a predictive biomarker of response in colorectal cancer
Authors: Justin Chen, May Cho, Maike Zimmermann, Thomas Semrad, Chun-Yi Wu, Aiming Yu, Chong-Xian Pan, Paul T. Henderson, Edward J. Kim
Journal: Cancer Research (2019)

Abstract Background Combination 5-FU and oxaliplatin (FOLFOX) is standard therapy for colorectal cancer (CRC) in neoadjuvant, adjuvant, and metastatic settings. However, oxaliplatin neuropathy is the main dose-limiting toxicity that often necessitates dose reduction or discontinuation before progression. Prediction of oxaliplatin sensitivity in tumor cells would be valuable for dose optimization to maximize anti-tumorigenic effect and limit sensory neuropathy. Oxaliplatin functions via the formation of covalent drug-DNA adducts which ultimately inhibit cell replication and promote apoptosis. Detection of these drug-DNA adducts could serve as a biomarker of oxaliplatin efficacy. We therefore hypothesized that drug-DNA adduct levels induced by sub-therapeutic "diagnostic microdoses" are proportional to those induced by therapeutic doses and are predictive of tumor responses. Methods The feasibility of this predictive diagnostic microdosing approach was assessed in CRC cell culture and a pilot clinical trial of six CRC patients. Four CRC cell lines were cultured with therapeutically relevant (100 µM) or diagnostic microdose (1 µM) concentrations of [14C]oxaliplatin. The C-14 label enabled quantification of oxaliplatin-DNA adduct levels with accelerator mass spectrometry, an ultrasensitive isotope analysis technique. Adduct formation was correlated with oxaliplatin cytotoxicity as measured by the MTT viability assay. In a pilot clinical trial (NCT02569723), six CRC patients received an intravenous diagnostic microdose containing [14C]oxaliplatin prior to treatment and a second [14C]oxaliplatin dose during FOLFOX chemotherapy. Adduct levels from peripheral blood mononuclear cells (PBMC), used as surrogates for tumor cells, were correlated to mean tumor volume change of evaluable target lesions. Results Drug-DNA adduct levels were linearly proportional between microdoses and therapeutically relevant concentrations in cell culture (R2 = 0.91, p &amp;lt; 0.0001) and patient samples (R2 = 0.63, p &amp;lt; 0.0001). Plasma pharmacokinetics of microdoses were consistent with those of therapeutic dosing. No microdose-associated toxicity was observed in this patient population. PBMC adduct levels significantly correlated with tumor shrinkage (microdose: R2 = 0.82, p = 0.033; therapeutic dose: R2=0.65, p = 0.099). Conclusion Diagnostic microdosing with oxaliplatin is feasible and is predictive of oxaliplatin sensitivity in CRC patients. Citation Format: Justin Chen, May Cho, Maike Zimmermann, Thomas Semrad, Chun-Yi Wu, Aiming Yu, Chong-Xian Pan, Paul T. Henderson, Edward J. Kim. Microdose induced oxaliplatin-DNA adducts as a predictive biomarker of response in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT055.