tbuckley/cabot-search huggingface dataset:
The Potential and Pitfalls of Crowdsourced Algorithm Development in Radiation Oncology
Authors: Hesham Elhalawani, Clifton David Fuller, Reid F. Thompson
Journal: JAMA Oncology (2019)

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Ligand-Binding-Site Structure Shapes Allosteric Signal Transduction and the Evolution of Allostery in Protein Complexes
Authors: György Abrusán, Joseph A Marsh
Journal: Molecular Biology and Evolution (2019)

Abstract The structure of ligand-binding sites has been shown to profoundly influence the evolution of function in homomeric protein complexes. Complexes with multichain binding sites (MBSs) have more conserved quaternary structure, more similar binding sites and ligands between homologs, and evolve new functions slower than homomers with single-chain binding sites (SBSs). Here, using in silico analyses of protein dynamics, we investigate whether ligand-binding-site structure shapes allosteric signal transduction pathways, and whether the structural similarity of binding sites influences the evolution of allostery. Our analyses show that: 1) allostery is more frequent among MBS complexes than in SBS complexes, particularly in homomers; 2) in MBS homomers, semirigid communities and critical residues frequently connect interfaces and thus they are characterized by signal transduction pathways that cross protein–protein interfaces, whereas SBS homomers usually not; 3) ligand binding alters community structure differently in MBS and SBS homomers; and 4) except MBS homomers, allosteric proteins are more likely to have homologs with similar binding site than nonallosteric proteins, suggesting that binding site similarity is an important factor driving the evolution of allostery.
Correlation of overexpression of p-EGFR Y1173 with previous irradiation of metastatic triple-negative breast cancer (metTNBC) in African American (AA) women.
Authors: Joyce O'Shaughnessy, Corinne Ramos, Nicholas N Hoke, Irene Cherni, Maren K. Levin, John D. Carpten, Lance A. Liotta, Virginia A. Espina
Journal: Journal of Clinical Oncology (2015)

e12073 Background: We have characterized the genomic alterations (GAs) and phosphoproteome of matched primary and metTNBCs from AA women. Methods: Microdissected fresh metTNBCs (N = 6) were analyzed by whole genome sequencing (WGS)(Craig Mol Cancer Ther 2013) and microdissected FFPE primary TNBCs (N = 4) were analyzed by whole exome sequencing (Cherni SABCS 2014 P2-03-04). Laser capture microdissection and reverse phase microarray (RPMA) analyzing 70 signal transduction proteins in 6 AA pts’ metTNBC (Espina AACR 2014, 1067)and RPMA in 6 pts’ FFPE primary TNBC analyzing 14 proteins in the HER1/2/3 pathway were performed. Results: Median age was 58 (32-63) and sites of metTNBC for WGS/RPMA were chest wall (3), lymph node (2), contralateral pleura (1). All metTNBC pts received prior chemotherapy and 5 of 6 pts received breast/chest wall radiation therapy. Alterations in TP53 occurred in all 6 TNBCs as did activating GAs in the PI3K pathway including PTEN del, FBXW7 del, FGFR1 or KRAS amp, mutant NF1*, mutant NEDD4* (regulates PTEN; N = 1 each), mutant HERC1*(regulates TSC2), ERBB4 structural variant (N = 2 each) [*present in metTNBC only]. Two metTNBCs had CTNN1Adel. RPMA in primary TNBCs showed 3 of 6 BCs with elevated p-EGFR Y1068. Pts with KRAS amp, FGFR1 amp or mutant HERC1did not have elevated p-EGFR Y1068. All Pts showed high level of phosphorylation of p-mTOR and p-P70S6K. RPMA in metTNBCs showed high level phosphorylation of at least one p-EGFR moiety in all 6 pts with activated p-4EBP1 and p-MEK, and high levels of p-MET in 2 pts. 4 of 6 BCs had low PTEN; 5 of 6 had low AMPKα1; 5 of 6 had low β-catenin. Elevated levels of p-EGFR Y1173 (p = 0.022) and p-P70S6 (p = 0.004) were correlated with the harvested metTNBC having been previously irradiated. Conclusions: GAs which activate the PI3K pathway were present in all 6 primary and metTNBCs in AA women. All AA pts’ metTNBCs had high levels of one or more p-EGFR moiety. Radiation increases p-EGFR activation and DNA repair in tumor cells (Dittman FEBS Lett 2010), and tumor p-EGFR Y1173 increases during radiation (Sturla J Biol Chem 2005). Irradiation of TNBC may activate EGFR Y1173. RPMA of EGFR phosphosites in the pts’ primary TNBCs is planned.
Immunosenescence (iSenescence) correlates with progression (PD) to PD-(L)1 inhibitors (IO) and not to platinum-chemotherapy (PCT) in advanced non-small cell lung cancer (aNSCLC) patients (pts)
Authors: R. Ferrara, M. Naigeon, E. Auclin, B. Duchemann, L. Cassard, J.J. Medhi, L. Boselli, J. Grivel, A. Desnoyer, L. Mezquita, L. Hendriks, D. Planchard, C. Caramella, J. Remon-Masip, S. Sangaletti, M.C. Garassino, B. Besse, N. Chaput
Journal: Annals of Oncology (2019)

Background: iSenescence is a remodeling of immune functions with a multifactorial etiology (i.e. aging, chronic inflammation, cancer). Although the absence of CD28 and the expression of CD57 and KLRG1 on circulating T-lymphocytes are hallmarks of iSenescence, the characterization of such phenotype in aNSCLC pts and the correlation with clinical characteristics and benefit from IO or PCT are currently unknown. Methods: A senescent immune phenotype (SIP) defined as % of circulating CD8+CD28-CD57+KLRG1+ T-lymphocytes was assessed by flow cytometry (FC) on fresh blood from aNSCLC pts treated with IO or PCT in a single institution. A log-rank maximization method was used to identify a SIP cut-off level and dichotomize pts accordingly. The objective was to correlate SIP with clinical characteristics and RECIST response by univariate logistic regression analysis. Results: 37 aNSCLC pts were evaluable for SIP before IO: 32% ≥ 65 years, 91% non-squamous, 43% KRAS mutated, 51% with PD-L1 expression ≥1%, 8% chemotherapy naïve. 43% had PD, 41% stability (SD), 16% partial response (PR). Median PFS and OS were 2.7 (95% CI 1.8; 7.3) and 13 (95% CI 4.8-NR) months, respectively, median follow-up was 9.3 (95% CI 6.2-14.9) months. SIP (% CD28-CD57+KLRG1+) median value on circulating CD8+ lymphocytes was 12.2% (min 1.7%, max 56.1%). 32% of pts had >20.47% CD8+ lymphocytes with a CD28-CD57+KLRG1+ phenotype, being classified SIP+. SIP status did not significantly correlate with age, pts’ characteristics or CT exposure. 2 (17%) of 12 SIP+ had PR/SD (DCR), vs 19 (76%) of 25 SIP- pts (p = 0.001); median PFS was significantly lower in SIP+ (1.5 months 95% CI 1;2.2) vs SIP- pts (7.4 months 95% CI 5.5, 9.3) (p = 0.001). Among 61 aNSCLC pts treated with 1st line PCT, 18% had PD, 43% SD, 39% PR. SIP median value on circulating CD8+ lymphocytes was 17.9% (min 0.89%, max 66.1%), 43% of pts were SIP+. SIP did not significantly correlate with DCR (OR: 0.82, 95% CI 0.22-3.13, p = 0.82) upon PCT. Conclusions: iSenescence, monitored by FC measurement of 3 surface molecules on circulating CD8 + lymphocytes, is observed in 32% and 43% of aNSCLC pts before IO or PCT, respectively. SIP correlated with lower DCR upon IO and not PCT. Legal entity responsible for the study: Institut Gustave Roussy. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
The efficacy and safety of pemetrexed plus bevacizumab in previously treated patients with advanced nonsquamous non-small cell lung cancer.
Authors: Lingyu Ding
Journal: Journal of Clinical Oncology (2015)

e19041 Background: Bevacizumab (Bev), a monoclonal antibody against vascular endothelial growth factor, when combined with standard first-line chemotherapy, shows impressive clinical benefit in advanced non-squamous non-small-cell-lung-cancer (ns-NSCLC). Our study aims to investigate whether the addition of Bev to pemetrexed improves progression-free survival (PFS) in advanced ns-NSCLC patients after the failure of at least one prior chemotherapy regimens. Methods: Patients with locally advanced, recurrent, or metastatic ns-NSCLC, after failure of platinum-based therapy, with a performance status 0 to 2 were eligible. Patients received 500 mg/m2 of pemetrexed intravenously (IV) day 1 with vitamin B12, folic acid, and dexamethasone and Bev 7.5 mg/kg IV day 1 of a 21-day cycle until unacceptable toxicity, disease progression or the patient requested therapy discontinuation. The primary end point was PFS. Between Dec 2011 and Oct 2013, 33 patients were enrolled, with median age of 55 years and 36.4% men. Twenty-three patients (69.7%) had received two or more prior regimens and Twenty-eight patients (84.8%) had received chemotherapy containing pemetrexed. Results: The median number of the protocol regimens was 4. Median PFS was 4.37 months (95%CI: 2.64–6.09 months). Median overall survival (OS) was 15.83 months (95% CI: 10.52–21.15 months). Overall response rates were 6.45%. Disease control rate was 54.84%. No new safety signals were detected. No patient experienced drug-related deaths. Conclusions: The combination of bev and pemetrexed every 21 days is effective in ns-NSCLC patients who failed of prior therapies with improved PFS. Toxicities are similar with historical data of these two agents and are tolerable. Our results may provide more a regimen containing Bev and pemetrexed for Chinese clinical practice in previously treated ns-NSCLC.
Analysis of the prognostic value of the tumor immunologic profile in resectable NSCLC.
Authors: Marta Usó, Eloisa Jantus-Lewintre, Rafael Sirera, Silvia Calabuig-Fariñas, Ana Blasco, Ricardo Guijarro, Enrique Pastor, Carlos Camps
Journal: Journal of Clinical Oncology (2015)

11052 Background: The analysis of immune features of tumor microenvironment is leading to the development of new immunotherapies and the identification of new biomarkers. In this study, we have investigated the prognostic value of immune markers, especially those related to immune-regulation in resectable NSCLC. Methods: RNA was isolated from fresh-frozen lung specimens (tumor and normal lung) (n = 178). RT-PCR was performed to analyze the expression of 20 genes: CCL2, CCL22, CD1C, CD127, CD209, CD25, CD4, CD8, CLEC4, CTLA4, FOXP3, IDO1, IL10, IL23A, LGALS1, LGALS2, NRP1, PD1, PDL1 and TGFB1, by the use of hydrolysis probes. Relative gene expression was assessed by Pfaffl formula and normalized by the use of ACTB, GUSB and CDKN1B as endogenous genes. Statistical analyses were considered significant at p < 0.05. Results: Unsupervised hierarchical analysis according to gene expression levels classified patients in two clusters. Cluster I (n = 70) was composed by samples showing lower expression levels of the analyzed genes, whilst cluster Cluster II (n = 84) grouped samples that, in general have higher gene expression levels. Survival analysis showed that patients in Cluster II had better OS (NR vs 46.6 months, p = 0.040) and longer PFS (81.22 vs 26.28 months, p = 0.027) than patients in Cluster I. In order to obtain a more clinically valid biomarker, an expression score based on the regression coefficients from a multivariate model was built: (IL23A x 0.016) + (IL10 x 0.077) + (CCL2 x 0.154) + (PD1 x 0.132) + (CTLA4 x 0.173). Patients with high expression score have longer OS (NR vs 42.9 months, p = 0.007) and longer PFS (82.6 vs 23.4 months, p = 0.011). Multivariate analysis, including all significant variables found in the study, indicated that the expression score, along with KRAS status, was an independent biomarker of prognosis for OS [HR: 0.368; 95%CI, 0.190-0.715; p = 0.003] in our cohort. Conclusions: We identified a unique immune-reaction related profile associated with survival which leaded to the creation of an expression score composed by five genes. Furthermore, this expression score was found to be an independent prognostic biomarker in resectable NSCLC. Supported by grants PI1202838 and RD12/0036/0025 from ISCIII.
SAT-435-Quantitative MRCP imaging (MRCP+): Accuracy, repeatability and reproducibility evaluation in healthy and liver disease patients
Authors: Gary Woodward, Neelam Hassanali, Marija Mavar, Ged Ridgway, Andrea Borghetto, Carlos Ferreira, Hayley Simpson, Matt Kelly, Rajarshi Banerjee
Journal: Journal of Hepatology (2019)
A Phase II Study of Dasatinib and Dexamethasone As Primary Therapy Followed By Transplantation for Adults with Newly Diagnosed Ph/BCR-ABL1-Positive Acute Lymphoblastic Leukemia (Ph+ ALL): Final Results of Alliance/CALGB Study 10701
Authors: Matthew J. Wieduwilt, Jun Yin, Meir Wetzler, Geoffrey L. Uy, Bayard L. Powell, Jonathan E. Kolitz, Michaela Liedtke, Wendy Stock, Jan H Beumer, Ryan J. Mattison, Elizabeth Storrick, Steven Devine, Scott E. Smith, Richard M. Stone, Richard A. Larson
Journal: Blood (2018)
Evaluating causes of screen failure (SF) in non-small cell lung cancer (NSCLC) clinical trials requiring specific biomarker (BioM) results for enrollment.
Authors: Danielle J. Nameth, Jonathan Wade Goldman, Brian R. Wolf, Deborah Jean Lee Wong, Blanca A. Ledezma, Melody A. Mendenhall, Olayinka Oshodi, Steven R. Carrasco, Carlos R. Adame, Phillip A. Abarca, Mary Han, William Sago, Marshall L. Spiegel, John M. Horton, Darren D. Pan, Daria Gaut, Carmel Diamant, Sarah M. Rosales, Edward B. Garon
Journal: Journal of Clinical Oncology (2015)

7517 Background: Trials for NSCLC have increasingly targeted specific molecular abnormalities. This approach has led to approval of multiple drugs based on results in specific BioM populations prior to completion of randomized trials. As a result, many trials now require evaluation of a fresh biopsy prior to enrollment. Implications of potentially increased duration of screening on interpretation of clinical outcomes have not been completely explored. Methods: We reviewed charts of patients (pts) with NSCLC consented to 26 trials between January 2012 and December 2014 through the UCLA Jonsson Comprehensive Cancer Center lung cancer program to assess factors associated with lack of enrollment. Results: 385 pts consented to participate in therapeutic clinical trials, 280 of whom signed consent for one of several trials requiring specific results from a recent biopsy with 139 pts ultimately enrolling in such trials. In treated pts in whom a new biopsy was required, median number of days from informed consent to biopsy was10 and from biopsy to first dose was 25. Of the 141 SF pts, 34 (24.1%) were eligible based on BioM status. Of these, SF was due to worsening performance status (PS) in 18 (52.9%), pursuing alternate therapy in 3 (8.8%), screening labs out-of-range in 3 (8.8%), withdrawal of consent in 2 (5.8%), and other reasons (prohibited medications, etc.) in 8 (23.5%). Conclusions: Approximately one-quarter of screened pts who did not enroll on trials requiring BioM interpretation from a recent biopsy were eligible based on BioM results, most of whom experienced SF based on worsening PS. Whether these patients would have enrolled if the clinical trial had a more traditional design cannot be known. Implications of these findings for accurately assessing trial efficacy should be assessed, as should the generalizability of our results. Whether the delay in enrollment based on the duration of screening either excludes pts who would have been more likely to experience early decline or enrolls pts who have become more ill during screening should be more fully explored.
Abstract 14160: Rest and Reserve Functions in Fontan Patients With Right Ventricular Morphology are Worse Than Those With Left Ventricular Morphology
Authors: Satoshi Masutani, Seiko Kuwata, Clara Kurishima, Yoichi Iwamoto, Hirofumi Saiki, Hirotaka Ishido, Masanori Tamura, Hideaki Senzaki
Journal: Circulation (2015)

Introduction: Fontan patients with right ventricular morphology (RV-F) are associated with worse outcome and exercise capacity compared with those with left ventricular morphology (LV-F). Diminished cardiac reserve is one of major mechanisms of impaired exercise capacity in heart failure patients. However, it remains unclear whether and how rest and reserve functions differ between RV-F and LV-F. Hypothesis: We assessed the hypothesis that rest and reserve functions in RV-F may be worse than those in LV-F. Methods: This study included 28 RV-F and 17 LV-F (6.0 vs 6.2 years. p=N.S.). Ventricular pressure-area relationships were determined during cardiac catheterization, both before and after β-adrenergic stimulation with dobutamine (5 microg/kg/min) and increased heart rates by atrial pacing. Results: There were no significant differences in heart rate, central venous pressure, and pulmonary vascular resistance between RV-F and LV-F. End-systolic pressure in RV-F was lower than that in LV-F (89 vs 97mmHg), while end-systolic and end-diastolic volume in RV-F were larger than those in LV-F. Consistently, contractile function in RV-F was worse than that in LV-F (20.1±10.5 vs 30.8±19.7 mmHg/cm2 хm2 in Ees index; and 978±237 vs 1186±297 mmHg/s in dp/dt max). The worse contractile function in RV-F was persisted after dobutamine (24.9 vs 45.1 mmHg/cm2 хm2 in Ees index; and 1721 vs 2241 mmHg/s in dp/dt max). Furthermore, the response of Ees index to faster heart rate in RV-F was blunted, which was in striking contrast to positive chronotropic response in LV-F (Figure). Conclusions: Compared with LV-F, RV-F has worse systolic function at rest and markedly attenuated chronotropic reserve in systolic function, which can be responsible for worse outcome in RV-F. Given the lack of definitive therapy for Fontan failure, development of medical therapy to improve rest and reserve function should be pursued for better prognosis in Fontan patients.
PS-209-Whole Human liver decellularisation-recellularisation for future liver transplantation and extracorporeal device application
Authors: Walid Al-Akkad, Eric Felli, Bettina M Buchholz, Joerg-Matthias Pollok, Tariq Al-Akkad, Toby Proctor, Luca Frenguelli, Simone Canestrari, Domenico Bagordo, Gabriele Spoletini, Domenico Tamburrino, Maria Giovanna Vilia, Krista Rombouts, Massimo Malago, Paolo De Coppi, Etienne Sokal, Massimo Pinzani, Giuseppe Mazza
Journal: Journal of Hepatology (2019)
SAT-427-The role of liver and spleen stiffness measurement in predicting hepatic decompensation after HCV eradication with direct antiviral agents therapy
Authors: Elton Dajti, Federico Ravaioli, Antonio Colecchia, Giovanni Marasco, Maria Letizia Bacchi Reggiani, Luigina Vanessa Alemanni, Mariarosa Tamé, Stefano Brillanti, Francesco Azzaroli, Giuseppe Mazzella, Davide Festi
Journal: Journal of Hepatology (2019)
Characterization of patients with metastatic non-small cell lung cancer obtaining long term benefit from immunotherapy
Authors: G. Galli, C. Proto, D. Signorelli, M. Imbimbo, R. Ferrara, A. Prelaj, A. De Toma, G. Randon, B. Trevisan, M. Ganzinelli, N. Zilembo, M.C. Garassino, G. Lo Russo
Journal: Annals of Oncology (2019)

Background: The indications of Immunotherapy (IO) for metastatic Non Small Cell Lung Cancer (mNSCLC) are broadening. Although different studies have proved the efficacy of IO in this setting, only a minority of patients (pts) gains advantage from IO and predictive variables of Long Term Benefit (LTB) are incompletely understood. Methods: We retrospectively collected data about all consecutive mNSCLC pts treated with IO at Istituto Nazionale dei Tumori, Milan, Italy, from 04/2013 to 07/2017. We defined pts with LTB as those obtaining a Complete Response (CR), a Partial Response (PR) or a Stable Disease (SD) as best response from IO and maintaining it for ≥12 months (mos). Pts were defined to have a Short Term Benefit (STB) if they obtained a CR, a PR or a SD as best response but maintained it for <12 mos. Pts were defined as Progressors (P) If they obtained a progression as best response. Fisher's test was used to compare variables. Multivariate analyses were performed with logistic regression. Survival was estimated with Kaplan-Meier method. Results: One hundred forty-seven pts were identified. IO was an antiPD1 in 87 cases, an antiPDL1 in 52 cases, a combination antiPDL1/PD1 + antiCTLA4 in 7 cases, an antiCTLA4 in 1 case. First line IO was administered in 19 pts, II line IO in 63 pts, ≥III line IO in 64 pts. After a median follow up of 28.5 mos, 35 pts obtained LTB from IO. A higher proportion of LTB pts compared with controls (STB + P) showed CR/PR as first (12/35 vs 10/112, p = 0.0007) and best response (19/35 vs 14/112, p < 0.0001) to IO. More LTB pts than controls had a neutrophil/lymphocyte ratio<5 (p = 0.0378) and did not receive steroids (p = 0.0023), but only the evidence of a CR/PR during IO retained association to LTB at multivariate analyses (p = 0.0002). All other clinical and pathologic variables appeared unremarkable. A second analysis comparing pts with LTB and STB confirmed this result (odds ratio for CR/PR vs SD: 2.629, 95%CI: 1.051-6.579; p = 0.0427). Conclusions: Objective response appears to be a central factor in predicting LTB from IO, irrespective of all other variables. If confirmed, this observation could help in identifying the pts with mNSCLC candidate to gain the highest advantage from IO. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
THU-123-No effect of alcohol consumption or dependence on treatment outcome in chronic hepatitis C patients treated with Elbasvir/Grazoprevir in a real-world setting
Authors: Jean-Pierre Bronowicki, Patrick Miailhes, Bertrand Hanslik, Armand Abergel, Dominique Larrey, Dr. Dan Pospait, Régine Truchi, Denis Ouzan, Vincent Jouannaud, Ms. Stéphanie Perot, Jérémy Skrzypski, Ms. Camille Liautard, Ms. Emilie Estrabaud, Axelle SpampinatoMs, Dr. Amir Guidoum, Philippe Sogni
Journal: Journal of Hepatology (2019)