tbuckley/cabot-search huggingface dataset:
Correlation of Structure and Function in Idiopathic Pulmonary Fibrosis
Authors: Reuben M. Cherniack, Thomas V. Colby, Andrew Flint, William M. Thurlbeck, James A. Waldron, Lynn Ackerson, Marvin I. Schwarz, Talmadge E. King
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

The early stage of idiopathic pulmonary fibrosis (IPF) is thought to involve a smaller number of alveoli and to be characterized predominantly by cellularity and minimal fibrosis, whereas advanced disease involves a large number of alveoli and is characterized predominantly by fibrosis with minimal cellularity. In addition, correlative studies have indicated that prognosis and response to therapy is determined in part by the extent of fibrosis and cellularity. This study was undertaken to determine whether pulmonary function assessment would help distinguish between the cellular and fibrotic phases of this disorder, as determined by a semiquantitative pathology scoring system that comprised four factor scores: fibrosis, cellularity, granulation/connective tissue, and desquamation. Ninety-six untreated patients with biopsy-confirmed IPF (27 never smokers, 32 current smokers, and 37 ex-smokers) were evaluated. In the group as a whole, there was no significant relationship between the fibrosis or the connective/granulation tissue factor scores and any of the physiologic parameters. The Dlco correlated with the "desquamation" and the total pathology scores, whereas the TLC and FVC correlated with the cellularity factor score. In the current smokers, the coefficient of elastic retraction, Dlco/Va, and FEV1/FVC ratio were significantly lower than in never smokers and ex-smokers, and TLC and FVC were higher than in never smokers. Also, the mean cellularity and granulation/connective tissue factor scores were significantly lower, and the desquamation factor score was significantly higher than those in never smokers and ex-smokers. Both age and smoking status were significant for the cellularity factor score, whereas for the connective/granulation tissue factor score, age was not significant but smoking status was. For the desquamation factor score, age was significant but smoking status was not. There were significant differences between never smokers and ever smokers in the relationship between the pathology factors and measurements of respiratory function, and this may explain some of the difficulty in assessing structure-function correlation in patients with IPF. In the never smokers, the correlations between structure and function were likely the direct result of IPF per se. In the current smokers, bronchiolar and/or emphysematous changes associated with cigarette smoking may have complicated the pathologic alterations caused by IPF, as well as influencing the functional derangements.
Abstract 31: Regulation of Acetylation Restores Proteolytic Function in Diseased Myocardium
Authors: Ding Wang, Caiyun Fang, Nobel Zong, Tae-Young Kim, David Liem, Mario Deng, Peipei Ping
Journal: Circulation Research (2012)

RATIONALE: Proteasome complexes play essential roles in maintaining cardiac protein homeostasis in normal and stressed conditions. However, proteasomal function is often compromised in diseased myocardium; and the regulation of proteasomal dynamics remains poorly understood. METHODS AND RESULTS: We studied cardiac proteolytic function and its regulation by acetylation in murine and human models of heart disease. Proteasomes, from both normal and diseased myocardium, were treated with histone de-acetylases (HDACs) inhibitors and they exhibited enhanced proteolytic capacity in vitro and in vivo. This unique regulatory paradigm was first examined in a murine model of ischemic injury (n=5); where diminished proteolytic function in the ischemic hearts was restored by HDACs inhibition (either by SAHA or by Sodium Valproate) in a dose-dependent fashion. Importantly, this phenomenon was validated in human samples, where inhibition of HDACs augmented proteolytic functions in the diseased myocardium (n=5). Using high resolution LC-MS/MS coupled with a combined collision-induced dissociation and electron-transfer dissociation approach, the acetylome (N-terminal and lysine) of cardiac 20S proteasomes was delineated. Targeted enrichment strategy of the posttranslationally modified peptides enabled the capture of eight lysine and nine N-terminal acetylation sites in the murine heart, contributing to the first comprehensive acetylome map for the cardiac 20S proteasomes. Among them, at least six lysine acetylation sites were inducible by HDACs inhibitors. Furthermore, parallel investigations using cardiac 20S proteasomes pinpointed the functional impact of HDAC inhibitions to specific acetylation sites on the 20S proteasomal subunits. CONCLUSIONS: Proteasomal biology is modulated by acetylation modifications in the heart. This regulatory mechanism is punctual and potent; and it was observed both in an acutely pathological murine model of ischemia-reperfusion injury as well as in a chronic human disease of end-stage heart failure. These findings demonstrate the utility of pharmacological interventions (e.g., HDAC inhibition) to restore damaged proteolytic function in diseased myocardium.
Hepatocellular cancer (HCC) patients on phase I clinical trials in sorafenib era: Analysis of a single institution experience in last 10 years.
Authors: Vinu Madhusudanannair, Brad H. Pollock, Norma Ketchum, Steven D. Weitman, John Sarantopoulos, Devalingam Mahalingam
Journal: Journal of Clinical Oncology (2014)

e15134 Background: Sorafenib is the only approved systemic therapy in HCC. Clinical trials in HCC often exclude patients with Child-Pugh Stage (CPS) B/C cirrhosis. Furthermore, limited information on outcomes specific to HCC population are reported from early clinical trials. We evaluated the efficacy and safety of early phase clinical trial agents in HCC. Methods: We analyzed 53 Phase I clinical trials that enrolled HCC patients at our institution between 2003–2013. Median progression free survival (mPFS) and overall survival (mOS) were estimated from Kaplan-Meier curves along with medians and groups were compared with the log rank test. The magnitude of association and survival was estimated with the hazard ratio (HR). Results: Median age 63 (33–84), males 75 %, ECOG PS 0–1 92%, CPS A 19%, B 71.7% and C 9.4%. 41.5% subjects were treated with prior Sorafenib. Class of agents used included cytotoxics such as microtubule inhibitors (26.4%), anti-folates (5.7%), alkylators (1.9%), topoisomerase inhibitors (5.7%), and non-cytotoxic agents such as pro-apoptotic therapies (15.1%), anti-VEGF (17%) mTOR/ EGFR/ IGFR (22.6%), and HDAC inhibitors (5.7%). When evaluating for efficacy for all patients, the mPFS (95% CI) = 2.3 (1.9, 3.9) months and 12 month OS ± SEM = 59% ± 15%. The mPFS was 3.7 months versus 2.1 months for CPS A subjects and CPS B/C subjects respectively (HR 1.5, CI: 0.7–3.5, p = 0.31). The 12-month OS was 80 ± 18% among pts with CPS A vs 74 ± 8% in CPS B. Grade 3–4 toxicity included hematologic (13.2%) and hepatic (20.8%), with no significant difference in toxicity between the two CPS groups. Finally, cytotoxic agents had a mPFS of 3.1 months (95% CI: 2.1- 4.4) vs 1.9 months (95% CI: 1.1–2.3) for non-cytotoxic therapy (HR 1.56, 95% CI: 0.8–3.07, p = 0.19). The 12 month OS was 46% vs 50% between these two groups (HR 6.2, CI: 1.3–29.3, p = 0.009). Conclusions: Patients with advanced HCC have a modest survival that is compounded further by poor liver function. Our data suggests that there are no significant differences in efficacy and safety between HCC patients with varying liver dysfunction based on CPS status and that cytotoxic drugs were as effective as targeted therapy in Phase I setting.
Nivolumab As Salvage Therapy in Pediatric Patients with Relapsed and Refractory Lymphomas
Authors: Nora Naumann-Bartsch, Daniel Stachel, Martin Chada, Torsten Fritscher, Oliver Rompel, Florian Haller, Arndt Hartmann, Wilhelm Wößmann, Markus Metzler
Journal: Blood (2016)
Immune-Related Gene Expression Profiling After PD-1 Blockade in Non–Small Cell Lung Carcinoma, Head and Neck Squamous Cell Carcinoma, and Melanoma
Authors: Aleix Prat, Alejandro Navarro, Laia Paré, Noemí Reguart, Patricia Galván, Tomás Pascual, Alex Martínez, Paolo Nuciforo, Laura Comerma, Llucia Alos, Nuria Pardo, Susana Cedrés, Cheng Fan, Joel S. Parker, Lydia Gaba, Iván Victoria, Nuria Viñolas, Ana Vivancos, Ana Arance, Enriqueta Felip
Journal: Cancer Research (2017)

Antibody targeting of the immune checkpoint receptor PD1 produces therapeutic activity in a variety of solid tumors, but most patients exhibit partial or complete resistance to treatment for reasons that are unclear. In this study, we evaluated tumor specimens from 65 patients with melanoma, lung nonsquamous, squamous cell lung or head and neck cancers who were treated with the approved PD1-targeting antibodies pembrolizumab or nivolumab. Tumor RNA before anti-PD1 therapy was analyzed on the nCounter system using the PanCancer 730-Immune Panel, and we identified 23 immune-related genes or signatures linked to response and progression-free survival (PFS). In addition, we evaluated intra- and interbiopsy variability of PD1, PD-L1, CD8A, and CD4 mRNAs and their relationship with tumor-infiltrating lymphocytes (TIL) and PD-L1 IHC expression. Among the biomarkers examined, PD1 gene expression along with 12 signatures tracking CD8 and CD4 T-cell activation, natural killer cells, and IFN activation associated significantly with nonprogressive disease and PFS. These associations were independent of sample timing, drug used, or cancer type. TIL correlated moderately (∼0.50) with PD1 and CD8A mRNA levels and weakly (∼0.35) with CD4 and PD-L1. IHC expression of PD-L1 correlated strongly with PD-L1 (0.90), moderately with CD4 and CD8A, and weakly with PD1. Reproducibility of gene expression in intra- and interbiopsy specimens was very high (total SD <3%). Overall, our results support the hypothesis that identification of a preexisting and stable adaptive immune response as defined by mRNA expression pattern is reproducible and sufficient to predict clinical outcome, regardless of the type of cancer or the PD1 therapeutic antibody administered to patients. Cancer Res; 77(13); 3540-50. ©2017 AACR.
HepCom: impact of co-morbidities on the final success of direct antiviral agents therapy in hepatitis C
Authors: J. Ampuero, C.J. Maté, R. Quiles, N. Palomo, J.M. Rosales, S. Llerena, P. Cordero, F.J. Serrano, J.J. Urquijo, M. Maraver, G. Ontanilla, A. Ortega, M. Hernández, M. Bonacci, X. Forns, J.L. Calleja, R. Andrade, J.M. Pascasio, M. Diago, M. De la Mata, I. Carmona, B. Figueruela, J. Crespo, J.M. Navarro, M. Buti, J. Salmeron, M. Romero-Gomez
Journal: Journal of Hepatology (2017)
Plasma microvesicles levels can predict the development of hepatocellular carcinoma in patients with cirrhosis
Authors: C. Levi, A. Payancé, J. Bissonnette, M. Tanguy, O. Roux, M. Bouattour, O. Soubrane, C. Francoz, D. Lebrec, V. Vilgrain, V. Paradis, D. Valla, F. Durand, C.M. Boulanger, P.-E. Rautou
Journal: Journal of Hepatology (2017)
Interim results of an open-label, single-arm trial of ultratrace I-131-iobenguane in patients with metastatic pheochromocytoma/paraganglioma (Pheo).
Authors: Daniel A. Pryma, R. Edward Coleman, Richard Noto, Stanley J. Goldsmith, Rodolfo F. Perini, Camilo Jimenez, Miguel H Pampaloni, Aldo N. Serafini, Richard L. Wahl, Lale Kostakoglu, Jennifer Conley, Kathy Ford, Norman David LaFrance, John W. Babich
Journal: Journal of Clinical Oncology (2012)

e13592 Background: To evaluate the therapeutic efficacy of no carrier added (nca) I-131-MIBG in pheo as measured by &gt; 50% reduction of all antihypertensive medication for ≥ 6 months. Secondarily, to evaluate safety (including radiation absorbed dose to normal organs) and the proportion of subjects with objective response per modified RECIST and biomarker response by change in Chromogranin A (CgA). Methods: Pts with metastatic pheo causing secondary hypertension were treated with up to two 500 mCi doses of 131 I-nca-MIBG 3-6 months apart. The administered dose was limited by pretreatment organ dosimetry and normal tissue tolerance estimates of Emami (1991). Response and toxicity were evaluated for a minimum of 1 year. Results: To date, 41 pts (17-72 years) received at least one treatment (full analysis; FA); 34 pts received 2 treatments (per protocol; PP); All patients have been followed at least 1 year or until death. The primary endpoint of sustained reduction in HTN meds was achieved in 32% and 29% of PP and FA, respectively. In total, 25/41 subjects who received at least 1 treatment had ≥ 50% reduction in their HTN meds. Mean duration of the reduction was 7.7 ± 6.6 months (range 0.1 – 22.1 months). Objective PR was seen in 41% (PP) and 34% (FA). 56% of PP had at least objective MR. All subjects in PP had at least stable disease and 90% in FA had at least stable disease. At 8 months there was a 60±33% reduction in CgA from baseline in PP. Primary toxicity was myelosupression: grade 3 (17%), grade 4 (20%). Grade 3 GI disorders were 15%. There were 3 deaths during follow up, all due to disease. Biomarker response correlated well to objective response and HTN improvement. Thrombocytopenia was the most common treatment-emergent SAE (n=9) considered related to study drug. No other treatment-emergent SAE was considered related to study drug in &gt; 2 subjects. Conclusions: 11 of 34 pts in PP in this ongoing study met the primary endpoint of a positive clinical benefit (decreased HTN meds), which correlated with objective tumor response and biomarker levels in this disease with no approved, efficacious therapies. Toxicity for all patients (n=41) was tolerable and predominantly limited to myelosupression.
DAAs treatment in hepatitis C virus recurrence after Liver Transplantation: clinical usefulness of non-invasive methods
Authors: F. Ravaioli, M.R. Tamè, G. Marasco, L. Vizioli, M.C. Morelli, A.D. Pinna, F. Conti, P. Andreone, A. Colecchia, D. Festi
Journal: Journal of Hepatology (2017)
A non-interventional biomarker study in patients (pts) with non-small cell lung cancer (NSCLC) of adenocarcinoma histology who are treated with nintedanib according to the approved label (LUME-BioNIS)
Authors: M. Reck, A.J. Staal-van den Brekel, A. Mellemgaard, N. Morsli, A.-M. Ellingboe, R. Kaiser, K. Pietzko, T. Kitzing, J. Braunger, K. Kerr
Journal: Annals of Oncology (2017)
Case 14-2017
Authors: Eli M. Miloslavsky, John H. Stone, Andrea P. Moy
Journal: New England Journal of Medicine (2017)

A 20-year-old man with a history of Crohn’s disease was evaluated for pain and swelling of the left calf and a purpuric rash. Three weeks earlier, sore throat, cough, rhinorrhea, and chills had developed. Diagnostic tests were performed.
Real-world effectiveness and safety of Ombitasvir, Paritaprevir/r ± Dasabuvir ± Ribavirin in patients receiving opiate substitution therapy: results from the German observational study LIFE-C
Authors: G. Teuber, P. Buggisch, U. Naumann, R. Link, K. Lohmann, J. Huelsenbeck, M.R. Kraus
Journal: Journal of Hepatology (2017)
Lineage-specific functions of TET1 in the postimplantation mouse embryo
Authors: Rita Khoueiry, Abhishek Sohni, Bernard Thienpont, Xinlong Luo, Joris Vande Velde, Michela Bartoccetti, Bram Boeckx, An Zwijsen, Anjana Rao, Diether Lambrechts, Kian Peng Koh
Journal: Nature Genetics (2017)
Primitive Quiescent CD34+ Cells in Chronic Myeloid Leukemia Are Targeted by In Vitro Expanded Allogeneic Natural Killer Cells, Which Are Functionally Enhanced by Bortezomib Treatment.
Authors: Agnes S.M. Yong, Keyvan Keyvanfar, Nancy Hensel, Rhoda Eniafe, Bipin N. Savani, Maria Berg, Andreas Lundqvist, Elaine M. Sloand, John M. Goldman, Richard W. Childs, A. John Barrett
Journal: Blood (2007)
In hepatitis C virus-related advanced fibrosis and cirrhosis, early decline of liver stiffness following antiviral therapy with DAAs is related to decline in liver inflammation
Authors: A. Winters, S. Luedtke, A. Moreland, P. Jangouk, G. Weng, M. Silveira, P. Davitkov, A. Duarte-Rojo, R. Cheung, G. Garcia-Tsao, Y. Falck-Ytter, A. Branch, N. Bräu
Journal: Journal of Hepatology (2017)
Kinetics of serum HBsAg and HBcrAg in predicting response to pegylated interferon-based therapy in patients with HBeAg-negative chronic hepatitis B
Authors: N. Chuaypen, S. Chittmittraprap, N. Hirankarn, S. Treeprasertsuk, Y. Tanaka, Y. Poovorawan, P. Tangkijvanich
Journal: Journal of Hepatology (2017)
Novel PCR-based method to detect fungal colonization of ascites, bile and duodenal fluid in patients with acute on chronic liver failure (ACLF) or after orthotope liver transplantation (OLT)
Authors: A. Herber, C. Engelmann, S. Krohn, K. Zeller, N.F. Müller, S. Petros, S. Bercker, S. Laudi, A. Hoffmeister, T. Berg
Journal: Journal of Hepatology (2017)
A revisit of anti-HBc IgM in the differentiation of acute HBV infection from chronic HBV infection with acute flare-up
Authors: Y.-C. Chen, C.-H. Lee, Y.-C. Hsieh, W. Teng, C.-H. Huang, W.-J. Jeng, C.-Y. Lin, I.-S. Sheen
Journal: Journal of Hepatology (2017)
Early prediction of response to tyrosine kinase inhibitors by quantification of EGFR mutations in plasma of non-small cell lung cancer patients.
Authors: Antonio Marchetti, John F. Palma, Lara Felicioni, Tommaso Martino De Pas, Rita Chiari, Maela Del Grammastro, Giampaolo Filice, Vienna Ludovini, Alba Ariela Brandes, Antonio Chella, Francesco Malorgio, Flavio Guglielmi, Michele De Tursi, Armando Santoro, Lucio Crino, Fiamma Buttitta
Journal: Journal of Clinical Oncology (2015)

8079 Background: Several studies have investigated the feasibility of detecting EGFR mutations in liquid biopsies of Non-Small Cell Lung Cancer (NSCLC) patients. However, the potential to accurately quantify EGFR mutations in plasma for clinical purposes is largely unexplored. Methods: Plasma samples were obtained from 79 subjects: (a) 42 NSCLC patients with EGFR mutations in primary tumors tissue, from a prospective trial, where blood samples were collected at baseline prior to first-line erlotinib therapy and immediately after progression; (b) 15 previously untreated stage IIIB-IV NSCLC patients, with EGFR mutation positive tumor specimens, where plasma samples were collected at baseline and serially at 4-60 days during TKI therapy; (c) 22 negative control cases. EGFR mutation analysis in plasma was conducted by the cobas EGFR Mutation Test (EGFR test, under development, RMS, Pleasanton, CA) and ultra-deep next generation sequencing (UDNGS) by Roche 454-GS Junior and Illumina MiSeq. A semi-quantitative index (SQI) was derived from a dilution series of known mutation copy numbers. Clinical response, expressed as percent tumor shrinkage (PTS), was evaluated according to RECIST criteria. Results: The sensitivity and specificity of the EGFR test and UDNGS assay in plasma versus tissue was 72% and 100%, and 74% and 100%, respectively. Quantitative indices by the EGFR test and UDNGS showed a significant positive correlation (p < 0.0001). Serial testing of EGFR mutations revealed a progressive decrease in the EGFR semi-quantitative index (SQI) during therapy in all of the patients, starting from the 4thday of treatment in 90% of cases. The rate of SQI decrease was more than 50% at 15 days in 73% of patients (rapid responders) and less than 50% at 15 days in 27% of patients (slow responders) and was correlated with PTS at 2 months. Conclusions: Quantification of EGFR mutations with the cobas test in plasma is feasible. The variation of EGFR SQI during therapy could be useful for early prediction of response and diagnosis of relapse, with further implications for patient management. A prospective trial has been planned to confirm these results. Clinical trial information: EudraCT Number: 2010-023892-24.
Abstract B54: Sustained exposure to TGFβ1 increases the stability of Snail and Slug via integrin β3-Akt-GSK3β signaling, facilitating tumor cell invasion
Authors: Gab-Yong Bae, Hyuk-Jin Cha
Journal: Cancer Research (2016)

Abstract TGFβ is considered as a strong inducer of epithelial-mesenchymal transition (EMT) of tumor cells, promoting metastasis. Whereas acute TGFβ exposure induces growth arrest, chronic TGFβ exposure provokes invasive properties with resistance to TGFβ-induced growth arrest. However, the effect of chronic TGFβ exposure on acquired invasive characteristics of tumor cells is not fully determined. We established a trans-differentiated (TD) A549 cell model by chronic exposure of TGFβ1, with clear EMT phenotypes including high invasiveness. Of interest, elevated invasiveness of TD cells after additional TGFβ1 treatment was achieved even in the significantly downregulated Smad2/3 dependent signaling compared to control cells. We demonstrated that Snail and Slug, the expression of which was highly correlated with poor prognosis of lung cancer patients, were clearly increased in TD cells upon TGFβ1 stimulation due to high protein stability. The increased stability of Snail and Slug in TD cells was attributed to elevated inhibitory phosphorylation of GSK3β, which was caused by higher Akt activity. We demonstrated that dramatically increased integrin β3 by prolong TGFβ1 exposure was responsible for high activity of Akt and subsequent high protein stability of Snail and Slug. Thereby, our data suggest that targeting of integrin β3-mediated signaling would be a potential therapeutic strategy to inhibit invasive properties of TGFβ-stimulated lung cancer. Citation Format: Gab-Yong Bae, Hyuk-Jin Cha. Sustained exposure to TGFβ1 increases the stability of Snail and Slug via integrin β3-Akt-GSK3β signaling, facilitating tumor cell invasion. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B54.
CD38 Chimeric Antigen Receptor Engineered T Cells As Therapeutic Tools for Multiple Myeloma
Authors: Esther Drent, Richard Groen, Willy A. Noort, Jeroen Lammerts van Bueren, Paul W.H.I. Parren, Jurgen H Kuball, Zsolt Sebestyen, Niels W.C.J. van de Donk, Anton C. Martens, Henk M. Lokhorst, Tuna Mutis
Journal: Blood (2014)