tbuckley/cabot-search huggingface dataset:
Water‐Dispersible Polydopamine‐Coated Nanofibers for Stimulation of Neuronal Growth and Adhesion
Authors: Stefanie Sieste, Thomas Mack, Christopher V. Synatschke, Corinna Schilling, Christopher Meyer zu Reckendorf, Laura Pendi, Sean Harvey, Francesco S. Ruggeri, Tuomas P. J. Knowles, Christoph Meier, David Y. W. Ng, Tanja Weil, Bernd Knöll
Journal: Advanced Healthcare Materials (2018)

Abstract Hybrid nanomaterials have shown great potential in regenerative medicine due to the unique opportunities to customize materials properties for effectively controlling cellular growth. The peptide nanofiber‐mediated auto‐oxidative polymerization of dopamine, resulting in stable aqueous dispersions of polydopamine‐coated peptide hybrid nanofibers, is demonstrated. The catechol residues of the polydopamine coating on the hybrid nanofibers are accessible and provide a platform for introducing functionalities in a pH‐responsive polymer analogous reaction, which is demonstrated using a boronic acid modified fluorophore. The resulting hybrid nanofibers exhibit attractive properties in their cellular interactions: they enhance neuronal cell adhesion, nerve fiber growth, and growth cone area, thus providing great potential in regenerative medicine. Furthermore, the facile modification by pH‐responsive supramolecular polymer analog reactions allows tailoring the functional properties of the hybrid nanofibers in a reversible fashion.
Prognostic model based on immune checkpoint proteins expression and clinicopathological factors to predict outcome of patients with gastric cancer.
Authors: Ti Wen, Xiujuan Qu, Yi Li, Yuee Teng, Jingdong Zhang, Bo Jin, Mingfang Zhao, Xiaofang Che, Zhi Li, Yunpeng Liu
Journal: Journal of Clinical Oncology (2016)

e15570 Background: Gastric cancer is a leading cause of cancer death worldwide, and its prognostic factors remain unclear. TNM staging was used to predict the prognosis of GC, however, it cannot meet current demands. To improve prediction efficiency, a model that reflects both tumor-related factor and host's local immune response in tumor microenvironment (TME) is needed. Immune checkpoint proteins regulate T-cell function to promote cancer immune escape. PDL1/PD-1 pathway, one of the immune checkpoint pathways, has become a new target in cancer treatment. Here, we aimed to illuminate the prognostic roles of immune checkpoint protein in GC. Methods: Immune checkpoint proteins expressed in tumor microenvironment (TME) were detected by IHC staining. Survival analysis was performed by the Kaplan-Meier method. A prognostic model was constructed from 174 gastric cancer patients using a scoring system, which was based on hazard ratios in a Cox proportional hazard model. Results: We examined PD-L1, PD-1, CD8 protein expression in TME from 174 GC patients (pts), and explored their effects on pt’s overall survival (OS). Our results showed that TC PD-L1+ was associated with better clinical outcomes, including longer OS et al (P < 0.05). However, PD-L1+ or PD-1+ IC was correlated with poorer OS (P = 0.0244, P = 0.024). Furthermore, multivariate analysis identified PD-L1+ TC, PD-L1+ IC, PD-1+ IC, CD8high IC, lauren classify, lymphatic invasion and AJCC stage were independent prognostic factors. A prognostic model was established by combination of these factors. Patients were categorized into low-/median-/high-risk groups according to their scores, and the 5-year survival rates were 96%, 56.23% and 18.36%, respectively (P < 0.0001). Our seven-factors prognostic model yielded an area under the ROC curve (AUC) of 0.855 for prediction of mortality at 5 years, which was superior to TNM stage with an AUC of 0.685. Conclusions: This study showed a prognostic model based on different prognostic roles of immune checkpoint proteins, which was more accuracy than TNM staging and might provide guidance for immunotherapy options in GC.
Cell death markers in patients with cirrhosis and acute decompensation
Authors: Stewart Macdonald, Fausto Andreola, Patrik Bachtiger, Alex Amoros, Marco Pavesi, Rajeshwar Mookerjee, Yu Bao Zheng, Henning Gronbaek, Alexander L. Gerbes, Elsa Sola, Paolo Caraceni, Richard Moreau, Pere Gines, Vicente Arroyo, Rajiv Jalan
Journal: Hepatology (2017)

The aims of this study were to determine the role of cell death in patients with cirrhosis and acute decompensation (AD) and acute on chronic liver failure (ACLF) using plasma‐based biomarkers. The patients studied were part of the CANONIC (CLIF Acute‐on‐Chronic Liver Failure in Cirrhosis) study (N = 337; AD, 258; ACLF, 79); additional cohorts included healthy volunteers, stable patients with cirrhosis, and a group of 16 AD patients for histological studies. Caspase‐cleaved keratin 18 (cK18) and keratin 18 (K18), which reflect apoptotic and total cell death, respectively, and cK18:K18 ratio (apoptotic index) were measured in plasma by enzyme‐linked immunosorbent assay. The concentrations of cK18 and K18 increased and the cK18:K18 ratio decreased with increasing severity of AD and ACLF ( P &lt; 0.001, respectively). Alcohol etiology, no previous decompensation, and alcohol abuse were associated with increased cell death markers whereas underlying infection was not. Close correlation was observed between the cell death markers and, markers of systemic inflammation, hepatic failure, alanine aminotransferase, and bilirubin, but not with markers of extrahepatic organ injury. Terminal deoxynucleotidyl transferase dUTP nick‐end labeling staining confirmed evidence of greater hepatic cell death in patients with ACLF as opposed to AD. Inclusion of cK18 and K18 improved the performance of the CLIF‐C AD score in prediction of progression from AD to ACLF ( P &lt; 0.05). Conclusion : Cell death, likely hepatic, is an important feature of AD and ACLF and its magnitude correlates with clinical severity. Nonapoptotic forms of cell death predominate with increasing severity of AD and ACLF. The data suggests that ACLF is a heterogeneous entity and shows that the importance of cell death in its pathophysiology is dependent on predisposing factors, precipitating illness, response to injury, and type of organ failure. (H epatology 2018;67:989–1002)
Genomic Features of Response to Combination Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer
Authors: Matthew D. Hellmann, Tavi Nathanson, Hira Rizvi, Benjamin C. Creelan, Francisco Sanchez-Vega, Arun Ahuja, Ai Ni, Jacki B. Novik, Levi M.B. Mangarin, Mohsen Abu-Akeel, Cailian Liu, Jennifer L. Sauter, Natasha Rekhtman, Eliza Chang, Margaret K. Callahan, Jamie E. Chaft, Martin H. Voss, Megan Tenet, Xue-Mei Li, Kelly Covello, Andrea Renninger, Patrik Vitazka, William J. Geese, Hossein Borghaei, Charles M. Rudin, Scott J. Antonia, Charles Swanton, Jeff Hammerbacher, Taha Merghoub, Nicholas McGranahan, Alexandra Snyder, Jedd D. Wolchok
Journal: Cancer Cell (2018)

Combination immune checkpoint blockade has demonstrated promising benefit in lung cancer, but predictors of response to combination therapy are unknown. Using whole-exome sequencing to examine non-small-cell lung cancer (NSCLC) treated with PD-1 plus CTLA-4 blockade, we found that high tumor mutation burden (TMB) predicted improved objective response, durable benefit, and progression-free survival. TMB was independent of PD-L1 expression and the strongest feature associated with efficacy in multivariable analysis. The low response rate in TMB low NSCLCs demonstrates that combination immunotherapy does not overcome the negative predictive impact of low TMB. This study demonstrates the association between TMB and benefit to combination immunotherapy in NSCLC. TMB should be incorporated in future trials examining PD-(L)1 with CTLA-4 blockade in NSCLC.
β-catenin-activated hepatocellular carcinomas are addicted to fatty acids
Authors: Nadia Senni, Mathilde Savall, David Cabrerizo Granados, Marie-Clotilde Alves-Guerra, Chiara Sartor, Isabelle Lagoutte, Angélique Gougelet, Benoit Terris, Hélène Gilgenkrantz, Christine Perret, Sabine Colnot, Pascale Bossard
Journal: Gut (2018)

Objectives CTNNB1 -mutated hepatocellular carcinomas (HCCs) constitute a major part of human HCC and are largely inaccessible to target therapy. Yet, little is known about the metabolic reprogramming induced by β-catenin oncogenic activation in the liver. We aimed to decipher such reprogramming and assess whether it may represent a new avenue for targeted therapy of CTNNB1 -mutated HCC. Design We used mice with hepatocyte-specific oncogenic activation of β-catenin to evaluate metabolic reprogramming using metabolic fluxes on tumourous explants and primary hepatocytes. We assess the role of Pparα in knock-out mice and analysed the consequences of fatty acid oxidation (FAO) using etomoxir. We explored the expression of the FAO pathway in an annotated human HCC dataset. Results β-catenin-activated HCC were not glycolytic but intensively oxidised fatty acids. We found that Pparα is a β-catenin target involved in FAO metabolic reprograming. Deletion of Pparα was sufficient to block the initiation and progression of β-catenin-dependent HCC development. FAO was also enriched in human CTNNB1 -mutated HCC, under the control of the transcription factor PPARα. Conclusions FAO induced by β-catenin oncogenic activation in the liver is the driving force of the β-catenin-induced HCC. Inhibiting FAO by genetic and pharmacological approaches blocks HCC development, showing that inhibition of FAO is a suitable therapeutic approach for CTNNB1 -mutated HCC.
Hippocampus-driven feed-forward inhibition of the prefrontal cortex mediates relapse of extinguished fear
Authors: Roger Marek, Jingji Jin, Travis D. Goode, Thomas F. Giustino, Qian Wang, Gillian M. Acca, Roopashri Holehonnur, Jonathan E. Ploski, Paul J. Fitzgerald, Timothy Lynagh, Joseph W. Lynch, Stephen Maren, Pankaj Sah
Journal: Nature Neuroscience (2018)
Single-center experience of PD1 inhibition in metastatic uveal melanoma.
Authors: Tan Xu, Jung Min Song, Michael J. McNamara, Brian Gastman, Arun D Singh, Pauline Funchain
Journal: Journal of Clinical Oncology (2017)

87 Background: Metastatic uveal melanoma (MUM) is a rare histology with poor prognosis. Therapies used in cutaneous melanoma with success have limited to no efficacy in uveal melanoma. Limited data exists regarding the efficacy of PD-1 inhibition in this disease. Methods: Patients carrying a diagnosis of MUM that had been treated with any PD1 inhibitor at the Cleveland Clinic were analyzed. Median overall survival from the diagnosis of metastatic disease and from the start of PD-1 inhibition were calculated. RECIST 1.1 criteria were used to assess response to therapy. Results: 10 patients with MUM have been treated with a PD1 inhibitor. Mean age at initiation of PD1 inhibition was 74. Five (50%) were female. Median time from initial diagnosis to metastatic disease was 67 months (range, 5-204). All 6 patients with a genetic profiling result available were classified as poor risk either by cytogenetics or gene expression profiling. Median overall survival from diagnosis of metastatic disease was 24 months (range, 9-46). Six patients had also been treated with ipilimumab, 4 had prior treatment, 1 had PD-1 prior to ipilimumab, and one had concurrent treatment with combination ipilimumab/nivolumab. Adjunct local radiation occurred in 6 patients: 5 of the liver (4 embolization, 1 SBRT), one of osseous metastases. Median time on PD1 treatment was 2 months (range, 1-6). Two patients had SD, 6 PD, 3 have not yet been reevaluated. Median survival from initiation of PD1 inhibition was 9 months (range, 7-12). Adverse events were as expected from published experiences with PD-1 inhibition. All patients with median survival from initial diagnosis of metastatic disease over one year received both PD-1 and CTLA-4 inhibition as well as radiation. Conclusions: In this single center experience, no patients had tumor response to PD-1 inhibition. Combination therapies may be worth exploring in the treatment of MUM.
Abstract 15500: The Role of Pericardial Delayed Hyper-Enhancement in Predicting Patients With Chronic Refractory Pericarditis Needing Treatment With Disease-Modifying Antirheumatic Drugs or Biological Agents
Authors: Kimi Sato, Arnav Kumar, Edlira Yzeiraj, Jorge Betancor, Lin Lin, Veena Raizada, Deborah H Kwon, Apostolos Kontzias, Allan L Klein
Journal: Circulation (2016)

Background:  Pericardial delayed hyperenhancement (DHE) on cardiac magnetic resonance (CMR) imaging indicates chronic inflammatory pericarditis. We hypothesized that increased baseline DHE might identify patients at higher risk of developing chronic refractory recurrent pericarditis needing initiation of Disease-Modifying Antirheumatic Drugs (DMARDs) or biological agents.   Methods:  This is a retrospective study of recurrent pericarditis (RP) patients who underwent DHE imaging and had follow-up. Patients already on or those started on DMARDs/Biological agents immediately after CMR were excluded. Pericardial inflammation was quantified on short-axis DHE sequences by contouring the pericardium, selecting normal septal myocardium as a reference region, and then quantifying the pericardial signal that was > 6 SD above the reference. Primary outcome was initiation of DMARDs/Biological agents. Secondary outcome was clinical improvement defined as successful tapering of Anti-inflammatory agents to a stable minimal dose with no recurrence for at least 3 months.   Results:  Among 144 patients with RP, 31 patients (22%) were started on DMARDs/Biological agents and 59(42%) had clinical improvement at the end of follow up period. In multivariate Cox proportional-hazards model, patients with higher baseline quantitative pericardial DHE (HR: 1.01; 95 % CI: 1.00-1.02; p = 0.03) had earlier initiation of DMARDs/Biologics after adjusting for age, gender, medication use, etiology and disease activity. Kaplan-Meier curves showed that patients with quantitative DHE > 46 cm 3  had significantly higher chances of being started on DMARDs/Biologics (p=0.03). Patients with lower baseline quantitative DHE had higher chances of clinical improvement (HR: 0.99; 95% CI: 0.98-0.99;p=0.006).   Conclusions:  Baseline quantitative DHE predicted patients who were at higher risk of developing chronic refractory recurrent pericarditis needing DMARDs/Biologics.
Hydrogen sulfide, nitric oxide, and neurodegenerative disorders
Authors: Sandesh Panthi, Sumeet Manandhar, Kripa Gautam
Journal: Translational Neurodegeneration (2018)

Hydrogen Sulfide (H2S) and Nitric Oxide (NO) have become recognized as important gaseous signaling molecules with enormous pharmacological effects, therapeutic value, and central physiological roles. NO is one of the most important regulators of the pathophysiological condition in central nervous system (CNS). It is critical in the various functioning of the brain; however, beyond certain concentration/level, it is toxic. H2S was regarded as toxic gas with the smell like rotten egg. But, it is now regarded as emerging neuroprotectant and neuromodulator. Recently, the use of donors and inhibitors of these signaling molecules have helped us to identify their accurate and precise biological effects. The most abundant neurotransmitter of CNS (glutamate) is the initiator of the reaction that forms NO, and H2S is highly expressed in brain. These molecules are shedding light on the pathogenesis of various neurological disorders. This review is mainly focused on the importance of H2S and NO for normal functioning of CNS.
Treating juvenile idiopathic arthritis to target: recommendations of an international task force
Authors: Angelo Ravelli, Alessandro Consolaro, Gerd Horneff, Ronald M Laxer, Daniel J Lovell, Nico M Wulffraat, Jonathan D Akikusa, Sulaiman M Al-Mayouf, Jordi Antón, Tadej Avcin, Roberta A Berard, Michael W Beresford, Ruben Burgos-Vargas, Rolando Cimaz, Fabrizio De Benedetti, Erkan Demirkaya, Dirk Foell, Yasuhiko Itoh, Pekka Lahdenne, Esi M Morgan, Pierre Quartier, Nicolino Ruperto, Ricardo Russo, Claudia Saad-Magalhães, Sujata Sawhney, Christiaan Scott, Susan Shenoi, Joost F Swart, Yosef Uziel, Sebastiaan J Vastert, Josef S Smolen
Journal: Annals of the Rheumatic Diseases (2018)

Recent therapeutic advances in juvenile idiopathic arthritis (JIA) have made remission an achievable goal for most patients. Reaching this target leads to improved outcomes. The objective was to develop recommendations for treating JIA to target. A Steering Committee formulated a set of recommendations based on evidence derived from a systematic literature review. These were subsequently discussed, amended and voted on by an international Task Force of 30 paediatric rheumatologists in a consensus-based, Delphi-like procedure. Although the literature review did not reveal trials that compared a treat-to-target approach with another or no strategy, it provided indirect evidence regarding an optimised approach to therapy that facilitated development of recommendations. The group agreed on six overarching principles and eight recommendations. The main treatment target, which should be based on a shared decision with parents/patients, was defined as remission, with the alternative target of low disease activity. The frequency and timeline of follow-up evaluations to ensure achievement and maintenance of the target depend on JIA category and level of disease activity. Additional recommendations emphasise the importance of ensuring adequate growth and development and avoiding long-term systemic glucocorticoid administration to maintain the target. All items were agreed on by more than 80% of the members of the Task Force. A research agenda was formulated. The Task Force developed recommendations for treating JIA to target, being aware that the evidence is not strong and needs to be expanded by future research. These recommendations can inform various stakeholders about strategies to reach optimal outcomes for JIA.
Tumour infiltrating lymphocytes and tumour associated macrophages in chronic obstructive pulmonary disease (COPD) patients with non-small cell lung cancer (NSCLC) and in patients with NSCLC
Authors: Piera Boschetto, Natalina Lo Cascio, Deborah Miotto, Lucia Mazzetti, Elena Zeni, Massimo Pedriali, Patrizia Querzoli, S. Chiarelli, Edoardo De Rosa, Lm Fabbri, Cristina Mapp
Journal: European Respiratory Journal (2005)
Exosomal miRNAs in hepatocellular carcinoma development and clinical responses
Authors: Shuangshuang Li, Jiping Yao, Mingjie Xie, Yanning Liu, Min Zheng
Journal: Journal of Hematology & Oncology (2018)

Hepatocellular carcinoma remains the sixth most lethal malignancy in the world. While HCC is often diagnosed via current biomarkers at a late stage, early detection of HCC has proven to be very difficult. Recent studies have focused on using exosomal miRNAs in clinical diagnostics and therapeutics, because they have improved stability in exosomes than as free miRNAs themselves. Exosomal miRNAs act through novel mechanisms for inducing cellular responses in a variety of biological circumstances. Dysregulated expression of miRNAs in exosomes can also accelerate HCC progression, including cell proliferation and metastasis, via alteration of a network of genes. Growing evidence demonstrates that exosomal miRNAs can affect many aspects of physiological and pathological conditions in HCC and indicates that miRNAs in exosomes can not only serve as sensitive biomarkers for cancer diagnostics and recurrence but can also potentially be used as therapeutics to target HCC progression. In this review, we summarize the latest findings between exosomal miRNAs and HCC, in order to better comprehend the functions and applications in HCC. Moreover, we discuss critical issues to consider when developing anti-tumor exosomal miRNAs as a novel therapeutic strategy for treating HCC in the clinic.
Resistance to Antibody–Drug Conjugates
Authors: Sara García-Alonso, Alberto Ocaña, Atanasio Pandiella
Journal: Cancer Research (2018)

Abstract Antibody–drug conjugates (ADC) are multicomponent molecules constituted by an antibody covalently linked to a potent cytotoxic agent. ADCs combine high target specificity provided by the antibody together with strong antitumoral properties provided by the attached cytotoxic agent. At present, four ADCs have been approved and over 60 are being explored in clinical trials. Despite their effectiveness, resistance to these drugs unfortunately occurs. Efforts to understand the bases underlying such resistance are being carried out with the final purpose of counteracting them. In this review, we report described mechanisms of resistance to ADCs used in the clinic along with other potential ones that may contribute to resistance acquisition. We also discuss strategies to overcome resistance to ADCs. Cancer Res; 78(9); 2159–65. ©2018 AACR.
Abstract 16243: Dose-response Relationships Between Exercise Intensity, Mood States, and Quality of Life in Heart Failure Patients
Authors: Marysol C Cacciata, Anna Stromberg, Lorraine Evangelista
Journal: Circulation (2016)

Background: The beneficial effects of exercise training on mood disorders and quality of life (QOL) in patients with heart failure (HF) remains controversial, with investigators documenting both po...
Insulin resistance and atherosclerosis
Authors: Clay F Semenkovich
Journal: Journal of Clinical Investigation (2006)

Considerable evidence supports the association between insulin resistance and vascular disease, and this has led to wide acceptance of the clustering of hyperlipidemia, glucose intolerance, hypertension, and obesity as a clinical entity, the metabolic syndrome. While insulin resistance, by promoting dyslipidemia and other metabolic abnormalities, is part of the proatherogenic milieu, it is possible that insulin resistance itself in the vascular wall does not promote atherosclerosis. Recent findings suggest that insulin resistance and atherosclerosis could represent independent and ultimately maladaptive responses to the disruption of cellular homeostasis caused by the excess delivery of fuel.