tbuckley/cabot-search huggingface dataset:
Plectin-targeted liposomes enhance the therapeutic efficacy of a PARP inhibitor in the treatment of ovarian cancer
Authors: Siva Sai Krishna Dasa, Galina Diakova, Ryo Suzuki, Anne M. Mills, Michael F. Gutknecht, Alexander L. Klibanov, Jill K. Slack-Davis, Kimberly A. Kelly
Journal: Theranostics (2018)

Advances in genomics and proteomics drive precision medicine by providing actionable genetic alterations and molecularly targeted therapies, respectively.While genomic analysis and medicinal chemistry have advanced patient stratification with treatments tailored to the genetic profile of a patient's tumor, proteomic targeting has the potential to enhance the therapeutic index of drugs like poly(ADP-ribose) polymerase (PARP) inhibitors.PARP inhibitors in breast and ovarian cancer patients with BRCA1/2 mutations have shown promise.About 10% of the patients who received Olaparib (PARP inhibitor) showed adverse side effects including neutropenia, thrombocytopenia and in some cases resulted in myelodysplastic syndrome, indicating that off-target effects were substantial in these patients.Through proteomic analysis, our lab previously identified plectin, a cytolinker protein that mislocalized onto the cell surface during malignant transformation of healthy ovarian tissue.This cancer specific phenotype allowed us to image pancreatic cancer successfully using plectin targeted peptide (PTP) conjugated to nanoparticles or displayed on capsid protein of adeno-associated virus (AAV) particles.Objective: The goal of this study was to integrate the available pharmacogenomics and proteomic data to develop effective anti-tumor therapies using a targeted drug delivery approach.Methods: Plectin expression and localization in human ovarian tumor specimens were analyzed followed by in vitro confirmation of cell surface plectin localization in healthy and ovarian cancer cell lines.PTP-conjugated liposomes were prepared and their specificity for plectin+ cells was determined in vitro and in vivo.A remote loading method was employed to encapsulate a PARP inhibitor (AZ7379) into liposomes.An ideal buffer exchange method and remote loading conditions were determined based on the amount of lipid and drug recovered at the end of a remote loading process.Finally, in vivo tumor growth studies were performed to determine the efficacy of PTP liposomes in preventing PARP activity in mice bearing OVCAR8 (high grade epithelial ovarian cancer (EOC)) tumors.Results: PTP liposomal AZ7379 delivery not only enhanced PARP inhibition but also resulted in decelerated tumor growth in mice bearing subcutaneous and intraperitoneal OVCAR8 tumors.In mice bearing subcutaneous or intraperitoneal tumors, treatment with PTP liposomes resulted in a 3-and 1.7-fold decrease in tumor volume, respectively, compared to systemic drug treatment.Conclusion: Targeted drug delivery assisted by genomic and proteomic data provides an adaptable model system that can be extended to effectively treat other cancers and diseases.
Dynamic human immune and tumour cells cross-talk in PDX-humanised mice warrants checkpoint inhibitor cancer immunotherapies assessment
Authors: Nicolas Poirier, Bernard Vanhove
Journal: Gut (2018)

The concept of exploiting the host’s immune system to fight cancer relies on the concept of tumour immune surveillance, the insight that the immune system should eliminate malignant cells. Immunotherapy is a form of treatment aimed at manipulating the immune system to activate, break, regulate or reinforce immune functions. Cancer immunotherapy is revolutionising cancer treatment through the discovery and development of novel approaches that enhance the body’s antitumour immune functions by ‘releasing the brake’ on the immune system: the so-called immune checkpoints (eg, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed death 1 (PD-1)) whose physiological functions are to limit autoimmune processes but are also co-opted by tumours allowing cancer immune escape mechanisms. In initial trials, checkpoint blockade showed success in promoting anti-tumour immunity and durable responses in patients with solid tumours. Several antibodies against the PD-1/PD-ligand-1 (PD-L1) checkpoint pathway have recently been approved in diverse indications (melanoma, non-small-cell lung cancer, head and neck squamous cell carcinoma, renal cell carcinoma, Hodgkin lymphoma, bladder cancer, Merkel cell carcinoma and microsatellite instability high or mismatch repair-deficient solid tumour), and the clinical use of these antibodies is rapidly expanding including in some first-line therapy (eg, metastatic non-squamous non-small cell lung cancer). Although the results are impressive for a fraction of patients, most patients do not show complete responses or long-lasting remission, and several cancers, including GI cancers (eg, pancreatic cancer), remain refractory to checkpoint blockade. While anti-PD1 therapy has been approved last year by the Food and Drug Administration for the treatment of advanced hepatocellular carcinoma (HCC) in patients who have been previously treated with sorafenib, the study (CHECKMATE-040, NCT01658878) showed an overall response rate of only 14.3%.1 A better understanding of why checkpoint inhibitor immunotherapies result in significant clinical benefit in some patients …
Brief Report: Circulating Cytokine Profiles and Antineutrophil Cytoplasmic Antibody Specificity in Patients With Antineutrophil Cytoplasmic Antibody–Associated Vasculitis
Authors: Alvise Berti, Roscoe Warner, Kent Johnson, Divi Cornec, Darrell Schroeder, Brian Kabat, Carol A. Langford, Gary S. Hoffman, Fernanado C. Fervenza, Cees G. M. Kallenberg, Philip Seo, Robert Spiera, E. William St.Clair, Paul Brunetta, John H. Stone, Peter A. Merkel, Ulrich Specks, Paul A. Monach
Journal: Arthritis & Rheumatology (2018)

Objective To evaluate circulating cytokine profiles in patients with antineutrophil cytoplasmic antibody–associated vasculitis ( AAV ), classified by antineutrophil cytoplasmic antibody ( ANCA ) specificity (proteinase 3 ANCA [ PR 3‐ ANCA ] versus myeloperoxidase ANCA [ MPO ‐ ANCA ]) or by clinical diagnosis (granulomatosis with polyangiitis [ GPA ] versus microscopic polyangiitis [ MPA ]). Methods A panel of 29 cytokines was tested in 186 patients with active AAV at inclusion into the Rituximab in AAV trial. Cytokine concentrations were compared between groups within each classification system. Multivariable analyses adjusted for age, sex, and renal insufficiency were performed, with each biomarker as a dependent variable and ANCA specificity and clinical diagnosis as explanatory variables of interest. Results Levels of 9 circulating cytokines (interleukin‐6 [ IL ‐6], granulocyte–macrophage colony‐stimulating factor [ GM ‐ CSF ], IL ‐15, IL ‐18, CXCL 8/ IL ‐8, CCL ‐17/thymus and activation–regulated chemokine [ TARC ], IL ‐18 binding protein [ IL ‐18 BP ], soluble IL ‐2 receptor α [ sIL ‐2Rα], and nerve growth factor β [ NGF β]) were significantly higher in PR 3‐ AAV than MPO ‐ AAV , 4 cytokines ( sIL 6R, soluble tumor necrosis factor receptor type II [ sTNFRII ], neutrophil gelatinase–associated lipocalin [ NGAL ], and soluble intercellular adhesion molecule 1 [ sICAM ‐1]) were higher in MPO ‐ AAV than in PR 3‐ AAV , 6 cytokines ( IL ‐6, GM ‐ CSF , IL ‐15, IL ‐18, sIL ‐2Rα, and NGF β) were higher in GPA than in MPA , and 3 cytokines (osteopontin, sTNFRII , and NGAL ) were higher in MPA than in GPA (all P &lt; 0.05). For nearly all cytokines, the difference between PR 3‐ AAV and MPO ‐ AAV was larger than that between GPA and MPA . The multivariate analysis showed that 8 cytokines ( IL ‐15, IL ‐8, IL ‐18 BP , NGF ‐β, sICAM ‐1, TARC , osteopontin, and kidney injury molecule 1 ( P &lt; 0.05) distinguished patients with AAV better (lower P values and larger effect sizes) when grouped by ANCA specificity than by clinical diagnosis. Conclusion Distinct cytokine profiles were identified for PR 3‐ AAV versus MPO ‐ AAV and for GPA versus MPA . Differences in these circulating immune mediators are more strongly associated with ANCA specificity than with clinical diagnosis, suggesting that heterogeneity in the AAV subtypes extends beyond clinical phenotypes.
Ectopic pancreas mimicking gastrointestinal stromal tumor in the stomach fundus
Authors: Cătălina Diaconu, Mihai Ciocîrlan, Mariana Jinga, Raluca Costache, Gabriel Constantinescu, Mădălina Ilie, Mircea Diculescu
Journal: Endoscopy (2018)

Ectopic or heterotopic pancreas refers to healthy pancreatic tissue that lacks anatomical, vascular or neural communication with the normal pancreas. However, heterotopic pancreas is seldom considered as a diagnostic hypothesis when symptomatic or when located outside of the gastric antral wall [1]. This case report describes the clinical and paraclinical features of pancreatic heterotopia in the gastric fundus in a previously healthy 25-year-old woman.
Development and validation of a Hospital Frailty Risk Score focusing on older people in acute care settings using electronic hospital records: an observational study
Authors: Thomas Gilbert, Jenny Neuburger, Joshua Kraindler, Eilis Keeble, Paul Smith, Cono Ariti, Sandeepa Arora, Andrew Street, Stuart Parker, Helen C Roberts, Martin Bardsley, Simon Conroy
Journal: The Lancet (2018)

BackgroundOlder people are increasing users of health care globally. We aimed to establish whether older people with characteristics of frailty and who are at risk of adverse health-care outcomes could be identified using routinely collected data.MethodsA three-step approach was used to develop and validate a Hospital Frailty Risk Score from International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnostic codes. First, we carried out a cluster analysis to identify a group of older people (≥75 years) admitted to hospital who had high resource use and diagnoses associated with frailty. Second, we created a Hospital Frailty Risk Score based on ICD-10 codes that characterised this group. Third, in separate cohorts, we tested how well the score predicted adverse outcomes and whether it identified similar groups as other frailty tools.FindingsIn the development cohort (n=22 139), older people with frailty diagnoses formed a distinct group and had higher non-elective hospital use (33·6 bed-days over 2 years compared with 23·0 bed-days for the group with the next highest number of bed-days). In the national validation cohort (n=1 013 590), compared with the 429 762 (42·4%) patients with the lowest risk scores, the 202 718 (20·0%) patients with the highest Hospital Frailty Risk Scores had increased odds of 30-day mortality (odds ratio 1·71, 95% CI 1·68–1·75), long hospital stay (6·03, 5·92–6·10), and 30-day readmission (1·48, 1·46–1·50). The c statistics (ie, model discrimination) between individuals for these three outcomes were 0·60, 0·68, and 0·56, respectively. The Hospital Frailty Risk Score showed fair overlap with dichotomised Fried and Rockwood scales (kappa scores 0·22, 95% CI 0·15–0·30 and 0·30, 0·22–0·38, respectively) and moderate agreement with the Rockwood Frailty Index (Pearson's correlation coefficient 0·41, 95% CI 0·38–0·47).InterpretationThe Hospital Frailty Risk Score provides hospitals and health systems with a low-cost, systematic way to screen for frailty and identify a group of patients who are at greater risk of adverse outcomes and for whom a frailty-attuned approach might be useful.FundingNational Institute for Health Research.
Relapse of autoimmune hepatitis is associated with a low intrahepatic ratio of regulatory T cells to cytotoxic T cells prior to immunosuppression withdrawal
Authors: F. Derben, J. Hartl, J. Schlue, A. Lohse, M.P. Manns, C. Schramm, E. Jaeckel, R. Taubert
Journal: Journal of Hepatology (2018)
Daratumumab, lenalidomide, and dexamethasone in East Asian patients with relapsed or refractory multiple myeloma: subgroup analyses of the phase 3 POLLUX study
Authors: Kenshi Suzuki, Meletios A. Dimopoulos, Naoki Takezako, Shinichiro Okamoto, Atsushi Shinagawa, Morio Matsumoto, Hiroshi Kosugi, Sung-Soo Yoon, Shang-Yi Huang, Xiang Qin, Ming Qi, Shinsuke Iida
Journal: Blood Cancer Journal (2018)

In the phase 3 POLLUX study, daratumumab plus lenalidomide and dexamethasone (DRd) significantly reduced the risk of progression/death and induced deeper responses vs. lenalidomide and dexamethasone alone (Rd) in patients with relapsed/refractory multiple myeloma (RRMM). We report a subgroup analysis of East Asian (Japanese, Korean, and Taiwanese) patients from POLLUX based on a longer follow-up of 24.7 months. Median progression-free survival was not reached (NR) for DRd vs. 13.8 months for Rd (hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.23-0.76), and overall response rates were higher for DRd vs. Rd (90.2 vs. 72.1%). DRd extended the median duration of response vs. Rd (NR vs. 20.2 months), and minimal residual disease-negative rates at the 10-5 sensitivity threshold were 21.2 vs. 9.1% for DRd vs. Rd. No new safety signals were observed. Similar efficacy and safety were observed in the smaller subgroup of Japanese patients treated with DRd vs. Rd. These results demonstrate favorable efficacy and safety of DRd vs. Rd in East Asian patients and also in the Japanese-only patient subgroup that are consistent with findings in the overall patient population of POLLUX.
Pharmacological treatment of COPD: the devil is always in the detail
Authors: Dave Singh, Peter J. Barnes, Robert Stockley, Maria Victorina Lopez Valera, Claus Vogelmeier, Alvar Agusti
Journal: European Respiratory Journal (2018)

Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition with considerable pathophysiological and clinical variability across patients [1]. For this reason, the current Global Initiative for the Management of Chronic Obstructive Lung Disease (GOLD) report recommends an individualised treatment approach for patients with a diagnosis of COPD that has been established by appropriate clinical and spirometric criteria [2]. This approach is based on symptom severity and exacerbation history (which predicts future exacerbation risk) [2], and categorises patients into four "phenotypic" groups (A, B, C or D) [2, 3]. Each group has distinct pharmacological treatment algorithms where the clinical response to treatment (improvement, no change or deterioration) is used to escalate, de-escalate or switch treatment. It is straightforward in treatment-naïve individuals seen at initial presentation by healthcare workers but it may become more complex and cumbersome during follow-up . GOLD ABCD should be used for initial assessment and treatment, but follow-up treatment should focus on treatable traits <http://ow.ly/Vm5l30iXYYU> While the authors are members of the GOLD science committee, this article is not part of the GOLD report. The views expressed here are the personal opinions of the authors.
211High glucose exposure promotes epigenetic activation of pro-inflammatory RELA/p65 gene in cord blood-derived CD34+ stem cells
Authors: V Vigorelli, J Resta, G Pompilio, M C Vinci
Journal: Cardiovascular Research (2018)

Introduction:The changing landscape of chromatin activity is a crucial factor in transcriptional gene regulation.It is an important hallmark of diseases, however it has not yet been investigated systematically in human remodelled myocardium.Purpose: To address this gap of knowledge, we aim to reveal genome-wide chromatin activity based on myocardial samples from patients either with acquired myocardial remodelling due to severe aortic stenosis (AS) or inherited myocardial remodelling in patients with hypertrophic cardiomyopathy (HCM) due to mutated MYBPC3 gene; and donors without myocardial remodelling.Methods: Myocardial samples from 20 AS patients, 14 HCM patients and 5 healthy controls were included.We performed chromatin immunoprecipitation followed by sequencing using H3K27ac histon mark to identify differentially acetylated regions among three groups on a genome-wide scale.Comprehensive in silico analyses were performed, including (1) gene and pathway annotation of the whole dataset, (2) identification of transcription factor binding motifs and interacting genes, (3) identification of acquired-and inherited-specific H3K27ac signatures in remodelled myocardium.Results: In total, 5,634 regions with more activity (hyperacetylated) and 5,724 regions with less activity (hypoacetylated) were detected in acquired myocardial remodelling group compared to controls (FDR<0.05); while 7,216 hyperacetylated regions and 7,214 hypoacetylated regions were detected in inherited myocardial remodelling group compared to controls.Pathway annotation showed that genes in the vicinity of differentially acetylated regions were most enriched for fibrosis formation and decreased cell metabolism.Conclusions: This study presents for the first time a genome wide overview of H3K27ac profile using human cardiac tissue to study chromatin regulatory regions in both acquired and inherited myocardial remodelling.It demonstrates that chromatin regulatory signatures can provide valuable new information and aid in discovery of key pathways and transcription mechanisms in disease aetiology. 211High glucose exposure promotes epigenetic activation of pro-inflammatory RELA/p65 gene in cord blood-derived CD341 stem cells
The effect of anti-acid therapy on survival in idiopathic pulmonary fibrosis: a methodological review of observational studies
Authors: Tanja Tran, Samy Suissa
Journal: European Respiratory Journal (2018)

International treatment guidelines for idiopathic pulmonary fibrosis (IPF) give a conditional recommendation for anti-acid therapy. As some observational studies reported discrepant findings on the effectiveness of anti-acid therapy on mortality in IPF, we reviewed all studies to evaluate whether immortal time bias explains these discrepancies. We searched the Embase and MEDLINE databases up to July 2017 for observational studies assessing the effectiveness of anti-acid therapy on mortality in IPF. Hazard ratios of mortality with anti-acid therapy were pooled across studies using random-effect models, stratified by the presence of immortal time bias. We identified 10 observational studies. Four of the five studies reporting beneficial effects of anti-acid therapy use on mortality were affected by immortal time bias (pooled hazard ratio 0.46; 95% CI 0.30–0.69), while it was unclear whether the fifth was affected. The five studies that avoided immortal time bias reported no effect of anti-acid therapy on mortality (pooled hazard ratio 0.99; 95% CI 0.81–1.22). The apparent beneficial effects of anti-acid therapy on mortality in patients with IPF result from observational studies affected by immortal time bias. Thus, the effectiveness of anti-acid therapy in IPF remains uncertain and needs to be reassessed with more accurate observational study methods and randomised trials.
Hepatitis C Virus eradication by direct antiviral agents improves carotid atherosclerosis in patients with advanced fibrosis/compensated cirrhosis
Authors: S. Petta, L.E. Adinolfi, A.L. Fracanzani, V. Calvaruso, F. Rini, C. Camma, V.D. Marco, M. Giordano, A. Marrone, R. Nevola, A. Pinto, L. Rinaldi, D. Torres, A. Tuttolomondo, L. Valenti, S. Fargion, A. Craxi
Journal: Journal of Hepatology (2018)
Latest clinical evidence and further development of PARP inhibitors in ovarian cancer
Authors: M.R. Mirza, S. Pignata, J.A. Ledermann
Journal: Annals of Oncology (2018)

For several decades, the systemic treatment of ovarian cancer has involved chemotherapy, with the relatively recent addition of antiangiogenic strategies given with chemotherapy and in the maintenance setting. In the past decade, numerous poly(ADP-ribose) polymerase (PARP)-inhibiting agents have been assessed. We review key trials that have led to the approval of three PARP inhibitors-olaparib, niraparib and rucaparib-as maintenance therapy for platinum-sensitive recurrent ovarian cancer. We discuss the efficacy and safety of these agents in the populations studied in clinical trials. We then provide an overview of the numerous avenues of ongoing research for PARP inhibitors in different treatment settings: as treatment rather than maintenance strategies and in combination with other anticancer approaches, including antiangiogenic and immunotherapeutic agents. Three phase III trials (NOVA, SOLO2 and ARIEL3) demonstrated remarkable improvement in progression-free survival (PFS) with PARP inhibitors given as maintenance therapy in patients with complete or partial response after platinum-based therapy for platinum-sensitive ovarian cancer. Differences in trial design and patient populations influence the conclusions that can be drawn from these trials. Overall survival data are pending and there is a limited experience regarding long-term safety. PARP inhibitors have transformed the management of ovarian cancer and have changed the course of disease for many patients. Although recent approvals are irrespective of BRCA mutation or homologous repair deficiency status, genetic profiles, as well as dosing schedules, tolerability and affordability, may influence patient selection and the setting in which PARP inhibitors are used. The development and evolution of PARP inhibitors continue, with new agents, strategies, combinations and indications under intensive evaluation.
Efficacy, safety and clinical outcomes of Paritaprevir/Ombitasvir/r + Dasabuvir 8 weeks: results from a Spanish real world cohort (Hepa-C)
Authors: M. Puigvehí, B.D. Cuenca, D. Giménez, F. Gea, M. Diago, S. Lens, E. Badia-Aranda, J. Turnés, A.O. Martin, J. Salmerón, J.M. Pascasio, J.L.C. Urda, J.L.C. Panero, J. Cabezas, X. Torras, E. Molina, J.M. Moreno, J. Sánchez-Ruano, J. De la Vega, S. Montoliu, P. Cordero, J.J. Moreno, J.A. Carrión
Journal: Journal of Hepatology (2018)
Characterization of changes in lipoprotein profiles of patients with nonalcoholic steatohepatitis treated with the acetyl-CoA carboxylase inhibitor GS-0976
Authors: P. Mantry, Z. Kayali, M. Noureddin, P. Ruane, B. Mccolgan, J. Tarrant, L. Wang, T. Nguyen, E. Harting, S. Djedjos, A. Ray, R. Myers, M. Lai, M. Charlton, E. Lawitz, S. Harrison, R. Loomba
Journal: Journal of Hepatology (2018)