tbuckley/cabot-search huggingface dataset:
AB0156 Thymic stromal lymphopoietin (TSLP) in primary sjÖgren's syndrome and related lymphoma: the possible contribution of a novel growth factor
Authors: S Gandolfo, C Fabro, M Bulfoni, S Russi, P Masolini, L Quartuccio, D Cesselli, S De Vita
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Primary Sjögren9s syndrome (pSS) is an autoimmune lymphoproliferative systemic disease with a higher risk of non-Hodgkin B cell lymphoma (NHL) evolution. In SS, salivary gland (SG) epithelium plays a crucial role in initiating and perpetuating the autoimmune response. Thymic stromal lymphopoietin (TSLP) is both an epithelial and lymphopoietic cytokine involved in the maintenance of immune tolerance at interfaces between body and environment and in the regulation of lymphocytes homeostasis. <h3>Objectives</h3> To study TSLP in serum and SG biopsies of pSS patients stratified by the lymphoproliferative histopathologic status, from fully benign lesions (fbSS) to myoepithelial sialoadenitis (MESA) and to NHL, in order to evaluate a possible role of TSLP in SS pathogenesis and in lymphoma evolution. <h3>Methods</h3> Serum TSLP levels were determined by ELISA in pSS patients (n=30: 12 fbSS, 10 MESA, 8 NHL) and in controls (healthy blood donors - HD n=20; non-autoimmune sicca without SS - nSS n=10). TSLP was also studied by immunohistochemistry in SG biopsies of the same patients and nSS controls. Correlations with clinical and histopathologic parameters were performed. Of note, sequential samples were also included from three patients evolving from fbSS to NHL. <h3>Results</h3> TSLP serum levels were significantly higher in pSS compared to nSS (p=0.03) and HD (p=0.0002), with a progressive significant increase from fbSS to MESA (p=0.004) and finally to NHL (NHL vs fbSS p&lt;0.0001; NHL vs MESA p=0.003), where the increase was dramatic. This was observed also in metachronous samples from the three pSS patients evolving to NHL. A positive significant correlation between TSLP serum levels and disease activity assessed by ESSDAI was found (p&lt;0.0001). Of note, in the affected tissue, TSLP showed an opposite pattern of expression than in the serum. Concerning the salivary epithelium, a declining expression of TSLP was shown from fbSS (expression was similar to nSS) to MESA and finally to NHL. Strikingly, however, the three pSS patients evolving to lymphoma were the only ones showing a low TSLP epithelial expression also at baseline. Concerning the glandular lymphoid infiltrate, the TSLP expression again decreased with progression to NHL. Again, the three pSS patients evolving to lymphoma were the only ones showing a low TSLP inflammatory expression also at baseline. <h3>Conclusions</h3> Serum TSLP increases in pSS and correlates with lymphoma progression. Discrepancies are however observed between serum levels and tissue TSLP expression: while the baseline TSLP tissue expression is evident and similar to controls, tissue TSLP decreases with lymphoma progression. TSLP likely represents an additional growth factor and biomarker for pSS pathogenesis and lymphoproliferation. <h3>Disclosure of Interest</h3> None declared
BAG3 plays a central role in proteostasis in the heart
Authors: Wataru Mizushima, Junichi Sadoshima
Journal: Journal of Clinical Investigation (2017)

Proteinopathies are characterized by the accumulation of misfolded proteins, which ultimately interfere with normal cell function. While neurological diseases, such as Huntington disease and Alzheimer disease, are well-characterized proteinopathies, cardiac diseases have recently been associated with alterations in proteostasis. In this issue of the JCI, Fang and colleagues demonstrate that mice with cardiac-specific deficiency of the co-chaperone protein BCL2-associated athanogene 3 (BAG3) develop dilated cardiomyopathy that is associated with a destabilization of small HSPs as the result of a disrupted interaction between BAG3 and HSP70. Together, the results of this study suggest that strategies to upregulate BAG3 during cardiac dysfunction may be beneficial.
Targeted Nanotherapeutics Encapsulating Liver X Receptor Agonist GW3965 Enhance Antiatherogenic Effects without Adverse Effects on Hepatic Lipid Metabolism in <i>Ldlr<sup>−/−</sup></i> Mice
Authors: Mikyung Yu, Jaume Amengual, Arjun Menon, Nazila Kamaly, Felix Zhou, Xiaoding Xu, Phei Er Saw, Seung‐Joo Lee, Kevin Si, Carleena Angelica Ortega, Won Il Choi, In‐Hyun Lee, Yazan Bdour, Jinjun Shi, Morteza Mahmoudi, Sangyong Jon, Edward A. Fisher, Omid C. Farokhzad
Journal: Advanced Healthcare Materials (2017)

Abstract The pharmacological manipulation of liver X receptors (LXRs) has been an attractive therapeutic strategy for atherosclerosis treatment as they control reverse cholesterol transport and inflammatory response. This study presents the development and efficacy of nanoparticles (NPs) incorporating the synthetic LXR agonist GW3965 (GW) in targeting atherosclerotic lesions. Collagen IV (Col IV) targeting ligands are employed to functionalize the NPs to improve targeting to the atherosclerotic plaque, and formulation parameters such as the length of the polyethylene glycol (PEG) coating molecules are systematically optimized. In vitro studies indicate that the GW‐encapsulated NPs upregulate the LXR target genes and downregulate proinflammatory mediator in macrophages. The Col IV‐targeted NPs encapsulating GW (Col IV–GW–NPs) successfully reaches atherosclerotic lesions when administered for 5 weeks to mice with preexisting lesions, substantially reducing macrophage content (≈30%) compared to the PBS group, which is with greater efficacy versus nontargeting NPs encapsulating GW (GW–NPs) (≈18%). In addition, mice administered the Col IV–GW–NPs do not demonstrate increased hepatic lipid biosynthesis or hyperlipidemia during the treatment period, unlike mice injected with the free GW. These findings suggest a new form of LXR‐based therapeutics capable of enhanced delivery of the LXR agonist to atherosclerotic lesions without altering hepatic lipid metabolism.
Protein Coating of DNA Nanostructures for Enhanced Stability and Immunocompatibility
Authors: Henni Auvinen, Hongbo Zhang, None Nonappa, Alisa Kopilow, Elina H. Niemelä, Sami Nummelin, Alexandra Correia, Hélder A. Santos, Veikko Linko, Mauri A. Kostiainen
Journal: Advanced Healthcare Materials (2017)

Fully addressable DNA nanostructures, especially DNA origami, possess huge potential to serve as inherently biocompatible and versatile molecular platforms. However, their use as delivery vehicles in therapeutics is compromised by their low stability and poor transfection rates. This study shows that DNA origami can be coated by precisely defined one‐to‐one protein‐dendron conjugates to tackle the aforementioned issues. The dendron part of the conjugate serves as a cationic binding domain that attaches to the negatively charged DNA origami surface via electrostatic interactions. The protein is attached to dendron through cysteine‐maleimide bond, making the modular approach highly versatile. This work demonstrates the coating using two different proteins: bovine serum albumin (BSA) and class II hydrophobin (HFBI). The results reveal that BSA‐coating significantly improves the origami stability against endonucleases (DNase I) and enhances the transfection into human embryonic kidney (HEK293) cells. Importantly, it is observed that BSA‐coating attenuates the activation of immune response in mouse primary splenocytes. Serum albumin is the most abundant protein in the blood with a long circulation half‐life and has already found clinically approved applications in drug delivery. It is therefore envisioned that the proposed system can open up further opportunities to tune the properties of DNA nanostructures in biological environment, and enable their use in various delivery applications.
A new unsupervised clustering algorithm applied to genome-wide profiles of breast cancers in The Cancer Genome Atlas proper subsets triple-negative samples.
Authors: Jason Mezey, Steven Schwager, Sushila Shenoy, Jef Benbanaste, Michael Elashoff, Anuja Kelkar, Pramod Somashekar, David S. Lee
Journal: Journal of Clinical Oncology (2017)

e23195 Background: Clustering algorithms have identified subtypes of major cancers from analysis of genome-wide gene expression (GE) and somatic mutation (SM) profiles. These algorithms almost never discover a proper subset cluster, a recovered cluster that includes all the samples of a specific subtype. For breast cancer (BC), clustering of genome-wide profiles has been unable to proper subset triple negatives (TNs), TN subtypes, or other major subtypes. Methods: To search for a proper subset cluster for TNs, we applied a new clustering algorithm to the public domain GE and SM data of BC samples in The Cancer Genome Atlas (TCGA). A module of Medidata’s Clinical Trial Genomics (CTG) platform for automated clinical and genomic data integration and analysis, it uses a hierarchical component with tree learned cut points applied to a principal component dimension reduced similarity matrix calculated from a genome-wide data profile. Results: Our analysis of 540 TCGA BC samples run without human supervision produced a proper subset cluster that included all 55 TN samples and only 74 non-TN samples. GE data have previously indicated TN status, but this is the first demonstration that these TCGA BC data contain enough information to proper subset TNs, implying that this broad BC subtype has a strong, quantifiable impact on GE. We show that the genome-wide SMs of TCGA BC samples can be used to proper subset 4 novel subtypes distinguished as classes “TP53 mutated”, “PIK3CA mutated”, “both TP53 and PIK3CA mutated”, and “neither mutated”, signifying an important role for these known driver mutations in producing the subtypes’ genome-wide mutation profiles. We find that most ( &gt; 80%) TN BCs are in “TP53 mutated” but only 1 TN sample ( &lt; 2%) is in “PIK3CA mutated”, indicating distinct biology for these TNs with potential implications for TN therapy. Conclusions: CTG clustering achieves proper subset cancer subtype clustering of TCGA BC samples. These results illustrate the therapeutic discovery potential possible from genomic data of the high quality present in TCGA if combined with detailed clinical data with the Medidata CTG integration and annotation platform.
AB1193 Developing the korean educational needs assessment tool (KOREAN-ENAT) in rheumatoid arthritis: a cross-cultural validation using rasch analysis
Authors: Y-K Sung, D Kim, SJ Cha, D Yoo, S-H Kim, M Ndosi, S-K Cho
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> The Educational Needs Assessment Tool (ENAT) is a 39-item patient-completed questionnaire designed to help patients identify and prioritize their educational needs. It was originally developed in the UK and validated in 7 rheumatic diseases including rheumatoid arthritis (RA).<sup>1</sup> <h3>Objectives</h3> This study aimed to undertake cross-cultural adaptation and validation of the ENAT in RA for use in Korea. <h3>Methods</h3> The study involved two main phases: (1) Cross-cultural adaptation of the ENAT from English into Korean and (2) validation of the Korean-ENAT. The first phase followed an established process of cross-cultural adaptation of self-report measures.<sup>2</sup> For the second phase, patients with RA completed the Korean-ENAT at the outpatient clinic of a university hospital and Rasch measurement computer program, WINSTEPS, was used to analyze the data. Fit to the model was determined by the observed data Infit and Outfit statistics (≥0.50 and ≤1.50); where a value of 1.00 suggests a perfect fit to the model expectations. The unidimensionality of the scale was determined by item (and person) separation index ≥2.00 and reliability ≥0.80. <h3>Results</h3> An adequate conceptual equivalence was achieved following the adaptation process. A total of 123 patients completed the Korean-ENAT. Their mean ± SD age was 46.7±12.3, disease duration 53.7±71.2 months and the majority (81.3%) were female. Thirty-five of the 39 items displayed good fit to the model. The 4 items deviating from the model had Infit and Outfit &gt;1.50. The item separation index (5.26) and item reliability index (0.97) provided evidence for good reliability of items. All the 7 domains of the Korean-ENAT were found to fit the Rasch model. The internal consistency of the Korean-ENAT was high and unidimensionality was confirmed (Person separation index =3.41 reliability index =0.92; item separation index =16.82 and reliability index =1.00). <h3>Conclusions</h3> Using a standard process in cross-cultural adaptation, the ENAT was adapted into Korean and Rasch analysis confirmed that the construct validity, reliability, and unidimensionality of the Korean-ENAT. The Korean-ENAT provides valid and reliable estimates of educational needs of people with RA in Korea. <h3>References</h3> Ndosi M, et al. Validation of the educational needs assessment tool as a generic instrument for rheumatic diseases in seven European countries. Ann Rheum Dis 2014; 73: 2122–9. Beaton DE, et al. Guidelines for the process of cross-cultural adaptation of self-report measures. Spine 2000; 25: 3186–91. <h3>Disclosure of Interest</h3> None declared
Use of everolimus in advanced hormone receptor–positive metastatic breast cancer in a multicenter national observational study.
Authors: Paul H. Cottu, Audrey Lardy-Cleaud, Sophie Frank, Olivia Le Saux, Sylvie Chabaud, Damien Parent, Barbara Pistilli, Marc Debled, Audrey Mailliez, Corinne Veyret, Thierry Petit, Lionel Uwer, Severine Guiu Lahaye, Emmanuel Chamorey, Mony Ung, Patrick Arveux, Tahar Guesmia, Paule Augereau, Gaetane Simon, Thomas Denis Bachelot
Journal: Journal of Clinical Oncology (2017)

e12548 Background: The everolimus-exemestane combination has been included in the International guidelines for advanced HR+ breast cancer (mBC) since the results of the Bolero-2 trial. Marketing authorization has been granted in France in July 2012 and reimbursement in Nov. 2014. Very few real life data of everolimus (EVE) use have been reported. Methods: All patients who initiated treatment for a newly diagnosed mBC between Jan. 2008 and Dec. 2015 in all 18 French Comprehensive Cancer Centers have been included in the real life ESME database, which collects retrospective data using a clinical trial-like methodology with quality assessments. Primary endpoint of the current analysis was to evaluate the incidence and indication of EVE use before and after marketing authorization and reimbursement Results: The ESME program included a total of 16,703 patients of which 9,921 had HR+/HER2- mBC. Median age at metastatic diagnosis was 62.0 year (range 23-96). Visceral metastases were present in 60.3% of cases. Only 4123 patients (41.6%) received endocrine therapy alone as first-line therapy, and 60% were deemed endocrine resistant Overall, 1,217 (12.3%) pts have received EVE during therapy as of Dec. 2015 (all lines). EVE was given as first line therapy in 117 pts (10% of all EVE pts and 1.2% of pts receiving a first line therapy). In 99/117 pts (85%) EVE was combined with exemestane. Before 2012, EVE was barely used and mostly within clinical trials. After 2012, use of EVE increased steadily (table). Percentages refer to the total of pts who received any kind of treatment during a given year of observation (e.g., 506/4435 pts took EVE in 2015). Median duration of EVE use was 6.0 months (0-65) as first line treatment and 3.9 months (0-65) in pretreated patients. Main causes of EVE cessation were recorded and will be detailed at the meeting. Conclusions: In this very large French national and representative cohort of HR+ HER2- mBC, EVE use rose quickly as soon as marketed. EVE was mostly used in pretreated mBC albeit in probably too advanced pts. These data underline the need for physician and patient education for oral therapies. [Table: see text]
Lymphocytes transiently expressing virus-specific T cell receptors reduce hepatitis B virus infection
Authors: Janine Kah, Sarene Koh, Tassilo Volz, Erica Ceccarello, Lena Allweiss, Marc Lütgehetmann, Antonio Bertoletti, Maura Dandri
Journal: Journal of Clinical Investigation (2017)

Adoptive transfer of T cells engineered to express a hepatitis B virus-specific (HBV-specific) T cell receptor (TCR) may supplement HBV-specific immune responses in chronic HBV patients and facilitate HBV control. However, the risk of triggering unrestrained proliferation of permanently engineered T cells raises safety concerns that have hampered testing of this approach in patients. The aim of the present study was to generate T cells that transiently express HBV-specific TCRs using mRNA electroporation and to assess their antiviral and pathogenetic activity in vitro and in HBV-infected human liver chimeric mice. We assessed virological and gene-expression changes using quantitative reverse-transcriptase PCR (qRT-PCR), immunofluorescence, and Luminex technology. HBV-specific T cells lysed HBV-producing hepatoma cells in vitro. In vivo, 3 injections of HBV-specific T cells caused progressive viremia reduction within 12 days of treatment in animals reconstituted with haplotype-matched hepatocytes, whereas viremia remained stable in mice receiving irrelevant T cells redirected toward hepatitis C virus-specific TCRs. Notably, increases in alanine aminotransferase levels, apoptotic markers, and human inflammatory cytokines returned to pretreatment levels within 9 days after the last injection. T cell transfer did not trigger inflammation in uninfected mice. These data support the feasibility of using mRNA electroporation to engineer HBV TCR-redirected T cells in patients with chronic HBV infection.
Duration of maintenance therapy for ANCA-associated vasculitis: more questions than answers
Authors: Pavel I Novikov, Ilya Smitienko, Sergey V Moiseev
Journal: Annals of the Rheumatic Diseases (2017)

Over the last decades, numerous randomised clinical trials and long-term observational studies were conducted in dozens or hundreds patients with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV) and provided a basis for an evidence-based treatment. With immunosuppressive therapy, up to 85%–90% of patients will achieve remission, though the disease can follow a relapsing course in a significant proportion of patients, and prolonged exposure to glucocorticoids and immunosuppressive agents may have devastating consequences. However, the attempts to shorten maintenance therapy can lead to recurrent exacerbations of AAV and an accumulation of irreversible organ damage.

In the recent randomised, prospective REMAIN (prolonged REmission-MAINtenance therapy in systemic vasculitis) study, conducted in 117 patients with AAV in stable remission after cyclophosphamide/prednisolone-based induction, Karras et al showed that prolonged maintenance therapy with azathioprine/prednisolone (up to 48 months from diagnosis) was relatively safe and more effective than withdrawal of azathioprine/prednisolone by 24 months1. Extension of immunosuppression was associated with a significantly lower risk both of any and major relapses (22% vs 63%, p<0.0001, and 14% vs 35%, p<0.007, respectively) and resulted in a better renal survival. Notably, almost all patients completed the prolonged follow-up. The results of the REMAIN study were satisfying to us since prolonged immunosuppression with low dose cyclophosphamide and currently azathioprine or metothrexate in combination with corticosteroids for many years remains a preferred treatment option for patients with AAV in our clinic.

However, there is the other side of the coin. A paradigm for treating patients with AAV has changed significantly over recent years. Currently, it is apparent that …
Pediatric Infectious Diseases
Journal: JAMA (1998)

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Tumor kinetic modeling and identification of predictive factors for tumor response to durvalumab in patients with non-small cell lung cancer (NSCLC).
Authors: Yanan Zheng, Rajesh Narwal, Chaoyu Jin, Bing Wang, Xiaoping Jin, Pralay Mukhopadhyay, Brandon W. Higgs, Ashok Kumar Gupta, Phillip A. Dennis, Lorin Roskos
Journal: Journal of Clinical Oncology (2017)

11555 Background: Durvalumab is a human monoclonal antibody that binds to PD-L1 and blocks its interaction with PD-1 and CD80. The primary objectives of this analysis were to describe the longitudinal tumor size profiles and identify the key factors predicting tumor growth and regression following durvalumab. Methods: Longitudinal tumor size data obtained from NSCLC patients in study 1108 (all lines of therapy) and ATLANTIC (third line and beyond) following durvalumab treatment were modeled using nonlinear mixed effect modeling. Tumor kinetics were described by four key parameters: tumor growth and killing rate constants, fraction of durvalumab-sensitive tumor cells, and delay time for tumor killing. Potential predictive factors for tumor growth and regression were evaluated in a multi-variable covariate analysis. The model was used to simulate response rates at different tumor PD-L1 expression cutoffs. Results: Tumor kinetic modeling accurately described the longitudinal tumor response profiles from NSCLC patients in both studies. The factors associated with more rapid tumor growth were liver metastases, ECOG score &gt; 0, high neutrophil-to-lymphocyte ratio and EGFR/ALK mutation. Tumor cell PD-L1 expression, baseline tumor size and smoking history were identified as significant predictive factors for tumor killing or the fraction of sensitive tumor cells. Simulations using the tumor kinetic model showed increased response rates in patients with higher tumor cell PD-L1 expression (increased by 9-11% and 10-14% with 25% and 50% cutoff, respectively), patients receiving durvalumab as first-line therapy (increased by 12% vs. 2 nd line/above), and patients with smoking histories (increased by 4-5% vs. non-smokers). Conclusions: Tumor kinetic modeling identified factors that predict tumor progression and response following durvalumab in NSCLC patients. The multivariate analysis accounts for various predictive factors within predictive biomarker strata, allowing better interpretation of different biomarker cutoffs. The modeling technique can potentially guide patient selection/enrichment, clinical trial design strategies and tumor biology. Clinical trial information: NCT02087423 and NCT01693562.