tbuckley/cabot-search huggingface dataset:
Annealing novel nucleobase-lipids with oligonucleotides or plasmid DNA based on H-bonding or π-π interaction: Assemblies and transfections
Authors: Yuan Ma, Yuejie Zhu, Chao Wang, Delin Pan, Shuang Liu, Mengyi Yang, Zhangping Xiao, Xiantao Yang, Wenting Zhao, Xinyang Zhou, Yiding Li, Yufei Pan, Jing Sun, Shuhe Wang, Zhu Guan, Lihe Zhang, Zhenjun Yang
Journal: Biomaterials (2018)

Lipid derivatives of nucleoside analogs have been highlighted for their potential for effective gene delivery. A novel class of nucleobase-lipids are rationally designed and readily synthesized, comprising thymine/cytosine, an ester/amide linker and an oleyl lipid. The diversity of four nucleobase-lipids termed DXBAs (DOTA, DNTA, DOCA and DNCA) is investigated. Besides, DNCA is demonstrated to be an effective neutral transfection material for nucleic acid delivery, which enbles to bind to oligonucleotides via H-bonding and π-π stacking with reduced toxicity in vitro and in vivo. Several kinds of nucleic acid drugs including aptamer, ssRNA, antisense oligonucleotide, and plasmid DNAs can be delivered by DXBAs, especially DNCA. In particular, G4-aptamer AS1411 encapsulated by DNCA exhibits cellular uptake enhancement, lysosome degradation reduction, cell apoptosis promotion, cell cycle phase alteration in vitro and duration prolongation in vivo, resulting in significant anti-proliferative activity. Our results demonstrate that DNCA is a promising transfection agent for G4-aptamers and exhibites bright application prospects in the permeation improvement of single-stranded oligonucleotides or plasmid DNAs.
Reducing Calories to Lose Weight
Authors: Kevin D. Hall, Dale A. Schoeller, Andrew W. Brown
Journal: JAMA (2018)

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Pembrolizumab for Patients With Refractory or Relapsed Thymic Epithelial Tumor: An Open-Label Phase II Trial
Authors: Jinhyun Cho, Hae Su Kim, Bo Mi Ku, Yoon-La Choi, Razvan Cristescu, Joungho Han, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn
Journal: Journal of Clinical Oncology (2018)

Limited treatment options exist for patients with thymic epithelial tumor (TET) whose disease progresses after platinum-based chemotherapy. We conducted a phase II study of pembrolizumab in patients with TET to evaluate its efficacy and safety.Patients with histologically confirmed TET whose disease progressed after at least one line of platinum-based chemotherapy were eligible for the study. Patients were excluded if they had an active autoimmune disease requiring systemic treatment within the past year or documented history of clinically severe autoimmune disease. Patients received 200 mg of pembrolizumab intravenously every 3 weeks until tumor progression or unacceptable toxicity. The primary objective of response rate was assessed every 9 weeks by investigators.Of 33 patients enrolled, 26 had thymic carcinoma and seven had thymoma. Of seven thymoma, two (28.6%; 95% CI, 8.2% to 64.1%) had partial response, and five (71.6%) had stable disease. Of 26 thymic carcinoma, five (19.2%; 95% CI, 8.5% to 37.9%) had partial response and 14 (53.8%) had stable disease. The median progression-free survival was 6.1 months for both groups. The most common adverse events of any grade included dyspnea (11; 33.3%), chest wall pain (10; 30.3%), anorexia (seven; 21.2%), and fatigue (seven; 21.2%). Five (71.4%) of seven patients with thymoma and four (15.4%) of 26 patients with thymic carcinoma reported grade ≥ 3 immune-related adverse events, including hepatitis (four; 12.1%), myocarditis (three; 9.1%), myasthenia gravis (two; 6.1%), thyroiditis (one; 3.0%), antineutrophil cytoplasmic antibody-associated rapidly progressive glomerulonephritis (one; 3.0%), colitis (one; 3.0%), and subacute myoclonus (one; 3.0%).Pembrolizumab showed encouraging antitumor activity in patients with advanced TET. Given the high incidence of autoimmunity, additional studies are needed to identify those who can benefit from pembrolizumab without immune-related adverse events.
Ambulatory Medication Reconciliation and Frequency of Hospitalizations and Emergency Department Visits in Patients With Diabetes
Authors: Alexander Turchin, Olukayode Sosina, Huabing Zhang, Maria Shubina, Sonali P. Desai, Donald C. Simonson, Marcia A. Testa
Journal: Diabetes Care (2018)

OBJECTIVE To investigate the association between ambulatory medication reconciliation and health care utilization in patients with diabetes. RESEARCH DESIGN AND METHODS In this retrospective cohort analysis, we studied adults taking at least one diabetes medication treated in primary care practices affiliated with two academic medical centers between 2000 and 2014. We assessed the relationship between the fraction of outpatient diabetes medications reconciled over a 6-month period and the composite primary outcome of combined frequency of emergency department (ED) visits and hospitalizations over the subsequent 6 months. RESULTS Among 261,765 reconciliation assessment periods contributed by 31,689 patients, 176,274 (67.3%), 27,775 (10.6%), and 57,716 (22.1%) had all, some, or none of the diabetes medications reconciled, respectively. Patients with all, some, or no diabetes medications reconciled had 0.354, 0.377, and 0.384 primary outcome events per 6 months, respectively (P &amp;lt; 0.0001). In a multivariable analysis adjusted for demographics and comorbidities, having some or all versus no diabetes medications reconciled was associated with a lower risk of the primary outcome (rate ratio 0.94 [95% CI 0.90–0.98; P = 0.0046] vs. 0.92 [0.89–0.95; P &amp;lt; 0.0001], respectively). Introduction of feedback to individual providers was associated with a significant increase in the odds of all diabetes medications being reconciled (2.634 [2.524–2.749]; P &amp;lt; 0.0001). CONCLUSIONS A higher fraction of reconciled outpatient diabetes medications was associated with a lower frequency of ED visits and hospitalizations. Individual performance feedback could help to achieve more comprehensive medication reconciliation.
Integrated DNA/RNA targeted genomic profiling of diffuse large B-cell lymphoma using a clinical assay
Authors: Andrew M. Intlekofer, Erel Joffe, Connie L. Batlevi, Patrick Hilden, Jie He, Venkatraman E. Seshan, Andrew D. Zelenetz, M. Lia Palomba, Craig H. Moskowitz, Carol Portlock, David J. Straus, Ariela Noy, Steven M. Horwitz, John F. Gerecitano, Alison Moskowitz, Paul Hamlin, Matthew J Matasar, Anita Kumar, Marcel R. van den Brink, Kristina M. Knapp, Janine D. Pichardo, Michelle K. Nahas, Sally E. Trabucco, Tariq Mughal, Amanda R. Copeland, Elli Papaemmanuil, Mathai Moarii, Ross L. Levine, Ahmet Dogan, Vincent A. Miller, Anas Younes
Journal: Blood Cancer Journal (2018)

Abstract We sought to define the genomic landscape of diffuse large B-cell lymphoma (DLBCL) by using formalin-fixed paraffin-embedded (FFPE) biopsy specimens. We used targeted sequencing of genes altered in hematologic malignancies, including DNA coding sequence for 405 genes, noncoding sequence for 31 genes, and RNA coding sequence for 265 genes (FoundationOne-Heme). Short variants, rearrangements, and copy number alterations were determined. We studied 198 samples (114 de novo, 58 previously treated, and 26 large-cell transformation from follicular lymphoma). Median number of GAs per case was 6, with 97% of patients harboring at least one alteration. Recurrent GAs were detected in genes with established roles in DLBCL pathogenesis (e.g. MYD88 , CREBBP , CD79B , EZH2 ), as well as notable differences compared to prior studies such as inactivating mutations in TET2 (5%). Less common GAs identified potential targets for approved or investigational therapies, including BRAF , CD274 (PD-L1), IDH2 , and JAK1/2 . TP53 mutations were more frequently observed in relapsed/refractory DLBCL, and predicted for lack of response to first-line chemotherapy, identifying a subset of patients that could be prioritized for novel therapies. Overall, 90% ( n = 169) of the patients harbored a GA which could be explored for therapeutic intervention, with 54% ( n = 107) harboring more than one putative target.
AB0149 Decreased microrna-130a expression drives activation of classical dendritic cells from patients with primary sjögren’s syndrome
Authors: A.P. Lopes, J.A. van Roon, S.L. Blokland, M. Wang, E. Chouri, A.A. Kruize, B.M. Burgering, M. Rossato, T.R. Radstake, M.R. Hillen
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease characterized by lymphocytic infiltration of the exocrine glands and dryness of mouth and eyes. Classical dendritic cells are very potent antigen presenting cells known to induce strong T-cell proliferation and cytokine production. <h3>Objectives</h3> Considering the critical role of microRNAs (miRNAs) in regulation of gene expression, we investigated miRNA expression in circulating CD1c<sup>+</sup> dendritic cells (cDCs) of patients with pSS. <h3>Methods</h3> Two independent cohorts consisting of pSS patients and healthy controls were established: a discovery cohort (15 pSS, 6 HC) was used to screen the expression of a large panel of 758 miRNAs. An independent validation cohort (14 pSS, 11 HC) was used to test the reproducibility of the results. cDCs were isolated from peripheral blood using MACS and miRNA profiling of 758 targets was performed using the OpenArray platform in the discovery cohort. A selection of 16 differentially expressed miRNAs was measured in the validation cohort using a custom-made array. Isolated cDCs from HC were stimulated with a panel of Toll-like receptor (TLR) ligands and the expression of miR-130a and miR-708 was measured by qPCR. The effect of transfection with miR-130a on protein synthesis was analysed by using the pulsed stable isotope labelling by amino acids in cell culture (pSILAC) method (quantitative mass spectrometry-based technique) in a HEK-293T cell-line. <h3>Results</h3> A total of 24 miRNAs was downregulated in pSS patients versus HC in the discovery cohort (p&lt;0.05, with a difference between the groups of &gt;log2). Of the 16 miRNAs that were selected for replication, the decreased expression of miR-130a and miR-708 in pSS was validated. Activation of cDCs via TLR3 and TLR7/8 induced downregulation of both miRNA-130a and miRNA-708. Transfection with a miR-130a mimic resulted in downregulation of several proteins with a seed match for the miRNA. These proteins are known to be involved in membrane trafficking and cell activation trough CREB/NF-kB signalling. <h3>Conclusions</h3> miR-130a and miR-708 are significantly downregulated in cDCs of patients with pSS. We show that the expression of these miRNAs is decreased upon cDC activation and that upregulation of miR-130a decreases the expression of proteins involved in the CREB/NF-kB pathway. As such, these miRNAs seem to be involved in cDC activation and reflect enhanced activation of circulating cDCs from pSS patients. <h3>Disclosure of Interest</h3> None declared
AB1039 Diet may play essential role for the success of the urate lowering therapy in gout
Authors: N.B. Kalkan, M.E. Tezcan
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Chronic deposition of monosodium urate crystals, in case of hyperuricemia, is the main cause of the gout.<sup>1</sup> Furthermore, lowering uric acid to the targeted levels is the main therapeutic objective in chronic gout treatment. Uric acid lowering treatment (ULT) has three main arms: Practicing lifestyle modifications, pharmacologic ULT and targeting co-morbid illnesses.<sup>2</sup> Thus, patients' medical and therapeutic properties may have a role in successful ULT. <h3>Objectives</h3> We evaluated the demographic and therapeutic properties; co-illnesses and disease features of the patients that would relate with the success of ULT. Then, we compared these parameters between the gout patients with successful ULT and inadequate ULT. <h3>Methods</h3> 66 gout patients on pharmacologic ULT were enrolled to the study. Non-adherence to pharmacologic ULT was accepted an exclusion criteria. Demographic and therapeutic features; co-illnesses and disease features of the patients were obtained during the study. Then, we compared these parameters between the patients with successful ULT and inadequate ULT. <h3>Results</h3> Adherence to diet was found different between groups (OR, 7.00; CL%95 2.27–21.56). All other features including maximum allopurinol dosage were similar. Only one patient from sucessful ULT group and none of the patients in inadequate group had an drinking habit. <h3>Conclusions</h3> We found that diet was the only factor that relate with success of ULT while patients were on pharmacologic ULT. So, clinicians should emphasise the importance of all part of ULT including diet with informing patients about the nature of disease and benefits of ULT during visits. <h3>References</h3> [1] Dalbeth N, Merriman TR, Stamp LK. Gout. Lancet2016; 388: 2039–52. [2] Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh MK, Neogi T, et al. 2012American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken)2012; 64: 1431–46. <h3>Acknowledgements</h3> None <h3>Disclosure of Interest</h3> None declared
Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial
Authors: Katherine R Tuttle, Mark C Lakshmanan, Brian Rayner, Robert S Busch, Alan G Zimmermann, D Bradley Woodward, Fady T Botros
Journal: The Lancet Diabetes & Endocrinology (2018)
OP0152 Is sonographic phenotype of late-onset rheumatoid arthritis different from young-onset rheumatoid arthritis? results from the birmingham early arthritis cohort
Authors: R Singh, I. Sahbudin, M. Maybury, K. Raza, A. Filer
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> The incidence of rheumatoid arthritis (RA) is generally seen as a bimodal age distribution, which consists of young-onset RA (YORA) and late-onset RA (LORA). Although a retrospective study has reported some differences in sonographic changes between LORA and YORA, little is known whether there are any differences in the clinical and sonographic phenotypes between these two groups during the early disease phases. <h3>Objectives</h3> To compare the clinical and sonographic characteristics between YORA and LORA during the early phases of disease. <h3>Methods</h3> DMARD–naïve patients with clinically apparent synovitis of at least one joint and symptom duration of three months or less were included in the analysis. Patients underwent clinical, ultrasonography and radiological assessments at baseline and final outcomes were determined at 18 months; patients were classified as having RA (according to either the 1987 ACR and/or 2010 ACR/EULAR criteria), a non-RA persistent arthritis or a resolving arthritis. Sonographic assessment included MCP, PIP, wrist, MTP, knee, ankle, elbow joints and wrist, hand flexor, bicep tendon, anteromedial-lateral tendon compartments. The presence and absence of joint synovitis and tenosynovitis were recorded according to the EULAR/OMERACT consensus definition. <h3>Results</h3> 150 patients were included in the analysis. At 18 months, 37 patients developed YORA, 36 developed LORA, 27 developed non-RA inflammatory arthritis and 50 patients had resolving arthritis. The clinical characteristics between YORA and LORA were not significantly different at initial presentation (table 1). The ultrasound characteristics differed between these two groups. LORA patients were more likely to have shoulder biceps tendon tenosynovitis (GS; p=0.026, PD; 0.037), elbow joint synovitis (GS; p=0.010, PD; p=0.037), MCP1 (PD; p=0.032) and MCP5 (GS; p=0.035) synovitis, compared to YORA patient. YORA patients were more likely to have MTP synovitis (GS; p=0.013) compared to LORA patients. <h3>Conclusions</h3> This is the first study to describe the difference of both clinical and sonographic inflammation of YORA and LORA in recent-onset DMARD-naïve RA patients in a longitudinal study. There are differences in US-detected joint and tendon inflammation despite similarities in clinical characteristics. The prognostic value of the differences in US pathology between these two groups should be further explored. <h3>Disclosure of Interest</h3> None declared
Early Versus Delayed Initiation of Salvage Androgen Deprivation Therapy and Risk of Prostate Cancer–Specific Mortality
Authors: Brandon A. Mahal, Ming-Hui Chen, Andrew A. Renshaw, Marian J. Loffredo, Philip W. Kantoff, Anthony V. D'Amico
Journal: Journal of the National Comprehensive Cancer Network (2018)

Background: This study sought to ascertain whether there is an association between prostate cancer (PC)–specific mortality (PCSM) and timing of salvage androgen deprivation therapy (ADT) among men with short versus long prostate-specific antigen doubling times (PSA-DTs). Methods: The study cohort was selected from 206 men with localized unfavorable-risk PC randomized to radiation therapy (RT) or RT plus 6 months of ADT between 1995 and 2001. A total of 54 men who received salvage ADT for PSA failure after a median follow-up of 18.72 years following randomization defined the study cohort. The Fine-Gray competing risks regression model was used to analyze whether the timing of salvage ADT was associated with an increased risk of PCSM after adjusting for age, comorbidity, known PC prognostic factors, and previously identified interactions. Results: After a median follow-up of 5.68 years (interquartile range, 3.05–9.56) following salvage ADT, 49 of the 54 men (91%) died, of which 27 from PC (54% of deaths). Increasing PSA-DT as a continuous covariate (per month increase) was associated with a decreasing risk of PCSM (adjusted hazard ratio [HR], 0.33; 95% CI, 0.13–0.82; P=.02). Among men with a long PSA-DT (≥6 months), initiating salvage ADT later (PSA level >12 ng/mL, upper quartile) versus earlier was associated with an increased risk of PCSM (adjusted HR, 8.84; 95% CI, 1.99–39.27; P=.004), whereas for those with a short PSA-DT (<6 months; adjusted HR, 1.16; 95% CI, 0.38–3.54; P=.79) this was not true. Conclusions: Early initiation of salvage ADT for post-RT PSA failure in men with a PSA-DT of ≥6 months may reduce the risk of PCSM.
YAP Is Essential for Treg-Mediated Suppression of Antitumor Immunity
Authors: Xuhao Ni, Jinhui Tao, Joseph Barbi, Qian Chen, Benjamin V. Park, Zhiguang Li, Nailing Zhang, Andriana Lebid, Anjali Ramaswamy, Ping Wei, Ying Zheng, Xuehong Zhang, Xingmei Wu, Paolo Vignali, Cui-Ping Yang, Huabin Li, Drew Pardoll, Ling Lu, Duojia Pan, Fan Pan
Journal: Cancer Discovery (2018)

Abstract Regulatory T cells (Treg) are critical for maintaining self-tolerance and immune homeostasis, but their suppressive function can impede effective antitumor immune responses. FOXP3 is a transcription factor expressed in Tregs that is required for their function. However, the pathways and microenvironmental cues governing FOXP3 expression and Treg function are not completely understood. Herein, we report that YAP, a coactivator of the Hippo pathway, is highly expressed in Tregs and bolsters FOXP3 expression and Treg function in vitro and in vivo. This potentiation stemmed from YAP-dependent upregulation of activin signaling, which amplifies TGFβ/SMAD activation in Tregs. YAP deficiency resulted in dysfunctional Tregs unable to suppress antitumor immunity or promote tumor growth in mice. Chemical YAP antagonism and knockout or blockade of the YAP-regulated activin receptor similarly improved antitumor immunity. Thus, we identify YAP as an unexpected amplifier of a Treg-reinforcing pathway with significant potential as an anticancer immunotherapeutic target. Significance: Tregs suppress antitumor immunity, and pathways supporting their function can be novel immunotherapy targets. Here, the selective expression of YAP by Tregs, its importance for their function, and its unexpected enhancement of pro-Treg Activin/SMAD signaling are reported, as are validations of potential cancer-fighting antagonists of YAP and its regulatory targets. Cancer Discov; 8(8); 1026–43. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 899
Parasite Sensing of Host Nutrients and Environmental Cues
Authors: Vanessa Zuzarte-Luís, Maria M. Mota
Journal: Cell Host & Microbe (2018)

Parasites undergo complex life cycles that comprise a wide variety of cellular differentiation events in different host compartments and transmission across multiple hosts. As parasites depend on host resources, it is not surprising they have developed efficient mechanisms to sense alterations and adapt to the available resources in a wide range of environments. Here we provide an overview of the nutritional needs of different parasites throughout their diverse life stages and highlight recent insights into strategies that both hosts and parasites have developed to meet these nutritional requirements needed for defense, survival, and replication. These studies will provide the foundation for a systems-level understanding of host-parasite interactions, which will require the integration of molecular, epidemiologic, and mechanistic data and the application of interdisciplinary approaches to model parasite regulatory networks that are triggered by alterations in host resources.
Ultra-low coverage exome sequencing of FFPE tumor specimens identifies exposure to carcinogenic aristolochic acid.
Authors: Xavier Castells, Sandra Karanović, Magali Olivier, Maude Ardin, Florence Le Calvez-Kelm, Catherine Voegele, James McKay, Damir Dittrich, Karla Tomić, Kathleen Dickman, Arthur Grollman, Bojan Jelaković, Jiri Zavadil
Journal: Cancer Research (2015)