tbuckley/cabot-search huggingface dataset:
Fixed-dose combination antihypertensive medications, adherence, and clinical outcomes: A population-based retrospective cohort study
Authors: Amol A. Verma, Wayne Khuu, Mina Tadrous, Tara Gomes, Muhammad M. Mamdani
Journal: PLoS Medicine (2018)

Background The majority of people with hypertension require more than one medication to achieve blood pressure control. Many patients are prescribed multipill antihypertensive regimens rather than single-pill fixed-dose combination (FDC) treatment. Although FDC use may improve medication adherence, the impact on patient outcomes is unclear. We compared clinical outcomes and medication adherence with FDC therapy versus multipill combination therapy in a real-world setting using linked clinical and administrative databases. Methods and findings We conducted a population-based retrospective cohort study of 13,350 individuals 66 years and older in Ontario, Canada with up to 5 years of follow-up. We included individuals who were newly initiated on one angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II-receptor blocker (ARB) plus one thiazide diuretic. High-dimensional propensity score matching was used to compare individuals receiving FDC versus multipill therapy. The primary outcome was a composite of death or hospitalization for acute myocardial infarction (AMI), heart failure, or stroke. We conducted 2 analyses to examine the association between adherence and patient outcomes. First, we performed an on-treatment analysis to determine whether outcomes differed between groups while patients were on treatment, censoring patients when they first discontinued treatment, defined as not receiving medications within 150% of the previous days’ supply. Second, we conducted an intention-to-treat analysis that followed individuals allowing for breaks in treatment to quantify the difference in drug adherence between groups and assess its impact on clinical outcomes. As expected, there was no significant difference in the primary outcome between groups in the on-treatment analysis (HR 1.06, 95% CI 0.86–1.31, P = 0.60). In the intention-to-treat analysis, the proportion of total follow-up days covered with medications was significantly greater in the FDC group (70%; IQR 19–98) than in the multipill group (42%, IQR 11–91, P < 0.01), and the primary outcome was less frequent in FDC recipients (3.4 versus 3.9 events per 100 person-years; HR 0.89, 95% CI 0.81–0.97, P < 0.01). The main limitations of this study were the lack of data regarding cause of death and blood pressure measurements and the possibility of residual confounding. Conclusions Among older adults initiating combination antihypertensive treatment, FDC therapy was associated with a significantly lower risk of composite clinical outcomes, which may be related to better medication adherence.
Rate of Progression of Aortic Stenosis and its Impact on Outcomes in Patients With Radiation-Associated Cardiac Disease
Authors: Eoin Donnellan, Brian P Griffin, Douglas R Johnston, Zoran B Popovic, Alaa Alashi, Samir R Kapadia, E Murat Tuzcu, Amar Krishnaswamy, Stephanie Mick, Lars G Svensson, Milind Y Desai
Journal: JACC. Cardiovascular imaging (2018)
AB0875 Quality of life improvement in patients with axial spondyloarthritis treated with nsaids and biological therapy from the patient’s perspective: results from the atlas-2017
Authors: M. Garrido-Cumbrera, D. Gálvez-Ruiz, J. Gratacós, C. Blanch Mur, V. Navarro-Compán
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> In patients with axial spondyloarthritis (axSpA), the main long-term outcome is quality of life. Clinical trials and observational studies have shown the efficacy of biological therapy (BT) on improving the signs and symptoms of the disease. However, data assessing the impact of BT on quality of life is scarce and mainly comes from clinical trials. <h3>Objectives</h3> To assess in clinical practice the improvement in quality of life from the patient's perception as a result of pharmacological treatments in axSpA. <h3>Methods</h3> A sample of 680 patients diagnosed with axSpA was interviewed through an online survey as part of the Spanish Atlas-2017, which aimed to promote early referral, improve healthcare, and the use of effective treatments in patients with axSpA. For this study, self-reported data from patients who had received both NSAIDs and BT were analysed. Patients were asked about the improvement they had experienced on 7 different aspects of quality of life after starting treatment with NSAIDs or BT: independence, leisure and free time, social relations, sport and physical activity, and mood and sexual relations. Improvements were measured on a 0 to 10 Likert Scale and classified as low (≤5) and high (≥6). Non-parametric (Wilcoxon) tests were used to compare the degree of improvement between patients with biological therapy and those with NSAIDs. <h3>Results</h3> A total of 189 patients who had received both types of drugs were included. The mean (SD) age was 44.03 (±10.11) years, 50.3% were females, 70.9% married and 47.1% belong to a patients' association. The mean (SD) disease duration was 21.3±10.7 years and 67.7% were HLA-B27+. A higher percentage of patients perceived a high level of improvement after receiving a BT than after receiving an NSAID, for both overall quality of life assessment (57% vs 22%, respectively) and the different quality of life-related aspects. Additionally, the mean degree of improvement for overall quality of life assessment and the different aspects related to this were reported to be significantly higher after receiving BT than after NSAIDs (overall improvement: 5.46±2.59 vs 3.19±2.45; p&lt;0.001, respectively). <h3>Conclusions</h3> In clinical practice, patients' self-reported satisfaction overall and related to different aspects of quality of life is substantially greater after being treated with BT than with NSAIDs. However, these results need to be confirmed in a longitudinal study <h3>Acknowledgements</h3> The Atlas was promoted by CEADE and funded by Novartis <h3>Disclosure of Interest</h3> M. Garrido-Cumbrera: None declared, D. Gálvez-Ruiz: None declared, J. Gratacós: None declared, C. Blanch Mur Employee of: Novartis, V. Navarro-Compán: None declared
The Spatiotemporal Evolution of Lymph Node Spread in Early Breast Cancer
Authors: Peter Barry, Alexandra Vatsiou, Inmaculada Spiteri, Daniel Nichol, George D. Cresswell, Ahmet Acar, Nicholas Trahearn, Sarah Hrebien, Isaac Garcia-Murillas, Kate Chkhaidze, Luca Ermini, Ian Said Huntingford, Hannah Cottom, Lila Zabaglo, Konrad Koelble, Saira Khalique, Jennifer E. Rusby, Francesca Muscara, Mitch Dowsett, Carlo C. Maley, Rachael Natrajan, Yinyin Yuan, Gaia Schiavon, Nicholas Turner, Andrea Sottoriva
Journal: Clinical Cancer Research (2018)

The most significant prognostic factor in early breast cancer is lymph node involvement. This stage between localized and systemic disease is key to understanding breast cancer progression; however, our knowledge of the evolution of lymph node malignant invasion remains limited, as most currently available data are derived from primary tumors.
Comparative profiling of analog targets: a case study on resveratrol for mouse melanoma metastasis suppression
Authors: Xiao Chen, Wei Li, Chengchao Xu, Jie Wang, Bo Zhu, Qilai Huang, Dianhua Chen, Jianfei Sheng, Yong Zou, Yew Mun Lee, Renxiang Tan, Pingping Shen, Yin Kwan Wong, Qingsong Lin, Jigang Wang, Zichun Hua
Journal: Theranostics (2018)

Many plant-specialized metabolites have remedial properties and provide an endless chemical resource for drug discovery. However, most of these metabolites have promiscuous binding targets in mammalian cells and elicit a series of responses that collectively change the physiology of the cells. To explore the potential of these multi-functional and multi-targeted drugs, it is critical to understand the direct relationships between their key chemical features, the corresponding binding targets and the relevant biological effects, which is a prerequisite for future drug modification and optimization. Methods: We introduced and demonstrated a general workflow, called Comparative Profiling of Analog Targets (CPAT), to connect specific biological effects with defined chemical structures of drugs. Using resveratrol (RSV) as an example, we have synthesized and characterized a series of partial functional analogs of RSV. An analog (named RSVN) that specifically lost the inhibitory effect of RSV in cell migration was identified. The binding targets of RSVN and RSV was profiled and compared. Results: Comparative profiling of the RSV and RSVN binding targets showed that, unlike RSV, RSVN failed to target specific components involved in DNA methylation (histone deacetylase 1 [HDAC1] and DNA methyltransferase 3 alpha [DNMT3a]), suggesting that RSV suppresses cell migration through epigenetic regulation. Indeed, RSV treatment recruited HDAC1 and DNMT3a to the promoter region of the focal adhesion kinase (FAK), a key factor involved in cell adhesion, enhanced the promoter methylation, and thus attenuated the protein expression. The inhibitory effect of RSV in cell migration was diminished once FAK expression was restored. Thus, the mechanism of RSV in inhibiting cell migration could be largely accounted to epigenetically control of FAK expression. Conclusion: Our results showed that even though RSV exhibits promiscuous binding, its inhibitory effect on cell migration can be mechanistically understood. First, the presence of 4'-hydroxystilbene within the RSV structure is essential for this activity. Second, it inhibits cell migration through epigenetically based downregulation of FAK expression. Taken together, we propose that CPAT might also be adapted to delineate the specific function of other natural products (NPs) that exhibit binding promiscuity.
Radiotherapy in the Multidisciplinary Management of Merkel Cell Carcinoma
Authors: Michael D. Green, James A. Hayman
Journal: Journal of the National Comprehensive Cancer Network (2018)

The management of Merkel cell carcinoma (MCC) requires multidisciplinary care for optimal patient outcomes. Radiotherapy (RT) is most commonly used as adjuvant therapy to improve locoregional control in patients with MCC who undergo surgery. Additionally, it can sometimes be used as definitive monotherapy for patients who decline or are not candidates for surgery and as palliative treatment in those with metastatic MCC. This article discusses the indications, treatment considerations, and recommended dose prescriptions for RT in the management of early- and advanced-stage disease. Considerable hope exists that immunotherapy advances will synergize with RT to further enhance clinical outcomes.
Low-frequency cortical activity is a neuromodulatory target that tracks recovery after stroke
Authors: Dhakshin S. Ramanathan, Ling Guo, Tanuj Gulati, Gray Davidson, April K. Hishinuma, Seok-Joon Won, Robert T. Knight, Edward F. Chang, Raymond A. Swanson, Karunesh Ganguly
Journal: Nature Medicine (2018)
A novel HPV16 E7-affitoxin for targeted therapy of HPV16-induced human cervical cancer
Authors: Pengfei Jiang, Lude Wang, Bailong Hou, Jinshun Zhu, Meng Zhou, Jie Jiang, Ledan Wang, Shao Chen, Shanli Zhu, Jun Chen, Lifang Zhang
Journal: Theranostics (2018)

Cervical cancer, the second most common cause of cancer death in women worldwide, is significantly associated with infection of high-risk human papillomaviruses (HPVs), especially the most common genotype, HPV 16.To date, there is no established noninvasive therapy to treat cervical cancer.Methods: Here, we report a novel affitoxin that targets HPV16 E7 protein, one of the primary target proteins in molecular targeted therapy for HPV-induced cervical cancer.The affitoxin, ZHPV16E7 affitoxin384 was generated by fusing the modified Pseudomonas Exotoxin A (PE38KDEL) to the HPV16 E7-specific affibody.The expressed and purified ZHPV16E7 affitoxin384 was characterized using numerous methods.SPR assay, indirect immunofluorescence assay, and near-infrared (NIR) optical imaging were respectively performed to assess the targeting ability of ZHPV16E7 affitoxin384 to HPV16 E7 protein both in vitro and in vivo.Cell viability assays and SiHa tumor-bearing nude mice were used to evaluate the efficacy of ZHPV16 E7 affitoxin384 in vitro and in vivo, respectively.Results: Using in vitro methods the SPR assay and indirect immunofluorescence assay showed that ZHPV16E7 affitoxin384 targeted HPV16 E7 with high binding affinity and specificity.Significant reduction of cell viability in HPV16 positive cells was observed in the presence of ZHPV16 E7 affitoxin384.By NIR optical imaging, ZHPV16 E7 affitoxin384 specifically targeted HPV16 positive tumors in vivo.ZHPV16E7 affitoxin384 showed significant in vivo antitumor efficacy in two kinds of tumor-bearing nude mouse models.Conclusions: ZHPV16E7 affitoxin384 is a potent anti-cervical cancer therapeutic agent that could be effective against HPV16 positive tumors in humans.
SAT0698 Mortality of patients with diagnosed rheumatoid arthritis (RA) in germany 2012: analysis of claims data from 60 million people
Authors: I. Haase, G. Pongratz, O. Sander, M. Schneider, R. Brinks
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Mortality data of RA patients in Germany are sparse. Recently, data on the prevalence and incidence of RA comprising about 75% of the German population became available.<sup>1</sup> In case of chronic diseases, it is possible to estimate excess mortality of diseased people compared to non-diseased people if prevalence and incidence are known. <h3>Objectives</h3> To compute the mortality in RA patients in comparison to the population without RA in Germany, utilising claims data from 60 million people. <h3>Methods</h3> We used a mathematical relation between the age-specific prevalence, incidence and mortality to estimate the age- and sex-specific hazard ratio (HR) of mortality rates for patients with diagnosed RA compared to patients without RA.<sup>2</sup> Standardised mortality ratios (SMRs) for men and women were calculated using the sex-specific age distributions in Germany in 2012. In addition, we calculated years of lost life (YLL) for men and women aged 40 and 60 years with diagnosed RA. <h3>Results</h3> Estimation of sex-specific HR in the age range of 40 to 95 years is possible from the data in.<sup>1</sup> The age-specific HRs are elevated in both male and female RA patients (figure 1, left panel and right panel, respectively) with a particular increase in the younger. SMRs in the age range of 40 to 95 are 1.93 and 2.15 for men and women, respectively. YLL at age 40 are 12.0 and 7.5 years for men and women with RA, respectively. The associated YLLs at age 60 are 5.2 and 4.7 years. <h3>Conclusions</h3> Despite the limitation of the data source (claims data), an estimation of excess mortality in terms of the HR is possible and yields plausible results. The obtained SMRs are similar to comparable populations.<sup>3</sup> At age 40 men with RA suffer more from reduced life expectancy than women with RA. At age 60 the difference in YLL between men and women with RA is virtually vanished. <h3>References</h3> [1] Steffen A, et al. doi:10.20364/VA-17.08 [2] Brinks R, Landwehr S, DOI: 10.1093/imammb/dqu024 [3] Dadoun S, et al. doi:10.1016/j.jbspin.2012.02.005 <h3>Acknowledgements</h3> We are grateful to Steffen et al. for sharing the data from.<sup>1</sup> <h3>Disclosure of Interest</h3> None declared
Advances in B‐cell Precursor Acute Lymphoblastic Leukemia Genomics
Authors: Claire Schwab, Christine J. Harrison
Journal: HemaSphere (2018)

Abstract In childhood B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL), cytogenetic abnormalities remain important diagnostic and prognostic tools. A number of well‐established abnormalities are routinely used in risk stratification for treatment. These include high hyperdiploidy and ETV6‐RUNX1 fusion, classified as good risk, while Philadelphia chromosome (Ph) positive ALL and rearrangements of the KMT2A ( MLL ) gene define poor risk. A poor risk subgroup of intrachromosomal amplification of chromosome 21 (iAMP21‐ALL) has been described, in which intensification of therapy has greatly improved outcome. Until recently, no consistent molecular features were defined in around 30% of BCP‐ALL (known as B‐other‐ALL). Recent studies are classifying them into distinct subgroups, some with clear potential for novel therapeutic approaches. For example, in 1 poor risk subtype, known as Ph‐like/BCR‐ABL1‐like ALL, approximately 10% have rearrangements of ABL‐class tyrosine kinases: including ABL1 , ABL2 , PDGFRB , PDGFRA , and CSF1R . Notably, they show a poor response to standard chemotherapy, while they respond to treatment with tyrosine kinase inhibitors, such as imatinib. In other Ph‐like‐ALL patients, deregulation of the cytokine receptor, CRLF2, and JAK2 rearrangements lead to activation of the JAK‐STAT signaling pathway, implicating a specific role for JAK inhibitors in their treatment. Other novel subgroups within B‐other‐ALL are defined by the IGH‐DUX4 translocation, related to deletions of the ERG gene and a good outcome, while fusions involving ZNF384 , MEF2D , and intragenic PAX5 amplification ( PAX5 AMP ) are linked to a poor outcome. Continued genetic screening will eventually lead to complete genomic classification of BCP‐ALL and define more molecular targets for less toxic therapies.
AB0965 Medicamental and non-medicamental therapy pregnant women with hip osteoarthritis
Authors: E. Trofimov, V. Mazurov, A. Trofimova, E. Melnikov, I. Gaydukova
Journal: Annals of the Rheumatic Diseases (2018)

effusion.Age, physical exercise, knee osteoarthritis symptoms duration and different anthropometric measurements were collected.Radiographic severity was evaluated according to Kellgren-Lawrence scale.Pain and disability were assessed by WOMAC-pain and WOMAN-function.Calprotectin, TNF-alfa, IL-6 and high-sensitivity C-reactive protein (hs-CRP) were measured by ELISA in synovial fluid.Summary of clinical data and laboratory parameters and their association with WOMAC scales were performed using non-parametric methods.Medians and Spearman correlation (r) were used for continuous measures, and Mann-Whitney test was applied to categorical variables.This study was approved by the local ethics committee.Results: Median higher synovial calprotectin levels were associated with worse WOMAC pain (671.5 vs 431.8 ng/mL, p<0.05).) and function (713.4 vs 400.1 ng/ mL, p<0.05).)scores than patients with inferior levels.Patients with moderate to severe synovial effusion (>8 mm on midline suprapatellar line) had higher calprotectin levels compared with those with mild effusion (626.1 vs 417.5 ng/mL, p<0.05).Synovial calprotectin levels showed moderate correlations with intraarticular TNF-alfa levels (r=0.26),hs-CRP (r=0.27) and a high correlation with synovial IL-6 levels (r=0.53).Conclusions: Calprotectin showed association with inflammatory features as measured by ultrasound and inflammatory markers such as hs-CRP, TNF-alfa and IL-6, and was related to pain and function in patients with knee osteoarthritis with inflammatory features.Calprotectin appears to be a useful marker of inflammation and could be a useful marker for assessing response to treatments targeting inflammation.
AB0170 Ccr9+ pathogenic thelper cells from primary sjÖgren’s syndrome patients are characterised by deregulated pathways associated with effector t cell function
Authors: S. Blokland, C.G. Wichers, A. Pandit, A.A. Kruize, T.R. Radstake, J.A. van Roon
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> CCR9 +Th cells produce large amounts of IFN-γ and IL-10, lack CXCR5 expression but have features similar to Tfh cells and the recently described pathogenic PD1 +CXCR5 cells, including expression of ICOS, PD-1, IL-21 and Bcl6, but no CXCR5 expression. CCR9 Th cells and their ligand CCL25 are elevated in salivary glands of primary Sjögren's syndrome (pSS) patients. Since CCR9 Th cells strongly induce antibody production and robustly respond to IL-7, which is indicated to play an essential role in pSS pathogenesis and in formation of ectopic lymphoid structures, these cells may play an important role in pSS immunopathology. <h3>Objectives</h3> The goal of this study was to identify the molecular dysregulation of CCR9 Th cells in pSS patients. <h3>Methods</h3> CCR9+, CXCR5 +and CCR9-CXCR5- Th cells were sorted from peripheral blood of 7 healthy individuals and 7 pSS patients and RNA sequencing of these sorted cell subsets was performed. Computational analysis identified differentially expressed genes (DEG) and gene expression networks. Pathway enrichment analysis was performed in order to assess differentially regulated pathways. Target genes are technically validated and knockdown experiments will assess the functional role of identified targets. <h3>Results</h3> The sorted Th subsets could robustly be distinguished based on their transcriptomes. In the CCR9 +Th cell subset 2777 DEGs (1249 up and 1528 down) were identified between healthy controls and pSS patients, and 1416 and 1077 in the CXCR5 +and CCR9-CXCR5- subsets, respectively. Using network analysis 15 modules were constructed, consisting of genes showing coherent expression patterns. Four modules of interest were selected based on pathway enrichment analysis, revealing pathways involved in e.g. cytokine and chemokine production, proliferation and migration. DEGs of interest within these networks were selected, including upregulated expression of integrin αE, integrin α1 and downregulation of regulatory T cell associated genes FoxP3 and IL2RA. Expression of these markers is being validated using flow cytometry. In addition, knockdown of predicted key transcription factors is studied to reveal their role in the pathogenic potential of CCR9 +Th cells. <h3>Conclusions</h3> Transcriptomic analysis of CCR9 +Th cells from pSS patients revealed multiple dysregulated pathways previously shown to be involved in increased effector T cell function. Upregulation of genes associated with pathogenicity and downregulation of regulatory T cell associated genes were found in pSS patients. Targeting predicted key molecules might reveal (novel) therapeutic targets to halt pathogenic processes induced by CCR9 +Th cells. <h3>Disclosure of Interest</h3> None declared
Bacterial tRNase–Based Gene Therapy with Poly(β‐Amino Ester) Nanoparticles for Suppressing Melanoma Tumor Growth and Relapse
Authors: Sungjin Min, Yoonhee Jin, Chen Yuan Hou, Jayoung Kim, Jordan J. Green, Taek Jin Kang, Seung‐Woo Cho
Journal: Advanced Healthcare Materials (2018)

Abstract Here, a novel anticancer gene therapy with a bacterial tRNase gene, colicin D or virulence associated protein C (VapC), is suggested using biodegradable polymeric nanoparticles, such as poly(β‐amino esters) (PBAEs) as carriers. These genes are meticulously selected, aiming at inhibiting translation in the recipients by hydrolyzing specific tRNA species. In terms of nanoparticles, out of 9 PBAE formulations, a leading polymer, (polyethylene oxide) 4 ‐bis‐amine end‐capped poly(1,4‐butanediol diacrylate‐ co ‐5‐amino‐1‐pentanol) (B4S5E5), is identified that displays higher gene delivery efficacy to cancer cells compared with the leading commercial reagent Lipofectamine 2000. Interestingly, the B4S5E5 PBAE nanoparticles complexed with colicin D or VapC plasmid DNA induce significant toxicity highly specific to cancer cells by triggering apoptosis. In contrast, the PBAE nanoparticles do not induce these cytotoxic effects in noncancerous cells. In a mouse melanoma model of grafted murine B16‐F10 cells, it is demonstrated that treatment with PBAE nanoparticles complexed with these tRNase genes significantly reduces tumor growth rate and delays tumor relapse. Moreover, increased stability of PBAE by PEGylation further enhances the therapeutic effect of tRNase gene treatment and improves survival of animals. This study highlights a nonviral gene therapy that is highly promising for the treatment of cancer.