tbuckley/cabot-search huggingface dataset:
Radiographic endophenotyping in hip osteoarthritis improves the precision of genetic association analysis
Authors: Kalliope Panoutsopoulou, Shankar Thiagarajah, Eleni Zengini, Aaron G Day-Williams, Yolande FM Ramos, Jennifer MTA Meessen, Kasper Huetink, Rob GHH Nelissen, Lorraine Southam, N William Rayner, Michael Doherty, Ingrid Meulenbelt, Eleftheria Zeggini, J Mark Wilkinson
Journal: Annals of the Rheumatic Diseases (2016)

Osteoarthritis (OA) has a strong genetic component but the success of previous genome-wide association studies (GWAS) has been restricted due to insufficient sample sizes and phenotype heterogeneity. Our aim was to examine the effect of clinically relevant endophenotyping according to site of maximal joint space narrowing (maxJSN) and bone remodelling response on GWAS signal detection in hip OA.A stratified GWAS meta-analysis was conducted in 2118 radiographically defined hip OA cases and 6500 population-based controls. Signals were followed up by analysing differential expression of proximal genes for bone remodelling endophenotypes in 33 pairs of macroscopically intact and OA-affected cartilage.We report suggestive evidence (p<5×10-6) of association at 6 variants with OA endophenotypes that would have been missed by using presence of hip OA as the disease end point. For example, in the analysis of hip OA cases with superior maxJSN versus cases with non-superior maxJSN we detected association with a variant in the LRCH1 gene (rs754106, p=1.49×10-7, OR (95% CIs) 0.70 (0.61 to 0.80)). In the comparison of hypertrophic with non-hypertrophic OA the most significant variant was located between STT3B and GADL1 (rs6766414, p=3.13×10-6, OR (95% CIs) 1.45 (1.24 to 1.69)). Both of these associations were fully attenuated in non-stratified analyses of all hip OA cases versus population controls (p>0.05). STT3B was significantly upregulated in OA-affected versus intact cartilage, particularly in the analysis of hypertrophic and normotrophic compared with atrophic bone remodelling pattern (p=4.2×10-4).Our findings demonstrate that stratification of OA cases into more homogeneous endophenotypes can identify genes of potential functional importance otherwise obscured by disease heterogeneity.
Abstract 3263: Investigating TIP60's role in regulating cancer metastasis
Authors: Yanzhou Zhang
Journal: Cancer Research (2015)

Abstract HIV-Tat-interacting protein 60 KDa (TIP60) is a lysine acetyltransferase implicated in multiple cellular pathways such as transcription, DNA damage-induced checkpoint activation, and apoptosis. TIP60 is a haploinsufficient tumor suppressor and known to be down-regulated in cancers, including virus induced cancers. Cell migration or epithelial-mesenchymal transition (EMT) is a highly conserved cellular program that allows polarized, immotile epithelial cells to convert to motile mesenchymal cells. Recent studies show that down-regulation of TIP60 correlate with cancer metastasis with higher tumor node metastasis (TNM) and poor survival rates. Yet the mechanism of how TIP60 regulate EMT remains unknown. In this study we found TIP60 acts as an inhibitor of cell migration and negatively regulates metastasis capability of breast cancer cells. By using in vitro and in vivo models we show that overexpression of TIP60 inhibit breast cancer metastasis. Furthermore, analyses of our expression data reveal that the levels of cell adhesion genes are significantly changed in the absence of TIP60. Mechanistically, we show TIP60 to interact with Snail2 and regulate its ability to bind to its target promoters. Interestingly, we also found that TIP60 is significantly down-regulated in the breast cancer patient, and levels of TIP60 were significantly decreased as the disease progressed and its expression negatively correlates with metastasis. In summary, our data suggests that patients with lower TIP60 expression have a poor prognosis of overall and disease free survival. Citation Format: Yanzhou Zhang. Investigating TIP60's role in regulating cancer metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3263. doi:10.1158/1538-7445.AM2015-3263
P159 Therapeutic benefit of mepolizumab in the scottish medicines consortium (SMC) restricted sub-population – a post-hoc meta-analysis of phase iib/iii trials
Authors: RA Mehta, CEA Hartmann, NB Gunsoy, FC Albers
Journal: Thorax (2016)

<h3>Rationale</h3> The Scottish Medicines Consortium provides advice to NHS boards and Area Drug and Therapeutics Committees across Scotland about the status of newly licensed medicines. In June 2016 positive advice was issued for mepolizumab, an anti-IL-5 mAb licensed for adult severe refractory eosinophilic asthma, for use in a restricted sub-population: patients who have eosinophils of ≥150 cells per microlitre (0.15 × 109/L) at initiation of treatment and had ≥4 asthma exacerbations in the preceding year or are receiving maintenance treatment with oral corticosteroids (mOCS). Here we present the results for this sub-population comparing the effect of mepolizumab with placebo in this subgroup. <h3>Methods</h3> Three randomised, double-blind, placebo-controlled studies of mepolizumab in severe eosinophilic asthma were identified, which used the licensed 100 mg SC dose or the corresponding 75 mg IV dose of mepolizumab. For analysis purposes, these two treatment arms were combined. A post-hoc meta-analysis assessing the key outcome measures in the three phase IIb/III trials (DREAM [NCT01000506] and MENSA [NCT01691521] with a sensitivity analysis including SIRIUS [NCT01691508]) were run for the sub-population using individual patient data. <h3>Results</h3> The post-hoc meta-analysis included 197 patients from DREAM and MENSA and 251 when including the SIRIUS trial. The mean age was 51.2 and 51.3 years of which 62% and 64% were female, respectively. A 59% (95% CI: 0.31, 0.55; p &lt; 0.001) reduction in clinically significant exacerbations was seen in the meta-analysis of DREAM and MENSA (50% [95% CI: 0.40, 0.64, p &lt; 0.001] sensitivity analysis with SIRIUS). The ACQ score showed an improvement of −0.56 (95% CI: −0.79,−0.33; p &lt; 0.001) and −0.58 (95% CI: −0.79,−0.38; p &lt; 0.001, sensitivity analysis with SIRIUS). The SGRQ was only used in MENSA and SIRIUS and showed an improvement in total score of −8.0 (−12.0, −3.9, p &lt; 0.001). <h3>Conclusion</h3> Mepolizumab treatment was effective in SMC advice population (adult severe refractory eosinophilic asthma patients with a blood eosinophil count of ≥150 cells/µL at initiation of treatment, and ≥4 exacerbations in the previous year or dependency on mOCS). The use of a post-hoc meta-analysis is a helpful approach to increase our understanding of mepolizumab’s treatment effect in the SMC restricted sub-population. <h3>Funding</h3> GSK (NCT01000506, NCT01691521, NCT01691508).
PO45A SYSTEMATIC REVIEW STRATEGY IDENTIFIES CHEMOTHERAPEUTIC CANDIDATES FOR EFFICACIOUS INTRA-CRANIAL DELIVERY IN GLIOBLASTOMA
Authors: Frazer Cowgill, Stuart J. Smith, Toby W. Gould, Richard G. Grundy, Ruman Rahman
Journal: Neuro-Oncology (2015)

INTRODUCTION: Surgically delivering chemotherapy to a resection cavity offers hope in targeting residual glioblastoma cells responsible for tumour recurrence. We conducted a systematic review of 311 agents combining scientific literature, clinical trial databases and chemical structure directories, to identify candidates suitable to repurpose for localised glioblastoma drug delivery. METHOD: All known anti-neoplastic drugs from Martindale's Online Drug Library were systematically reviewed. Martindale, the British National Formulary, OvidSP, and ChemSpider were used to assess neurotoxicity, efficacy, and Blood Brain Barrier (BBB) penetration to generate inclusion/exclusion criteria: criterion 1 excluded neurotoxic agents, but included those associated with systemic side-effects; criterion 2 included efficacious agents in vitro; criterion 3 included agents with no/low in vivo or Phase II/III clinical efficacy; criterion 4 included agents with observed/predicted lack of, or poor BBB penetration. RESULTS: Seventy-seven drugs were excluded due to neurotoxicity, 107 excluded due to poor in vitro efficacy and 68 excluded due to lack of in vivo or clinical efficacy despite good/moderate BBB penetration. Of the remaining 59 drugs, 13 were recommended as good candidates, where lack of in vivo or clinical efficacy may be due to poor BBB penetration. Candidates included carmustine (already delivered as Gliadel), demonstrating proof-of-concept of our review strategy, cilengitide, irinotecan, bevacizumab diaziquone, docetaxel and trabedersen. CONCLUSION: Localised drug delivery candidates were identified using a systematic review strategy which may be applied in the evaluation of future novel experimental or repurposed agents.
EnSite CFE map機能を用いた発作性心房細動に対するカテーテルアブレーション治療の1例
Authors: 武田晋作, 天谷直貴, 竹内雄三, 西尾壮示, 張田健志, 石井充, 岡田正治, 羽田龍彦, 小菅邦彦, 池口滋
Journal: Circulation (2009)
Host Fibrinogen and the S. Aureus-Encoded Procoagulant Vwbp Are Context-Dependent Determinants of Bacterial Virulence.
Authors: Joni M Prasad, Xinli Du, Eric S. Mullins, Senad Divanovic, Kathryn E Talmage, Keith W Kombrinck, Alice G Cheng, Olaf Schneewind, Matthew J. Flick, Jay L. Degen
Journal: Blood (2010)
Potential Synergic Effect of Lenalidomide-Rituximab Combination: Durable Complete Remissions in Refractory Diffuse Large B Cell Lymphoma
Authors: Vadim Ivanov, Diane Coso, Therese Aurran-Schleinitz, Jean-Marc Schiano de Colella, Anne-Marie Stoppa, Jerome Rey, Florence Broussais, Didier Blaise, Reda Bouabdallah
Journal: Blood (2011)
Abstract 2160: PTEN deletion is associated with metastatic disease and worse prognosis in pancreatic cancer
Authors: Martin Wartenberg, Irene Centeno, Inti Zlobec, Alessandro Lugli, Aurel Perren, Eva Karamitopoulou
Journal: Cancer Research (2015)

Abstract Background: PTEN is a tumor suppressor gene encoding a phosphatase. PTEN inactivation is a frequent event in cancer, occurring through various genetic and epigenetic alterations. Here we investigate the role of PTEN alterations in the microenvironment of ductal pancreatic adenocarcinoma (PDAC). Methods: Presence of PTEN was investigated by immunohistochemistry and mRNA-in-situ-hybridization (mRNA-ISH) by using multi-punch tissue microarrays (TMAs)containing at least 4 punches per tumor, in a set of 120 well characterized PDACs with full clinicopathological information. Expression was assessed separately in tumor and stromal cells. Multiplex ligation-dependent probe amplification (MLPA) of DNA probes to identify loss of heterozygosity (LOH) of the PTEN gene was additionally performed in 61 cases. Results were correlated with clinicopathological features including survival of the patients. Results: Loss of PTEN protein (i.e. average immunohistochemical expression in &amp;lt;10% of the neoplastic cells across all tumor punches) was found in 62% of PDAC cases, mostly paralleled by the results of mRNA-ISH. In 22.2% of the cases PTEN protein and/or mRNA loss was additionally observed in the tumor stroma. Interestingly, protein loss in the stromal cells was associated with distant metastasis (p = 0.0045). MLPA identified PTEN LOH (all exons or only exon 1) in 51% of all examined cases and in 73.5% of the cases with PTEN protein/mRNA loss. The occurrence of PTEN LOH was slightly more frequent among cases with concomitant PTEN protein loss in tumor and stromal cells (80%). PTEN LOH as identified by MLPA was associated with higher tumor grade (p = 0.0412), vascular invasion (p = 0.0176), presence of distant metastases (p = 0.0082) and decreased overall survival (p = 0.0127). In 26.5% of the cases with PTEN protein/mRNA loss, no PTEN deletion could be found suggesting occurrence of other genetic changes or epigenetic mechanisms. Conclusion: PTEN LOH is a major cause of PTEN loss in PDAC and is associated with aggressive tumor characteristics and worse patient prognosis. This is intensified by concomitant PTEN loss in tumor and stromal cells. Citation Format: Martin Wartenberg, Irene Centeno, Inti Zlobec, Alessandro Lugli, Aurel Perren, Eva Karamitopoulou. PTEN deletion is associated with metastatic disease and worse prognosis in pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2160. doi:10.1158/1538-7445.AM2015-2160
Women in Medicine and Patient Outcomes
Authors: Anna L. Parks, Rita F. Redberg
Journal: JAMA Internal Medicine (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Prediction of tumor recurrence in stage II colon cancer through genetic variants in formyl peptide receptor 2 (FPR2).
Authors: R. D. Ladner, W. Zhang, M. J. Labonte, D. Yang, Y. Ning, A. Gerger, P. O. Bohanes, T. Winder, A. B. El-Khoueiry, S. Iqbal, N. Petasis, H. Lenz
Journal: Journal of Clinical Oncology (2011)

3604 Background: The formyl peptide receptor (FPR) is a G-protein-coupled receptor (GPCR) that mediates chemotaxis of phagocytic leucocytes induced by bacterial and host-derived chemotactic peptides. Recent studies found that it is selectively expressed in highly malignant gliomas and contributes to tumor growth and angiogenesis. Previously we demonstrated that polymorphisms in the VEGF pathway predict tumor recurrence in adjuvant colon cancer. Here we tested the hypothesis that two genetic variants in the FPR2 gene (rs17834679 and rs17694990) may predict tumor recurrence in a cohort of adjuvant colon cancer patients. Methods: Between 1992 - 2007, blood samples were obtained from 234 adjuvant colon caner patients (109: stage II and 125: stage III) at the USC medical facilities. Genomic DNA was extracted from peripheral blood and two potentially functional genotypes (rs17834679 and rs17694990) within the FPR2 gene were determined utilizing the PCR-RFLP technique. The median follow-up was 4.4 years (range: 0.3-16.8). 90 of 234 patients (38.5%) developed tumor recurrence with a 3-year probability of 0.34 ± 0.05. Results: In multivariable Cox proportional hazards regression analysis, FPR2 polymorphism rs17834679 was significantly associated with time to tumor recurrence (TTR) in stage II colon cancer (adjusted P = 0.027). Patients with CC genotype were at greatest risk of developing tumor recurrence (adjusted hazard ratio [HR]: 2.819 [95%CI: 1.127-7.051]) compared to those with GC and GG genotypes. In the dominant inheritance model, patients with any G allele had longer TTR (16.8 years+, median was not reached) compared to those with CC genotype (median TTR 5.4 years [95%CI: 3.2-10.7]) (p=0.007, log-rank test). There are no significantly associations between FPR2 polymorphisms and TTR in stage III colon cancer. Conclusions: Polymorphisms in the FPR2 gene may serve as molecular markers for tumor recurrence in stage II colon cancer, indicating that the analysis of genetic variants of FPR2 may help to identify patient subgroups at high risk for tumor recurrence. These findings may also support the development of novel FPR2 targeting chemotherapeutic agents, such as agonists of its anti-inflammatory binding site.
Abstract 5201: Antimetastatic effect of a Dializable Leucocyte Extract in a murine model of prostate cancer
Authors: Miguel A. Hernandez-Esquivel, Sonia M. Perez-Tapia, Richard G. Pestell, Marco A. Velasco-Velazquez
Journal: Cancer Research (2015)

Abstract Prostate cancer remains the most common non-dermatological cancer in the United States and the second leading cause of cancer death amongst men. The majority of men with progressive prostate cancer develop metastases, being the skeleton the most prevalent metastatic site. Dialyzable leukocyte extracts (DLEs) are heterogeneous mixtures of low-molecular-weight (&amp;lt;10 kDa) peptides that improve clinical responses in various diseases. Our group has shown that DLEs change cytokine serum concentrations in patients and reduce experimental metastasis in a melanoma model. In this work we analyzed the in vitro effects of a human DLE produced under good manufacturing procedures and facilities [1] and evaluated its possible antimetastatic effect in vivo. We employed PC-3 cells and murine Src-transformed Prostate Epithelial Cells (PEC-Src) to assess the direct effects of DLE in prostate cancer cells. Both cell lines were exposed in vitro to the DLE (1 pg/mL- 1 μg/mL) in proliferating (+FBS) or non-proliferating (-FBS) conditions, and cell number was estimated by MTS assays. The effects on cell motility and cell invasion were evaluated by wound healing assays and invasion from collagen-embedded spheroids, respectively. Since DLEs are immunomodulators, we used an experimental metastasis model that consistently produces bone and brain metastasis in inmunocompetent mice [2]. PEC-Src expressing Luciferase2-RFP were intracardiacally injected to FVB mice and metastatic growth in DLE-treated (1, 5, or 25 μg/kg p.o.) animals was quantified weekly by bioluminescence imaging. In vitro exposure to a wide range of DLE concentrations did not alter proliferation or survival in PC-3 or PEC-Src cells, indicating that the evaluated DLE does not has direct antineoplastic effect. Similarly, treatments did not alter prostate cancer cell motility or invasion. In contrast, DLE (1 μg/kg) reduced metastatic tumor burden in brain and bones in inmunocompetent mice. The absence of direct effect on prostate cancer cells suggests that DLE-treatment may be changing cellular or soluble facilitators in the metastatic microenvironments. Supported by PAPIIT-UNAM IN219613. [1] Medina-Rivero E, et al. J Pharma Biomed Anal 88: 289-294, 2014 [2] Sicoli D, et al. Cancer Res 74: 7103-14, 2014 Citation Format: Miguel A. Hernandez-Esquivel, Sonia M. Perez-Tapia, Richard G. Pestell, Marco A. Velasco-Velazquez. Antimetastatic effect of a Dializable Leucocyte Extract in a murine model of prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5201. doi:10.1158/1538-7445.AM2015-5201
346. Targeting the RPGR Gene for Gene Therapy with Highly Specific Nucleases
Authors: Mert Yanik, Brigitte Müller, Knut Stieger
Journal: Molecular Therapy (2015)

Background: Retinitis pigmentosa comprises a heterogeneous group of retinal dystrophies with a prevalence of 1 in 3500 people. Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene are causing the severe X-linked form of retinitis pigmentosa. More than 80% of the mutations are located in the terminal exon ORF15 of the RPGR gene. Currently, no treatment option exists. The aim of the project "REGAIN" is to develop gene therapeutic approaches to treat XLRP through genomic editing. The common strategy for targeted gene editing is based on highly specific nucleases which cleave only once within the complex genome at a desired position and the homologous recombination (HR) to repair and correct the mutation with the help of a donor template. So far this strategy is based on work with mitotic cells and there are no experiences with postmitotic cells like photoreceptors in situ. Besides HR and the pathway of non-homologous end-joining (NHEJ), the so called micro homology mediated repair (MHMR) could be an alternative in neurons to increase the efficiency of gene therapy. Methods: Several sequences within the ORF15 gene have been targeted for the induction of double or single strand breaks of the DNA by CRISPR/Cas and TALEN variants. These sequences have been cloned into the traffic light reporter (TLR) gene expression system at the homing endonuclease I-SceI site. The TLR system has been modified to express either GFP in case of successful HR or BFP in case of NHEJ or MHMR. Plasmids containing substrate, nucleases and template DNA were transfected into HEK293 cells. Efficiency of DNA modification was measured by FACS analysis and T7 surveyor assay, and toxicity was assessed by cell survival assay. Results: Using modified CRISPR/Cas9-FokI variant, targeting of sequences inside the ORF15 can be as efficient as using the gold standard I-SceI. Toxicity was best for TALEN or CRISPR/Cas9-FokI variants, while standard CRISPR/Cas9 variants showed slightly increased toxicity. Conclusion: The characterization of the activity and toxicity of the tested endonucleases helped us to identify the most promising tailored nuclease and its target sequence in our gene targeting approach to treat XLRP. With the help of mouse retinal explants we are studying the efficacy of our strategy in photoreceptors.
Cancer-specific changes in DNA methylation reveal aberrant silencing and activation of enhancers in leukemia
Authors: Ying Qu, Lee Siggens, Lina Cordeddu, Verena I. Gaidzik, Kasper Karlsson, Lars Bullinger, Konstanze Döhner, Karl Ekwall, Sören Lehmann, Andreas Lennartsson
Journal: Blood (2016)