tbuckley/cabot-search huggingface dataset:
Abstract 4138: miRNA-362-3p is associated with recurrence of colorectal cancer and targets E2F1, USF2 and PTPN1
Authors: Heidi Tobiasen, Lise Lotte Christensen, Anja Holm, Troels Schepeler, Kasper Thorsen, Mads H. Rasmussen, Karin Birkenkamp-Demtroeder, Oliver M. Sieber, Peter Gibbs, Philippe Lamy, Søren Laurberg, Bodil Øster, Kristian Q. Hansen, Rikke Hagemann-Madsen, Kristina Byskov, Torben F. Ørntoft, Claus L. Andersen
Journal: Cancer Research (2012)

Abstract Colorectal cancer (CRC) is one of the leading causes of cancer death in Western countries. A significant number of CRC patients undergoing curative-intented surgery subsequently develop recurrence and die from the disease. MicroRNAs (miRNAs) are aberrantly expressed in cancers and appear to have both diagnostic and prognostic significance. In this study we identified novel miRNAs associated with recurrence of CRC. TaqMan® Human MicroRNA Array Set v2.0 was used to profile the expression of 667 miRNAs in 14 normal colon mucosas and 46 microsatellite stable CRC tumors. Four miRNAs (miR-362-3p, miR-570, miR-148a* and miR-944) were expressed at a lower level in the tumors from patients with recurrence (p &amp;lt; 0.015) compared to tumors from patients with no recurrence. A significant association of low expression with reduced disease free survival was confirmed for miR-362-3p in a second independent cohort of 43 CRC patients using single TaqMan® microRNA assays. In vitro functional analysis showed that over-expression of miR-362-3p in colon cancer cell lines (HCT116, LS174T, and DLD1) reduced cell viability and proliferation mainly due to cell cycle arrest. E2F1, USF2 and PTPN1 were identified as potential miR-362-3p targets by mRNA profiling of HCT116 cells over-expressing miR-362-3p. Subsequently, these genes were confirmed as direct targets by Luciferase reporter assays. In vitro knock-down confirmed that these targets are important players in the miR-362-3p target network. We conclude that miR-362-3p may be a novel prognostic marker in CRC and hypothesize that augmented expression of miR-362-3p may prevent the development of distant metastasis by targeting E2F1, USF2 and PTPN1. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4138. doi:1538-7445.AM2012-4138
CALCIFIED CORONARY LESIONS WITH MINIMAL STENOSIS: AN ENTITY DIFFERENT FROM ATHEROSCLEROSIS
Authors: Sirous Darabian, Yanting Luo, Nasim Sheidaee, Anas Alani, Rine Nakanishi, Negin Nezarat, Suguru Matsumoto, Matthew Budoff
Journal: Journal of the American College of Cardiology (2015)
Abstract P4-09-04: Gene expression profile that predict outcome of Tamoxifen-treated estrogen receptor-positive, high-risk, primary breast cancer patients: a DBCG study.
Authors: MB Lyng, A-V Lænkholm, Q Tan, W Vach, KH Gravgaard, A Knoop, HJ Ditzel
Journal: Cancer Research (2012)

Abstract Background: Tamoxifen significantly improves outcome for estrogen receptor-positive (ER+) breast cancer, but the 15-year recurrence rate remains 30%. The aim of this study was to identify gene profiles that accurately predicted the outcome of ER+ breast cancer patients who received adjuvant Tamoxifen mono-therapy. Methods: Post-menopausal breast cancer patients diagnosed no later than 2002, being ER+ as defined by &amp;gt;1% IHC staining and having a frozen tumor sample with &amp;gt;50% tumor content were included. Tumor samples from 108 patients treated with adjuvant Tamoxifen were analyzed for the expression of 59 genes using quantitative-PCR. End-point was clinically verified recurrence to distant organs or ipsilateral breast. Gene profiles were identified using a model building procedure based on conditional logistic regression and leave-one-out cross-validation, followed by a non-parametric boostrap (1000x re-sampling). The optimal profiles were further examined in 5 previously-reported datasets containing similar patient populations that were either treated with Tamoxifen or left untreated (N = 623). Results: Three gene profiles were identified, the strongest being a 2-gene combination of BCL2-CDKN1A exhibiting an accuracy of 75% for prediction of outcome. Independent examination using 4 previously-reported microarray datasets of Tamoxifen-treated patient samples (N = 503) confirmed the potential of BCL2-CDKN1A (average accuracy: 68%, range: 53%–85%). The predictive value was further determined by comparing the ability of the genes to predict recurrence in an additional, previously-published, cohort consisting of Tamoxifen-treated (n = 58, p = 0.015) and untreated patients (n = 62, p = 0.25). Conclusion: A novel gene expression profile predictive of outcome of Tamoxifen-treated patients was identified. The validation suggests that BCL2-CDKN1A exhibit strong predictive potential. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-09-04.
Abstract 2018: Genome-wide analysis of DNA methylation and copy number changes in breast cancers.
Authors: Olafur A. Stefansson, Sebastian Moran, Antonio Gomez, Sergi Sayols Puig, Jorunn Eyfjord, Manel Esteller
Journal: Cancer Research (2013)

Abstract Epigenetic modifications are known to be critical in regulating normal developmental processes and cellular differentiation. DNA methylation of CpG dinucleotides is a well-characterized epigenetic marker frequently associated with transcriptional silencing. CpG dinucleotides are non-randomly distributed throughout the genome with regions enriched for CpGs being known as CpG islands. It is now well established that epigenetic inactivation of tumor suppressor genes can occur by CpG island promoter methylation. For example, BRCA1 promoter methylation occurs in approximately 10 - 15% of all breast cancers and is associated with gene silencing. Recent technological advances have enabled DNA methylation to be profiled genome-wide. Using the Infinium 450 thousand probe arrays, we have studied DNA methylation and copy number changes to discover new markers of potential clinical relevance in breast cancer. Expression analyses by immunohistochemisty on tissue arrays for subtype-specific markers (ER, PR, HER2, Ki-67, EGFR, CK5/6, CK8, CK18, MUC1 and Claudin-3) carried out previously were used to establish DNA methylation markers of breast cancer subtypes. This integrated approach is presented in clinical context with available data on histological grade, disease stage and breast cancer-specific survival outcomes. Citation Format: Olafur A. Stefansson, Sebastian Moran, Antonio Gomez, Sergi Sayols Puig, Jorunn Eyfjord, Manel Esteller. Genome-wide analysis of DNA methylation and copy number changes in breast cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2018. doi:10.1158/1538-7445.AM2013-2018
P1024 PRESENCE OF HEPATIC STEATOSIS AS PER NON-INVASIVE BIOMARKERS OVERESTIMATES FIBROSIS STAGES BASED ON LIVER STIFFNESS MEASUREMENT (LSM) BY TRANSIENT ELASTOGRAPHY IN TYPE-2 DIABETIC (T2D) PATIENTS
Authors: H. Perazzo, M. Munteanu, Y. Ngo, P. Lebray, E. Lukina, N. Seurat, F. Rutka, M. Couteau, S. Jacqueminet, D. Monneret, F. Imbert-Bismut, V. Ratziu, A. Hartemann-Huertier, C. Housset, T. Poynard
Journal: Journal of Hepatology (2014)
Indebted to international medical graduates
Authors: D. Spence
Journal: BMJ (2013)

In 1979 I moved from Oxford to Orkney. I landed at a small rural Presbyterian school in an Afghan jacket, flared embroidered jeans, and a necklace, sporting shoulder length hair. I smelt of goat. Framed by the doorway, my future classmates looked at me, and I looked at them. This was more a Roswell than a Ring of Bright Water moment. Looking and sounding different, even when you speak the same language, breeds feelings of isolation, resentment, frustration, judgment, discrimination, and anger. All you can do is wait and hope for change.

Much has been written about the exam performance …
PTU-101 Patients with Schistosomal Portal Hypertension have High Concentration of Fibrotic and Inflammatory Markers
Authors: E Sinkala, P kelly
Journal: Gut (2013)

<h3>Introduction</h3> Worldwide the commonest cause of portal hypertension is cirrhosis, but in tropics schistosomiasis is a major cause. Parts of Zambia are hyper-endemic, with up to 77% prevalence in some areas. Due to preservation of hepatocellular function, prognosis of gastrointestinal bleed due to hepato-splenic schistosomiasis is considered better than in cirrhosis. To confirm liver fibrosis the gold standard is a liver biopsy but this is invasive and and prone to sampling error. We set out to observe the fibrotic markers and also evaluate inflammatory makers in patients with hepato- splenic schistosomiasis at the University Teaching Hospital (UTH) in Zambia. <h3>Methods</h3> This is a case control study of schistosomal related portal hypertension at the University Teaching Hospital in Lusaka Zambia. 40 patients have been recruited since mid September 2012 and the study is ongoing. All patients had varices. Blood was drawn to cheque full blood count, viral hepatitis profile, renal and liver function tests. Laminin and hyaluronic acid were used as markers of liver fibrosis while TNF receptor 1 and sCD14 were used as markers of inflammation. Serology for Schistosoma antibodies was done. Stool for parasitology and abdominal ultrasound were done. All patients were on propranolol or nadolol aiming for the pulse of less than 60/minute. <h3>Results</h3> 40 patients were evaluated. The sex ratio was M:F 23:17 and the mean age was 40.5. Serology for schistosomiasis was positive in 34 (85%) and negative in 6 (15%) patients. All patients were sero-negative for HIV except one and were sero-negative for hepatitis B and C viruses. All patients had marked thrombocytopenia with the median being 49 × 109/L (IQR 33.5–69.5) × 109/L. Median ALT was 29.35 U/l ( IQR 22.1–41.2) with 77.5% in the normal range. Of the 28 patients who submitted stool for parasitology 17 (61%) had no organism isolated, 4 (14%) had hook worms, 3 (11%) had Schistosoma eggs, 2 (7%) had ascaris and 2 (7%) had other organisms. Laminin levels (median 1608 ng/l, IQR 1416–1898) were all above normal. Hyaluronic acid levels were all higher than any of the standards in the ELISA kits and will have to be diluted to obtain precise values. All patients had elevated inflammatory markers: TNF receptor 1 concentrations were 10965 pg/ml (IQR 7990–15660; upper limit of normal 1966 pg/ml). Soluble CD14 values measured in ng/ml were equally found to be higher, median being 2469 (IQR1792–3119); upper limit of normal 2200ng/ml. <h3>Conclusion</h3> Schistosomiasis is a leading cause of portal hypertension in Zambia and it is associated with high levels of liver fibrotic markers which could be used to assess disease severity. It appears like hepato-splenic schistosomiasis induces high levels of inflammatory markers such as TNF receptor 1 and s CD14. <h3>Disclosure of Interest</h3> None Declared.
Abstract 628: Functional characterization of a diverse set of ERBB3 inhibitory antibodies
Authors: Sylvie Vincent, Solly Weiler, Christina Fleet, Steve Bottega, Michael Di Prima, Fang Wang, Donna McIntosh, Lyne Breault, Steven Tyler, Kristan Meetze, William Winston, Jeno Gyuris
Journal: Cancer Research (2011)

Abstract One important manifestation of the plasticity of cancer is the rapid escape from the effect of anti-cancer agents following initial therapeutic response. ERBB3, a kinase inactive member of the epidermal growth factor (EGFR) receptor family, which also includes EGFR, HER-2 and ERBB-4, has been linked to the development of resistance to multiple cancer therapies. The reactivation of ERBB3 following treatments with EGFR or HER-2 inhibitors has been observed in multiple tumor types following initial responses. The reactivation of ERBB3 signaling is thought to be the consequence of the formation of kinase active heterodimers of ERBB3 with EGFR, HER-2 and c-Met. ERBB3 heterodimer formation is consequence of a conformational change in the ErbB3 ECD (extracellular domain) in response to increased presence of the ERBB3 ligand NRG (neuregulin) or increased membrane concentrations of ERBB3 partners or ERBB3 itself which is often due overexpression or increased membrane localization. To understand the role of NRG dependent and independent ERBB3 activation mechanisms in the development of resistance to EGFR and/or HER-2 inhibitors, we set out to identify a diverse set of ERBB3 specific inhibitory monoclonal antibodies with different mechanisms of action. Immunizations with a mixture of tethered and opened ERBB3 ECD antigens allowed us to identify a large variety of potent ERBB3 inhibitors. Competition binding experiments have identified at least 5 independent binding sites for these antibodies on ERBB3. Some of these antibodies inhibited NRG binding (ligand neutralizers) while others did not interfere with ligand binding. Since a few of these antibodies bound to the dimerization domain (domain II) of ERBB3, we have inferred that they most likely inhibit the formation of ERBB3 heterodimers (dimerization inhibitors). In vivo activity of these antibodies was tested in tumor models driven by ligand independent and dependent activation of ERBB3 to identify the most promising candidate for the development of a highly potent ERBB3 therapeutic antibody with superior activity against both ligand dependent and independent ERBB3 heterodimers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 628. doi:10.1158/1538-7445.AM2011-628
Abstract 4479: Polymorphisms in the nucleotide excision repair genes, ERCC1 and ERCC2/XPD and carcinogen DNA adducts in human lung
Authors: Mi-Sun Lee, Chen-yu Liu, Li Su, John C. Wain, Eugene J. Mark, David C. Christiani
Journal: Cancer Research (2012)

Abstract Objectives Excision repair cross-complementing group 1 (ERCC1) and excision repair cross-complementing group 2/xeroderma pigmentosum group D (ERCC2/XPD) in the nucleotide excision repair (NER) pathways that removes DNA damage caused by tobacco smoking carcinogen such as polycyclic aromatic hydrocarbons (PAHs). However, no studies have examined their role in DNA adducts in target human lung tissue, a dosimeter for lung cancer risk. Therefore, we investigated whether the polymorphisms in SNPs in NER pathways associated with the DNA adduct formation in human lung tissue. We further analyzed these relationship divided by adenocarcinoma and squamous cell carcinoma, main type of non-small cell lung cancer (NSCLC). Methods The study population consisted of 135 lung cancer patients from the Massachusetts General Hospital (MGH). Genotyping was completed for SNPs in ERCC1 [C8092A (rs3212986) and C118T (rs11615)] and ERCC2/XPD [Asp312Asn (rs1799793) and Lys751Gln (rs1052559)] using PCR-RFLP method and the PCR with fluorescent allele-specific oligonucleotide probes (TaqMan method). DNA adduct levels were measured as relative adduct levels per 1010 nucleotides by 32P-postlabeling in the lung. Multiple regression models were used to estimate adjusted percent change in DNA adduct levels associated with genotypes of the NER genes ERCC1 and ERCC2/XPD. Results After adjusting for potential confounders, DNA adduct levels in lung increased by 73.5% [95% confidence interval (CI), –22.6 to 288.9] for the ERCC2/XPD rs1799793AA genotype and by 43.7% (95% CI, –30.0 to 194.6) for ERCC2/XPD rs1052559GG genotype compared with their corresponding wild type homozygous genotypes in overall lung cancer patients, but it did not reach statistical significance. We found that DNA adducts levels in lung increased by 166.6% (95% CI, –5.0 to 648.3, P = 0.07) for ERCC2/XPD rs1799793AA genotype in patients with squamous cell carcinoma and the trend was borderline significant (P for trend = 0.06). Conclusions Polymorphisms of DNA repair genes, ERCC2/XPD Asp312Asn, may affect increased level of DNA adducts in the lung. Further large scale studies are needed to confirm our findings. Supported by NIH grants CA074386, CA092824, and CA90578. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4479. doi:1538-7445.AM2012-4479
Antibiotics/antimicrobials: systemic and local administration in the therapy of mild to moderately advanced periodontitis
Authors: Karin Jepsen, Søren Jepsen
Journal: Periodontology 2000 (2016)

Abstract This review gives an update of the current scientific evidence on the efficacy of the adjunctive use of systemic and local antibiotics/antimicrobials in the treatment of periodontitis. In particular, it addresses whether their use can improve the results of nonsurgical mechanical therapy in mild‐to‐moderate forms of the disease. Large numbers of randomized clinical trials and systematic reviews with meta‐analyses have clearly established that adjunctive systemic antibiotics, combined with mechanical debridement, offer clinical improvements additional to those obtained with scaling and root planing alone. These effects are more pronounced in aggressive periodontitis and in initially deep pockets, whereas more limited additional improvements, of 0.3 mm for additional pocket reduction and 0.2 mm for additional clinical attachment gain, have been documented for moderately deep sites (4–6 mm) in patients with chronic periodontitis. The marginal clinical benefit in patients with moderate disease has to be balanced against possible side effects. Notably, it has to be realized that an increasing number of warnings have been articulated against the unrestricted use of antibiotics in treating periodontal diseases because of the emerging global public health issue of bacterial resistance. The effects of the adjunctive local administration of antimicrobials have also been very well documented in several systematic reviews. Overall, in persistent or recurrent localized deep sites, the application of antimicrobials by sustained‐delivery devices may offer a benefit of an additional 0.4 mm in pocket depth reduction and 0.3 mm in clinical attachment level gain. In conclusion, the slight additional benefits of adjunctive antimicrobials, which were shown for moderate forms of periodontitis, have to be balanced against their side effects and therefore their prescription should be limited as much as possible.
P28 The Use Of Smartphone Application (copd Assist) To Support The Implementation Of Local Primary Care Guidelines On The Management Of Patients With Copd
Authors: N. D. Bakerly, S. McCorkindale, G. Patel
Journal: Thorax (2014)

<h3>Introduction</h3> Smartphone applications (apps) have become increasingly popular and offer us up-to-date access to information “on the go”. Many national and international societies, medical journals and healthcare organisations develop their own apps; However using apps on a local level to promote implementation of local COPD guidelines and education has not been previously evaluated. <h3>Methods</h3> Funding was provided by Salford’s CCG innovation fund. A Smartphone app developing firm was commissioned and a development plan was agreed as follows: Close liaison with the lead respiratory physician throughout the project. A primary care focus group helped develop a Beta version for testing prior to launch. App launched as “COPD Assist” Promotion to primary care clinicians via newsletter articles, press releases, seminars, and the intranet Regular data collection on app downloads to measure usability Users’ feedback and suggestions via app reviews App downloads initially restricted to Salford clinicians <h3>Objectives</h3> Provide primary care clinicians with access to local guidelines and relevant contact details for COPD services anytime, anywhere. Provide the most up-to-date guidelines Offer clinicians access to educational material including videos (inhaler technique, spirometry, and pulmonary rehabilitation) and the opportunity to share this information with patients. Provide up to date pricing of various inhaled therapies <h3>Outcomes</h3> COPD Assist was launched in March 2014, then publicised to all Salford’s primary care clinicians supported by 5 training seminars with over 70 clinicians attending. Within 4 months following its launch, COPD assist was downloaded 622 times by different users, with an average use time of 7 min and average of 9 screens viewed per session. 52% of users have used the app more than once. Feedback was excellent, particularly around ease of use and simplicity. <h3>Conclusions</h3> This bespoke smartphone app to support the implementation of local primary care COPD guidelines appears to be widely acceptable to users and could potentially promote these guidelines. However, more research around clinically meaningful outcomes, such as adherence to guidelines and impact on prescribing, is required to assess the true impact of such technology on the management of COPD in primary care.
Abstract 4530: Nanoparticle formulation of KU55933 as a potent radiosensitizer.
Authors: Haydee Lara, Michael B. Foote, Edina C. Wang, Manish Sethi, Patricia Casbas-Hernandez, Andrew Z. Wang
Journal: Cancer Research (2013)

Abstract KU55933 is a potent and specific inhibitor of the Ataxia Telangiectasia Mutated (ATM) protein. Given ATM's critical role in DNA damage repair, specifically double-strand break repair, KU55933 holds high potential as a radiosensitizer. Indeed, previous preclinical studies have demonstrated the radiosentization effect of KU55933. However, clinical translation of KU55933 as a radiosensitizer has been prevented due to concerns of its potential toxicity. Systemic administration of KU55933 would sensitize normal cells as well as cancer cells to the effects of radiotherapy. Such sensitization would not improve the therapeutic index of radiotherapy. Therefore, the key challenge in the translation of KU55933 is to identify methods that can selectively deliver KU55933 to tumors while minimizing normal tissue dose. While traditional drug delivery methods cannot overcome this challenge, the development of nanoparticle (NP) drug delivery vehicles offers a unique opportunity. NPs are known to preferentially accumulate in tumors while provide low drug dose to nearby normal tissues. We hypothesize that NP delivery of KU55933 can not only improve the therapeutic efficacy of KU55933, but also lower its toxicity. In this study, we engineered a NP formulation of KU55933 using a biodegradable lipid-polymer NP. We then compared the radiosensitization effect of NP KU55933 to that of KU55933 in vitro using the non-small cell lung cancer (NSCLC) cell lines H23, A549 and H460. Clonogenic survival assays showed that NP KU55933 is a more potent radiosensitizer than KU55933. The differential radiosensitization effect of both KU55933 formulations was also evaluated in a xenograft mouse model of NSCLC. We validated our in vitro results by demonstrating that NP KU55933 is more effective than KU55933 as radiosensitizer in flank xenograft models of NSCLC. To compare the toxicity of NP KU55933 and KU55933, we determined the skin toxicity after radiotherapy with the two drug formulations. We found lower skin toxicity in mice treated with the NP KU55933 than that for KU55933. In conclusion, our studies demonstrate that NP formulation of KU55933 can enhance the radiosensitization effect and decreases the toxicity in vitro and in vivo. Our results suggest that NP KU55933 holds potential for clinical translation. Citation Format: Haydee Lara, Michael B. Foote, Edina C. Wang, Manish Sethi, Patricia Casbas-Hernandez, Andrew Z. Wang. Nanoparticle formulation of KU55933 as a potent radiosensitizer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4530. doi:10.1158/1538-7445.AM2013-4530