tbuckley/cabot-search huggingface dataset:
Abstract 5682: Tanshinones in Salvia miltiorrhiza as potential chemopreventive agents against lung cancer
Authors: Yanli Li, Yi Gong, Linglin Li, Jin-Rong Zhou
Journal: Cancer Research (2010)

Abstract The search for effective regimens with minimal adverse effects for the prevention and treatment of lung cancer remains the top priority research to eradicate this devastating disease. Several essential components determine the opportunity of success in identifying the candidate compounds, which include enhanced tissue levels, preferably in lungs after administration, safety use profiles, and more importantly preclinical evidence that is derived from clinically relevant in vivo systems. A Chinese herb medicine Salvia miltiorrhiza (Danshen) has been widely used for centuries for treatment of cardiovascular diseases without reported side effects to healthy humans. After oral administration, tanshinones are preferably accumulated at the highest levels in lungs. Several Danshen compounds, such as tanshinone IIA (T2A), tanshinone I (T1) and cryptotanshinone (CT), have also been reported to have potent activities in vitro against several cancer types including lung cancer. These promising findings strongly support that tanshinones may have potent anti-cancer, especially anti-lung cancer activities. The long-term goal of this research is to develop tanshinones as effective and safe agents for the prevention and treatment of lung cancer. We first evaluated the effects of tanshinones on the growth inhibition of lung cancer cell lines in vitro. All three tanshinones showed dose-dependent inhibition to the growth of human (H1299, H23, and A549) and murine (LLC) lung cancer cell lines at low μM ranges with T1 the most potent. Interestingly, LLC, which is usually resistant to drug treatment, was the most sensitive cell line to T1 treatment (IC50 at 3μM), but it was insensitive to T2A treatment. Cell cycle analysis showed that CT and T1 arrested cells (H1299) at S phase, whereas T2A arrested cells at G2/M phase. The growth inhibition and cell cycle arrest activities of tanshinones were associated with downregulation of cdc2 and Aurora A expression. Because T1 showed the most potent activity, we are evaluating its effect on the growth inhibition of lung tumors in mice and on the modulation of cellular and molecular markers. It is expected that the studies will provide experimental evidence to support the chemopreventive and/or therapeutic activities of tanshinones against lung cancer. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5682.
A1.71 Reduced dicer expression correlates with rheumatoid arthritis
Authors: Ghada Alsaleh, Stephan Bluml, Ramzi Nehmar, Angélique Pichot, Jacques-Eric Gottenberg, Laurent Vallat, Gernot Schabbauer, Seiamak Bahram, Jean Sibilia, Philippe Georgel
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background and Objectives</h3> A large body of evidence supports the role of microRNAs (miRNAs) in inflammatory diseases. Concerning rheumatoid arthritis (RA), several miRNAs exhibiting deregulated expression pattern were identified in various fluids (serum or synovial) or different cell types (macrophages, synoviocytes). The potential interest of these molecules as biomarkers is increasingly considered, but their precise mode of action still remains largely hypothetical because the identification of their physiological mRNA targets is challenging. To evaluate the overall importance of miRNAS in the pathogenesis of RA, we investigated the expression of genes involved in miRNA biogenesis in FLS isolated from healthy donors and RA patients. We also used a mouse mutant line carrying a hypomorphic mutation in the Dicer gene to monitor the impact of reduced miRNA maturation on experimental arthritis triggered by K/BxN serum transfer. <h3>Materials and Methods</h3> Human FLS were isolated from synovial tissues from RA and OA patients and healthy controls after informed consent. Mice FLS were isolated from Dicer d/d and littermates controls. IL-6 release was measured in culture supernatants and following RNA extraction using TRIzol and reverse transcription, real-time quantitative RT-qPCR was performed. Handling of mice and procedures were in accordance with the French Law for the Protection of Laboratory Animals and reviewed by the Regional Ethical Committee for Animal Experimentation (CREMEAS) of the Strasbourg University (authorisation number A-67-345). Serum collected from 9-week old arthritic K/BxN mice was used to trigger arthritis in adult Dicer <sup>d/d</sup> and + / + mice by two successive i.p. injection (150 μL). The articular arthritis index was visually determined on a 0–4 scale (0 = no swelling or erythema, 4 = excessive edema with joint rigidity). <h3>Results</h3> Dicer is the only gene involved in the miRNA biogenesis pathway showing significantly reduced expression in FLS isolated from RA patients compared to controls or OA. Similarly, mutant mice (Dicer <sup>d/d</sup>) with reduced Dicer expression exhibit more severe arthritis symptoms upon K/BxN serum transfer. <h3>Conclusions</h3> miRNAs are important players to keep pro inflammatory molecules under tight control. Mutations globally affecting mature miRNAs production represent a previously unidentified risk factor for RA.
Abstract 4321: Development of pyrrolobenzodiazepine-based antibody-drug conjugates for cancer.
Authors: Scott C. Jeffrey, Patrick J. Burke, May K. Sutherland, David W. Meyer, Robert P. Lyon, Julie A. McEarchern, Che-Leung Law, Peter D. Senter
Journal: Cancer Research (2013)

Abstract Pyrrolobenzodiazepine (PBD) dimers are highly cytotoxic minor groove binding DNA crosslinking agents derived from the anthramycin class of natural products. In our efforts to develop highly effective and well-tolerated treatment options for cancer patients, we have investigated several antibody-drug conjugates (ADCs) based on a PBD dimer. The fully synthetic PBD-linker, comprised of a protease-cleavable val-ala sequence and a reactive maleimide group, was conjugated via engineered cysteine residues to humanized monoclonal antibodies specific for their binding to the well-characterized cancer antigen targets, CD33 and CD70. The resulting ADCs were well-defined, monomeric and showed pronounced in vitro and in vivo activity against both hematologic and solid tumor cancer models. These included models of acute myelogenous leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma and renal cell carcinoma. The ADCs were immunologically specific, and showed potent activity in MDR-positive models, including models resistant to other ADCs. These results underscore the importance of the drug component in developing highly efficacious ADCs for cancer therapy. Citation Format: Scott C. Jeffrey, Patrick J. Burke, May K. Sutherland, David W. Meyer, Robert P. Lyon, Julie A. McEarchern, Che-Leung Law, Peter D. Senter. Development of pyrrolobenzodiazepine-based antibody-drug conjugates for cancer. [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 4321. doi:10.1158/1538-7445.AM2013-4321
TCT-755 Sex-differences in Post-procedural Aortic Regurgitation and Mid-term Mortality after Transcatheter Aortic Valve Implantation
Authors: Giuseppe Ferrante, Paolo Pagnotta, Anna Sonia Petronio, Francesco Bedogni, NEdy Brambilla, Claudia Fiorina, Cristina Giannini, Marco G. Mennuni, Federico De Marco, Silvio Klugmann, Federica Ettori, Patrizia Presbitero
Journal: Journal of the American College of Cardiology (2013)
First NHS club drug clinic opens its doors
Authors: J. Wise
Journal: BMJ (2011)

The number of people experiencing problems after taking club drugs such as ketamine and mephedrone is rising, says the founder of the first NHS clinic in the United Kingdom set up specifically to tackle the issue.

The Club Drug Clinic in west London opened its doors this week to deal with problems associated with excessive use of drugs such as ketamine, mephedrone, GHB (γ-hydroxybutyric acid) and GBL (γ-butyrolactone), crystal methamphetamine, ecstasy, and the growing number of “legal highs.” The founders of the clinic say that current drug services primarily focus on crack cocaine and heroin use, which is actually in decline.

Owen Bowden-Jones, a consultant psychiatrist at Imperial College London and a founder of the clinic, said, “Patterns of drug use in the UK are changing, and over the last two or three years we have continued to see an increase in …
Discrimination against People with AIDS
Authors: Robert J. Blendon, Karen Donelan
Journal: New England Journal of Medicine (1988)

ON June 2, 1988, Retired Admiral James D. Watkins, chairman of the President's Commission on AIDS (acquired immunodeficiency syndrome), called for a federal law barring discrimination against those who are infected with the human immunodeficiency virus (HIV). As he envisioned the law, the federal statutes now designed to protect the rights of the disabled and the handicapped would be expanded to prohibit discrimination against persons infected with HIV.1 In his press conference, Watkins stated that the threat of discrimination is "the most significant obstacle to progress" against the epidemic. "If the nation does not address this issue squarely," he said, . . .
A transcriptional regulatory mechanism in invasive breast cancer; role of AIB-1 and PEA-3.
Authors: Z Al-Hilli, AM Redmond, AD Hill, LS Young
Journal: Cancer Research (2009)

Abstract Abstract #2056 The invasive potential of cancer cells is mediated in part through the action of matrix metalloproteinases (MMP), which degrade the extra-cellular membrane and promote metastasis. The transcription regulatory region of MMP genes contains binding sites for Ets transcription factors. While the underlying mechanism of MMP regulation is unclear, the Ets transcription factor PEA3 has been shown to be involved. We have previously reported that expression of PEA-3 is associated with the co-activator AIB-1, HER2 positivity, metastasis, and reduced disease free survival. Furthermore, an AIB-1 knockout mouse exhibited PEA-3 dependant MMP production, resulting in reduced metastatic potential. In this study we combined translational and molecular approaches to study the role of PEA-3 and AIB-1 in the transcriptional regulation of MMPs in breast cancer.&amp;#x2028; The expression of PEA-3, AIB-1, and MMP-9 was assessed in a tissue microarray of breast cancer patients (n=560). Strong associations were observed between both PEA-3, AIB-1, and their target gene MMP-9 (p= 0.007, p= 0.0016 respectively). In HER2 positive patients PEA-3, but not AIB-1 or MMP-9, was associated with reduced disease free survival (p&amp;lt;0.0044, p= 0.4491, and p= 0.0666 respectively). A stable breast cancer cell line over-expressing PEA-3 was created. Upregulation of the growth factor pathway in this cell line resulted in the increased expression of MMP-9. Furthermore, silencing AIB-1 resulted in reduced MMP-9 production in breast cancer cells in vitro.&amp;#x2028; Ets transcription factors are important mediators of breast tumour invasion. This data supports a role for the transcription factor PEA-3 and its co-activator AIB-1 in the production of MMPs in breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2056.
P89 Osteopontin promotes lymphocyte recruitment in steatohepatitis
Authors: E. Liaskou, L. C. Claridge, H. Shah, Y. Oo, J. Shaw, Z. Mi, P. C. Kuo, A. Canbay, A. M. Diehl, D. H. Adams, W.-K. Syn
Journal: Gut (2011)

<h3>Introduction</h3> Steatohepatitis is the critical step in the progression to fibrosis, and is characterised by increased inflammatory cell recruitment from the circulation. The cytokine Osteopontin (OPN) is intricately involved in cell-recruitment and tissue-repair, and we reported that OPN is significantly upregulated during non-alcoholic steatohepatitis (NASH). <h3>Aim</h3> Thus, we hypothesised that OPN promotes steatohepatitis by supporting leucocyte migration across hepatic sinusoidal endothelium. <h3>Method</h3> Wild-type mice were fed chow or methionine-choline deficient (MCD) diet to induce NASH. After 4 weeks, mice were sacrificed; severity of disease assessed by serum aminotransferase (AST), hepatic OPN quantified by QRTPCR and immunohistochemistry, serum OPN measured by ELISA. In separate experiments, MCD-fed mice were treated with anti-OPN or IgG, and flow cytometry used to quantify numbers of liver infiltrating lymphocytes (LIL). Primary human hepatic sinusoidal endothelial cells (HSEC) were stimulated with recombinant (r) OPN (0–1000 ng/ml), and expression of adhesion molecules (ICAM-1, VCAM-1, CD31) quantified by western blot. To assess lymphocyte transendothelial migration, lymphocytes were perfused over rOPN- or vehicle-treated-HSEC, with or without TNFa (20 ng/ml) + IFNa (100 ng/ml). In separate experiments, TNFa+IFNa stimulated-HSEC were treated with sham or OPN-aptamers and total lymphocyte adhesion recorded. Human livers with NASH were immunostained for OPN, and FACS used to quantify LIL isolated from control or NASH-cirrhotic patients. <h3>Results</h3> In mice, diet-induced NASH upregulated expression of hepatic OPN by threefold (p&lt;0.05), serum OPN by twofold (p&lt;0.05), and increased intrahepatic CD4 by 2.2-fold, CD8 by 4.5-fold, and NKT cells by 3.2-fold (p&lt;0.05). MCD-fed mice treated with anti-OPN accumulated fewer CD3, CD4, CD8 and NKT cells (p&lt;0.05), and exhibited attenuated injury (ALT: threefold reduction; p&lt;0.02). rOPN induced expression of ICAM-1, VCAM-1 and CD31 on human HSEC, enhanced lymphocyte recruitment under conditions of flow (41%), and amplified recruitment capacity of TNFα+IFNγ stimulated HSEC (23%), while OPN neutralisation with RNA-aptamers reduced lymphocyte recruitment by 50% (all p&lt;0.05). In humans, expression of OPN was significantly upregulated in NASH; livers from NASH-cirrhosis harboured twofold more CD4 and threefold more CD8 and NKT cells (p&lt;0.05) than normal. <h3>Conclusion</h3> OPN is upregulated during steatohepatitis in mice and humans, and promotes lymphocyte recruitment across HSEC. Neutralisation of OPN significantly reduces lymphocyte recruitment and liver injury. Our results suggest that OPN is a promising anti-inflammatory target in steatohepatitis.
Abstract 3176: Preclinical validation of the sensitivity and specificity of a fluorescent nanobeacon for its application in colonoscopy-based imaging of colorectal cancer
Authors: Wellington Pham, Hironori Kumagai, Ken-Ichiro Hiwatari, Hiroyuki Tachikawa, Ryoji Kimura, Kunio Nakamura, Makoto Kataoka, Shinji Yamashita, Shinji Sakuma
Journal: Cancer Research (2011)

Abstract Colorectal cancer is the third most commonly diagnosed type of cancer and the second leading cause of cancer-related death in the U.S. Currently, the key element in the control, prevention, and treatment of this disease is recognition of its early symptoms. In this work, we describe the development and validation of a specific fluorescent nanobeacon that targets the Thomsen-Friedenreich (Tf) antigen, potential biomarkers of this disease, via the terminal carbohydrate Gal-β(1-3)GalNAc. The imaging agent is comprised of a submicron-sized polystyrene nanosphere encapsulated with a hydrophobic fluorescent dye. The surface of the nanosphere was modified with the peanut agglutinin (PNA) and poly(N-vinylacetamide (PNVA) moieties. The former binds to Gal-β(1-3)GalNAc with high affinity, while the latter enhances the specificity of PNA for the carbohydrates. This nanobeacon detects colorectal tumors by recognizing the tumor-specific antigen through the surface-immobilized PNA, and identification is made via the fluorescence signal obtained from the coumarin-6 encapsulated in the nanosphere's core. Biorecognition by the probe has been demonstrated in cell lines and orthotopic mouse models. Here, we assessed the sensitivity and specificity of the probe in a pre-clinical MUC1 transgenic mouse model. Of note, the probe reported that the Tf antigen expression level is high in the colon and intestine of that model compared to wild- type mice. Data obtained by fluorescence imaging using this probe correlates well with those obtained via immunohistochemistry. Most importantly, the probe was not absorbed systemically upon topical application in the host. As a result, no registered toxicity is associated with the probe. Using the Tf antigen imaging approach, we are evaluating the binding specificity of the nanobeacon in panel of human colorectal cancer tissues. Thus far, the study has indicated quantitatively a 5-fold enhancement of the Tf expression in colon cancer tissue versus the control tissue. In sum, these data demonstrate the potential for the use of this novel nanobeacon in imaging the Tf antigen as a biomarker for the early detection and prediction of the progression of colorectal cancer. Currently, several probe optimization processes are presently being carried out in our laboratory, including the incorporation of near-infrared fluorescent dyes to enhance the signal-to-noise ratio. Detailed results of the biometric validation of the nanobeacon will be reported in a timely manner. 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 3176. doi:10.1158/1538-7445.AM2011-3176
Middle East perspectives: Call for papers
Authors: Christiane Rehwagen, Tessa Richards
Journal: BMJ (2006)

On 21 October the BMJ will publish a cluster of articles drawing attention to some of the key health problems, policy challenges, and research priorities in the Middle East region. The issue will be linked to the 10th meeting of the Global Forum for Health Research, which is being held in Cairo (29 October to 2 November) with the broad theme of combating disease and promoting health.

The richly diverse countries of the eastern Mediterranean and Middle East region contain both some of the wealthiest and some of the most deprived populations of any region. Sociocultural contrasts are marked, and health challenges, priorities, and expectations are equally varied. There are, nevertheless, issues of common concern. These include the growing burden of non-communicable disease, a high incidence of genetic and inherited disorders, rising rates of injury, rising rates of communicable disease including HIV/AIDS, poor access to reproductive health services, the relatively weak position of women and civil society, and the searing impact on health of political unrest and armed conflict.

We welcome submission of original research papers, particularly in relation to the topics outlined above. Brief papers for the Analysis and comment section of the journal, aimed at airing regional debates and controversies and drawing attention to innovative health initiatives and the positive impact of strong social and cultural values, are equally welcome, along with personal views and letters. We want to hear from clinicians and researchers who have much to say but whose voices are heard infrequently in Western journals.

Detailed guidance on paper format and online submission is given on www.bmj.com. Papers will be peer reviewed in the usual way and should reach us by 10 June.

To further this exchange, please send us your views on topics for this issue to cover via our rapid responses facility on bmj.com and respond to the questions we have linked to the online version of this editorial.

Advisers to the issue are Dr Mohamed Abdurrab, Dr Abdul Ghaffar, and Dr Zulfiqar Bhutta.
What Is Professionalism and How Can We Promote It?
Authors: Jay Harolds
Journal: Clinical Nuclear Medicine (2011)

Professionalism is understood differently by members of different professions and within the medical profession itself. In its broadest sense, medical professionalism encompasses all of the aspects of the higher attributes of being a physician. This article explores some of the characteristics of being a professional, some of its challenges, and what we can do to promote professionalism.
THU0480 Candidate Gene Discovery in Autoimmunity by Using Extreme Phenotypes and Whole Exome Capture
Authors: M. Arcos-Burgos, A. Johar, J. Amaya-Amaya, R.D. Mantilla, D. Andrews, A. Rojas-Villarraga, J.-M. Anaya
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> The multiple autoimmune syndrome (MAS) is defined as a condition characterized by the presence of three or more autoimmune diseases (ADs) in one patient. We demonstrated that MAS identifies extreme forms of ADs and is frequently clustered in families. MAS phenotypes present in families often displays Mendelian segregation ratios, representing crucial evidence for identifying major genes associated with autoimmunity. <h3>Objectives</h3> To finds new autoimmune genes. <h3>Methods</h3> We applied whole exome capture (WEC) and next generation sequencing (NGS) to 12 MAS sporadic cases and 24 individuals ascertained from pedigrees segregating MAS. WEC was performed using the Nimblegen kit and NGS was performed using the Illumina HiSeq platform. Our variant calling pipeline generated 22,000 - 23,000 variants per individual. To filter these variants, we devised appropriate strategies including minor allele frequency (MAF) in the dbSNP database, implementation effect predictor tools (PolyPhen and Sift, among others) and genes inherited as potential compound heterozygotes, and homozygotes in individuals. <h3>Results</h3> In total we found several genes with variants that had the following characteristics: inherited in patients as a compound heterozygous or homozygous form and creating deleterious amino acid substitutions. In addition these mutations were either novel (not annotated in dbSNP) or rare (MAF less than 5%). We then implemented the Kernel Based Adaptive Cluster (KBAC) to collectively weight rare variants at candidate loci and determined which multi locus genotypes in patients were significantly enriched in cases over controls. This information was compared with data from our initial variant filtration strategies as well as pathway and network analysis tools from the Metacore Software Suite. In summary, we obtained several candidate genes with multi site variant genotypes that were substantially prevalent in autoimmune patients compared to unaffected individuals. These genes include PKD1, ALPK2 and OBSCN. Two of the 3 aforementioned genes are involved in important immunological processes such as calcium signalling, T cell activation, and immunoglobulin domain phosphorylation. <h3>Conclusions</h3> These results suggest that these genes might be important themes for deeper studies in larger cohort of patients affected by autoimmune disorders and polyautoimmunity. <h3>Acknowledgements</h3> Financed by Colciencias (122254531722), Bogota, Colombia. <h3>Disclosure of Interest</h3> : None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.4809