tbuckley/cabot-search huggingface dataset:
Abstract 4613: SMYD3-mediated lysine methylation is critical for the activation of AKT1 in human cancer
Authors: Yuichiro Yoshioka, Yusuke Nakamura, Ryuji Hamamoto
Journal: Cancer Research (2016)

Abstract v-Akt Murine Thymoma Viral Oncogene Homolog 1 (AKT1), a serine/threonine-protein kinase also known as protein kinase B Alpha (PKB Alpha), is a key mediator of a signaling pathway that governs various cellular processes regulating cell growth, survival, glucose metabolism, genome stability and neovascularization. It is known that dysregulation of AKT1 activity is one of the critical factors for the development and/or progression of a variety of human cancers. Posttranslational modifications of AKT1, including phosphorylation, ubiquitination and glycosylation, are well-analyzed, and it is known that the phosphorylation status of AKT1 is strongly correlated with its oncogenic activity. However, biological functions of methylation on AKT1 have never been analyzed so far. In the present study, we demonstrated that the protein lysine methyltrasnferase SMYD3 methylates lysine 14 in the PH domain of AKT1, which is known to play a critical role in the regulation of AKT1 activity through binding to phosphatidylinositol-3,4,5-triphosphate (PtdIns(3,4,5)P3) or phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P2), in vitro and in vivo. Lysine 14-substituted AKT1 shows significantly lower levels of phosphorylation at threonine 308, which is the major indicator of AKT1 activity, than wild-type AKT1, and knockdown of SMYD3 as well as treatment with a SMYD3 inhibitor significantly attenuates this phosphorylation in cancer cells. Furthermore, substitution of lysine 14 diminishes the plasma membrane accumulation of AKT1, and cancer cells overexpressing lysine 14-substiuted AKT1 shows lower growth rate than those overexpressing wild-type AKT1. These results imply that SMYD3-mediated methylation of AKT1 at lysine 14 plays a central role in the oncogenic activity of AKT1. Although Phosphatidylinositide 3-kinase (PI3K)-dependent AKT1 phosphorylation by Pyruvate Dehydrogenase Kinase, Isozyme 1 (PDK1) and mTOR Complex 2 (mTORC2) has long been considered to be the primary mechanism accounting for AKT1 activation, these members are not sufficient enough to explain how AKT1 hyperactivation can occur in tumors with normal levels of PI3K/Phosphatase And Tensin Homolog (PTEN) activity. Our findings unveiled the novel mechanism of constitutive hyperphosphorylation on AKT1 in cancer cells, mediated by SMYD3-mediated methylation. The inhibition of this methylation pathway appears to be a promising strategy to develop anti-cancer drugs. Citation Format: Yuichiro Yoshioka, Yusuke Nakamura, Ryuji Hamamoto. SMYD3-mediated lysine methylation is critical for the activation of AKT1 in human cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4613.
“Pragmatic” clinical trials: from whose perspective?
Authors: Paul J. Karanicolas
Journal: Annals of Internal Medicine (2009)

Over the past 40 years, methodologists have become increasingly enthusiastic about conducting “pragmatic” clinical trials, which aim to simulate real-world settings as much as possible.1 In contrast to explanatory trials that are conducted under idealised circumstances, successful pragmatic trials will have the intended benefit of directly informing healthcare decision making. We wholeheartedly support the notion that, to the extent possible, trials should inform real-world decisions. In this editorial, we will, however, argue that the current conceptualisation of pragmatic trials sometimes serves the needs of only a small proportion of healthcare decision makers. Furthermore, a truly pragmatic or practical trial requires that clinical trialists carefully define the real-world context to which they hope their results apply, and design their trials accordingly.2

Authors’ descriptions of pragmatic trials have varied slightly, but most agree that such trials should enrol all patients to whom healthcare providers might offer the intervention, allow clinicians to administer the intervention and co-interventions without restrictions, and measure patient-important outcomes. In this discussion, we will focus on one tenet of pragmatic trials: that these trials should include patients who do not take the intervention as prescribed, presumably in the same proportion as they are likely to be seen in the community. We will interpret the results of a recent self-described pragmatic trial of nortriptyline as an adjunct to nicotine replacement for smoking cessation3 from 3 perspectives. We show that although it may be pragmatic for some, it certainly isn’t for all healthcare decision makers.

The policy-maker is an employee of a third-party payer, who must decide which pharmaceutical products his organisation will fund for its members. His organisation is currently deciding whether to approve nortriptyline as an adjunct to nicotine …
Meta-analysis looks at effectiveness of MoodGYM programme in computerised cognitive behavioural therapy
Authors: Conal Twomey, Gary O’Reilly
Journal: BMJ (2016)

The REEACT trial (computerised cognitive behaviour therapy as treatment for depression in primary care) raised some unresolved research issues—for example, the predominance of developer led trials and the unclear effectiveness of the popular and free-to-use MoodGYM programme.1 Our meta-analysis of MoodGYM …
Lack of Prognostic Implications of Induction Response to Total Therapy 2 (TT-2) in Newly Diagnosed Patients with Multiple Myeloma (MM) for Post-Transplant Even-Free Survival (EFS) and Overall Survival (OS).
Authors: Guido Tricot, John Crowley, Julie Stover, Teresa Milner, Athanasios Fassas, Maurizio Zangari, Raymond Thertulien, Elias Anaissie, Frits van Rhee, Giampalamo Talamo, Klaus Hollmig, Bart Barlogie
Journal: Blood (2004)
Clinical Outcome After Occurrence Of Vitamin K-Antagonist Related Major Bleeding Complication: A Two-Year Observational Follow-Up Study
Authors: Nakisa Khorsand, Reinier M van Hest, Shakiba Zahedin Labbaf, Paula Ypma, Helga W Vermaas, Nic J.G.M. Veeger, Karina Meijer
Journal: Blood (2013)
Abstract 4537: Hexavalent chromium induces H4K16 hypoacetylation by NUPR1-mediated inactivation of histone acetyltransferase hMOF
Authors: Qiao Yi Chen, Xiaoru Zhang, Thomas Kluz, Max Costa, Hong Sun
Journal: Cancer Research (2016)

Abstract Hexavalent chromium [Cr(VI)] is a well-established carcinogen linked to respiratory cancer and has been found at half of US toxic waste sites. In spite of considerable research efforts, the mechanism of Cr(VI)-induced carcinogenesis remains largely unknown. A growing body of evidence suggests that Cr is capable of inducing epigenetic changes, such as DNA methylation, histone modification, and microRNA. Acetylation of histone lysine residues neutralizes the positive charge from their side chains and decreases the affinity between histone tails and DNA, which subsequently leads to increased DNA accessibility and transcriptional activation in the gene promoter region. However, the effect of Cr(VI) on histone acetylation is still not clear. Here, we report that BEAS-2B cells exposed to 5 or 10 uM of Cr(VI) for 24 hours resulted in a striking and dose dependent decrease in H4K16ac. Co-treatment with Cr(VI) and Benzo(a)pyrene diolepoxide (BPDE) induced further decrease in H4K16ac. Cr (VI) transformed cells showed considerable decrease in H4K16ac compared to the control cells, which further indicates the correlation between Cr(VI) exposure and hypoacetylation of H4K16. H4K16 acetylation is known as an important determinant in higher-order chromatin structure and active gene expression. Male Absent on the First gene (MOF) is a H4K16 specific acetyltransferase. Our results indicate that Cr(VI) exposure significantly reduced MOF activity while its expression levels remained the same, thus suggesting that Cr(VI) may affect MOF activity rather than its expression. Moreover, Nuclear protein 1 (NUPR1), a MOF inhibitor, was increased in Cr(VI)-exposed cells. Depletion of NUPR1 in cells by small RNA interference rescued Cr(VI)- reduced H4K16ac. Together, our results indicate that Cr(VI) inhibits MOF activity through inducing NUPR1 expression which subsequently leads to H4K16 hypoacetylation. Since hypoacetylation of H4K16 is a known hallmark of human cancer, the results from our study presents strong evidence supporting the role of H4K16 hypoacetylation in chromium carcinogenesis. . Citation Format: Qiao Yi Chen, Xiaoru Zhang, Thomas Kluz, Max Costa, Hong Sun. Hexavalent chromium induces H4K16 hypoacetylation by NUPR1-mediated inactivation of histone acetyltransferase hMOF. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4537.
S47 Neural respiratory drive responses to increases in continuous positive airway pressure in healthy subjects: Abstract S47 Table 1
Authors: ES Suh, S Mandal, MC Ramsay, G Rafferty, J Moxham, N Hart
Journal: Thorax (2015)

<h3>Introduction</h3> Dynamic hyperinflation (DH) is characterised by an increase in end-expiratory lung volume (EELV) and contributes to exercise limitation in Chronic Obstructive Pulmonary Disease (COPD) patients. Neural respiratory drive (NRD) directly reflects the load-capacity relationship of the respiratory system and is therefore expected to increase with DH. However, there are limited data investigating the effects of isolated increases in EELV on NRD. We hypothesised that 1) increases in EELV induced by continuous positive airway pressure (CPAP) would increase NRD in healthy subjects and 2) with the change in lung volume, NRD to the parasternal intercostal muscles would increase to a greater extent than that to the diaphragm at higher levels of CPAP. <h3>Method</h3> CPAP was applied to healthy subjects at 0, 4, 8, 12 and 16 cmH<sub>2</sub>O in a random order and inspiratory capacity (IC) measured at each CPAP level as an indicator of EELV. Transdiaphragmatic pressure swings (ΔP<sub>di</sub>), tidal volume (V<sub>T</sub>) and respiratory rate (RR) were measured. NRD was assessed with second intercostal space parasternal muscle electromyography (EMG<sub>para</sub>) and diaphragm electromyography (EMG<sub>di</sub>) using surface electrodes and a multipair oesophageal electrodes, respectively. EMG<sub>para</sub>/EMG<sub>di</sub> ratio was calculated. <h3>Results</h3> 10 healthy subjects were recruited. Increasing levels of CPAP led to a reduction in IC (p &lt; 0.0001, Table 1). Both EMG<sub>para</sub> and EMG<sub>di</sub> increased with progressive increases in CPAP (Table 1). Interestingly, respiratory rate and tidal volume did not change with the increases in CPAP. Similarly, EMG<sub>para</sub>/EMG<sub>di</sub> ratio and ΔP<sub>di</sub> remained unchanged. <h3>Conclusion</h3> This detailed physiological study has demonstrated that escalating levels of CPAP increased EELV, shown by the reduction in IC, in healthy subjects. The increase in EELV was associated with an increase in NRD to both the parasternal intercostal muscles and to the diaphragm. However, contrary to the original hypothesis and observations in COPD patients (O’Donoghue <i>et al</i>., Thorax 2001), NRD was not preferentially distributed to the parasternal intercostal muscles at higher lung volumes. These data indicate that the differential NRD to the parasternal and diaphragm in COPD patients is not solely a consequence of a rise in EELV and alternative mechanisms for the differential NRD should be sought. <h3>Reference</h3> 1 O’Donoghue FJ, Catcheside PG, Jordan AS, <i>et al.</i> Effect of CPAP on intrinsic PEEP, inspiratory effort, and lung volume in severe stable COPD.<i> Thorax</i>. 2002;<b>57</b>:533–9
Case 50-1968
Authors: Charles A. Sanders, Benjamin Castleman
Journal: New England Journal of Medicine (1968)

Presentation of Case First admission. A seventy-two-year-old semi-retired, self-employed man was admitted to the hospital because of progressive dyspnea.He had been well until ten years previously, when he began to experience dyspnea after walking two blocks. There had been no pain in the chest or syncope. Examination at that time disclosed third-degree heart block. During the seven years before admission, because of intermittent symptoms of congestive heart failure, he was maintained on a low-salt diet and diuretics. Six weeks before entry there was the onset of progressive dyspnea, and four weeks later he was forced to discontinue working. . . .
IL-33 Drives Augmented Responses to Ozone in Obese Mice
Authors: Joel A. Mathews, Nandini Krishnamoorthy, David Itiro Kasahara, Youngji Cho, Allison Patricia Wurmbrand, Luiza Ribeiro, Dirk Smith, Dale Umetsu, Bruce D. Levy, Stephanie Ann Shore
Journal: Environmental Health Perspectives (2016)

Ozone increases IL-33 in the lungs, and obesity augments the pulmonary effects of acute ozone exposure.We assessed the role of IL-33 in the augmented effects of ozone observed in obese mice.Lean wildtype and obese db/db mice were pretreated with antibodies blocking the IL-33 receptor, ST2, and then exposed to ozone (2 ppm for 3 hr). Airway responsiveness was assessed, bronchoalveolar lavage (BAL) was performed, and lung cells harvested for flow cytometry 24 hr later. Effects of ozone were also assessed in obese and lean mice deficient in γδ T cells and their wildtype controls.Ozone caused greater increases in BAL IL-33, neutrophils, and airway responsiveness in obese than lean mice. Anti-ST2 reduced ozone-induced airway hyperresponsiveness and inflammation in obese mice but had no effect in lean mice. Obesity also augmented ozone-induced increases in BAL CXCL1 and IL-6, and in BAL type 2 cytokines, whereas anti-ST2 treatment reduced these cytokines. In obese mice, ozone increased lung IL-13+ innate lymphoid cells type 2 (ILC2) and IL-13+ γδ T cells. Ozone increased ST2+ γδ T cells, indicating that these cells can be targets of IL-33, and γδ T cell deficiency reduced obesity-related increases in the response to ozone, including increases in type 2 cytokines.Our data indicate that IL-33 contributes to augmented responses to ozone in obese mice. Obesity and ozone also interacted to promote type 2 cytokine production in γδ T cells and ILC2 in the lungs, which may contribute to the observed effects of IL-33. Citation: Mathews JA, Krishnamoorthy N, Kasahara DI, Cho Y, Wurmbrand AP, Ribeiro L, Smith D, Umetsu D, Levy BD, Shore SA. 2017. IL-33 drives augmented responses to ozone in obese mice. Environ Health Perspect 125:246-253; http://dx.doi.org/10.1289/EHP272.
Abstract 1590: N-cadherin is a key marker for epithelial-to-mesenchymal transition in clinical prostate cancer
Authors: Kimberley Kolijn, Esther I. Verhoef, Geert J.L.H. van Leenders.
Journal: Cancer Research (2016)

Abstract Purpose of the study: Epithelial-to-mesenchymal transition (EMT) is characterized by E cadherin downregulation and simultaneous upregulation of mesenchymal markers such as vimentin, fibronectin and N cadherin. Studies on EMT are generally performed in cell lines and mouse models, while the histopathological and phenotypical properties in clinical prostate cancer (PCa) are still unclear. Our objective was to analyze the expression of various EMT markers in clinical PCa samples. Experimental procedures: We performed immunofluorescent double stainings with E cadherin and the mesenchymal markers N cadherin, vimentin or fibronectin, Zeb1, Twist1, and β catenin on fresh frozen radical prostatectomies. Summary: Immunofluorescent double stainings with E cadherin and the mesenchymal markers N cadherin, vimentin or fibronectin demonstrate that E cadherin was consistently downregulated in N cadherin positive PCa cells, but not vimentin or fibronectin positive PCa cells. Moreover, co expression of mesenchymal markers was uncommon, as PCa cells did not co express N-cadherin with fibronectin and only rarely (&amp;lt;1%) cells with vimentin. Membranous expression of β-catenin was unaltered in N cadherin positive PCa cells, while nuclear staining could not detected. Zeb1 was expressed in the nuclei of surrounding fibroblasts, but not in PCa cells. Twist1 was localized to the nucleus of some N-cadherin negative PCa cells, but not in N-cadherin positive cells. Conclusions: We demonstrated that N cadherin was the most reliable marker for EMT in clinical PCa as compared to vimentin and fibronectin, and that these mesenchymal markers were generally not expressed within the same cell population. The expression of N-cadherin was not associated with Twist1, Zeb1 or β-catenin expression. Despite extensive knowledge of EMT in PCa cell lines, the molecular mechanisms involved in EMT in clinical PCa is still unknown. Citation Format: Kimberley Kolijn, Esther I. Verhoef, Geert J.L.H. van Leenders. N-cadherin is a key marker for epithelial-to-mesenchymal transition in clinical prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1590.
Abstract 1085: Serum miR-30e and miR-223 are promising non-invasive biomarkers for hepatocellular carcinoma
Authors: Ratna B. Ray, Sourav Bhattacharya, Robert Steele, Adrian M. Di Bisceglie, Sounak chakraborty
Journal: Cancer Research (2016)

Abstract Hepatocellular carcinoma (HCC) is the world's third most common cancer and causes 600,000 deaths annually. Early detection is the key for improving the survival of HCC patients. Current diagnostic markers, such as alpha fetoprotein or fibroscan have their own limitations. Investigating serum microRNA as biomarkers for early diagnosis of cancer has become an important tool in clinical research. In this study, we tested the hypothesis that serum microRNAs (miRNAs) can be used as a potential biomarker for HCC. We analyzed serum miRNA using reverse transcriptase-quantitative PCR (qRT-PCR) from serum samples. Our study revealed that two miRNAs, miR-30e and miR-223, were expressed at significantly lower levels (P &amp;lt; 0.003) in the sera of HCC patients as compared to healthy volunteers. Further, expression of these miRNA was compared between sera from chronic liver disease (CLD) and HCC patients. miR-30e and miR-223 expression was significantly lower in HCC sera as compared to sera from CLD patients. Both miRNA expression levels were lower in HCC liver biopsy specimens as compared to normal liver RNA. Taken together, our results indicated that serum miR-30e and miR-223 are useful biomarkers of HCC irrespective of etiology. Citation Format: Ratna B. Ray, Sourav Bhattacharya, Robert Steele, Adrian M. Di Bisceglie, Sounak chakraborty. Serum miR-30e and miR-223 are promising non-invasive biomarkers for hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1085.
Abstract 673: The role of MYPT1/2, ASPP2 and MYH9 in invasive lobular carcinoma
Authors: Koen Schipper, Julian de Ruiter, Sjors Kas, Eva Schut, Marco Koudijs, David Addams, Jos Jonkers
Journal: Cancer Research (2016)

Abstract Invasive lobular carcinoma (ILC) accounts for 10-15% of breast cancer cases in women. One of the characteristics of this type of cancer is the loss of intercellular adhesion which is facilitated by inactivating mutations in E-cadherin. However the loss of E-cadherin alone is not enough to induce ILC. An in vivo Sleeping Beauty insertional mutagenesis screen was performed to identify genes that together with E-cadherin loss contribute to ILC development in mice. In around 85% of the tumors that were analyzed during this screen one of four hits were observed, namely MYPT1, MYPT2, ASPP2 and MYH9. Interestingly these four hits appear to be mutually exclusive indicating a shared mechanism of action. To investigate how these genes might affect tumorigenesis we first looked at the location of the transposon insertions. This revealed that for MYPT1, MYPT2 and ASPP2 the transposons appeared to localize to a specific region in the gene indicating that these insertions could result in a truncation variant. In the case of MYH9 no clear localization of insertions was found which in combination with the recently published data indicates a loss of function. Northern blot analysis revealed the presence of truncation variants for MYPT1/2 and ASPP2 which for MYPT1 were confirmed to also result in truncated protein variants. In order to identify the tumorigenic potential of truncated MYPT1 and ASPP2 we overexpressed them in spontaneously immortalized mammary epithelial cell lines HC11 and NMuMG. We are using these cell lines to analyse differences in cell proliferation, anchorage independent growth, sensitivity to apoptosis in vitro and tumor formation in vivo. To further analyse the hits in an E-cadherin negative setting we made use of primary mammary epithelial cells (MECs) isolated from genetically engineered mice with mammary gland specific E-cadherin loss. These MECs normally do not grow past several passages in vitro. However, these MECs when we overexpress truncated MYPT1 or ASPP2, or use shRNA mediated knockdown of MYH9 can be passaged and grown in vitro consistently. Finally we are generating conditional mouse models with mammary gland specific E-cadherin loss in combination of expression of the truncated variants of MYPT1 or ASPP2, or loss of MYH9. We will to monitor whether these mice are prone to developing ILC. Citation Format: Koen Schipper, Julian de Ruiter, Sjors Kas, Eva Schut, Marco Koudijs, David Addams, Jos Jonkers. The role of MYPT1/2, ASPP2 and MYH9 in invasive lobular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 673.