tbuckley/cabot-search huggingface dataset:
Abstract 1873: The role of p21-activated kinase 4 (PAK4) in cancer stemness and epithelial-to-mesenchymal transition
Authors: Asfar S. Azmi, Irfana Muqbil, Amro Aboukameel, William Senapedis, Erkan Baloglu, Yosef Landesman, Sharon Shacham, Michael Kauffman, Philip A. Philip, Ramzi M. Mohammad
Journal: Cancer Research (2016)

Abstract The p21-activated kinase 4 (PAK4) is a key downstream effector of the Rho family GTPases. PAK4 is found to be over-expressed in many oncogenic Ras-driven cancers and cell lines but not in their normal counterparts. Mesenchymal pancreatic ductal adenocarcinoma (PDAC) stem cells (CSCs) that are triple positive for stemness markers (CD133+, CD44+, and EpCam+) as well as Ras and snail transduced human mammary epithelial cells (HMLER-snail) showed enhanced expression of PAK4 along with activation of Rho, Rac1 and CDC42. PAK4 RNA interference resulted in disruption of PDAC CSC spheroids, reduction of mesenchymal markers (i.e. vimentin and snail) and suppression of CSCs potential to form subcutaneous tumors in mice. These findings point to a novel role of PAK4 in promoting oncogenic Ras-driven EMT and stemness. Using PDAC CSCs (MiaPaCa-2 and L3.6pl) and human mammary epithelial cells (HMECs) that are transduced with Ras and the EMT promoter snail (HMLE-Snail and HMLER-Snail), we investigated the impact of PAK4 allosteric modulators [PAMs (KPT-7189, KPT-7523, KPT-9274 and KPT-9307)] on the reversal of EMT and stemness. The toxicity and efficacy of PAMs were evaluated in vitro and in multiple sub-cutaneous xenograft models. PAMs show anti-proliferative activity in vitro against different PDAC CSCs and HMECs while sparing normal cells. Cell growth inhibition was concurrent with apoptosis induction, suppression of colony formation and reversal of mesenchymal morphology to epithelial (MET). PAMs not only reduced PAK4 RNA and protein steady state levels but also inhibited proliferative and anti-apoptotic signals downstream of PAK4. PAMs caused suppression of EMT markers (EpCAM, vimentin and snail) and re-expression of an epithelial promoter E-cadherin. PAM treatment inhibited RhoA, Rac1 and CDC42 activation in GLISA assays. KPT-9274 showed remarkable anti-tumor activity in sub-cutaneous xenograft models of CSCs and residual tumors showed suppression of EMT markers that was concurrent with inhibition of PAK4 signaling. These studies open a novel therapeutic opportunity against EMT and cancer stem cells through PAK4 inhibition. Citation Format: Asfar S. Azmi, Irfana Muqbil, Amro Aboukameel, William Senapedis, Erkan Baloglu, Yosef Landesman, Sharon Shacham, Michael Kauffman, Philip A. Philip, Ramzi M. Mohammad. The role of p21-activated kinase 4 (PAK4) in cancer stemness and epithelial-to-mesenchymal transition. [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 1873.
Dissonance reduction as prominent coping strategy in phase I study participants.
Authors: Diane A.J. van der Biessen, Dennis Klein, Peer G.H. P. van der Helm, Martijn P. Lolkema, Ron H.J. Mathijssen, Maja J. De Jonge
Journal: Journal of Clinical Oncology (2015)

9551 Background: Phase I trials are essential for progress in cancer treatment but the reasons for patients to participate in these trials remain relatively ill-explored (Van der Biessen et al, 2013). This study aims to understand how psychological factors like coping strategies, locus of control, and hope affect the motivation to participate in these trials. Methods: In this prospective study we asked patients to complete a survey before initial informed consent for the phase I study was obtained for the first time. We used questionnaires regarding treatment motivation (TM, Van der Helm et al, 2012), hope (Herth Hope Index), coping (assimilation and accommodation coping-scale of Brandtstädter and Renner), locus of control (Rotter locus of control scale) and Quality of Life (QoL, EORTC QLQ-C30). To investigate relations between the scales a structural equation model (SEM) was fitted to the data. Results: During 18 months 135 patients enrolled in the questionnaire survey. 65 (48%) of the patients were male, with a mean age of 62 (range 30-83). The SEM-analysis showed ‘hope’ was significantly predicting treatment motivation X2 (5) = 5.119. Fit indices showed a close fit: NFI = 0.996; CFI = 0.999; TLI = 0.996; RMSEA = 0.013. An unique combination of flexible (p < 0.01) and tenacious (p < 0.01) coping, together with internal locus of control (p < 0.01) was predicting for ‘hope’. Conclusions: Patients entering phase I studies seem to combine seemingly contradictory coping strategies: tenacity and flexibility. Also locus of control contributes towards hope. These data suggest a specific psychological adaptation, called dissonance reduction. This process that unconsciously discounts threatening information (i.e. about fatal prognosis of the disease) predicts for the motivation to participate in oncology phase I trials. Clinical trial information: NTR3354.
P106 Validity of the Clinical COPD Questionaire (CCQ) in Non-COPD Patients: Abstract P106 Table 1
Authors: MM Mittal, SSC Kon, AL Clark, D Dilaver, MM Peasey, JL Canavan, SE Jones, MGS Ng, MI Polkey, WD-C Man
Journal: Thorax (2012)

<h3>Background</h3> The Clinical COPD Questionnaire (CCQ) is a 10-item health status instrument that takes only two minutes to complete, and has been shown to be reliable and valid in patients with COPD (van der Molen T et al 2003, Damato S et al 2005). In COPD patients, the CCQ correlates with established health status instruments such as the Chronic Respiratory Disease Questionnaire (CRQ), COPD Assessment Test (CAT) and St George’s Respiratory Questionnaire (SGRQ) (Tsiligianni IG et al 2012). Although the CRQ and SGRQ were originally developed in patients with chronic airway obstruction, they are commonly used in clinical practise in chronic respiratory diseases other than COPD. We hypothesised that the CCQ would correlate with existing health status measures and exercise capacity in a survey of non-COPD patients <h3>Methods</h3> 60 patients were recruited from respiratory outpatient clinics. Disease classifications included interstitial lung disease (n=23), asthma (n=10), bronchiectasis (n=17), extrathoracic restriction (n=8) and thoracic surgery for lung cancer (n=2). CCQ, CAT, CRQ, SGRQ and incremental shuttle walk (ISW) were recorded. Spearman’s rank correlation was used to assess the relationship between CCQ and other outcome measures. <h3>Results</h3> Baseline characteristics are presented as mean (standard deviation) or median (25th, 75th percentiles); Age 65 (58, 77), FEV1% predicted 69.8 (24.4), BMI 28.0 (25.4, 32.3), MRC 3(1), CCQ 2.1 (1.5, 3.8) and ISW 210 (90, 320). There was a significant correlation between the total CCQ and CAT, SGRQ, CRDQ, MRC and ISW (all p&lt;0.01 see Table. 1). In addition individual domains of the CCQ correlated significantly with MRC, CAT and individual domains of the CRQ (p&lt;0.01). <h3>Conclusions</h3> The CCQ correlates well with existing health status and functional outcome measures in non-COPD patients. CCQ may be a useful assessment tool to test the efficacy of interventions such as pulmonary rehabilitation in this population, but longitudinal studies are required to confirm.
Abstract P6-08-20: Prognostic significance of the interferon metagene in node-negative breast cancer depends on the molecular subtype
Authors: Marcus Schmidt, Leonie van de Sandt, Karolina Edlund, Isabel Sicking, Marco Battista, Anne-Sophie Heimes, Antje Lebrecht, Gerald Hoffmann, Mathias Gehrmann, Jörg Rahnenführer, Jan G Hengstler
Journal: Cancer Research (2015)

Abstract Background: Interferons are crucial for adaptive immunity and play an important role as central coordinators of tumor-immune system interactions. We examined the subtype specific prognostic significance of an interferon (IFN) metagene in node-negative breast cancer. Methods: Using microarray based gene-expression data, we identified co-regulated genes related to biological processes. After hierarchical clustering, we defined an interferon (IFN) metagene which was composed of 36 interferon-stimulated genes. The subtype specific prognostic role of the IFN metagene was analysed in four previously published cohorts (Mainz, Rotterdam, Transbig, Yu) of node-negative breast cancer patients not treated with adjuvant therapy (n=824). A meta-analysis of previously published cohorts was performed using a random effects model. Prognostic significance of the IFN metagene for metastasis-free survival (MFS) was examined in different molecular subtypes: luminal A (ER+/HER2-/aurora kinase A [AURKA]low, luminal B (ER+/HER2-/AURKAhigh), basal-like (ER-/HER2-), and HER2+. Results: Prognostic significance of the IFN metagene was restricted to the HER2+ positive molecular subtype (HR 0.50, 95% CI 0.28-0.88, P=0.0056). Prognostic effects were not seen in luminal A (HR 1.00, 95% CI 0.65-1.53, P=0.8819), luminal B (HR 1.00, 95% CI 0.76-1.32, P=0.9770) or basal-like (HR 0.87, 95% CI 0.66-1.15, P=0.3282) carcinomas of the breast. Conclusions: The prognostic significance of the interferon metagene in node-negative breast cancer is subtype specific and confined to the HER2+ molecular subtype. A higher expression of the IFN metagene is associated with improved outcome in HER2+ breast cancer. Citation Format: Marcus Schmidt, Leonie van de Sandt, Karolina Edlund, Isabel Sicking, Marco Battista, Anne-Sophie Heimes, Antje Lebrecht, Gerald Hoffmann, Mathias Gehrmann, Jörg Rahnenführer, Jan G Hengstler. Prognostic significance of the interferon metagene in node-negative breast cancer depends on the molecular subtype [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-08-20.
Variation in Mammographic Breast Density Assessments Among Radiologists in Clinical Practice
Authors: Brian L. Sprague, Emily F. Conant, Tracy Onega, Michael P. Garcia, Elisabeth F. Beaber, Sally D. Herschorn, Constance D. Lehman, Anna N.A. Tosteson, Ronilda Lacson, Mitchell D. Schnall, Despina Kontos, Jennifer S. Haas, Donald L. Weaver, William E. Barlow
Journal: Annals of Internal Medicine (2016)

About half of the United States has legislation requiring radiology facilities to disclose mammographic breast density information to women, often with language recommending discussion of supplemental screening options for women with dense breasts.To examine variation in breast density assessment across radiologists in clinical practice.Cross-sectional and longitudinal analyses of prospectively collected observational data.30 radiology facilities within the 3 breast cancer screening research centers of the Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium.Radiologists who interpreted at least 500 screening mammograms during 2011 to 2013 (n = 83). Data on 216 783 screening mammograms from 145 123 women aged 40 to 89 years were included.Mammographic breast density, as clinically recorded using the 4 Breast Imaging Reporting and Data System categories (heterogeneously dense and extremely dense categories were considered "dense" for analyses), and patient age, race, and body mass index (BMI).Overall, 36.9% of mammograms were rated as showing dense breasts. Across radiologists, this percentage ranged from 6.3% to 84.5% (median, 38.7% [interquartile range, 28.9% to 50.9%]), with multivariable adjustment for patient characteristics having little effect (interquartile range, 29.9% to 50.8%). Examination of patient subgroups revealed that variation in density assessment across radiologists was pervasive in all but the most extreme patient age and BMI combinations. Among women with consecutive mammograms interpreted by different radiologists, 17.2% (5909 of 34 271) had discordant assessments of dense versus nondense status.Quantitative measures of mammographic breast density were not available for comparison.There is wide variation in density assessment across radiologists that should be carefully considered by providers and policymakers when considering supplemental screening strategies. The likelihood of a woman being told she has dense breasts varies substantially according to which radiologist interprets her mammogram.National Institutes of Health.
ctDNA Determination of EGFR Mutation Status in European and Japanese Patients with Advanced NSCLC: The ASSESS Study
Authors: Martin Reck, Koichi Hagiwara, Baohui Han, Sergei Tjulandin, Christian Grohé, Takashi Yokoi, Alessandro Morabito, Silvia Novello, Edurne Arriola, Olivier Molinier, Rose McCormack, Marianne Ratcliffe, Nicola Normanno
Journal: Journal of Thoracic Oncology (2016)

IntroductionTo offer patients with EGFR mutation–positive advanced NSCLC appropriate EGFR tyrosine kinase inhibitor treatment, mutation testing of tumor samples is required. However, tissue/cytologic samples are not always available or evaluable. The large, noninterventional diagnostic ASSESS study (NCT01785888) evaluated the utility of circulating free tumor-derived DNA (ctDNA) from plasma for EGFR mutation testing.MethodsASSESS was conducted in 56 centers (in Europe and Japan). Eligible patients (with newly diagnosed locally advanced/metastatic treatment-naive advanced NSCLC) provided diagnostic tissue/cytologic and plasma samples. DNA extracted from tissue/cytologic samples was subjected to EGFR mutation testing using local practices; designated laboratories performed DNA extraction/mutation testing of blood samples. The primary end point was level of concordance of EGFR mutation status between matched tissue/cytologic and plasma samples.ResultsOf 1311 patients enrolled, 1288 were eligible. Concordance of mutation status in 1162 matched samples was 89% (sensitivity 46%, specificity 97%, positive predictive value 78%, and negative predictive value 90%). A group of 25 patients with apparent false-positive plasma results was overrepresented for cytologic samples, use of less sensitive tissue testing methodologies, and smoking habits associated with high EGFR mutation frequency, indicative of false-negative tumor results. In cases in which plasma and tumor samples were tested with identical highly sensitive methods, positive predictive value/sensitivity were generally improved.ConclusionsThese real-world data suggest that ctDNA is a feasible sample for EGFR mutation analysis. It is important to conduct mutation testing of both tumor and plasma samples in specialized laboratories, using robust/sensitive methods to ensure that patients receive appropriate treatments that target the molecular features of their disease.
Pravastatin improves pregnancy outcomes in obstetric antiphospholipid syndrome refractory to antithrombotic therapy
Authors: Eleftheria Lefkou, Apostolos Mamopoulos, Themistoklis Dagklis, Christos Vosnakis, David Rousso, Guillermina Girardi
Journal: Journal of Clinical Investigation (2016)

Administration of conventional antithrombotic treatment (low-dose aspirin plus low-molecular weight heparin [LDA+LMWH]) for obstetric antiphospholipid syndrome (APS) does not prevent life-threatening placenta insufficiency-associated complications such as preeclampsia (PE) and intrauterine growth restriction (IUGR) in 20% of patients. Statins have been linked to improved pregnancy outcomes in mouse models of PE and APS, possibly due to their protective effects on endothelium. Here, we investigated the use of pravastatin in LDA+LMWH-refractory APS in patients at an increased risk of adverse pregnancy outcomes.We studied 21 pregnant women with APS who developed PE and/or IUGR during treatment with LDA+LMWH. A control group of 10 patients received only LDA+LMWH. Eleven patients received pravastatin (20 mg/d) in addition to LDA+LMWH at the onset of PE and/or IUGR. Uteroplacental blood hemodynamics, progression of PE features (hypertension and proteinuria), and fetal/neonatal outcomes were evaluated.In the control group, all deliveries occurred preterm and only 6 of 11 neonates survived. Of the 6 surviving neonates, 3 showed abnormal development. Patients who received both pravastatin and LDA+LMWH exhibited increased placental blood flow and improvements in PE features. These beneficial effects were observed as early as 10 days after pravastatin treatment onset. Pravastatin treatment combined with LDA+LMWH was also associated with live births that occurred close to full term in all patients.The present study suggests that pravastatin may improve pregnancy outcomes in women with refractory obstetric APS when taken at the onset of PE or IUGR until the end of pregnancy.
How can endoscopic R0 resection be ensured for relatively small gastric gastrointestinal stromal tumors?
Authors: Qiang Zhang, Si-De Liu
Journal: Endoscopy (2016)

Endoscopic resection of gastrointestinal stromal tumors (GISTs) has been reported in some clinical studies [1] [2] [3] [4]. These studies involved GISTs with an average size smaller than 2 cm, and demonstrated high en bloc resection rates, low recurrence rates at short-term follow-ups, and low risk of postoperative complications. The resection methods used in these studies mainly included endoscopic submucosal excavation (ESE), endoscopic band ligation (EBL), endoscopic submucosal dissection (ESD), and endoscopic full-thickness resection (EFTR). The results of these studies suggested that relatively small GISTs can be safely removed by endoscopic resection.
S46 An RCT of 28 day treatment with Fostair® pMDI 200/12 BD on platelet biomarkers in patients with Idiopathic Pulmonary Fibrosis: Abstract S46 Table 1
Authors: CE Wright, K Arnell, S Fraser, M Crookes, Y Hayman, S Hart, S Thackray-Nocera, AH Morice
Journal: Thorax (2015)

<h3>Introduction and objectives</h3> We have recently studied platelet activation in idiopathic pulmonary fibrosis (IPF) and found that IPF patients exhibit a significant increase in platelet reactivity. This was demonstrated by an ADP (Adenosine diphosphate) concentration dependent increase in platelet-monocyte aggregates (PMA), platelet P-selectin expression, and platelet fibrinogen binding.<sup>1</sup> We have suggested this may have a potentially important role in the initiation and/or progression of tissue injury in IPF. Systemic corticosteroid treatment may alter platelet adhesion, as seen with suppression of p-selectin expression in the spontaneously hypertensive rat.<sup>2</sup> We hypothesised that peripherally deposited inhaled corticosteroid may have similar activity. In this study we evaluate the effect of beclomethasone/formoterol pMDI (B/F Fostair) on clinical parameters and biomarkers of platelet activation in IPF. <h3>Methods</h3> Twenty non-smoking patients with IPF and no evidence of COPD were randomly assigned to either Fostair 100/6, 2puffs BD for 28 days or matched placebo inhaler. There was 28 days washout between crossover. Biomarkers, PMA, p-selectin and fibrinogen were measured at baseline and post treatment periods. Clinical outcomes of six minute walk (6MWT), spirometry, average daily activity over 7 days (Sense Wear) and Quality of life (KBILD) were also measured. <h3>Results</h3> 17 patients (11 males, mean age 71.2 yrs) completed the study. Table 1 shows the 95% CI on differences between the baseline and two treatments on biomarkers of platelet adhesion obtained from ANOVA and using the Tukey <i>post hoc</i> test for multiple comparisons. Change from baseline spirometric measurements of FEV1(L), FEV/FVC,% pred FEF25–75 were significantly improved following 28 days B/F by (mean ±SD), 0.88 ± 0.16 L (p = 0.03), 0.03 ± 0.03 (p = 0.03), 12.4 ± 19.1% (p = 0.02) respectively when compared to placebo. There was no change in quality of life or exercise measures. <h3>Conclusion</h3> The effects of B/F in this study may represent delivery of corticosteroid to the peripheral airways ameliorating local injury and altering platelet activation. Bronchodilation may represent an effect on the small airways in IPF. Whether these effects are important in disease progression remains to be established. <h3>References</h3> 1 Crooks MG. <i>PLoS One</i> 2014;<b>9</b>(10):e111347. doi: 10.1371/journal.pone.0111347GG 2 Susuki H. <i>Leukoc Biol</i>. 1995;<b>57</b>(1):20–6
Modulation of Natural Killer Cell Activity in the Setting of Oncolytic Virotherapy and with a Chimeric Antigen Receptor
Authors: Chen Xilin, Jianfeng Han, Chu Jianhong, Walter Meisen, Zhang Jianying, E. Antonio Chiocca, Balveen Kaur, Michael A. Caligiuri, Jianhua Yu
Journal: Blood (2015)
Antithrombotic Treatment of Splanchnic Vein Thrombosis
Authors: Walter Ageno, Nicoletta Riva, Soo-Mee Bang, Maria Teresa Sartori, Elvira Grandone, Jan Beyer-Westendorf, Giovanni Barillari, Matteo N. D. Di Minno, Rita Duce, Alessandra Malato, Rita Santoro, Daniela Poli, Peter Verhamme, Ida Martinelli, Pieter Willem Kamphuisen, Adriano Alatri, Doyeun Oh, Elbio D. Amico, Sam Schulman, Francesco Dentali
Journal: Blood (2012)
Global Burden of Mental Illness in China and India
Authors: M. J. Friedrich
Journal: JAMA (2016)

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