tbuckley/cabot-search huggingface dataset:
Abstract A38: MTH1 Inhibition as an effective tumor-suppressive strategy in RAS-driven cancer
Authors: Govindi Jayanika Samaranayake, Clara Issabella Troccoli, Tyler Andrew Cunningham, Priyamvada Rai
Journal: Clinical Cancer Research (2017)

Abstract Oncogenic RAS mutations confer multiple malignant traits to cancer cells, many of which are mediated by oncogene-induced reactive oxygen species (ROS). However, oncogenic ROS also create vulnerabilities in the cancer cells, sensitizing them to oxidative DNA damage and strand breaks which can trigger cellular senescence or cell death. Thus RAS-driven tumor cells require adaptive redox protective mechanisms to inhibit ROS-associated tumor suppression. We previously reported that MutT Homolog 1 (MTH1), the mammalian 8-oxodGTPase, comprises one such critical adaptation. We have shown MTH1 is important for facilitating the full gamut of RAS-driven malignancy by promoting evasion of the first barrier to transformation, viz. oncogene-induced senescence (OIS), enhancing RAS-mediated transformation and related pro-malignant traits, and maintaining proliferation and tumorigenicity in established RAS-driven tumor cells. Recently chemical inhibitors against MTH1 have been developed, although there is some controversy surrounding their efficacy and mode of action. Our work here discusses RAS regulation of MTH1 expression, and the molecular contexts under which MTH1 inhibition can synergize with oncogenic oxidative stress in RAS-driven tumor cells for optimal tumor suppressive response. Citation Format: Govindi Jayanika Samaranayake, Clara Issabella Troccoli, Tyler Andrew Cunningham, Priyamvada Rai. MTH1 Inhibition as an effective tumor-suppressive strategy in RAS-driven cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A38.
P97 Gastro-oesophageal reflux in cystic fibrosis
Authors: RW Lord, JS Pearson, PJ Barry, PJ Whorwell, RB Jones, P McNamara, R Beynon, JA Smith, AM Jones
Journal: Thorax (2016)

<h3>Background</h3> Initial small studies using combined pH and impedance (pH-MII) have suggested increased gastro-oesophageal reflux (GOR) in adult cystic fibrosis (CF) patients. Reflux episodes frequently reach the proximal oesophagus and occur whilst supine, which may predispose to micro-aspiration. <h3>Aims</h3> To investigate the relationship between GOR and CF lung disease. <h3>Methods</h3> We conducted a prospective observational study in stable adult CF patients undergoing 24 hour pH-MII. Reflux symptoms (using validated RESQ-7 questionnaire) and spirometry were also recorded. <h3>Results</h3> 10/12 subjects recruited completed pH-MII the study (mean age 28.5 years, mean FEV1 48.8% predicted, 100% male). An increased number of reflux episodes per 24 hours were noted in 80% of participants (median 104.1, IQR 78.6 –164.4, normal range &lt;75 episodes), with increased ‘high-risk’ proximal reflux or supine reflux noted in 60% (Table 1). In this small preliminary patient sample there were no significant correlations between FEV1% and total, proximal or supine reflux episodes, or RESQ-7 heartburn scores and any reflux measure. 7/10 subjects completed the study on a PPI and had data available for acid reflux (pH &lt; 4) parameters. 4/7 had an abnormal acid exposure despite standard dose PPI therapy. 5/7 had prolonged acid reflux events; the longest was 66.5 minutes (see Table 1). <h3>Conclusions</h3> In this preliminary data set, CF patients appear to have a pattern of GOR that puts them at risk of reflux micro-aspiration and have significant acid reflux despite antacid therapy. Reflux symptoms and spirometry were not related to reflux parameters. The clinical implications of these findings are that standard PPI dosing maybe insufficient in CF patients to control acid reflux. In addition silent reflux aspiration maybe occurring and as such could be a potential area for future therapies.
P1.04-009 Bacterial Population Dynamics in Colonization of Airway Stents in Patients with Cancer
Authors: Marta Diez-Ferrer, Laura Calatayud, Cristina Lopez-Delgado, Rosa Lopez-Lisbona, Noelia Cubero, Nikos Koufos, Sara Marti, Carmen Ardanuy, Jordi Dorca, Josefina Liñares, Antoni Rosell
Journal: Journal of Thoracic Oncology (2017)
Allergen immunotherapy for IgE‐mediated food allergy: a systematic review and meta‐analysis
Authors: U. Nurmatov, S. Dhami, S. Arasi, G. B. Pajno, M. Fernandez‐Rivas, A. Muraro, G. Roberts, C. Akdis, M. Alvaro‐Lozano, K. Beyer, C. Bindslev‐Jensen, W. Burks, G. du Toit, M. Ebisawa, P. Eigenmann, E. Knol, M. Makela, K. C. Nadeau, L. O'Mahony, N. Papadopoulos, L. K. Poulsen, C. Sackesen, H. Sampson, A. F. Santos, R. van Ree, F. Timmermans, A. Sheikh
Journal: Allergy (2017)

The European Academy of Allergy and Clinical Immunology (EAACI) is developing Guidelines for Allergen Immunotherapy (AIT) for IgE-mediated Food Allergy. To inform the development of clinical recommendations, we sought to critically assess evidence on the effectiveness, safety and cost-effectiveness of AIT in the management of food allergy.We undertook a systematic review and meta-analysis that involved searching nine international electronic databases for randomized controlled trials (RCTs) and nonrandomized studies (NRS). Eligible studies were independently assessed by two reviewers against predefined eligibility criteria. The quality of studies was assessed using the Cochrane Risk of Bias tool for RCTs and the Cochrane ACROBAT-NRS tool for quasi-RCTs. Random-effects meta-analyses were undertaken, with planned subgroup and sensitivity analyses.We identified 1814 potentially relevant papers from which we selected 31 eligible studies, comprising of 25 RCTs and six NRS, studying a total of 1259 patients. Twenty-five trials evaluated oral immunotherapy (OIT), five studies investigated sublingual immunotherapy, and one study evaluated epicutaneous immunotherapy. The majority of these studies were in children. Twenty-seven studies assessed desensitization, and eight studies investigated sustained unresponsiveness postdiscontinuation of AIT. Meta-analyses demonstrated a substantial benefit in terms of desensitization (risk ratio (RR) = 0.16, 95% CI 0.10, 0.26) and suggested, but did not confirm sustained unresponsiveness (RR = 0.29, 95% CI 0.08, 1.13). Only one study reported on disease-specific quality of life (QoL), which reported no comparative results between OIT and control group. Meta-analyses revealed that the risk of experiencing a systemic adverse reaction was higher in those receiving AIT, with a more marked increase in the risk of local adverse reactions. Sensitivity analysis excluding those studies judged to be at high risk of bias demonstrated the robustness of summary estimates of effectiveness and safety of AIT for food allergy. None of the studies reported data on health economic analyses.AIT may be effective in raising the threshold of reactivity to a range of foods in children with IgE-mediated food allergy whilst receiving (i.e. desensitization) and post-discontinuation of AIT. It is, however, associated with a modest increased risk in serious systemic adverse reactions and a substantial increase in minor local adverse reactions. More data are needed in relation to adults, long term effects, the impact on QoL and the cost-effectiveness of AIT.
Osteoglycin’s embracement of VEGF receptor-2 limits angiogenesis and collateralization
Authors: Victor W.M. van Hinsbergh
Journal: Cardiovascular Research (2016)

This editorial refers to ‘Loss of osteoglycin promotes angiogenesis in limb ischaemia mouse models via modulation of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 signalling pathway’ by Gao et al. , pp. 70–80. 

The circulatory system regulates adequate distribution of blood and delivery of oxygen and nutrients to the tissues. When arterial blood flow is interrupted a rapid neovascularization response occurs by expansion of collateral blood vessels and angiogenic sprouting in the hypoxic tissue. VEGF-A plays a central role in hypoxia-induced angiogenesis.1 According to insight obtained from developing tissues, VEGF-A binds to VEGF receptor-2 dimers on the protruding filopodia of sprouting endothelial tips. The receptor is subsequently internalized, after which intracellular signalling evokes a proper sprouting response.2 However, clinical studies in which VEGF was used to induce angiogenesis in chronically ischemic heart or limb have been unsuccessful.3,4 Apparently these tissues are refractory to VEGF stimulation.

It is generally assumed that the extracellular matrix harbours information that regulates and guides endothelial sprouting. Matrix association of VEGF-A via its heparin-binding domain can direct the invading sprout, while angiogenesis inhibitors such as thrombospondin and matrikines (proteolytically generated matrix fragments that modulate angiogenesis) do the opposite. In this issue of Cardiovascular Research , Wu et al .5 report on a potentially important role of osteoglycin in limiting the cellular response to VEGF. Osteoglycin inhibits the VEGF-VEGFR2 interaction in healthy tissue, while its absence in the ischemic mouse hindleg enhances both sprouting angiogenesis and collateralization.

Osteoglycin (gene symbol: OGN), also called mimecan (UniProt entry name: MIME), is a member of the small leucine-rich proteoglycans (SLRPs) and is expressed in most cells of the body.6 Many SLRPs including osteoglycin can bind to matrix proteins, can expose a binding site to collagen fibrils, and can act …
P71 Can postural OSA be identified from oximetry alone?
Authors: A Johar, CD Turnbull, JR Stradling
Journal: Thorax (2016)

<h3>Introduction</h3> Positional treatments have a long history of usage in obstructive sleep apnoea (OSA). Recent developments of more sophisticated therapies reported good response in patients with an AHI of &lt;60 and predominately supine OSA (arbitrarily defined as total AHI: non-supine AHI ≥ 1.5).<sup>1,2</sup> We hypothesised that patients with mild to moderate OSA usually have periods both with and without OSA, and that the OSA periods will be mainly due to supine OSA. Such patients might therefore be trialled on positional therapies without specific assessment of posture. <h3>Methods</h3> Patients included had OSA and underwent an in-hospital respiratory sleep study between May- July 2016. Sleep studies included video review for identification of supine sleep. The oxygen desaturation index &gt;4% (ODI) was recorded in supine and non-supine positions. The ratio of the total to non-supine ODI was calculated. <h3>Results</h3> 40 patients’ sleep studies were suitable for analysis. 7 patients were excluded: 3 due to comorbidities (hypoventilation/CSA), 3 due to lack of supine sleep ( &lt;30 minutes) and one due to having minimal OSA. Patients had a mean age of 53.8 years (SD 12.7) and mean BMI of 34.9 kg/m<sup>2</sup> (SD 9.0). The median supine ODI was significantly higher than the median total ODI (supine ODI 54.3/h, IQR 47.9; total ODI 28.6/h, IQR 34.4; p &lt; 0.001). There was a significant relationship between the ratio of total ODI to non-supine ODI versus the total ODI (Spearman’s rho = 0.37, p = 0.02; Figure 1). <h3>Discussion</h3> Our data suggests that patients with lower ODIs are more likely to have supine predominant OSA. At ODI values over 40 it is very unlikely that there is a posturally dependant component to a patient’s OSA. However, the reverse is not the case; although many patients with low ODIs do have a postural component, many do not. It is therefore necessary to objectively assess the degree of supine predominant OSA in future trials of positional therapies, but patients with ODIs over 40 could be excluded at the outset. <h3>References</h3> Levendowski DJ, <i>et al</i>. Assessment of a neck-based treatment and monitoring device for positional obstructive sleep apnea. <i>J Clin Sleep Med</i> 2014;<b>10</b>(8):863–71. Levendowski DJ, <i>et al</i>. Capability of a neck worn device to measure sleep/wake, airway position, and differentiate benign snoring from obstructive sleep apnea. <i>J Clin Monit Comput</i> 2015;<b>29</b>:53–64.
The Multi-Kinase/ABL Inhibitor R763/AS703569 Induces DNA Endoreduplication and Apoptosis In Imatinib-Resistant CML Cells and Synergizes with Nilotinib, Dasatinib, and the Plk-1 Inhibitor BI 2536, In Producing Growth Inhibition.
Authors: Karoline V. Gleixner, Harald Herrmann, Barbara Peter, Katharina Blatt, Karina Schuch, Winfried F Pickl, Christian Sillaber, Peter Valent
Journal: Blood (2010)
<i>Notes from the Field</i>: Botulism Outbreak from Drinking Prison-Made Illicit Alcohol in a Federal Correctional Facility — Mississippi, June 2016
Authors: Lindsey McCrickard, Mariel Marlow, Julie L. Self, Louise Francois Watkins, Kevin Chatham-Stephens, Jannifer Anderson, Sheryl Hand, Kathryn Taylor, Jennifer Hanson, Keiundria Patrick, Carolina Luquez, Janet Dykes, Suzanne R. Kalb, Kaitlin Hoyt, John R. Barr, Todd Crawford, Anthony Chambers, Brian Douthit, Robert Cox, Matt Craig, John Spurzem, Joseph Doherty, Michael Allswede, Paul Byers, Thomas Dobbs
Journal: MMWR Morbidity and Mortality Weekly Report (2017)
Clarifying a “Penicillin” Allergy
Authors: Alon Vaisman, Janine McCready, Jeff Powis
Journal: JAMA Internal Medicine (2017)

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P3.02b-035 Cell Free Tumor DNA to Monitor Response to Tyrosine Kinase Inhibitors in Patients with EGFR-Mutant Non-Small Cell Lung Cancer
Authors: Paola Ulivi, Elisa Chiadini, Giorgia Marisi, Vienna Ludovini, Nicoletta De Luigi, Claudio Dazzi, Marita Mariotti, Lucio Crinò, Angelo Delmonte
Journal: Journal of Thoracic Oncology (2017)
Reduced-Intensity Allogeneic Stem Cell Transplantation for Relapsed/Refractory Hodgkin and Non-Hodgkin Lymphoma.
Authors: Decio Lerner, Alexandre M. Azevedo, Marta Colares, Rita de Cássia B. Tavares, Simone C. Maradei, Joana Lima, Ana Maria G. Lobo, Daniel G. Tabak, Katia Urago, Maria Claudia Lima, Angelo Maiolino, Luis Fernando S. Bouzas
Journal: Blood (2005)
The Vent-Like Homeobox Gene VENTX Promotes Human Myeloid Development and Is Highly Expressed In Acute Myeloid Leukemia
Authors: Vijay P. S. Rawat, Natalia Arseni, Farid Ahmed, Medhanie A. Mulaw, Silvia Thoene, Bernhard Heilmeier, Tim Sadlon, J. D.' Andrea, Wolfgang Hiddemann, S. K Bohlander, Christian Buske, Michaela Feuring-Buskea
Journal: Blood (2010)
P112 Serum inflammatory biomarkers as predictors of treatment outcome in pulmonary tuberculosis
Authors: A Ritchie, A Singanayagam, K Manalan, D Connell, J Chalmers, S Sridhar, A Lalvani, M Wickremasinghe, OM Kon
Journal: Thorax (2016)

<h3>Background</h3> The aim of this study was to evaluate C-reactive protein(CRP), globulin and white cell count as predictors of treatment outcome in pulmonary tuberculosis. <h3>Methods</h3> An observational study of patients with active pulmonary tuberculosis was conducted at a tertiary centre. All patients had serum CRP, globulin and white cell count measured at baseline and two months following commencement of therapy. The outcome of interest was requirement for extension of therapy beyond 6 months. <h3>Results</h3> There were 226 patients included in the study. Serum globulin &gt;45 g/L was the only baseline biomarker evaluated that independently predicted requirement for therapy extension (OR 3.59 (1.79–7.57; p &lt; 0.001)). An elevated globulin level that failed to normalise at 2 months was also associated with increased requirement for treatment extension(63.9% versus 5.1%;p &lt; 0.001) and had low negative likelihood ratio(0.07) for exclusion of requirement for therapy extension. On multivariable analysis, an elevated globulin that failed to normalise at 2 months was independently associated with requirement for therapy extension (OR 6.12 (2.23–16.80); p &lt; 0.001). <h3>Conclusions</h3> Serum globulin independently predicts requirement for treatment extension in pulmonary TB and outperforms CRP and white cell count as a predictive biomarker. Normalisation of globulin at two months following treatment commencement is associated with low risk of requirement for treatment extension.
A phase I trial of the DNA-hypomethylating agent 5-Aza-2'-Deoxycytidine in combination with carboplatin both given 4 weekly by intravenous injection in patients with advanced solid tumours
Authors: C. Lee, K. Appleton, J. Plumb, S. Kaye, C. Cruickshank, C. Twelves, P. Vasey, I. Judson, R. Brown, H. Mackay
Journal: Journal of Clinical Oncology (2004)

2005 Background: There is increasing evidence that DNA hypermethylation of CpG islands at key genes is associated with chemo resistance. For instance, methylation of a CpG-island at the hMLH1 promoter may be a major mechanism for loss of MLH1 expression associated with chemo resistance. Decitabine (5-Aza-2'-deoxycytidine) is a demethylating agent which has been shown in in vivo studies to reactivate MLH1 expression leading to sensitisation of chemo resistant tumours to a range of cytotoxic drugs. This Phase I study investigated the feasibility of delivering a dose of decitabine which would cause demethylation and hence potential sensitisation without causing prohibitive myelosuppression in combination with carboplatin. Methods: Pts with a variety of malignancies were enrolled. The starting dose of decitabine (on Day 1) was 45mg/m2. This was escalated in steps of 45mg/m2. Carboplatin at a fixed dose of AUC5 was given on Day 8. The interval between decitabine and carboplatin was 8 days which was within the optimal time for demethylation from xenograft studies. Treatment was repeated every 4 weeks. Results: 14 heavily-pretreated pts have been enrolled to date (6M/8F). Median age: 55; mean PS (ECOG): 1. Pts have been treated at 3 dose levels of decitabine: 45, 90 and 135mg/m2. Median number of cycles: 2 (range 0.5–6). 13/14 patients were evaluable for toxicity. MTD was identified as decitabine 135mg/m2 with grade 4 febrile neutropenia (1 pt), and grade 4 neutropenia necessitating delay of cycle 2 for >7 days (1 pt). Other possible treatment-related toxicities included: nausea, vomiting, diarrhoea, fatigue, anorexia, anaemia (all ≤grade 2 and easily manageable). PD studies showed reduction in 5-methylcytosine to total cytosine ratios in DNA isolated from peripheral mononuclear cells at all dose levels, and was maximal between Days 8 and 12 following decitabine infusion Conclusion: This study confirms that the combination of decitabine and carboplatin is feasible. Futher patients are being accrued to assess PD effects in tumour as well as peripheral blood and buccal smears. No significant financial relationships to disclose.
Outcomes of Autologous Transplantation for Treatment-Related AML and MDS in Previously Treated Multiple Myeloma Patients (pts)
Authors: Shebli Atrash, Bart Barlogie, Maurizio Zangari, Frits van Rhee, Sarah Waheed, Clyde Bailey, Nathan Petty, Christoph Heuck, Gareth J Morgan, Yogesh Jethava
Journal: Blood (2015)
Clinical Spectrum of RAS-Associated Autoimmune Leukoproliferative Disorder (RALD): A Distinct Clinical Entity Mimicking Juvenile Myelomonocytioc Leukemia (JMML) or Chronic Myelomonocytic Leukemia (CMML)
Authors: V. Koneti Rao, Joao Bosco Oliveira, Julie Niemela, Joie Davis, Susan Price, Hyesun Kuehn, Katherine R Calvo, Stefania Pittaluga, Eric J. Werner, Joohee Lee, Mustafa Barbour, Marc Natter, Mignon L. Loh, Thomas A Fleisher
Journal: Blood (2012)
Construction and validation of a novel disease-specific quality-of-life instrument for patients with primary antibody deficiency disease (PADQOL-16)
Authors: Mark Ballow, Mark R. Conaway, Panida Sriaroon, Rima A. Rachid, Filiz O. Seeborg, Carla M. Duff, Francisco A. Bonilla, M. Elizabeth M. Younger, Ralph Shapiro, Ted M. Burns
Journal: Journal of Allergy and Clinical Immunology (2017)
Cellular and Intracellular Network Characterization of Cytokine JAK/STAT Signaling In Whole Blood Across Multiple Healthy Individuals: Defining “Normal”
Authors: Todd M. Covey, Michael Gulrajani, Blossom Marimpietri, Annie P. Chiang, Lootsee Panganiban-Lustan, James Cordeiro, Diane Longo, David B. Rosen, Alessandra Cesano
Journal: Blood (2010)
P279 Feasibility of an 8-week out-patient inspiratory muscle training (IMT) programme in patients with interstitial lung disease (ILD)
Authors: M Koulopoulou, S Greenwood, C Reilly, F Chua
Journal: Thorax (2016)

<h3>Introduction</h3> The 2013 ATS/ERS guidelines on Pulmonary Rehabilitation suggest that IMT confers significant improvements in various outcomes in chronic obstructive pulmonary disease (COPD). IMT may play a role in dyspnoea and exercise tolerance in patients with ILD; Feasibility of delivering an outpatient IMT programme for ILD is yet to be determined. <h3>Aim</h3> The aim of this pilot-feasibility study was to assess the acceptability and practicality of delivering an outpatient IMT programme in patients with ILD. <h3>Methods</h3> Radomised trial recruited 17 patients with ILD from St George’s Hospital chest clinic, London. Inclusion criteria were: ILD patients on stable medical treatment, with breathlessness MRC &gt;3. 9 patients (intervention group); median (IQR) DLco predicted 44 [28, 45]% underwent H-IMT; exercised at 60% of sustained maximal inspiratory pressure (SMIP); 8 patients (control group) median (IQR) DLco 39.5 [24, 60]% underwent low intensity IMT (S-IMT); exercised at 15% of SMIP. Data collection included pre-post IMT in the following outcomes: six minute walk test (6MWT), quality of life (SGRQ-I), dyspnoea: (Borg and Dyspnoea-12), maximal inspiratory pressure (MIP) and sniff nasal inspiratory pressure (Sniff-P). <h3>Results</h3> 76 patients were screened; 26 meet the criteria to participate. 19 (75%) consented to partake in the study. Completion rates for HIIMT was 89% (8/9), and 75% (6/8) for LIMT. HI-IMT-G exhibited significantly higher MIP compared to LI-IMT-G (p = 0.043).There were no significant between-group differences in the other parameters. Within group analysis demonstrated that: HI-IMT improved significantly on 6MWT, MIP, Sniff-P, and SGRQ-I. LI-IMT, improved significantly on 6MWT, Borg and D-12 (Table 1). <h3>Conclusions</h3> HI-IMT was well tolerated and accepted by ILD patients, and it demonstrated improvements in measured outcomes; IMT requires close monitoring and input to enhance motivation; this type of training can only fit small groups of patients and the extra cost should be considered. IMT may be an alternative option to exercise training for ILD patients to ameliorate dyspnoea and combat exercise deconditioning; larger studies are required to explore effectiveness and cost effectiveness of IMT in ILD.
P1.06-036 Post-Recurrence Survival Analysis of Stage I Non-Small Cell Lung Cancer: Prognostic Significance of Local Treatment
Authors: Kanghoon Lee, Hyeong Ryul Kim, Dong Kwan Kim, Yong-Hee Kim, Seung-Il Park, Se Hoon Choi, Su Kyung Hwang, Jin San Bok, Han Pil Lee, Byung Kwon Chong
Journal: Journal of Thoracic Oncology (2017)