tbuckley/cabot-search huggingface dataset:
Abstract 2853: Sunitinib induces anti-angiogenic splice-variant VEGF165b through induction of CLK1 and CLK4 kinases in prostate cell line DU-145
Authors: Anne Monks, Curtis D. Hose, James H. Doroshow
Journal: Cancer Research (2011)

Abstract Sunitinib is an oral anti-tumor agent active in renal carcinoma and GIST, which inhibits specific receptor tyrosine kinases that includes targeting vascular endothelial growth factor receptors (VEGFR). To understand mechanisms which may drive this agent's activity, transcriptional profiling (GeneChip® HT Human Genome U133 Array Plate Set) of the NCI-60 human tumor cell lines treated with 200 and 2000 nM sunitinib was completed. Examination of the data indicated the CDC2-like genes, CLK1 and CLK4, were upregulated in multiple cell lines after 2 h drug incubation, with a decreasing level of expression over 6 and 24 h. These kinases are implicated in regulation of alternative splicing of mRNA and may favor selection of the distal splice site of exon 8 in the VEGFA gene. These splice variants of VEGFA are designated VEGFAxxxb and have been shown to have anti-angiogenic properties; regulation of this form of alternative splicing has been identified as a potential novel strategy for anti-angiogenic therapeutics. To confirm whether sunitinib-induced CLK1 and CLK4 expression was indicative of a change in the splice variants of VEGFA, specific primers were used in TaqMan® Q-RT/PCR to distinguish the exon 8 distal splice variant VEGFA165b (anti-angiogenic) from the proximal splice variant VEGFA165a (pro-angiogenic) of the dominant mRNA isoform, VEGFA165. VEGFA165b variant gene expression was induced 2-4 fold over 24h, compared to &amp;lt; 2-fold change in the VEGFA165a expression in 2 cell lines (DU-145 and NCI-H322M) with robust sunitinib-induced CLK1 and 4 expression compared to no change in VEGFA165b expression in a cell line with no increase in CLK1 and 4 after sunitinib treatment. Using DU-145 cells, we also demonstrated a sunitinib-induced, 2-fold increase in VEGFA165b protein expression over 24 h. Inhibition of CLK 1 and 4 kinases with a specific CLK inhibitor, TG003, decreased constitutive gene expression of VEGFA165b in DU-145, indicating the importance of the CLK genes in regulating distal splice variants of the VEGFA165 mRNA isoform. In combination with sunitinib, CLK inhibition by TG003, prevented sunitinib-induced upregulation of the VEGFA165b splice variant. Thus we have uncovered a novel mechanism underlying the activity of the VEGFR inhibitor, sunitinib, where induction of CLK kinases change the balance of VEGFA splice variants towards expression of anti-angiogenic species through which modulation of angiogenesis may occur. Funded by NCI Contract No. HHSN261200800001E. 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 2853. doi:10.1158/1538-7445.AM2011-2853
PWE-294 The significance of the rectal cancer regression grade (RCRG) in prognosis after neo-adjuvant chemoradiotherapy treatment of adenocarcinoma of the rectum
Authors: D Humes, J McGrane, J Wheeler, A Acheson, CJ Walter
Journal: Gut (2015)

<h3>Introduction</h3> Complete pathological response is widely accepted to be an independent predictor for better prognosis after neo-adjuvant chemoradiotherapy treatment (NCRT) of locally-advanced adenocarcinoma of the rectum.<sup>1</sup>Less is known about the role of the Rectal Cancer Regression Grades (RCRGs) in predicting prognosis where partial tumour regression is seen. The aim of this study was to examine the relationship between RCRG and mortality in patients with locally-advanced adenocarcinoma of the rectum treated with NCRT. <h3>Method</h3> A retrospective study of all patients treated with NCRT for locally-advanced rectal cancer between 2004–2009 in 3 UK centres was undertaken. Data was collected from oncology, radiology and laboratory databases as well as patient records. Differences in mortality rates were compared for patients within the 3 different RCRG groups using univariate and multivariate analysis. The multivariate analysis adjusted for the known confounders of age, sex and stage of disease at presentation. A subset analysis was performed on patients with partial tumour regression by excluding those patients with a complete pathological response. <h3>Results</h3> Of 273 patients treated, 183 (67%) were male. Median follow up time was 3.60 years (2.58–4.99). Univariate analysis demonstrated an association between higher RCRGs and increased mortality with hazard ratios (HRs) for RCRG1:RCRG2 of 2.05 (95% CI 1.67–3.59) and RCRG1:RCRG3 of 3.25 (95% CI 1.82–5.82). This association persisted when multivariate analysis was performed, with HRs for mortality of RGRC1:RCRG2 2.12 (95% CI 1.20–3.74) and RCRG1:RCRG3 of 3.14 (95% CI 1.74–5.67). Fifty-five patients demonstrated a complete pathological response and were excluded from the analysis of patients with partial tumour regression. Of the remaining 218 patients, univariate analysis demonstrated a HR for mortality in RCRG1:RCRG2 of 1.40 (95% CI 0.77–2.56) and RCRG1:RCRG3 of 2.30 (95% CI 1.24–4.26). Multivariate analysis of mortality gave HRs of 1.52 (95% CI 0.82–2.81) and 2.38 (95% CI 1.27–4.45) respectively. <h3>Conclusion</h3> This study demonstrated an association between higher rectal cancer regression grades and an increased risk of mortality. This association, although weakened, appeared to persist amongst the subset of rectal cancer patients who only demonstrated partial tumour regression following chemoradiation. <h3>Disclosure of interest</h3> None Declared. <h3>Reference</h3> Maas M, Nelemans PJ, Valentini V, <i>et al</i>. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol. 2010;11:835–44
Abstract 3570: Cervical cancer screening practices among Hispanic migrant and seasonal farmworkers of Michigan
Authors: Jayne S. Knoff, Amr S. Soliman, Sioban D. Harlow, May Yassine, Kelly Barnhardt
Journal: Cancer Research (2012)

Abstract Cervical cancer incidence among all racial/ethnic groups in the United States is highest among Hispanics. Previous studies have found that migrant and seasonal farmworkers have limited access to health care and may therefore be less likely to follow screening recommendations for early cervical cancer detection. The objective of this study was to describe Pap test utilization and identify barriers, attitudes and knowledge regarding cervical cancer screening among Hispanic migrant and seasonal farmworkers served by Northwest Michigan Health Services, Inc (NMHSI) in Shelby and Traverse City, Michigan. This cross-sectional study surveyed the patient population of NMHSI. A questionnaire addressing knowledge, attitude and practice of cervical cancer screening was administered to 309 participants in NMHSI clinics or in participants’ residences. The Hispanic study population included 184 seasonal and 125 migrant farmworkers. Of all Hispanics surveyed (mean age 38.7), 94.2% had ever received a Pap test. Comparatively, 87.7% had received a Pap test recently (in the last two years for 21-29 year olds, in the last three years for those over 30) and 14.5% had an abnormal Pap test result in the last ten years. There was no significant difference between migrant and seasonal farmworkers in terms of ever having had a Pap test or having had a recent Pap test (p-value 0.88 for both comparisons). Consistent with these findings, participants reported that they understood the benefits of and experienced few barriers to getting Pap tests. These findings suggest that migrant farmworkers may not experience more difficulty in receiving Pap tests than seasonal farmworkers in Michigan. Farmworkers in general recognize the importance of receiving Pap tests even though both groups of women have low levels of acculturation. Furthermore, findings suggest that recent efforts to increase cervical cancer screening have been effective. While cervical cancer screening rates are high, knowledge is low and this continuing research will aid in identifying specific gaps in cervical cancer screening knowledge and attitudes to address in future interventions. 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 3570. doi:1538-7445.AM2012-3570
FRI0069 Performance of rapid radiographic progression prediction matrices in the early rheumatoid arthritis patients of the espoir cohort
Authors: B. Fautrel, B. Granger, B. Combe, X. Le Loet
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Three matrices, ASPIRE<sup>1</sup>, BEST<sup>2</sup> and SWEFOT<sup>3</sup>, have been proposed to identify early rheumatoid arthritis (ERA) patients at high risk of rapid radiographic progression (RRP), defined as an increase of the vdH-Sharp score ≥5 points at 1 year, despite initial treatment with methotrexate. <h3>Objectives</h3> To test the validity of 3 RRP-prediction matrices in ERA patients from the ESPOIR cohort. <h3>Methods</h3> The ESPOIR cohort included 813 patients with recent arthritis in ≤2 joints for ≤6 months. Patient data were collected every 6 months during the 2 first years of follow-up. Structural damage progression on X-rays was measured by the vdH-Sharp score. The capacity of the matrices to identify RRP patients at 1 year, was tested by Receiver Operation Curve (ROC) analysis in which the area under the curve (AUC) reflected the discriminating power. <h3>Results</h3> 398 ESPOIR patients started MTX for ≥3 months during the 1st year. Their average characteristics were: age 49.3 y, female 74%, FR/ACPA+ 62%, RA erosion 18%, DAS28 5.35. The mean X-ray progression was 1.7 and 46 patients (11.6%) were classified RRP. The performance of the ASPIRE and SWEFOT matrices displayed only moderate validity, with AUC below 0.7. The BEST matrix seems to perform more optimally, with an AUC close to the ESPOIR matrix<sup>4</sup>, 0.79 vs. 0.75 (Figure). <h3>Conclusions</h3> Tested in a different population of ERA patient, the BEST matrix seems to display good validity to identify patients at risk of RRP. <h3>References</h3> Vastesaeger et al, Rheumatology 2009. Visser K et al, ARD 2010. Saevarsdottir S, ACR 2011. Fautrel B et al, ACR 2011. <h3>Disclosure of Interest</h3> None Declared
418 ASSOCIATION OF POLYMORPHISM IN microRNA 219–1 WITH CLEARANCE OF HEPATITIS B VIRUS INFECTION
Authors: M. Lee, Y.B. Lee, D.H. Lee, Y. Cho, J.-J. Yoo, W.M. Choi, H.D. Shin, S.W. Cho, J.Y. Cheong, Y.J. Kim
Journal: Journal of Hepatology (2013)
Particulate Matter Exposure and Preterm Birth: Estimates of U.S. Attributable Burden and Economic Costs
Authors: Leonardo Trasande, Patrick Malecha, Teresa M. Attina
Journal: Environmental Health Perspectives (2016)

Preterm birth (PTB) rates (11.4% in 2013) in the United States remain high and are a substantial cause of morbidity. Studies of prenatal exposure have associated particulate matter ≤ 2.5 μm in diameter (PM2.5) and other ambient air pollutants with adverse birth outcomes; yet, to our knowledge, burden and costs of PM2.5-attributable PTB have not been estimated in the United States.We aimed to estimate burden of PTB in the United States and economic costs attributable to PM2.5 exposure in 2010.Annual deciles of PM2.5 were obtained from the U.S. Environmental Protection Agency. We converted PTB odds ratio (OR), identified in a previous meta-analysis (1.15 per 10 μg/m3 for our base case, 1.07-1.16 for low- and high-end scenarios) to relative risk (RRs), to obtain an estimate that better represents the true relative risk. A reference level (RL) of 8.8 μg/m3 was applied. We then used the RR estimates and county-level PTB prevalence to quantify PM2.5-attributable PTB. Direct medical costs were obtained from the 2007 Institute of Medicine report, and lost economic productivity (LEP) was estimated using a meta-analysis of PTB-associated IQ loss, and well-established relationships of IQ loss with LEP. All costs were calculated using 2010 dollars.An estimated 3.32% of PTBs nationally (corresponding to 15,808 PTBs) in 2010 could be attributed to PM2.5 (PM2.5 > 8.8 μg/m3). Attributable PTBs cost were estimated at $5.09 billion [sensitivity analysis (SA): $2.43-9.66 B], of which $760 million were spent for medical care (SA: $362 M-1.44 B). The estimated PM2.5 attributable fraction (AF) of PTB was highest in urban counties, with highest AFs in the Ohio Valley and the southern United States.PM2.5 may contribute substantially to burden and costs of PTB in the United States, and considerable health and economic benefits could be achieved through environmental regulatory interventions that reduce PM2.5 exposure in pregnancy. Citation: Trasande L, Malecha P, Attina TM. 2016. Particulate matter exposure and preterm birth: estimates of U.S. attributable burden and economic costs. Environ Health Perspect 124:1913-1918; http://dx.doi.org/10.1289/ehp.1510810.
Abstract SY12-03: Getting abreast of the mammary epithelial hierarchy and breast cancer
Authors: Jane E. Visvader, Marie-Liesse Asselin-Labat, François Vaillant, Elgene Lim, Toula Bouras, Bhupinder Pal, Di Wu, Gordon Smyth, Geoff Lindeman
Journal: Cancer Research (2011)

Abstract To understand relationships between breast tissue, cells of origin and cancer stem cells in breast tumors, it is necessary to dissect the normal mammary epithelial hierarchy. We have isolated discrete populations of mouse and human mammary epithelial cells on the basis of cell-surface markers and defined subpopulations that are highly enriched for mammary stem, luminal progenitor and mature luminal cells. Transcriptome analyses of mouse and human mammary epithelial populations has led to the identification of multiple conserved genes and pathways. Analysis of different mouse models of mammary tumorigenesis using syngeneic transplantation assays and interrogation of molecular profiles has revealed potential cells of origin in preneoplastic tissue and the presence of a definitive cancer stem cell subset in different mouse mammary tumors. The role of the zinc finger transcription factor Gata-3, a critical regulator of luminal cell differentiation and a favourable prognostic indicator in breast cancer, has recently been explored in tumor initiation using mouse models. Gata-3 deficiency was found to increase the tumorigenicity of different epithelial subpopulations, with accompanying cell-fate changes. In the context of human breast tissue, analogous studies have enabled us to pinpoint the cellular defect occurring in precancerous tissue from BRCA1 mutation carriers. These carriers were shown to harbor aberrant luminal progenitor cells. Combined with interrogation of the molecular profiles of the different subtypes of breast cancer, the luminal progenitor was identified as the likely cell of origin for BRCA1-associated basal cancers. 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 SY12-03. doi:10.1158/1538-7445.AM2011-SY12-03
Abstract 735: Metaplastic columnar lined esophagus without goblet cells show phenotypic similarities to Barrett's Esophagus
Authors: Supriya Srivastava, Mei Shan Liew, Frank McKeon, Wa Xian, Khek Yu Ho, Ming Teh
Journal: Cancer Research (2012)

Abstract Aim: Barrett's esophagus (BE) is a premalignant condition, predisposing to esophageal adenocarcinoma (EAC). However, some EAC arise in columnar lined esophageal mucosa devoid of goblet cells. Therefore, the purpose of this study was to evaluate the biological properties of non-goblet columnar lined esophagus (CLE) and elucidate the relationship between BE and high grade dysplasia of esophagus (HGD). Material and Methods: Endoscopic biopsies from esophagus of 47 patients with columnar metaplasia with goblet cells (BE; n=28), columnar metaplasia with non-goblet cell (CLE; n=10), BE associated high grade dysplasia (HGD; n=9) and cardia with intestinal metaplasia (CIM; n=5) were included in the study. These groups were immunostained for, Villin (intestinal marker), CK7 (columnar epithelium marker), Claudin 3 (epithelial tight-junction marker) and MUC4 (membranous mucin). Statistical analysis between different groups was performed using the paired or unpaired t- test using SPSS v 15.0. A p value &amp;lt;0.05 was considered significant. Results: Patients with BE, CLE and HGD showed positivity for Villin, Claudin 3 and CK7 in 79%, 93%, 54% in BE group; 60%, 100% and 80% in CLE group and 78%, 100% and 34% in HGD group respectively. In metaplastic epithelium (BE and CLE) there was no statistically significant difference in expression of these markers (p&amp;gt;0.05). Patients with CLE without goblet cells showed immunopositive results for these markers, statistically similar to those of HGD group and also revealed significantly higher values compared to those of controls (cardia with intestinal metaplasia). MUC4 was expressed higher in 96% of BE cases as compared to 67% of HGD cases (mean, 81.85±27.74 vs 48.89±45.12). CLE without goblet cells did not express MUC4. Conclusion: Our results indicate that metaplastic columnar lined epithelium without goblet cells suggest biological properties of intestinal differentiation. It also shows that apart from BE, CLE without goblet cells may also have neoplastic potential. 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 735. doi:1538-7445.AM2012-735
Abstract LB-144: <i>In vivo</i> detection of bone metastases in a mouse model by positron emission tomography (PET) with [F-18]-labeled tyrosine derivative (D-FMT)
Authors: Sabine Zitzmann-Kolbe, Anne Strube, Anna-Lena Frisk, Sanna-Maria Käkönen, Hideo Tsukada, Peter Hauff, Dietmar Berndorff, Volker Gekeler, Keith Graham
Journal: Cancer Research (2010)

Abstract Objective: Detection and localization of metastatic lesions in advanced stages of cancer is still a difficult obstacle for diagnosis and subsequent treatment decisions for an optimized cancer patient management and therapy control. Whole body molecular imaging applying positron emission tomography (PET) allows the sensitive detection of radioactive labeled molecules, which specifically accumulate in tumor tissue. This offers a promising tool to assess the stage of the disease comprehensively. At present [F-18]-fluorodeoxyglucose (FDG) is the mostly used PET-tracer in oncology. However, FDG has the disadvantageof limited specificity by accumulating also in inflammatory cells due to their increased glucose metabolism. To overcome this problem, amino acids have been radiolabeled to study their potential imaging characteristics. D-[F-18]-fluoromethyl tyrosine (D-FMT, (R)-2-amino-3-(4-[F-18]fluoromethoxy-phenyl)-propionic acid) has shown good uptake into HeLa tumors in nude mice with no accumulation in sterile induced inflammation sites. The aim of this study was to investigate if D-FMT can also be used to image bone metastases besides primary soft tissue tumors. Methods: Human 786-O/luciferase renal cell adenocarcinoma cells were injected intracardially, which gave rise to the formation of several bone metastases. The radiosynthesis of D-FMT was carried out using an indirect labeling method via the [F-18]-fluoromethyl bromide synthon. Micro-PET imaging was performed 51 and 65 days after tumor cell inoculation. Results: The formation of metastases was monitored using bioluminescence imaging indicating the presence of tumor cells in the regions of hind limbs, forelimbs, spine and skull. A bone scan with [F-18]-fluoride confirmed skeletal metabolic activity at sites of osteolytic bone metastases. The i.v. application of [F-18]-D-FMT showed a very specific accumulation of the amino acid tracer in these bone metastases and, together with the low background, allowed very good imaging of these lesions. Based on the PET scan of [F-18]-D-FMT, sites of accumulation were excised. All imaged metastases could be verified histologically. Conclusion: These data suggest D-FMT as a new potential imaging tracer for the detection of primary tumors as well as bone metastases. In addition, the sensitivity of this tracer suggests the possibility for substantial benefit in detecting soft tissue metastases as well. 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 LB-144.
S133 Observational cohort study of outcome of patients referred to a regional weaning centre
Authors: D Mifsud Bonnici, T Sanctuary, B Creagh-Brown, N Hart
Journal: Thorax (2013)

<h3>Introduction</h3> Data on outcome of the patients referred to weaning and rehabilitation centres are limited. In this observational cohort study, we report the outcomes of patients referred to a specialist complex home ventilation, weaning and rehabilitation centre. <h3>Methods</h3> Data from the LFRU database from February 2005 to February 2011 were analysed. The primary diagnosis causing prolonged mechanical ventilation (MV) were classified into five groups: (1) neuromuscular and chest wall disease (NMD-CWD); (2) chronic obstructive pulmonary disease (COPD); (3) post-surgical patients; (4) obesity related respiratory failure (ORRF); and (5) other causes. The principal outcomes measured were weaning success, hospital mortality, 1-year and 2-year survival following discharge. <h3>Results</h3> A total of 369 patients were referred over the 6 year period. Of these, 194 (52.6%) were admitted. The commonest outcome was total liberation from all forms of MV (45%). The remainder were shown to (1) require nocturnal non-invasive ventilation (NIV) (22%); (2) require nocturnal and intermittent daytime NIV (1%); (3) require long-term tracheostomy ventilation (24%); and (4) died in hospital (8%). Post-surgical and COPD patients had the highest rate of total liberation from mechanical ventilation at 60% and 54%, respectively. The median time from admission to tracheostomy decannulation was 18 days (9–33). NMD-CWD patients had the lowest hospital mortality (7%), whereas COPD patients had the highest hospital mortality (29%). The overall survival at 12 and 24 months was 60% and 50%, respectively. 25% of the COPD patients were alive and 59% of the NMD-CWD patients were alive at 24 months (Figure 1). <h3>Conclusions</h3> The majority of patients with weaning failure were successfully liberated from mechanical ventilation. The weaning time was less than 3 weeks and only one-fifth of patients required nocturnal non-invasive ventilation. NMD-CWD patients were most likely to survive hospital but almost one-third of COPD patients died during the weaning process. COPD patients had the worst outcome at 2-years, whereas over half of the NMD-CWD patients were alive at 2-years. These data strongly support the Department of Health9s plan to develop 9Complex Home Ventilation, Weaning and Rehabilitation Centres9 as part of the investment in specialist respiratory services to enhance patient outcome.