tbuckley/cabot-search huggingface dataset:
Abstract 330A: Differential expression of angiogenic genes in invasive high grade serous ovarian carcinomas.
Authors: Sharareh Siamakpour- Reihani, Chen Jiang, Taylor Turner, Kouros Owzar, Andrew Berchuck, Mark Dewhirst, Angeles Alvarez Secord
Journal: Cancer Research (2013)

Abstract Our objective is to establish quantifiable and reproducible biomarkers that can aid in prognosis, and predicting treatment outcome in invasive high-grade serous ovarian cancer (HGSC). The goal of this project is to identify genomic determinants that affect the tumor angiogenesis as defined by microvascular density (MVD) count. Our central hypothesis is: differences in angiogenic gene expression profiles are associated with variations in MVD. This is a retrospective pilot study. Under an approved IRB protocol, between 1988 and 2001, sixty five snap frozen invasive serous ovarian cancer tissue samples were gathered at Duke University Medical Center. RNA from those samples were extracted and analyzed by the Affymetrix U133A microarray. Fifty-one of those samples belonged to patients with HGSC. MVD counts were determined for those samples using CD31 and CD105. CD31 and 105 are markers of proliferating endothelial cells and neoangiogenesis. Approximately 285 probe sets (associated with 148 genes) involved in angiogenesis and vasculogenesis were screened. Association between the gene expression levels and MVD counts based on a continuous variable and overall survival of the patients were evaluated. Our results indicate that: i) median CD105-MVD and CD31-MVD counts were 30 and 33, respectively; ii) there was a marginal association between CD105-MVD and overall survival (p-value =0.045) and CD31-MVD and overall survival (OS) (p-value =0.028); iii) CUL7, a member of CULLIN family of ubiquitin ligases, is associated with overall survival of the HGSC patients. Higher expression levels of CUL7 is related to worsening of OS (p-value= 8.17E−05); iv) a stronger association between CD105-MVD count and CUL7 expression (p-value= 0.001), compared to the association between CD31-MVD count and CUL7 expression (p-value= 0.024). In conclusion: CUL 7 has previously been implicated as an antiapoptotic oncogene and a P53 suppressor. Mutations in CUL7 have been linked to abnormal vasculogenesis. CUL2, another member of CULLIN family of ubiquitin ligases has also been implicated in the activity of Hypoxia-Inducible Factor (HIFα) and vasculogenesis. In this study we report that higher expression of CUL7 is significantly associated with worsening of the OS of patients with HGSC. These are considered preliminary results which need to be further verified and validated in an independent data set in future studies. Citation Format: Sharareh Siamakpour- Reihani, Chen Jiang, Taylor Turner, Kouros Owzar, Andrew Berchuck, Mark Dewhirst, Angeles Alvarez Secord. Differential expression of angiogenic genes in invasive high grade serous ovarian carcinomas. [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 330A. doi:10.1158/1538-7445.AM2013-330A
Abstract LB-266: Expression of AGR2 in lung cancer cells needs an active Hippo pathway co-activator, YAP1
Authors: Aiwen Dong, May Tun, Dariusz Wodziak, Aparna Gupta, Anson Lowe
Journal: Cancer Research (2012)

Abstract Background/Objective: We have previously established that Anterior Gradient-2 (AGR2) affects cancer cell growth by activating YAP1 of the Hippo pathway and inducing AREG of the EGF pathway. Although significant advances have been made concerning the growth promoting effects of AGR2 on cancer cells, including those derived from the pancreas, lung and esophagus, little is known about how AGR2 expression is regulated. Because of AGR2's potential role in human cancer and its established role in organ development in lower vertebrates, we explored the mechanisms responsible for its expression. Methods: ShRNA mediated specific knockdown of YAP1 was conducted in H460 human lung cancer cells. Quantitative real-time PCR was performed to confirm the knockdown efficiency. The expression of AGR2, AREG, and the YAP1-induced genes CTGF, CYR61, COL8A1 was assayed by quantitative real time PCR after YAP1knockdown. The effect of YAP1 knockdown on AGR2 protein was evaluated by immunoblotting. Finally, an AGR2 expression reporter based on the firefly luciferase gene was employed to evaluate whether YAP1 acts on AGR2 promoter activity. Results: Reduced YAP1 expression by lentivirus mediated shRNAmir transduction was further confirmed by western blotting and was also supported by the decrease of YAP1 readouts, such as CTGF. A 95% knockdown of YAP1 expression in H460 cells resulted in a significant morphological change and a 275-fold decrease in AGR2 mRNA. As demonstrated in previously published work, AREG expression was also decreased by 40-fold. Western blots showed that in YAP1 knockdown cells (YAP1KD), there was only negligible levels of AGR2 protein. The data suggested that active YAP1 protein is required for AGR2 expression. The decrease of AGR2 mRNA expression by YAP1KD could be transcriptional or posttranscriptional. To address this question, an AGR2 promoter assay to answer whether YAP1 affects AGR2 transcription. Our AGR2 reporter assay showed that there was more than 5 times more luciferase activity in YAP1KD cells compared to cells infected with the control lentivirus not targeting to any known gene, suggesting that AGR2 expression is regulated in a post-transcriptional manner. Conclusion: YAP1 decreases AGR2 mRNA through a post-transcriptional mechanism, which may include microRNAs. There are four potential miRNA binding sites in the 3-UTR region of AGR2 transcripts. Future experiments will explore if any of these miRNAs are induced upon YAP1 knockdown. This work provides insight into the crosstalk between YAP1 and AGR2, which may have significant implications in lung cancer carcinogenesis. 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 LB-266. doi:1538-7445.AM2012-LB-266
Instability in Chromosomes 9, 7, and 5 Correlate with Lymph Node Metastasis at Presentation in Basal Phenotype Carcinoma.
Authors: G. Oakley III, A. Brufsky, M. Chivukula
Journal: Cancer Research (2009)

Abstract Introduction: Basal phenotype breast carcinoma has been described as an aggressive variant with comparatively poor prognosis; however, increasing experience suggests that only a subset show increased mortality. We performed microarray analysis of DNA from 11 basal phenotype carcinomas (from 10 patients) and paired normal breast tissue with copy number and loss of heterozygosity analysis with hierarchical clustering to see if characteristic genetic changes were present that correlated to lymph node metastasis at presentation.Materials and Methods: Electronic search of the medical records from 2006-2008 of our institution by an honest broker for all cases of basal phenotype carcinoma (based on medullary-like histology and immunohistochemistry positive for at least two of CK14, CK17, CK5/6 and EGFR) with known lymph node status at presentation and archived snap frozen fresh and tumor samples returned 10 cases (one with bilateral basal phenotype carcinoma), which were de-identified. 5 of these cases had lymph node metastasis at presentation. DNA isolation by column extraction was performed on 0.25 g of paired tumor and normal samples (confirmed by pathologist review before extraction). An Affymetrix 5.0 mapping microarray was performed on isolated DNA per manufacturer's protocols, and analyzed with Partek Genomics Suite software using copy number/LOH workflows using hidden Markov model and genomic segmentation in separate analyses with unsupervised hierarchical clustering.Results: Copy number and LOH analysis using hidden Markov model and genomic segmentation methods gave equivalent hierarchical clustering for our data set. Adjusting the obtained cluster analysis for known lymph node metastasis showed that changes in chromosomes 9, 7, and 5 that differentially clustered 4 of 5 cases which presented with lymph node metastasis (and 2 closely related initially lymph node negative cases).Discussion: Our results suggest that changes on chromosomes 9, 7 and 5 may correlate with the most important prognostic indicator in breast cancer, lymph node status, in basal phenotype carcinomas. Globally suboptimal amplification prevented accurate quantitation of copy number changes or precise loss of heterozygosity localization on these chromosomes. Additional studies to confirm these results using separate molecular techniques are underway, as well as correlation with 5 year survival when the cohort reaches that milestone. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6133.
Oral squamous cell carcinoma: microRNA expression profiling and integrative analyses for elucidation of tumourigenesis mechanism
Authors: Mayakannan Manikandan, Arungiri Kuha Deva Magendhra Rao, Ganesan Arunkumar, Meenakshisundaram Manickavasagam, Kottayasamy Seenivasagam Rajkumar, Ramamurthy Rajaraman, Arasambattu Kannan Munirajan
Journal: Molecular Cancer (2016)

The advantages and utility of microRNAs (miRNAs) as diagnostic and prognostic cancer markers is at the vanguard in recent years. In this study, we attempted to identify and validate the differential expression of miRNAs in oral squamous cell carcinoma (OSCC), to correlate their expression with the clinico-pathological profile of tumours and to identify the signaling pathways through which the aberrantly expressed miRNAs effect tumourigenesis.miRCURY LNA™ array with probes specific to 1168 miRNAs and TaqMan assays specific for 10 miRNAs was employed to evaluate and validate miRNA expression in a discovery cohort (n = 29) and validation cohort (n = 61) of primary OSCC tissue specimens, respectively. A computational pipeline with sequential integration of data from miRTarBase, CytoScape, UniProtKB and DIANA-miRPath was utilized to map the target genes of deregulated miRNAs and associated molecular pathways.Microarray profiling identified 46 miRNAs that were differentially expressed in OSCC. Unsupervised clustering demonstrated a high degree of molecular heterogeneity across the tumour samples as the clusters did not represent any of their clinico-pathological characteristics. The differential expression of 10 miRNAs were validated by RT-qPCR (let-7a, let-7d, let-7f and miR-16 were downregulated while miR-29b, miR-142-3p, miR-144, miR-203, and miR-223 were upregulated in OSCC; the expression of miR-1275 was variable in tumours, with high levels associated to regional lymph node invasion; additionally, miR-223 exhibited an association with advanced tumour stage/size). In silico analyses of the experimentally confirmed target genes of miRNAs revamp the relationship of upregulated miRNAs with tumour suppressor genes and of downregulated miRNAs with oncogenes. Further, the differentially expressed miRNAs may play a role by simultaneously activating genes of PI3K/Akt signaling on one hand and by repressing genes of p53 signaling pathway on the other.The identified differentially expressed miRNAs and signaling pathways deregulated in OSCC have implications for the development of novel therapeutic strategies. To the best of our knowledge, this is the first report to show the association of miR-1275 with nodal invasion and the upregulation of miR-144 in OSCC.
THE OTHER SIDE OF HALLUCINATIONS
Authors: JONATHAN LANG
Journal: American Journal of Psychiatry (1939)

The problem of hallucinations looms as an important one for the understanding of the nature of psychopathological conditions. From the viewpoint of actual experience, hallucinations form the epicenter from which the psychosis spreads. The clarification of the hallucinatory process will lead far toward the understanding of psychopathology. Nine years of actual experience have led me to the belief that the crucial factor of the hallucinatory phenomena is the overcoming of the afferent-to- efferent principle. In my experience hallucinations involved complex stimulations of complex patterns of the sensory nervous system. These stimulations were not and could not have been produced by the self of the individual. The complexity of the patterns of the hallucinations suggests the existence of some form of organizing factor. Already existing knowledge as to the physico-chemical nature of the nervous system implies that this factor must at least operate as a physico-chemical agent—say some form of energy system. Difficulties in locating and isolating such a factor within the human organism suggest the possibility of the entrance of an external agent. The question is raised as to whether the prevalent theory of spontaneous generation of psychopathological phenomena may not be retarding the clarification of the actuality behind hallucinations. The possibility that hallucinations may be produced by the intrusion of some psychic infective agent is one that requires attention.
IMPROVEMENT IN DIASTOLIC INDICES BY RANOLAZINE: A POTENTIAL MECHANISM FOR ITS ANTI-ISCHEMIC AND ANTIARRHYTHMIC EFFECTS
Authors: Hamid Reza Assadi, Hossein Shenasa, Shahriar Heidary, Seyedeh-Atiyeh Afjei, Shayan Aminilari, Mohammad Shenasa
Journal: Journal of the American College of Cardiology (2015)
ddI — a Good Start, but Still Phase I
Authors: Anthony S. Fauci
Journal: New England Journal of Medicine (1990)

Ever since the human immunodeficiency virus (HIV) was identified as the causative agent of the acquired immunodeficiency syndrome (AIDS), investigators have mounted an intensive effort to develop antiviral drugs with activity against HIV. In early 1987, zidovudine was approved for use in adults with AIDS or symptomatic HIV infection and fewer than 200 CD4+ T lymphocytes per cubic millimeter. In early 1990, zidovudine was further approved for use in asymptomatic HIV-infected persons with fewer than 500 CD4+ T lymphocytes per cubic millimeter. At present, zidovudine is the only drug approved for use as an anti-HIV agent. Since its approval by . . .
Abstract IA-2: PI3-Kinase and cancer metabolism
Authors: Lewis C. Cantley
Journal: Cancer Research (2009)

Abstract Mutations in Phosphoinositide 3-Kinase (PI3K) are among the most common events in solid tumors. Recent studies have revealed a highly conserved pathway by which PI3K regulates cell growth and glucose metabolism. Mice with activating mutations in the PIK3CA gene develop cancers that have high rates of glucose uptake and metabolism and pharmacological inhibitors of PI3K block glucose uptake and cause tumor shrinkage. We have also shown that the embryonic form of pyruvate kinase plays a critical role in tumor cell growth by diverting glucose metabolites into anabolic processes. The biochemical basis for these observations and their importance for tumor growth will be discussed. Citation Information: Cancer Res 2009;69(23 Suppl):IA-2.
Abstract 1589: LKB1 overexpression regulates DNA repair pathway and sensitivity to radiation in LKB1 mutant non-small cell lung cancer cell lines .
Authors: Chao Yang, Uma Giri, Maria Angelica Cortez, Jayanthi Gudikote, YouHong Fan, Lixia Diao, Lauren A. Byers, John V. Heymach
Journal: Cancer Research (2013)

Abstract Background: LKB1 is a serine/threonine kinase which is mutated in 20-30% of non-small cell lung cancers (NSCLC).In general, DNA repair pathway activation leads cellular resistant to DNA damaging agents. The loss of LKB1 leads NSCLC to be more invasive and resistant to DNA damage based therapies. We hypothesize that loss of LKB1 may contribute to DNA damage response. We investigated LKB1- mediated signaling pathways by stably overexpressing LKB1 in its mutated NSCLC cell lines, A549 and H460. Methods: Expression of 139 proteins was analyzed by reverse phase protein array (RPPA) in LKB1 overexpressing cell lines along with the appropriate vector control lines. Differences in protein expression at baseline in clones with LKB1 versus clones with vector control were assessed by unpaired T-test with Welch's correction. Ionizing radiation sensitivity (reproductive cell death) was assessed by clonogenic cell survival assay (CSA). Results: LKB1 overexpression in A549 and H460 showed a significant downregulation of genes involved in DNA damage and repair pathway, such as RAD50 (1.4-fold relative expression, p&amp;lt; 0.05 and 1.5-fold relative expression p&amp;lt;0.02 respectively), XRCC1 (1.2-fold relative expression p&amp;lt;0.005 and 1.1-fold relative expression p&amp;lt;0.05, respectively), and DNA-PKCS (1.2-fold relative expression p≈0.067 and 1.2-fold relative expression p&amp;lt;0.01. Also, CSA showed that A549 with LKB1 overexpression led to enhanced sensitization of cells to radiation (DER = 2) which is in consistent with the downregulation of RAD50, XRCC1 and DNA-PKCS. Furthermore, expression of CHK2 and phosphorylation of CHK1 are downregulated, H460 with LKB1 overexpression showed a significant decreasing of CHK1 phosphorylation level (p&amp;lt;0.05). Conclusion: Our results suggest that LKB1 overexpression modulates DNA repair capacity through downregulation of RAD50, XRCC1, DNA-PKCS, CHK1 and CHK2. LKB1 loss may lead to the resistance to DNA damaging induced cell death. Citation Format: Chao Yang, Uma Giri, Maria Angelica Cortez, Jayanthi Gudikote, YouHong Fan, Lixia Diao, Lauren A. Byers, John V. Heymach. LKB1 overexpression regulates DNA repair pathway and sensitivity to radiation in LKB1 mutant non-small cell lung cancer cell lines . [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 1589. doi:10.1158/1538-7445.AM2013-1589
SAT0541 Gout Patients Treated with Conventional Urate-Lowering Therapy: Association between Disease Control and Health-Related Quality of Life
Authors: R. Wood, J. Johnson, R. Morlock, S. Baumgartner, S. Ramachandran
Journal: Annals of the Rheumatic Diseases (2014)

Background Gout patients have impaired quality of life compared with the general population [1]. Gout is a chronic, progressive disease and many patients treated with conventional urate-lowering therapy (ULT) are inadequately controlled [2]. Implications of inadequate control can be assessed by studying the health-related quality of life (HRQoL) of patients receiving conventional ULT who are adequately controlled versus those who are not. Objectives To evaluate the impact of inadequate control on HRQoL in gout patients. Methods A retrospective database analysis of gout patients currently receiving conventional ULT for at least 3 months. Data were drawn from the Adelphi Disease Specific Programme (DSP)™, a cross-sectional survey of patients with gout in France, Germany, UK and US. Participating physicians submitted extensive clinical data for each patient including most recent serum uric acid (sUA) level and number of flares in last 12 mos. Patients were invited to complete a patient self-completion questionnaire, containing the EQ-5D (3L) and PROMIS HAQ. Inadequate control was defined as sUA level >6 mg/dL or ≥2 flares. Adequate control was defined as sUA level ≤6 mg/dL and 0 flares. Mann-Whitney tests investigated differences between inadequately controlled and adequately controlled patients in HRQoL. Results Of 1204 gout patients in this analysis, 836 (69%) were inadequately controlled; 82% of patients were male, mean age was 61 yrs, and mean duration on current ULT was 32 mos. 368 (31%) patients were adequately controlled with a mean age of 63 yrs and mean duration on current ULT of 57 mos. There were no significant differences between patients deemed adequately controlled vs inadequately controlled on number of renal, autoimmune, GI or CV comorbidities. However, there was a significant difference in total EQ-5D scores between inadequately controlled and adequately controlled patients (-0.087; p<0.0001). Inadequately controlled patients had significantly worse PROMIS HAQ scores (-6.302; p<0.0001) compared with adequately controlled patients. Conclusions Less than one-third of patients with gout were controlled. Patients with inadequately controlled gout reported significantly worse functioning and quality of life compared with adequately controlled patients, as measured by EQ-5D and PROMIS HAQ scales. New therapeutic approaches are needed to improve control in gout patients. References 1. Roddy E. Rheumatology (Oxford) 2007;46:1441-4. 2. Perez-Ruiz F. Adv Ther 2012;29:935-46. Acknowledgements Research sponsored by Ardea Biosciences/AstraZeneca. Disclosure of Interest R. Wood Employee of: Adelphi Real World, J. Johnson Employee of: Adelphi Real World, R. Morlock Employee of: Ardea Biosciences, Inc, S. Baumgartner Employee of: Ardea Biosciences, Inc, S. Ramachandran Employee of: AstraZeneca DOI 10.1136/annrheumdis-2014-eular.4429
PTU-117 Cutaneous Stigmata Of Chronic Liver Disease; What Do They Mean?
Authors: L Vine, G McCracken, S Needs, N Ryley, K George
Journal: Gut (2014)

<h3>Introduction</h3> As clinicians we are taught to assess all patients for cutaneous signs of chronic liver disease (CLD). However, there is limited evidence available in the literature regarding their significance or prognostic value for diagnosing the presence or severity of CLD. The aim of this prospective study, therefore, was to assess the frequency and significance of cutaneous stigmata in patients with suspected CLD. <h3>Methods</h3> Between 2006 and 2011 outpatients with suspected CLD attending for liver biopsy were assessed by an experienced gastroenterology registrar, who undertook the liver biopsy, and documented the presence of palmar erythema, Dupuytren’s contracture, spider naevi, clubbing or gynaecomastia. Correlation between these cutaneous stigmata and the presence and degree of liver damage was assessed by the chi square test. <h3>Results</h3> 124 consecutive outpatients underwent assessment and liver biopsy; 42 (34%) female and 82 (66%) male, median age 46 years (range 18–78). Bloods tests showed median bilirubin 11 µmol/l (range 3–500), median ALT 74 IU/l (range 11–562) and median INR 1 (range 0.8–1.7). The commonest clinicopathological diagnoses were chronic hepatitis C 31%, non-alcohol related fatty liver disease 19% and alcohol related liver disease 12%. 19 patients had cirrhosis, 56 fibrosis and 49 had no fibrosis. Overall only 36/124 (29%) patients had any stigmata of CLD. 13/19 cirrhotic patients had stigmata compared to 23/105 non cirrhotic patients (c <sup>2 </sup>= 18.5, p &lt; 0.001). 26/75 patients with any degree of fibrosis had stigmata compared to 10/49 patients with no fibrosis (c<sup>2 </sup>= 1.8, p = NS). 7 patients had 2 different stigmata of CLD, of whom 5 had cirrhosis and 2 had fibrosis. Females (14/42) were no more likely to have stigmata than males (25/82) (c <sup>2 </sup>= 0.1, p = NS). Patients with viral hepatitis were no more likely to have stigmata than those with fatty liver disease (c <sup>2 </sup>= 1, p=NS). <h3>Conclusion</h3> Cutaneous stigmata of CLD are absent in the majority of patients with suspected CLD and a significant minority of patients with cirrhosis. This may contribute to the under diagnosis of chronic liver disease at all stages of severity. <h3>Disclosure of Interest</h3> None Declared.