tbuckley/cabot-search huggingface dataset:
Abstract 3911: Dysegulation of Sox9-dependent gene expression leads to enhancement of angiogenesis and metastases in pancreatic cancer
Authors: Peter Camaj, Ivan Ischenko, Hendrik Seeliger, Stefan Krebs, Andrea Renner, Karl W. Jauch, Christiane J. Bruns
Journal: Cancer Research (2010)

Abstract Background: The understanding of invasion, angiogenesis and metastasis is essential for the development of new targeted molecular therapy against pancreatic cancer. The aim of this study is to analyse the regulation of differentially expressed genes in highly proangiogenic and prometastatic compared to low metastatic and low angiogenic pancreatic cancer cells Materials and methods: The transcriptome of the low metastatic pancreatic cancer cell line and its highly angiogenic and metastatic derivate L3.6pl have been compared under the normoxic and hypoxic conditions using Affymetrix HGU133plus 2.0 arrays. The hierarchic cluster analysis has been performed using SOTA algorithm. Promoters of the differentially expressed genes have been analysed using oPOSSUM 2 program. Affymetrix data have been validated via qRT-PCR and via ELISA. Chromosomal DNA containing promoters of the relevant genes has been amplified via PCR and sequenced. Results: The Affymetrix analysis revealed clusters of differentially regulated genes with regard to the cell line and the oxygen level. While VEGF expression was upregulated in FG cells under hypoxic condition, it was constitutively upregulated already under normoxic conditions in L3.6pl and no further stimulation was observed under hypoxic conditions. This regulation pattern was similar in a cluster of genes that share a promoter sequence coding for a binding site for the transcription factor Sox9. Sox9 itself shows a similar regulation, leading to the assumption that expression changes of Sox9 are involved in the different hypoxic gene expressions. Promoter analysis of Sox9 in FG and L3.6pl cells showed mutations in the promoter region in L3.6pl, while the VEGF promoter was unchanged. Further analysis has shown that this mutation is not relevant for biological function. Refined analysis revealed differential Sox9 promoter methylation as reason for observed phenomenon. Conclusions: Proangiogenic genes such as VEGF are upregulated in the more aggressive cell line L3.6pl, compared to FG. We identified a gene cluster that is constitutively upregulated in L3.6pl, independent of hypoxia. These genes are controlled by the transcription factor Sox9. A Sox9 promoter differential methylation may be the reason for the escape from hypoxic regulation in L3.6pl cells and thus may contribute to the higher angiogenic and metastatic potential. Taken together, Sox9 may be an interesting new diagnostic and therapeutic target in pancreatic cancer progression. 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 3911.
Abstract 2900: Phylogenetic classification, structural evolution, and functional divergence of the Ras superfamily of GTPases as tracked by the Conserved Domain Database (CDD)..
Authors: James S. Song, Narmada Thanki, Myra K. Derbyshire, Marc Gwadz, Noreen R. Gonzales, Aron Marchler-Bauer, Stephen H. Bryant
Journal: Cancer Research (2013)

Abstract The Conserved Domain Database (CDD, http://www.ncbi.nlm.nih.gov/Structure/cdd/cdd.shtml) is part of NCBI's Entrez query and retrieval system and is a collection of annotated multiple sequence alignment (MSA) models representing ancient conserved protein domains, basic units of protein function and protein evolution.These MSA models are available as position specific score matrices (PSSMs) for fast identification of conserved domains in protein sequences via Reverse Position Specific -BLAST (RPS-BLAST), a variation of the commonly used PSI-BLAST. The domain models can be viewed and examined interactively using NCBI's CDTree/Cn3D software applications. Conserved functional annotations such as key catalytic and ligand-binding sites are displayed on protein structures sharing significant homology to the query, thereby inferring the underlying mechanism(s) of the protein domain family. Here, we present the current, functionally annotated, evolutionary classification of the Ras GTPase superfamily, including the circularly permuted Ras-like domain, and its downstream effectors such as RasGAP and RasGEF. Using CDTree/Cn3D tools, subfamilies in diverse organisms were inferred from the MSAs, phylogenetic trees, and domain architectures of the Ras superfamily. Furthermore, several subfamilies comprising of only uncharacterized protein sequences have their functions annotated by inference from the molecular and cellular functions of known related proteins having 3D structure, and based on the available literature. We demonstrate the utility of CDTree/Cn3D in studying molecular evolution of protein domain families, and in accelerating the pace of biological discovery by enabling researchers to obtain valuable clues regarding as-yet-unidentified molecular properties and mechanisms. CDTree/Cn3D software is freely available for download via the CDD website. Citation Format: James S. Song, Narmada Thanki, Myra K. Derbyshire, Marc Gwadz, Noreen R. Gonzales, Aron Marchler-Bauer, Stephen H. Bryant. Phylogenetic classification, structural evolution, and functional divergence of the Ras superfamily of GTPases as tracked by the Conserved Domain Database (CDD). [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 2900. doi:10.1158/1538-7445.AM2013-2900
Abstract 610: Metformin augments rituximab and chemotherapeutic agents-induced apoptosis via mTOR inhibition in rituximab-resistant B lymphoma cell lines
Authors: Min Kyoung Kim, Eun Kyung Yoo, Nam-Yi Kim, Kyung Hee Lee, Myung Soo Hyun, Min Kyu Kang, ChuHee Lee
Journal: Cancer Research (2010)

Abstract With elusive mechanisms, a subgroup of NHL patients who treated with rituximab in combination with cytotoxic chemotherapeutic agents becomes unresponsive. Patients who relapsed lymphoma are known to have poorer outcome when treated with rituximab compared with treated without rituximab. Since activation of mTOR pathway has been recently suggested for progression of NHL, especially in salvage setting, we'd like to examine the effect of metformin which inhibits mTOR pathway in rituximab-resistant NHL. Three lymphoma cell lines (Raji, Raji-2R, Raji-4RH) were used, which were kindly given by Dr Czuczman MS from Rosewell Park Cancer Institute (Ref. Czuczmana MS et al. Clin Cancer Res 2008;14:1561, 2008;14:1550). These cells were treated with cisplatin, adriamycin, vincristine and rituximab in the absence or presence of metformin for 24, 48, 72 hrs. Cell growth and proliferation was evaluated by MTT assay and cell cycle progression was determined FACS analysis. To characterize molecular mechanisms involved in metformin-induced inhibition of cell proliferation, the level of BAX, BAK, Bcl-2, Bcl-XL, Mcl-1, AMPK, pAMPK, pACC, mTOR, p70S6K and S6K was determined by western blot analysis. Compared with rituximab-sensitive cell line (RSCL) which is parental lymphoma cell, Raji, rituximab-resistant cell lines (RRCLs), that are Raji-2R and Raji-4RH, have shown decreased cytotoxicity in response to chemotherapeutic agents including cisplatin, adriamycin and vincristine as well as rituximab. However, cytotoxic effect of these chemotherapeutic agents and rituximab was improved in combination of metformin in both RSCL and RRCLs. To us surprise, a better synergistic inhibition of cell proliferation was found in RRCLs as a result of combination of metformin and chemotherapeutic agents or rituximab, suggesting that intracellular signaling pathway induced by metformin might not be overlapped to that by chemotherapeutic agent and rituximab. Notably, it has known that in RRCLs, the level of proapototic proteins, BAX, BAK, is relatively low compared to in RSCL decreased, but the expression of anti-apoptotic protein and AMPK activity is increased and dysregulation of mTOR pathway is found. Our data showed that metformin restored dysregulation of mTOR pathway in RRCLs, since activation of p70S6K and S6K posphorylation was decreased. At the same time, expression of BAX and BAK was increased and that of anti-apoptotic proteins was decreased. Metformin enhances rituximab-induced and chemotherapy-induced apoptosis via mTOR inhibition in rituximab-resistant NHL. 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 610.
Abstract 2000: Impact of delay to cryopreservation on RNA integrity and genome-wide expression profiles in resected tumor samples.
Authors: Florence Le Calvez-Kelm, Elodie Caboux, Maria Paciencia, Geoffroy Durand, Nivonirina Robinot, Magdalena Wozniak, Francoise Galateau-Salle, Graham Byrnes, Pierre Hainaut
Journal: Cancer Research (2013)

Abstract Background: The quality of tissue samples and extracted mRNA is a major source of variability in tumor transcriptome analysis using genome-wide expression microarrays. During and immediately after surgical tumor resection, tissues are exposed to metabolic, biochemical and physical stresses characterized as “warm ischemia”. Current practice advocates cryopreservation of biosamples within 30 minutes of resection, but this recommendation has not been systematically validated by measurements of mRNA decay over time. Methods: Using Illumina HumanHT-12 v3 Expression BeadChips, providing a genome-wide coverage of over 24,000 genes, we have analysed gene expression variation in samples of 3 hepatocellular carcinomas (HCC) and 3 lung carcinomas (LC) cryopreserved at times up to 2 hours after resection. Results: RNA Integrity Numbers (RIN) revealed no significant deterioration of mRNA up to 2 hours after resection. Genome-wide transcriptome analysis detected non-significant gene expression variations of -2.4%/hr (95% CI: -5.5%/hr to 0.6%/hr; p=0.12). In LC, no consistent gene expression pattern was detected in relation with warm ischemia. In HCC, a signature of 6 up-regulated genes (CYP2E1, IGLL1, CABYR, CLDN2, NQO1, SCL13A5) and 6 down-regulated (MT1G, MT1H, MT1E, MT1F, HABP2, SPINK1) was identified (FDR &amp;lt;0.05). Conclusions: Overall, our observations support current recommendation of time to cryopreservation of up to 30 minutes and emphasize the need for identifying tissue-specific genes deregulated following resection to avoid misinterpreting expression changes induced by warm ischemia as pathologically significant changes. Citation Format: Florence Le Calvez-Kelm, Elodie Caboux, Maria Paciencia, Geoffroy Durand, Nivonirina Robinot, Magdalena Wozniak, Francoise Galateau-Salle, Graham Byrnes, Pierre Hainaut. Impact of delay to cryopreservation on RNA integrity and genome-wide expression profiles in resected tumor samples. [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 2000. doi:10.1158/1538-7445.AM2013-2000
Abstract P2-11-04: Chemotherapy Induces Neuroinflammation and Cognitive Deficits in Female Mice
Authors: BL Jarrett, MB Lustberg, A Hinzey, KA Stuller, CL Shapiro, C DeVries
Journal: Cancer Research (2012)

Abstract Introduction: Advances in cancer detection and treatment have substantially increased the survival rate for breast cancer patients. Chemotherapeutic drugs, particularly anthracyclines, have potentially toxic side effects in the brain- impacting memory, processing time and verbal fluency. More than 30% of patients undergoing chemotherapy for breast cancer report cognitive deficits during and after treatment. Despite the high incidence and significant impact on quality of life, little is known about the cause of the cognitive deficits and no effective treatment currently exists. Our hypothesis is that chemotherapy-induced neuroinflammation impairs cognition. Methods: Adult female BALB/C mice were ovariectomized and then two weeks later injected intravenous (IV) with a single dose of chemotherapy (45 mg/m2 doxorubicin + 450 mg/m2 cyclophosphamide) or vehicle (n = 10–12/group). The mice were trained for three trials per day across six days in the Barnes Maze, a well-characterized spatial memory task. Results: Both the chemotherapy-treated and vehicle-treated mice were able to acquire the task by the final day of training. However, the vehicle-treated mice reached asymptotic performance after fewer training sessions than the chemotherapy-treated mice. Furthermore, the chemotherapy-treated mice took significantly longer to find the escape box than the vehicle-treated mice on training days 2–5 (p &amp;lt; 0.05). In contrast, there were no group differences in overall locomotor activity level, suggesting that the observed difference in maze performance was not due to a fatigue. (p &amp;gt; 0.05) In addition, chemotherapy increased proinflammatory cytokine expression (TNF-α, IL-1β, and IL-6) in the hippocampus (p &amp;lt; 0.05), a region of the brain that is critical for spatial learning and memory. Likewise, microglia from chemotherapy-treated mice exhibited increased expression of MHCII and CD80 relative to vehicle-treated mice (p &amp;lt; 0.05), thereby suggesting a proinflammatory phenotype. Conclusions: Together, these data suggest that the administration of doxorubicin and cyclophosphamide in doses that are approximately 25% lower than the typical dose for women treated for breast cancer, produce neuroinflammation, including microglia activation, increased proinflammatory cytokine expression and concomitant cognitive deficits in female mice. Additional studies will establish whether a causal relationship exists between chemotherapy-induced neuroinflammation and cognitive deficits. Identifying the mechanism through which chemotherapy induces cognitive deficits is the first step toward designing therapeutic interventions. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-11-04.
Abstract 1431: An optimized in vitro method to evaluate primary tumor cell invasion using optical imaging technology
Authors: Jessica Bockhorn, Ya-Fang Chang, Huiping Liu, Geoffrey Greene
Journal: Cancer Research (2011)

Abstract The recent development of human-in-mouse tumor models has provided better representative working models to understand tumor initiation and progression than previous mouse tumor models or cell lines. However, it has not been feasible to use these models for high-throughput functional or therapeutic screening. Our aim was to establish a complementary in vitro culturing system for high-throughput functional studies or therapeutic screening of breast cancer stem cells (BCSCs). We hypothesize that with extracellular matrix and stromal cell support, three-dimensional (3D) cultures can support the survival and invasion of primary human tumors in vitro. We report here a new method to objectively evaluate and quantify invasion of primary breast cancer tumor cells using Transwells and bioluminescence imaging (BLI) technology. We optimized the adhesion and invasion conditions for these primary tumor cells. We also labeled cells using Luc2-EGFP or -tdTomato lentiviral vectors so that the signal of all invaded cells could be quantified using BLI or fluorescence imaging of the entire bottom chamber of the Transwell system. Our results demonstrate that stromal cells are not only necessary for the survival of the primary tumor cells but also facilitate their invasion in vitro. This work establishes a new method for screening candidate genes, miRNAs and compounds that regulate growth, survival, invasion and drug sensitivity of primary tumor cells, including both BCSCs and non-BCSCs. 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 1431. doi:10.1158/1538-7445.AM2011-1431
Genetically Dissecting Cortical Neurons Involved in Epilepsy in Angelman Syndrome
Authors: Emanuela Santini, Eric Klann
Journal: Neuron (2016)

Epilepsy in Angelman Syndrome is thought to originate from an imbalance between local excitatory-inhibitory circuits that results in a generalized hyperexcitability. In this issue of Neuron, Judson et al. (2016) demonstrate that selective maternal deletion of Ube3a in cortical GABAergic neurons causes circuit hyperexcitability, increased seizure severity, and EEG abnormalities.
PWE-196 Endoscopic mucosal resection of flat and sessile polyps in the colon: safety, efficacy and clinical outcomes from a large data base in the UK tertiary referral centre
Authors: S Ahmad, R Shukla, E Telakis, S Sami, J mannath, R Teli, A Jawhari, K Ragunath
Journal: Gut (2012)

<h3>Introduction</h3> Endoscopic Mucosal Resection (EMR) is now well established as the procedure of choice for removing flat and sessile polyps in the colon. It stems from large scale studies in Japan that is increasingly practised in the UK, thus potentially avoiding surgery for benign polyps. Our aim was to assess the safety, efficacy and clinical outcomes of EMR procedures at Nottingham University Hospitals NHS Trust. <h3>Methods</h3> We searched our prospectively collected database for all sessile and flat colonic polyps &gt;10 mm (Paris0–Is, 0–II) removed by injection and snare EMR technique in our centre over a 7-year period (2004–2011). Follow-up examinations were done as per BSG guidelines. Parameters analysed included patient9s demographics; type of resection; completeness of resection; endoscopic success rate; as well as recurrence and complication rates. <h3>Results</h3> All procedures were done by endoscopists trained in EMR. 338 EMRs were done in 325 patients, age range 20–90 yrs, male 55% (180). 77% (261) had sedation and one patient had GA for the procedure. 53% (180) had en bloc resection, 39% (132) had piecemeal while 4.7% (16) had incomplete or partial resection. 2.9% (10) were unable to resect. Endoscopic success at 1st attempt was achieved in 82% (278) and over all endoscopic cure was 92% (310). 4.4% (15) were referred for surgery. A follow-up procedure was performed in 77% (242) within 12 months Recurrence rate for enbloc resection was 5.7% (9/156), for piecemeal resection it was 18% (16/86). Overall recurrence rate was 10.3% (25/242). Adenocarcinoma was present in 4.1% (14) patients while in eight of these patients had complete resection with no evidence of recurrence at follow-up. Over all Complication rate was 9.1% (31). 6.5% (22) had immediate bleeding requiring therapy. 15/22 were left sided Polyps (11 rectum, 4 sigmoid) with mean size &gt;20 mm. 1.1% (4) patients had delayed bleeding. While two required repeat colonoscopy and haemostasis one had right hemicolectomy as bleeding was complicated by delayed perforation. 0.5% (2) patients had immediate while one patient had delayed perforation at second day requiring surgery. There was no procedure related death. <h3>Conclusion</h3> EMR is effective and safe therapy in well trained hands with minor and acceptable complication rate. There is high recurrence rate especially after piecemeal resection within the first 12 months that requires a strict follow-up protocol. Rectal polyps and size &gt;20 mm were associated with high risk of bleeding. Currently there are no guidelines and standards measuring EMR outcome. Nationwide EMR audit/database is needed to help form recommendations. <h3>Competing interests</h3> None declared.
Conceptual structure is constrained functionally, not formally
Authors: Richard Hudson
Journal: Behavioral and Brain Sciences (2010)

Abstract Kinship systems are best explained functionally, in terms of the conflicting needs of the society concerned, rather than in terms of universal constraints, whether Optimality Theory or other; but OT is particularly unsuitable as it rules out taxonomies. A conceptual analysis of kinship terminology shows, not that “grammar” extends to kinship, but that general cognition has the formal power to handle grammar.
FRI0447 Epidemiology of idiopathic inflammatory myopathies in england – a database analysis
Authors: T.N. Tran, A. Steffey, H. Caspard
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> The idiopathic inflammatory myopathies (IIM) are a rare, heterogeneous group of autoimmune muscle disorders, including dermatomyositis (DM), polymyositis (PM), and inclusion body myositis. Data on the epidemiology of IIM are limited and quite variable with the reported incidence and prevalence ranging from 0.4 to 5.8 per 100,000 person-years (PY) and 3.5 to 25.0 per 100,000 population, respectively. Differences in methods of case identification, small study sizes, geographical differences, and changes in coding and reporting practices may contribute to the variation. <h3>Objectives</h3> To describe the epidemiology of IIM patients in England using medical record databases. <h3>Methods</h3> By linking the General Practice Research Database (GPRD) and the Hospital Episode Statistics (HES) database, we identified IIM patients with a diagnosis code of myositis (DM, PM, juvenile DM, and unspecified dermatopolymyositis) in either database and retrospectively measured epidemiologic indicators of IIM. <h3>Results</h3> From 2000-2009, 326 incident IIM cases were identified of which 62% were female and 81% were in those 45 years of age or older. The overall incidence of IIM was 1.9/100,000 PY (95% CI: 1.7-2.1/100,000 PY) ranging from 1.6 in 2000 to 2.0 in 2009. Among the incident cases, the 5- and 10-year survival was 77% and 74%, respectively. There were 465 prevalent IIM cases identified in 2009 corresponding to the overall prevalence of 27.2/100,000 people (95% CI: 24.8-29.8/100,000 people). The prevalence was positively associated with female gender and older age. Among prevalent IIM cases, 14% had a diagnosis of other autoimmune conditions including rheumatoid arthritis (9%), systemic lupus erythematosus (3%), systemic sclerosis (4%), or Sjogren's disease (2%). In 2009, the hospitalization rate for IIM was 5.6 per 100,000 in the general populations. <h3>Conclusions</h3> We found a higher IIM prevalence in England than previously reported in other countries. Studies that confirm the electronic diagnoses are needed to validate the findings. <h3>Disclosure of Interest</h3> T. Tran Employee of: MedImmune LLC, A. Steffey Employee of: MedImmune LLC, H. Caspard Employee of: MedImmune LLC