tbuckley/cabot-search huggingface dataset:
Abstract 2896: Genomic determinants and signature of MET-targeted therapy in glioblastoma.
Authors: Qian Xie, Jennifer Johnson, Maria Libera Ascierto, Liang Kang, Robert Bradley, Sandeep Mittal, Kyle Furge, Michael Briggs, Kirk Tanner, Michael E. Berens, Francesco M. Marincola, George F. Vande Woude
Journal: Cancer Research (2013)

Abstract Glioblastoma (GBM) is one of the most devastating cancers, because the intrinsic capability of single tumor cells to invade normal brain impedes surgical eradication, predictably resulting in early local recurrence and death. The goal of this study is to develop therapeutic strategies for treating GBM patients by identifying and targeting the molecular mechanisms of GBM invasiveness through inhibiting MET signaling pathway. Overexpression of hepatocyte growth factor (HGF) and its receptor MET are associated with poor prognosis of GBM. Genomic analysis of primary GBM tumors indicates that MET is overexpressed in tumors of the mesenchymal phenotype, which is more invasive and results in short patient survival. More recently, MET activation was found to contribute to recurrence in GBM patients after bevacizumab treatment, further highlighting the utility of blocking the MET pathway in this disease. With MET inhibitors’ entering clinical trials, there is increased need to find the molecular determinants of MET sensitivity. Because GBM is a heterogeneous disease in which drug response in the individual patient can be regulated by different mechanisms, approaches for understanding and predicting treatment outcomes based on the molecular features of individual tumor will be of a high value. Based on our previous finding that HGF-autocrine activation predicts sensitivity to MET inhibition, we have developed a two-step methodology using microarray technology and bioinformatics analysis to identify and test genomic determinants in order to effectively deploy MET-targeted therapy in GBM patients. By analyzing the data sets from The Cancer Genome Atlas Network (TCGA) and those from GBM xenograft models sensitive and insensitive to MET inhibitors, a 25-gene signature highly associated with HGF-autocrine activation is identified. When performing validation analysis, the signature scored 40 human GBM xenograft models by HGF expression level, providing a good rationale for further testing its predictive value in identifying tumors sensitive to MET inhibitors. We conclude that HGF-autocrine activation can result in oncogene addiction to MET signaling in GBM. Via a unique panel of signature genes we may be able to identify a subset of patients vulnerable to anti-MET drugs. Citation Format: Qian Xie, Jennifer Johnson, Maria Libera Ascierto, Liang Kang, Robert Bradley, Sandeep Mittal, Kyle Furge, Michael Briggs, Kirk Tanner, Michael E. Berens, Francesco M. Marincola, George F. Vande Woude. Genomic determinants and signature of MET-targeted therapy in glioblastoma. [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 2896. doi:10.1158/1538-7445.AM2013-2896
Abstract 4242: Methylation, SNP and expression analysis of the Vitamin D receptor (VDR) gene in different tumor tissues.
Authors: Matthew L. Poulin, Ann Meyer, Gregory Gonzalez, Kevin Bi, Liying Yan
Journal: Cancer Research (2013)

Abstract The vitamin D receptor gene encodes the nuclear hormone receptor for vitamin D3 and belongs to the family of trans-acting transcriptional regulatory factors and shows sequence similarity to the steroid and thyroid hormone receptors. Downstream targets of this nuclear hormone receptor are principally involved in mineral metabolism though the receptor regulates a variety of other metabolic pathways, such as those involved in the immune response and cancer. In light of evidence for promoter methylation of the vitamin D receptor in the control of the expression of this gene, we have designed methylation assays that cover many regions of this gene in order to determine its methylation profile in normal individuals, ovarian tumors and ovarian cell lines. We have isolated the DNA from ten tumor tissues and their adjacent normal tissue from four different tumor types; ovarian, breast, colon and cervical. By utilizing a combination of bisulfite sequencing, SNP genotyping, and expression analysis, we show that there are distinct patterns of methylation levels between different regions of the VDR gene in each of the cancers observed. We have also analyzed a number of SNPs within these genes and show a possible correlation with the methylation and /or expression of the genes and the SNP genotypes. These data may provide information that could lead to the development of biomarkers for different cancers. Citation Format: Matthew L. Poulin, Ann Meyer, Gregory Gonzalez, Kevin Bi, Liying Yan. Methylation, SNP and expression analysis of the Vitamin D receptor (VDR) gene in different tumor tissues. [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 4242. doi:10.1158/1538-7445.AM2013-4242
S24 Repeatability And Effect Of Incentives On An Office Based Advanced Driving Simulator (miniuolds) To Assess Driving Performance In Obstructive Sleep Apnoea Syndrome (osas)
Authors: A. Dwarakanath, S. Jamson, P. Baxter, M. Elliott
Journal: Thorax (2014)

<h3>Introduction</h3> Some patients with OSAS are at higher risk of being involved in road traffic accidents. No objective tests have been shown to predict reliably whether an individual is safe to drive or not and there is significant variation in the advice given by the clinicians. Using continuously measured variables in an advanced PC-based driving simulator the at risk patients can be identified with a high degree of accuracy. We have investigated whether this finding is repeatable. Individuals may “raise their game” if they know that their licence is at stake. We have therefore also investigated the effect of an incentive on the test. <h3>Methods</h3> 150 untreated OSAS patients (males-131) were randomised to either the repeatability (n = 50) or incentive arm (n = 100). All performed a simulator run, after initial acclimatisation. In the repeatability arm, patients performed the simulator run on two separate occasions with no knowledge of the results. In the incentive arm, patients performed the simulator run on two separate occasions but just prior to the second run were told about their performance and offered a prize if they could improve their performance by 10%. SDLP in epoch 3 and “veer” reaction time (Veer-RT) were the co-primary outcome variables. Classification of patients into "pass", "fail" and "indeterminate" were the secondary outcome variables. Results were analysed using paired and unpaired T tests with the level of significance set at p &lt; 0.05. <h3>Results</h3> 137 patients (repeatability arm-48, incentive arm-89) completed the trial. The median duration between the two simulator runs was 13 days (range, 5–55). SDLP in epoch 3 and Veer-RT were repeatable (P- 0.54, Δ SDLP- 0.01 and P- 0.37, Δ Veer-RT- 0.13) respectively. There was no effect of an incentive on SDLP in epoch 3 (P-0.18) and Veer-RT (P-0.57). There was no difference in the simulator outcome between the two runs [pass (P- 0.70), indeterminate (0.06), fail (P- 0.16)]. <h3>Conclusions</h3> SDLP and Veer-RT are consistent between runs on the MiniUoLDS and this is not affected by a simple incentive. Advanced office PC based simulators may be helpful when advising patients with OSAS about driving.
Abstract 4966: The anti-apoptotic activity of caspase-2 short isoform is regulated by XPC protein
Authors: Qi-En Wang, Chunhua Han, Altaf A. Wani
Journal: Cancer Research (2012)

Abstract Caspase-2 (casp-2) is the most conserved caspase across species. The casp-2 gene produces several alternative splicing isoforms. The inclusion of exon 9 leads to the inclusion of an in-frame stop codon in casp-2 short isoform (casp-2S) mRNA, thus producing a truncated protein that inhibits cell death, whereas the exclusion of exon 9 results in casp-2 long isoform (casp-2L) mRNA, whose protein product induces cell death. Earlier it has been reported that casp-2 is required for stress-induced apoptosis. However, that study could not have separated the roles of casp-2L and casp-2S, since the siRNA used in their experiments actually targeted both casp-2 isoforms. We have reported that targeted RNAi-mediated down-regulation of casp-2S enhanced the UV-induced apoptosis in XPC-deficient but not in XPC-proficient cells. However, by using the siRNA targeting both casp-2L and casp-2S, we failed to find any influence of casp-2 down-regulation on UV-induced apoptosis in these fibroblasts. Similarly, casp-2 specific inhibitor z-VDVAD was unable to reduce UV-induced apoptosis. In addition, the expression of casp-2S, but not casp-2L is regulated by XPC protein. To gain insight into the mechanism by which XPC down-regulates casp-2S, we examined the casp-2S promoter activity and the enrichment of XPC protein on casp-2S promoter. Our data clearly demonstrated that XPC protein can inhibit casp-2S promoter through binding to the promoter region. Furthermore, our cellular fractionation study demonstrated that casp-2L exclusively resides in cytoplasm, while casp-2S can be detected in both cytoplasm and nucleus. UV irradiation reduced the amount of nuclear casp-2S in XPC-proficient cells, while this reduction is not prominent in XPC-deficient cells, indicating that XPC protein facilitates the depletion of nuclear casp-2S upon UV irradiation. This finding provides an additional mechanism by which XPC facilitates DNA damage-induced apoptosis. (Supported by NIH grants CA151248 to QEW and ES12991 to AAW.) 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 4966. doi:1538-7445.AM2012-4966
PTH-116 Microscopic Colitis in Tayside – Further Observations on Clinical Features and outcome
Authors: T Heron, C Mowat, M Groome, S Walsh, S Siddhi, A Meritsi
Journal: Gut (2013)

<h3>Introduction</h3> The aetiology of microscopic colitis remains unknown. We have previously reported our experience of microscopic colitis diagnosed in our region between 1999 – 2004(1). Although data continue to emerge, the natural history of microscopic colitis remains unclear. Furthermore, there are reports of macroscopic changes in the mucosa at endoscopy. <h3>Methods</h3> Cases from 2004–2011 were identified from pathology records. Case notes were retrospectively reviewed and data extracted including subtype of microscopic colitis and clinical details where possible. <h3>Results</h3> 82 case notes were obtained and reviewed. 8 cases did not have a clear diagnosis and were excluded. Of the remaining 74 cases, 56 were collagenous colitis, 18 lymphocytic colitis. 17 patients had macroscopic abnormalities (excluding diverticulosis) at endoscopy; 16 of these in the collagenous colitis group, representing 28% of this subgroup. The mean age was 46.1 (range 33–87), female: male ratio of 4.3:1. 18 reported an autoimmune condition including 2 coeliac disease and 7 hypothyroidism. 30(40%) were on a proton pump inhibitor at the time of diagnosis and 15(24%) were on non-steroidal anti-inflammatories. Follow up data was available for 66 patients. Of these 47(71%) reported complete resolution of symptoms and 15(22%) partial resolution. 5(7%) did not respond in the follow up period. Therapeutic strategies included either alone or a combination of stopping/switching PPI, loperamide, mesalazine and steroids. 24/47(65%) of complete responders required simple intervention (PPI withdrawal, switch in brand of PPI, loperamide or even spontaneous resolution) whereas 10/47(21%) required steroids. 7/15(47%) partial responders received steroids. <h3>Conclusion</h3> Since microscopic colitis was last studied in our region, the female predominance has increased, the mean age has dropped by almost 20yrs, and the ratio of collagenous : lymphocytic colitis has increased from 2:1 to 3:1. This could represent a change in the number of younger people investigated or missing data in our cohort. A significant number of patients with a diagnosis of collagenous colitis had endoscopic abnormalities in comparison to the lymphocytic colitis group, which does raise the question of the nomenclature. The majority of patients have complete resolution of symptoms with simple intervention. <h3>Disclosure of Interest</h3> None Declared. <h3>Reference</h3> Microscopic Colitis in Tayside: Clinical features, associations and behaviour. Mowat C, Heron T, Walsh S. Gastroenterology 2005: 128 (4); A331
Abstract 2184: Complex formation between the DLC1 START domain and Cav1 contributes to the tumor suppressor function of DLC1
Authors: Xiaoli Du, Xiaolan Qian, Alex Papageorge, William C. Vass, Richard Braverman, Douglas R. Lowy
Journal: Cancer Research (2011)

Abstract Deleted in live cancer (DLC1), a tumor suppressor gene with Rho GTPase-activating (RhoGAP) activity, is frequently inactivated in a variety of cancers. DLC1 encodes a 1091 amino acid multi-domain protein whose RhoGAP catalytic domain (aa 609-878) is flanked by an amino-terminal sterile alpha motif (SAM; aa 17-76) and a carboxy-terminal steroidogenic acute regulatory (StAR)-related lipid transfer (START; aa 879-1080) domain. Caveolin-1 (Cav1), a key constituent of caveolae, plays an important role in signal transduction, endocytosis, and cholesterol transport, behaves as a tumor suppressor in most contexts, and is reported to form a complex with DLC1. Here, we have sought to assess the biological relevance of the DLC1-Cav1 interaction and to determine the region of DLC1 that interacts with Cav1. After confirming that endogenous DLC1 and Cav1 co-localize with each other by immunomicroscopy and form a complex in vivo as assessed by co-immunoprecipitation, we determined the DLC1 sequences that were required for complex formation. Using GST-Pull down of a GST-Cav1 fusion protein that had been co-transfected with a series of GFP-DLC1 fragments, we identified a polypeptide of DLC1 (aa 899-996), composed of residues from the START domain that was necessary and sufficient for complex formation. A full-length GFP-DLC1 mutant lacking some of these START residues (aa 929-957) was deficient for complex formation with endogenous Cav1. When stably expressed in a human lung cancer cell line that did not express endogenous DLC1, the mutant was severely compromised in suppressing cell migration, colony formation, and anchorage-independent growth in soft agar compared to cells stably expressing the wild type GFP-DLC1. We conclude that the START domain of DLC1 is required for its complex formation with Cav1, and that this interaction contributes to the tumor suppressor activity of DLC1. To our knowledge, this is the first identified function for the DLC1 START domain. 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 2184. doi:10.1158/1538-7445.AM2011-2184
Abstract 206: High mobility group A1(HMGA1) proteins localize at the mitochondria and inhibit the p53-mediated intrinsic-apoptotic pathway
Authors: Francesco Esposito, Mara Tornincasa, Eleonora Borbone, Giovanna Maria Pierantoni
Journal: Cancer Research (2011)

Abstract The high mobility group A (HMGA) non-histone chromosomal proteins play key roles in chromatin architecture and orchestrate the assembly of nucleoprotein complexes involved in gene transcription, replication, and chromatin structure. HMGA overexpression and gene rearrangements are frequent events in human cancer, but the molecular basis of HMGA oncogenic activity has not been completely elucidated. Recently, we have defined a new physical and functional interaction between HMGA1 and p53. This interaction modulates the transcription of p53 target genes such as Mdm2, p21waf1, Bax, Bcl-2, and inhibits p53-mediated apoptosis. Here we report that HMGA1 does not act only at transcriptional level but it has also a direct, anti-apoptogenic role at the mitochondria. In fact, we found that in mouse embryonic fibroblast (MEF) and several tumour cell lines overexpressing HMGA1, this protein is present at cytoplasmic level other than in the nucleus. Moreover, we demonstrate that HMGA1 stably localizes at the mitochondria, in which it binds Bcl-2, displacing it from the binding to p53, thus counteracting the release of cytochrome C. In agreement with this observation, the HMGA1-overexpressing cells show a significant reduction of cytochrome C release, after lethal dose of Ultraviolet (UV) light, whereas HMGA1-depleted cells are more susceptibile to UV treatment. These data define a new localization of HMGA1 at the mitochondria level that allows HMGA1 to inhibit by a new mechanism the p53-mediated intrinsic-apoptotic pathway. This mechanism may also have a role in the resistance of malignant cells to chemo- and radio-therapy, in particularly for the tumor cells harboring wild-type form of p53. 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 206. doi:10.1158/1538-7445.AM2011-206
Shock-Wave Lithotripsy of Gallbladder Stones
Authors: Michael Sackmann, Michael Delius, Tilman Sauerbruch, Joseph Holl, Werner Weber, Ernst Ippisch, Ulrich Hagelauer, Othmar Wess, Wolfgang Hepp, Walter Brendel, Gustav Paumgartner
Journal: New England Journal of Medicine (1988)

To substantiate the early results of extracorporeal shock-wave fragmentation of gallstones, we used this nonsurgical procedure to treat 175 patients with radiolucent gallbladder calculi. Chenodeoxycholic acid and ursodeoxycholic acid were administered as adjuvant litholytic therapy. The gallstones disintegrated in all patients except one and completely disappeared in 30 percent of all patients within 2 months after lithotripsy, in 48 percent at 2 to 4 months, in 63 percent at 4 to 8 months, in 78 percent at 8 to 12 months, and in 91 percent at 12 to 18 months. In patients with solitary stones up to 20 mm in diameter, the corresponding values were 45, 69, 78, 86, and 95 percent, respectively. Shock-wave therapy had no adverse effects except cutaneous petechiae (14 percent) and transient gross hematuria (3 percent). One third of the patients had one or more episodes of biliary colic before all the fragments disappeared. Two patients had mild pancreatitis, which necessitated endoscopic sphincterotomy in one. The patient with insufficient stone fragmentation underwent elective cholecystectomy; no additional operations were necessary. Extracorporeal shock-wave lithotripsy combined with medical therapy for stone dissolution is a safe and effective treatment in selected patients with radiolucent gallbladder calculi. (N Engl J Med 1988; 318:393–7.)
Abstract 1858: Inhibition of oral carcinogenesis in rats by the histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA)
Authors: David L. McCormick, Thomas L. Horn, William D. Johnson, Ronald A. Lubet, Vernon E. Steele
Journal: Cancer Research (2011)

Abstract Suberoylanilide hydroxamic acid (SAHA; N-hydroxy-N′-phenyl-octanediamide; vorinostat) is a potent inhibitor of cell proliferation, inducer of cellular differentiation, and inducer of apoptosis in cancer cells. The anticancer action of SAHA is likely to result from its activity as an inhibitor of histone deacetylase, which mediates alterations in the expression of cancer-associated genes. SAHA has been shown to be an effective inhibitor of carcinogenesis in animal models for breast, lung, and colon cancer; the present study was performed to evaluate the activity of SAHA as an inhibitor of oral carcinogenesis. Squamous cell carcinomas of the tongue were induced in male F344 rats by administration of 4-nitroquinoline-1-oxide (NQO; 20 ppm) in the drinking water for 10 weeks. After completion of NQO administration, rats were randomized into groups of 25 and received either unsupplemented basal diet (dietary control); basal diet supplemented with SAHA (500 mg/kg diet); or basal diet supplemented with SAHA (1000 mg/kg diet). All experimental diets were fed continuously until the end of the study at week 26. Dietary administration of SAHA induced a dose-related reduction in oral cancer incidence (64% and 29% in the low and high dose groups, respectively, versus 80% in the dietary control group; p &amp;lt; 0.01). In addition, the high dose of SAHA increased the percentage of animals without any evidence of oral pathology from 4% in dietary controls to 25% (p &amp;lt; 0.05). In addition to its effects on cancer incidence, SAHA reduced the invasiveness of induced oral cancers in NQO-treated rats: whereas 60% of rats in the dietary control group demonstrated advanced oral cancers (invasion scores of +3 or +4), advanced cancers were seen in 40% and 25% of rats fed the low and high doses of SAHA, respectively (p &amp;lt; 0.05 for high dose). SAHA increased the incidence of squamous epithelial hyperplasia (28% and 38% in low and high dose groups, respectively, versus 16% in dietary controls; p &amp;lt; 0.05 for high dose). This effect suggests that SAHA prevented the progression of hyperplastic lesions into invasive oral cancers. SAHA also prevented the body weight loss that is commonly seen in this model in animals with advanced oral cancer. These data demonstrate SAHA is a potent inhibitor of carcinogen-induced squamous cell carcinoma in rats, and suggest that inhibitors of histone deacetylase should be considered for further development as inhibitors of oral cancer development. (Supported by N01-CN-25113 from the NCI.) 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 1858. doi:10.1158/1538-7445.AM2011-1858
Bone Scintigraphy in an Uncommon Presentation of Metastatic Lung Carcinoma
Authors: GEOFFREY R. STOREY, LUCY MORGAN, MATTHEW J. PETERS, PETER J. KENNEDY, HANS Van der WALL, KEVIN C. ALLMAN
Journal: Clinical Nuclear Medicine (1997)

A 66-year-old male smoker with a history of peptic ulcer disease had hemoptysis and weight loss. Bronchoscopy revealed a tumor in the right main bronchus. Thoracic CT scan showed a right hilar mass with tumor extension into the esophagus. Biopsy of the tumor confirmed squamous cell carcinoma. The patient underwent radical radiotherapy plus adjuvant chemotherapy. Four months later, left maxillary pain with local swelling and loosening of teeth developed, which progressed despite parenteral antibiotic therapy. A bone scan revealed diffuse symmetric increase in tracer accumulation throughout the maxilla. CT scan showed extensive palatal destruction by tumor. Maxillary biopsy confirmed squamous cell carcinoma with histologic features consistent with metastasis from the primary lung carcinoma.
The Nuclear-Arms Race and the Physician
Authors: Bernard Lown, Eric Chivian, James Muller, Herbert Abrams
Journal: New England Journal of Medicine (1981)

The possibility that nuclear weapons may cause an unprecedented catastrophe for humanity has not halted the nuclear-arms race. On the contrary, the insecurity resulting from these weapons is a factor in their multiplication. Nuclear devices of varying size, sophistication, and destructiveness now number in excess of 40,000.1 Prof. George Kistiakowsky, a former head of the Explosives Division of the Manhattan Project and science advisor to President Eisenhower, recently stated that it would be a miracle if no nuclear warheads were exploded in anger before the end of this century, and only a slightly smaller miracle if that did not lead . . .