tbuckley/cabot-search huggingface dataset:
Abstract LB-364: G(alpha)12 is required for thromboxane A2 to regulate tumor cell motility
Authors: Babar Malik, Xuejing Zhang, Daotai Nie
Journal: Cancer Research (2011)

Abstract Introduction: Thromboxane (TX) A2 is a prostaglandin produced by metabolism of arachidonic acid through cyclooxygenase and thromboxane synthase. TXA2 is biologically active, mainly through activating its cognate, seven transmembrane, G protein coupled receptor. We previously reported that thromboxane A2 receptor (TP) was expressed in prostate cancer, and further activation of this receptor elicited cell contraction and modulated tumor cell motility through regulating small GTPase RhoA (Nie et al., Cancer Res 68: 115–121, 2008). This study aims to identify G alpha protein(s) involved in thromboxane A2 signaling in tumor cell motility. Methods: The expression of G alpha proteins in the PC3MM cells was studied by real-time PCR. Cell contraction assay was performed by staining cells with TRITC phalliodin and evaluated under an epifluorescence microscope. Tumor cell motility and invasion were evaluated using wound healing assay and transwell Boyden Chamber assay. To determine the roles of G alpha protein in thromboxane A2 signaling, we expressed different alleles of G alpha proteins (wild type, constitutive active) in PC3MM cells and then the subsequent effects on cell contractions was determined. We also depleted G alpha protein expression by short hairpin RNA and examined subsequent changes in cell contraction and migration after activation of TP. Results: PC3 MM cell line had the endogenous level of all the G alpha protein (G alpha 12, G alpha i1, G alpha 11, G alpha 13), but not G alpha q. Overexpressionof G alpha 12/13 increased cell contraction after activation of thromboxane A2 receptor with U46619. Expression of constitutively active G alpha 12 by itself was sufficient to cause cell contraction, regardless whether TP is activated or not. Depletion of G alpha 12 via shRNAs reduced cell contraction after TP activation. Tumor cells with G alpha 12 depleted had tumor cell motility and invasiveness. Conclusion: The findings indicate that G alpha 12 is required for TP to induce cell contraction and to regulate tumor cell motility. The studies suggest G alpha 12 may be a promising target of intervention to reduce tumor cell motility and metastasis in prostate cancer. 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 LB-364. doi:10.1158/1538-7445.AM2011-LB-364
A1.28 Synovial fibroblasts suppress TH1, but not TH2 or TH17 cells, through tryptophan metabolism
Authors: LO Tykocinski, AM Lauffer, A Bohnen, S Krienke, T Tretter, I Adam, SR Mohapatra, P Saikali, M Löhning, M Neidhart, S Gay, I Oezen, M Platten, CA Opitz, HM Lorenz
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background and objectives</h3> Fibroblasts strongly participate in the initiation and modulation of immune responses. The development of rheumatoid arthritis (RA) is linked to functional changes of synovial fibroblasts (SF) and a local infiltration of immune cells such as T lymphocytes. So far, little is known about the cross-talk between SF and T cells under normal and pathological conditions. Here, we analysed the influence of normal SF as well as of RASF on the activation, proliferation and cytokine production of T helper (Th) cell subsets <i>in vitro</i>. <h3>Materials and methods</h3> SF were isolated from synovectomy tissues of patients with osteoarthritis (OA) or RA. Th1, Th2 and Th17 cells were differentiated <i>in vitro</i> or directly isolated from peripheral blood. Complete Th cells or Th cell subsets were stimulated in the presence or absence of SF, in direct contact or separated by transwell chambers. T cell proliferation was measured by [<sup>3</sup>H] thymidine incorporation or by PKH-26 labelling. Secretion of cytokines and prostaglandin E2 (PGE2) was quantified by ELISA. MRNA levels of matrix metalloproteases (MMPs) and indoleamine 2,3-dioxygenase 1 (IDO1) were quantified by real-time PCR. Tryptophan and kynurenine amounts were detected by HPLC. IDO1 activity was blocked by 1-L-methyl-tryprophan (1-L-MT), cyclooxigenases 1 and 2 were inhibited by indomethacin. <h3>Results</h3> SF supported the activation of T cells at early time points of co-culture and in return the T cells induced the expression of interleukin (IL)-6, IL-8, MMP1 and 3, as well as of PGE2 and IDO1 by the SF. In the end, the stimulated SF strongly suppressed the secretion of interferon (IFN)-g and the proliferation of co-cultured Th cells in a cell contact-independent manner. Strikingly, Th1 cells, but not Th2 or Th17 cells, were affected. A decrease of tryptophan and an increase of kynurenines in the culture supernatants correlated with the T cell suppression. Blockade of IDO1 completely restored the Th cell proliferation, but not the IFNg secretion, indicating that the suppression of T cell proliferation by SF is mediated by tryptophan metabolism. Importantly, RASF had a weaker T cell suppressive capacity compared to OASF. <h3>Conclusions</h3> The suppression of activated T cells by SF through tryptophan metabolism may play an important role in preventing inappropriate T cell responses under normal conditions. Th17 cells that escape the suppression by SF and the inferior efficiency of RASF to restrict T cell proliferation may likely support the initiation and propagation of synovitis in RA.
Repetitive Phosphorus-32 Peritoneal Instillations in a Patient with Malignant Ascites
Authors: HANS BALINK, EDITH A. SIJMONS, BERNARD A. ZONNENBERG, JOHN M. H. DE KLERK
Journal: Clinical Nuclear Medicine (2003)

During the last decade, intraperitoneal injection of phosphorus-32 chromic phosphate (P-32 CP) has been used principally for its initial intended purpose, the palliative management of malignant ascites. The authors describe a patient with a stage IIIB well-differentiated extraovarian peritoneal serous papillary adenocarcinoma. As a palliative treatment for malignant ascites, P-32 CP was instilled intraabdominally eight times. Adverse effects were limited to the third instillation, when abdominal pain occurred as a result of leakage of the P-32 CP in the subcutaneous tissue. The P-32 CP instillations reduced the frequency of paracentesis for almost 1 year, until disease progression prevented palliation. Considering the few palliative options, there could be more widespread use of P-32 CP as a palliative treatment for patients with malignant ascites caused by ovarian cancer or extraovarian peritoneal adenocarcinoma. However, intraperitoneal P-32 CP is not without potential intestinal complications, which must be considered before it is recommended.
Abstract 1468: Cerium oxide nanoparticles sensitize pancreatic cancer cells to radiation by modulating the JNK pathway
Authors: Melissa S. Wason, Jimmie Colon, Jihe Zhao, Cheryl H. Baker
Journal: Cancer Research (2012)

Abstract Pancreatic cancer, one of the most lethal cancers, has a poor prognosis and a high mortality rate. Currently, the absence of effective therapies increases reliance on radiation therapy (RT) to treat pancreatic cancer. We have previously reported that Cerium Oxide Nanoparticles (CONPs) are selectively toxic to cancer cells and possess the ability to selectively sensitize pancreatic cancer cells to radiation-induced cell death. Radiation-induced H2O2 production was significantly increased in the presence of less than or equal to 10 µM of CONPs and radiation-induced ROS production was increased in human L3.6pl pancreatic cancer cells pre-treated with 10 µM CONPs, which correlated with a significant decrease in cell viability and clonogenicity as compared to radiation alone. Conversely, ROS production was decreased in normal hTERT-HPNE pancreatic cells without impacting cell viability. The volume of pancreatic tumors was reduced by 48% in mice treated with combination therapy compared to radiation alone. Immunohistochemical (IHC) analysis revealed that combination therapy resulted in a significant increase in tumor cell apoptosis. In the most recent study, we determined the mechanism responsible for the increase in apoptosis as a result of increased ROS levels. L3.6pl cells (radiation sensitive), PANC-1 (radiation resistant) and HPNE (normal pancreatic cells) were treated with 5 Gy radiation in the presence or absence of 10 µM CONPs. CONPs selectively increased RT-induced Thioredoxin (TRX) oxidation in the cancer cells (L3.6pl: 14.2%, p&amp;lt;0.001; PANC-1: 23.5%, p&amp;lt;0.005) which correlated with a 35-40% increase in ASK-1 phosphorylation in both cell lines. Excitingly, western blot analyses showed a selective increase in JNK phosphorylation in both radiation sensitive (L3.6pl: JNK1 at 15%, JNK2 at 20%) and radiation resistant (PANC-1: JNK1 at 36%, JNK2 at 37%) cells which correlated with an increase in Caspase 3/7 activity (L3.6pl: 36.4%, p&amp;lt;0.05; PANC-1: 43.1%, p&amp;lt;0.05) compared to radiation alone. Knockdown of JNK expression by siRNA resulted in abrogation of Caspase 3/7 activity and corresponding cell death. Combination therapy of CONPs and radiation in an orthotopic murine model produced significant increases in JNK phosphorylation and Caspase 3 cleavage shown by IHC analysis. These data suggest that CONPs may act as a radiosensitizer in treatment of pancreatic cancer through the induction of JNK activation. 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 1468. doi:1538-7445.AM2012-1468
Abstract 5098: Targeting the cholesterol pathway gene <i>SC4MOL</i> sensitizes cancer to EGFR inhibitors
Authors: Anna L. Sukhanova, Tetyana Bagnyukova, Lisa E. Kratz, Richard I. Kelley, Ilya G. Serebriiskii, Louis M. Weiner, Erica A. Golemis, Igor A. Astsaturov
Journal: Cancer Research (2010)

Abstract Epidermal growth factor receptor (EGFR) has been exploited as a target for blockade in cancer therapy, based on the known central role of EGFR signaling in promoting cancer cell growth. We have identified a novel mechanism for influencing EGFR activity that involves the sterol biosynthesis pathway enzyme sterol C4-methyl oxidase-like (SC4MOL). SC4MOL, in conjunction with other members of the ergosome complex (erg26/NSDHL; erg27/HSD17B7), catalyzes a non-redundant, irreversible step of demethylation at C4 of 14-demethylated lanosterol and dihydrolanosterol to produce zymosterol and 8(9)-cholestenol, respectively. Depletion of SC4MOL with siRNA caused accumulation of methylsterol intermediaries; inhibition of the key EGFR effectors, ERK and AKT; and a 3-fold increase in apoptosis specifically in the presence of EGFR antagonists. Metabolic block upstream of SC4MOL with ketoconazole or CYP51A1 siRNA eliminated methylsterols and completely reversed the effect of SC4MOL depletion, while added cholesterol did not rescue cancer cells from accelerated apoptosis upon concurrent SC4MOL and EGFR blockade. These results indicate that accumulation of specific cholesterol precursors enhances efficacy of anti-EGFR drugs. Further, we found that SC4MOL and the other ergosome components are transcriptionally regulated by EGFR signaling, suggesting involvement of C4 methylsterols in physiological activation of the EGFR signaling pathway. A metabolic effect of sterol intermediaries on EGFR signaling has not been previously characterized. Such an effect could be exploited in cancer therapeutically by employing already existing drugs such as synthetic 4,4-dimethylsterols currently in use for in vitro fertilization. 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 5098.
Ascites detected on Endoscopic Ultrasound (EUS) but not helical multi-slice CT is a predictor of inoperablity for gastric and junctional adenocarcinoma
Authors: J Sultan, S Robinson, N Jennings, D Karat, N Hayes, SM Griffin, DL Richardson, SR Preston
Journal: Endoscopy (2006)

EUS is capable of detecting low volume ascites (LVA) not seen with high resolution CT. The aim of the study was to assess the significance of this finding upon the management of patients with oesophago-gastric (OG) cancer.
Abstract 2997: SOX2 contributes towards invasive phenotype of serous ovarian cancer by up-regulating MMP2.
Authors: Gayatry Mohapatra, Junko Kikuchi, Michael J. Birrer
Journal: Cancer Research (2013)

Abstract SOX2 encodes a member of the SRY-related HMG-box (SOX) family of transcription factors involved in the regulation of embryonic development and in the determination of cell fate. SOX2 maps to 3q26.33, a region frequently amplified in HGSOvCa as reported in the TCGA and other large array-based CGH studies. However, the role of SOX2 in HGSOvCa oncogenesis and progression has not been studied yet. Given the importance of SOX2 in maintenance of stem cell phenotype and its overexpression in solid tumors, we sought to define the role of SOX2 in HGSOvCa. In order to establish a direct role for SOX2 in vivo, we conducted DNA copy number analysis and qRT-PCR analysis in two independent panels of primary HGSOvCa and 25 serous OVCA lines. We overexpressed SOX2 in T29, OVCA433, A2780, SKOV3 and OVCAR5 cells and/or knockdown SOX2 in UCI101 and OV90 cells. Ectopic expression of SOX2 resulted in decreased cell proliferation, soft agar colony formation, in vivo tumorigenicity but higher degree of invasion relative to cells with empty vectors. SOX2 overexpression increased MMP2 activity as determined by gelatin zymography. We also performed mRNA profiling to identify SOX2 target genes. SOX2 knockdown cells decreased migration,andinvasion but increased tumorigenicity. Differentially expressed genes in cells overexpressing SOX2 will be presented. Increased SOX2 expression in HGSOvCa appears to produce a more invasive yet quiestant cell. Overexpression of SOX2 may induce a stem-like transcriptional program in HGSOvCa. Thus, identifying SOX2 target genes may offer new insight into the understanding of ovarian cancer biology. Citation Format: Gayatry Mohapatra, Junko Kikuchi, Michael J. Birrer. SOX2 contributes towards invasive phenotype of serous ovarian cancer by up-regulating MMP2. [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 2997. doi:10.1158/1538-7445.AM2013-2997
Abstract 961: Pathways of tumorigenesis promoted by the growth factor progranulin in SW-13 adrenocortical carcinoma cells
Authors: Yonghua Zhang, Amin Ismail, Andrew Bateman
Journal: Cancer Research (2012)

Abstract Adrenocortical carcinomas are highly malignant cancers, with a very low 5 year survival rate. The SW-13 cell line originated from a stage IV adrenocortical carcinoma, but is only poorly tumorigenic in mice. It can, however, be made highly tumorigenic in vivo if it is engineered to express a limited number of growth factors including progranulin (PGRN, also called PCDGF, granulin epithelin precursor, or proepithelin) and secreted FGFs. This provides a model system to study the transition of an adrenocortical carcinoma from low to a high malignant potential. PGRN is a secreted glycoprotein growth factor that is over produced by many cancers including those of the breast, ovary, endometrium, prostate, bladder, and liver. It acts on cancer growth by increasing mitosis, decreasing apoptosis and stimulating invasion. In addition, PGRN has been implicated as a stimulator of tumor stroma growth in breast cancer. We examined the expression of PGRN in SW-13 cells at different stages of the cell cycle. Cells were synchronized using two independent agents, L-Mimosine and aphidicolin to arrest cell division. Washout of the drugs released the SW-13 cells into the cell cycles with slow (L-Mimosine) or rapid (aphidicolin) kinetics, and PGRN expression increased in parallel with the increased proportion of cells in active cell division. Depleting PGRN mRNA levels slowed reentry into the cell cycle following drug removal. Inhibition of MEK1/2, phosphatidylinositol-3 kinase (PI3K), protein kinase C (PKC) and phospholipase-C-α (PLCγ) impairs proliferation of SW-13 cells carrying only empty vector (SW-13V) with differential effects on mitosis and apoptosis. In cells with elevated PGRN, (SW-13P), the anti-proliferative effects of inhibiting MEK1/2, PI3K and PKC, but not PLCγ, are attenuated. Inhibition of the stress kinase p38 increases proliferation of SW-13V, but not SW-13P cells, suggesting that PGRN and p38 have opposing effects on proliferation. Inhibition of p38 enhances the phosphorylation of MEK1/2 in SW-13V cells, while inhibiting PKC decreases it, suggesting that PKC and p38 pathways interact with the PGRN-regulated MEK1/2 signaling cascade. Transcriptional profiling indicated that expression of PGRN modulated levels of proteins in the Wnt and Notch-signaling pathways. These results suggest that PGRN expression may be coordinated with the cell cycle, and, may promote tumorigenesis by intervening in several signaling pathways. 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 961. doi:1538-7445.AM2012-961
S26 Severe hospitalised exacerbations of COPD with an eosinophilic phenotype have favourable outcomes with prednisolone therapy: sub-analysis from a prospective multi-centre randomised control trial
Authors: M Bafadhel, NJ Greening, T Harvey-Dunston, J Williams, MDL Morgan, F Hussain, Ld Pavord, SJ Singh, MC Steiner
Journal: Thorax (2013)

<h3>Introduction</h3> In moderate exacerbations of COPD, patients with the eosinophilic phenotype (&gt;2% of the total leukocyte count) have better outcomes with prednisolone. However, it remains unclear whether patients with severe exacerbations displaying the eosinophilic phenotype have accentuated recovery following corticosteroid therapy compared to non-eosinophilic COPD exacerbations. <h3>Aim</h3> Measure the incidence of eosinophilic and non-eosinophilic severe exacerbations of COPD, from a large prospective enhanced recovery multi-centre randomised control trial and investigate severity and recovery between these groups. <h3>Methods</h3> COPD patients entering the programme delivered immediately on hospitalisation for an acute exacerbation of chronic respiratory disease to improve long term health outcomes (clinical trial registration ISRCTN05557928) were analysed using admission details, length of stay and proceeding exacerbation history. All patients were dichotomised into eosinophilic (&gt;200 x10<sup>6</sup> cells/mL and/or &gt;2% of the total leukocyte count) and non-eosinophilic. CRP was measured on admission. <h3>Results</h3> There were 243 COPD patients (117 males) identified. The mean (range) age was 71 years (45–93) and the majority of patients (55%) had been hospitalised for an exacerbation of COPD in the previous 12 months. Of all exacerbations, the inpatient mortality rate was 3% (median time to death 12 days, range 9–16) and approximately 90% received both antibiotic and corticosteroid treatment. The incidence of an eosinophilic exacerbation was 25% (median absolute eosinophil count 100 x10<sup>6</sup>cells/ml; range 10 to 1500). In patients with eosinophilic exacerbations compared to non-eosinophilic exacerbations the median (IQR) CRP concentration was significantly lower (12mg/L (5–47) vs. 55mg/L (18–139), p &lt; 0.001); and the presence of an elevated eosinophil count and elevated CRP (&gt;200 x10<sup>6</sup> eosinophils/mL and CRP&gt;50mg/L) occurred in only 5% of all exacerbations. The length of stay was significantly shorter in patients with eosinophilic exacerbations compared to non-eosinophilic exacerbations (mean (range) 5.0 (1–19) vs. 6.5 (1–33), p = 0.015). The severity of the index exacerbation or the rate of exacerbations or hospitalisations in the following 12 months was not statistically significant between groups. <h3>Conclusions</h3> In severe hospitalised exacerbations of COPD, a proportion have an associated eosinophilic phenotype. These exacerbations are usually not associated with an elevated CRP. Eosinophilic exacerbations have better responses to oral corticosteroids with shortened length of stay.
Abstract 394: Close association between subsided inflammation and the development of histologically less malignant HCC in HCV-associated LC
Authors: Kazuo Tarao, Kaoru Miyakawa, Satoshi Kobayashi, Makoto Ueno, Shinichi Ohkawa, Soichiro Morinaga, Yoshiyasu Nakamura, Yohei Miyagi, Masahiko Okudaira
Journal: Cancer Research (2012)

Abstract Aim: We recently demonstrated that severe inflammation in the background cirrhotic tissue correlate with the development of histologically more malignant hepatocellular carcinoma (Edmondson III HCC) in HCV-associated liver cirrhosis (LC), and that histology activity index (HAI) was the only one significant contributor to the development of Edmondson III (Ed III) HCC in small nodular HCC. There is a possibility, in the contrary of this phenomenon, that subsided inflammation correlates with the development of histologically less malignant HCC (Ed I type HCC) and that long-term subsided inflammation correlates with the development of large Ed I HCC. We examined the possibility. Methods: Curative hepatic resection for HCC with LC was performed in 264 patients during the past 10 years in Kanagawa Cancer Center hospital. Of 264 patients 197 patients were anti-HCV-positive or HCV-RNA positive. Out of the 197 patients, 32 patients whose HCC revealed only one small HCC nodule (≤ 3 cm) were selected for this study. Furthermore, the cases whose HCC nodules were large (&amp;gt; 3 cm), but consisted of predominantly Ed I component, were also examined. For the evaluation of inflammation in the background LC, modified Knodell's histology activity index (HAI) was used. (for the evaluation of pure inflammation, items of fibrosis was omitted); piece meal necrosis (1-4), intra lobular cellular degeneration and focal necrosis (1-4), portal cellular inflammation (1-4), were estimated by two well experienced pathologist. In each case, the HAI score was estimated in five field and average HAI score was calculated. All the sections of resected HCC tissue was examined pathologically in all patients for determining the grade of malignancy according to Edmondson Steiner's classification; Ed I (well differentiated), Ed II (moderately diff.), Ed III (poorly diff.). Results: The average HAI score in 7 Ed I HCC patients was as low as 3.61 ± 0.70 (mean ± SD), and was significantly lower than that in 17 Ed III HCC patients (5.21 ± 1.15, P &amp;lt;0.001). Furthermore, the average HAI in the 5 cases whose HCC nodules were more than 3 cm and whose major component of HCC nodules were Ed I, was also as low as 3.55 ± 0.74. Conclusions: It is suggested that subsiding inflammation in the background non-cancerous cirrhotic portion might correlate with the development of histologically less malignant HCC. 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 394. doi:1538-7445.AM2012-394