tbuckley/cabot-search huggingface dataset:
PTU-175 Quadruple, Clinical, Radiological, Cytological and Biochemical Analysis of Pancreatic Cystic Lesions are Necessary Prior to Therapeutic Planning
Authors: M Uppara, A Rasheed
Journal: Gut (2013)

<h3>Introduction Back ground</h3> Distinguishing benign from malignant or pre-malignant pancreatic cystic lesions is essential when formulating the surgical therapeutic strategy. Lack of a well-defined pre-operative predictability criteria makes therapeutic planning challenging. <h3>Aims</h3> To study the correlation between pre-operative morphological and biochemical features of resected pancreatic cystic lesions and predictive power of these features in relation to biological behaviour and final histology. <h3>Methods</h3> We systematically reviewed the literature to identify the relevant variables that are used to predict the nature of pancreatic cystic lesions and aid therapeutic planning; this was followed by designing a template encompassing all these variables to collate data of resected pancreatic cystic lesions from two centres. We collated clinico-pathological and biochemical data, pre-operative CT, MRI, EUS, PET CT, FNA analysis and final post-operative pathology reports. <h3>Results</h3> 63 patients with pancreatic cystic lesions were identified; 3 were drained endoscopically out of which two were psuedocyst and 1 was abscess,12 underwent resection, 3 were serous, 1 mucinous, 1 IPMN, 4 ductal adenocarcinomas, 1 endocrine neoplasm, 1 psuedocyst with abscess, one patient’s final histology results was missing. Three patients had neoplastic cells on FNAC, 2 patients had FNAC results suspicious for neoplasm, 26 were reported to have benign findings at EUS and FNAC and managed conservatively. 10 had elevated intra-cystic CEA levels, 3 patients had elevated CA 19–9 levels at FNAC. 1 patient was diagnosed having VHL, 1 patient had lymphatic cyst, 1 patient was diagnosed having Giardiasis, 1 patient was stented for palliation, 7 patients were undergoing further definitive treatment, and 1 patient with IPMN had therapeutic ERCP. <h3>Conclusion</h3> Our interim results suggest that quadruple assessment including clinical, radiological (CT/PET/MRI/EUS), FNAC and biochemical analysis is necessary prior to therapeutic planning. <h3>Disclosure of Interest</h3> None Declared.
Abstract 4287: Intracellular trafficking of androgen receptor splice variant AR8.
Authors: Ciny John, Michael L. Lu
Journal: Cancer Research (2013)

Abstract In a classic paradigm, the intracellular trafficking of a ligand-stimulated androgen receptor involves receptor dimerization, dissociating from chaperones (such as HSPs), interact with nuclear membrane importin and Ran-GTPase to gain access to nucleus; once there, it complexes with transcriptional regulators and binding to target sites. Despite the compelling evidence for AR non-genomic signaling events, the molecular mechanism of how does AR signaling from cytoplasmic or membrane remains undetermined. Several recent studies suggested that membrane association of AR is mediated by palmitoylation of AR at cysteine-806. Two plamitoylation enzymes, DHHC7 and DHHC21, have been implicated in the process of AR palmitoylation. In the current study, we determined the intracellular trafficking of a newly identified AR isoform, AR8. AR8 is a splice variant of the original full-length AR. AR8 was demonstrated to be up-regulated in castration-resistant prostate cancer cells. Structurally, AR8 protein sequence is different from other AR variants with a substitution of all the amino acids after N-terminal domain (NTD) of a conventional AR with an unique C-terminal sequence. Coincidentally, two cysteine residues within the unique c-terminus, positions 558 and 560, were identified to be palmitoylated. The palmitoylation was determined to be responsible for the localization of AR8 to plasma membrane. Using a fluorescent protein mCherry-tagged AR8 and confocal microscopy, we confirmed the plasma membrane localization of AR8 as previously described. We determined that AR8 co-localized with a Golgi marker GM-130 at peri-nuclear regions by immunofluorescence microscopy. The result was further substantiated by co-localizing mCherry-AR8 with galactosyltransferase (GalT) golgi-targeting sequence-fused GFP (GalT-GFP; green fluorescent protein) at Golgi compartments. We also demonstrated that mCherry-AR8 co-localized with EGFR-GFP (epidermal growth factor receptor-GFP) on the plasma membrane within in the cholesterol rich raft domain. Using time-lapse confocal microscopy, we observed that AR8 co-migrated with EGFR in a retrograde fashion and become associated with endosomal compartments at the onset of EGF (5ng/ml) stimulation. Part of these endosomes was later fused with lysosomes as evident from co-localizations of mCherry-AR8 with GFP-LAMP-1. Although the significance of AR8 expression in the progression of prostate cancer remains to be determined, our observations underline a potential intracellular trafficking pathway associated with AR8 are consistent with the original report that EGF stimulation promotes the interactions between AR8 and EGFR. Citation Format: Ciny John, Michael L. Lu. Intracellular trafficking of androgen receptor splice variant AR8. [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 4287. doi:10.1158/1538-7445.AM2013-4287
Abstract 1805: LSD1 regulation of SKP2 expression in prostate cancer.
Authors: Liya Ding, Haojie Huang
Journal: Cancer Research (2013)

Abstract Prostate carcinogenesis is a complicated process involving both genetic and epigenetic changes. Aberrant expression of LSD1 (Lysine-specific demethylase 1) has been reported in human prostate cancers. Although high expression of LSD1 is implicated in prostate tumorigenesis, the underlying molecular mechanisms are not fully understood. Here we reported that LSD1 promotes proliferation and migration of prostate cancer cells via up-regulation of SKP2 expression. Knockdown of LSD1 using small interfering RNA (siRNA) decreases SKP2 expression and inhibits prostate cancer cell proliferation and migration. Promoter luciferase reporter and chromatin immunoprecipitation (ChIP) experiments show that LSD1 regulates SKP2 expression by controlling the levels of H3K4 methylation in SKP2 promoter and this function of LSD1 is mediated through its demethylase activity. As demonstrated by immunohistochemistry, LSD1 and SKP2 proteins positively correlate with each other and their expression is associated with cell proliferation in human prostate cancer tissues. Our data not only identify SKP2 as a direct regulated target gene of LSD1 but also reveal that SKP2 plays an important role in contributing LSD1 mediated prostate cancer cell proliferation and migration, suggesting that the LSD1-SKP2 axis can serve as therapeutic targets for treatment of prostate cancers. Citation Format: Liya Ding, Haojie Huang. LSD1 regulation of SKP2 expression in prostate cancer. [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 1805. doi:10.1158/1538-7445.AM2013-1805
Stat Bite
Authors: Kate Duffy Mazan
Journal: JNCI Journal of the National Cancer Institute (1993)

Journal Article Stat Bite: Cancer Information Service: Telephone Inquiries Get access Kate Duffy Mazan Kate Duffy Mazan Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 85, Issue 20, 20 October 1993, Page 1628, https://doi.org/10.1093/jnci/85.20.1628 Published: 20 October 1993
Trimetrexate, methotrexate, and pemetrexed results of comparative in vitro cytotoxicity and modulation by fluphenazine-N-2-chloroethane and leucovorin
Authors: D. R. Ishmael, J. A. Nordquist
Journal: Journal of Clinical Oncology (2005)

2601 Background: Antifolate compounds are useful anticancer agents. They inhibit the enzyme dihydrofolate reductase and thymidylate synthase. Trimetrexate and methotrexate are available for treatment of various malignancies. A new antifol, pemetrexed is approved for treatment of mesothelioma and non-small cell lung cancer. Premetrexed has greater inhibition of thymidylate synthase than other antifols and is classified as a multi-targeted antifol. Fluphenazine-N-2-chloroethane is a potent irreversible inactivator of calmodulin. It possesses potent antiproliferative and cytotoxic activity. Methods: The BOT-2 human breast cancer cell line was used for the in vitro cytotoxicity studies. The cells were plated into microtiter plates. Drugs were added after 24 hours in 1:4 serial dilutions. The plates were read at 24, 48 and 144 hours. The endpoint was 100% cell death. MTT was applied at 144 hours. Further studies were done with combinations of the antifols and agents with specific targeting. Serial dilutions were made of the antifol and the adjunct or modulating agent. Results: The results of the cytotoxicity assays revealed that the antifols; methotrexate and pemetrexed were inactive against the BOT-2 human breast cancer cell line. Trimetrexate was active. Leucovorin increased the cytotoxicity of methotrexate and premetrexed to became active but no effect on the cytotoxicity of trimetrexate. Fluphenazine-N-2-chloroethane had minimal cytotoxic activity. It did not effect trimetrexate but modestly increased cytotoxicity of methotrexate. It had profound effect on premetrexed increasing cytotoxicity by twelve fold. Conclusions: Methotrexate and pemetrexed were inactive probably from poor penetration of the cancer cell. Trimetrexate is more lipid soluble and does not require carrier mechanisms to enter the cell. Leucovorin increased activity of methotrexate and pemetrexed but had no effect on trimetrexate. The calmodulin inhibitor fluphenazine-N-2-chloroethane increased the cytotoxicity of methotrexate and pemetrexed. No significant financial relationships to disclose.
Organ donors could be given priority for transplants under new rules
Authors: I. Torjesen
Journal: BMJ (2012)

The UK public is being asked whether organ donors should be given priority to receive organs if they ever need them, in forthcoming changes to the rules on organ transplantation.

NHS Blood and Transplant is surveying medical and scientific as well as public opinion on what changes they find acceptable and think would make the most difference to boosting the number of organs available for transplantation and the success of transplant procedures.

The survey will inform the changes to the organ donor and transplantation strategy being made from 2013. The changes are expected to be the largest ever shake-up of the ethical, legal, and professional rules governing transplantation in the United Kingdom.

The most contentious proposal would be to …
Abstract P1-11-20: Open-Label Phase II Study of Neoadjuvant Bevacizumab Combined with FEC→Paclitaxel in Patients with Inflammatory or Locally Advanced Breast Cancer
Authors: M Venturini, L Del Mastro, E Aitini, S Saracchini, O Garrone, A Durando, S De Placido, C Boni, A Levaggi, R Scalamogna, A Galli, M. Clavarezza
Journal: Cancer Research (2010)

Abstract Background: There is strong evidence that VEGF plays an important role in the pathogenesis and progression of human breast cancer. Bevacizumab, a monoclonal antibody, specifically inhibits VEGF. The combination of first-line bevacizumab with chemotherapy significantly improved the activity in comparison to chemotherapy alone in three randomized phase III trials in metastatic breast cancer patients (pts). In early breast cancer, the FEC→Paclitaxel regimen is a highly active standard therapy. Therefore we initiated a trial to evaluate the combination of bevacizumab with this efficacious chemotherapy regimen for the treatment of stage III or inflammatory early breast cancer (LABC). Patients and Methods: The study is designed to evaluate a sequential regimen of FEC90 followed by the combination of paclitaxel and bevacizumab as neoadjuvant therapy in patients with HER2-negative locally advanced (stage III or inflammatory) breast cancer. Patients are treated with neoadjuvant FEC 600/90/600 mg/m2 q21d x 4, followed by paclitaxel 80 mg/m2 weekly x 12 combined with bevacizumab 10 mg/kg q2w x 6. Patients undergo surgery 4 weeks after completing chemotherapy. Pathologic complete response (pCR), the primary endpoint, is defined as no evidence of invasive tumor in the final surgical sample both in the breast and axilla. Secondary endpoints include objective clinical response rate (RR), disease-free interval, overall survival, rate of breast-conserving surgery, and the safety of the regimen. Results: Between Feb 2008 and Dec 2009, 54 pts (mean age of 51±7.5 years) were enrolled into the study. To date, 32 pts have completed neoadjuvant treatment and surgery and are evaluable for response. Baseline characteristics in these 32 patients were as follows: cT3/cT4b: 20 (63%) and/or cN2/cN3: 14 (43%); estrogen receptor (ER) positive: 24 (75%) and 8 (25%) triple-negative (TN), defined as ER negative, progesterone receptor-(PgR-) negative, and HER2 negative. Histological type was ductal carcinoma in 24 patients (75%), lobular carcinoma in 4 (13%), inflammatory breast cancer in 1 (3%), and other in 3 (9%). Mastectomy was performed in 22 patients (69%) and breast-conserving surgery in 10 patients (31%). After neoadjuvant treatment, 8/32 patients (25%) achieved a pCR. Conclusions: This open-label, multicenter, phase II study demonstrated that the FEC→Paclitaxel plus bevacizumab combination is a highly active neoadjuvant treatment for HER2-negative locally advanced breast cancer. A 25% of pCR in this group of pts with high tumor burden, i.e. the LABC, is oneof the most promising chemotherapeutic regimen if confirmed in the final analyis. Results for all 54 pts enrolled will be presented at the meeting. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-11-20.
Abstract 2500: The pivotal role of p53 in doxorubicin-induced acute versus chronic cardiotoxicity
Authors: Wuqiang Zhu, Sean Reuter, Wenjun Zhang, Gregory R. Wagner, Ronald M. Payne, Randall L. Caldwell, Weinian Shou, Loren J. Field
Journal: Cancer Research (2012)

Abstract Introduction: Doxorubicin (DOX) is an effective anticancer chemotherapeutic which also induces acute and chronic cardiotoxicities. Inhibition of p53 activity is cardioprotective against acute cardiotoxicity in adult mice receiving high doses of DOX. However, functional p53 also reduces DOX-induced mitochondrial DNA oxidation. To explain these paradoxical results, we examined the role of p53 in DOX-induced acute and chronic cardiotoxicity with a clinically relevant juvenile mouse model. Methods: Two week old MHC-CB7 mice (which express dominant-interfering p53 in cardiomyocytes, CMs) and their non-transgenic (NON-TXG) littermates were given weekly DOX injections for 5 weeks (25 mg/kg total dose). Animals were studied 1 week (acute stage) or 13 weeks (late stage) after the last DOX injection. Cardiac function was measured with echocardiography. CM apoptosis was quantified using anti-active caspase-3 staining. The level of p53, Akt (an anti-apoptotic protein), and ataxia telangiectasia mutated (ATM, a marker for DNA-damage response) was measured by western blot using whole cell and mitochondrial fractions. Results: During acute stage, left ventricular (LV) systolic function was preserved (Fractional Shortening, FS, 58 ± 2.0% vs. 45 ± 1.3%, p&amp;lt;0.008) and CM apoptosis was reduced (0.003 ± 0.002/mm2 vs. 0.011 ± 0.002/mm2, p&amp;lt;0.008) in MHC-CB7 mice vs. NON-TXG mice. DOX increased mitochondrial p53 and decreased phosphorylated Akt in NON-TXG mice, and increased phosphorylated ATM in MHC-CB7 mice. During late stage, LV systolic function in MHC-CB7 mice markedly deteriorated, reaching values similar to those in NON-TXG mice (FS = 52 ± 2.5% vs. 50 ± 2.0%, p&amp;gt;0.05). CM apoptosis was elevated in MHC-CB7 mice as compared to NON-TXG mice (0.076 ± 0.007 mm2 vs. 0.042 ± 0.008 mm2, p&amp;lt;0.008). Phosphorylated Akt and ATM were normalized during late stage. Conclusions: Although inhibition of p53 activity protects against DOX-induced CM apoptosis and preserves cardiac function during acute stage, it exacerbates CM apoptosis and cardiac dysfunction during late stage. Ongoing experiments will determine the correlation between mitochondrial DNA damage during acute stage and CM apoptosis during late stage in DOX-treated MHC-CB7 mice. Acknowledgement: This work was supported by a grant (HL85098) from National Institutes of Health (to L.J.F.). Wuqiang Zhu was supported by a postdoctoral fellowship (121101) from American Cancer Society. 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 2500. doi:1538-7445.AM2012-2500
PMO-226 Differing phenotype in elderly IBD; should Montreal include an A4 category
Authors: A A McNicol, N Kennedy, J Satsangi, I D Arnott
Journal: Gut (2012)

<h3>Introduction</h3> The phenotype of elderly-onset IBD is poorly described and knowledge lags behind that of other age-groups. While not the dominant age-group in the disease population, those diagnosed over 60 will compose a larger proportion it as the general population ages over the next decade. The Montreal classification for IBD stratifies related to age into three categories, 40(A3) the study aims to ascertain if disease phenotype varies between those aged 40–59 and those &gt;60 with possibility of an A4 group becoming viable if variance is noted. <h3>Methods</h3> 1957 patients with IBD were identified using the IBD database at the Western General Hospital. We selected all those UC (n=306) and CD (n=135) diagnosed at age 40 and over (A3) and subdivided the group in to those over and under 60. The diagnosis adhered to the criteria of Lennard-Jones and IBD was categorised according to the Montréal classification. Data collected included diagnosis, age at diagnosis, disease distribution, disease behaviour and smoking history. Follow-up were available for 5 years following diagnosis. Analysis of the groups was undertaken using χ<sup>2</sup> and Fishers exact test. <h3>Results</h3> Gender of CD patients in the different age groups (40–59; M/F=53/96. &gt;60; M/F=10/49 p=0.0115) illustrated a higher proportion of women in the &gt;60 group. CD patients who were diagnosed over the age of 60 had more isolated colonic disease at diagnosis. (L2; 40–59 N=28/77, &gt;60 N=37/58, p=0.0032 L3; 40–59 N=15/77, &gt;60 N=2/58 p=0.0073). By 5 years of follow-up these differences were no longer significant. There was do difference in disease behaviour or smoking history. UC patients had more left sided disease and less distal disease at diagnosis (E1; 40–59 N=70/204, &gt;60 N=20/102, p=0.0079 E2; 40–59 N=88/204, &gt;60 N=57/102 p=0.039). Smoking history showed a greater proportion of former smokers in the &gt;60 group (40–59 N=108/216, &gt;60 N=70/107 p=0.0058). <h3>Conclusion</h3> Disease phenotype at Dx in both UC and Crohn9s differs in the over-60s at diagnosis but normalises to that of the A3 population at follow-up. This data suggests that the introduction of an additional Montreal age classification, A4, would be clinically meaningful. Further analysis will demonstrate whether response to treatment differs in this age group. <h3>Competing interests</h3> None declared.
Abstract 1092: Alterations of the retinoblastoma gene in stage III breast cancers
Authors: Elisabet O. Berge, Stian Knappskog, Stephanie Geisler, Vidar Staalesen, Pål Puntervoll, Marek Pacal, Anne-Lise Børresen-Dale, Johan R. Lillehaug, Per E. Lønning
Journal: Cancer Research (2010)

Abstract We report the novel finding of point mutations affecting the RB1 gene in breast cancer tissue. Analyzing 73 locally advanced (stage III) breast cancers, we identified two somatic and one germline single nucleotide changes, each leading to amino acid substitution; Leu607Ile, Arg698Trp, and Arg621Cys, respectively. In addition, MLPA analysis revealed two large multiexon deletions (exons 13 to 27 and exons 21 to 23) with the exons 21-23 deletion occurring in the tumor also harboring Leu607Ile. All three RB1 point mutations encoded stable nuclear proteins with impaired ability to induce apoptosis compared to wild-type pRb in vitro. Interestingly, Leu607Ile and Arg621Cys are both located within the spacer region of the protein. Mutations in this part of the RB1 gene have previously been identified in retinoblastoma-prone families. Multiple sequence alignment across species indicates this area to be evolutionary conserved. Notably, three out of four tumors harboring RB1 mutations displayed primary resistance to treatment with either mitomycin or doxorubicin while only 14 out of 64 tumors without mutations were resistant (p = 0.046). Although rare, our findings suggest RB1 mutations to be of biological importance in breast cancer. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 1092.
Abstract 227: Overexpression of EphB1 leads to Stat3 phosphorylation
Authors: Zev Gechtman
Journal: Cancer Research (2012)

Abstract The Receptor Tyrosine Kinase (RTK) family comprises some important disease drivers. Over-expressed or mutated RTKs in disease may lead to aberrant phosphorylation of intracellular signaling molecules. Therefore it is desirable to monitor simultaneously the activation levels of RTKs and signaling nodes. Here we used a multiplexed antibody array to monitor the phosphorylation of 28 RTKs and 11 intracellular signaling molecules simultaneously. We have observed a strong signal on a spot corresponding to phospho-STAT3 Tyr705 with lysates derived from CHO cells transiently over-expressing EphB1. The strong Phospho-STAT3 signal was not seen in non-transfected cells or in lysates made form cells transfected with several other Eph family members. Western blotting with phospho-specific antibodies showed an increase in STAT3 phosphorylation on Tyr705 in CHO cells upon EphB1 ectopic expression. The amounts of Tyr705 STAT3 phosphorylation positively correlated with the levels of EphB1 protein. Co-precipitation experiments showed that EphB1 and STAT3 interact both in CHO cells and MCF-7 breast cancer cells. Phosphorylated JAK2 was not found in these immuno-precipitates suggesting an involvement of another tyrosine kinase in STAT3 phosphorylation in cells over-expressing EphB1. Consistently with these observations, a potent JAK1 and JAK2 inhibitor INCB018424 inhibited the basal but not the EphB1-induced STAT3 Tyr705 phosphorylation in transfected CHO cells. These results suggest that EphB1 over-expression may bypass the requirement in Jak kinase and lead to STAT3 activation either directly or through another receptor-tethered kinase. 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 227. doi:1538-7445.AM2012-227