tbuckley/cabot-search huggingface dataset:
The developmental protein HOXc11 as a mediator of endocrine resistance in breast cancer.
Authors: DP McCartan, M McIlroy, S Eary, AD Hill, LS Young
Journal: Cancer Research (2009)

Abstract Abstract #3034 The nuclear receptor coactivator, SRC-1, has been implicated as an important mediator of resistance to endocrine therapy in breast cancer through work from our group and others. Using mass spectrometry we identified the homeobox protein HOXc11 as an interacting partner for the nuclear receptor coactivator SRC-1 in endocrine resistant breast cancer cells. Homeobox genes control cell differentiation. The processes of neoplasia and normal development are closely linked, therefore it is little surprise that increasing evidence implicates these genes in neoplasia development.&amp;#x2028; We propose that the interaction between SRC-1 and HOXc11 plays an important role in the development of endocrine resistance. Our aim was to identify potential HOXc11/SRC-1 target genes and assess the clinical significance of these genes.&amp;#x2028; Co-immunprecipitation assays confirmed the SRC-1 and HOXc11 interaction after treatment with tamoxifen for 2 hours in the endocrine resistant LY2 breast cancer cell line, an interaction that was not present in endocrine sensitive MCF-7 cells under the same treatment conditions. A target gene for HOXc11, S100β, has previously been identified in neuronal cells. Based on this we sought the presence of either protein at the promoter region for S100β. Chromatin immunoprecipitation (ChIP) assays in LY2 cells confirmed recruitment of both HOXc11 and SRC-1 to the promoter region of S100β after treatment with tamoxifen at both 45 minutes and 2 hours when compared to control.&amp;#x2028; To assess the clinical significance of S100β, we used immunohistochemistry on a paraffin embedded tissue microarray to examine itÂs expression in a large cohort of breast cancer patients (n=560). S100β was a strong predictor of reduced disease free survival in patients receiving adjuvant endocrine treatment (Hazard ratio 5.82; p&amp;lt;0.0001). This also showed that expression of S100β was associated with expression of HOXc11 and SRC-1. Given that S100β is a secreted protein, we hypothesized that elevated levels could be detected in patients with breast cancer at time of diagnosis. Using an ELISA to measure S100β levels, we found elevated levels in one quarter of breast cancer patients, pre treatment, when compared to age matched controls.&amp;#x2028; Investigation into non steroidal SRC-1 binding partners in endocrine resistant breast cancer identified the homeobox protein HOXc11. A target gene for the interaction between SRC-1 and HOXc11, S100β, is a secreted protein and raises the exciting possibility that it may offer potential as a biomarker for endocrine resistance in breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3034.
Pathogenesis of Fecal Incontinence in Diabetes Mellitus
Authors: Lawrence R. Schiller, Carol A. Santa Ana, A. Carl Schmulen, Robert S. Hendler, William V. Harford, John S. Fordtran
Journal: New England Journal of Medicine (1982)

We studied 16 patients with diabetes and fecal incontinence. The onset of incontinence coincided with the onset of chronic diarrhea in most patients. Episodes of incontinence occurred when stools were frequent and loose; however, 24-hour stool weights were usually within normal limits. All patients had evidence of autonomic neuropathy, and one third had steatorrhea. Incontinent diabetics had a lower mean basal anal-sphincter pressure than 35 normal subjects (63 +/- 4 vs. 37 +/- 4 mm Hg; P less than 0.001), reflecting abnormal internal-anal-sphincter function. The increment in sphincter pressure with voluntary contraction (external-sphincter function) was not significantly different from normal. Incontinent diabetics also had impaired continence for a solid sphere and for rectally infused saline. In contrast, 14 diabetics without diarrhea or incontinence had normal sphincter pressures and normal results on tests of continence, even though 79 per cent had evidence of autonomic neuropathy and nearly half had steatorrhea. We conclude that incontinence in diabetic patients is related to abnormal internal-anal-sphincter function, and that as a group, diabetics without diarrhea do not have latent defects in continence.
Abstract 5386: Investigating the role of N-terminal protein methylation in colon cancer progression.
Authors: John G. Tooley, John O. Trent, Christine E. Schaner Tooley
Journal: Cancer Research (2013)

Abstract We have recently identified the first mammalian N-terminal methyltransferase, NRMT. NRMT is a highly conserved, ubiquitously expressed nuclear enzyme that is predicted to methylate more than 300 target proteins, including the proven targets Retinoblastoma Protein (RB), DDB2, and the oncoprotein SET. N-terminal methylation has been shown to regulate protein-DNA interactions and has also been implicated in regulating protein stability. Multiple microarray analyses have shown that NRMT is overexpressed in human colon cancer, and our preliminary data indicate the more aggressive the cancer, the higher the NRMT expression. However, there are currently no commercially available inhibitors specific for this enzyme and very little is known about the downstream signaling consequences of NRMT misregulation. We have used in silico screening of the ZINC small molecule library to identify potential NRMT-specific inhibitors. Screening of the top 100 candidates produced 10 compounds that could inhibit NRMT methyltransferase activity in vitro. The top compound of these 10 can also inhibit NRMT methyltransferase activity in cell culture and specifically stops the growth of colon cancer cell lines that have high NRMT expression. We are currently working to optimize this small molecule inhibitor for stability and solubility, understand its downstream signaling consequences, and test its efficacy in a murine model system. We are especially interested in the potential of NRMT inhibitors as a treatment for patients with mutant kRAS. These patients are often insensitive to anti-EGFR therapy, but oncogenic RAS seems to require functional RB. Therefore, impairment of NRMT activity could also impair oncogenic RAS signaling through destabilization of RB. Data from this study will enhance our understanding of how colon cancer develops and could lead to novel treatments for the disease. Citation Format: John G. Tooley, John O. Trent, Christine E. Schaner Tooley. Investigating the role of N-terminal protein methylation in colon cancer progression. [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 5386. doi:10.1158/1538-7445.AM2013-5386
Fibroblasts from different tissues promote entry but retain lymphocytes in 3D models of tissue.
Authors: Hannah C Jeffery, Andrew Filer, Christopher D Buckley, G Ed Rainger, Gerard B Nash, Helen M McGettrick
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background and objectives</h3> Fibroblasts actively regulate the recruitment of leucocytes by endothelial cells, acting in a pro- or anti-inflammatory manner depending on their site of origin.1 Effects of fibroblasts on leucocyte migration through tissue and their subsequent fate remain unclear. Here, the authors explored the concept that fibroblasts from different tissues modulate the migration patterns of peripheral blood lymphocyte (PBL) in a site specific manner. <h3>Materials and methods</h3> Fibroblasts were isolated from the skin, bone marrow and synovium of patients with rheumatoid arthritis (RA) undergoing joint replacement surgery. Two forms of co-cultures were developed, appropriate to answer specific questions: (1) endothelial cells and fibroblasts cultured on separate 3.0 µm porous filters, one above the other; (2) endothelial monolayers formed on a filter above a collagen gel in which fibroblasts were incorporated. In the multi-filter model, PBL adhesion and migration was assessed at 24 h by flow cytometry. In the collagen construct, PBL migration into the gel and their depth of penetration was assessed at intervals over 48 h. <h3>Results</h3> The authors used the multi-filter model to assess the ability of fibroblasts to influence PBL migration through resting endothelial monolayers. Fibroblasts, synovial and dermal, enhanced the ability of endothelial cells to support T cell adhesion, and significantly promoted their onward transendothelial migration. Although fibroblasts generate CXCL12 and IL-6, blockade of either protein had no effect on T cell migration. Interestingly, fibroblasts appeared to restrain onward motion of recruited T cells. This indicated that the process of migration changed the migratory phenotype of recruited T cells and/or that fibroblasts were providing ‘stop’ signals resulting in T cell retention within the fibroblast layer. Next, the authors employed the multi-cellular collagen gel construct to visually observe the effects of fibroblasts on PBL migration into and retention within tissue. Once again, all fibroblast types promoted PBL transendothelial migration, while reducing their onward penetration of the collagen gel. Notably, migrating PBL tracked closely to fibroblast rich regions of the gel, indicating that fibroblasts are capable of retaining recruited cells. <h3>Conclusions</h3> Collectively these data suggest a novel regulated step in lymphocyte migration, where stromal-derived ‘go’ and ‘stop’ signals control lymphocyte migration into and within tissues, respectively.
Abstract 5384: Tanshinone IIA synergizes with arsenic trioxide to promote human NB4 promyelocytic leukemia cell differentiation and apoptosis
Authors: Zhibo Wang, Daniel E. Johnson, Naiqiang Cui, Xianzhong Wu, Ronald Herberman, Soldano Ferrone, Wenjun Wang
Journal: Cancer Research (2010)

Abstract Background: Tanshinone IIA (TIIA), a natural compound isolated from Salvia Miltiorrhiza, has been used for hematological malignancies as an adjunctive therapy in combination with arsenic in other countries. However, the molecular mechanism of TIIA as an adjunctive therapy has not been well documented. The goal of this study is to develop novel strategies to treat human promyelocytic leukemia. Methods: Purified TIIA was used for this pilot study; and purified arsenic trioxide (ATO) was purchased from Sigma. Western blotting and flow cytometry were employed to evaluate biomarker expression in human NB4 promyelocytic leukemia cells prior to treatment and 2-5 days after treatment. Results: TIIA induced NB4 cell apoptosis at the concentrations above 0.75 µM, a concentration that is below plasma concentrations that can be achieved in vivo. TIIA was not toxic to peripheral blood mononuclear cells (PBMC) from healthy individuals at 3 µM, the highest concentration tested. TIIA also promoted NB4 differentiation at and above 0.75 µM. TIIA up-regulated the percentage of CD11b+ NB4 cells, as well as increasing the percentage of NBT+ cells. In addition, There were not significant differences between TIIA (1µM) and ATRA (1 µM), in terms of their impact on NB4 cell differentiation, as assessed by NBT and CD11b assays. TIIA also inhibited NB4 cell colony formation in CFU-L assays. Western blotting demonstrated that TIIA down-regulated c-Myc expression in NB4 cells. The combination of ATO and TIIA increased NB4 cell death when compared with single drug treatment (TIIA or ATO). In addition, the combination of TIIA and ATO had stronger impact on the induction of NB4 cell differentiation, as assessed by CD11b expression. Conclusion: TIIA is a potential novel adjunctive agent to be considered in combination with ATO for the treatment of human promyelocytic leukemia. 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 5384.
Transesophageal Echocardiography — Sound Diagnostic Technique or Two-Edged Sword?
Authors: Alan S. Pearlman
Journal: New England Journal of Medicine (1991)

Over the past 30 years, cardiac ultrasound examinations have been used in an ever-increasing number of clinical applications. Echocardiography currently has important uses in a range of disorders, including valvular, ischemic, myocardial, pericardial, congenital, infectious, and neoplastic diseases.1 To an important extent, this development has been made possible by a sequence of new diagnostic methods arising from technological innovations. From early time—motion studies, echocardiography now has evolved to include two-dimensional imaging, spectral Doppler measurement of blood-flow velocity with pulsed-wave and continuous-wave techniques, color Doppler flow imaging, contrast echocardiography, and stress echocardiography. The latest method is transesophageal echocardiography.In simple terms, . . .
Abstract 5004: CpG island methylator phenotype in bladder cancer
Authors: Woonbok Chung, Jolanta Bondaruk, Nianxiang Zhang, Jaroslav Jelinek, Marcos Estecio, Shoudan Liang, Bogdan Czerniak, Jean-Pierre J. Issa
Journal: Cancer Research (2012)

Abstract DNA hypermethylation is a common epigenetic abnormality in cancer, and some cancers are characterized by the presence of intense hypermethylation at multiple loci, termed CpG island methylation phenotype (CIMP). CIMP has not been fully characterized in bladder cancer. In a pilot study, we examined the methylation status of 38 loci in a panel of 26 bladder cancer and identified 14 genes whose methylation was concordant, supporting the presence of CIMP. In an expanded series of 108 cancers, we found that a distinct subset displays concerted hypermethylation at a large number of genes, confirming the existence of CIMP in bladder cancer. Unsupervised hierarchical K-means clustering identified three distinct DNA methylation groups of bladder cancers, CIMP-N (negative), CIMP-L (low), and CIMP-H (high) representing 39%, 33% and 28% of cancer overall. Compared to CIMP-N cases, CIMP-H cases were more frequently current smokers (p&amp;lt;0.05), had more H-RAS and K-RAS mutation (15% vs. 0 %, P&amp;lt; 0.05), had less FGFR3 mutations (8% vs. 32 %, P&amp;lt;0.05) and more RB1 loss (35% vs. 10%, P&amp;lt;0.05). Genome wide analysis of 85 bladder cancers by MCAM (methylated CpG island amplification microarray) showed an average of 12.4 % of genes hypermethylated in CIMP-H, 6.5 % in CIMP-L and 4.4 % in CIMP-N (CIMP-N vs. CIMP-L, p=0.0006 and CIMP-L vs. CIMP-H, p&amp;lt;0.0001). Affected genes were enriched for PcG targets, and gene ontology analysis showed clustering at Homeobox and voltage-gated cation channel based on gene expression of CIMP targets. Our study suggests that CIMP is an important molecular variable in bladder cancer heterogeneity. 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 5004. doi:1538-7445.AM2012-5004
Concordance of Hospital Cancer Registry- and Physician-Collected Data for Patients With Melanoma
Authors: L. L. Hourani, J. Jakowatz, M. Goodman, G. Mueller, G. Brodie, A. Jaffery
Journal: JNCI Journal of the National Cancer Institute (1992)

Journal Article Concordance of Hospital Cancer Registry- and Physician-Collected Data for Patients With Melanoma Get access Laurel Lockwood Hourani, Laurel Lockwood Hourani * University of California Irvine Medical CenterOrange, Calif *Correspondence to: Laurel Lockwood Hourani, Ph. D., Clinical Cancer Center, University of California Irvine Medical Center, 101 The City Drive, Rt. 81, Bldg. 44, Orange, CA 92668. Search for other works by this author on: Oxford Academic PubMed Google Scholar James Jakowatz, James Jakowatz University of California Irvine Medical CenterOrange, Calif Search for other works by this author on: Oxford Academic PubMed Google Scholar Matthew Goodman, Matthew Goodman University of California Irvine Medical CenterOrange, Calif Search for other works by this author on: Oxford Academic PubMed Google Scholar Greg Mueller, Greg Mueller University of California Irvine Medical CenterOrange, Calif Search for other works by this author on: Oxford Academic PubMed Google Scholar Grace Brodie, Grace Brodie University of California Irvine Medical CenterOrange, Calif Search for other works by this author on: Oxford Academic PubMed Google Scholar Ali Jaffery Ali Jaffery University of California Irvine Medical CenterOrange, Calif Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 84, Issue 22, 18 November 1992, Pages 1749–1750, https://doi.org/10.1093/jnci/84.22.1749 Published: 18 November 1992 Article history Received: 20 April 1992 Revision received: 09 September 1992 Accepted: 16 September 1992 Published: 18 November 1992
Abstract IA-1: From chromosome engineering to chromatin remodeler: CHD5 is a tumor suppressor mapping to human 1p36
Authors: Alea A. Mills
Journal: Cancer Research (2009)

Abstract Deletions encompassing the 1p36 region of human chromosome 1 have been associated with a spectrum of malignancies, however the tumor suppressor had not been identified. In an effort to identify tumor suppressors within this interval, we used chromosome engineering to generate mouse models with loss- and gain of regions of the genome corresponding to human 1p36. This strategy allowed us to identify a 4.3 megabase interval with potent tumor suppressive activity. Whereas loss of this region caused a marked increase in cellular proliferation that culminated in cancer in vivo, gain of the same interval triggered excessive tumor suppression as observed by augmented cellular senescence in cultured cells and apoptosis in vivo. Using genetic and molecular analyses, we identified the chromatin remodeling protein Chromodomain, helicase, DNA-binding domain protein 5 (Chd5) as the tumor suppressor within the interval, and revealed that Chd5 functions as a master regulator that facilitates p16/Rb- and p19/p53-modulated pathways. Analyses of human gliomas revealed that CHD5 is frequently deleted, suggesting that CHD5 loss contributes to malignancy. Here I will present our current efforts aimed at elucidating the epigenetic role of CHD5 in tumor suppression. Citation Information: Cancer Res 2009;69(23 Suppl):IA-1.
P16.24 * MULTIMODAL IMAGING ELUCIDATES PHYSIOLOGICAL AND METABOLIC CHANGES INDUCED BY ANTI-ANGIOGENIC THERAPY IN GLIOBLASTOMA
Authors: O. Keunen, N. Obad, H. Espedal, R. Ji ik, C. B. Rygh, T. Taxt, P. Sakariassen, F. Fack, S. P. Niclou, R. Bjerkvig
Journal: Neuro-Oncology (2014)

Treatment of primary and recurrent glioblastoma with anti-angiogenic therapies, either alone or in combination with chemotherapy, fails to extend overall survival, despite the often reported improvements in progression free survival and patient health condition. To improve the efficacy of these therapies, a better understanding of the mechanisms of tumour adaptation and treatment escape is warranted, while at the same time adopting imaging protocols that evaluate tumour progression without ambiguity. The complementary roles of Magnetic Resonance Imaging and Positron Emission Tomography can help to elucidate the physiologic and metabolic changes induced by anti-angiogenic agents, and better appreciate the clinical response at early stages of the treatment. In the present study, we have used this multi-modal imaging approach to investigate the changes induced by bevacizumab in pre-clinical models of glioblastomas obtained from patient-derived biopsies. We report longitudinal changes in vascular morphology and function, and describe how the changes in blood supply lead to increased intratumoral hypoxia, resulting in high glycolytic activity and tumour invasiveness.
Abstract POSTER-BIOL-1325: Ovarian cancer-associated CDK12 mutations disable its kinase activity and cause defects in homologous recombination
Authors: Poorval M. Joshi, Shari L. Sutor, Catherine J. Huntoon, Larry M. Karnitz
Journal: Clinical Cancer Research (2015)

Abstract PURPOSE: The purpose of this study was to determine whether a) high-grade serous ovarian cancer-associated CDK12 kinase domain mutations affect catalytic activity, b) loss of CDK12 affects BRCA1 expression levels and Homologous Recombination (HR) in ovarian cancer, c) tumor-associated CDK12 mutations cause HR defects in ovarian cancer, and d) loss of CDK12 sensitizes ovarian cancer to chemotherapy and Poly(ADP-ribose) Polymerase [PARP] inhibitors. EXPERIMENTAL PROCEDURES: We compared the kinase activities of wild-type CDK12 and tumor-associated CDK12 kinase domain mutants using in-vitro kinase assays. To determine the impact of CDK12 activity on HR, we assessed RAD51 foci formation and HR using a DR-GFP construct. To analyze the effect of tumor-associated CDK12 mutations on HR, CDK12-depleted OVCAR-8 cells were reconstituted with either wild-type CDK12 or the tumor-associated CDK12 mutant (G909R), irradiated and stained for RAD51 foci. We performed clonogenic assays using ovarian cancer cell lines (OVCAR-8, OVCAR-5 and OVCAR-3) to measure sensitivity to DNA cross-linking agents (melphalan and cisplatin) and the PARP inhibitor, veliparib, in the presence or absence of CDK12 activity. CDK12 depletion was carried out using at least two independent short-interfering RNAs (siRNAs). RESULTS: We showed that many, but not all, ovarian cancer-associated CDK12 kinase domain mutations severely disrupted kinase activity. Moreover, we found that disabling CDK12 activity in ovarian cancer cells decreased BRCA1 levels and disrupted HR. Additionally, the tumor-associated CDK12 G909R mutant did not restore impaired RAD51 foci formation in CDK12-depleted OVCAR-8 cells. Finally we show that CDK12 depletion sensitized multiple ovarian cancer cells to the DNA cross-linking agents melphalan and cisplatin and to the PARP inhibitor veliparib. CONCLUSION: Ovarian cancer-associated CDK12 mutations disrupt kinase activity and cause defects in HR, suggesting that ovarian tumors harboring deleterious CDK12 mutations may predict sensitivity to chemotherapeutic agents, including PARP inhibitors. Citation Format: Poorval M. Joshi, Shari L. Sutor, Catherine J. Huntoon, Larry M. Karnitz. Ovarian cancer-associated CDK12 mutations disable its kinase activity and cause defects in homologous recombination [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1325.