tbuckley/cabot-search huggingface dataset:
Heterogeneity for Allelic Loss in Human Breast Cancer
Authors: L.-c. Chen, W. Kurisu, B.-M. Ljung, E. S. Goldman, D. Moore, H. S. Smith
Journal: JNCI Journal of the National Cancer Institute (1992)

Background: Loss of heterozygosity (LOH) at specific chromosomal regions in the tumor cells implicates the presence of tumor suppressor genes. However, it is also possible for an LOH to be randomly acquired and irrelevant to tumor development. Purpose: To determine whether a particular LOH in human breast carcinomas represents a loss of tumor suppressor gene or merely a random loss, we analyzed untreated primary breast cancers for LOH. Methods: Ninety-eight primary human breast cancers from previously untreated patients were analyzed for LOH at 12 chromosomal regions including five randomly selected regions and seven regions previously reported in other cancer types and/or breast cancers. Results: The baseline incidence of LOH was five out of 124 tests (4%) using randomly selected probes on chromosomes 1p, 2p, 4p, 11q, and Xq. Incidences of LOH significantly greater than background were seen in the following chromosomal regions: 22q (10 of 26 cases, 38%); 18p (five of 24 cases, 21%); 17p (30 of 59 cases, 51%); 13q (five of 14 cases, 36%); 3p (13 of 28 cases, 46%); and 1q (18 of 70 cases, 26%). In contrast to previous reports, the incidence of LOH was not significantly different from background for 11p15. In all cases, results were the same for metastatic lymph nodes and primary tumors, suggesting that the losses occurred early in the malignant progression. In cases with LOH at more than one locus, the same DNA sample often varied in degree of signal reduction for the missing alleles. Conclusion: These observations indicate the presence of both intrtumor and intratumor heterogeneity for LOH. [J Natl Cancer Inst 84: 506–510, 1992]
Ovarian Cancer Screening: New Trial Tries New Twists
Authors: C. McNeil
Journal: JNCI Journal of the National Cancer Institute (1995)

Journal Article Ovarian Cancer Screening: New Trial Tries New Twists Get access Caroline McNeil Caroline McNeil Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 87, Issue 17, 6 September 1995, Pages 1283–1284, https://doi.org/10.1093/jnci/87.17.1283 Published: 06 September 1995
Abstract 3310: Human artificial chromosome (HAC) vector with a conditional centromere for correction of human genetic deficiencies.
Authors: Jung-Hyun Kim, Artem Kononenko, Indri Erliandri, Tae-Aug Kim, Megumi Nakano, Yuichi Iida, J. Carl Barrett, Mitsuo Oshimura, Hiroshi Masumoto, William C. Earnshaw, Vladimir Larionov, Natalay Kouprina
Journal: Cancer Research (2013)

Abstract Human artificial chromosome (HAC)-based vectors offer a promising system for delivery and expression of full-length human genes of any size. Due to their unique maintenance features and unlimited cloning capacity, HACs avoid the lack of copy number control and insertional mutagenesis caused by integration into host chromosomes that plague viral vectors. We previously described a synthetic HAC that can be easily eliminated from cell populations by inactivation of its conditional kinetochore. Here, we demonstrate the utility of this HAC, which has a unique gene acceptor site, for delivery of full-length genes and correction of genetic deficiencies in human cells. A battery of functional tests was performed to demonstrate expression of NBS1 and VHL genes from the HAC at physiological levels. We also show that phenotypes arising from stable gene expression can be reversed when cells are “cured” of the HAC by inactivating its kinetochore in proliferating cell populations, a feature that provides a control for phenotypic changes attributed to expression of HAC-encoded genes. This generation of human artificial chromosomes should be suitable for studies of gene function and therapeutic applications. Citation Format: Jung-Hyun Kim, Artem Kononenko, Indri Erliandri, Tae-Aug Kim, Megumi Nakano, Yuichi Iida, J. Carl Barrett, Mitsuo Oshimura, Hiroshi Masumoto, William C. Earnshaw, Vladimir Larionov, Natalay Kouprina. Human artificial chromosome (HAC) vector with a conditional centromere for correction of human genetic deficiencies. [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 3310. doi:10.1158/1538-7445.AM2013-3310
Emergency Coronary Angioplasty in Refractory Unstable Angina
Authors: Pim J. de Feyter, Patrick W. Serruys, Marcel van den Brand, Kulasekaram Balakumaran, Bahamshir Mochtar, Alan L. Soward, Alf E.R. Arnold, Paul G. Hugenholtz
Journal: New England Journal of Medicine (1985)

We performed percutaneous transluminal coronary angioplasty as an emergency procedure in 60 patients with unstable angina pectoris that was refractory to treatment with maximally tolerated doses of beta-blockers, calcium antagonists, and intravenous nitroglycerin. The initial success rate for angioplasty was 93 per cent (56 patients). There were no deaths related to the procedure, although total occlusion occurred in four patients. Despite emergency bypass grafting, all four sustained a myocardial infarction. All the patients were followed for at least six months. Late cardiac death occurred in one patient, whereas eight had recurrent angina pectoris. There was no progression to myocardial infarction. The re-Stenosis rate was 28 per cent (13 of 46) in the patients with initially successful coronary angioplasty who had repeat angiography. Improved cardiac functional status after sustained successful coronary angioplasty was demonstrated by an almost normal capacity on bicycle exercise testing and the absence of ischemia during thallium isotope studies in 80 per cent. We conclude that emergency percutaneous transluminal coronary angioplasty may be useful for the treatment of selected patients with unstable angina pectoris who are unresponsive to intensive pharmacologic treatment. (N Engl J Med 1985; 313:342–6.)
Abstract 5719: Epigallocatechin-3-gallate, a green tea polyphenol, reactivates silenced tumor suppressor gene by modifying DNA methylation and histones in human skin cancer cells
Authors: Mudit Vaid, Vijayalakshmi Nandakumar, Santosh K. Katiyar
Journal: Cancer Research (2010)

Abstract Epigenetics, the heritable processes that modulate gene activity without changes in the DNA sequence, have gained considerable interest in cancer development and molecular targets of cancer treatment. Cancer epigenetics deal with important processes like DNA methylation and histone modification patterns that can either activate oncogenes or inactivate tumor suppressor genes, the crucial steps in tumor development. Accumulating data suggest that dietary factors may alter cancer risk by modifications of epigenetic processes in the cancer cell. Therefore, the present study was designed to investigate whether (−)-epigallocatechin-3-gallate (EGCG), a most potent polyphenol from green tea which has anti-carcinogenic activity, would alter epigenetic events to regulate methylation-silenced tumor suppressor genes in human skin cancer cells. DNA methylation, histone modification and gene expression profile were studied using human epidermoid carcinoma A431 cells and melanoma cells as an in vitro model after EGCG treatment using RT-PCR, western blot analysis, cytostaining, southwestern dot-blot analysis, chromatin immunoprecipitation, enzymatic activity assays and fluorescence activated cell sorting (FACS) analysis of apoptotic cell death. Our study shows that treatment of A431 cells for 3 or 6 days with EGCG at lower concentrations (5, 10 and 20 μg/ml) resulted in DNA demethylation and reduction in the mRNA and protein levels of DNA methyltransferases (DNMTs) 1 and 3a and 3b and the activity of DNMTs in A431 cells in a dose- and time-dependent manner. EGCG also increased the levels of acetylated lysine 9 and lysine 14 on histone H3 (H3-Lys 9, H3-Lys 14), but decreased levels of methylated H3-Lys 9. Under identical conditions, EGCG re-expressed mRNA and protein levels of tumor suppressor genes, p16INK4a and p21WAF1/CIP1, in A431 cells in a dose-dependent manner. Re-expression of p16INK4a and p21 by EGCG treatment of the A431 cells leads to the inhibition of cell proliferation and induction of apoptosis of A431 cells. Together, our study demonstrates that EGCG can epigenetically modulate DNA and histones to activate methylation-silenced tumor suppressor genes. These epigenetic modifications by EGCG may contribute to skin cancer prevention/treatment strategies in humans. 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 5719.
Treatment of Men with Erectile Dysfunction with Transurethral Alprostadil
Authors: Harin Padma-Nathan, Wayne J.G. Hellstrom, Fran E. Kaiser, Richard F. Labasky, Tom F. Lue, Wolfram E. Nolten, Paul C. Norwood, Craig A. Peterson, Ridwan Shabsigh, Peter Y. Tam, Virgil A. Place, Neil Gesundheit, Christy Cowley, Kerry J. Nemo, Alfred P. Spivack, Darby E. Stephens, Leslie K. Todd
Journal: New England Journal of Medicine (1997)

Erectile dysfunction in men is common. We evaluated a system by which alprostadil (prostaglandin E1) is delivered transurethrally to treat this disorder.
AT-31A CANADIAN QUESTIONNAIRE ON THE MANAGEMENT OF ADULT DIFFUSE LOW GRADE GLIOMAS
Authors: Osaama Khan, Warren Mason, Paul Kongkham, Mark Bernstein, Gelareh Zadeh
Journal: Neuro-Oncology (2014)

Adult diffuse low-grade gliomas (LGG) are slow growing, World Health Organization (WHO) grade II lesions with insidious onset and ultimate anaplastic transformation. The timing of surgery remains controversial with polarized practices continuing to govern patient management. As a result, the comprehensive management of these patients is variable. The goal of this questionnaire was to evaluate practice patterns in Canada. An online invitation for a questionnaire including diagnostic, preoperative, perioperative, and postoperative parameters and three cases with magnetic resonance imaging data with questions to various treatment options in these patients was sent to practicing neurosurgeons and trainees. 356 emails were sent with 87 (24.7%) responses collected. The range of years of practice was less then 10 years 36% (n = 23), 11-20 years 28% (n = 18), over 21 years 37% (n = 24). 90% of surgeons do not obtain formal preoperative neurocognitive assessments. 21% (n = 13) perform a biopsy upon first presentation. A gross total resection was believed to increase progression free survival (75%, n = 46) and to increase overall survival (64%, n = 39). Intraoperative MRI was only used by 8% of surgeons. Using the aid of three hypothetical cases with progressive complexities in tumor eloquence there was a trend for younger surgeons to operate earlier, and use awake craniotomy to obtain greater extent of resection with the aid of cortical stimulation when compared to senior surgeons who still more often preferred a “wait-and-see” approach. Despite the limitations of an online survey study, it provided insights into the variability in surgeon practice patterns in Canada and the need for a consensus on the workup and surgical management of this disease.
Abstract 2542: EXO1 is required for SN1 methylator-induced DNA damage response
Authors: Eugene G. Izumchenko, Kevin D. Brown
Journal: Cancer Research (2012)

Abstract SN1 methylating agents are therapeutics that methylate the O6 position of guanine (O6meG) forcing mispairing with thymine during DNA replication. The mismatch repair (MMR) system recognizes O6meG:T mispairs and activates DNA damage response (DDR). Exonuclease I (EXO1) functions during MMR by excising the damaged strand; however, how MMR mechanistically contributes to DDR activation and if EXO1 is required to activate MMR-dependent response remains unknown. Here we show that Exo1 knockdown in mouse embryonic fibroblasts (MEFs) results in decreased G2/M arrest and checkpoint response (ie, Cdc2/Chk1 phosphorylation), and increased cell proliferation and viability following exposure to the SN1 methylator MNNG. Moreover, ectopic expression of full-length human hEXO1 restored normal response to MNNG. We next examined gamma-H2AX foci formation as a surrogate marker of MMR-dependent DNA repair. 12h after MNNG treatment, 40% of MEFs scored positive for multiple gamma-H2AX foci and this population further increased with prolonged treatment. In contrast, Exo1 depleted MEFs displayed a significantly diminished number of gamma-H2AX foci-positive cells following MNNG. Increased association of Msh2/Msh6 with chromatin was observed in MNNG treated MEFs; however, Exo1 depletion resulted in no upregulation of MMR proteins within the chromatin fraction. Furthermore, MNNG-induced Msh2/Chk1 association was disrupted upon Exo1 depletion. Taken together, we conclude that Exo1 is required to activate DDR following SN1 methylator exposure. Data gathered suggests that Exo1 functions in activating MMR-dependent DNA repair, promoting assembly of MMR complexes with alkylated chromatin, and enhancing the association of MMR components with critical checkpoint mediators. Experiments designed to determine if Exo1 functions in a structural (ie, scaffolding) or catalytic (ie, nucleolytic) manner during SN1 methylator-induced DDR are currently underway. 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 2542. doi:1538-7445.AM2012-2542
Abstract LB-380: Apo2L/TRAIL reduces interstitial fluid pressure and enhances gemicitabine uptake in patient pancreatic tumor xenografts
Authors: Bonnie L. Hylander, Arindam Sen, Sarah Beachy, John Gibbs, Rose Pitoniak, Joshua Prey, Gerald Fetterly, Elizabeth A. Repasky
Journal: Cancer Research (2010)

Abstract Tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) has promising anti-tumor therapeutic potential and is in clinical trials. It is known that microenvironmental factors such as elevated interstitial fluid pressure limits uptake and greatly inhibits anti-tumor efficacy of many therapeutics. We are investigating the role of interstitial fluid pressure in the anti-tumor effect of Apo2L/TRAIL alone and in combination with gemcitabine. We first carried out a histological analysis of Colo205 tumors treated with a single 1000 g dose of Apo2L/TRAIL. Apoptosis (ck18+ cells) and infiltration of macrophages (F4/80+ cells) peaks by 8 hrs; by 24 and 48 hours, apoptotic debris has been cleared and the lumen of tumor vessels is clearly apparent. This is in sharp contrast to untreated tumors in which cells are densely packed and vessels with an open lumen are seldom seen. Correspondingly, measurements of tumor interstitial fluid pressure (IFP) taken 48 hrs after a single treatment of Apo2L/TRAIL revealed a significant reduction in IFP compared to tumors in the untreated mice (n=5; 0.3 cm H2O vs. 3.4 cm H2O, P= 0.002). We have characterized the Apo2L/TRAIL sensitivity of a panel of patient pancreatic tumor xenografts and found a range of responses to Apo2L/TRAIL from actual regression (tumor growth inhibition, TGI, of 108%) to complete resistance (TGI of 0%). Histological analysis of a sensitive tumor showed that Apo2L/TRAIL induced both the physical changes seen in Colo205 as well as a similarly significant reduction in IFP (n=7; P= 0.003). Importantly, in these patient xenografts, combination therapy with Apo2L/TRAIL and chemotherapy has been shown to enhance the antitumor effect of gemcitabine. Therefore, we investigated the effect of Apo2L/TRAIL induced lowering of IFP on gemcitabine uptake. In these studies, a single dose of gemcitabine was administered 48 hrs after Apo2L/TRAIL administration. Pharmacological analysis reveals a 33% increase in gemcitabine uptake in tumors in the 6 hours following Apo2L/TRAIL administration; no such increase was observed in normal liver. These results support the idea that pretreatment of a tumor with Apo2L/TRAIL leads to “decompression” of the tumor and will selectively improve tumor uptake of chemotherapeutics. We are currently investigating different schedules of administration in order to maximize the uptake of gemcitabine and optimize the anti-tumor efficacy of this combination therapy. 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 LB-380.
THU0386 Hip Structural Analysis (HSA) and Prediction of Hip Fractures in Men
Authors: J. Parker, A. Oldroyd, M. Bukhari
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> It is well documented that low bone mineral density is a predictor of hip fracture. <sup>1</sup> Hip structural analysis (HSA) is also useful for predicting fractures in women. <sup>2,3</sup> It is important to better understand predictors of fractures in men, which like women may include HSA. To date, studies have focused on populations with specific age ranges or co-morbidities and tend to use small sample sizes when analysing the relationship between HSA and fracture in males. <sup>4,5</sup> <h3>Objectives</h3> To investigate the association between HSA and fractures in a large cohort of men. <h3>Methods</h3> Data was collected from male patients referred to a District General Hospital for DXA scanning between April 2004 and September 2010. Numerous variables were recorded including: age, BMI, traditional risk factors for osteoporosis (OP), social deprivation score (IMD) and HSA (<i>Table1)</i>. Patients were divided into groups depending on hip fracture status and baseline characteristics were compared using a T-test and Chi2 for continuous and categorical variables respectively. HSA measurements were compared between groups using a logistic regression model and repeated adjusting for possible confounders. <h3>Results</h3> 2,564 males were included in the study, of these 738 (28.8%) had sustained a previous hip fracture. The mean age of the fracture and non-fracture group was 66.4 years (SD 13.2) and 64.4 years (SD 13.5) respectivley (p=1). The mean BMI was 24.2kg/m<sup>2</sup> (SD 2.7) and 26.9kg/m<sup>2</sup>(SD 4.5) in the fracture and non-fracture groups respectively, (p&lt;0.05). Mean IMD in the fracture group was 19.5 (SD 0.6) and 18.2 (SD 0.3) in the non-fracture group. Odds ratio for logistic regression anaylsis for comparison of HSA between the groups is shown in <i>Table1.</i> <h3>Conclusions</h3> This study has shown that there are structural differences in the hip of males who have sustained a hip fracture compared to those who have not. Geometrical differences included a weaker, shorter, wider femoral neck as shown by SI, D2 and D3 and y respectively; in addition to a reduced cross sectional area (CSA). The results of this study correlate well with findings in women.<sup>2</sup> Further research in alternative cohorts is required to validate this. <h3>References</h3> J Bone Miner Res. 2005 Jul;20(7):1185-94 Osteoporos Int. 2006;17(4):593-9 Osteoporos Int. 2010 June; 21(6): 919–929 Eur J Endocrinol. 2007 Jan;156(1):123-7 J Bone Miner Res. 2005 Oct;20(10):1820-7 <h3>Disclosure of Interest</h3> None Declared
Abstract 1643: Physical and functional interactions between acid sensing ion channel 1 (ASIC1) and integrin β1 in glioma cells.
Authors: Arun K. Rooj, Carmel M. McNicholas, Catherine M. Fuller
Journal: Cancer Research (2013)

Abstract The local microenvironment of a cancer cell plays important roles in tumor metastasis. Major components of this local niche are ion channels, integrin receptors, and the extracellular matrix. Glioma cells express a specific amiloride-sensitive and constitutively active non-selective cation channel composed of ASIC1, α- and gENaC subunits, members of the Deg/ENaC superfamily of non-voltage gated sodium channels. Inhibition of this channel is associated with reduced migration and proliferation of the glioma cell. As gliomas are highly invasive, we hypothesized that channel activity was engaging an intracellular signaling pathway regulating migration and proliferation by interacting with integrin β1. We have shown the physical proximity of the ASIC1 subunit and integrin β1 by co-immunoprecipitation in D54MG glioma cells. A functional interaction between these two proteins was demonstrated when we found that stable (shRNA) knock-down of integrin β1 attenuated the amiloride-sensitive current by 89±24% (n≥9; ±SD P&amp;lt;0.001). Furthermore, prolonged (24h) inhibition of this glioma channel by PcTX-1, a specific ASIC1 inhibitor, down-regulated integrin β1 expression (by 60% ± 12% (SD) n≥3 P&amp;lt;0.001). The surface expression of ASIC1 in glioma cells is also regulated by integrin β1. Using biotinylation, we found that stably knocking down integrin β1 inhibited the surface expression of ASIC1. In contrast, up-regulating membrane expression of integrin β1 by coating dishes with either fibronectin or vitronectin, increased the surface expression of ASIC1. This effect was not observed when dishes were coated with poly-L-lysine. We have previously shown that knockdown of ASIC1 reduced the phosphorylation level of ERK1/2, a key mediator of tumor cell proliferation and migration (Rooj et al. J. Biol. Chem. 287:4053, 2012). In the present study, phosphorylation of ERK1/2 was also reduced by knockdown of integrin β1 (by 58% ± 20% (SD) n≥3 P&amp;lt;0.001). Our data reveal a novel interaction between ASIC1 and integrin β1 in the regulation of the MAPK pathway that may form a mechanism by which changes in Na+ current can modulate cell proliferation and migration. Citation Format: Arun K. Rooj, Carmel M. McNicholas, Catherine M. Fuller. Physical and functional interactions between acid sensing ion channel 1 (ASIC1) and integrin β1 in glioma cells. [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 1643. doi:10.1158/1538-7445.AM2013-1643