tbuckley/cabot-search huggingface dataset:
Expression of DNA Double-Strand Break Repair Proteins ATM and BRCA1 Predicts Survival in Colorectal Cancer
Authors: Heike Grabsch, Mit Dattani, Lisa Barker, Nicola Maughan, Karen Maude, Olaf Hansen, Helmut E. Gabbert, Phil Quirke, Wolfram Mueller
Journal: Clinical Cancer Research (2006)

Abstract Purpose: The double-strand break (DSB) is the major DNA lesion leading to chromosomal aberrations and faithful repair is crucial for maintaining genomic instability. Very little is known about the expression of DNA DSB repair proteins in colorectal cancer. To address this issue, we examined the expression pattern of DSB repair key proteins ATM, BRCA1, BRCA2, Ku70, and Ku80 and their putative role in patients survival in a large series of colorectal cancer. Experimental Design: 342 sporadic colorectal cancer were subjected to immunohistochemistry by using specific antibodies for the various proteins investigated. Staining results were compared with clinicopathologic data, patient survival, as well as expression of mismatch repair proteins MLH1 and MSH2. Results: The expression pattern of both ATM and BRCA1 predicted survival in all colorectal cancer patients as well as in the small subgroup of patients that received adjuvant therapy. Low expression of ATM and BRCA1 was associated with loss of MLH1 or MSH2 expression. Conclusions: This is the first study to show a relationship between the expression of DNA DSB repair proteins ATM and BRCA1 and survival in colorectal cancer patients. Studies in tumors from large randomized trials are now necessary to validate our pilot data and establish the clinical usefulness of the immunohistochemical assay in predicting response to a particular adjuvant therapy regimen. Furthermore, our results indicate a possible link between expression of DNA mismatch repair and DNA DSB repair proteins in sporadic colorectal cancer, which warrants further investigation.
Topical rectal beclomethasone dipropionate treatment for the prevention of radiation-induced bleeding
Authors: Lorenzo Fuccio, Alessandra Guido
Journal: Gut (2011)

We read with great interest the recently published guideline on the management of gastrointestinal problems after cancer treatment.1 Dr Andreyev and coworkers provide a detailed and highly exhaustive literature review and a very useful practice guidance that will change and substantially improve the current approach to the management of radiation-induced gastrointestinal side effects.

We totally agree that in case of rectal bleeding from radiation-induced telangiectasia after pelvic radiotherapy, application of corticosteroid enemas, although very frequently prescribed, does not provide any beneficial effect.

The development of chronic toxicity is, at least …
Induction of interleukin-8 preserves the angiogenic response in HIF-1α–deficient colon cancer cells
Authors: Yusuke Mizukami, Won-Seok Jo, Eva-Maria Duerr, Manish Gala, Jingnan Li, Xiaobo Zhang, Michael A Zimmer, Othon Iliopoulos, Lawrence R Zukerberg, Yutaka Kohgo, Maureen P Lynch, Bo R Rueda, Daniel C Chung
Journal: Nature Medicine (2005)
Health Changes in Fishermen 2 Years After Clean-up of the Prestige Oil Spill
Authors: Gema Rodríguez-Trigo
Journal: Annals of Internal Medicine (2010)

Background: In 2002, the oil tanker Prestige spilled more than 67 000 tons of bunker oil, heavily contaminating the coast of northwestern Spain. Objective: To assess respiratory effects and chromosomal damage in clean-up workers of the oil spill 2 years after the exposure. Design: Cross-sectional study. Setting: Fishermen cooperatives in coastal villages. Participants: Local fishermen who were highly exposed (n = 501) or not exposed (n = 177) to oil 2 years after the spill. Measurements: Respiratory symptoms; forced spirometry; methacholine challenge; markers of oxidative stress (8-isoprostane), airway inflammation (interleukins, tumor necrosis factor-α, and interferon-γ), and growth factor activity in exhaled breath condensate; and chromosomal lesions and structural alterations in circulating lymphocytes. Results: Compared with nonexposed participants, persons exposed to oil were at increased risk for lower respiratory tract symptoms (risk difference, 8.0 [95% CI, 1.1 to 14.8]). Lung function did not significantly differ between the groups. Among nonsmoking participants, exposed individuals had higher exhaled 8-isoprostane levels than nonexposed individuals (geometric mean ratio, 2.5 [CI, 1.7 to 3.7]), and exposed individuals with lower respiratory tract symptoms had higher 8-isoprostane levels than those of exposed individuals without symptoms. Exposed nonsmoking participants also had higher levels of exhaled vascular endothelial growth factor (risk difference, 44.8 [CI, 27.9 to 61.6]) and basic fibroblast growth factor (risk difference, 16.0 [CI, 3.5 to 28.6]). A higher proportion of exposed participants had structural chromosomal alterations (risk difference, 27.4 [CI, 10.0 to 44.8]), predominantly unbalanced alterations. The risk for elevated levels of exhaled 8-isoprostane, vascular endothelial growth factor, and basic fibroblast growth factor and structural chromosomal alterations seemed to increase with intensity of exposure to clean-up work. Limitations: The clinical significance of exhaled biomarkers and chromosomal findings are uncertain. The association between oil exposure and the observed changes may not be causal. The findings may not apply to spills involving other types of oil or to different populations of oil spill workers. Conclusion: Participation in clean-up of a major oil spill was associated with persistent respiratory symptoms, elevated markers of airway injury in breath condensate, and chromosomal damage. Primary Funding Source: Instituto de Salud Carlos III.
A double‐blind, randomized, parallel, placebo‐controlled study examining the effect of cross‐linked polyelectrolyte in heart failure patients with chronic kidney disease
Authors: Maria Rosa Costanzo, J. Thomas Heywood, Barry M. Massie, Julie Iwashita, Lee Henderson, Merab Mamatsashvili, Hamayak Sisakian, Hamlet Hayrapetyan, Philip Sager, Dirk J. van Veldhuisen, Detlef Albrecht
Journal: European Journal of Heart Failure (2012)
Durability of HBeAg seroconversion following antiviral therapy for chronic hepatitis B: relation to type of therapy and pretreatment serum hepatitis B virus DNA and alanine aminotransferase
Authors: A B van Nunen
Journal: Gut (2003)

<b>Background and aims:</b> Interferon (IFN) induced hepatitis B e antigen (HBeAg) seroconversion is durable in 80–90% of chronic hepatitis B patients. Preliminary reports on the durability of HBeAg seroconversion following lamivudine are contradictory. We investigated the durability of response following IFN, lamivudine, or IFN-lamivudine combination therapy in a meta-analysis of individual patient data. <b>Patients and methods:</b> Twenty four centres included 130 patients in total with an HBeAg seroconversion (HBeAg negative, antibodies to hepatitis B e antigen positive) at the end of antiviral therapy: 59 with lamivudine, 49 with interferon, and 22 with combination therapy. Relapse was defined as confirmed reappearance of HBeAg. <b>Results:</b> The three year cumulative HBeAg relapse rate by the Kaplan-Meier method was 54% for lamivudine, 32% for IFN, and 23% for combination therapy (p=0.01). Cox regression analysis identified pretreatment hepatitis B virus (HBV) DNA, alanine aminotransferase (ALT), sex, and therapy as independent predictive factors of post-treatment relapse; Asian race, previous therapy, centre, and type of study were not predictive of relapse. The relative HBeAg relapse risk of lamivudine compared with IFN therapy was 4.6 and that of combination therapy to IFN therapy 0.7 (p<sub>overall</sub>=0.01). <b>Conclusions:</b> The durability of HBeAg seroconversion following lamivudine treatment was significantly lower than that following IFN or IFN-lamivudine combination therapy. The risk of relapse after HBeAg seroconversion was also related to pretreatment levels of serum ALT and HBV DNA, but independent of Asian race.
A randomised trial comparing 5-FU with 5-FU plus cisplatin in advanced pancreatic carcinoma
Authors: M. Ducreux, P. Rougier, J.-P. Pignon, J.-Y. Douillard, J.-F. Seitz, R. Bugat, J.-F. Bosset, Y. Merouche, J.-L. Raoul, M. Ychou, A. Adenis, F. Berthault-Cvitkovic, M. Luboinski
Journal: Annals of Oncology (2002)
Promoter Hypermethylation Profile of Ovarian Epithelial Neoplasms
Authors: Prakash B. Makarla, M. Hossein Saboorian, Raheela Ashfaq, Kiyomi O. Toyooka, Shinichi Toyooka, John D. Minna, Adi F. Gazdar, John O. Schorge
Journal: Clinical Cancer Research (2005)

Ovarian carcinomas are believed to arise de novo from surface epithelium, but the actual molecular pathogenesis is unknown. The aim of this study was to compare the promoter hypermethylation profiles of ovarian epithelial neoplasms to better understand the role of epigenetic silencing in carcinogenesis.We analyzed the DNA promoter methylation status of eight tumor suppressor and cancer-related genes (p16, RARbeta, E-cadherin,H-cadherin, APC, GSTP1, MGMT, RASSF1A) in 23 benign cystadenomas, 23 low malignant potential (LMP) tumors, and 23 invasive carcinomas by methylation-specific PCR.Benign cystadenomas exhibited promoter hypermethylation in only two genes, p16 (13%) and E-cadherin (13%). LMP tumors also showed p16 (22%) and E-cadherin (17%) methylation, in addition to RARbeta (9%) and H-cadherin (4%). All eight genes were hypermethylated in invasive cancers at a frequency of 9% to 30%. The mean methylation index was highest in invasive tumors [0.20 versus 0.065 (LMP) and 0.033 (cystadenomas); P = 0.001]. Promoter methylation of at least one gene was most commonly observed among invasive cancers [78% versus 44% (LMP; P = 0.03) and 26% (cystadenomas; P = 0.0009)]. Three genes exhibited higher methylation frequencies in invasive tumors: RASSF1A (30% versus 0%; P = 0.0002), H-cadherin (22% versus 2%; P = 0.013), and APC (22% versus 0%; P = 0.003).Promoter hypermethylation is a frequent epigenetic event that occurs most commonly in invasive epithelial ovarian carcinomas. The profile of aberrant methylation suggests that an accumulation of events at specific genes may trigger malignant transformation of some benign cystadenomas and LMP tumors.
Chemoradiotherapy of Locally Advanced Esophageal Cancer
Authors: Jay S. Cooper, Matthew D. Guo, Arnold Herskovic, John S. Macdonald, James A. Martenson, Jr, Muhyi Al-Sarraf, Roger Byhardt, Anthony H. Russell, Jonathan J. Beitler, Sharon Spencer, Sucha O. Asbell, Mary V. Graham, Lawrence L. Leichman
Journal: JAMA (1999)

ContextCarcinoma of the esophagus traditionally has been treated by surgery or radiation therapy (RT), but 5-year overall survival rates have been only 5% to 10%. We previously reported results of a study conducted from January 1986 to April 1990 of combined chemotherapy and RT vs RT alone when an interim analysis revealed significant benefit for combined therapy.ObjectiveTo report the long-term outcomes of a previously reported trial designed to determine if adding chemotherapy during RT improves the survival rate of patients with esophageal carcinoma.DesignRandomized controlled trial conducted 1985 to 1990 with follow-up of at least 5 years, followed by a prospective cohort study conducted between May 1990 and April 1991.SettingMulti-institution participation, ranging from tertiary academic referral centers to general community practices.PatientsPatients had squamous cell or adenocarcinoma of the esophagus, T1-3 N0-1 M0, adequate renal and bone marrow reserve, and a Karnofsky score of at least 50.InterventionsCombined modality therapy (n=134): 50 Gy in 25 fractions over 5 weeks, plus cisplatin intravenously on the first day of weeks 1, 5, 8, and 11, and fluorouracil, 1 g/m2 per day by continuous infusion on the first 4 days of weeks 1, 5, 8, and 11. In the randomized study, combined therapy was compared with RT only (n=62): 64 Gy in 32 fractions over 6.4 weeks.Main Outcome MeasuresOverall survival, patterns of failure, and toxic effects.ResultsCombined therapy significantly increased overall survival compared with RT alone. In the randomized part of the trial, at 5 years of follow-up the overall survival for combined therapy was 26% (95% confidence interval [CI], 15%-37%) compared with 0% following RT. In the succeeding nonrandomized part, combined therapy produced a 5-year overall survival of 14% (95% CI, 6%-23%). Persistence of disease (despite therapy) was the most common mode of treatment failure; however, it was less common in the groups receiving combined therapy (34/130 [26%]) than in the group treated with RT only (23/62 [37%]). Severe acute toxic effects also were greater in the combined therapy groups. There were no significant differences in severe late toxic effects between the groups. However, chemotherapy could be administered as planned in only 89 (68%) of 130 patients (10% had life-threatening toxic effects with combined therapy vs 2% in the RT only group).ConclusionCombined therapy increases the survival of patients who have squamous cell or adenocarcinoma of the esophagus, T1-3 N0-1 M0, compared with RT alone.
L1 Antibodies Block Lymph Node Fibroblastic Reticular Matrix Remodeling In Vivo
Authors: Gino Di Sciullo, Tim Donahue, Melitta Schachner, Steven A. Bogen
Journal: The Journal of Experimental Medicine (1998)

L1 is an immunoglobulin superfamily adhesion molecule highly expressed on neurons and involved in cell motility, neurite outgrowth, axon fasciculation, myelination, and synaptic plasticity. L1 is also expressed by nonneural cells, but its function outside of the nervous system has not been studied extensively. We find that administration of an L1 monoclonal antibody in vivo disrupts the normal remodeling of lymph node reticular matrix during an immune response. Ultrastructural examination reveals that reticular fibroblasts in mice treated with L1 monoclonal antibodies fail to spread and envelop collagen fibers with their cellular processes. The induced defect in the remodeling of the fibroblastic reticular system results in the loss of normal nodal architecture, collapsed cortical sinusoids, and macrophage accumulation in malformed sinuses. Surprisingly, such profound architectural abnormalities have no detectable effects on the primary immune response to protein antigens.
Insulin-Like Growth Factor-1 Receptor Inhibition Induces a Resistance Mechanism via the Epidermal Growth Factor Receptor/HER3/AKT Signaling Pathway: Rational Basis for Cotargeting Insulin-Like Growth Factor-1 Receptor and Epidermal Growth Factor Receptor in Hepatocellular Carcinoma
Authors: Christèle Desbois-Mouthon, Aurore Baron, Marie-José Blivet-Van Eggelpoël, Laetitia Fartoux, Corinne Venot, Friedhelm Bladt, Chantal Housset, Olivier Rosmorduc
Journal: Clinical Cancer Research (2009)

The insulin-like growth factor (IGF) signaling axis is frequently dysregulated in hepatocellular carcinoma (HCC). Therefore, we investigated whether the specific targeting of the IGF type 1 receptor (IGF-1R) might represent a new therapeutic approach for this tumor.Total and phosphorylated levels of IGF-1R were measured in 21 paired samples of human HCCs and adjacent nontumoral livers using ELISA. The antineoplastic potency of a novel anti-IGF-1R antibody, AVE1642, was examined in five human hepatoma cell lines.Overexpression of IGF-1R was detected in 33% of HCCs and increased activation of IGF-1R was observed in 52% of tumors. AVE1642 alone had moderate inhibitory effects on cell viability. However, its combination with gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, induced supra-additive effects in all cell lines that were associated with cell cycle blockage and inhibition of AKT phosphorylation. The combination of AVE1642 with rapamycin also induced a synergistic reduction of viability and of AKT phosphorylation. Of marked interest, AVE1642 alone up-regulated the phosphorylated and total levels of HER3, the main partner of EGFR, and AVE1642-induced phosphorylation of HER3 was prevented by gefitinib. Moreover, the down-regulation of HER3 expression with siRNA reduced AKT phosphorylation and increased cell sensitivity to AVE1642.These findings indicate that hepatoma cells overcome IGF-1R inhibition through HER3 activation in an EGFR-dependent mechanism, and that HER3 represents a critical mediator in acquired resistance to anti-IGF-1R therapy. These results provide a strong rational for targeting simultaneously EGFR and IGF-1R in clinical trials for HCC].
Differentiation of CD3-4-8- human fetal thymocytes in vivo: characterization of a CD3-4+8- intermediate.
Authors: D L Kraft, I L Weissman, E K Waller
Journal: The Journal of Experimental Medicine (1993)

Human thymocyte differentiation was examined by injecting fetal thymic progenitor populations into human thymic xenografts in SCID-hu mice. Thymic progenitors were fluorescently labeled with the lipophilic dye PKH2. The phenotypes of their progeny could be identified by flow cytometric analysis of cells with a very high fluorescent PKH2 signal. Intrathymic injection of purified triple negative (TN) CD3-4-8- thymocytes resulted in the sequential appearance of CD3-4+8-, CD3-4+8+, and CD3+4+8+ cells, with the subsequent appearance of small numbers of phenotypically mature CD3+4+8- and CD3+4-8+ cells over a 4-d period. Sorted CD3-4+8- thymocytes injected intrathymically rapidly differentiated to CD4+8+ cells. CD4+8+ fetal thymocytes in cell cycle differentiated into phenotypically mature CD3+4+8- and CD3+4-8+ populations, whereas nondividing CD4+8+ cells failed to differentiate after intrathymic transfer. The number of cell divisions that occurred between the injection of TN thymocytes and their progeny at different time points was estimated based on the decrease in the intensity of the PKH2 label. The average length of the cell cycle for the TN population was calculated to be 24 h. The SCID-hu model thus provides a useful tool for studying the kinetics of cell division and differentiation of human thymocytes in vivo.
No Long-Term Increase in Sperm Aneuploidy Rates after Anticancer Therapy
Authors: Claire Thomas, Christine Cans, Roberte Pelletier, Christine De Robertis, Mira Hazzouri, Bernard Sele, Sophie Rousseaux, Sylviane Hennebicq
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Lymphomas and testicular cancers are the most frequent malignancies among young men. With recent improvement of survival rates, for many patients, the question is raised of the consequences of the anticancer treatments on their fertility and more specifically of a potential genetic risk for the offspring. This article presents the study of sperm aneuploidy rates in the largest population of cancer-treated patients studied thus far. Experimental Design: In the present study, 38 patients were initially included 7 months to 5 years after a cancer treatment by chemotherapy and/or radiotherapy for testicular cancer (n = 19) or lymphoma (n = 19). Twelve of them were azoospermic. Sperm aneuploidy rates of chromosomes X, Y, 13, 18, and 21 were analyzed by multicolor fluorescent in situ hybridization in the 26 other patients. Results: In most cases, the disomy/diploidy rates after cancer therapy did not significantly differ from those observed in the group of control healthy donors. Only five patients (one lymphoma and four testicular cancer) showed significant but still moderate increases in disomic and/or diploid sperm. For the lymphoma patient, the short posttherapeutic delay after the treatment could explain the elevated aneuploidy rates, whereas no risk factor in the clinical, biological, or therapeutic records could be identified in any of the four testicular cancer patients with elevated sperm aneuploidy rates. Conclusions: These data suggest an absence of long-term effect of anticancer therapy on sperm aneuploidy rates, and therefore, no long-term increased risk of aneuploidy for the offspring obtained either spontaneously or after assisted reproductive techniques.
PRL Tyrosine Phosphatases Regulate Rho Family GTPases to Promote Invasion and Motility
Authors: James J. Fiordalisi, Patricia J. Keller, Adrienne D. Cox
Journal: Cancer Research (2006)

Abstract Phosphatase found in regenerating liver (PRL)-1, PRL-2, and PRL-3 [also known as PTP4A1, PTP4A2, and PTP4A3, respectively] constitute a unique family of putative protein tyrosine phosphatases (PTPs) modified by farnesylation. PRL-3 is amplified and its message is up-regulated in colorectal carcinoma metastases. Its ectopic expression promotes invasive and metastatic properties, supporting a causal link between PRL-3 and late-stage cancer development. However, neither PRL phosphatase substrates nor their signaling pathways have been defined. To address possible mechanisms for the biological activity of PRL-3, we sought to identify its downstream targets, reasoning that regulators of motility and invasion, such as the Rho family of small GTPases, might be logical candidates. We found that levels of active RhoA and RhoC were increased 4- to 7-fold in SW480 colorectal carcinoma cells expressing exogenous PRL-1 and PRL-3, and that PRL-mediated motility and Matrigel invasion were blocked by pharmacologic inhibition of Rho kinase (ROCK), a key Rho effector. In contrast, the activity of Rac was reduced by PRL PTPs, whereas Cdc42 activity was unaffected. PRL-3 stimulated transcription driven by the serum response element in a Rho-dependent manner. We also confirmed that the ability of PRL PTPs to induce invasion and motility is dependent on farnesylation. Catalytic PRL-3 mutants (C104A or D72A) were impaired in PRL-3-induced invasion and Rho activation, indicating that these properties require phosphatase activity. We conclude that PRL PTPs stimulate Rho signaling pathways to promote motility and invasion. Characterization of PRL activity and regulatory pathways should enhance efforts to understand and interfere with PRL-mediated events in invasion and metastasis. (Cancer Res 2006; 66(6): 3153-61)
A Microfluidic Platform for Systems Pathology: Multiparameter Single-Cell Signaling Measurements of Clinical Brain Tumor Specimens
Authors: Jing Sun, Michael D. Masterman-Smith, Nicholas A. Graham, Jing Jiao, Jack Mottahedeh, Dan R. Laks, Minori Ohashi, Jason DeJesus, Ken-ichiro Kamei, Ki-Bum Lee, Hao Wang, Zeta T.F. Yu, Yi-Tsung Lu, Shuang Hou, Keyu Li, Max Liu, Nangang Zhang, Shutao Wang, Brigitte Angenieux, Eduard Panosyan, Eric R. Samuels, Jun Park, Dirk Williams, Vera Konkankit, David Nathanson, R. Michael van Dam, Michael E. Phelps, Hong Wu, Linda M. Liau, Paul S. Mischel, Jorge A. Lazareff, Harley I. Kornblum, William H. Yong, Thomas G. Graeber, Hsian-Rong Tseng
Journal: Cancer Research (2010)

The clinical practice of oncology is being transformed by molecular diagnostics that will enable predictive and personalized medicine. Current technologies for quantitation of the cancer proteome are either qualitative (e.g., immunohistochemistry) or require large sample sizes (e.g., flow cytometry). Here, we report a microfluidic platform-microfluidic image cytometry (MIC)-capable of quantitative, single-cell proteomic analysis of multiple signaling molecules using only 1,000 to 2,800 cells. Using cultured cell lines, we show simultaneous measurement of four critical signaling proteins (EGFR, PTEN, phospho-Akt, and phospho-S6) within the oncogenic phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway. To show the clinical application of the MIC platform to solid tumors, we analyzed a panel of 19 human brain tumor biopsies, including glioblastomas. Our MIC measurements were validated by clinical immunohistochemistry and confirmed the striking intertumoral and intratumoral heterogeneity characteristic of glioblastoma. To interpret the multiparameter, single-cell MIC measurements, we adapted bioinformatic methods including self-organizing maps that stratify patients into clusters that predict tumor progression and patient survival. Together with bioinformatic analysis, the MIC platform represents a robust, enabling in vitro molecular diagnostic technology for systems pathology analysis and personalized medicine.