tbuckley/cabot-search huggingface dataset:
Racial differences in breast cancer risk to relatives of cases in the women's contraceptive and reproductive experiences (CARE) study
Authors: M. S. Simon, J. F. Korczak, C. L. Yee, A. G. Schwartz
Journal: Journal of Clinical Oncology (2004)

9514 Background: Family history of breast cancer (BRCA) is a well-recognized risk factor for the disease, suggesting a role for genes, shared environment and/or cultural factors. Familial aggregation studies based primarily on Caucasian (CAU) women have given rise to age-specific and lifetime BRCA risk estimates, but less information is available on comparable risks for African American (AA) women. Methods: We used the family cancer history collected from CAU and AA participants with BRCA (cases) in the National Institute of Child Health and Human Development Women's CARE Study to compare the age-specific BRCA rates in their first-degree relatives (FDR). Kaplan-Meier cumulative hazard curves were obtained for FDR of CARE cases using PROC LIFETEST (SAS version 8.2). Analyses were pooled over all ages at diagnosis and stratified by age at diagnosis (< 45 vs. = 45) and race. Results: Age-specific risks (and standard errors) of BRCA to FDR of CARE cases, by race and age at BRCA diagnosis in the case, are presented in the table. By 40 years of age, BRCA risk to FDR is greater in AA than CAU, with the greatest risk, .023, in FDR of AA cases diagnosed by 45 years of age. By 70 years of age, BRCA risk to FDR is greater in CAU than AA, with the greatest risk, 0.16, in FDR of CAU cases diagnosed by 45 years of age. Conclusions: These results illustrate racial differences in age-specific BRCA risk and provide a recent update of these risks for both CAU and AA women that can be utilized in the clinical setting. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration National Institute of Child Health and Human Development; National Cancer Institute; Emory University; Fred Hutchinson Cancer Research Center; Karmanos Cancer Institute at Wayne State University; University of Pennsylvania; University of Southern California; Centers for Disease Control and Prevention; The Barbara Ann Karmanos Cancer Institute; United Foundation of Detroit; Michigan Health Care Education and Research Foundation
Abstract 4753: An effective detection method for the EGFR single mutation T790M using BNA-NC clamping real-time PCR
Authors: Sung-Kun Kim, Xiaoyun Liu, Aaron Castro, Leticia Loredo, Miguel Castro
Journal: Cancer Research (2015)

Abstract Mutations on epidermal growth factor receptor (EGFR) cause a variety of cancers including breast and lung cancers. The single mutation T790M on tyrosine kinase domain of EGFR signifies the response to the popular cancer drug gefitinib, which leads to the development of resistance to gefitinib. Detecting the mutation thus guide effective therapeutical options for patients who are in need of cancer drug treatments. We sought to develop a rapid, reliable detection method for the T790M mutation using bridged nucleic acids (BNA), which has been known to enhance the hybridization affinity of oligonucleotides that contain BNA bases. Oligonucleotides containing BNA bases designed to block PCR reaction against wild-type genes, called BNA-clamp, were used to discriminate the presence of mutant genes mixed with a large number of wild-type genes. Real-time PCR in conjugation with BNA-clamping allows us to view the different levels of PCR amplifications in the degree of mixture of wild-type and mutant genes. In an effort to explore this possibility, 13mer long clamps were prepared with various numbers of BNA bases. The clamps containing 9 BNA bases appear to be most effective in blocking the PCR reactions at an optimized concentration to distinguish the mutant from the wild-type genes. In addition to PCR results, the difference in the Tm values for the 7 BNA bases in the 13mer was the largest among differently designed clamps, which is consistent with the results obtained by real-time PCR. We also examined the degree of sensitivity using the clamp containing 9 BNA bases, revealing that the clamp has the ability to determine the level of mutation as low as 1% mixture of the mutant and wild-type gene. The effectiveness of blocking the PCR reaction with only 13mers containing BNA bases allowed us to detect a single mutation, and thus, this BNA-clamping real time PCR technology may offer a promising, new avenue to detect clinically important mutations in the future. Citation Format: Sung-Kun Kim, Xiaoyun Liu, Aaron Castro, Leticia Loredo, Miguel Castro. An effective detection method for the EGFR single mutation T790M using BNA-NC clamping real-time PCR. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4753. doi:10.1158/1538-7445.AM2015-4753
292. Lentivirus Vector Mediated Gene Correction in Artemis-Deficient Severe Combined Immunodeficiency
Authors: Divya Punwani, Misako Stillion, Jason Yu, Harry L. Malech, Denise Carbonaro, Donald B. Kohn, Scott McIvor, Jennifer M. Puck, Morton J. Cowan
Journal: Molecular Therapy (2015)

Mutations in DCLRE1C/Artemis, a DNA repair gene, cause T-B-NK+ SCID by preventing V(D)J recombination in T and B cell progenitors and also confer heightened sensitivity to irradiation and alkylator chemotherapy. SCID newborn screening identifies Artemis-deficient SCID (ART-SCID) early in life and while allogeneic hematopoietic cell transplantation can cure ART-SCID, preparative regimens for conditioning are poorly tolerated. Without alkylating chemotherapy patients may have graft failure while toxic effects of chemotherapy include increased mortality, short stature and abnormal dental development. Thus, building on experience with X-linked and ADA deficient SCID, we found addition of a normal Artemis gene to hematopoietic stem cells (HSC) an attractive strategy to treat ART-SCID. Since overexpression of Artemis protein causes cellular cytotoxicity, a lentivirus vector with human Artemis cDNA and its endogenous promoter (Apro-hART) was produced and used to transduce fibroblasts from ART-SCID patients and controls. Apro-hART transduced ART-SCID fibroblasts showed correction of radiosensitivity by enumeration of foci of DNA damage and proliferation assays. Radiosensitivity of cells lacking the DNA repair enzyme Ligase-4 was not corrected. Mobilized peripheral blood CD34+ cells from an ART-SCID patient, incapable of differentiation into T and B cells, were transduced with Apro-hART or GFP lentivirus and cultured on OP9 cells or injected into irradiated newborn NSG mice. OP9 cocultures and blood and spleen cells from NSG mice showed that Apro-hART-corrected, but not GFP-transduced, ART-SCID CD34+ cells differentiated into B cells and T and B cells, respectively, as did GFP-transduced control CD34+ cells. Lymphocyte maturation was proven by lineage specific surface markers and measures of V(D)J diversity and recombination, T cell receptor Vbeta spectratyping and Kappa chain receptor excision circles (KRECs), respectively. Colony forming assays with transduced cells revealed transduction efficiency of 28.6%, a mean vector copy number of 3/cell and a diverse profile of lentivirus integration sites. This successful gene correction and restoration of Artemis function in fibroblasts and HSCs from ART-SCID patients supports institution of a clinical trial of gene addition therapy for ART-SCID.
703. Liver-Directed Gene Therapy for Primary Hyperoxaluria Type 1
Authors: Raffaele Castello, Roberta Borzone, Patrizia Annunziata, Pasquale Piccolo, Nicola Brunetti-Pierri
Journal: Molecular Therapy (2015)

Primary hyperoxaluria type 1 (PH1) is an inborn error of liver metabolism due to deficiency of peroxisomal enzyme alanine:glyoxylate-aminotransferase (AGT) which catalyzes the conversion of glyoxylate to glycine. In PH1 patients, glyoxylate cannot be converted into glycine and is oxidized to oxalate resulting in hyperoxaluria. The excess of oxalate causes deposition of insoluble calcium oxalate in the kidney and other tissues leading to nephrolithiasis, nephrocalcinosis, kidney failure, and systemic tissue damage. Combined liver/kidney transplantation is the only available therapeutic strategy for disease treatment. Gene therapy is an attractive option to provide a definitive cure for PH1. Towards this goal, we investigated helper-dependent adenoviral (HDAd) vectors for liver-directed gene therapy of PH1. We injected PH1 mice with an HDAd encoding AGT under the control of a liver-specific promoter and observed normalization of urinary oxalate at the doses of 5×10e12 and 1×10e13 vector particles (vp)/kg and partial correction with 1×10e12 vp/kg. Following challenge with Ethylene Glycol (EG), a precursor of glyoxylate, we observed reduced elevations of urinary oxalate in HDAd-injected mice compared to saline controls. Next, we hypothesized that overexpression of glyoxylate reductase/hydroxypyruvate reductase (GRHPR) or glutamate-pyruvate transaminase (GPT) results in reduction of hyperoxaluria in PH1 by steering glyoxylate towards glycolate synthesis or transamination, respectively. To test this hypothesis, we injected PH1 mice with HDAd vectors expressing GRHPR or GPT. Both vectors resulted in significant reduction of hyperoxaluria and co-injection of the two vectors resulted in long-term normalization of oxalate excretion. Therefore, metabolic diversion towards non-toxic metabolites has potential for treatment of hyperoxaluria and vector-mediated GRHPR and/or GPT overexpression may be an alternative or adjunctive strategy to enhance efficiency of gene replacement therapy for PH1. We have recently developed a minimally invasive method to improve the therapeutic index of HDAd based on balloon occlusion catheter to achieve preferential delivery of the vector to the liver (Brunetti-Pierri et al., 2009 and 2012). This method may permit in humans correction of PH1 using clinically relevant lower doses of HDAd. Based on risk:benefit assessment, PH1 is an attractive disease for clinical application of this method.
High Frequency of Familial Hemophagocytic Lymphocytosis Associated Immune Gene Defects In Refractory Viral Infection of Unknown Origin
Authors: Chunrong Tong, Hongxing Liu, Jianjun Xie, Hui Wang, Xian Zhang, Fang Wang, Juan Zhu, Wen Teng, Jiangying Gu, Yali Zhang, Wenjun Ling, Tong Wu, Dao-Pei Lu
Journal: Blood (2010)
Abstract 4168: Robo1 promotes angiogenesis through CDC42/Rho GTPases signaling pathway in hepatocellular carcinoma
Authors: Hui-Chuan Sun, Jian-Yang Ao, Zong-Tao Chai, Yuan-Yuan Zhang
Journal: Cancer Research (2015)

Abstract Angiogenesis is essential for cancer growth and metastasis. Since present anti-angiogenesis strategies could not fulfill the expected clinical efficacy in hepatocellular carcinoma (HCC), novel key regulatory molecules involving this process are still under investigation. It has been reported that the axon guidance receptor gene Robo1 is involved in tumor angiogenesis. Here, we report the function of Robo1 in human umbilical vein endothelial cells (HUVEC) as well as the hepatocellular carcinoma endothelial cells. High Robo1 expression in the tumor vessels associated with a poor survival in patients. Over-expression of Robo1 in HUVEC cell lines results in increased proliferation, migration and tube formation in HUVECs. These changes could be reversed by knockdown of Robo1. Moreover, we show that Robo1 expression promoted CDC42 and Rho expression in HUVEC. We demonstrated that Robo1/CDC42/Rho signaling axis in HUVECs, which is important for function of HUVECs. Taken together, our results showed that Robo1 promoted angiogenesis in hepatocellular carcinoma and provide new target for anti-angiogenesis therapy in HCC Note: This abstract was not presented at the meeting. Citation Format: Hui-Chuan Sun, Jian-Yang Ao, Zong-Tao Chai, Yuan-Yuan Zhang. Robo1 promotes angiogenesis through CDC42/Rho GTPases signaling pathway in hepatocellular carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4168. doi:10.1158/1538-7445.AM2015-4168
Influence of Single Nucleotide Polymorphisms in Anthracycline Metabolism Pathway in Standard Induction of Acute Myeloid Leukemia
Authors: Juan Eduardo Megías, Pau Montesinos, María José Herrero, Federico Moscardó, Virginia Bosó, David Martínez-Cuadrón, Luis Rojas, Rebeca Rodríguez-Veiga, Blanca Boluda, Jesús Martínez, Jaime Sanz, Francisca López, Isabel Cano, Aima Lancharro, Jose Cervera, David Hervás, José Luis Poveda, Salvador F Aliño, Miguel Ángel Sanz
Journal: Blood (2015)
Identification of a Thrombin-Interactive Site within Factor VIII A2 Domain Responsible for the Cleavage at Arg372.
Authors: Keiji Nogami, Midori Shima, Evgueni L. Saenko, Masahiro Takeyama, Kohei Tatsumi, Yuri Fujita, Ichiro Tanaka, Akira Yoshioka
Journal: Blood (2006)
PTH-078 Safety and efficacy of a nurse-led hepatitis C service in a district general hospital
Authors: V Mitra, A Soloman, T Cocksedge, K Kapur
Journal: Gut (2010)

<h3>Introduction</h3> In England and Wales, approximately 200 000–500 000 people are infected with hepatitis C virus (HCV).1 In 2005, a survey carried out by the department of health revealed a relatively low uptake of HCV treatment. Traditionally, patients diagnosed with HCV infection have been managed in the tertiary centres. However, with the recognised increasing load of HCV infection in the UK, there has been a trend towards setting up of specialist nurse-led hepatitis C clinics in the district general hospitals. <h3>Methods</h3> A specialist nurse-led hepatitis C clinic was established in Barnsley hospital in November 2008. The aim of this service was to streamline the care of patients diagnosed with HCV infection ensuring a quick and efficient route to diagnosis and treatment. After the confirmation of active HCV infection, patients are assessed in the nurse-led clinic with a detail history, examination, psychological assessment and relevant investigations. Once they are deemed suitable to undergo treatment by a consultant gastroenterologist, patients are counselled by the nurse and treatment is initiated. Follow-ups are arranged in the review clinic in line with NICE guidelines. 43 patients have been initiated on treatment for HCV infection between November 2008 and November 2009 in this clinic. The aim of our audit was to assess the safety and efficacy of this nurse-led service. <h3>Results</h3> Of the 43 patients (mean age 35 years), 62.7% are males and 37.3% are females. Incidence of different HCV genotypes are as follows – 1a (18.6%), 1b (7%), 2b (18.6%), 3a (53.5%) and 4a (2.5%). All the 12 patients belonging to the type 1 or 4 genotype had a 2 log drop in their viral load at 12 weeks and are currently on course for completing 48 weeks of treatment. Of the 31 patients belonging to the type 2b/3a genotype, 20 have completed 24 weeks of treatment (18 patients had an end of treatment viral count of zero and 2 patients did not attend to have their bloods checked. All are currently waiting to have their 6-month post treatment viral load checked), 9 are undergoing treatment, 1 dropped out of treatment and treatment was stopped in one patient because of development of decompensated liver disease. Five patients developed dyspnoea and anaemia which required a dose reduction of ribavirin initially and increased to the usual dose subsequently. Of these, three required blood transfusion. There has been no major morbidity or mortality. <h3>Conclusion</h3> The nurse-led clinic has been a safe and effective way to streamline the management of patients with HCV infection. Patients have been highly satisfied with this locally available service and appreciate the continuity of care provided by the specialist nurse. This has led to increased uptake of HCV treatment locally and reduction in the number of patients referred to the local tertiary unit.
Abstract 5179: An endothelial-mesenchymal transition of brain endothelial cells is required for metastatic extravasation
Authors: Istvan A. Krizbai, Akos Gasparics, Peter Nagyoszi, Csilla Fazakas, Imola Wilhelm, Rita Bencs, Laszlo Rosivall, Attila Sebe
Journal: Cancer Research (2015)

Abstract Endothelial-mesenchymal transition (EndMT) is an embryonic program necessary for organ development. Despite being normally dormant in adult organisms, this mechanism can be reactivated during several pathological conditions, such as cancer and fibrosis. EndMT is characterized by the downregulation of the endothelial program, activation of the mesenchymal-fibrogenic program, and finally the activation of the myogenic program. Cancer progression towards metastasis follows a defined sequence of events described as the metastatic cascade. For extravasation and transendothelial migration metastatic cells interact first with endothelial cells. Yet the role of endothelial cells during the process of metastasis formation and extravasation is still unclear, and the interaction between metastatic and endothelial cells during transendothelial migration is poorly understood. Since tumor cells are well known to express TGF-β, and the compact endothelial layer undergoes a series of changes during metastatic extravasation (cell contact disruption, cytoskeletal reorganization, contractility), we hypothesized that an EndMT may be necessary for metastatic extravasation. We show that primary rat brain endothelial cells (BECs) undergo EndMT upon TGF-β1 treatment, characterized by the loss of tight and adherent junction proteins, the expression of fibronectin, β1-integrin, calponin and α-smooth muscle actin (SMA), and an increase in N-cadherin levels. B16/F10 activated conditioned medium (ACM) induced claudin-5 downregulation, fibronectin and SMA expression in BECs. Inhibition of TGF-β signaling during B16/F10 ACM stimulation using SB-431542 maintained claudin-5 levels and mitigated fibronectin and SMA expression. SB-431542 prevented SMA upregulation upon stimulation of BECs with A2058, MCF-7 and MDA-MB231 ACM. Moreover, B16/F10 ACM caused a reduction in transdendothelial electrical resistance and enhanced the number of melanoma cells adhering to the endothelial layer, both in a TGF- β dependent manner. Finally, pretreatment with TGF-β1 or B16/F10 ACM enhanced transendothelial migration of B16/F10 cells. Our results indicate that an EndMT may be necessary for metastatic transendothelial migration, and may play a relevant role during the complex phenomenon known as metastatic extravasation. Citation Format: Istvan A. Krizbai, Akos Gasparics, Peter Nagyoszi, Csilla Fazakas, Imola Wilhelm, Rita Bencs, Laszlo Rosivall, Attila Sebe. An endothelial-mesenchymal transition of brain endothelial cells is required for metastatic extravasation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5179. doi:10.1158/1538-7445.AM2015-5179
Does circulating tumor necrosis factor (TNF) play a role in post-chemotherapy cerebral dysfunction in breast cancer survivors (BCS)?.
Authors: P. A. Ganz, S. A. Castellon, D. H. S. Silverman, L. Kwan, J. E. Bower, M. R. Irwin, S. W. Cole
Journal: Journal of Clinical Oncology (2011)

9008 Background: Cognitive complaints (CC) are common in BCS, and are associated with adjuvant chemotherapy (CTx). The biology of these symptoms is poorly understood, enduring in 25% of BCS. We tested the hypothesis that CTx-induced alterations in TNF inflammatory signaling might underlie observed cerebral dysfunction. Methods: We enrolled 93 BCS in a prospective observational study within 1 month of completing primary treatment (surgery, radiation, chemotherapy), prior to initiating endocrine therapy. At entry, 6 and 12 months later, BCS completed self-report measures of CC and a 2 hr neuropsychological (NP) battery and had blood drawn for markers of proinflammatory cytokine activity: IL-6, IL-1 receptor antagonist, soluble TNF receptor type 2 (sTNFr2), and C reactive protein. A subset of BCS (n=14) had brain FDG-PET scans at entry and 12 mos. Multivariate models and ANOVA were used to examine relationships of cytokine activity with CC and CTx, controlling for covariates. Results: 53% of BCS sample had received CTx. At entry, sTNFr2 was the only cytokine measure that was significantly elevated in CTx patients compared with non-CTx (p=0.005), and its level declined significantly by 12 months to a level similar to non CTx group (p = 0.003). CTx was also associated with increased CC at entry (p=0.05), controlling for time since CTx, age, IQ and BMI. CC were significantly associated with sTNFr2 (p=0.05) at entry. Entry CC predicted subsequent NP test abnormalities at 6 months. PET scan substudy showed: among CTx patients, higher levels of sTNFr2 correlated with lower levels of baseline metabolism in left inferior frontal gyrus, including Broca’s area (p=0.002). Entry sTNFr2 levels correlated with increases over 1 year in Broca’s area for the CTx group (r=0.75, p=0.02), suggesting greater recovery of function in this area. Conclusions: Relationships between sTNFr2 and CC and brain metabolism in BCS are consistent with animal studies that show increased peripheral and brain TNF after CTx, and suggest CTx-induced TNF might represent a biological target for pharmacologic remediation of “chemobrain.” Funding: NCI R01 CA 109650 and the BCRF.
BEAM-Campath Allogeneic Stem Cell Transplantation for Aggressive Non-Hodgkin's Lymphomas. An Analysis of Outcomes From the BSBMT
Authors: Stephen Robinson, Christopher P Fox, Rachel M Pearce, Julia Perry, Keiren Kirkland, Charles F. Craddock, Nigel H Russell, Grant McQuaker, Antonio Pagliuca, Peter R. E. Johnson, Gordon Cook
Journal: Blood (2012)