tbuckley/cabot-search huggingface dataset:
Role of UGT1A1, MTHFR AND TS gene polymorphisms in the prediction of irinotecan (CPT11) and raltitrexed (TOM) gastrointestinal toxicity in pre-treated patients (pts) with metastatic colorectal cancer (CRC)
Authors: C. Massacesi, S. Terrazzino, F. Marcucci, M. B. L. Rocchi, C. Cappelletti, L. Giustini, M. Lombardo, L. Rinaldi, R. Mattioli, M. Bonsignori
Journal: Journal of Clinical Oncology (2004)

2064 Background: In this phase II study we evaluated the association of genetic variants of uridine diphosphate glucuronosyl transferase (UGT1A1), thymidylate synthase (TS) and methylene-tetrahydrofolate reductase (MTHFR) with toxicity following CPT11 and TOM administration, in pre-treated pts with metastatic CRC. Methods: Fifty-six pre-treated pts received CPT11 (80 mg/m2 days 1, 8, 15, 22 q5wks), combined with TOM (3 mg/m2 q3wks). Genotyping for MTHFR C677T polymorphism, TATA box region in UGT1A1 promoter and tandem repeats in TS promoter was assessed on genomic DNA extracted from blood samples. Results: Characteristics of pts were: M/F 29/27; median age 64 (42–78); refractory disease in 32 pts. Previous chemotherapy for advanced disease: Folfox-4, infusional 5FU, Folfiri, bolus 5FU, and TOM/l-OHP in 64%, 30%, 21%, 14%, and 13% of the patients respectively. Genotypic distribution for each polymorphism was in Hardy-Weinberg equilibrium. Pts evaluable for response were 53: PR in 19% of pts, SD in 51% (median duration 4.8 mo), and PD in 30%. NCI-CTC toxicities were evaluated in 154 cycles: G3–4 leuco-neutropenia in 7% of cycles; G2–4 Nausea 19%; G2–4 vomit 10%; G2–4 hepatic 27%; G2–4 diarrhea 17%, G2–3 asthenia 11%. Many variables related to pts, disease and treatment characteristics, together with genotypes, were included in a logistic regression model to evaluate association with main toxicities. Homozygosis for six TA repeats (6/6) in the promoter region of UGT1A1 gene was the main protective factor for diarrhea (p<.00005), emesis (p=.0001), and asthenia (p=.006). Homozygosis for two tandem repeats in TS promoter (2/2) was associated with less incidence of asthenia (p=.04). No differences in toxicity were observed with regard to MTHFR C677T polymorphism. Conclusions: CPT11/TOM regimen has shown acceptable toxicity profile and good antitumor activity in pre-treated metastatic CRC pts. Screening for UGT1A1 promoter polymorphism is clinically useful to identify patients with greater susceptibility to CPT11-induced gastrointestinal toxicity. No significant financial relationships to disclose.
Long-Term T Cell Immune Reconstitution in Patients Surviving 10 or More Years after Allogeneic Stem Cell Transplantation for Hematologic Malignancies
Authors: Quan Le, J. Joseph Melenhorst, Bipin N. Savani, Brenna Hill, Sarfraz Memon, Aarthi Shenoy, Nancy F. Hensel, Elefteria K Koklanaris, Keyvan Keyvanfar, Fran Hakim, Daniel Douek, A. John Barrett
Journal: Blood (2008)
Allogeneic Hematopoietic Stem Cell Transplantation in HIV-Positive Patients with Malignant and Non-Malignant Disorders: A Report from the Center for International Blood and Marrow Transplant Research (CIBMTR).
Authors: Vikas Gupta, Marcie Tomblyn, Tanya Pederson, Jill Thompson, Ron Gress, Jan Storek, Jo-Anne van Burik, Mary Horowitz, Armand Keating
Journal: Blood (2006)
Role of Wnt/β-Catenin Signalling in Acute Myeloid Leukemia (AML) Cell Response to Chemotherapy
Authors: Paul Takam Kamga, Adriana Cassaro, Giada Dal Collo, Annalisa Adamo, Alessandro Gatti, Roberta Carusone, Martina Midolo, Mariano Di Trapani, Federica Resci, Massimiliano Bonifacio, Mauro Krampera
Journal: Blood (2016)
Abstract 1397: Identification of a hepatocellular carcinoma cell line capable of monitoring the differentiation of CD13(+)CD166(-) cancer stem cells and effects of sorafenib
Authors: Takeshi Yamada, Masato Abei, Inaho Danjoh, Ryoko Shirota, Taro Yamashita, Shinji Endo, Ichinosuke Hyodo, Yukio Nakamura
Journal: Cancer Research (2015)

Abstract Background: Recent cancer stem cell (CSC) research has highlighted the necessity to develop drugs targeting CSCs. However, only few in vitro models are available which show CSC hierarchy and allow monitoring of CSC differentiation and screening of drugs targeting CSC. Aim: In the present study, we aimed to identify such hepatocellular carcinoma (HCC) cell line(s). Methods: Based on a hypothesis that the proportion of CSCs would decrease during culture because of their differentiation into progenitors (population switch), we tested the positivity of several markers (CD13, EpCAM, CD133, CD44, CD90, CD24, CD166) in HCC cell lines (HuH-7, Li-7, PLC/PRF/5, HLF, HLE) before and after 2 months culture. Results: Only Li-7 cells showed relevant population switch: the proportion of CD13 decreased, while that of CD166 increased during the culture. High tumorigenicity of Li-7 was lost after the population switch. CD13(+)/CD166(-) cells showed slow growth and reconstructed the bulk Li-7 populations composed of CD13(+)/CD166(-), CD13(-)/CD166(-) and CD13(-)/CD166(+) fractions, while CD13(-)/CD166(+) cells showed rapid growth but could not reproduce any other cell populations. CD13(+)/CD166(-) cells showed high ALDH activity, spheroid forming ability and resistance to 5FU. Microarray analysis demonstrated higher expression of stemness-related genes in CD166(-) than CD166(+) fraction. These results indicated the hierarchy of Li-7 cells, in which CD13(+)/CD166(-) and CD13(-)/CD166(+) cells serve as slow growing CSCs and rapid growing progenitors, respectively. Interestingly, sorafenib selectively targeted CD166(-) fraction including CD13(+) CSCs, which exhibited higher mRNA expression of FGF3 and FGF4, candidate biomarkers for sorafenib. 5-FU followed by sorafenib inhibited the growth of bulk Li-7 cells more effectively than reverse sequence or either alone. Conclusions: We identified an useful cell line Li-7 capable of monitoring the CD13 (+) CSC differentiation and screening the drugs targeting the CSCs of HCC and found that sorafenib preferentially targeted CD13(+) CSCs in vitro. Screening cell lines for “population switch” may be useful to identify novel candidate model systems for screening drugs targeting CSCs. Citation Format: Takeshi Yamada, Masato Abei, Inaho Danjoh, Ryoko Shirota, Taro Yamashita, Shinji Endo, Ichinosuke Hyodo, Yukio Nakamura. Identification of a hepatocellular carcinoma cell line capable of monitoring the differentiation of CD13(+)CD166(-) cancer stem cells and effects of sorafenib. [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 1397. doi:10.1158/1538-7445.AM2015-1397
Effects of Hydroxyurea (HU) and Magnesium Pidolate (Mg) in Hemoglobin SC Disease (HbSC): the “CHAMPS” Trial.
Authors: Winfred C. Wang, Cathie Snyder, Carlo Brugnara, Marilyn J. Telen, Martin H Steinberg, Lynn W Wynn, Julie McAfee, Zora R. Rogers, Karen Kalinyak, Clinton H. Joiner, Karen Kesler
Journal: Blood (2009)
A phase II study (CTONG0803) of erlotinib as second-line treatment in advanced non-small cell lung cancer (NSCLC) patients (pts) with asymptomatic brain metastases (BM) after first-line chemotherapy (CT).
Authors: Y. L. Wu, C. Zhou, Y. Cheng, S. Lu, G. Chen, C. Huang, Y. Huang, H. h. Yan, J. Yang
Journal: Journal of Clinical Oncology (2011)

7605 Background: About 20–30% of all pts with NSCLC develop BM, leading to a poor prognosis and a median survival of <6 months after whole brain radiotherapy. The role of systemic CT in the management of BM is limited and controversial. The CTONG0803 study (NCT00663689) was designed to evaluate 2nd-line erlotinib in NSCLC pts with BM. Methods: Eligible pts had confirmed adenocarcinoma or activating EGFR mutation-positive NSCLC and asymptomatic BM (≥1 lesion of ≥10mm diameter or ≥3 lesions of <10mm); without extracranial progressive disease (PD) after 2–6 cycles of 1st-line platinum-doublet CT; aged 18–75y with ECOG PS of 0–2, and life expectancy >3 months. Pts received erlotinib 150mg/d until radiologically-verified intracranial PD or clinically symptomatic BM. The primary endpoint was PFS (time from starting erlotinib to occurrence of either clinically symptomatic BM or confirmed intracranial PD). Secondary endpoints included ORR, 6-month and 1-year OS rates and safety. Results: From June 2008 to April 2010, 48 pts were enrolled in the study; 1 pt withdrew consent to receive erlotinib after 7 days, without efficacy assessment. Demographics were: median age 56y (range 21–75y); male/female: 19/29; PS 1/2: 18/30; adeno/BAC/other: 45/1/2; no. of BM: ≤3/>3 23/25; non-smoker/smoker/unknown: 38/8/1. As of December 2010, 26 pts had intracranial PD; 16 pts had non-PD and continued on erlotinib; and 5 pts stopped erlotinib due to extracranial PD. Median PFS was 10.1 months (95% CI 8.97–13.966) overall; for pts with ≤3 or >3 BM, median PFS was 10.2 and 8.3 months, respectively (p=0.35). ORR considered both intracranial and extracranial lesions: 2 pts (4.2%) had a CR and 25 (52.1%) had a PR, giving an ORR of 56.3%. Six-month and 1-year OS rates were 87% and 74%, respectively. Adverse events (AEs) occurred in 72.9% (35/48) of pts; 7.3% of AEs were grade 3/4 and no SAEs have been reported to date. The most common AE was rash (64.6%). No unexpected AEs or ILD-like events were reported. Conclusions: Erlotinib as monotherapy after 1st-line CT for NSCLC pts with asymptomatic BM has promising efficacy and is well tolerated.
Patient-Level Discordance in Population Percentiles of the Total Cholesterol to High-Density Lipoprotein Cholesterol Ratio in Comparison With Low-Density Lipoprotein Cholesterol and Non–High-Density Lipoprotein Cholesterol
Authors: Mohamed B. Elshazly, Renato Quispe, Erin D. Michos, Allan D. Sniderman, Peter P. Toth, Maciej Banach, Krishnaji R. Kulkarni, Josef Coresh, Roger S. Blumenthal, Steven R. Jones, Seth S. Martin
Journal: Circulation (2015)

The total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C) ratio, estimated low-density lipoprotein cholesterol (LDL-C), and non-HDL-C are routinely available from the standard lipid profile. We aimed to assess the extent of patient-level discordance of TC/HDL-C with LDL-C and non-HDL-C, because discordance suggests the possibility of additional information.
Hedgehog Inhibitors Reduce the Survival and Drug Resistance in CD34+ Leukemic Cells.
Authors: Masayoshi Kobune, Kazuyuki Murase, Satoshi Iyama, Tsutomu Sato, Yutaka Kawano, Shohei Kikuchi, Koji Miyanishi, Rishu Takimoto, Junji Kato
Journal: Blood (2008)
592. A Comparison of Length on the Potency and Toxicity of Small Interfering and Short Hairpin RNAs Targeting a Highly Conserved Site in HIV-1 RNA Coding for the Gag Polyprotein
Authors: Robert J. Scarborough, Kelsey Adams, Aicha Daher, Anne Gatignol
Journal: Molecular Therapy (2015)

Small interfering RNAs (siRNAs) and their precursors, short hairpin RNAs (shRNAs), are being developed for the treatment of HIV-1 infection as drug and gene therapies, respectively. We have previously identified a target site in HIV-1 RNA coding for the Gag polyprotein that was highly conserved across diverse HIV-1 genomes and particularly accessible to a ribozyme. An shRNA targeting this site was also shown to be a potent inhibitor of HIV-1 production from diverse strains. Several studies have shown that the gene silencing effects of siRNAs and shRNAs are highly dependent on their lengths. While optimal lengths have been proposed, conflicting results suggest that empirical data is required to identify the best format for any particular target site. Using the target site identified in our previous study, we designed siRNAs and shRNAs with different lengths to identify the optimal therapeutic format for further development. Symmetrical and asymmetrical siRNAs, with intended sense-strand lengths of 17 to 29 bases, showed a similar trend in potency against HIV-1 production and the most effective molecules had sense-strand lengths of 27 and 29 bases. In contrast, shRNAs with stem lengths of 20 and 21 base pairs were most effective, with a gradual decrease in potency as the stem length was increased to 29 base pairs. To compare potential immune stimulation and toxicity of the different siRNAs designed, cellular proliferation and phosphorylation of protein kinase R (PKR) were evaluated in HEK293T and MCF7 cells. While phosphorylation of PKR was not detected, minor effects on cell proliferation were observed for some siRNAs at concentrations several fold higher compared to their minimum inhibitory concentrations against HIV-1 production in HEK293T cells. Our results are consistent with reports suggesting that longer siRNAs are more potent compared to their sequence matched canonical formats; however, a standard longer siRNA format, with a 25 base pair sense-strand, was not long enough to observe an increase in potency over canonical formats. Our results also suggest that for certain target sites, there is no correlation between the optimal length of siRNAs and shRNAs. Overall, our results highlight the importance of obtaining empirical data on the optimal si/shRNA format for any particular target site, and provide a set of optimized molecules targeting the Gag coding sequence of HIV-1 RNA for further development.
87. Rationally Designed Inverted Terminal Repeats Enhance Transduction of Embryonic Stem Cells
Authors: Nolan Brown, Matthew Hirsch
Journal: Molecular Therapy (2016)

Despite the prevalence of AAV vectors in gene therapy, treatments combining AAV vectors and cell therapy have not progressed into the clinic despite previous reports of successful transduction of stem cells by AAV vectors. One potential explanation is AAV vector toxicity in stem and stem-like cells, as demonstrated in previous studies. In particular, the AAV inverted terminal repeat (ITR) sequence was shown to induce apoptosis in human embryonic stem cells (hESCs) in a p53 dependent manner. A bioinformatic analysis of putative transcription factor binding sites in the AAV2 ITR sequence revealed six putative p53 binding sites. A panel of rationally designed AAV2 ITRs was generated which abrogated putative p53 binding sites and demonstrated reduced p53 binding in an in vitro binding assay. The synthetic ITRs were capable of all of the vector production requirements and were verified by sequencing directly from vector preparations. AAV vector transduction and the hESC DNA damage response was altered by the synthetic ITRs. Importantly, our ITRs demonstrated reduced toxicity in hESCs compared to an AAV vector having the AAV2 ITR sequence. The collective results allude to modulation of the host's DNA damage response using rationally designed ITRs, which may enhance the relevancy of AAV vectors in stem cell therapies.
Bortezomib-Thalidomide-Dexamethasone as Primary Induction Therapy for Newly Diagnosed Multiple Myeloma Significantly Decreases Bone Resorption While Sparing Bone Formation as Compared to Thalidomide-Dexamethasone
Authors: Patrizia Tosi, Elena Zamagni, Paola Tacchetti, Giulia Perrone, Michela Ceccolini, Anna Maria Brioli, Maria Caterina Pallotti, Lucia Pantani, Alessandro Petrucci, Michele Baccarani, Michele Cavo
Journal: Blood (2008)
New version of the Epidemic Intelligence Information System for food- and waterborne diseases and zoonoses (EPIS-FWD) launched
Authors: Celine M Gossner
Journal: Eurosurveillance (2016)

Preview this article: New version of the Epidemic Intelligence Information System for food- and waterborne diseases and zoonoses (EPIS-FWD) launched, Page 1 of 1 < Previous page | Next page > /docserver/preview/fulltext/eurosurveillance/21/49/eurosurv-21-30422-4-1.gif
FTY720 Demonstrates Promising in-Vitro and in-Vivo Pre-Clinical Activity by Down-Modulation of Cyclin D1 and Pakt in Mantle Cell Lymphoma.
Authors: Lapo Alinari, Qing Liu, Ching-Shih Chen, Fengting Yan, James T Dalton, Rosa Lapalombella, Xiaoli Zhang, Teresa Lin, John C. Byrd, Robert A. Baiocchi, Natarajan Muthusamy
Journal: Blood (2009)
Role of Survivin in Drug Resistant B-Cell Acute Lymphoblastic Leukemia.
Authors: Eugene Park, Enzi Jiang, Gregor von Levetzow, Cihangir Duy, Lars Klemm, Yao-Te Hsieh, Asha Kadavallore, Hong Ma, Yi Zhao, Cu Nguyen, John Groffen, Nora Heisterkamp, Markus Muschen, Michael Kahn, Yong-Mi Kim
Journal: Blood (2009)
Abstract 446: Reciprocal paracrine signaling between epithelial and stromal cells alters the pancreatic tumor microenvironment
Authors: Matthew C. Stout, Danielle R. Cole, Paul M. Campbell
Journal: Cancer Research (2015)

Abstract Despite considerable clinical and basic research efforts, the 5-year survival rate of pancreatic ductal adenocarcinoma (PDAC) remains a dismal 6 percent in the United States. Much of the mortality of the disease is a result, in part, of the unique microenvironment of PDAC tumors. The stroma, a heterogeneous population including fibroblasts, immune cells, vasculature and extracellular matrix, comprises the bulk of the PDAC tumor volume. We and others hypothesize that disparate cell populations within this tumor microenvironment are receptive to paracrine signaling from one another to drive tumor survival and metastatic progression. Previous work has shown that the ELR+ CXC-chemokines and their CXCR2 receptor are upregulated in PDAC and can promote tumor-associated phenotypes such as angiogenesis. Our current research seeks to demonstrate that the ubiquitous PDAC oncogene, K-Ras, affects additional elements of the tumor microenvironment through paracrine CXCR2 chemokine signaling. In particular, we are interested on the interdependence of proliferation, migration, senescence, survival and death between fibroblasts and pancreatic epithelial cells. We show that activated epithelial K-Ras increases CXCL release and CXCR2 expression, but remarkably, paracrine signals from PDAC cells decrease the number of fibroblasts. These data suggest potentially both pro and antitumor effects of paracrine signaling in pancreatic cancer. Experiments are ongoing to further investigate how CXC chemokines modulate the tumor microenvironment in order to reveal novel therapeutic targets and diagnostic biomarkers. Citation Format: Matthew C. Stout, Danielle R. Cole, Paul M. Campbell. Reciprocal paracrine signaling between epithelial and stromal cells alters the pancreatic tumor microenvironment. [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 446. doi:10.1158/1538-7445.AM2015-446
Trends in Utilization and Outcomes of Autologous Hematopoietic Cell Transplantation (AHCT) in the Upfront Management of Patients with Multiple Myeloma: A Cibmtr Analysis
Authors: Luciano J. Costa, Xiaobo Zhong, Mei-Jie Zhang, Sagar Lonial, Amrita Krishnan, Angela Dispenzieri, Parameswaran Hari
Journal: Blood (2012)
Abstract 2267: Defining roles of SIN3 isoforms in breast cancer metastasis
Authors: Monica J. Lewis, Jianzhong Liu, Douglas R. Hurst
Journal: Cancer Research (2015)

Abstract Metastasis continues to be the most difficult clinical challenge for breast cancer. These patients have unacceptable survival rates that have not changed in the past 20 years. Therefore, more effective therapeutic options are needed. The purpose of this study is to better understand molecular mechanisms of the SIN3 chromatin complexes that have been functionally associated with breast cancer progression to identify novel targeting strategies. Alteration of the composition of SIN3 complexes regulates the metastatic potential of breast cancer cells; and inhibition of SIN3 complexes induces differentiation and inhibits invasion of breast cancer cells. However, differences in the function of SIN3 isoforms (SIN3A and SIN3B) in breast cancer metastasis have not been characterized. To better define the role of SIN3 isoforms in breast cancer metastasis, we generated stable knockdown of SIN3 isoforms individually and in combination using 3 non-overlapping shRNA in two different metastatic breast cancer cell lines (MDA-MB-231 and -435). No significant change was noted in the proliferation rate of the transduced cells in vitro. Stable knockdown of SIN3B caused a significant decrease in invasion through Matrigel (28 ± 4 invaded cells/field compared to 50 ± 8 for control; p = 0.027) using a modified Boyden chamber that was corroborated by the decreased presence of stellate projections and a more epithelial phenotypic growth in 3D. Surprisingly, stable knockdown of SIN3A significantly increased invasion through Matrigel (98 ± 14 invaded cells/field; p = 0.008) and increased the presence of stellate projections in the 3D growth assay. Dual knockdown of SIN3A and SIN3B caused a significant decrease in invasiveness (19 ± 5 invaded cells/field; p = 0.003) and decreased presence of stellate projections similar to the phenotype noted with individual knockdown of SIN3B. These results were confirmed in vivo with an experimental metastasis assay (lateral tail vein injection in athymic nude mice) in which SIN3B knockdown significantly decreased lung metastasis (70% decrease compared to control; p = 0.009) and SIN3A knockdown increased metastasis (163% increase compared to control; p = 0.096). These results demonstrate key functional differences between SIN3 isoforms in regulating the process of metastasis. Our data suggests metastasis suppressive roles of SIN3A and metastasis promoting roles of SIN3B that will be important in discovering novel therapeutic strategies for metastatic breast cancer patients. Citation Format: Monica J. Lewis, Jianzhong Liu, Douglas R. Hurst. Defining roles of SIN3 isoforms in breast cancer metastasis. [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 2267. doi:10.1158/1538-7445.AM2015-2267
C/EBPβ Promotes Initial Expansion and Exhaustion of Hematopoietic Stem and Progenitor Cells in Response to Hematopoietic Stresses
Authors: Atsushi Sato, Hideyo Hirai, Akihiro Tamura, Asumi Yokota, Yoshihiro Hayashi, Hisayuki Yao, Masaki Iwasa, Aya Fujishiro, Eishi Ashihara, Yasuo Miura, Taira Maekawa
Journal: Blood (2014)
The Entire Primary Sequence of Factor VIII Is Synthesized As Two Polypeptide Chains in Hemophilia A Patients with the Intron-22-Inversion
Authors: Gouri Shankar Pandey, Susan Garfield, Joanne E Curran, Eric K. Moses, Chava Kimchi-Sarfaty, Chen Yanover, Tom E. Howard, Zuben E. Sauna
Journal: Blood (2011)