bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B31: Pharmacogenetics and pharmacoepigenetics of childhood acute lymphoblastic leukemia
Authors: Lopez-Lopez Elixabet , Martin-Guerrero Idoia , Ballesteros Javier , Uriz Javier , de Andoin Nagore Garcia , Piñan M. Angeles , Garcia-Miguel Pura , Navajas Aurora , Garcia-Orad Africa 
Published: January 2011

Abstract
Acute lymphoblastic leukaemia (ALL) is the most common childhood cancer, and still an important cause of cancer-related death in children. Although the introduction of treatment protocols has improved survival, inter-individual differences in drug responses are an important cause of resistance to treatment and adverse drug reactions. These differences can be due to different factors, including genetic polymorphisms and epigenetic variations.
The aim of the present study was to determine if there was a correlation between genetic and epigenetic variation and toxicity and/or outcome during therapy in paediatric ALL patients treated according to the LAL/SHOP protocol (high-dose methotrexate [MTX] and 6-mercaptopurine [6-MP]).
We analyzed genetic polymorphisms and epigenetic variations of 12 genes in paediatric ALL patients: 6 genes of the MTX pathway (MTHFR, TYMS, SHMT1, RFC1, ABCB1 and ABCG2), 1 gene of the 6-MP pathway (TPMT) and 5 genes involved in xenobiotic detoxification (CYP1A1, NQO1 and the GSTs GSTM1, GSTT1 and GSTP1).
Several associations were found between polymorphisms and clinical parameters, such as that of the MTHFR C677T and A1298C polymorphisms and hepatotoxicity and gastrointestinal toxicity respectively.
Our results indicate that polymorphisms in the MTX pathway may be useful as predictors of toxicity and outcome in ALL patients. This project was supported by RTICS (RD/06/0020/0048) and Basque Government (IT-463-07 and 2006111015).
Citation Information: Clin Cancer Res 2010;16(7 Suppl):B31
Abstract B32: DNA demethylation and inhibition of HDAC1 and HDAC2 and is sufficient to reactivate epigenetically silenced tumor suppressor genes
Authors: Geutjes Ernst , Bernards Rene 
Published: January 2011

Abstract
Loss of tumor suppressor gene (TSG) function contributes heavily to both the initiation and progression of cancer and can be the result of mutations in the DNA sequence, but can also be caused by epigenetic disruptions. In contrast to somatic mutations of tumor suppressor genes, epigenetic alterations are essentially reversible. Promoter hypermethylation and histone hypoacetylation play a key role in epigenetic silencing of TSGs. Indeed, the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (DAC) and the broad spectrum histone deactelyase (HDAC) inhibitor vorinostat are promising anti-cancer drugs. HDAC inhibitors and DAC are currently explored as combination therapy as they synergistically reactivate epigenetically silenced TSGs and may thus have enhanced therapeutic responses when combined. Although pan-HDAC inhibitors have clear anti-tumor activity in the clinic they induce side effects. In addition, as low expression of some HDACs has been associated with cancer development, their further inhibition may actually contribute to tumor progression. Thus, there is great interest to develop selective HDAC inhibitors. However, it is currently unclear which HDAC(s) to hit.
We thus screened a HDAC siRNA library for their ability to synergize with DAC in reactivation of silenced TSGs. We found that only HDAC1 knockdown synergized with DAC treatment in the re-expression of epigenetically silenced TSGs. Additional knockdown of HDAC2 dramatically enhanced this effect, suggesting that both HDAC1 and HDAC2 are involved in the silencing of TSGs. We found that the HDAC inhibitor MS-275, which only targets HDAC1-3, was also able to synergize with DAC in reactivation of silenced TSGs which confirms our finding that HDAC1&2 are essential for epigenetic silencing of TSGs.
Treatment of cancer cells with DAC and MS-275 resulted in caspase activation which correlated with reactivation of silenced TSGs. We found a strong synergy with DAC and MS-275 in induction of caspase activity and mitochrondrial membrane permeabilization. Collectively, these data show that DNA demethylation and inhibition of HDAC1&2 is sufficient to reactivate silenced TSGs. In addition, these studies suggest that compounds that inhibit HDAC1&2 might be as effective as pan-HDACi as anti-cancer drugs.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):B32
Abstract B33: A novel isoform of the major 8p22 tumor suppressor Deleted in Liver Cancer 1 (DLC1) gene with growth suppression function is frequently silenced epigenetically in multiple tumors
Authors: Low John S.W. , Tao Qian , Goh Hwee Koon , Ng Ka Man , Woo Wan Lu , Ambinder Richard F. , Srivastava Gopesh , Shamay Meir , Chan Anthony T.C. , Popescu Nicholas C. , Hsieh Wen-son 
Published: January 2011

Abstract
Aberrant DNA methylation of Tumor Suppressor Gene (TSG) promoter regions, in addition to being a hallmark of cellular transformation, could provide potential tumor markers for early detection and monitoring of treatment effect. In a previous study to identify candidate TSGs relevant in Nasopharyngeal Carcinoma (NPC), our group identified the Deleted in Liver Cancer 1 (DLC1) gene to be epigenetically silenced not just in NPC, but in esophageal, breast and cervical carcinomas also. In this study, we report the cloning and characterization of a novel isoform of the human DLC1 gene with growth suppression function transcribing from a functional alternative promoter and silenced epigenetically in multiple tumors. Designated as DLC1 isoform 4 (DLC1-i4), this novel isoform encodes a protein of 1125 amino acids with a distinct N-terminus as compared to the other known isoforms. DLC1-i4 was expressed ubiquitously in normal tissues and immortalized normal epithelial cells, but significantly down-regulated in multiple tumor cell lines. Promoter DNA methylation was further found in 6/16 (38%) esophageal, 3/4 (75%) cervical, 2/2 (100%) colorectal, 4/4 (100%) NPC cell lines, and in 37/39 (95%) and 12/31 (39%) of primary NPC and esophageal tumors respectively. In contrast, no DNA methylation was found in normal cell lines and tissues. Pharmacological treatment with 5-aza-2′-deoxycytidine or genetic double knock-out of DNMT1 and DNMT3B could demethylate the DLC1-i4 promoter and activate transcription, indicating a direct epigenetic mechanism. Ectopic expression of DLC1-i4 had a strong inhibitory effect on the growth and colony formation ability of silenced tumor cell lines. As a whole, our results suggest that transcription of multiple DLC1 isoforms driven off alternative promoters could modulate the activity of the candidate tumor suppressor DLC1 protein in the pathogenesis of these tumors, and should be further tested as a tumor specific molecular biomarker.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):B33
Abstract B34: Identifying sources of medical radiation in a population of children diagnosed with acute lymphoblastic leukemia: Single institution study
Authors: Roher Robin L. 
Published: January 2011

Abstract
Purpose of study: Through record review including parental interview author will identify children diagnosed with acute lymphoblastic leukemia at the Children's Hospital of Pittsburgh in the period 1999–2009 who have had a preconception, prenatal or postnatal exposure to medical radiation.
Description of experimental procedures: The necessity of identifying children at increased risk of childhood cancer through envirnomental exposures and genetics is increasing as the diagnosis rate remains fairly constant and even in the case of very successful therapy for children with acute lymphoblastic leukemia the relapse and refractory rates are significant. This study investigates correlation among a regional group of children in the United States through record review and construction and implementation of parental/family questionnaire.
Summary of data: Preliminary study finds a variety of medical radiation exposures, primarily preconception in this cohort. There is a stronger correlation in children diagnosed with T cell acute lymphoblastic leukemia. This data is indicative of the first five years of the study which is still in progress.
Conclusions: This study supports and documents the role of medical radiation in a cohort of children diagnosed with acute lymphoblastic leukemia in a five year period. Extension of the study and careful correlation with relevant genetic data on these identified children will be critical to the longitudinal study and its usefulness.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):B34
Abstract B35: Serum inflammatory biomarkers of acute and persistent fatigue in a preclinical breast cancer treatment model
Authors: Wood Lisa J. , Nail Lillian M. , Elsea Collin R. , Druker Brian J. 
Published: January 2011

Abstract
Aims: Cancer treatment related fatigue (CTRF) is a debilitating symptom of cancer chemotherapy. The acute CTRF that occurs during chemotherapy can become persistent lasting for weeks, month, or years after treatment has ended. Although, treatment-related increases in IL-1β and TNF-α have been implicated in CTRF, the role that these cytokines play in CTRF is unclear. The aim of this study was to determine the relationship between chemotherapy-induced IL-1β and TNF-α production and acute and persistent CTRF in a pre-clinical mouse model.
Methods: Blood levels of IL-1β, TNF-α and several other inflammatory biomarkers were measured in acutely fatigued, non-fatigued, and persistently fatigued mice following administration of cytoxan-adriamycin-5-fluorouracil (CAF), a commonly used adjuvant chemotherapy regimen for the treatment of breast cancer, by assessing changes in voluntary wheel running activity as a proxy for fatigue.
Results: Fatigued mice showed increased blood levels of IL-1β, TNF-α as well as several other inflammatory markers including, IL-5, IL-6, IL-7, IL-9, IP-10, G-CSF, KC, MCP-1 and MIP-1β. Importantly, serum levels of these fatigue associated biomarkers were not significantly increased in non-fatigued CAF treated mice. CAF-treated mice with persistent fatigue had elevated serum levels of IL-6, IL-17, and MIP-1α.
Conclusions: This study advances the science of symptom management by providing evidence that treatment induced increases in IL-1β and TNF-α play a role in acute CTRF. Similar temporal analyses between serum inflammatory biomarkers in the clinical setting may lead to a better understanding of the role of immune dysfunction in the etiology of acute and persistent fatigue.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):B35
Abstract B36: Induction of IL-6 by breast cancer chemotherapy mediates loss of fat-free lean body mass in tumor-free mice by decreasing systemic IGF-1
Authors: Wood Lisa J. , Elsea Collin R. , Nail Lillian M. , Winters Kerri A. , Druker Brian J. 
Published: January 2011

Abstract
Aims: Cancer patients treated with cytotoxic chemotherapy often experience changes in body composition that occur independent of changes in food intake or physical activity. These changes may impact physical functioning and quality of life. Interleukin-6 (IL-6), an inflammatory cytokine that is up-regulated in cancer patients treated with cytotoxic chemotherapies, plays an important role in the regulation of body composition. The purpose of this study was to determine the role of IL-6 in the regulation of systemic insulin-like growth factor I (IGF-1) levels and treatment induced changes in body composition using a pre-clinical model.
Methods: Changes in body composition and systemic IGF-1 levels were assessed in IL-6−/− mice and their wild type counterparts before and after 4 cycles of cytoxan-adriamycin-5-fluorouracil (CAF) a common adjuvant breast cancer chemotherapy regimen. Daily food intake and physical activity were monitored throughout treatment.
Results: We found that CAF decreased systemic IGF-1 production in an IL-6-dependent manner. Similar to cancer patients, CAF treatment in WT mice led to a reduction in fat free LBM and bone mass but not fat mass (FM). These changes occurred independently of food intake and level of physical activity. In contrast, IL-6 deficient mice were protected from the treatment induced loss of fat free LBM but not bone mass.
Conclusions: These preclinical findings implicate IL-6 mediated reduction in systemic IGF-1 as a possible mechanism underlying the loss of fat free LBM in cancer patients undergoing cytotoxic chemotherapy. Based upon these pre-clinical findings, examination of these relationships in the clinical setting is warranted.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):B36
Abstract B38: Cellular uptake of exogenous Arf6 inhibits the proliferation, invasion, and migration of MDA-MB-231 breast cancer cells
Authors: Afroze Syeda , Uddin M. Nasir , Cao Xiaobo , Gizachew Dawit 
Published: January 2011

Abstract
The two isoforms of the Small GTP binding proteins of the ADP riboyslation factor (Arf1 and Arf6), which are involved in membrane trafficking events are extensively studied. As with most members of the ras superfamily, Arf proteins cycle between a GTP-bound and a GDP-bound form. This cycle is regulated by two groups of proteins: GEFs, which facilitate the exchange of GDP for GTP, and GTPase-activating proteins (GAPs), which promote the hydrolysis of bound GTP. Arf1 and Arf6 have distinct cellular functions despite sharing approximately 70% sequence identity. Arf1 regulates the recruitment of vesicle coat polymers, including COPI, to the Golgi apparatus. In contrast, Arf6 is located at the plasma membrane and implicated in endocytotic pathways and vesicle trafficking [1–3]. Recent studies, using mice injected with invasive melanoma cell lines (LOX) that express a dominantly inhibitory Arf6, have shown that Arf6 is an important regulator of tumor growth and metastasis [4]. Our goal is to study is the internalization of exogenous Arf6 and its effect on MDA-MB-231 breast cancer cells in order to explore Arf6 as a therapeutic agent.
Methods and Results: MDA-MB-231 breast cancer cells were incubated for 24 h with either purified Arf6-GTPγS (GTPγS is the nonhydorlysable form of GTP) or Arf6-GDP at various concentrations (60–500 nM) at 37°C and 4°C and the internalization of the proteins were evaluated using western blot analysis and fluorescence microscopy. Both forms of Arf6 proteins were significantly internalized in MDA-MB-231 breast cancer cells, and the internalized proteins inhibited cell invasion, migration and proliferation when compared to PBS (vehicle)-treated cells (p°C and 4°C, internalization mechanisms other than endocytosis must have been involved. We have also observed the internalization of Arf6 in colon and lung cancer cells at 37°C.
Conclusions and Perspectives: Our findings show that when MDA-MB-231 breast cancer cells are incubated with either Arf6-GTPγS or Arf6-GDP in the cell culture media, the proteins are internalized at both 37°C and 4°C. Though further studies are required in order to understand the internalization mechanisms of Arf6, it is known that direct membrane translocation of some peptides including TAT protein is observed in several cell types treated at 4°C. Arf6 is more basic protein (pls in the range of 8.5–9.5) than Arf1 (pls in the range of 6.0–7.0), which might explain why Arf6 is internalized, but not Arf1. The inhibition of proliferation, migration and invasion of the cells might have been induced by defective Arf6 cycling due to the internalized Arf6, which indicates the potential to exploit Arf6 as therapeutic agent for cancer.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):B38
Abstract B39: Molecular diagnostics strategy to identify hereditary non-polyposis colorectal cancer patients
Authors: Kostina Olga , Rebane Egle , Anderson Wally , Kask Martin , Valkna Andres 
Published: January 2011

Abstract
Introduction: Hereditary non-polyposis colorectal cancer (HNPCC), also called Lynch syndrome, is an autosomal dominantly inherited syndrome predisposing to the early development of cancers of colon, rectum, endometrial, small bowel and urinary tract and accounts for ∼5% of all colon cancer cases. Molecular investigations have shown that most HNPCC families are associated with constitutional mutations in a class of genes (called MLH1, MSH2, MSH6, PMS2 and probably others) involved in DNA mismatch repair. MLH1 and MSH2 genes account for approximately 90% of HNPCC families identified germline mutations. Most of these mutations are point mutations and small insertions or deletions. The large genomic deletions in MMR genes and germline epimutations in MLH1 explain a proportion of point mutation-negative families suspected of Lynch syndrome. At the same time the methylation in promoter of MLH1 gene in colon tissue frequently causes MLH1 protein loss in sporadic tumors. The aim of the study is to characterize the mismatch repair gene mutations of Estonian hereditary non-polyposis colorectal cancer families and to improve the screening strategy.
Methods: A systematic analysis of 75 unrelated patients from suspected HNPCC families in Estonia was performed by immunohistochemistry, microsatellite instability, and gene mutation and methylation detection.
Results. The study is still continuing. Systematic and comprehensive analysis of samples from 75 HNPCC-suspected patients is proceeding using various methods.
Conclusion: Based on traditional molecular genetics, combined with epigenetics, multiple detection methods can accurately diagnose HNPCC. As the results of the study, the precise molecular diagnostic scheme for diagnosing HNPCC will be worked out for clinical use in Estonia.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):B39
Abstract B4: A microRNA screen to identify modulators of sensitivity to Bcl-2 inhibitor ABT-263
Authors: Semizarov Dimitri , Lam Lloyd , Lu Xin 
Published: January 2011

Abstract
Evasion of apoptosis is a known feature of cancer cells. One mechanism of deregulating the apoptotic pathway is through overexpression of anti-apoptotic Bcl-2 family members. ABT-263 is a first-in-class Bcl-2 family inhibitor that restores the ability of cancer cells to undergo apoptosis. However, many cancer cells are resistant to ABT-263 due to high levels of a Bcl-2 family member Mcl-1, which is not targeted by the drug. Mcl-1 expression is known to be regulated transcriptionally, translationally, and through proteosome-mediated degradation. Recently, Mcl-1 expression was shown to be affected by microRNAs (miRNAs). In order to identify miRNAs that modulate the sensitivity of cancer cells to ABT-263, we screened a library of 810 human miRNA mimics in HCT-116 cells in the presence of ABT-263. The screen revealed 19 miRNAs that sensitize HCT-116 cells to ABT-263. Fifteen of these miRNAs were also shown to sensitize CHL1 melanoma cells to the same agent. We further evaluated twelve of the strongest sensitizers in these cell lines. We found that these sensitizers induced apoptosis only in the presence of ABT-263. In addition, while all twelve of these miRNAs reduced Mcl-1 protein expression, only ten of them targeted Mcl-1 through direct binding to the Mcl-1 3′ untranslated regions (3′-UTR) of the gene. Other resistance pathways and regulators of Mcl-1 expression may be identified using this method. Our data can be used to design miRNA replacement therapies to increase sensitivity to Bcl-2 antagonists. The expression of the 12 marker microRNAs is now being correlated to the sensitivity to ABT-263 in order to enable rational patient selection in ABT-263 clinical trials.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):B4
Abstract B48: Expression of metalloproteinases mmp-2, mmp-9 in sentinel lymph node and sera of patients with breast cancer
Authors: Daniele Antonella , Quaranta Michele , Divella Rosa , Zito Alfredo Francesco , Giannelli Gianluigi , Asselti Maria Consiglia , Mazzocca Antonio , Paradiso Angelo 
Published: January 2011

Abstract
Background: A sentinel lymph node is the first lymph node to receive lymphatic drainage from a tumour. In patients with breast cancer, several studies suggest that sentinel lymph node biopsy can accurately predict the status of axillary lymph nodes and so avoid them removal. Invasion and metastasis are the most important problems in the management of breast cancer. These events require diverse proteolytic enzymes among which MMP-2 and MMP-9 play a significant role in degradation of type IV collagen, the major component of the Basement Membrane (BM). The main objective of this study is to evaluate the expression of MMP-2 and MMP-9 in sentinel lymph node and serum of breast cancer patients at the aim to evaluate their clinical usefulness as diagnostic tumour markers in breast cancer.
Material and Methods: Expression of MMP-2 and MMP-9 was performed on sentinel lymph node by immunohistochemistry while gelatine zymography was used to determinate the serum expression of both Metalloproteinases. The association of MMP-2 and MMP-9 with clinicopathological features, including histological type, estrogen (ER) and progesterone (PgR), cancer familiarity and CA 15.3 levels were also analysed. In all 50 metastatic e non metastatic breast cancer patients and 34 healthy women were involved.
Results: MMP-2 and MMP-9 expression were statistically significant higher in metastatic breast cancer patients respect to non metastatic cancer patients and control group both in the sentinel lymph node and serum (p&lt; 0.01). Besides our results show a statistically significant correlation between higher of MMP-2 and MMP-9 and cancer familiarity (p &lt;0.01; p&lt; 0.05) and between MMP-9 and CA 15.3 levels and MMP-9 and grade (G3).
Conclusion: Our date suggest a possible significant clinical utility of these proteolytic markers in malignant tumour, growth, invasion and metastasis in breast cancer and the role of sentinel lymph node to predict a possible involvement of axillary lymph nodes.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):B48