bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PL01-02: The mechanism of Epstein-Barr virus persistent infection and the origins of associated lymphomas
Authors: Thorley-Lawson David A. 
Published: June 2012

Abstract
Epstein-Barr virus is a human herpesvirus that is a paradigm for understanding persistent infection. It infects &gt;90% of the human population usually early in life and then remains for the life of the human host. This persistent infection is almost always benign but occasionally is associated with the development of cancers several of which constitute significant health problems. These include immunoblastic, Hodgkin's and Burkitt's lymphomas. We have presented a large body of evidence in support of a model, which is now generally accepted, of how EBV establishes and maintains this infection. The essence of this model is that EBV usurps the normal biology of the B lymphocyte. Specifically EBV uses a series of B cell stage specific transcription programs to first activate the newly infected B cell then drive it through a germinal center reaction (the site where B cells usually undergo affinity maturation of their immunoglobulin genes) to emerge as a latently infected resting memory B cell – the site of long term persistence. Ultimately reactivation of the virus from these cells occurs when they are triggered into terminal differentiation to become plasma cells. This infectious virus then becomes amplified through lytic infection of the epithelium at the mucosal surface prior to release into saliva – the vehicle via which the infection is spread. When the progression of newly infected cells into the memory compartment is compromised at any given stage this can give rise to EBV associated lymphoma. In this presentation I will review the model of EBV persistence, where and how it becomes dysregulated leading to lymphoma with especial focus on Burkitt's lymphoma This will include new evidence implicating viral miRNAs in the development of these tumors.
Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):PL01-02.
Abstract PL01-03: Molecular patterns of endemic, sporadic, and AIDS-related Burkitt's lymphoma: Clues to distinct biology of subtypes
Authors: Mbulaiteye Sam M. 
Published: June 2012

Abstract
Burkitt's lymphoma (BL) is a monoclonal B-cell non-Hodgkin lymphoma (NHL) with three clinical-epidemiological subtypes: endemic BL occurs mostly in Africa, tropical areas of Latin America, and Papua New Guinea and is linked to Epstein-Barr virus (EBV); sporadic BL occurs worldwide in children and young adults less than 20% of cases are linked to EBV; and AIDS-associated BL, which occurs in the setting of HIV infection in developed countries. Except for the later, BL is generally recognized to be a pediatric lymphoma with some cases that occur in young adults and, rarely, in the elderly. The central molecular abnormality in all subtypes is deregulation of cellular MYC gene, due to t(8;14), or infrequently, variant translocations. All subtypes are histologically indistinguishable. We have recently observed non-monotonic age-specific incidence peaks in sporadic and AIDS-related BL in the U.S., suggesting a mixture of BL with different etiologies and/or biology, and peaks during childhood, adulthood, and in the elderly. The molecular correlates of age-specific peaks of BL are not well established, but may include viral markers linked to BL (EBV and HIV) or other unknown factors. The presentation will compare and contrast age, sex, anatomic site, viral, and molecular patterns of endemic, sporadic, and AIDS-related BL and advance the hypothesis that age-related peaks may represent an alternative approach to identify BL with different etiology and/or biology.
Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):PL01-03.
Abstract PL02-02: Community-centered HBV/liver cancer control interventions for Asian Americans
Authors: Chen Moon S. , Stewart Susan L. , Bastani Roshan , Maxwell Annette E. , Dang Julie H.T. , Nguyen Tung T. 
Published: June 2012

Abstract
Hepatitis B virus (HBV) induced liver cancer represents the most glaring cancer health disparity facing Asian Americans. While liver cancer is relatively uncommon in the U.S., it leads all other cancer sites in the percentage increase in mortality, with dismal survival rates. The disease disproportionately affects all populations of color, but particularly Asian Americans, who experience the highest rates of liver cancer.
Community-centered interventions to control HBV/liver cancer among Asian Americans, operationally defined as organized activities to increase awareness of HBV risks among Asian Americans and the promotion of HBV screening and vaccination, include programs working in policy/advocacy, screening, and community-based controlled intervention trials.
These interventions have led to: 1) fostering the adoption of universal hepatitis B vaccination at birth, credited with averting at least 700,000 deaths annually; 2) community-based screenings that reach more than 21,000 individuals per year, catalyzing referrals for additional screening and treatment; and 3) the initiation of at least seven community-centered controlled intervention trials to increase vaccination or serological testing among Asian Americans. Despite the many advantages and accomplishments of community-centered interventions, large numbers of Asian Americans remain unaware of their HBV status and concerns exist regarding the validity of self-reported serological testing or vaccination for HBV as the measure of intervention effectiveness. In addition, in order to reduce the rate of liver cancer and other complications, there is a need to ensure continued community-centered HBV education and appropriate quality of care provided to those who have chronic hepatitis B diagnosed by screening. Greater integration of community-centered efforts with clinic-based interventions, which have complementary assets, appears to be a promising approach to reduce the unnecessary HBV/liver cancer disparities among Asian Americans as well as all populations at risk.
Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):PL02-02.
Abstract PL06-04: Patient navigation and patient satisfaction with cancer-related care
Authors: Fiscella Kevin 
Published: June 2012

Abstract
Patient navigation represents a promising means to address racial, ethnic, and socioeconomic disparities in cancer-related outcomes. The Patient Navigation Research Program sponsored by the National Cancer Institute and the American Cancer Society was designed to assess the impact of patient navigation on patient outcomes. Patients with breast, cervical, colorectal, or prostate cancer screening abnormalities and/or diagnosed cancer from nine sites across the country were assigned to patient navigators or to usual care. A trained patient navigator met with assigned patients, collaboratively assessed patient barriers to cancer-related care and sought to address patient barriers. Using a validated measure of patient satisfaction with cancer related care, this presentation compares scores from navigated and un-navigated patients and discusses implications of these findings.
Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):PL06-04.
Abstract A1: The physiological form of MetAP2 can be inhibited through binding to either of the two active-site metals
Authors: Wallis Nicola G. , Berdini Valerio , Besong Gilbert , Chessari Gianni , Coyle Joe , Graham Brent , Madin Andrew , O'Brien Alistair , Richardson Caroline J. , Smith Kirsten , Thompson Neil T. , Vinkovic Mladen , Williams Pamela A. 
Published: June 2012

Abstract
Methionine aminopeptidases (MetAP) are metalloenzymes that remove the N-terminal initiator methionine from newly synthesized polypeptides allowing essential post-translational modifications such as acetylation and myristoylation to take place. MetAP2, one of the two eukaryotic forms of the enzyme, was identified as the target of fumagillin, a natural product with anti-angiogenic properties that inhibits the proliferation of endothelial cells. Clinical activity has been seen for a semi-synthetic analogue of fumagillin, TNP470, suggesting MetAP2 is a good target for inhibiting angiogenesis. In vitro, MetAP2 appears to have sites for two divalent metal ions within its active site but there has been much discussion around the identity and number of metal ions actually present in the physiological states of the various MetAPs. An understanding of the physiologically relevant metalloform of the enzyme is essential for designing inhibitors that are active in cells. We have used tool compounds that bind the active site metals in diverse ways to investigate the relevance of the two potential metal binding sites in MetAP2.
Using our fragment-based screening approach, Pyramid™, we screened the manganese-form of the MetAP2 enzyme. We identified multiple low-molecular weight fragment hits and confirmed their modes of binding to the two metals in the active site of MetAP2 by X-ray crystallography. Three hit series, which bound metal 1 only, metal 2 only or both metals 1 and 2 were chosen for further optimization using structure-based drug design. Optimized lead compounds had potent inhibitory activity against the in vitro MetAP2 enzyme (∼100 nM) and in HUVEC proliferation assays, whilst also showing greater than 1000-fold selectivity for MetAP2 over MetAP1. Examples from each series, representing different active site metal binding modes, were used as tool compounds to investigate the mechanism of action in cells. The levels of the MetAP2 substrate, 14-3-3, were monitored by western blot in HUVECs treated with these compounds. Levels of methionylated 14-3-3 increased upon treatment with compounds from each of our series indicating the substrate was not being processed and that in each case the compound was inhibiting MetAP2 in these cells.
These data indicate that the physiological form of MetAP2 can be inhibited by compounds which bind solely to either of the two active-site metals, suggesting that both metals must be present in the intra-cellular form of MetAP2 and allowing multiple approaches to inhibiting this key angiogenic target. The lead series identified here provide chemically diverse scaffolds for further optimization of drug like properties.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A1.
Abstract A10: Antiangiogenic therapy (VEGF-R1–3 and PDGFR inhibitor) increases tumor hemoglobin saturation and decreases interstitial pressure, and microvessel density
Authors: Hanna Gabi , Tailor Tina , Palmer Greg , Herbert Joseph , Vlahovic Gordana , Dewhirst Mark 
Published: June 2012

Abstract
Methods: We evaluate the effects of pazopanib, a novel multi-targeted tyrosine kinase inhibitor, by examining its effects on tumor oxygenation, interstitial pressure (IFP), and vascularity as compared to an untreated control group.
Nude mice (n=35) were injected with A-549 NSCLC tumor cells. Tumors reached an average volume of 650 mm3 before treatment with pazobanib 100mg/kg/day, Pazobanib 30mg/kg/day. or Vehicle (Control). Animals were treated daily for 14 days.
Spectroscopic Measurements: A novel Skinskan spectrofluorometer was used to obtain non-invasive measurements of hemoglobin saturation (Hbsat) and total Hb for each tumor. Measurements were performed every other day, starting the day of treatment. These values were analyzed by a custom MATLAB program.
IFP Measurements: IFP was measured on the last day of treatment(day 14), prior to sacrifice.
Immunohistochemical staining: The number of vessels, determined by positive CD31 staining, was averaged over 6–8 image fields to obtain microvessel density (MVD).
Results:
Optical Spectroscopy: A significant increase in Hbsat was observed at day 8 for the low and high pazopanib dose groups, compared to control (p=0.0109, p=0.0290, respectively). After the 8th treatment day, Hbsat trended downward toward baseline.
Tumor IFP: Tumor IFP for animals treated with pazopanib 100mg/kg was significantly reduced, compared to control (p=0.0026). Treatment with pazopanib 30mg/kg also demonstrated a strong trend towards IFP reduction, compared to control (p=0.0645).
MVD: MVD was significantly reduced in mice treated with low and high dose pazopanib, compared to control (p=0.0271, p=0.0107, respectively).
Conclusions: Treatment with pazopanib lead to a significant reduction in IFP, MVD, and increase in tumor Hb sat. This result demonstrates that pazopanib enhances efficiency of tumor perfusion which could lead to better drug distribution into the tumor, and increased of tumor Hb saturation would correlate with better oxygenation and predicts better response to radiotherapy.
Work supported by a grant from GlaxoSmithKline.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A10.
Abstract A110: A phase 1 study of PF-04929113 (SNX5422), an orally bioavailable heat shock protein 90 (Hsp90) inhibitor administered twice weekly in patients with refractory solid tumor malignancies and lymphoma
Authors: Giaccone Giuseppe , Rajan Arun , Crandon Sonja , Gutierrez Martin , Kummar Shivaani , Jain Lokesh , Figg William D. , Houk Brett E. , Shnaidman Michael , Skillings Jamey 
Published: June 2012

Abstract
Introduction: Hsp90 inhibitors have the potential for broad anti-cancer effects based on the spectrum of known client proteins and increased effect on mutations that drive malignant transformation and cancer growth. PF-04929113 (SNX5422; 113) is a novel, oral, non-antibiotic, selective Hsp90 inhibitor prodrug, with preclinical anti-tumor activity in multiple tumor models. The objective of this study was to evaluate the tolerability and describe the PK of 113 and its active moiety (PF- 04928473 /SNX2112; 473) in patients with refractory solid tumor malignancies and lymphoma.
Methods: Twenty-six subjects have been enrolled to date in this Phase 1, open-label, dose-escalation study. Subjects were treated with oral 113 twice weekly without interruption at doses ranging from 4 to 100 mg/m2. PBMCs were isolated and collected at baseline and various time points after-treatment. Cell lysates from PBMCs were assayed for Hsp70 and AKT protein level using Meso Scale Discovery (MSD) technology. Serial plasma concentrations of 473 were measured by LC-MS/MS after the first dose (Day 1) and after 6 doses (Day 18). PK parameters (mean ± standard deviation) were calculated using non-compartmental methods in WinNonlin v5.0.
Results: MTD for this schedule has not yet been reached. So far it has been well tolerated. Related adverse events were mainly low grade (most frequent nausea 31%) with grade ≥ 3 were reported in 8% (diarrhea and arthritis, 1 patient each). Based on results of interim pharmacokinetic analysis for doses 4 to 44 mg/m2, median time to 473 peak plasma concentrations was 2 h (range 0.33–4 h) and median half-life was ∼8.5h both at days 1 and 18. The median (range) CL/Fm at day 1 and day 18 were, 24.7 (12.9–81.2) L/hr and 22.6 (8.6–55.6) L/hr, respectively and was consistent across the dose range. Hsp70 was elevated with drug treatment, and further elevations were noted with increasing weekly dose. Although to date, no patients have achieved PR, several have experienced prolonged stable disease including medullary thyroid cancer (&gt;450 days), lymphoma (&gt;150 days), and esophagus, colon, adenoid cystic, lung carcinoid, and peritoneal mesothelioma (&gt;100 days).
Conclusions: This schedule is well tolerated with no significant drug accumulation, few severe toxicities and potential for efficacy based on prolonged stable disease. Maximal concentrations of 113 were observed 2 h after oral administration of prodrug 113. Concentrations achieved were consistent with the preclinical activity. Accrual to the study to establish MTD is ongoing.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A110.
Abstract A113: Involvement of heme oxygenase-1 (HO-1) in the differentiation of human promyelocytic leukemic cells by DMSO
Authors: Kim Jong-Suk , Noh Eun-Mi , Lee Young-Rae , Park Jinny 
Published: June 2012

Abstract
Heme oxygenase-1 (HO-1), an inducible enzyme with broad tissue expression, is up-regulated in response to hematopoietic stress and preserves vascular homeostasis. We investigated the involvement of HO-1 in the differentiation of HL-60 cells. Dimethylsulfoxide (DMSO), a representative differentiation inducer of HL-60 cells, induced completely decrease HO-1 expression in a time-dependent manner, but increase CD11b, indicating that HO-1 might have negative function in DMSO-induced differentiation of HL-60 cells. Zinc protoporphyrin (ZnPP), a strong inhibitor of HO-1, induced differentiation of HL-60 cells, as evidenced by a marked increase in the expression of CD11b following ZnPP treatment. In contrast, treatment with cobalt protoporphyrin (CoPP), an activator of HO-1, decreased CD11b expression. ZnPP induced down-regulation of HO-1 protein expression in HL-60 cells, while CoPP induced up-regulation. In addition, ZnPP treatment caused a decrease in pRb and cyclin D1 expression and an increase in p21 and p27 expression. These results suggest that down-regulation of HO-1 might be necessary for DMSO-induced HL-60 differentiation. This study provides the first evidence that HO-1 plays an important role in DMSO-induced differentiation of HL-60 cells.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A113.
Abstract A116: Radio- and chemosensitization through inhibition of DNA-PK by KU-0060648
Authors: Bardos Julia , Shea Kerry , Parveen Nahida , Peacock Marcus , Deacon William , Cranston Aaron , Albertella Mark , Menear Keith , Smith Graeme , Martin Niall 
Published: June 2012

Abstract
DNA double strand breaks (DSBs) are profoundly cytotoxic unless rapidly repaired. Non-homologous end joining (NHEJ) is the predominant pathway of DSB repair in mammalian cells. DNA-dependent protein kinase (DNA-PK), a member of the PI3-kinase like kinase (PIKK) family, is an essential component of NHEJ, and DNA-PK inhibition in combination with radio- or chemotherapy therefore represents an attractive therapeutic approach in cancer therapy. Through medicinal chemistry, a series of DNA-PK inhibitors of increasing potency was identified, resulting in KU-0060648, a potent DNA-PK inhibitor with an IC50 value of 10nM against the enzyme and high selectivity for DNA-PK over other PIKKs and a panel of 60 kinases.
In cellular assays, KU-0060648 significantly increases cell death induced by ionising radiation (IR) or chemotherapeutic treatments, such as doxorubicin or etoposide. KU-0060648 does not sensitise DNA-PK-deficient cells to IR or chemotherapeutic treatments, further highlighting its selective nature. The compound was also found to preferentially kill DNA repair-defective cells in combination with IR or chemotherapy, indicating a therapeutic advantage for this class of agent in DNA repair-compromised tumor cells.
Auto-phosphorylation of DNA-PK at serine 2056 is inhibited by KU-0060648, and significant changes in IR- or chemotherapy-induced H2AX- and KAP-1 phosphorylation in the presence KU-0060648 over time clearly indicates inhibition of DNA damage repair by this compound. Pharmacokinetic and pharmacodynamic profiling of KU-0060648 revealed that the compound has very good oral bioavailability and a favourable half life. In a fractionated IR xenograft model, dosing with KU-0060648 caused significant tumor growth delay compared to the control group. PK/PD relationships were established to define the exposures and level of DNA-PK inhibition required for effective radiosensitisation. Our results to date support further in vitro and in vivo evaluation of this novel class of therapeutic agents as a potential clinical radio- and chemosensitiser.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A116.
Abstract A117: Chk1-dependent up-regulation of ribonucleotide reductase R2 in response to camptothecin-induced DNA damage
Authors: Zhang Yong-Wei , Jones Tamara , Martin Scott , Caplen Natasha , Pommier Yves 
Published: June 2012

Abstract
To investigate drug mechanisms of action and identify molecular targets for the development of rational drug combinations, we are conducting synthetic siRNA-based RNAi screens to identify genes whose silencing affects anti-cancer drug responses. One such screen indicated that the silencing of RRM1 and RRM2, which encode the large and small subunits of the human ribonucleotide reductase (RNR) complex respectively, markedly enhances the cytotoxicity of the Topoisomerase 1 (Top1) inhibitor camptothecin (CPT). Silencing of RRM2 was also found to enhance DNA damage as measured by -H2AX. Further studies showed that CPT up-regulates both RRM1 and RRM2 mRNA and protein levels, and induces the nuclear translocation of RRM2. The Checkpoint kinase 1 (Chk1) was also up-regulated and activated in response to CPT. CHEK1 down-regulation by siRNA and small molecule inhibition of Chk1 activity blocked induction of RRM2 by CPT. CHEK1 siRNA also suppressed E2F1 up-regulation by CPT, and silencing of E2F1 suppressed the up-regulation of RRM2. Silencing of ATR or ATM, and inhibition of ATM activity by KU-55933 blocked Chk1 activation and RRM2 up-regulation. This study links the function of known components of CPT-induced DNA damage response with proteins required for the synthesis of dNTPs, presumably in preparation for DNA repair. Specifically, we propose that, upon DNA damage, Chk1 activation, mediated by ATM and ATR, regulates RRM2 expression through the E2F1 transcription factor. Up-regulation in RRM2 levels, coupled with its nuclear recruitment suggests an active role for RNR in the cellular response to CPT-mediated DNA damage that could potentially be exploited as strategy for enhancing the efficacy of Top 1inhibitors.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A117.
Abstract A118: The PARP1 inhibitor olaparib (AZD2281) enhances radiation-induced DNA damage in BRCA1/BRCA2 wild-type head and neck squamous cell carcinoma cell lines
Authors: Frederick Barbara A. , Fletcher Ashley , Raben David 
Published: June 2012

Abstract
Introduction: In 2008, there were approximately 65,000 cases of head and neck cancer diagnosed in the United States, with over 500,000 cases worldwide. For many patients with locally advanced disease, multiple treatment modalities are combined and typically include radiotherapy, which induces DNA damage in tumor cells. Poly (ADP-ribose) polymerase 1 (PARP1) is involved in maintenance of genome integrity, and functions as a key mediator of DNA repair. The objective of this study was to determine if combining the PARP1 inhibitor olaparib (AZD2281) with radiation in head and neck squamous cell carcinoma (HNSCC) cell lines results in enhanced DNA damage and cell death.
Materials and Methods: The effects of olaparib and radiation were assessed in the BRCA1/BRCA2 wild-type HNSCC cell lines UMSCC2, HN31, MDA-584, and UMSCC25. DNA damage following treatment was determined 2 hours post-radiation by immunofluorescence and flow cytometry using γ-H2A.X-Alexa488 conjugated antibodies. Single cell electrophoresis (comet assay) 24 hours post-radiation was used to measure DNA fragmentation, and long-term cell survival was evaluated by clonogenic survival.
Results: In all cell lines tested, both radiation and olaparib alone induced DNA damage as measured by γ-H2A.X foci formation, and the combination of olaparib and radiation significantly enhanced this response. DNA fragmentation was also greater in combination treatments, and this lead to a lower clonogenic survival for all cell lines.
Conclusions. The combination the PARP inhibitor olaparib with radiation enhanced DNA damage in HNSCC cell lines and lead to greater cell death. This study demonstrated that PARP1 inhibition combined with a DNA damaging agent such as radiation was effective in inhibiting growth of BRCA1/BRCA2 wild-type cell lines.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A118.