bluuebunny/crossref_metadata_2025_split huggingface dataset:
Equitable treatment for HIV/AIDS clinical trial participants: a focus group study of patients, clinician researchers, and administrators in western Kenya
Authors: Shaffer D N , Yebei V N , Ballidawa J B , Sidle J E , Greene J Y , Meslin E M , Kimaiyo S J N , Tierney W M 
Published: December 2005

Objectives:To describe the concerns and priorities of key stakeholders in a developing country regarding ethical obligations held by researchers and perceptions of equity or “what is fair” for study participants in an HIV/AIDS clinical drug trial.Design:Qualitative study with focus groups.Setting:Teaching and referral hospital and rural health centre in western Kenya.Participants:Potential HIV/AIDS clinical trial participants, clinician researchers, and administrators.Results:Eighty nine individuals participated in a total of 11 focus groups over a four month period. The desire for continued drug therapy, most often life long, following an HIV/AIDS clinical trial was the most common priority expressed in all focus groups. Patients with and without HIV/AIDS also thought subsidisation of drug therapies and education were critical forms of compensation for clinical trial participation. Financial incentives were considered important primarily for purchasing drug therapy as well as obtaining food. Patients noted a concern for the potential mismanagement of any money offered. Clinician researchers and administrators felt strongly that researchers have a moral obligation to participants following a trial to provide continued drug therapy, adverse event monitoring, and primary care. Finally, clinician researchers and administrators stressed the need for thorough informed consent to avoid coercion of study participants.Conclusions:Kenyan patients, clinician researchers, and administrators believe that it would be unfair to stop antiretroviral therapy following an HIV/AIDS clinical trial and that researchers have a long term obligation to participants.
Mutation of Lkb1 and p53 Genes Exert a Cooperative Effect on Tumorigenesis
Authors: Wei Chongjuan , Amos Christopher I. , Stephens L. Clifton , Campos Imelda , Deng Jian Min , Behringer Richard R. , Rashid Asif , Frazier Marsha L. 
Published: December 2005

Abstract
Peutz-Jeghers syndrome (PJS) is a dominantly inherited disorder characterized by gastrointestinal hamartomatous polyps and mucocutaneous melanin pigmentation. Germ line mutations in LKB1 cause PJS. We have generated mice carrying an Lkb1 exon 2 to 8 deletion by gene targeting in embryonic stem cells. Heterozygotes develop gastric hamartomas that are histologically similar to those found in humans with PJS. LKB1 is also reportedly a mediator of p53-dependent apoptosis. To explore the potential combined effects of p53 and Lkb1 alterations on tumorigenesis, we carried out a series of matings with Lkb1+/− and p53 null mice to generate Lkb1+/−/p53+/− and Lkb1+/−/p53−/− mice. Similar to the Lkb1+/− mice, gastrointestinal hamartomas have also been detected in the mice with these two genotypes. The Lkb1+/−/p53+/− mice displayed a dramatically reduced life span and increased tumor incidence compared to the mice with either Lkb1 or p53 single gene knockout. The time to onset of polyposis in Lkb1+/−/p53−/− mice is ∼2 months earlier than Lkb1+/−/p53+/− and Lkb1+/− mice, whereas the latter two show a similar time to onset which is at ∼6 months of age. These results strongly suggested that mutations of p53 and Lkb1 gene cooperate in the acceleration of tumorigenesis. (Cancer Res 2005; 65(24): 11297-303)
Widespread CXCR4 Activation in Astrocytomas Revealed by Phospho-CXCR4-Specific Antibodies
Authors: Woerner B. Mark , Warrington Nicole M. , Kung Andrew L. , Perry Arie , Rubin Joshua B. 
Published: December 2005

AbstractThe chemokine receptor CXCR4 is expressed in many cancers where it may regulate tumor cell growth and migration. The role of CXCR4 in cancer will depend on it being in an activated, signaling state. To better define the significance of CXCR4 expression in cancer, we developed an antibody that can distinguish CXCR4 phosphorylated on serine 339, a residue previously identified as a site for ligand-induced phosphorylation. With this antibody, we investigated the mechanisms of CXCR4 phosphorylation and evaluated the phosphorylation status of CXCR4 in human astrocytomas. In vitro, phosphorylation of serine 339 occurred in response to CXCL12 or epidermal growth factor (EGF) treatment and was increased by protein kinase C activation. In all grades of astrocytomas, CXCR4 was expressed in tumor cells and some endothelial cells, whereas CXCL12 was present in endothelial cells and infiltrating microglia. We found that CXCR4 phosphorylated on serine 339 was present in tumor cells and vascular endothelial cells in all grades of astrocytoma. These data indicate that CXCR4 is expressed and activated in astrocytomas and that phosphorylation of CXCR4 can occur through ligand activation or transactivation via the EGF receptor. These studies extend the potential roles of CXCR4 in cancer to include functions associated with benign (grade 1) tumors. The ability to distinguish phosphorylated CXCR4 will be invaluable for the continued analysis of the role of CXCR4 in cancer and the development of CXCR4 antagonist therapy for patients suffering with primary tumors of the brain and other sites. (Cancer Res 2005; 65(24): 11392-9)
FBXO31 Is the Chromosome 16q24.3 Senescence Gene, a Candidate Breast Tumor Suppressor, and a Component of an SCF Complex
Authors: Kumar Raman , Neilsen Paul M. , Crawford Joanne , McKirdy Ross , Lee Jaclyn , Powell Jason A. , Saif Zarqa , Martin Julie M. , Lombaerts Marc , Cornelisse Cees J. , Cleton-Jansen Anne-Marie , Callen David F. 
Published: December 2005

Abstract
A BAC located in the 16q24.3 breast cancer loss of heterozygosity region was previously shown to restore cellular senescence when transferred into breast tumor cell lines. We have shown that FBXO31, although located just distal to this BAC, can induce cellular senescence in the breast cancer cell line MCF-7 and is the likely candidate senescence gene. FBXO31 has properties consistent with a tumor suppressor, because ectopic expression of FBXO31 in two breast cancer cell lines inhibited colony growth on plastic and inhibited cell proliferation in the MCF-7 cell line. In addition, compared with the relative expression in normal breast, levels of FBXO31 were down-regulated in breast tumor cell lines and primary tumors. FBXO31 was cell cycle regulated in the breast cell lines MCF-10A and SKBR3 with maximal expression from late G2 to early G1 phase. Ectopic expression of FBXO31 in the breast cancer cell line MDA-MB-468 resulted in the accumulation of cells at the G1 phase of the cell cycle. FBXO31 contains an F-box domain and is associated with the proteins Skp1, Roc-1, and Cullin-1, suggesting that FBXO31 is a component of a SCF ubiquitination complex. We propose that FBXO31 functions as a tumor suppressor by generating SCFFBXO31 complexes that target particular substrates, critical for the normal execution of the cell cycle, for ubiquitination and subsequent degradation. (Cancer Res 2005; 65(24): 11304-313)
Methyl CpG–Binding Domain Protein 3 Mediates Cancer-Selective Cytotoxicity by Histone Deacetylase Inhibitors via Differential Transcriptional Reprogramming in Lung Cancer Cells
Authors: Noh Eun Joo , Jang Eun Ryoung , Jeong Gajin , Lee You Mie , Min Churl Ki , Lee Jong-Soo 
Published: December 2005

Abstract
Histone deacetylase inhibitors (HDI) have been reported to inhibit the growth and survival of cancer cells while leaving normal cells untouched. However, the mechanisms underlying this selective cell death are poorly understood. Gene expression analysis revealed that HDI treatment induced up-regulation of p21WAF1/Cip1 and down-regulation of ErbB2 in cancer cells but not normal cells. Overexpression of p21WAF1/Cip1 and/or silencing of ErbB2 enhanced cancer cell growth inhibition, suggesting that HDI-induced up-regulation/down-regulation of these genes play critical roles in HDI-induced growth inhibition of cancer cells. Most importantly, we found that the gene silencing factor methyl CpG–binding domain protein 3 (MBD3) was not only released from cancer-selective promoter of the HDI up-regulated p21WAF1/Cip1 gene but also recruited to that of the HDI-down-regulated ErbB2 gene. Furthermore, silencing of MBD3 by small interfering RNA abrogated the HDI-induced gene regulation and growth inhibition in lung cancer but not in normal cells. Together, our results support the critical potential of MBD3 in HDI-induced cancer-selective cell death via cancer differential gene expression. (Cancer Res 2005; 65(24): 11400-10)
Cancer Cells Regulate Lymphocyte Recruitment and Leukocyte-Endothelium Interactions in the Tumor-Draining Lymph Node
Authors: Carrière Virginie , Colisson Renaud , Jiguet-Jiglaire Carine , Bellard Elisabeth , Bouche Gérard , Al Saati Talal , Amalric François , Girard Jean-Philippe , M'Rini Christine 
Published: December 2005

AbstractThe physiologic function of the secondary lymphoid organs to recruit large numbers of naïve lymphocytes increases the probability that antigens encounter their rare, sometimes unique, specific T lymphocytes and initiate a specific immune response. In peripheral lymph nodes (LNs), this recruitment is a multistep process, initiated predominantly within the high endothelial venules (HEVs), beginning with rolling and chemokine-dependent firm adhesion of the lymphocytes on the venular endothelium surface. We report here that, in C57BL/6 mice, the recruitment of naïve lymphocytes is impaired in LNs draining a B16 melanoma tumor. Intravital microscopy analysis of the tumor-draining LNs revealed that this effect is associated with an important defect in lymphocyte adhesion in the HEVs and a progressive decrease in the expression of the LN chemokine CCL21. In parallel with these effects, the tumor up-regulated, essentially through a P-selectin–dependent mechanism, the rolling and sticking of circulating polymorphonuclear cells within the LN low-order venules where few rolling and sticking events are usually observed. These effects of the tumor were independent of the presence of metastasis into the LN and occurred as long as the tumor developed. Together, these results indicate that the tumor proximity disturbs the LN physiology by modifying the molecular, spatial, and cellular rules that usually control leukocyte-endothelium interactions into the peripheral LNs. In addition, they emphasize a new role for the low-order venules of the peripheral LNs, which compared with the HEVs, seem to be the preferential port of entry for cells linked to inflammatory processes. (Cancer Res 2005; 65(24): 11639-48)
Activation of Tumor-Associated Macrophages by the Vascular Disrupting Agent 5,6-Dimethylxanthenone-4-Acetic Acid Induces an Effective CD8+ T-Cell–Mediated Antitumor Immune Response in Murine Models of Lung Cancer and Mesothelioma
Authors: Jassar Arminder S. , Suzuki Eiji , Kapoor Veena , Sun Jing , Silverberg Michael B. , Cheung Lumei , Burdick Marie D. , Strieter Robert M. , Ching Lai-Ming , Kaiser Larry R. , Albelda Steven M. 
Published: December 2005

Abstract5,6-Dimethylxanthenone-4-acetic acid (DMXAA) is a small molecule in the flavanoid class that has antitumor activity thought to be due to ability to induce high local levels of tumor necrosis factor (TNF)-α that disrupt established blood vessels within tumors. The drug has completed phase 1 testing in humans and is currently in phase 2 trials in combination with chemotherapy. Although characterized as a “vascular disrupting agent,” there are some studies suggesting that DMXAA also has effects on the immune system that are important for its efficacy. The goal of this study was to carefully define the immune effects of DMXAA in a series of murine lung cancer and mesothelioma cell lines with varying immunologic characteristics. We show that DMXAA efficiently activated tumor-associated macrophages to release a variety of immunostimulatory cytokines and chemokines, including TNF-α; IFN-inducible protein-10; interleukin-6; macrophage inflammatory protein-2; monocyte chemotactic protein-1; and regulated on activation, normal T-cell expressed, and secreted. DMXAA treatment was highly effective in both small and large flank tumors. Animals cured of tumors by DMXAA generated a systemic memory response and were resistant to tumor cell rechallenge. DMXAA treatment led to initial tumor infiltration with macrophages that was followed by an influx of CD8+ T cells. These CD8+ T cells were required for antitumor efficacy because tumor inhibitory activity was lost in nude mice, mice depleted of CD8+ T cells, and perforin knockout mice, but not in CD4+ T-cell–depleted mice. These data show that activation of tumor-associated macrophages by DMXAA is an efficient way to generate a CD8+ T-cell–dependent antitumor immune response even in animals with relatively nonimmunogenic tumors. Given these properties, DMXAA might also be useful in boosting other forms of immunotherapy. (Cancer Res 2005; 65(24): 11752-61)
High Expression of ErbB Family Members and Their Ligands in Lung Adenocarcinomas That Are Sensitive to Inhibition of Epidermal Growth Factor Receptor
Authors: Fujimoto Nobukazu , Wislez Marie , Zhang Jie , Iwanaga Kentaro , Dackor Jennifer , Hanna Amy E. , Kalyankrishna Shailaja , Cody Dianna D. , Price Roger E. , Sato Mitsuo , Shay Jerry W. , Minna John D. , Peyton Michael , Tang Ximing , Massarelli Erminia , Herbst Roy , Threadgill David W. , Wistuba Ignacio I. , Kurie Jonathan M. 
Published: December 2005

AbstractRecent findings in tumor biopsies from lung adenocarcinoma patients suggest that somatic mutations in the genes encoding epidermal growth factor receptor (EGFR) and Kirsten ras (KRAS) confer sensitivity and resistance, respectively, to EGFR inhibition. Here, we provide evidence that these genetic mutations are not sufficient to modulate the biological response of lung adenocarcinoma cells to EGFR inhibition. We found high expression of ErbB family members, ErbB ligands, or both in three models that were sensitive to EGFR inhibition, including alveolar epithelial neoplastic lesions in mice that develop lung adenocarcinoma by oncogenic KRAS, human lung adenocarcinoma cell lines, and tumor biopsies from lung adenocarcinoma patients. Thus, lung adenocarcinoma cells that depend on EGFR for survival constitutively activate the receptor through a combination of genetic mutations and overexpression of EGFR dimeric partners and their ligands. (Cancer Res 2005; 65(24): 11478-85)
Checkpoint Abrogation in G2 Compromises Repair of Chromosomal Breaks in Ataxia Telangiectasia Cells
Authors: Terzoudi Georgia I. , Manola Kaliopi N. , Pantelias Gabriel E. , Iliakis George 
Published: December 2005

Abstract
Checkpoint abrogation in G2 compromises repair of DNA double-strand breaks (DSB) and confers enhanced G2 chromosomal radiosensitivity in ataxia telangiectasia (AT) cells. To directly test this hypothesis, we combined calyculin A–induced premature chromosome condensation with conventional cytogenetics to evaluate chromosome damage before and after the G2 checkpoint in irradiated primary AT and normal human lymphocytes and their lymphoblastoid derivatives. Direct analysis of radiation damage in G2 by premature chromosome condensation reveals practically indistinguishable levels of chromosomal breaks in AT and normal cells. Yet a 4-fold increase in metaphase chromosome damage is observed in AT cells as compared with normal cells which, in contrast to AT cells, exhibit a strong G2 arrest manifest as an abrupt reduction in the mitotic index. Thus, an active checkpoint facilitates repair of chromosomal breaks in normal cells. Treatment with caffeine that abrogates the G2 checkpoint without significantly affecting DSB rejoining increases metaphase chromosome damage of normal cells to the AT level but leaves unchanged interphase chromosome damage in G2. Caffeine has no effect on any of these end points in AT cells. These observations represent the first direct evidence that the G2 checkpoint facilitates repair of chromosome damage, presumably by supporting repair of DNA DSBs. Failure to arrest will lead to chromatin condensation and conversion of unrepaired DNA DSBs to chromosomal breaks during G2-to-M phase transition. (Cancer Res 2005; 65(24): 11292-6)
A Prospective Study of Meat and Meat Mutagens and Prostate Cancer Risk
Authors: Cross Amanda J. , Peters Ulrike , Kirsh Victoria A. , Andriole Gerald L. , Reding Douglas , Hayes Richard B. , Sinha Rashmi 
Published: December 2005

Abstract
High-temperature cooked meat contains heterocyclic amines, including 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), and polycyclic aromatic hydrocarbons, such as benzo(a)pyrene (BaP). In rodents, a high intake of PhIP induces prostate tumors. We prospectively investigated the association between meat and meat mutagens, specifically PhIP, and prostate cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Diet was assessed using a 137-item food frequency questionnaire and a detailed meat-cooking questionnaire linked to a database for BaP and the heterocyclic amines 2-amino-3,8-dimethylimidazo[4,5-b]quinoxaline (MeIQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx), and PhIP. During follow-up, we ascertained a total of 1,338 prostate cancer cases among 29,361 men; of these, 868 were incident cases (diagnosed after the first year of follow-up) and 520 were advanced cases (stage III or IV or a Gleason score of ≥7). Total, red, or white meat intake was not associated with prostate cancer risk. More than 10 g/d of very well done meat, compared with no consumption, was associated with a 1.4-fold increased risk of prostate cancer [95% confidence interval (95% CI), 1.05-1.92] and a 1.7-fold increased risk (95% CI, 1.19-2.40) of incident disease. Although there was no association with MeIQx and DiMeIQx, the highest quintile of PhIP was associated with a 1.2-fold increased risk of prostate cancer (95% CI, 1.01-1.48) and a 1.3-fold increased risk of incident disease (95% CI, 1.01-1.61). In conclusion, very well done meat was positively associated with prostate cancer risk. In addition, this study lends epidemiologic support to the animal studies, which have implicated PhIP as a prostate carcinogen. (Cancer Res 2005; 65(24): 11779-84)
Cyclophosphamide Allows for In vivo Dose Reduction of a Potent Oncolytic Virus
Authors: Kambara Hirokazu , Saeki Yoshinaga , Chiocca E. Antonio 
Published: December 2005

Abstract
The success of cancer virotherapy depends on its efficacy versus toxicity profile in human clinical trials. Progress towards clinical trials can be hampered by the relatively elevated doses of oncolytic viruses administered in animal models to achieve an anticancer effect and by the even higher doses required in humans to approximate an animal bioequivalent dose. Such elevated doses of injected viral proteins may also lead to undesirable toxicities and are also very difficult to produce in a biotechnological setting. We report that a relatively potent herpes simplex virus type 1 oncolytic virus (rQNestin34.5) produces 45% survivors at a dose of 3 × 104 plaque-forming units (pfu) in a 9-day-old mouse model of human glioma. Unlike our previous findings with less potent oncolytic viruses, though, the preadministration of cyclophosphamide did not enhance this survival or affect oncolytic virus tumor distribution and tumor volume. However, when oncolytic virus doses were reduced (3 × 103 and 3 × 102 pfu), cyclophosphamide significantly enhanced both animal survival and oncolytic virus tumor distribution and also reduced tumor volumes. These findings thus show that cyclophosphamide allows for dose reduction of doses of a relatively potent oncolytic virus, a finding with implications for the development of clinical trials. (Cancer Res 2005; 65(24): 11255-8)
Bcl-2/Adenovirus E1B 19 kDa Interacting Protein-3 Knockdown Enables Growth of Breast Cancer Metastases in the Lung, Liver, and Bone
Authors: Manka David , Spicer Zachary , Millhorn David E. 
Published: December 2005

AbstractThe mouse breast cancer cell lines 4T1, 4T07, and 67NR are highly tumorigenic but vary in metastatic potential: 4T1 widely disseminates, resulting in secondary tumors in the lung, liver, bone, and brain; 4T07 spreads to the lung and liver but is unable to establish metastatic nodules; 67NR is unable to metastasize. The Bcl-2/adenovirus E1B 19 kDa interacting protein-3 (Bnip-3) was recently shown to be absent after hypoxia in pancreatic cancer cell lines whereas its overexpression restored hypoxia-induced cell death. We found that Bnip-3 expression increased after 6 hours of hypoxia in all cell lines tested but was highest in the nonmetastatic 67NR cells and lowest in the highly metastatic 4T1 cells. Hypoxia-induced expression of Bnip-3 in the disseminating but nonmetastatic 4T07 cells was intermediate compared with 4T1 and 67NR cells. Cleaved caspase-3, a key downstream effector of cell death, increased after 6 hours of hypoxia in the 67NR and 4T07 cells by 1.9- and 2.5-fold, respectively. Conversely, cleaved caspase-3 decreased by 45% in the highly metastatic 4T1 cells after hypoxia. Small interfering RNA oligonucleotides targeting endogenous Bnip-3 blocked cell death and increased clonigenic survival after hypoxic challenge in vitro and increased primary tumor size and enabled metastasis to the lung, liver, and sternum of mice inoculated with 4T07 cells in vivo. These data inversely correlate the hypoxia-induced expression of the cell death protein Bnip-3 to metastatic potential and suggest that loss of Bnip-3 expression is critical for malignant and metastatic evasion of hypoxia-induced cell death. (Cancer Res 2005; 65(24): 11689-93)
Relationships between Gulf of California Moisture Surges and Tropical Cyclones in the Eastern Pacific Basin
Authors: Higgins R. W. , Shi W. 
Published: December 2005

Abstract
Relationships between Gulf of California moisture surges and tropical cyclones (TCs) in the eastern Pacific basin are examined. Standard surface observations are used to identify gulf surge events at Yuma, Arizona, for a multiyear (July–August 1979–2001) period. The surges are related to TCs using National Hurricane Center 6-hourly track data for the eastern Pacific basin. Climate Prediction Center (CPC)- observed daily precipitation analyses and the NCEP Regional Reanalysis are used to examine the relative differences in the precipitation, atmospheric circulation, and moisture fields for several categories of surge events, including those that are directly related to TCs, indirectly related to TCs, and not related to TCs.
It is shown that the response to the surge in the southwestern United States and northwestern Mexico is strongly discriminated by the presence or absence of TCs. Surges related to TCs tend to be associated with much stronger and deeper low-level southerly flow, deeper plumes of tropical moisture, and wetter conditions over the core monsoon region than surges that are unrelated to TCs. The response to the surge is also strongly influenced by the proximity of the TC to the Gulf of California (GOC) region. Tropical cyclones that track toward the GOC region exert a stronger, more direct influence on Yuma surges than those that track away from the GOC.