bluuebunny/crossref_metadata_2025 huggingface dataset:
SUSTAINABILITY ASSESSMENT: DRESSING UP SEA? — EXPERIENCES FROM SOUTH AFRICA
Authors: GOVENDER KOGI , HOUNSOME ROB , WEAVER ALEX
Published: September 2006

Sustainability Assessment is a recent addition to the environmental assessment toolbox that is not currently applied in South Africa in any formal way. However, there appear to be remarkable similarities between what is commonly proposed as Sustainability Assessment and how Strategic Environmental Assessment (SEA) has been conceptualised and promoted in South Africa. This paper therefore investigates the following questions:.

• Could the South African concept and application of SEA be what is required for Sustainability Assessment?

• If Sustainability Assessment is "dressing up" SEA, is there really a need to introduce a new tool?

• If there is a need for a new tool, are there lessons learnt from the application of SEA in South Africa, which can be used to inform the further development and indeed practice of Sustainability Assessment?

This paper identifies from the literature some key criteria that should underpin Sustainability Assessment that are then used to identify some of the shortcomings of SEA, both as promoted and as practised in South Africa. Two sets of criteria form the basis of the analysis: one relating to sustainability assessment processes and the other to the concept of sustainability itself. As a result of this analysis, the paper makes recommendations as to how the practice of SEA in South Africa may be improved to better align with the principles of Sustainability Assessment. These recommendations are also likely to be relevant to other countries seeking to develop Sustainability Assessment processes based upon SEA. Finally, the potential for the emerging field of sustainability science as an underpinning body of knowledge is introduced.
SUSTAINABILITY ASSESSMENT IN CONTEXT: ISSUES OF PROCESS, POLICY AND GOVERNANCE
Authors: POPE JENNY , GRACE WILLIAM
Published: September 2006

This paper seeks to contribute to the development of principles for effective sustainability assessment. Drawing upon three sustainability assessments of project proposals conducted recently in Western Australia, three important aspects of good process are identified: the "question" that guides the assessment process; the influence of the assessment process on the development of the final proposal; and the basis for sustainability decision-making. These three aspects are closely inter-related, and also influenced by and related to the prevailing policy context and institutional arrangements guiding the assessment. Recommendations are made for more effective sustainability assessment processes in Western Australia; and the ultimate contribution that effective sustainability assessments of project proposals could make to a more sustainable society is considered. The broader Western Australian political, cultural and social context within which the assessments have been conducted is described, in order to facilitate a deeper understanding of the issues discussed and therefore to maximise the potential for others to learn from these experiences.
The Epidermal Growth Factor Receptor Pathway: A Model for Targeted Therapy
Authors: Scaltriti Maurizio , Baselga José
Published: September 2006

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase receptor that is frequently expressed in epithelial tumors. The EGFR was the first receptor to be proposed as a target for cancer therapy, and after 2 decades of intensive research, there are several anti-EGFR agents available in the clinic. Recent advances in our understanding in the mechanisms of receptor activation and function, discovery of primary and secondary EGFR somatic mutations, as well as a new generation of anti-EGFR agents provide new leads on the clinical targeting of this receptor and may serve as a model for strategies aimed at targeting other receptors.
Polymorphisms of FAS and FAS Ligand Genes Involved in the Death Pathway and Risk and Progression of Squamous Cell Carcinoma of the Head and Neck
Authors: Zhang Zhengdong , Wang Li-E , Sturgis Erich M. , El-Naggar Adel K. , Hong Waun K. , Amos Christopher I. , Spitz Margaret R. , Wei Qingyi
Published: September 2006

Purpose: Alteration of the FAS/FAS ligand (FASLG) pathway regulating cell death may lead to cancer development, but the effects of functional promoter polymorphisms of the FAS and FASLG genes on risk of squamous cell carcinoma of the head and neck (SCCHN) are unknown.

Design: We genotyped the FAS −1377 G>A, FAS −670 A>G, FASLG −844 C>T, and FASLG IVS2nt −124 A>G polymorphisms in 721 case patients with SCCHN and 1,234 cancer-free non–Hispanic White control subjects frequency-matched by age and sex. Multivariate logistic regression was used to assess the adjusted odds ratios (OR) and 95% confidence intervals (CI).

Results: Compared with the FAS −1377 GG and −670 AA genotypes, the FAS −1377 AA and −670 (GG + AG) genotypes were associated with an increased risk of SCCHN (OR, 2.23; 95% CI, 1.07-4.64 and OR, 1.24; 95% CI, 1.01-1.52, respectively), whereas no risk of SCCHN was associated with any of the FASLG genotypes. When we used the combined FAS −1377 (GG + AG)/−670 AA genotypes as the reference, we found that the individuals carrying the FAS −1377 AA/−670 (GG + AG) had the highest risk (OR, 2.69; 95% CI, 1.24-5.83), whereas individuals carrying genotypes other than FAS −1377 (GG + AG)/−670 AA had a higher risk of SCCHN (OR, 1.24; 95% CI, 1.01-1.52). Furthermore, the elevated risk was particularly evident for pharyngeal cancer with the larger tumors without regional lymph metastasis (OR, 1.77; 95% CI, 1.07-2.94).

Conclusions: The FAS (but not FASLG) polymorphisms seem to contribute to risk of developing SCCHN, particularly the pharyngeal cancer in non–Hispanic Whites. However, potential selection bias warrants future population-based studies to verify the findings.
Tumor Hypoxia Imaging with [F-18] Fluoromisonidazole Positron Emission Tomography in Head and Neck Cancer
Authors: Rajendran Joseph G. , Schwartz David L. , O'Sullivan Janet , Peterson Lanell M. , Ng Patrick , Scharnhorst Jeffrey , Grierson John R. , Krohn Kenneth A.
Published: September 2006

Purpose: Advanced head and neck cancer shows hypoxia that results in biological changes to make the tumor cells more aggressive and less responsive to treatment resulting in poor survival. [F-18] fluoromisonidazole (FMISO) positron emission tomography (PET) has the ability to noninvasively quantify regional hypoxia. We investigated the prognostic effect of pretherapy FMISO-PET on survival in head and neck cancer.

Experimental Design: Seventy-three patients with head and neck cancer had pretherapy FMISO-PET and 53 also had fluorodeoxyglucose (FDG) PET under a research protocol from April 1994 to April 2004.

Results: Significant hypoxia was identified in 58 patients (79%). The mean FMISO tumor/bloodmax (T/Bmax) was 1.6 and the mean hypoxic volume (HV) was 40.2 mL. There were 28 deaths in the follow-up period. Mean FDG standard uptake value (SUV)max was 10.8. The median time for follow-up was 72 weeks. In a univariate analysis, T/Bmax (P = 0.002), HV (P = 0.04), and the presence of nodes (P = 0.01) were strong independent predictors. In a multivariate analysis, including FDG SUVmax, no variable was predictive at P < 0.05. When FDG SUVmax was removed from the model (resulting in n = 73 with 28 events), nodal status and T/Bmax (or HV) were both highly predictive (P = 0.02, 0.006 for node and T/Bmax, respectively; P = 0.02 and 0.001 for node and HV, respectively).

Conclusions: Pretherapy FMISO uptake shows a strong trend to be an independent prognostic measure in head and neck cancer.
Overexpression of Cyclase-Associated Protein 2 in Multistage Hepatocarcinogenesis
Authors: Shibata Rie , Mori Taisuke , Du Wenlin , Chuma Makoto , Gotoh Masahiro , Shimazu Motohide , Ueda Masakazu , Hirohashi Setsuo , Sakamoto Michiie
Published: September 2006

Purpose: Hepatocellular carcinoma (HCC) associated with chronic liver disease is known to show an obvious multistage process of tumor progression. We previously identified heat shock protein 70 as a molecular marker of early HCC during investigation of expression profiling in multistage hepatocarcinogenesis. In this report, we examined cyclase-associated protein 2 (CAP2), which is also listed as an up-regulated gene in early HCC.

Experimental Design: We measured the level of CAP2 mRNA by real-time quantitative PCR. We raised a polyclonal antibody against CAP2 and we confirmed the expression of CAP2 by immunoblotting and immunohistochemistry in HCC cell lines and HCC tissues.

Results: According to real-time quantitative PCR, the level of CAP2 mRNA was up-regulated in early HCC when compared with noncancerous liver tissue, and it was further up-regulated in progressed HCC. We raised a polyclonal antibody against CAP2, which showed a single 53-kDa band of strong intensity in the human HCC cell lines and HCC tissues but only a weak band in the noncancerous liver tissues in Western blot analysis. Immunohistochemical examination of CAP2 revealed its significant overexpression in early HCC when compared with noncancerous and precancerous lesions and in progressed HCC when compared with early HCC.

Conclusion: Our findings show that CAP2 is up-regulated in HCC when compared with noncancerous and precancerous lesions. This is the first report that proves that CAP2 is up-regulated in human cancers and that this is possibly related to multistage hepatocarcinogenesis.
Novel Thioredoxin Inhibitors Paradoxically Increase Hypoxia-Inducible Factor-α Expression but Decrease Functional Transcriptional Activity, DNA Binding, and Degradation
Authors: Jones Dylan T. , Pugh Christopher W. , Wigfield Simon , Stevens Malcolm F.G. , Harris Adrian L.
Published: September 2006

Purpose: Hypoxia-inducible factor-α (HIF-α) is a transcription factor that regulates the response to hypoxia. HIF-α protein is found at high levels in many cancers, and the redox protein thioredoxin-1 (Trx-1) increases both aerobic and hypoxia-induced HIF-α. Therefore, Trx-1 and HIF-α are attractive molecular targets for novel cancer therapeutics.

Experimental Design: We investigated whether two novel anticancer drugs AJM290 and AW464 (quinols), which inhibit Trx-1 function, can inhibit the HIF pathway.

Results: Treatment of several cancer cell lines with AJM290 or AW464 prevented the hypoxia-induced increase of vascular endothelial growth factor (VEGF) at subtoxic concentrations. AJM290 and AW464 also decreased VEGF in pVHL mutant renal cell carcinoma cells that constitutively overexpress HIF-α protein. They surprisingly up-regulated HIF-α expression in breast cancer cell lines in normoxia and hypoxia as well as in pVHL mutant cells. In the MDA-MB-468 breast cancer cell line, the compounds inhibited RNA and protein expression of the HIF-α target genes, carbonic anhydrase IX, VEGF, and BNIP3, concordantly with HIF-α up-regulation. Both compounds specifically inhibited HIF-α-dependent induction of hypoxia regulatory element-luciferase and HIF-1α hypoxia regulatory element-DNA binding. To analyze the HIF-1α domain inhibited by AJM290, we transfected cells with plasmids expressing a fusion protein of Gal linked to HIF-1α or HIF-1α COOH-terminal transactivation domain (CAD) with a Gal4-responsive luciferase reporter gene. AJM290 inhibited both the full-length HIF-1α and HIF-1α CAD transcriptional activity.

Conclusions: AJM290 and AW464 are inhibitors of HIF-1α CAD transcription activity and DNA binding, but they also inhibit degradation of HIF, in contrast to other Trx inhibitors.
Human Neural Stem Cells Target Experimental Intracranial Medulloblastoma and Deliver a Therapeutic Gene Leading to Tumor Regression
Authors: Kim Seung-Ki , Kim Seung U. , Park In Ho , Bang Jung Hee , Aboody Karen S. , Wang Kyu-Chang , Cho Byung-Kyu , Kim Manho , Menon Lata G. , Black Peter M. , Carroll Rona S.
Published: September 2006

Purpose: Medulloblastoma, a malignant pediatric brain tumor, is incurable in about one third of patients despite multimodal treatments. In addition, current therapies can lead to long-term disabilities. Based on studies of the extensive tropism of neural stem cells (NSC) toward malignant gliomas and the secretion of growth factors common to glioma and medulloblastoma, we hypothesized that NSCs could target medulloblastoma and be used as a cellular therapeutic delivery system.

Experimental Design: The migratory ability of HB1.F3 cells (an immortalized, clonal human NSC line) to medulloblastoma was studied both in vitro and in vivo. As proof-of-concept, we used HB1.F3 cells engineered to secrete the prodrug activating enzyme cytosine deaminase. We investigated the potential of human NSCs to deliver a therapeutic gene and reduce tumor growth.

Results: The migratory capacity of HB1.F3 cells was confirmed by an in vitro migration assay, and corroborated in vivo by injecting chloromethylbenzamido-Dil–labeled HB1.F3 cells into the hemisphere contralateral to established medulloblastoma in nude mice. In vitro studies showed the therapeutic efficacy of HB1.F3-CD on Daoy cells in coculture experiments. In vitro therapeutic studies were conducted in which animals bearing intracranial medulloblastoma were injected ipsilaterally with HB1.F3-CD cells followed by systemic 5-flourocytosine treatment. Histologic analyses showed that human NSCs migrate to the tumor bed and its boundary, resulting in a 76% reduction of tumor volume in the treatment group (P < 0.01).

Conclusion: These studies show for the first time the potential of human NSCs as an effective delivery system to target and disseminate therapeutic agents to medulloblastoma.
Phase I Study of Abagovomab in Patients with Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
Authors: Sabbatini Paul , Dupont Jakob , Aghajanian Carol , Derosa Felicia , Poynor Elizabeth , Anderson Sybil , Hensley Martee , Livingston Phillip , Iasonos Alexia , Spriggs David , McGuire William , Reinartz Silke , Schneider Sally , Grande Cathy , Lele Shashikant , Rodabaugh Kerry , Kepner James , Ferrone Soldano , Odunsi Kunle
Published: September 2006

Purpose: This open-label study assessed the safety and immunogenicity of two doses and two routes of the anti-idiotypic monoclonal antibody abagovomab (formerly ACA125) in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer.

Experimental Design: Eligible patients from the three participating institutions were any stage at diagnosis, had relapsed, and had complete or partial response to additional chemotherapy. Patients were randomized to receive abagovomab at 2.0 versus 0.2 mg and i.m. versus s.c. for four immunizations every 2 weeks and then monthly for two additional immunizations. Planned evaluation included interval physical examinations and laboratory assessments with immune assessment, including HLA typing, human anti-mouse antibody, ELISA, and enzyme-linked immunospot. Patients were required to remain on study until week 10 (the first post-baseline Ab3 determination) to be considered for immunologic assessment. The primary end points were safety and immunogenicity primarily determined by Ab3 response.

Results: Forty-two patients received at least one vaccination and were eligible for safety analysis. Thirty-three patients were available for Ab3 analysis (removed for progression of disease, 6; withdrawal of consent, 2; unrelated adverse event, 1). The most common adverse events were self-limited pain at injection site, myalgia, and fever. No hematologic or nonhematologic toxicity grade >2 related to immunization was seen. Ab3 was detectable in all patients (median, 236,794 ng/mL); none of route of administration (P = 0.6268), dose (P = 0.4602), or cohort (P = 0.4944) was statistically significant in terms of effect on maximum post-baseline Ab3 titer. Human anti-mouse antibody was not detectable at baseline but was present in all patients at week 16 (range, 488-45,000 ng/mL).

Conclusions: Immunization with abagovomab is well tolerated and induced robust Ab3 responses at the two doses and routes tested. A phase III randomized study with abagovomab (2.0 mg s.c.) is warranted.
Twist Overexpression Correlates with Hepatocellular Carcinoma Metastasis through Induction of Epithelial-Mesenchymal Transition
Authors: Lee Terence K. , Poon Ronnie T.P. , Yuen Anthony P. , Ling Ming Tat , Kwok Wei Kei , Wang Xiang Hong , Wong Yong Chuan , Guan Xin Yuan , Man Kwan , Chau King Lok , Fan Sheung Tat
Published: September 2006

Purpose: Hepatocellular carcinoma (HCC) is a rapidly growing tumor associated with a high propensity for vascular invasion and metastasis. Epithelial-mesenchymal transition (EMT) is a key event in the tumor invasion process. Recently, Twist has been identified to play an important role in EMT-mediated metastasis through the regulation of E-cadherin expression. However, the actual role of Twist in tumor invasiveness remains unclear. The purpose of this study is to investigate the expression and possible role of Twist in HCC.

Experimental Design: We evaluated Twist and E-cadherin expression in HCC tissue microarray of paired primary and metastatic HCC by immunohistochemical staining. The role of Twist in EMT-mediated invasiveness was also evaluated in vitro in HCC cell lines.

Results: We first showed that overexpression of Twist was correlated with HCC metastasis (P = 0.001) and its expression was negatively correlated with E-cadherin expression (P = 0.001, r = −0.443) by tissue microarray. A significant increase of Twist at the mRNA level was also found in metastatic HCC cell lines MHCC-97H, MHCC-97L, and H2M when compared with nonmetastatic Huh-7, H2P, and PLC cell lines. The MHCC-97H cell line, which has a higher metastatic ability, was found to have a higher level of Twist than MHCC-97L. Accompanied with increased Twist expression in the metastatic HCC cell lines when compared with the nonmetastatic primary ones, we found decreased E-cadherin mRNA expression in the metastatic HCC cell lines. By ectopic transfection of Twist into PLC cells, Twist was able to suppress E-cadherin expression and induce EMT changes, which was correlated with increased HCC cell invasiveness.

Conclusion: This study shows that Twist overexpression was correlated with HCC metastasis through induction of EMT changes and HCC cell invasiveness.
Interleukin 6, a Nuclear Factor-κB Target, Predicts Resistance to Docetaxel in Hormone-Independent Prostate Cancer and Nuclear Factor-κB Inhibition by PS-1145 Enhances Docetaxel Antitumor Activity
Authors: Domingo-Domenech Josep , Oliva Cristina , Rovira Ana , Codony-Servat Jordi , Bosch Marta , Filella Xavier , Montagut Clara , Tapia Marian , Campás Clara , Dang Lenny , Rolfe Mark , Ross Jeffrey S. , Gascon Pere , Albanell Joan , Mellado Begoña
Published: September 2006

Purpose: To investigate whether nuclear factor κB (NF-κB)/interleukin 6 (IL-6) was linked to docetaxel response in human prostate cancer cell lines, and whether inhibition of NF-κB sensitized tumor cells to docetaxel. We also aimed to correlate IL-6 (as a surrogate marker of NF-κB) and docetaxel response in hormone-independent prostate cancer (HIPC) patients.

Experimental Design: Hormone-dependent (LNCaP) and hormone-independent (PC-3 and DU-145) prostate cancer cell lines were exposed to docetaxel alone or combined with the NF-κB inhibitor PS-1145 (an inhibitor of IκB kinase-2). Effects of dose, exposure time, and schedule dependence were assessed. Activation of NF-κB was assayed by electrophoresis mobility shift assay and luciferase reporter assay, IL-6 levels by ELISA, and cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell cycle and apoptosis were assessed by fluorescence-activated cell sorting analysis. Apoptosis was also measured by detection of cleavage of poly(ADP-ribose) polymerase. In patients with metastatic HIPC receiving docetaxel-based chemotherapy, IL-6 serum levels were assayed before chemotherapy and every 3 to 4 weeks thereafter.

Results: PC-3 and DU-145 cells had higher NF-κB activity, secreted more IL-6, and were more resistant to docetaxel than LNCaP cells. NF-κB activity was induced by docetaxel. Cotreatment with docetaxel and PS-1145 prevented docetaxel-induced NF-κB activation, reduced IL-6 production, and increased docetaxel effects on cell viability in PC-3 and DU-145 cells but not in LNCaP. Synergism with docetaxel and PS-1145, as assayed by median-effect principle, was observed in DU-145 and PC-3. In HIPC patients, pretreatment IL-6 serum levels correlated to prostate-specific antigen (PSA) response: median IL-6 level was 10.8 ± 9.5 pg/mL in PSA responders versus 36.7 ± 20.8 pg/mL (P = 0.006) in nonresponders. A PSA response was also linked to a decline in IL-6 levels during treatment. Median overall survival was 6.8 months in patients with high IL-6 versus 16.6 months in those with low IL-6 (P = 0.0007). On multivariate analysis, pretreatment IL-6 (P = 0.05) was an independent prognostic factor for time to disease progression and survival.

Conclusions: Inhibition of NF-κB emerges as an attractive strategy to enhance docetaxel response in prostate cancer. The interest of this view is further supported by a significant association between high IL-6 in sera of HIPC patients and decreased response to docetaxel.
EWS-CREB1: A Recurrent Variant Fusion in Clear Cell Sarcoma—Association with Gastrointestinal Location and Absence of Melanocytic Differentiation
Authors: Antonescu Cristina R. , Nafa Khedoudja , Segal Neil H. , Dal Cin Paola , Ladanyi Marc
Published: September 2006

Purpose: Clear cell sarcoma (CCS) usually arises in the lower extremities of young adults and is typically associated with a t(12;22) translocation resulting in the fusion of EWS (EWSR1) with ATF1, a gene encoding a member of the cyclic AMP–responsive element binding protein (CREB) family of transcription factors. CCS arising in the gastrointestinal tract is rare and its pathologic and molecular features are not well defined.

Experimental Design: We report a novel variant fusion of EWS to CREB1, a gene at 2q32 encoding another CREB family member highly related to ATF1, detected in three women with gastrointestinal CCS. All three cases contained an identical EWS-CREB1 fusion transcript that was shown by reverse transcription-PCR. In two of the cases tested, EWS gene rearrangement was also confirmed by fluorescence in situ hybridization and the EWS-CREB1 genomic junction fragments were isolated by long-range DNA PCR.

Results: Morphologically, all three tumors lacked melanin pigmentation. By immunohistochemistry, there was a strong and diffuse S100 protein reactivity, whereas all melanocytic markers were negative. Ultrastructurally, two of the cases lacked melanosomes. The melanocyte-specific transcript of MITF was absent in two cases, and only weakly expressed in the third case. The Affymetrix gene expression data available in one case showed lower expression of the melanocytic genes MITF, TYR, and TYRP1, compared with four EWS-ATF1-positive CCSs of non-gastrointestinal origin.

Conclusions: EWS-CREB1 may define a novel subset of CCS that occurs preferentially in the gastrointestinal tract and shows little or no melanocytic differentiation. Thus, evidence of melanocytic lineage or differentiation is not a necessary feature of sarcomas with gene fusions involving CREB family members.
Human Regulatory T Cells Control Xenogeneic Graft-versus-Host Disease Induced by Autologous T Cells in RAG2−/−γc−/− Immunodeficient Mice
Authors: Mutis Tuna , van Rijn Rozemarijn S. , Simonetti Elles R. , Aarts-Riemens Tineke , Emmelot Maarten E. , van Bloois Louis , Martens Anton , Verdonck Leo F. , Ebeling Saskia B.
Published: September 2006

Purpose: Effective prevention of graft-versus-host disease (GvHD) is a major challenge to improve the safety of allogeneic stem cell transplantation for leukemia treatment. In murine transplantation models, administration of naturally occurring CD4+CD25+ regulatory T cells (Treg) can prevent GvHD. Toward understanding the role of human Treg in stem cell transplantation, we studied their capacity to modulate T-cell–dependent xenogeneic (x)-GvHD in a new model where x-GvHD is induced in RAG2−/−γc−/− mice by i.v. administration of human peripheral blood mononuclear cells (PBMC).

Experimental Design: Human PBMC, depleted of or supplemented with autologous CD25+ Tregs, were administered in mice at different doses. The development of x-GvHD, in vivo expansion of human T cells, and secretion of human cytokines were monitored at weekly intervals.

Results: Depletion of CD25+ cells from human PBMC significantly exacerbated x-GvHD and accelerated its lethality. In contrast, coadministration of Treg-enriched CD25+ cell fractions with autologous PBMC significantly reduced the lethality of x-GvHD. Treg administration significantly inhibited the explosive expansion of effector CD4+ and CD8+ T cells. Interestingly, protection from x-GvHD after Treg administration was associated with a significant increase in plasma levels of interleukin-10 and IFN-γ, suggesting the de novo development of TR1 cells.

Conclusions: These results show, for the first time, the potent in vivo capacity of naturally occurring human Tregs to control GvHD-inducing autologous T cells, and indicate that this xenogeneic in vivo model may provide a suitable platform to further explore the in vivo mechanisms of T-cell down-regulation by naturally occurring human Tregs.
Bispecific Antibody Pretargeting of Tumor Neovasculature for Improved Systemic Radiotherapy of Solid Tumors
Authors: Moosmayer Dieter , Berndorff Dietmar , Chang Chien-Hsing , Sharkey Robert M. , Rother Axel , Borkowski Sandra , Rossi Edmund A. , McBride William J. , Cardillo Thomas M. , Goldenberg David M. , Dinkelborg Ludger M.
Published: September 2006

Purpose: Extra domain B (ED-B) fibronectin is a specific tumor matrix marker for targeting angiogenesis in solid tumors. In this study, the radiotherapeutic potential of the directly radioiodinated divalent anti-ED-B antibody fragment, L19 small immunoprotein (L19-SIP; 75,000 Da), was compared with a pretargeting approach using the bispecific antibody AP39xm679 (bsMAb; 75,000 Da).

Experimental Design: The bsMAb was prepared by coupling an anti-ED-B single-chain Fv (AP39) to the Fab′ of the murine antibody m679, which binds to the small peptidic hapten histamine-succinyl-glycine (HSG). As an effector molecule for the pretargeting approach, the 111In-labeled HSG-DOTA complex was injected 25 or 41 hours after the bsMAb. The kinetics of both the iodinated bsMAb and the pretargeted 111In-labeled HSG hapten were investigated in mice bearing human glioblastoma xenografts (U251) and compared with the kinetics and tumor accumulation of radioiodinated L19-SIP. 111In and 125I were used as surrogate marker for the therapeutic radioisotopes 90Y/177Lu and 131I, respectively.

Results: Tumor uptake of the pretargeted 111In-labeled peptide was significantly higher than 125I-L19-SIP over 7 days. At the calculated maximally tolerated dose for each agent (with the kidney being the dose-limiting organ for pretargeting and the bone marrow for direct targeting), a mouse tumor dose of 146 Gy could be given by pretargeting versus 45 Gy delivered by the direct approach.

Conclusions: These data suggest that pretargeting of ED-B with AP39xm679 and subsequent injection of the 90Y-hapten-peptide would improve the therapeutic efficacy in solid tumors by >3-fold compared with directly radiolabeled 131I-L19-SIP.
S100A11, A Putative Tumor Suppressor Gene, Is Overexpressed in Pancreatic Carcinogenesis
Authors: Ohuchida Kenoki , Mizumoto Kazuhiro , Ohhashi Seiji , Yamaguchi Hiroshi , Konomi Hiroyuki , Nagai Eishi , Yamaguchi Koji , Tsuneyoshi Masazumi , Tanaka Masao
Published: September 2006

Purpose: Recent microarray analyses revealed that expression of S100A11 is up-regulated in pancreatic cancer. The aim of the present study was to evaluate the association of S100A11 with pancreatic carcinogenesis.

Experimental Design: We measured S100A11 mRNA expression in various clinical samples related to pancreatic cancer and its precursor lesions, intraductal papillary mucinous neoplasm (IPMN) and pancreatic intraepithelial neoplasia, by quantitative reverse transcription-PCR.

Results: Levels of S100A11 were significantly higher in pancreatic cancer (n = 22) and IPMN (n = 18) bulk tissues than in nonneoplastic bulk tissues (n = 22; P < 0.0001 for both). Levels of S100A11 did not differ between pancreatic cancer and IPMN bulk tissues. In microdissection analyses, however, IPMN cells (n = 21) expressed significantly higher levels of S100A11 than did cancer cells (n = 23; P = 0.003). The median level of S100A11 expression was higher in pancreatic intraepithelial neoplasia cells (n = 6) than in cancer cells. In pancreatic juice analyses, cancer-related (n = 24; P = 0.004) and IPMN-related (n = 18; P = 0.001) juice expressed significantly higher levels of S100A11 than did chronic pancreatitis–related juice (n = 23).

Conclusions: The present data suggest that expression of S100A11, a putative tumor suppressor gene, is increased in the early stage of pancreatic carcinogenesis and decreased during subsequent progression to cancer. Analysis of the S100A11 level in pancreatic juice may be an effective tool for screening of patients with high-risk lesions that could progress to pancreatic cancer or detecting early-stage pancreatic cancer.
Matrix Metalloproteinase Polymorphisms and Survival in Stage I Non–Small Cell Lung Cancer
Authors: Heist Rebecca Suk , Marshall Ariela L. , Liu Geoffrey , Zhou Wei , Su Li , Neuberg Donna , Lynch Thomas J. , Wain John , Christiani David C.
Published: September 2006

Purpose: The matrix metalloproteinases (MMP) are a family of enzymes that can degrade extracellular matrix and facilitate invasion through the basement membrane. Several polymorphisms in MMP-1, MMP-2, MMP-3, and MMP-12 have been described, some of which lead to differential transcription. We hypothesized that polymorphisms in these MMP genes may be associated with survival outcomes in early-stage non–small cell lung cancer (NSCLC).

Experimental Design: We evaluated the relationship between MMP-1, MMP-2, MMP-3, and MMP-12 polymorphisms and both recurrence-free survival (RFS) and overall survival (OS) among 382 patients with stage I NSCLC. Analyses of genotype associations with survival outcomes were done using Cox proportional hazards models and Kaplan-Meier methods and the log-rank test.

Results: Patients carrying the variant G allele of the MMP-12 1082A/G polymorphism had significantly worse outcomes [crude hazard ratio (HR) for OS 1.74; 95% confidence interval (95% CI), 1.18-2.58, P = 0.006; crude HR for RFS, 1.53; 95% CI, 1.05-2.23, P = 0.03]. After adjusting for age, sex, stage, pack-years of smoking, and histologic subtype, the MMP-12 1082A/G polymorphism remained significantly associated with survival outcomes [adjusted HR (AHR) for OS, 1.94; 95% CI, 1.28-2.97, P = 0.002; AHR for RFS, 1.61; 95% CI, 1.07-2.41, P = 0.02]. None of the other MMP polymorphisms was significantly associated with survival.

Conclusions: Our results show that patients with stage I NSCLC carrying the variant G allele of the MMP-12 1082A/G polymorphism have worse survival.
S100P Is an Early Developmental Marker of Pancreatic Carcinogenesis
Authors: Ohuchida Kenoki , Mizumoto Kazuhiro , Egami Takuya , Yamaguchi Hiroshi , Fujii Kei , Konomi Hiroyuki , Nagai Eishi , Yamaguchi Koji , Tsuneyoshi Masazumi , Tanaka Masao
Published: September 2006

Purpose: Our goal was to clarify the involvement and clinical significance of S100P in pancreatic carcinogenesis.

Experimental Design: We examined S100P expression in 45 bulk pancreatic tissues; in microdissected cells, including invasive ductal carcinoma (IDC) cells (20 sections), pancreatic intraepithelial neoplasia (PanIN) cells (12 sections), intraductal papillary mucinous neoplasm (IPMN) cells (19 sections), and normal epithelial cells (11 sections); and in pancreatic juice samples from 99 patients with pancreatic diseases (32 cancer, 35 IPMN, and 32 chronic pancreatitis samples). We used quantitative real-time reverse transcription-PCR with gene-specific priming to measure S100P in these various types of samples.

Results: In bulk tissue analyses, pancreatic cancer and IPMN expressed significantly higher levels of S100P than did nonneoplastic pancreas (P < 0.017 and P = 0.0013, respectively). Microdissection analyses revealed that IPMN expressed significantly higher levels of S100P than did IDC (P < 0.0001) and PanIN (P = 0.0031), although S100P expression did not differ between IDC and PanIN (P = 0.077). In pancreatic juice analyses, cancer and IPMN juice expressed significantly higher levels of S100P than did pancreatitis juice (both P < 0.0001). Receiver operating characteristic curve analyses revealed that measurement of S100P in pancreatic juice was useful for discriminating neoplastic disease from chronic pancreatitis (area under the curve = 0.837; 95% confidence interval, 0.749-0.903).

Conclusion: S100P may be an early developmental marker of pancreatic carcinogenesis, and measurement of S100P in pancreatic juice may be useful for early detection of pancreatic cancer or screening of early pancreatic carcinogenesis.
Pharmacogenetics of Capecitabine in Advanced Breast Cancer Patients
Authors: Largillier Rémy , Etienne-Grimaldi Marie-Christine , Formento Jean-Louis , Ciccolini Joseph , Nebbia Jean-François , Ginot Aurélie , Francoual Mireille , Renée Nicole , Ferrero Jean-Marc , Foa Cyril , Namer Moïse , Lacarelle Bruno , Milano Gérard
Published: September 2006

Purpose: Germinal gene polymorphisms can explain a part of the interpatient pharmacodynamic variability of anticancer drugs, particularly fluoropyrimidines. Genes for which polymorphisms may potentially influence pharmacodynamics of fluoropyrimidines, including capecitabine, are thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), and dihydropyrimidine dehydrogenase (DPD).

Experimental design: The aim of this prospective pilot study was to analyze the effect of TS, MTHFR, and DPD gene polymorphisms on toxicity and efficacy in advanced breast cancer patients receiving capecitabine as monotherapy. Germinal polymorphisms of TS (6 bp deletion in the 3′ region and 28 bp repeats, including G>C mutation in the 5′ region), MTHFR (677C>T and 1298A>C), and DPD (IVS14 + 1G>A) were determined in 105 consecutive patients.

Results: A trend toward a higher global toxicity grade 3 and 4 was observed in patients homozygous for the TS 3RG allele compared with patients heterozygous for the 3RG allele or patients not carrying the 3RG allele (50% versus 19% versus 13% respectively, P = 0.064). The sole patient bearing the DPD IVS14 + 1G>A mutation (heterozygous) deceased from hematologic toxicity. The median response duration was 5.8 months (95% confidence interval, 4.3-7.2). Duration of response was significantly shortened in patients homozygous for the 3RG allele compared with others (P = 0.037).

Conclusions: The present data suggest that 3RG3RG breast cancer patients are not good candidates for capecitabine therapy. In addition, attention should be paid to DPD deficiency in breast cancer patients receiving capecitabine. These preliminary data require further confirmation on a larger number of patients.
Antitumor Activity of Suberoylanilide Hydroxamic Acid against Thyroid Cancer Cell Lines In vitro and In vivo
Authors: Luong Quang T. , O'Kelly James , Braunstein Glenn D. , Hershman Jerome M. , Koeffler H. Phillip
Published: September 2006

Purpose: The histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), has multiple antitumor effects against a variety of human cancers.

Experimental design: We treated several anaplastic and papillary thyroid cancer cell lines with SAHA to determine if it could inhibit the growth of these cells in vitro and in vivo.

Results: SAHA effectively inhibited 50% clonal growth of the anaplastic thyroid cancer cell lines, ARO and FRO, and the papillary thyroid cancer cell line, BHP 7-13, at 1.3 × 10−7 to 5 × 10−7 mol/L, doses that are achievable in patients. In concert with growth inhibition, SAHA down-regulated the expression of cyclin D1 and up-regulated levels of p21WAF1. Annexin V and cleavage of poly(ADP)ribose polymerase were both increased by exposure of the thyroid cancer cells to SAHA. Expression of the death receptor 5 (DR5) gene was also increased by SAHA, but the combination of the DR5 ligand, tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), with SAHA had little effect compared with SAHA alone. Of note, the combination of paclitaxel, doxorubicin, or paraplatin with SAHA enhanced cell killing of the thyroid cancer cells. In addition, murine studies showed that SAHA administered daily by i.p. injection at 100 mg/kg inhibited the growth of human thyroid tumor cells.

Conclusion: Our data indicate that SAHA is a plausible adjuvant therapy for thyroid cancers.
Prevalence of FOXP3+ Regulatory T Cells Increases During the Progression of Pancreatic Ductal Adenocarcinoma and Its Premalignant Lesions
Authors: Hiraoka Nobuyoshi , Onozato Kaoru , Kosuge Tomoo , Hirohashi Setsuo
Published: September 2006

Purpose: Antitumor immune response changes drastically during the progression of cancers. Established cancers often escape from the host immune system, although specific immune surveillance operates in the early stages of tumorigenesis in murine models. CD4+CD25+ regulatory T cells (TR) play a central role in self-tolerance and suppress effective antitumor immune responses. The aim of this study was to investigate the clinical significance and roles of TR in the progression and multistep carcinogenesis of pancreatic ductal adenocarcinoma.

Experimental Design: We raised anti-FOXP3 antibodies and used them in immunohistochemical studies of the prevalence of FOXP3+CD4+CD25+ TR in the CD4+ T cells, which infiltrated in tissue and draining lymph nodes of 198 pancreatic ductal adenocarcinomas, their premalignant lesions (84 lesions of pancreatic intraepithelial neoplasias and 51 intraductal papillary-mucinous neoplasms), and 15 nonneoplastic pancreatic lesions.

Results: The prevalence of TR was significantly increased in the ductal adenocarcinomas compared with that in the stroma of nonneoplastic inflammation (P < 0.0001). The increased prevalence of TR was significantly correlated with certain clinicopathologic factors. A better prognosis was observed in patients with a low prevalence of TR, and this was independent of other survival factors (P < 0.0001). Infiltration of intraepithelial CD8+TIA-1+ cytotoxic T cells in pancreatic ducts was marked in low-grade premalignant lesions but diminished during the progression of both pancreatic intraepithelial neoplasias and intraductal papillary-mucinous neoplasms. Conversely, the prevalence of TR increased significantly during the progression of premalignant lesions.

Conclusions: TR play a role in controlling the immune response against pancreatic ductal carcinoma from the premalignant stage to established cancer. In pancreatic ductal carcinoma, a high prevalence of TR seems to be a marker of poor prognosis.
The Use of Targeted Mouse Models for Preclinical Testing of Novel Cancer Therapeutics
Authors: Olive Kenneth P. , Tuveson David A.
Published: September 2006

The use of genetically engineered cancer-prone mice as relevant surrogates for patients during the development of pertinent clinical applications is an unproven expectation that awaits direct demonstration. Despite the generally disappointing findings using tumor xenografts and certain early transgenic cancer models to predict therapeutic efficacy in patients, the dramatic progress of mouse models in recent years engenders optimism that the newest generation of mouse models will provide a higher standard of predictive utility in the process of drug development.
Using Genetically Engineered Mouse Models of Cancer to Aid Drug Development: An Industry Perspective
Authors: Singh Mallika , Johnson Leisa
Published: September 2006

Recent developments in the generation and characterization of genetically engineered mouse models of human cancer have resulted in notable improvements in these models as platforms for preclinical target validation and experimental therapeutics. In this review, we enumerate the criteria used to assess the accuracy of various models with respect to human disease and provide some examples of their prognostic and therapeutic utility, focusing on models for cancers that affect the largest populations. Technological advancements that allow greater exploitation of genetically engineered mouse models, such as RNA interference in vivo, are described in the context of target and drug validation. Finally, this review discusses stratagems for, and obstacles to, the application of these models in the drug development process.
A Mouse Model System to Genetically Dissect the Molecular Mechanisms Regulating Tumorigenesis
Authors: Degenhardt Kurt , White Eileen
Published: September 2006

The vast majority of human tumors are of epithelial origin and result from the accumulation of mutations that alter the function of pathways that control critical cellular processes, including proliferation, checkpoint regulation, and apoptosis. Authentically replicating these events in animal models is critical to understanding the biology of cancer and for testing the feasibility of novel therapies. We developed a mouse model that recapitulates the steps of epithelial tumor progression of multiple tissue types (kidney, breast, ovarian surface, and prostate epithelia), which takes advantage of the power of mouse genetics, and that allows for biochemical analysis, genetic selection, and screening. Moreover, this model enables functional interrogation of far more complex tumor genotypes, both of the tumor cells themselves, and of the cells in the tumor microenvironment. This is a crucial advantage, as human tumors result from multiple compound mutations, most of which are difficult to achieve through standard mutant mouse technology. We have applied this model to establish the role of apoptosis in epithelial solid tumor progression and in treatment response, which has provided novel opportunities for cancer therapies in humans.
Snail and Slug Play Distinct Roles during Breast Carcinoma Progression
Authors: Côme Christophe , Magnino Fabrice , Bibeau Frédéric , De Santa Barbara Pascal , Becker Karl Friedrich , Theillet Charles , Savagner Pierre
Published: September 2006

Purpose: Carcinoma progression is linked to a partially dedifferentiated epithelial cell phenotype. As previously suggested, this regulation could involve transcription factors, Snail and Slug, known to promote epithelial-mesenchymal transitions during development. Here, we investigate the role of Snail and Slug in human breast cancer progression.

Experimental Design: We analyzed Snail, Slug, and E-cadherin RNA expression levels and protein localization in large numbers of transformed cell lines and breast carcinomas, examined the correlation with tumor histologic features, and described, at the cellular level, Snail and Slug localization in carcinomas using combined in situ hybridization and immunolocalization.

Results: In contrast with transformed cell lines, Slug was found to colocalize with E-cadherin at the cellular level in normal mammary epithelial cells and all tested carcinomas. Snail also colocalized at the cellular level with E-cadherin in tumors expressing high levels of Snail RNA. In addition, Snail was significantly expressed in tumor stroma, varying with tumors. Slug and Snail genes were significantly overexpressed in tumors associated with lymph node metastasis. Finally, the presence of semidifferentiated tubules within ductal carcinomas was linked to Slug expression levels similar to or above normal breast samples.

Conclusions: These results suggest that Snail or Slug expression in carcinoma cells does not generally preclude significant E-cadherin expression. They emphasize a link between Snail, Slug, and lymph node metastasis in a large sampling of mammary carcinomas, and suggest a role for Slug in the maintenance of semidifferentiated structures. Snail and Slug proteins seem to support distinct tumor invasion modes and could provide new therapeutic targets.
Mouse Modeling in Oncologic Preclinical and Translational Research
Authors: Carver Brett S. , Pandolfi Pier P.
Published: September 2006

Through scientific and technological advancements, our ability to manipulate the mouse genome has allowed us to evaluate the effect of specific genetic alterations on in vivo tumorigenesis. This has allowed and will allow us to define molecular pathways describing the processes of tumor initiation, invasion, and progression to metastatic disease. Additionally, these models may serve as an excellent platform for the identification of novel molecular targets for therapy as well as to evaluate the efficacy of targeted therapies. Ultimately this will translate from preclinical mouse model trials to the development of clinical trials and protocols for cancer patients. Here we review the usefulness of mouse modeling in oncologic translational research.
Cancer-Testis Antigens: Expression and Correlation with Survival in Human Urothelial Carcinoma
Authors: Sharma Padmanee , Shen Yu , Wen Sijin , Bajorin Dean F. , Reuter Victor E. , Old Lloyd J. , Jungbluth Achim A.
Published: September 2006

Purpose: Vaccination against human cancer is a promising therapeutic approach but the optimal antigen or antigens remain undefined. Cancer-testis antigens (CTA), a family of tumor-associated antigens, have both potent immunogenicity and restricted expression patterns in normal adult tissues, highly desirable characteristics for targets of anticancer vaccines. These antigens were evaluated for both the degree of expression and prognostic value in cancer of the urothelium.

Experimental Design: The expression patterns of nine CTAs (NY-ESO-1, LAGE-1, MAGE-A1, MAGE-A3, MAGE-A4, MAGE-A10, CT7, CT10, and GAGE) were examined by immunohistochemistry and reverse transcription-PCR in a panel of high-grade urothelial carcinomas of the urinary bladder. Also assessed were correlations between the expression of CTAs by immunohistochemistry and both disease-free and overall survival.

Results: At least one CTA was expressed in 77% of samples and 61% of these tumors expressed more than one CTA. Additionally, patients with CT10-positive tumors had an improved disease-free survival (P = 0.008) and overall survival (P = 0.037) compared with patients with CT10-negative tumors.

Conclusions: These findings establish CTAs as potential prognostic markers and as target candidates for vaccine development for patients with urothelial carcinoma.