bluuebunny/crossref_metadata_2025 huggingface dataset:
Polymorphisms inCyclooxygenase-2andEpidermal Growth Factor ReceptorAre Associated with Progression-Free Survival Independent of K-ras in Metastatic Colorectal Cancer Patients Treated with Single-Agent Cetuximab
Authors: Lurje Georg , Nagashima Fumio , Zhang Wu , Yang Dongyun , Chang Heung M. , Gordon Michael A. , El-Khoueiry Anthony , Husain Hatim , Wilson Peter M. , Ladner Robert D. , Mauro David J. , Langer Christiane , Rowinsky Eric K. , Lenz Heinz-Josef
Published: December 2008

Purpose: Recently, an objective response rate of 12% was reported in a phase II study of cetuximab in patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer (mCRC) refractory to fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy (IMC-0144). In this large molecular correlates study, we tested whether K-ras mutation status and polymorphisms in genes involved in the EGFR-signaling pathway were associated with clinical outcome in IMC-0144.

Experimental Design: We analyzed all available tissue samples from 130 of 346 mCRC patients enrolled in the IMC-0144 phase II clinical trial of cetuximab. Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor tissues, and K-ras mutation status and the genotypes were analyzed using PCR-RFLP, direct DNA-sequencing, and 5′-end [γ-33P] ATP–labeled PCR-protocols.

Results: The PFS of patients with cyclooxygenase-2 (COX-2) −765 G>C [C/C; risk ratio (RR), 0.31; 95% confidence interval (95% CI), 0.12-0.84; P = 0.032], COX-2 +8473 T>C (C/C; RR, 0.67; 95% CI, 0.40-1.13; P = 0.003), EGF +61 A>G (G/G; RR, 0.57; 95% CI, 0.34-0.95; P = 0.042), and EGFR +497 G>A (A/G; RR, 0.82; 95% CI, 0.56-1.20; P = 0.017) genotypes was significantly longer compared with those with other genotypes. In addition, patients whose tumors did not have K-ras mutations showed better RR, PFS, and overall survival than patients with K-ras mutations. In multivariable analysis, COX-2 +8473 T>C (adjusted P = 0.013) and EGFR +497 G>A (adjusted P = 0.010) remained significantly associated with progression-free survival, independent of skin rash toxicity, K-ras mutation status, and Eastern Cooperative Group performance status.

Conclusions: Polymorphisms in COX-2 and EGFR may be useful independent molecular markers to predict clinical outcome in patients with mCRC treated with single-agent cetuximab, independent of skin rash toxicity, K-ras mutation, and Eastern Cooperative Oncology Group performance status.
Nucleosomes, ProGRP, NSE, CYFRA 21-1, and CEA in Monitoring First-Line Chemotherapy of Small Cell Lung Cancer
Authors: Holdenrieder Stefan , von Pawel Joachim , Dankelmann Elke , Duell Thomas , Faderl Bernhard , Markus Andreas , Siakavara Maria , Wagner Horst , Feldmann Knut , Hoffmann Harald , Raith Hannelore , Nagel Dorothea , Stieber Petra
Published: December 2008

Purpose: Besides new therapeutic drugs, effective diagnostic tools indicating early the efficacy of therapy are required to improve the individual management of patients with nonoperable cancer diseases.

Experimental Design: In prospectively collected sera of 128 patients with newly diagnosed small cell lung cancer receiving first-line chemotherapy, the courses of nucleosomes, progastrin-releasing peptide (ProGRP), neuron-specific enolase (NSE), cytokeratin-19 fragments (CYFRA 21-1), and carcinoembryonic antigen were investigated and correlated with therapy response objectified by computed tomography before start of the third treatment course.

Results: In univariate analyses, high levels and insufficient decreases of nucleosomes, ProGRP, NSE, and CYFRA 21-1 during the first and second cycles of therapy correlated with poor outcome. Insufficient response to therapy was most efficiently indicated by the baseline values of nucleosomes, ProGRP, and CYFRA 21-1 before the second therapy cycle reaching areas under the curve (AUC) of 81.8%, 71.3%, and 74.9% in receiver operating characteristic curves, respectively. Combinations of nucleosomes with ProGRP (AUC 84.1%), CYFRA 21-1 (AUC 82.5%), and NSE (AUC 83.6%) further improved the diagnostic power in the high specificity range and yielded sensitivities of 47.1%, 35.3%, and 35.3% at 95% specificity, respectively. In multivariate analyses, including clinical and biochemical variables, only performance score and nucleosomes before cycle 2 were found to independently indicate therapy response.

Conclusions: Biochemical markers specifically identified patients with insufficient therapy response at the early treatment phase and showed to be valuable for diseases management of small cell lung cancer.
Association between CCND1 G/A870 Polymorphism, Allele-Specific Amplification, Cyclin D1 Expression, and Survival in Esophageal and Lung Carcinoma
Authors: Gupta Vanita K. , Feber Andrew , Xi Liqiang , Pennathur Arjun , Wu Maoxin , Luketich James D. , Godfrey Tony E.
Published: December 2008

Purpose: Cyclin D1 is found on 11q13, which is a region frequently amplified in several tumor types. The CCND1 locus gives rise to at least two protein isoforms of D1 (D1a and D1b). A common G/A polymorphism (G/A870) is thought to influence the expression levels of D1a and D1b. D1b has been suggested to be increased in the presence of the A allele and more oncogenic than D1a. Furthermore, the A allele has been reported to correlate with increased risk of carcinoma in several tumor types, suggesting that this polymorphism and D1b are important in tumor progression. However, contradictory data about the polymorphism, D1 variant expression, and correlation with survival have been reported. We explored the relationship between gene amplification, G/A870 genotype, D1a and D1b expression, and overall survival in esophageal adenocarcinoma and non–small cell lung cancer.

Experimental Design: DNA and RNA were isolated from 54 esophageal adenocarcinoma samples and 89 non–small cell lung cancer samples and were analyzed for gene amplification, genotype at the polymorphism, gene expression, and association with overall survival.

Results: The D1 variant expression did not correlate with amplification, genotype, or overall survival in either tumor type. The total D1 expression correlated with decreased patient survival. Several other genes on 11q13 also seem to be overexpressed and correlated with decreased survival.

Conclusions: We report that the G/A870 polymorphism does not correlate with patient survival, or with D1a or D1b expression. However, the total D1 expression and the expression of several other genes on 11q13 seem to be associated with esophageal adenocarcinoma patient survival.
Cannabinoid Receptor Activation Induces Apoptosis through Tumor Necrosis Factor α–Mediated Ceramide De novo Synthesis in Colon Cancer Cells
Authors: Cianchi Fabio , Papucci Laura , Schiavone Nicola , Lulli Matteo , Magnelli Lucia , Vinci Maria Cristina , Messerini Luca , Manera Clementina , Ronconi Elisa , Romagnani Paola , Donnini Martino , Perigli Giuliano , Trallori Giacomo , Tanganelli Elisabetta , Capaccioli Sergio , Masini Emanuela
Published: December 2008

Purpose: Cannabinoids have been recently proposed as a new family of potential antitumor agents. The present study was undertaken to investigate the expression of the two cannabinoid receptors, CB1 and CB2, in colorectal cancer and to provide new insight into the molecular pathways underlying the apoptotic activity induced by their activation.

Experimental Design: Cannabinoid receptor expression was investigated in both human cancer specimens and in the DLD-1 and HT29 colon cancer cell lines. The effects of the CB1 agonist arachinodyl-2'-chloroethylamide and the CB2 agonist N-cyclopentyl-7-methyl-1-(2-morpholin-4-ylethyl)-1,8-naphthyridin-4(1H)-on-3-carboxamide (CB13) on tumor cell apoptosis and ceramide and tumor necrosis factor (TNF)-α production were evaluated. The knockdown of TNF-α mRNA was obtained with the use of selective small interfering RNA.

Results: We show that the CB1 receptor was mainly expressed in human normal colonic epithelium whereas tumor tissue was strongly positive for the CB2 receptor. The activation of the CB1 and, more efficiently, of the CB2 receptors induced apoptosis and increased ceramide levels in the DLD-1 and HT29 cells. Apoptosis was prevented by the pharmacologic inhibition of ceramide de novo synthesis. The CB2 agonist CB13 also reduced the growth of DLD-1 cells in a mouse model of colon cancer. The knockdown of TNF-α mRNA abrogated the ceramide increase and, therefore, the apoptotic effect induced by cannabinoid receptor activation.

Conclusions: The present study shows that either CB1 or CB2 receptor activation induces apoptosis through ceramide de novo synthesis in colon cancer cells. Our data unveiled, for the first time, that TNF-α acts as a link between cannabinoid receptor activation and ceramide production.
Targeted Inhibition of Cyclic AMP Phosphodiesterase-4 Promotes Brain Tumor Regression
Authors: Goldhoff Patricia , Warrington Nicole M. , Limbrick David D. , Hope Andrew , Woerner B. Mark , Jackson Erin , Perry Arie , Piwnica-Worms David , Rubin Joshua B.
Published: December 2008

Purpose: As favorable outcomes from malignant brain tumors remain limited by poor survival and treatment-related toxicity, novel approaches to cure are essential. Previously, we identified the cyclic AMP phosphodiesterase-4 (PDE4) inhibitor Rolipram as a potent antitumor agent. Here, we investigate the role of PDE4 in brain tumors and examine the utility of PDE4 as a therapeutic target.

Experimental Design: Immunohistochemistry was used to evaluate the expression pattern of a subfamily of PDE4, PDE4A, in multiple brain tumor types. To evaluate the effect of PDE4A on growth, a brain-specific isoform, PDE4A1 was overexpressed in xenografts of Daoy medulloblastoma and U87 glioblastoma cells. To determine therapeutic potential of PDE4 inhibition, Rolipram, temozolomide, and radiation were tested alone and in combination on mice bearing intracranial U87 xenografts.

Results: We found that PDE4A is expressed in medulloblastoma, glioblastoma, oligodendroglioma, ependymoma, and meningioma. Moreover, when PDE4A1 was overexpressed in Daoy medulloblastoma and U87 glioblastoma cells, in vivo doubling times were significantly shorter for PDE4A1-overexpressing xenografts compared with controls. In long-term survival and bioluminescence studies, Rolipram in combination with first-line therapy for malignant gliomas (temozolomide and conformal radiation therapy) enhanced the survival of mice bearing intracranial xenografts of U87 glioblastoma cells. Bioluminescence imaging indicated that whereas temozolomide and radiation therapy arrested intracranial tumor growth, the addition of Rolipram to this regimen resulted in tumor regression.

Conclusions: This study shows that PDE4 is widely expressed in brain tumors and promotes their growth and that inhibition with Rolipram overcomes tumor resistance and mediates tumor regression.
Phase I/II Study of G3139 (Bcl-2 Antisense Oligonucleotide) in Combination with Doxorubicin and Docetaxel in Breast Cancer
Authors: Moulder Stacy L. , Symmans W. Fraser , Booser Daniel J. , Madden Timothy L. , Lipsanen Cindy , Yuan Linda , Brewster Abenaa M. , Cristofanilli Massimo , Hunt Kelly K. , Buchholz Thomas A. , Zwiebel James , Valero Vicente , Hortobagyi Gabriel N. , Esteva Francisco J.
Published: December 2008

Purpose: Preclinical data showed enhancement of breast cancer cell death when G3139 was combined with anthracyclines and taxanes. We evaluated the efficacy and safety of a Bcl-2 antisense oligonucleotide, G3139, in combination with doxorubicin (A) and docetaxel (T) in patients with locally advanced breast cancer (LABC).

Experimental Design: Following a brief phase I to determine the phase II dose, patients with locally advanced breast cancer received G3139 administered by continuous i.v. infusion for 5 to 7 days with bolus A (50 mg/m2) and T (75 mg/m2) administered on either day 3 or 6 of therapy with G3139. Cycles were repeated every 21 days × 6 in the neoadjuvant setting. Serial plasma samples were obtained for pharmacokinetic analysis. Tissue samples were obtained before and after therapy for pharmacodynamic analysis of Bcl-2 expression.

Results: Thirty patients (median age, 49 years; range, 24-71 years) received 160 cycles. During the phase I portion of the trial, the dose of G3139 was escalated from 3 to 7 mg/kg/d (i.v. for 5 days) in combination with AT. During the phase II portion of the trial, several doses and schedules of G3139 were evaluated. There were no pathologic complete responses. Pharmacodynamic studies showed limited Bcl-2 down-regulation in the primary tumors.

Conclusions: G3139 in combination with doxorubicin and docetaxel is well tolerated. No pathologic complete response was seen and pharmacodynamic studies showed very little down-regulation of Bcl-2 in primary tumors, perhaps related to issues with insufficient drug delivery to the intact tumor.
A Phase I-II Study to Determine the Maximum Tolerated Infusion Rate of Rituximab with Special Emphasis on Monitoring the Effect of Rituximab on Cardiac Function
Authors: Siano Marco , Lerch Erika , Negretti Laura , Zucca Emanuele , Rodriguez-Abreu Delvys , Oberson Michel , Leoncini Leda , Mora Oreste , Sessa Cristiana , Gallino Augusto , Ghielmini Michele
Published: December 2008

Purpose: This phase I infusion rate escalation trial was undertaken to evaluate the maximum applicable infusion rate for rituximab without steroid premedication in patients having received one previous rituximab infusion.

Experimental Design: Cohorts of at least three patients were assigned to rituximab with or without concomitant chemotherapy. The initial infusion rate was 200 mg/h in the first cohort, and was increased by 100 mg/h in each subsequent cohort to a maximum of 700 mg/h. In each patient the infusion rate was increased by 100 mg/h every 30 minutes to the total dose (375 mg/m2). In the first six cohorts (21 patients), two well-tolerated rituximab administrations were required; in the 7th cohort (11 patients) one previously well-tolerated rituximab infusion was required. Patients did not receive steroid premedication and were monitored with electrocardiograms (ECG), echocardiograms, Holter ECGs, troponin, and brain natriuretic peptide (BNP).

Results: Thirty-two patients were included and 128 cycles were done, 85 at a rate of 700 mg/h. Patients tolerated infusion rates without major side effects. There were no new clinically relevant ECG alterations. Troponin (< 0.1 ng/L) and mean cardiac ejection fraction (65%) remained in the reference range; BNP baseline level increased significantly 24 hours after rituximab administration (from 30.4 to 64.1 ng/L; P < 0.0001).

Conclusions: Rituximab can be administered safely at 700 mg/h without steroid premedication in patients having received at least one rituximab dose in the previous 3 months.
Imatinib Targeting of KIT-Mutant Oncoprotein in Melanoma
Authors: Jiang Xiaofeng , Zhou Jun , Yuen Noah K. , Corless Christopher L. , Heinrich Michael C. , Fletcher Jonathan A. , Demetri George D. , Widlund Hans R. , Fisher David E. , Hodi F. Stephen
Published: December 2008

Purpose: Melanoma subtypes based on anatomic location and UV light exposure can be further classified based on genetic alterations recently identified. Mutations and gene amplification in KIT have been described in a significant percentage of mucosal and acral melanomas. We recently reported a patient with metastatic mucosal melanoma harboring a known KIT mutation treated with imatinib mesylate who experienced a major response. Biological effects of KIT inhibition in these melanomas remain poorly understood. We sought to investigate further the effects of imatinib in these melanoma subsets.

Experimental Design: Mucosal melanoma cells were analyzed for KIT aberrations by genomic sequencing, quantitative PCR, and single nucleotide polymorphism analyses. Imatinib effects were assayed by viability measurements and apoptotic cytotoxicity. Tumor cell lysates were assayed by Western blots to determine effects on multiple signaling pathways after imatinib exposure.

Results: Mucosal melanoma cells exhibited imatinib sensitivity correlating with KIT mutational status. Imatinib dramatically decreased proliferation and was cytotoxic to a KIT mutated and amplified cell culture. Exposure to drug affected the mitogen-activated protein kinase, phosphatidylinositol 3-kinase/AKT, JAK-STAT, and antiapoptotic pathways.

Conclusions: Rational targeting of KIT in melanoma offers a unique and potent clinical opportunity. In vitro analyses revealed major sensitivity to KIT kinase inhibition by imatinib, with potent induction of melanoma cell apoptosis. Biochemical studies identified changes in signaling molecules regulating proliferation and survival responses, which may serve as mediators and/or biomarkers of in vivo treatment efficacy. Pathways affected by KIT inhibition provide a model for understanding components in effective melanoma cell death and insights into targeting for resistance mechanisms.
Cancer-Related Axonogenesis and Neurogenesis in Prostate Cancer
Authors: Ayala Gustavo E. , Dai Hong , Powell Michael , Li Rile , Ding Yi , Wheeler Thomas M. , Shine David , Kadmon Dov , Thompson Timothy , Miles Brian J. , Ittmann Michael M. , Rowley David
Published: December 2008

Purpose: Perineural invasion is the only interaction between cancer cells and nerves studied to date. It is a symbiotic relationship between cancer and nerves that results in growth advantage for both. In this article, we present data on a novel biological phenomenon, cancer-related axonogenesis and neurogenesis.

Experimental Design: We identify spatial and temporal associations between increased nerve density and preneoplastic and neoplastic lesions of the human prostate.

Results: Nerve density was increased in cancer areas as well as in preneoplastic lesions compared with controls. Two- and three-dimensional reconstructions of entire prostates confirmed axonogenesis in human tumors. Furthermore, patients with prostate cancer had increased numbers of neurons in their prostatic ganglia compared with controls, corroborating neurogenesis. Finally, two in vitro models confirmed that cancer cells, particularly when interacting with nerves in perineural invasion, induce neurite outgrowth in prostate cancer. Neurogenesis is correlated with features of aggressive prostate cancer and with recurrence in prostate cancer. We also present a putative regulatory mechanism based on semaphorin 4F (S4F). S4F is overexpressed in cancers cells in the perineural in vitro model. Overexpression of S4F in prostate cancer cells induces neurogenesis in the N1E-115 neurogenesis assay and S4F inhibition by small interfering RNA blocks this effect.

Conclusions: This is the first description of cancer-related neurogenesis and its putative regulatory mechanism.
Silibinin Inhibits Established Prostate Tumor Growth, Progression, Invasion, and Metastasis and Suppresses Tumor Angiogenesis and Epithelial-Mesenchymal Transition in Transgenic Adenocarcinoma of the Mouse Prostate Model Mice
Authors: Singh Rana P. , Raina Komal , Sharma Girish , Agarwal Rajesh
Published: December 2008

Purpose: The chronic nature of prostate cancer growth and progression leading to metastasis provides a large window for intervention. Herein, for the first time, we investigated the effect and associated mechanisms of silibinin phosphatidylcholine (silybin-phytosome) on established prostate tumors in transgenic adenocarcinoma of the mouse prostate (TRAMP) model.

Experimental Design: Twenty-week-old TRAMP male mice having palpable prostate tumor were fed with control or 0.5% and 1%, w/w, silybin-phytosome diets for 11 weeks and then sacrificed.

Results: Dietary silibinin inhibited the growth of prostate tumors (up to 60%, P < 0.001) and suppressed tumor progression from prostatic intraepithelial neoplasia to differentiated adenocarcinoma and poorly differentiated adenocarcinoma, with a complete absence of poorly differentiated adenocarcinoma at higher doses. It also inhibited the incidence of tumor invasion of seminal vesicle (up to 81%, P < 0.001) with complete absence of distant metastasis. Silibinin moderately inhibited tumor cell proliferation and induced apoptosis, but strongly suppressed tumor microvessel density (up to 60%, P < 0.001), vascular endothelial growth factor, and vascular endothelial growth factor receptor-2 expression. Antibody array analysis of plasma showed a decrease in the circulatory levels of vascular endothelial growth factor and basic fibroblast growth factor. Decreased levels of matrix metalloproteinases (MMP), snail-1, and vimentin, and an increased level of E-cadherin were also observed, indicating the anti–epithelial-mesenchymal transition effect of silibinin in tumors.

Conclusions: Overall, silibinin treatment of TRAMP mice bearing prostate tumor inhibited tumor growth, progression, local invasion, and distant metastasis involving suppression of tumor angiogenesis and epithelial-mesenchymal transition. These findings would have greater relevance for the ongoing phase II clinical trial with silibinin-phytosome in prostate cancer patients.
Combination Immunotherapy for Tumors via Sequential Intratumoral Injections of Oncolytic Herpes Simplex Virus 1 and Immature Dendritic Cells
Authors: Farrell Christopher J. , Zaupa Cecile , Barnard Zachary , Maley Jason , Martuza Robert L. , Rabkin Samuel D. , Curry William T.
Published: December 2008

Purpose: Oncolytic herpes simplex virus 1 (oHSV) vectors treat tumors in preclinical models and have been used safely in phase I clinical trials for patients with cancer. Infection of tumors with oHSV also induces specific antitumor immunity. We investigated whether this immunotherapeutic effect is enhanced by combining oHSV infection with intratumoral administration of immature myeloid dendritic cells (iDC).

Experimental Design: Subcutaneous neuroblastoma tumors were established in syngeneic immunocompetent mice and sequentially treated with oHSV(G47Δ) and intratumoral iDCs. Tumor volumes and survival were monitored. Antitumor immune responses were evaluated by immunohistochemistry, IFN-γ ELISPOT, and CTL assay. Treatment was also evaluated in immunodeficient NOD-SCID mice.

Results: We observed significant reductions in tumor volumes in mice receiving G47Δ + iDCs compared with those treated with G47Δ or iDC monotherapy. Survival was prolonged, with ∼90% of tumors eradicated in the combination group. Combination therapy led to enhancement of antitumor immune responses, confirmed by increases in IFN-γ expression by splenocytes harvested from G47Δ + iDC-treated mice. Splenocytes harvested from G47Δ + iDC-treated mice were effective against neuroblastoma tumor cells in a CTL assay. Immunohistochemistry of combination-treated tumors revealed robust lymphocytic infiltrates. Adding iDCs to G47Δ infection in tumors in NOD-SCID mice did not reduce the rate of growth. Substitution of lipopolysaccharide-matured dendritic cells abrogated the enhanced tumor volume reduction seen with combination therapy with iDCs.

Conclusions: Combination treatment of murine tumors with oHSV and iDCs reduces the volume of established tumors and prolongs survival via enhancement of antitumor immunity.
14-3-3σ Modulates Pancreatic Cancer Cell Survival and Invasiveness
Authors: Neupane Divas , Korc Murray
Published: December 2008

Purpose: The purpose of the present study was to investigate the potential role of 14-3-3σ in pancreatic ductal adenocarcinoma (PDAC).

Experimental Design: 14-3-3 isoform expression was determined by real-time quantitative PCR in laser capture normal pancreatic ductal cells and pancreatic cancer cells and in 5 pancreatic cancer cell lines. PANC-1 cells, with low levels of 14-3-3σ, were stably transfected with a human 14-3-3σ cDNA. Conversely, high endogenous 14-3-3σ levels in T3M4 cells were suppressed by specific short hairpin RNA. Apoptosis, motility, and invasiveness were studied.

Results: The cancer cells in 7 PDAC samples expressed high levels of 14-3-3σ mRNA by quantitative PCR when compared with normal pancreatic duct cells. 14-3-3σ protein levels were high in BxPC3, COLO-357, and T3M4 cells, intermediate in ASPC-1 cells, and low in PANC-1 cells. Most cell lines released detectable amount of 14-3-3σ into conditioned medium. Overexpression of 14-3-3σ in PANC-1 cells led to resistance to cisplatinum-induced apoptosis, increased basal migration, and increased invasion in response to epidermal growth factor and insulin-like growth factor-I. By contrast, short hairpin RNA-mediated knockdown of endogenous 14-3-3σ in T3M4 cells did not alter migration but led to enhanced cisplatinum sensitivity, increased invasiveness in response to epidermal growth factor, and decreased invasiveness in response to insulin-like growth factor-I.

Conclusions: 14-3-3σ contributes to the chemoresistance of pancreatic cancer cells and exerts cell type-dependent effects on cell migration and invasion. Therefore, strategies aimed at suppressing 14-3-3σ expression and function may have a therapeutic benefit in subgroups of patients with PDAC.
Role of Hedgehog Signaling in Ovarian Cancer
Authors: Bhattacharya Resham , Kwon Junhye , Ali Bushra , Wang Enfeng , Patra Sujata , Shridhar Viji , Mukherjee Priyabrata
Published: December 2008

Purpose: In humans, several distinctive cancers result from mutations that aberrantly activate hedgehog (HH) signal transduction. Here, we investigate the role of HH signaling in ovarian cancer.

Experimental Design: We assessed the expression of different components of hedghehog pathway in primary tumor samples and cell lines. We used specific hedghehog pathway blocker to study the effect on clonal growth and proliferation of ovarian cancer cell both in vitro and in vivo.

Results: We show that the up-regulation of several HH pathway components is a common feature of primary ovarian tumors and cell lines. However, expression of PATCHED1 (PTCH1), a direct transcriptional target of the HH pathway, is down-regulated in ovarian cancer in direct contrast to the expression observed in other adult solid tumors. Cyclopamine, a specific HH pathway inhibitor, inhibits the proliferation and clonal growth of ovarian tumor cells in vitro and arrests ovarian tumor growth in vivo. Expression of BMI-1, a polycomb gene, is down-regulated in ovarian cancer cells following cyclopamine treatment. Overexpression of PTCH1 phenocopied the effects of cyclopamine; it down-regulated BMI-1 and reduced clonal growth in ovarian cancer cell lines. Furthermore, knocking down BMI-1 using small interfering RNA also inhibited the clonal growth of all the ovarian cancer cell lines tested.

Conclusions: In brief, the constitutive low-level expression of PTCH1 contributes to proliferation and clonal growth of ovarian cancer cells by an aberrant HH signal. Because the HH pathway can be inhibited by specific inhibitors, these findings point toward possible new treatments to inhibit ovarian cancer growth.
Cytokine Treatment Improves Parenchymal and Vascular Damage of Salivary Glands after Irradiation
Authors: Lombaert Isabelle M.A. , Brunsting Jeanette F. , Wierenga Pieter K. , Kampinga Harm H. , de Haan Gerald , Coppes Robert P.
Published: December 2008

Purpose: During radiotherapy for head and neck cancer, co-irradiation (IR) of salivary glands results in acute and often lifelong hyposalivation. Recently, we showed that bone marrow-derived cells (BMC) can partially facilitate postradiation regeneration of the mouse submandibular gland. In this study, we investigate whether optimized mobilization of BMCs can further facilitate regeneration of radiation-damaged salivary glands.

Experimental Design: Salivary glands of mice reconstituted with eGFP+ bone marrow cells were irradiated with a single dose of 15 Gy. One month later, BMCs were mobilized using granulocyte colony-stimulating factor (G-CSF) or the combination of FMS-like tyrosine kinase-3 ligand, stem cell factor, and G-CSF (termed F/S/G) as mobilizing agents. Salivary gland function and morphology were evaluated at 90 days post-IR by measuring the saliva flow rate, the number of acinar cells, and the functionality of the vasculature.

Results: Compared with G-CSF alone, the combined F/S/G treatment mobilized a 10-fold higher number and different types of BMCs to the bloodstream and increased the number of eGFP+ cells in the irradiated submandibular gland from 49% to 65%. Both treatments reduced radiation-induced hyposalivation from almost nothing in the untreated group to ∼20% of normal amount. Surprisingly, however, F/S/G treatment resulted in significant less damage to submandibular blood vessels and induced BMC-derived neovascularization.

Conclusions: Post-IR F/S/G treatment facilitates regeneration of the submandibular gland and ameliorates vascular damage. The latter is partly due to BMCs differentiating in vascular cells but is likely to also result from direct stimulation of existing blood vessel cells.
Surgical Complications of Deep Brain Stimulation
Authors: Bhatia Sanjay , Oh Michael , Whiting Taylor , Quigley Matthew , Whiting Donald
Published: December 2008

Background/Aims: Deep brain stimulation is a commonly performed procedure for intractable movement disorders. In this report we analyze the complications of a single surgeon at one institution over a 10-year period. Methods: A total of 191 patients received 330 electrode implants. Data was collected prospectively and analyzed retrospectively for the type and rate of complications. Results: The mean follow-up was 58.5 months. The overall surgical complication rate was 17.8% (59 complications in 330 implantations). These 59 complications involved 53 of 191 patients. The overall incidence of minor wound problems (hardware not removed), major wound problems (hardware removed) and hardware-related problems was 4.2% each, based on the total number of systems implanted. In addition 2.1% of the patients suffered minor bleeds while 1.6% had bleeds large enough to cause neurological deficits. The same percentage of patients (1.6%) either failed to benefit from the procedure or suffered complications unrelated to the procedure. A further 4/191 (2.1%) patients had neurological deficits without obvious hemorrhage on postoperative nonenhanced computerized tomography. Analysis of our complications from year to year shows a declining complication rate related to accumulated experience and better hardware design. Conclusion: Surgeon experience and hardware improvements have significantly reduced complications over time.
Left Ventricular Systolic and Diastolic Function in Healthy Adult Bonnet Macaques (Macaca radiata)
Authors: Lazar Jason M. , Qureshi Ghazanfar , Qureshi Mohammed Rehan , Smith Eric , Scharf Bruce , Rosenblum Leonard A. , Signaevsky Maxim , Kral John G. , Salciccioli Louis
Published: December 2008

Objectives: Macaques are used in cardiovascular and metabolic research. We determined echocardiographic-derived reference values of left ventricular (LV) systolic and diastolic function in healthy adult bonnet macaques (Macaca radiata). Methods: Transthoracic echocardiography was performed during ketamine sedation in 83 (67% female) healthy monkeys (age 7–26 years). Results: Technically adequate studies were obtained in all subjects and required 10.1 ± 1.3 min of scanning time. Age correlated inversely with the following Doppler indices: E (r = –0.44, p < 0.001), E/A (r = –0.26, p = 0.02), E′ (r = –0.45, p < 0.001, E′/A′ (r = –0.44, p < 0.001), E/E′ (r –0.25, p = 0.03), S′ (r = –0.33, p = 0.003), Vp (r = –0.26, p = 0.049). LV mass was more strongly correlated with crown rump length (r = 0.72, p < 0.001) and body surface area (r = 0.70, p < 0.001) than with body mass index (r = 0.47, p < 0.001) and weight (r = 0.63, p < 0.001). Conclusions: This study demonstrates echocardiography is feasible for characterizing LV function. Age-related changes in Doppler indices in primates are similar to those in humans. LV mass is more closely related to fat-free mass indices. We provide reference values for LV systolic and diastolic function in adult bonnet macaques across the captive life span.
Venous Air Embolism in Deep Brain Stimulation
Authors: Hooper Amanda K. , Okun Michael S. , Foote Kelly D. , Haq Ihtsham U. , Fernandez Hubert H. , Hegland Dustin , Robicsek Steven A.
Published: December 2008

Background/Aims: During the placement of electrodes for deep brain stimulation (DBS), patients are commonly in a seated position, awake, and spontaneously breathing. Air may be entrained through bone or dural veins causing venous air emboli (VAE) and this phenomenon can result in significant hemodynamic changes. Although VAEs have been described in many types of neurosurgical procedures, their incidence during DBS surgery is unknown. Methods: Following approval from the Institutional Review Board, the University of Florida Movement Disorders Center database comprising 286 DBS leads placed since 2002 was reviewed. Intraoperative cough, which has been associated with VAE, as well as hemodynamic instability were the focus of the review. Additionally, a prospective evaluation of the incidence of VAE using precordial Doppler ultrasound was undertaken over a 3-month period (June 2007–August 2007). Results: The retrospective review revealed a 3.2% incidence of cough per lead. Prospective monitoring in 21 consecutive patients with 22 leads yielded the detection of 1 VAE, and an incidence of 4.5% per lead. Conclusion: VAEs are rare but potentially serious complications of DBS surgery unless recognized. Patient positioning and the occurrence of cough are two important predictors to consider in VAE. Precordial Doppler is a safe, non-invasive monitor that can be used in the early detection of VAE in these procedures.
Carboplatin and Pegylated Liposomal Doxorubicin for Advanced Ovarian Cancer: Preliminary Activity Results of the MITO-2 Phase III Trial
Authors: Pignata S. , Scambia G. , Savarese A. , Breda E. , Sorio R. , Pisano C. , Lorusso D. , Cognetti F. , Vernaglia Lombardi A. , Gebbia V. , Scollo P. , Morabito A. , Signoriello G. , Perrone F.
Published: December 2008

Background: Based on the efficacy of pegylated liposomal doxorubicin (PLD) in relapsed ovarian cancer, we are conducting a phase III study comparing carboplatin plus either paclitaxel or PLD as first-line therapy in advanced ovarian cancer. Because of limited phase I and II data on PLD plus carboplatin in this setting, we conducted an interim activity analysis. Patients and Methods: Patients with stage 1c-IV epithelial ovarian cancer were randomized to carboplatin AUC 5 plus either paclitaxel 175 mg/m2 or PLD 30 mg/m2 every 3 weeks for 6 cycles. The interim activity analysis was planned according to a single-stage phase II design with an auspicated 50% response rate; 50 patients eligible for response assessment were required. Response was defined according to RECIST (Response Evaluation Criteria in Solid Tumors). Results: A complete response was achieved in 14 patients (28%) and a partial response in 20 (40%), which produced an overall response rate of 68%. The activity exceeded the minimum required for study continuation. Stable disease was reported in an additional 10 patients (20%). Conclusions: The adopted schedule of PLD plus carboplatin demonstrates activity as a first-line treatment for advanced ovarian cancer.
Renal Tubulointerstitial Fibrosis in OVE26 Type 1 Diabetic Mice
Authors: Powell David W. , Bertram Clinton C. , Cummins Timothy D. , Barati Michelle T. , Zheng Shirong , Epstein Paul N. , Klein Jon B.
Published: December 2008

Background/Aims: Tubulointerstitial fibrosis (TIF) is a prominent feature of progressive diabetic nephropathy. The goal of this study was to determine if hallmarks of TIF occur in the transgenic OVE26 type 1 diabetic mouse and define signaling events associated with TIF. Methods: The expression patterns of several phenotypic markers of TIF were determined in kidneys of OVE26 diabetic and control mice by immunohistochemistry and immunoblot analysis. Results: Pathological signatures of TIF are an accumulation of myofibroblasts and excessive deposition of extracellular matrix in the tubulointerstitium. Kidneys from OVE26 diabetic animals exhibited an increase in tubulointerstitial myofibroblast marker (α-smooth muscle actin), fibronectin and collagen I staining. Abundance of the pro-fibrotic cytokine TGF-β was also enhanced in diabetic tubules. As injury involving loss of epithelial cell-cell contact promotes tissue fibrosis, we examined expression of the adhesion protein, E-cadherin. The percent of E-cadherin-stained tubules was decreased in diabetic kidneys. Prominent regulators of TGF-β signaling, glycogen synthase kinase-3 (GSK-3) α and β, were also differentially expressed. Conclusions: These results indicate that TGF-β-induced TIF occurs in OVE26 diabetic mice, providing a practical in vivo model for defining novel regulatory events and treatment strategies for diabetes-induced TIF.
Urinary Oxidative Stress Markers Closely Reflect the Efficacy of Candesartan Treatment for Diabetic Nephropathy
Authors: Yoshida Shin-ichiro , Hashimoto Tatsuo , Kihara Minoru , Imai Nozomi , Yasuzaki Hiroaki , Nomura Kouichirou , Kiuchi Yoshihiro , Tamura Kouichi , Ishigami Tomoaki , Hirawa Nobuhito , Toya Yoshiyuki , Kitamura Hitoshi , Umemura Satoshi
Published: December 2008

Backgrounds/Aims: It has been reported that urinary oxidative stress markers are higher in diabetic patients with proteinuria. We performed the present study to elucidate the relationship between urinary excretion of oxidative stress markers, albumin excretion, and histological changes, and to confirm the potential utility of oxidative stress markers for clinical treatment. Methods: Diabetic db/db mice or nondiabetic db/m mice were administered candesartan (10 mg/kg/day) or hydralazine (50 mg/kg/day) for 18 weeks. Results: Thirty-week-old male db/db mice treated with control vehicle revealed elevated urinary excretion and immunohistological levels of 8-hydroxydeoxyguanosine in glomeruli when compared to db/m mice. Treatment with candesartan, but not hydralazine, reduced these values to levels in db/m mice. Increased mesangial expansion, urinary excretion of albumin and 8-isoprostane, and glomerular immunohistological levels of nitrotyrosine in db/db mice were also decreased markedly by candesartan but not hydralazine. Interestingly, correlations between levels of albumin and oxidative stress markers in urine were very high, even when groups undergoing long-term (44 weeks) treatment were included (correlation coefficient 0.767 with respect to 8-hydroxydeoxyguanosine, 0.888 with respect to 8-isoprostane). Conclusion: It is anticipated that urinary concentrations of oxidative stress markers will be direct barometers of glomerulus-derived oxidative stress and glomerular injury in diabetic nephropathy.
Proteome Patterns in Uremic Plasma
Authors: Naseeb Uzma , Shafqat Jawed , Jägerbrink Theres , Zarina Shamshad , Alvestrand Anders , Jörnvall Hans , Axelsson Jonas
Published: December 2008

In patients with chronic kidney disease (CKD), peptides and proteins circulate at altered concentrations versus in healthy individuals. We have characterized proteome samples from 7 pooled CKD stage 5 patients not yet on dialysis and with no known co-morbidities. We also analyzed pooled plasma samples from 7 healthy age- and sex-matched controls. After immunodepletion of the 6 most abundant plasma proteins, HPLC and SDS-PAGE patterns differed between the healthy and disease groups. The differing proteins were identified by peptide mass fingerprinting using MALDI mass spectrometry and verified with electrospray tandem mass spectrometry sequence analysis. Multiple differences in at least 19 HPLC fractions were observed, from which we identified 29 proteins, 25 in greater yield and 4 in lower yield than in the healthy controls, adding at least 6 protein components to those that were previously known to be altered in CKD.
Expression, Localisation and Functional Implications of the Transporter Protein PEPT2 in the Upper Respiratory Tract
Authors: Quarcoo David , Fischer Tanja C. , Heppt Werner , Lauenstein Hans-Dieter , Pilzner Carolin , Welte Tobias , Groneberg David A.
Published: December 2008

Infectious diseases of the upper respiratory tract are widespread and may initiate exacerbations of chronic respiratory diseases such as bronchial asthma or chronic obstructive pulmonary disease. Nebulisation of antibiotics as a topic treatment may lead to high local drug concentrations. To provide data on drug transport, the present study analysed a specific drug transport system on the molecular and functional level. Messenger RNA of the proton-coupled transporter PEPT2 that mediates physiological transport of oligopeptides as well as peptidomimetics like β-lactams and aminolevulinic acid was discovered in rat nasal mucosa by RT-PCR. Real-time PCR studies indicated a lower expression level than control kidney samples. PEPT2 immunoreactivity was identified in nasal mucosa tissue. The protein was expressed in epithelial cells, but goblet cells did not exhibit PEPT2 expression. Functional studies with rat preparations led to uptake of a fluorophore-conjugated substrate into epithelial cells of nasal mucosa. Goblet cells did not exhibit uptake activity. The uptake was competitively inhibited by dipeptides demonstrating similar substrate specificity as reported for PEPT2. Together, these data suggest that PEPT2 is likely to play an important role in mucosal peptide metabolism and may represent a novel target for therapeutic efforts in upper airway diseases.
A Tale of Two Worlds: The Late Tang Poetic Presentation of The Romance of the Peach Blossom Font
Authors: Chan Timothy Wai Keung
Published: December 2008

This article examines late Tang poetic representations of the early fifth-century tale of Liu Chen and Ruan Zhao's romance with divine maidens at a Shangri-La-like peach blossom font. Shi poems by such poets as Liu Yuxi (772-822) and Yuan Zhen (779-831), and a group of Huajian ("among the flowers") ci poems under the tune "Nüguanzi" ("The Daoist Priestess") by Wen Tingyun (ca. 812-866) and others, reveal the exploration of the old tale as a rich source of allegorical tropes. In particular, the late Tang poets consistently revitalize the Liu-Ruan tale's bifurcation between the immortal and the mortal worlds, a division between "two worlds" that enabled them to express a range of different meanings at different levels, for example in politics or when talking of love affairs. Cet article s'intéresse aux représentations chez les poètes de la fin des Tang du récit (remontant au début du ve siècle) de l'idylle entre Liu Chen et Ruan Zhao et de jeunes immortelles à une source aux pêchers évoquant le paradis terrestre. Les poèmes shi de Liu Yuxi (772-822) ou Yuan Zhen (779-831), ainsi qu'un groupe de ci "parmi les fleurs" (huajian) sur l'air de la "prêtresse taoïste" (Nüguanzi) par Wen Tingyun (ca. 812-866) et d'autres, montrent qu'on trouvait dans ce vieux récit une riche source de tropes allégoriques. En particulier, les poètes de la fin des Tang se sont systématiquement appliqués à revivifier le thème de la bifurcation entre le monde des immortels et celui des mortels sur laquelle repose l'histoire de Liu et Ruan. Cette division entre deux mondes leur permettait d'exprimer des contenus à des niveaux variés, par exemple dans le domaine politique ou dans celui des relations amoureuses.
The Economics of the Jiaxing Edition of the Buddhist Tripitaka
Authors: Dai Lianbin
Published: December 2008

This essay draws on economic information in the colophons and catalogues of the Jiaxing Tripitaka to examine the fluctuations of its costs and price in the late Ming and early Qing. The price of the texts included in the Jiaxing Tripitaka increased from the mid-seventeenth century onwards, as did the costs for transcribing and carving wood-blocks. Relative to the value of rice in the Yangzi Delta from 1589 to 1715, the value of a volume of the Tripitaka generally rose. Yet the relative value of a book is not the same as its affordability, which is determined by the book's price, its value relative to other commodities, the real income of the purchaser, and other economic and non-economic elements. It is hoped that this investigation will contribute new views to the history of books in late imperial China. Cette étude se fonde sur les données de nature économique contenues dans les colophons et les catalogues du Tripitaka publié à Jiaxing pour étudier les variations de par son coût de production et de son prix de vente à la fin des Ming et au début des Qing. Le prix des ouvrages inclus dans le Tripitaka de Jiaxing a augmenté à partir du milieu du XVIIe siècle, de même que le coût de la transcription et de la gravure. La valeur des volumes du Tripitaka s'est en général accrue par rapport à celle du riz dans le delta du Yangzi entre 1589 et 1715. Cependant la valeur relative d'un livre n'est pas la même chose que son accessibilité, déterminée par le prix de l'ouvrage, sa valeur par rapport à d'autres produits, le revenu réel de l'acheteur, ainsi que d'autres facteurs économiques ou non. L'on espère que cette recherche apportera de nouveaux éléments à l'histoire du livre dans la Chine impériale tardive.
Global Ethics, Christian Theology, and the Challenge of Sustainability
Authors: Jenkins Willis
Published: December 2008

This paper considers how theology confronts sustainability as a global problem, and what that confrontation can contribute to the challenge of global ethics. After reviewing major models of religious engagement with global ethics, I argue for an analogical conception in which Christian social practices generate moral patterns with the capacity to meet the integrative challenge of global ethics. Theological reflection on those practices then helps sustain the discourse of sustainability as an effective working concept.
Ecological Restoration as Public Spiritual Practice
Authors: Van Wieren Gretel
Published: December 2008

The practice of ecological restoration is the attempt to repair ecosystems that have been damaged or degraded, most often by past human activities. Restoration includes everything from removing dams to planting native trees, grasses and wildflowers to bio-reactivating soil to controlling invasive plants to recontouring land. Beyond this, ecological restoration is the attempt to restore humans' relationship with nature. In the actual activities of restoring land, humans are in important ways restored to land. This paper argues that one of the ways in which restoration practice reconnects humans to nature is in a spiritual-moral sense. In addition to performing ecological work, restoration performs sacred work and serves as a form of public witness; and it can engender spiritual-moral experiences within participants. For these reasons, we can view restoration not only as a promising contemporary environmental practice, but also as a burgeoning public spiritual practice.
An Alternative Theoretical Perspective to the Analysis of Global Trends on Consumer Debt
Authors: Biza-Khupe Simangaliso
Published: December 2008

Alarming global trends in consumer debt have remained a subject of interest for many decades. Despite literature being replete with studies on the subject, the role that information intermediaries play in influencing financial rationality of consumer credit decisions has remained unexplored. This article presents a perspective that is being proposed for the first time. It is proposed that the rationality of consumer credit decision in an economy is determined by the combined effect of a most commonly used primary financial information intermediary and the propensity for consumers to rely on the advice of a primary financial information intermediary. This perspective of analyzing consumer debt acquisition is instrumental to policymakers, consumer lobbyists, and marketers.
Soiling Cultural Studies
Authors: Sebina Tiro
Published: December 2008

This paper takes its cue from Leon Trotsky's formulation in Literature and Revolution that "Culture feeds on the sap of economics, and a material surplus is necessary, so that culture may grow, develop and become subtle" (Trotsky (1925) 1991:46). The discussion seeks to put Cultural Studies in its proper place by focusing on its materialist beginnings. The central concern of this deliberation is to underline the efficacy of insights proffered by materialist analyses of culture and cultural formations.