bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular Pathways Mediating Liver Metastasis in Patients with Uveal Melanoma
Authors: Bakalian Silvin , Marshall Jean-Claude , Logan Patrick , Faingold Dana , Maloney Shawn , Di Cesare Sebastian , Martins Claudia , Fernandes Bruno F. , Burnier Miguel N. 
Published: February 2008

AbstractUveal melanoma arises from melanocytes located in the uveal tract of the eye and is the most common primary intraocular tumor in adults. Metastatic liver disease is the overwhelming cause of death in uveal melanoma patients, with almost 50% of patients developing liver metastases up to 15 years after diagnosis. Most of these patients do not present with any evidence of overt metastasis at the time of initial diagnosis although it is assumed that they have undetectable micrometastases. Currently, there are no therapeutic modalities to prevent or efficiently treat the metastatic disease in uveal melanoma patients. Recent discoveries have shed light on the molecular pathways that may contribute to the progression of liver metastasis. The aim of this review is to describe new insights into the genetic and molecular pathways that may play a role in the development of liver metastases in uveal melanoma patients.
Targeting the Phosphoinositide 3-Kinase Isoform p110δ Impairs Growth and Survival in Neuroblastoma Cells
Authors: Boller Danielle , Schramm Alexander , Doepfner Kathrin T. , Shalaby Tarek , von Bueren André O. , Eggert Angelika , Grotzer Michael A. , Arcaro Alexandre 
Published: February 2008

AbstractPurpose: The phosphoinositide 3-kinase (PI3K)/Akt pathway is frequently activated in human cancer and plays a crucial role in neuroblastoma biology. We were interested in gaining further insight into the potential of targeting PI3K/Akt signaling as a novel antiproliferative approach in neuroblastoma.Experimental Design: The expression pattern and functions of class IA PI3K isoforms were investigated in tumor samples and cell lines. Effects on cell survival and downstream signaling were analyzed following down-regulation of p110α or p110δ in SH-SY5Y and LA-N-1 cells by means of RNA interference.Results: Overexpression of the catalytic p110δ and regulatory p85α isoforms was detected in a panel of primary neuroblastoma samples and cell lines, compared with normal adrenal gland tissue. Although down-regulation of either p110α or p110δ led to impaired cell growth, reduced expression of p110δ also had a selective effect on the survival of SH-SY5Y cells. Decreased levels of p110δ were found to induce apoptosis and lead to lower expression levels of antiapoptotic Bcl-2 family proteins. SH-SY5Y cells with decreased p110δ levels also displayed reduced activation of ribosomal protein S6 kinase in response to stimulation with epidermal growth factor and insulin-like growth factor-I.Conclusions: Together, our data reveal a novel function of p110δ in neuroblastoma growth and survival.
Irinophore C: A Liposome Formulation of Irinotecan with Substantially Improved Therapeutic Efficacy against a Panel of Human Xenograft Tumors
Authors: Ramsay Euan C. , Anantha Malathi , Zastre Jason , Meijs Marieke , Zonderhuis Jet , Strutt Dita , Webb Murray S. , Waterhouse Dawn , Bally Marcel B. 
Published: February 2008

Abstract
Purpose: To assess the pharmacokinetics, tumor drug accumulation, and therapeutic activity of Irinophore C, a novel liposomal formulation of irinotecan (CPT-11).
Experimental Design: The plasma lactone/carboxy levels of CPT-11 and SN-38 were determined in mice after a single i.v. dose of irinotecan (Camptosar), or Irinophore C, and the plasma t1/2, plasma area under the curve, plasma Cmax, and plasma clearance were calculated. Further, plasma and tumor drug levels were also measured in tumor-bearing mice following Irinophore C treatment. The efficacy of Irinophore C was compared with that of Camptosar in five s.c. human tumor xenografts using single-dose treatment (LS 180), a total of three doses administered at 4-day intervals (H460), or a total of three doses administered at 7-day intervals (Capan-1, PC-3, and HT-29).
Results: Compared with Camptosar, Irinophore C mediated an 8-fold increase in t1/2, a 100-fold increase in Cmax, a 1,000-fold increase in area under the curve, and a 1,000-fold decrease in clearance for the active lactone form of CPT-11. Further, the plasma and tumor SN-38 lactone levels were consistent for at least 48 h post-Irinophore C injection. Camptosar treatment (40 mg/kg) mediated a delay in the time required for tumors to increase to four times their pretreatment size compared with controls (T-C). T-Cs ranged from 2 days (LS 180 model) to 18 days (PC-3 model). Irinophore C (40 mg/kg) engendered T-Cs ranging from 14 days (LS 180 model) to 87 days (Capan-1 model).
Conclusion: Irinophore C improved CPT-11/SN-38 pharmacokinetics, promoted tumor drug accumulation, and increased therapeutic efficacy in a panel of five distinct human tumor xenografts.
Preclinical Toxicity, Toxicokinetics, and Antitumoral Efficacy Studies of DTS-201, a Tumor-Selective Peptidic Prodrug of Doxorubicin
Authors: Ravel Denis , Dubois Vincent , Quinonero Jérôme , Meyer-Losic Florence , Delord JeanPierre , Rochaix Philippe , Nicolazzi Céline , Ribes Fabien , Mazerolles Catherine , Assouly Elise , Vialatte Karine , Hor Inès , Kearsey Jonathan , Trouet André 
Published: February 2008

AbstractPurpose: There is a clear clinical need for cytotoxic drugs with a lower systemic toxicity. DTS-201 (CPI-0004Na) is a peptidic prodrug of doxorubicin that shows an improved therapeutic index in experimental models. The purpose of the current study was to complete its preclinical characterization before initiation of phase I clinical trials.Experimental Design: The preclinical development program consisted of a detailed assessment of the general and cardiac toxicity profiles of DTS-201 in mice, rats, and dogs, together with mass balance and antitumoral efficacy studies in rodents. Neprilysin and thimet oligopeptidase expression, two enzymatic activators of DTS-201, was also characterized in human breast and prostate tumor biopsies.Results: The target organs of DTS-201 toxicity in rodents and dogs are typically those of doxorubicin, albeit at much higher doses. Importantly, chronic treatment with DTS-201 proved to be significantly less cardiotoxic than with doxorubicin at doses up to 8-fold higher in rats. The mass balance study showed that [14C] DTS-201 does not accumulate in the body after intravenous administration. The improved therapeutic index of DTS-201 compared with free doxorubicin was confirmed in three tumor xenograft models of prostate, breast, and lung cancer. Neprilysin and/or thimet oligopeptidase are expressed in all experimental human tumor types thus far tested as well as in a large majority of human breast and prostate tumor biopsies.Conclusion: DTS-201 gave promising results in terms of general toxicity, cardiovascular tolerance, and in vivo efficacy in xenograft mouse models compared with free doxorubicin. Taken together, these results and the confirmation of the presence of activating enzymes in human tumor biopsies provide a strong rationale for a phase I clinical study in cancer patients.
Effects of Common Germ-Line Genetic Variation in Cell Cycle Genes on Ovarian Cancer Survival
Authors: Song Honglin , Hogdall Estrid , Ramus Susan J. , DiCioccio Richard A. , Hogdall Claus , Quaye Lydia , McGuire Valerie , Whittemore Alice S. , Shah Mitul , Greenberg David , Easton Douglas F. , Kjaer Susanne Kruger , Pharoah Paul D.P. , Gayther Simon A. 
Published: February 2008

Abstract
Purpose: Somatic alterations have been shown to correlate with ovarian cancer prognosis and survival, but less is known about the effects on survival of common inherited genetic variation. Of particular interest are genes involved in cell cycle pathways, which regulate cell division and could plausibly influence clinical characteristics of multiple tumors types.
Experimental Design: We examined associations between common germ-line genetic variation in 14 genes involved in cell cycle pathway (CCND1, CCND2, CCND3, CCNE1, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, CDKN2D, CDK2, CDK4, CDK6, and RB1) and survival among women with invasive ovarian cancer participating in a multicenter case-control study from United Kingdom, Denmark, and United States. DNAs from up to 1,499 women were genotyped for 97 single-nucleotide polymorphisms that tagged the known common variants (minor allele frequency ≥0.05) in these genes. The genotypes of each polymorphism were tested for association with survival by Cox regression analysis.
Results: A nominally statistically significant association between genotype and ovarian cancer survival was observed for polymorphisms in CCND2 and CCNE1. The per-allele hazard ratios (95% confidence intervals) were 1.16 (1.03-1.31; P = 0.02) for rs3217933, 1.14 (1.02-1.27; P = 0.024) for rs3217901, and 0.85 (0.73-1.00; P = 0.043) for rs3217862 in CCND2 and 1.39 (1.04-1.85; P = 0.033) for rs3218038 in CCNE1. However, these were not significant after adjusting for multiple hypothesis tests.
Conclusion: It is unlikely that common variants in cell cycle pathways examined above associated with moderate effect in survival after diagnosis of ovarian cancer. Much larger studies will be needed to exclude common variants with small effects.
High-Resolution DNA Copy Number Profiling of Malignant Peripheral Nerve Sheath Tumors Using Targeted Microarray-Based Comparative Genomic Hybridization
Authors: Mantripragada Kiran K. , Spurlock Gillian , Kluwe Lan , Chuzhanova Nadia , Ferner Rosalie E. , Frayling Ian M. , Dumanski Jan P. , Guha Abhijit , Mautner Victor , Upadhyaya Meena 
Published: February 2008

AbstractPurpose: Neurofibromatosis type 1 (NF1) is an autosomal dominant condition that predisposes to benign and malignant tumors. The lifetime risk of a malignant peripheral nerve sheath tumor (MPNST) in NF1 is ∼10%. These tumors have a poor survival rate and their molecular basis remains unclear. We report the first comprehensive investigation of DNA copy number across multitude of genes in NF1 tumors using high-resolution array comparative genomic hybridization (CGH), with the aim to identify molecular signatures that delineate malignant from benign NF1 tumors.Experimental Design: We constructed an exon-level resolution microarray encompassing 57 selected genes and profiled DNA from 35 MPNSTs, 16 plexiform, and 8 dermal neurofibromas. Bioinformatic analysis was done on array CGH data to identify concurrent aberrations in malignant tumors.Results: The array CGH profiles of MPNSTs and neurofibromas were markedly different. A number of MPNST-specific alterations were identified, including amplifications of ITGB4, PDGFRA, MET, TP73, and HGF plus deletions in NF1, HMMR/RHAMM, MMP13, L1CAM2, p16INK4A/CDKN2A, and TP53. Copy number changes of HMMR/RHAMM, MMP13, p16INK4A/CDKN2A, and ITGB4 were observed in 46%, 43%, 39%, and 32%, respectively of the malignant tumors, implicating these genes in MPNST pathogenesis. Concomitant amplifications of HGF, MET, and PDGFRA genes were also revealed in MPNSTs, suggesting the putative role of p70S6K pathway in NF1 tumor progression.Conclusions: This study highlights the potential of array CGH in identifying novel diagnostic markers for MPNSTs.
Oncolytic Efficacy of Recombinant Vesicular Stomatitis Virus and Myxoma Virus in Experimental Models of Rhabdoid Tumors
Authors: Wu Yushui , Lun Xueqing , Zhou Hongyuan , Wang Limei , Sun Beichen , Bell John C. , Barrett John W. , McFadden Grant , Biegel Jaclyn A. , Senger Donna L. , Forsyth Peter A. 
Published: February 2008

AbstractPurpose: Rhabdoid tumors are highly aggressive pediatric tumors that are usually refractory to available treatments. The purpose of this study was to evaluate the therapeutic potential of two oncolytic viruses, myxoma virus (MV) and an attenuated vesicular stomatitis virus (VSVΔM51), in experimental models of human rhabdoid tumor.Experimental Design: Four human rhabdoid tumor cell lines were cultured in vitro and treated with live or inactivated control virus. Cytopathic effect, viral gene expression, infectious viral titers, and cell viability were examined at various time points after infection. To study viral oncolysis in vivo, human rhabdoid tumor cells were implanted s.c. in the hind flank or intracranially in CD-1 nude mice and treated with intratumoral (i.t.) or i.v. injections of live or UV-inactivated virus. Viral distribution and effects on tumor size and survival were assessed.Results: All rhabdoid tumor cell lines tested in vitro were susceptible to productive lethal infections by MV and VSVΔM51. I.t. injection of live MV or VSVΔM51 dramatically reduced the size of s.c. rhabdoid tumor xenografts compared with control animals. I.v. administration of VSVΔM51 or i.t. injection of MV prolonged the median survival of mice with brain xenografts compared with controls (VSVΔM51: 25 days versus 21 days, log-rank test, P = 0.0036; MV: median survival not reached versus 21 days, log-rank test, P = 0.0007). Most of the MV-treated animals (4 of 6; 66.7%) were alive and apparently “cured” when the experiment was arbitrarily ended (&gt;180 days).Conclusions: These results suggest that VSVΔM51 and MV could be novel effective therapies against human rhabdoid tumor.
Proteomic Analysis of Laser-Captured Paraffin-Embedded Tissues: A Molecular Portrait of Head and Neck Cancer Progression
Authors: Patel Vyomesh , Hood Brian L. , Molinolo Alfredo A. , Lee Norman H. , Conrads Thomas P. , Braisted John C. , Krizman David B. , Veenstra Timothy D. , Gutkind J. Silvio 
Published: February 2008

Abstract
Purpose: Squamous cell carcinoma of the head and neck (HNSCC), the sixth most prevalent cancer among men worldwide, is associated with poor prognosis, which has improved only marginally over the past three decades. A proteomic analysis of HNSCC lesions may help identify novel molecular targets for the early detection, prevention, and treatment of HNSCC.
Experimental Design: Laser capture microdissection was combined with recently developed techniques for protein extraction from formalin-fixed paraffin-embedded (FFPE) tissues and a novel proteomics platform. Approximately 20,000 cells procured from FFPE tissue sections of normal oral epithelium and well, moderately, and poorly differentiated HNSCC were processed for mass spectrometry and bioinformatic analysis.
Results: A large number of proteins expressed in normal oral epithelium and HNSCC, including cytokeratins, intermediate filaments, differentiation markers, and proteins involved in stem cell maintenance, signal transduction, migration, cell cycle regulation, growth and angiogenesis, matrix degradation, and proteins with tumor suppressive and oncogenic potential, were readily detected. Of interest, the relative expression of many of these molecules followed a distinct pattern in normal squamous epithelia and well, moderately, and poorly differentiated HNSCC tumor tissues. Representative proteins were further validated using immunohistochemical studies in HNSCC tissue sections and tissue microarrays.
Conclusions: The ability to combine laser capture microdissection and in-depth proteomic analysis of FFPE tissues provided a wealth of information regarding the nature of the proteins expressed in normal squamous epithelium and during HNSCC progression, which may allow the development of novel biomarkers of diagnostic and prognostic value and the identification of novel targets for therapeutic intervention in HNSCC.
Thymidylate Synthase Expression in Gastroenteropancreatic and Pulmonary Neuroendocrine Tumors
Authors: Ceppi Paolo , Volante Marco , Ferrero Anna , Righi Luisella , Rapa Ida , Rosas Rosj , Berruti Alfredo , Dogliotti Luigi , Scagliotti Giorgio V. , Papotti Mauro 
Published: February 2008

Abstract
Purpose: The predictive role of the quantification of thymidylate synthase (TS) in tumors treated with antifolate drugs, such as 5-fluorouracil (5-FU), has been extensively reported in a variety of human tumors. Neuroendocrine tumors (NET) represent potential targets of antifolate agents, but no data on TS expression level in these tumors are currently available.
Experimental Design: A series of 116 NETs were collected, including 58 gastroenteropancreatic (GEP) and 58 lung NETs. In 24 well-differentiated GEP neuroendocrine carcinomas (WD-NEC), a 5-FU–based treatment was given. Total RNA was extracted from microdissected paraffin blocks. TS mRNA quantification was done by real-time PCR, whereas protein expression was evaluated by immunohistochemistry.
Results: By means of both quantification by real-time PCR and immunohistochemistry, a higher TS expression in pulmonary small cell lung cancer and large cell NEC compared with typical and atypical carcinoids was observed (P &lt; 0.01). Similarly, in GEP tumors, a higher TS expression in poorly differentiated carcinomas than both WD-NEC and benign tumors (P &lt; 0.01) was found. In patients with WD-NEC treated with 5-FU, high TS mRNA levels were associated with shorter time to progression (P = 0.002) and overall survival (P = 0.04). This negative prognostic role was confirmed in multivariate analysis adjusting for major prognostic variables (P = 0.01). No association between TS mRNA and survival was observed in WD-NEC patients not receiving 5-FU.
Conclusions: This study, for the first time, (a) reports the differential TS expression in the spectrum of NETs and (b) indicates TS as a possible predictive marker of treatment efficacy in WD-NEC patients treated with 5-FU.
Differential Wnt Pathway Gene Expression and E-Cadherin Truncation in Sporadic Colorectal Cancers with and without Microsatellite Instability
Authors: Ortega Paloma , Morán Alberto , de Juan Carmen , Frías Cristina , Hernández Susana , López-Asenjo Jose-Antonio , Sánchez-Pernaute Andrés , Torres Antonio , Iniesta Pilar , Benito Manuel 
Published: February 2008

Abstract
Purpose: Alterations in the Wnt pathway play a major role in colorectal cancer with high (MSI-H) or low microsatellite instability (MSS/MSI-L). However, the differential impact of the Wnt pathway components on these tumors is poorly understood. MMP-3 (stromelysin-1) promoter is a target of the mutator phenotype in sporadic colorectal cancer. Among MMP-3 targets, we investigated E-cadherin integrity status in both groups of tumors. Because beta-catenin is the main effector of the Wnt pathway, we have also investigated the differential cellular status of beta-catenin.
Experimental Design: Expression profiles of 114 genes related to the Wnt pathway were analyzed by oligo microarrays in 48 tumors classified by their MSI status. In addition, we analyzed 48 sporadic colorectal cancers for E-cadherin integrity status. We performed investigation of beta-catenin and cyclin D1 by immunohistochemistry using tissue arrays containing 96 tumors.
Results: Our data show that a group of genes that negatively regulate Wnt signaling are downregulated in MSS/MSI-L as compared with MSI-H colorectal tumors. E-cadherin truncation was significantly higher in MSS/MSI-L as compared with MSI-H tumors. Moreover, MSI-H tumors showed low or null beta-catenin nuclear presence, whereas the group of tumors classified as MSS or MSI-L displayed a high content of the nuclear beta-catenin location.
Conclusions: Our results suggest that the differential expression of genes that negatively regulate the Wnt pathway, as well as the status of E-cadherin and beta-catenin in MSI-H or MSS/MSI-L colorectal tumors, shed some light on the different clinical behavior showed by the two groups.
Epithelial Human Leukocyte Antigen-DR Expression Predicts Reduced Recurrence Rates and Prolonged Survival in Rectal Cancer Patients
Authors: de Bruin Elza C. , van de Velde Cornelis J.H. , van Krieken J. Han J.M. , Marijnen Corrie A.M. , Medema Jan Paul 
Published: February 2008

Abstract
Purpose: The development of local and distant recurrences is a major problem in the treatment of rectal cancer patients. In this study, we investigated whether epithelial human leukocyte antigen-DR (HLA-DR) expression allowed discrimination between high and low tumor recurrence rates, and analyzed the mechanism behind its expression.
Experimental Design: The role of IFNγ in HLA-DR expression was studied in rectal cancer cell lines and tumors by promoter-specific analyses of class II transactivator (CIITA). The predictive value of epithelial HLA-DR expression was investigated by immunohistochemical evaluation of 1,016 rectal tumors, obtained from a large prospective trial. Associations with recurrences and survival were determined by univariate and multivariate log-rank testing.
Results: HLA-DR was induced by IFNγ in rectal cancer cell lines. Activity of the IFNγ-inducible pIV-CIITA promoter correlated with epithelial HLA-DR expression in rectal tumors. Patients with HLA-DR–positive tumors developed less frequent local and distant recurrences [1.6% versus 9.1% (P = 0.0015) and 15.3% versus 29.9% (P &lt; 0.0001), respectively, after 5 years of follow-up] and had better survival (78.6% versus 61.3%; P &lt; 0.0001) than patients with HLA-DR–negative tumors. Epithelial HLA-DR was more often found in lower tumor-node-metastasis (TNM) stages. Next to TNM and circumferential resection margin, HLA-DR expression was independently associated with lower distant recurrence rates and prolonged survival.
Conclusions: Epithelial HLA-DR expression can be used as a marker to discriminate patients with high or low risk of developing recurrences. The possible involvement of IFNγ, the relationship with lower TNM stages, and the independent effect on recurrence development together suggest that the host immune response plays an important role in controlling tumor cells.
Identifying Breast Cancer Druggable Oncogenic Alterations: Lessons Learned and Future Targeted Options
Authors: Ocaña Alberto , Pandiella Atanasio 
Published: February 2008

AbstractAlthough the introduction of novel therapies and drug combinations has improved the prognosis of metastatic breast cancer, this disease remains incurable. It is therefore important to develop additional novel therapeutic strategies and agents. Increased understanding of the biology and the molecular alterations present in breast cancer is facilitating the design of targeted therapies directed to oncogenic proteins. Here, we review the signaling pathways and proteins that participate in breast cancer proliferation and survival, with special emphasis in those that are druggable. We will also comment on how the knowledge on the basic pathogenetic processes is translated into drug development strategies that are reaching the breast cancer clinic.