bluuebunny/crossref_metadata_2025_split huggingface dataset:
Significant Effect of Homologous Recombination DNA Repair Gene Polymorphisms on Pancreatic Cancer Survival
Authors: Li Donghui , Liu Hui , Jiao Li , Chang David Z. , Beinart Garth , Wolff Robert A. , Evans Douglas B. , Hassan Manal M. , Abbruzzese James L. 
Published: March 2006

Abstract
Genetic variation in DNA repair may affect the clinical response to cytotoxic therapies. We investigated the effect of six single nucleotide polymorphisms of the RecQ1, RAD54L, XRCC2, and XRCC3 genes on overall survival of 378 patients with pancreatic adenocarcinoma who were treated at University of Texas M.D. Anderson Cancer Center during February 1999 to October 2004 and were followed up to October 2005. Genotypes were determined using the MassCode method. Survival was determined from pathologic diagnosis to death. Patients who were alive at the last follow-up evaluation were censored at that time. Kaplan-Meier plot, log-rank test, and Cox regression were used to compare overall survival by genotypes. A significant effect on survival of all patients was observed for RecQ1 and RAD54L genes. The median survival time was 19.2, 14.7, and 13.2 months for the RecQ1 159 AA, AC, and CC genotypes, and 16.4, 13.3, and 10.3 months for RAD54L 157 CC, CT, and TT genotypes, respectively. A significantly reduced survival was associated with the variant alleles of XRCC2 R188H and XRCC3 A17893G in subgroup analysis. When the four genes were analyzed in combination, an increasing number of adverse alleles were associated with a significantly decreased survival. Subgroup analyses have shown that the genotype effect on survival was present among patients without metastatic disease or among patients who receive radiotherapy. These observations suggest that polymorphisms of genes involved in the repair of DNA double-strand breaks significantly affect the clinical outcome of patients with pancreatic cancer. (Cancer Res 2006; 66(6): 3323-30)
A Novel Mechanism of Synergistic Cytotoxicity with 5-Fluorocytosine and Ganciclovir in Double Suicide Gene Therapy
Authors: Boucher Paul D. , Im Michael M. , Freytag Svend O. , Shewach Donna S. 
Published: March 2006

Abstract
The combination of cytosine deaminase (CD) and herpes simplex virus thymidine kinase (HSV-TK) suicide gene protocols has resulted in enhanced antitumor activity in cultured tumor cells and animal models. In this study, we show that concurrent addition of prodrugs 5-fluorocytosine (5-FC) and ganciclovir (GCV) was less efficacious than sequential treatment in human DU145 prostate carcinoma cells infected with an adenovirus containing a CD/HSV-TK fusion gene. If cells were incubated for 24 hours with 5-FC followed by a 24-hour GCV treatment, GCV triphosphate levels were 2-fold higher, incorporation of GCV monophosphate into DNA was 2.5-fold higher, and growth inhibition was increased 4-fold compared with simultaneous treatment. As expected, cellular dTTP levels were reduced during the 5-FC preincubation. However, dGTP pools also declined parallel to the dTTP decrease. Similar results were obtained when 5-fluorouracil or 5-fluoro-2′-deoxyuridine was used instead of CD/5-FC. These data allowed us to propose a novel hypothesis for the synergistic interaction between CD/5-FC and HSV-TK/GCV treatments. We suggest that the CD/5-FC–mediated reduction of dTTP results in a concurrent decrease of dGTP due to allosteric regulation of ribonucleotide reductase. Because dGTP is the endogenous competitor of GCV triphosphate, depleted dGTP at the time of GCV addition results in increased GCV in DNA and cell kill. In fact, addition of deoxyguanosine during the 5-FC incubation reverses the dGTP depletion, reduces the amount of GCV monophosphate incorporated into DNA, and prevents the CD/5-FC–mediated enhancement of HSV-TK/GCV cytotoxicity. Understanding this mechanistic interaction may help recognize better strategies for creating more efficacious clinical protocols. (Cancer Res 2006; 66(6): 3230-7)
4-Oxo-Fenretinide, a Recently Identified Fenretinide Metabolite, Induces Marked G2-M Cell Cycle Arrest and Apoptosis in Fenretinide-Sensitive and Fenretinide-Resistant Cell Lines
Authors: Villani Maria Grazia , Appierto Valentina , Cavadini Elena , Bettiga Arianna , Prinetti Alessandro , Clagett-Dame Margaret , Curley Robert W. , Formelli Franca 
Published: March 2006

Abstract4-Oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR) is a recently identified metabolite of fenretinide (4-HPR). We explored the effectiveness of 4-oxo-4-HPR in inducing cell growth inhibition in ovarian, breast, and neuroblastoma tumor cell lines; moreover, we investigated the molecular events mediating this effect in two ovarian carcinoma cell lines, one sensitive (A2780) and one resistant (A2780/HPR) to 4-HPR. 4-Oxo-4-HPR was two to four times more effective than 4-HPR in most cell lines, was effective in both 4-HPR–sensitive and 4-HPR–resistant cells, and, in combination with 4-HPR, caused a synergistic effect. The tumor growth-inhibitory effects of 4-oxo-4-HPR seem to be independent of nuclear retinoid receptors (RAR), as indicated by the failure of RAR antagonists to inhibit its effects and by its poor ability to bind and transactivate RARs. Unlike 4-HPR, which only slightly affected the G1 phase of the cell cycle, 4-oxo-4-HPR caused a marked accumulation of cells in G2-M. This effect was associated with a reduction in the expression of regulatory proteins of G2-M (cyclin-dependent kinase 1 and cdc25c) and S (cyclin A) phases, and with an increase in the expression of apoptosis-related proteins, such as p53 and p21. Apoptosis was induced by 4-oxo-4-HPR in both 4-HPR–sensitive and 4-HPR–resistant cells and involved activation of caspase-3 and caspase-9 but not caspase-8. We also showed that 4-oxo-4-HPR, similarly to 4-HPR, increased reactive oxygen species generation and ceramide levels by de novo synthesis. In conclusion, 4-oxo-4-HPR is an effective 4-HPR metabolite that might act as therapeutic agent per se and, when combined with 4-HPR, might improve 4-HPR activity or overcome 4-HPR resistance. (Cancer Res 2006; 66(6): 3238-47)
Behavioral Profiling of Human Transitional Cell Carcinoma Ex vivo
Authors: Estrada Carlos R. , Salanga Matthew , Bielenberg Diane R. , Harrell W. Bruce , Zurakowski David , Zhu Xuping , Palmer Matthew R. , Freeman Michael R. , Adam Rosalyn M. 
Published: March 2006

Abstract
Outcome studies of many types of cancer have revealed that tumors of indistinguishable histologic appearance may differ significantly in aggressiveness and in their response to therapy. A strategy that would enable early identification of patients at high risk for disease progression and allow screening of multiple therapeutic agents simultaneously for efficacy would improve clinical management. We have developed an orthotopic organ culture model of bladder cancer in which quantum dot–based fluorescent imaging approaches are used to obtain quantitative measurements of tumor cell behavior. Human transitional cell carcinoma (TCC) cells are labeled with quantum dot nanoparticles, and the cells instilled into the rat bladder in vivo, after which the bladder is excised and cultured ex vivo. Cell implantation, proliferation, and invasion into the organ wall are monitored using epifluorescence imaging and two-photon laser scanning confocal microscopy. Using this approach, we were able to assign distinct phenotypes to two metastatic bladder cancer cell lines based on different patterns of invasiveness into the bladder wall. We also showed that established tumor cell masses regressed following intravesical administration of the chemotherapeutic drug thiotepa. Collectively, these findings suggest that this assay system, which we have named EViTAS (for ex vivo tumor assay system), can recapitulate salient aspects of tumor growth in the host and is amenable to behavioral profiling of human cancer. (Cancer Res 2006; 66(6): 3078-86)
Signal Transducers and Activators of Transcription 3 Activation Is Involved in Nuclear Accumulation of β-Catenin in Colorectal Cancer
Authors: Kawada Mayumi , Seno Hiroshi , Uenoyama Yoshito , Sawabu Tateo , Kanda Naoki , Fukui Hirokazu , Shimahara Yasuyuki , Chiba Tsutomu 
Published: March 2006

Abstract
Nuclear accumulation of β-catenin is a key event for the development of colorectal cancer. Little is known, however, about the mechanisms underlying translocation of β-catenin from the cytoplasm or the membrane to the nucleus. The present study examined whether signal transducers and activators of transcription 3 (STAT3) activation is involved in the nuclear accumulation of β-catenin in colorectal cancer cells. Of the 90 primary colorectal cancer tissues, 40 (44.4%) were positive for nuclear staining of p-STAT3 and 63 (70.0%) were positive for nuclear staining of β-catenin. The nuclear staining of both p-STAT3 and β-catenin were observed predominantly in the periphery of the cancer tissues. Importantly, of the 40 tumors with p-STAT3 nuclear staining, 37 (92.5%) were also positive for nuclear β-catenin staining and there was a significant correlation between p-STAT3 and β-catenin nuclear staining (P &lt; 0.01). Coexpression of nuclear p-STAT3 and β-catenin was associated with lower patient survival (P &lt; 0.01). In an in vitro study using a human colon cancer cell line, SW480, inhibition of STAT3 by dominant negative STAT3 or the Janus kinase inhibitor, AG490, induced translocation of β-catenin from the nucleus to the cytoplasm or membrane. Luciferase assays revealed that STAT3 inhibition resulted in significant suppression of β-catenin/T-cell factor transcription in association with significant inhibition of cell proliferation (P &lt; 0.05). These findings suggest that in colorectal cancer, STAT3 activation is involved in the nuclear accumulation of β-catenin, resulting in poor patient survival. (Cancer Res 2006; 66(6): 2913-7)
Enhanced Photocarcinogenesis in Interleukin-12–Deficient Mice
Authors: Maeda Akira , Schneider Stefan W. , Kojima Motohiro , Beissert Stefan , Schwarz Thomas , Schwarz Agatha 
Published: March 2006

AbstractUV-induced DNA damage is the basis for the development of UV-mediated skin cancer because reduction of DNA damage lowers the risk for photocarcinogenesis. The cytokine interleukin (IL)-12 was shown to exhibit the capacity to reduce UV-induced DNA damage presumably via induction of nucleotide excision repair. Because IL-12 is also produced in the skin, we wondered whether endogenous IL-12 protects from photocarcinogenesis. Therefore, we used knockout mice that lack the IL-12p40 chain and thus do not secrete biologically active IL-12. IL-12p40 knockout (IL-12p40−/−) and wild-type (wt) mice were exposed thrice weekly to UV. Skin biopsies obtained after 6 weeks revealed significantly increased numbers of sunburn cells in IL-12p40−/− mice. Additionally, a higher load of UV-induced pyrimidine dimers could be detected in the skin of UV-exposed IL-12p40−/− mice. Staining of epidermal sheets with an antibody against the tumor suppressor gene p53 revealed a higher number of p53 patches in the skin of IL-12p40−/− mice. After ∼200 days, first skin tumors developed. Kaplan-Meier analysis indicated a significantly increased probability of tumor development in the IL-12p40−/− mice. In addition, the number of tumors developing in the individual mice was significantly higher in IL-12p40−/− mice than in wt mice. Tumors obtained in IL-12p40−/− mice grew faster than those obtained from wt mice on inoculation into nu/nu mice. This was confirmed in an electrophysiologic assay evaluating the intrinsic invasive potency of tumor cells. Together, these data indicate that IL-12 deficiency is associated with an increased risk to develop UV-induced skin cancer, implying that endogenous IL-12 may protect from photocarcinogenesis. (Cancer Res 2006; 66(6): 2962-9)
Transplantable Tumor Lines Generated in Clonal Zebrafish
Authors: Mizgireuv Igor V. , Revskoy Sergei Y. 
Published: March 2006

Abstract
Transplantable zebrafish tumors are a novel and very promising model in cancer research. However, further progress in this field has been contained by a lack of true inbred lines in zebrafish. To overcome this problem, we generated two lines of homozygous diploid clonal zebrafish lines (i.e., CB1 and CW1), which allowed us to carry out transplantation of any tissue, including tumors, from one fish to another within a line without rejection of the graft. The primary tumors in CB1 fish were induced by N-nitrosodiethylamine (DEN). The histologic analysis of these tumors revealed different types of hepatocellular carcinomas, hepatoblastomas, hepatoma, cholangiocarcinoma, and pancreatic carcinoma. Four spontaneous acinar cell carcinomas of pancreas were also found in 10- to 18-month-old CB1 fish. Small pieces of tissue or cell suspensions of either DEN-induced or spontaneous tumors were serially transplanted into the peritoneal cavity of syngeneic fish at different stages of development from 5-day-old larvae to adult fish. The development of grossly visible tumors occurred from 2 weeks to 3 months after tumor grafting and grew either as solitary smooth nodules or as an amorphous jelly-like mass infiltrating abdominal organs. The majority of tumors were also successfully transplanted to isogeneic (F1 generation from crossing CB1 × CW1) fish. At the present time, 19 transplantable zebrafish tumor lines have been generated and maintained for as long as 3 to 25 passages. This model provides a novel tool for studying experimental tumor biology and therapy and will become a cost effective system for high throughput screening of anticancer drugs. (Cancer Res 2006; 66(6): 3120-5)
Levels of HdmX Expression Dictate the Sensitivity of Normal and Transformed Cells to Nutlin-3
Authors: Patton John T. , Mayo Lindsey D. , Singhi Aatur D. , Gudkov Andrei V. , Stark George R. , Jackson Mark W. 
Published: March 2006

Abstract
Hdm2 and HdmX coordinately regulate the stability and function of p53. Each is overexpressed in subsets of many different types of malignancy, and most of these subsets maintain wild-type p53. Nutlins, newly discovered small-molecule inhibitors of the Hdm2-p53 interaction, offer a novel strategy for therapy of tumors with wild-type p53. We now show that Nutlin-3 efficiently induces apoptosis and diminishes long-term survival of human fibroblasts transformed in vitro by Hdm2 but not HdmX. The resistance of cells overexpressing HdmX to Nutlin-3 is due to its inability to disrupt the p53-HdmX interaction, resulting in continued suppression of p53 activity. Although HdmX overexpression yielded cells resistant to Nutlin-3, ablation of HdmX expression by short hairpin RNA sensitized tumor cells to Nutlin-3–mediated cell death or arrest. Furthermore, deletion of the COOH-terminal RING finger domain of HdmX completely reversed the resistance to Nutlin-3, probably reflecting the requirement of the RING finger for interaction with Hdm2. Thus, the relative abundance of Hdm2 and HdmX and the specificity of Nutlin-3 for Hdm2 influence the sensitivity of cells to p53-dependent apoptosis or arrest in response to Nutlin-3. Our findings establish Hdm2 and HdmX as independent therapeutic targets with respect to reactivating wild-type p53 as a means for cancer therapy. (Cancer Res 2006; 66(6): 3169-76)
A Novel Transcriptional Inhibitor Induces Apoptosis in Tumor Cells and Exhibits Antiangiogenic Activity
Authors: Radhakrishnan Senthil K. , Gartel Andrei L. 
Published: March 2006

AbstractUsing a high-throughput cell-based assay, we identified a nucleoside analogue 4-amino-6-hydrazino-7-β-d-ribofuranosyl-7H-pyrrolo(2,3-d)-pyrimidine-5-carboxamide (ARC), which has the properties of a general transcriptional inhibitor. Specifically, ARC inhibits the phosphorylation of RNA polymerase II by positive transcription elongation factor-b, leading to a block in transcriptional elongation. ARC was able to potently repress p53 targets p21 and hdm2 (human homologue of mdm2) protein levels, but dramatically increased p53 levels similar to other transcriptional inhibitors, including flavopiridol. This increase in p53 corresponded to the down-regulation of short-lived protein hdm2, which is a well-established negative regulator of p53. Remarkably, ARC induced potent apoptosis in human tumor and transformed, but not in normal cells, and possessed strong antiangiogenic activity in vitro. Although ARC promoted the accumulation of p53, ARC-induced apoptosis in tumor cells was p53-independent, suggesting that it may be useful for the treatment of tumors with functionally inactive p53. Furthermore, cell death induced by ARC had a strong correlation with down-regulation of the antiapoptotic gene survivin, which is often overexpressed in human tumors. Taken together, our data suggests that ARC may be an attractive candidate for anticancer drug development. (Cancer Res 2006; 66(6): 3264-70)
Global Gene Expression Profiling of Circulating Endothelial Cells in Patients with Metastatic Carcinomas
Authors: Smirnov Denis A. , Foulk Bradley W. , Doyle Gerald V. , Connelly Mark C. , Terstappen Leon W.M.M. , O'Hara S. Mark 
Published: March 2006

Abstract
Increased numbers of endothelial cells are observed in peripheral blood of cancer patients. These circulating endothelial cells (CECs) may contribute to the formation of blood vessels in the tumor or reflect vascular damage caused by treatment or tumor growth. Characterization of these cells may aid in the understanding of the angiogenic process and may provide biomarkers for treatment efficacy of angiogenesis inhibitors. To identify markers typical for CECs in cancer patients, we assessed global gene expression profiles of CD146 immunomagnetically enriched CECs from healthy donors and patients with metastatic breast, colorectal, prostate, lung, and renal cancer. From the generated gene profiles, a list of 61 marker genes for CEC detection was generated, and their expression was measured by real-time quantitative PCR in blood samples from 81 metastatic cancer patients and 55 healthy donors that were immunomagnetically enriched for CECs. A set of 34 genes, among which novel CEC-associated genes, such as THBD, BST1, TIE1, POSTN1, SELE, SORT1, and DTR, were identified that were expressed at higher levels in cancer patients compared with healthy donors. Expression of the VWF, DTR, CDH5, TIE, and IGFBP7 genes were found to discriminate between cancer patients and “healthy” donors with a receiver operating characteristic curve accuracy of 0.93. Assessment of the expression of these genes may provide biomarkers to evaluate treatment efficacy. (Cancer Res 2006; 66(6): 2918-22)
Bcl-2 Inhibition of Autophagy: A New Route to Cancer?
Authors: Pattingre Sophie , Levine Beth 
Published: March 2006

Abstract
Bcl-2 was the first identified cellular protein that functions as an oncogene by blocking apoptotic cell death. Beclin 1, the first identified mammalian autophagy gene product, is a haploinsufficient tumor suppressor that was originally isolated as a Bcl-2-interacting protein. We recently showed that Bcl-2 negatively regulates Beclin 1-dependent autophagy and Beclin 1-dependent autophagic cell death. These findings raise the possibility that Bcl-2 family members may function as oncogenes not only by blocking apoptosis but also by blocking autophagy. (Cancer Res 2006; 66(6): 2885-8)
Angiotensin II Potentiates the Slow Component of Delayed Rectifier K+Current via the AT1Receptor in Guinea Pig Atrial Myocytes
Authors: Zankov Dimitar P. , Omatsu-Kanbe Mariko , Isono Takahiro , Toyoda Futoshi , Ding Wei-Guang , Matsuura Hiroshi , Horie Minoru 
Published: March 2006

Background—Angiotensin II (Ang II) has diverse actions on cardiac electrical activity. Little information is available, however, regarding immediate electrophysiological effects of Ang II on cardiac repolarization.Methods and Results—The present study investigated the immediate effects of Ang II on the slow component of delayed rectifier K+current (IKs) and action potentials in guinea pig atrial myocytes using the whole-cell patch-clamp technique. Bath application of Ang II increased the amplitude ofIKs(EC50, 6.16 nmol/L) concentration dependently. The stable analogue Sar1–Ang II was also effective at increasingIKs. The voltage dependence ofIKsactivation and the kinetics of deactivation were not significantly affected by these agonists. The enhancement ofIKswas blocked by the Ang II type 1 (AT1) receptor antagonist valsartan (1 μmol/L) and was markedly attenuated by inclusion of GDPβS (2 mmol/L) in the pipette, indicating an involvement of G protein–coupled AT1receptor. The stimulatory effect was also significantly reduced by the phospholipase C inhibitor compound 48/80 (100 μmol/L) and the protein kinase C inhibitors bisindolylmaleimide I (200 nmol/L) and H-7 (10 μmol/L), suggesting that AT1receptor acts through phospholipase C–protein kinase C signaling cascade to potentiateIKs. As expected from its stimulatory action onIKs, Sar1–Ang II markedly shortened the action potential duration, which could be reversed by valsartan.Conclusions—The potentiation ofIKsvia AT1stimulation in atrial myocytes, accompanied by a shortening of the action potential duration, suggests a potential mechanism by which elevated levels of Ang II may promote atrial fibrillation in heart failure and warrants further investigation.
The Criticism of Powerful Women by Western Han Dynasty Portent Experts
Authors: Hinsch Bret 
Published: March 2006

AbstractWestern Han portent experts investigated unusual natural phenomena that they considered signs of Heaven's will. Beginning as a marginal method of historical analysis and cosmological theory, portent studies matured into a standard form of political discourse and critique. Landmark research on portents by influential scholars such as Dong Zhongshu, Jing Fang, and Liu Xiang provided sophisticated metaphysical justifications for excluding certain women from political life. This article discusses the development of Western Han portent studies to demonstrate how a new politicized ideology of gender emerged from these historical and cosmological researches. Durant la période Han occidentale, les experts en divination s'intéressaient aux phénomènes naturels qu'ils interprétaient comme des manifestations de la volonté céleste. Les études divinatoires commencèrent comme une méthode marginale d'analyse historique et comme une théorie cosmologique ; elles se muèrent en un discours politique et critique. Des études importantes sur les signes divinatoires par des lettrés influent tels que Dong Zhongshu, Jin Fang et Liu Xiang fournirent des justification métaphysiques pour l'exclusion de certaines femmes de la vie politique. Cet article analyse le développement des études divinatoires durant la période Han occidentale et montre comment une nouvelle idéologique politiques des sexes a émergé de ces recherches historiques et cosmologiques.
Population dynamics of Pratylenchus coffeae on banana in North Vietnam
Authors: Nguyet Duong Thi Minh , Uyet Nguyen Thi , De Waele Dirk , Nhi Ho Huu , Van den Bergh Inge 
Published: March 2006

AbstractThe reproductive fitness of a Pratylenchus coffeae population, collected from banana roots in North Vietnam, was studied in relation to temperature and moisture under screenhouse and field conditions. In the screenhouse, the population grew much more slowly during the cooler winter months than during the summer and an excess of soil moisture reduced the nematode population drastically. The results were confirmed in the field. The nematode population in the roots of the banana plants initially increased over time but was reduced during the cooler winter months and remained nearly constant during the wettest months when the field was almost continuously flooded. These observations may explain why P. coffeae populations on Musa do not increase to dramatic levels in North Vietnam, with its cool winter temperatures and periods of abundant rainfall during several months of the year.