bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antagonism of endothelin-1 inhibits hypoxia-induced apoptosis in cardiomyocytesThis article is one of a selection of papers published in the special issue (part 2 of 2) on Forefronts in Endothelin.
Authors: Ren Anjing , Yan Xiaohong , Lu Hong , Shi Jingsong , Yin Yuanjun , Bai Jie , Yuan Wenjun , Lin Li 
Published: August 2008

Apoptosis is well documented to be a common feature of many pathological processes of the heart. Exogenous endothelin-1 (ET-1) has been shown to be proapoptotic or antiapoptotic, depending on ET-1 concentration, cell type, and the ratio of ETA/ETBreceptor subtypes. The role of endogenous ET-1 in cardiomyocyte apoptosis, however, is not clarified. This study observed the effects of the ETA-receptor antagonists BQ610 and BQ123 and the ETB-receptor antagonist BQ788 on hypoxia-induced apoptosis in primary cultured neonatal rat cardiomyocytes. Hypoxic apoptosis was induced by incubating cardiomyocytes in serum-free medium under 3% O2and 5% CO2for 24 h and evaluated by TUNEL analysis and flow cytometry. TUNEL analysis showed that the apoptotic cardiomyocytes constituted 24.2% ± 2.2% of the total cells under hypoxic conditions. Treatment with BQ610 (5 μmol/L) significantly reduced the apoptosis rate to 13.2% ± 3.7% (data from 4 independent experiments, p < 0.01 vs. hypoxia). Flow cytometry showed that the percentage of apoptotic cells positively stained with annexin V and propidium iodide was 42.76% ± 4.44% (n = 12) in cultures subjected to hypoxia. BQ123 at 0.04, 0.2, and 1.0 μmol/L dose-dependently reduced the apoptosis rate to 34.00% ± 10.35% (n = 6, p < 0.05), 30.38% ± 8.28% (n = 6, p < 0.01), and 22.89% ± 4.19% (n = 6, p < 0.01), respectively. In contrast, BQ788 did not affect hypoxic apoptosis. These findings suggested that endogenous ET-1 contributed to hypoxia-induced apoptosis in cultured cardiomyocytes, which was mediated by ETAreceptors, but not by ETBreceptors.
The endothelin axis in cancer: the promise and the challenges of molecularly targeted therapyThis article is one of a selection of papers published in the special issue (part 2 of 2) on Forefronts in Endothelin.
Authors: Bagnato Anna , Spinella Francesca , Rosanò Laura 
Published: August 2008

The endothelin (ET) axis, which includes ET-1, ET-2, ET-3, and 2 G protein-coupled receptor subtypes, ETAR and ETBR, promotes growth and progression of a variety of tumors, such as prostatic, ovarian, renal, pulmonary, colorectal, cervical, breast, lung, bladder, endometrial carcinoma, Kaposi’s sarcoma, brain tumors, and melanoma. Acting on selective receptors, ET-1 regulates mitogenesis, cell survival, angiogenesis, bone remodeling, stimulation of nociceptors, tumor-infiltrating immune cells, epithelial-to-mesenchymal transition, invasion, and metastatic dissemination. At the molecular level, endothelin receptor antagonists, besides providing ideal tools for dissecting the ET axis, have demonstrated their potential in developing novel therapeutic strategies. Emerging experimental and clinical data demonstrate that interfering with endothelin receptors provides an opportunity for the development of rational combinatorial approaches using endothelin receptor antagonists in combination with chemotherapy or molecularly targeted therapy.
A GRAPH-BASED ALGORITHM FOR CLUSTER DETECTION
Authors: FOGGIA PASQUALE , PERCANNELLA GENNARO , SANSONE CARLO , VENTO MARIO 
Published: September 2008

In some Computer Vision applications there is the need for grouping, in one or more clusters, only a part of the whole dataset. This happens, for example, when samples of interest for the application at hand are present together with several noisy samples. In this paper we present a graph-based algorithm for cluster detection that is particularly suited for detecting clusters of any size and shape, without the need of specifying either the actual number of clusters or the other parameters. The algorithm has been tested on data coming from two different computer vision applications. A comparison with other four state-of-the-art graph-based algorithms was also provided, demonstrating the effectiveness of the proposed approach.
An Extragradient Approximation Method for Equilibrium Problems and Fixed Point Problems of a Countable Family of Nonexpansive Mappings
Authors: Wangkeeree Rabian 
Published: September 2008

AbstractWe introduce a new iterative scheme for finding the common element of the set of common fixed points of nonexpansive mappings, the set of solutions of an equilibrium problem, and the set of solutions of the variational inequality. We show that the sequence converges strongly to a common element of the above three sets under some parameters controlling conditions. Moreover, we apply our result to the problem of finding a common fixed point of a countable family of nonexpansive mappings, and the problem of finding a zero of a monotone operator. This main theorem extends a recent result of Yao et al. (2007) and many others.
Nonsteroidal Anti-inflammatory Drugs Suppress Glioma via 15-Hydroxyprostaglandin Dehydrogenase
Authors: Wakimoto Naoki , Wolf Ido , Yin Dong , O'Kelly James , Akagi Tadayuki , Abramovitz Lilach , Black Keith L. , Tai Hsin-Hsiung , Koeffler H. Phillip 
Published: August 2008

Abstract
Studies have conjectured that nonsteroidal anti-inflammatory drugs (NSAID) inhibit growth of various malignancies by inhibiting cyclooxygenase-2 (COX-2) enzyme activity. Yet, several lines of evidence indicate that a COX-2–independent mechanism may also be involved in their antitumor effects. Here, we report that NSAIDs may inhibit the growth of glioblastoma multiforme (GBM) cells through COX-2–independent mechanisms, including up-regulation of both 15-hydroxyprostaglandin dehydrogenase (15-PGDH, the key prostaglandin catabolic enzyme) and the cell cycle inhibitor p21. Using Western blot and real-time PCR analysis in various GBM cell lines, we observed up-regulation of 15-PGDH and p21 after NSAIDs treatment. To elucidate the role of 15-PGDH in GBM, transfection assays were conducted using the T98G GBM cell line. Overexpression of 15-PGDH suppressed cell growth and was associated with increased expression of p21. In an attempt to investigate the roles of COX-2, 15-PGDH, and p21 in the inhibition of growth of GBM, small interfering RNA (siRNA) against each of these proteins was transfected into T98G cells. Inhibition of growth mediated by NSAIDs was partially reversed after knockdown of either 15-PGDH or p21, but not after COX-2 knockdown. Moreover, expression level of p21 was not affected in COX-2 siRNA transfected cells. Our studies provide evidence that the up-regulation of 15-PGDH induced by NSAIDs has the potential to inhibit growth of GBM, in part, by up-regulation of p21 possibly independent from COX-2 enzymatic function. [Cancer Res 2008;68(17):6978–86]
Nitric Oxide Is a Key Component in Inflammation-Accelerated Tumorigenesis
Authors: Hussain S. Perwez , He Peijun , Subleski Jeffery , Hofseth Lorne J. , Trivers Glenwood E. , Mechanic Leah , Hofseth Anne B. , Bernard Mark , Schwank Jonathan , Nguyen Giang , Mathe Ewy , Djurickovic Draginja , Haines Diana , Weiss Jonathan , Back Timothy , Gruys Eilene , Laubach Victor E. , Wiltrout Robert H. , Harris Curtis C. 
Published: August 2008

AbstractNitric oxide (NO•), an important signaling molecule and a component of inflammatory response, is involved in tumorigenesis. However, the quantity of NO• and the cellular microenvironment influences the role of NO• in tumor development. We used a genetic strategy to test the hypothesis that an inflammatory microenvironment with an enhanced level of NO• accelerates spontaneous tumor development. C. parvum–induced inflammation and increased NO• synthase-2 (NOS2) expression coincided with accelerated spontaneous tumor development, mostly lymphomas, in p53−/−NOS2+/+ C57BL6 mice when compared with the controls (P = 0.001). However, p53−/−NOS2−/− mice did not show any difference in tumor latency between C. parvum–treated and control groups. In C. parvum–treated p53−/−NOS2+/+ mice, tumor development was preceded by a higher expression of NOS2 and phosphorylated Akt-Ser473 (pAkt-Ser473) in spleen, increased cell proliferation measured by Ki-67 IHC in spleen and thymus, and a lower apoptotic index and CD95-L expression in spleen and thymus. C. parvum–treated p53−/−NOS2+/+ mice showed an increase in the number of Foxp3(+) T-reg cells, dendritic cells (DC), as well as increased CD80+, CD86+, CD40+, and CD83+ on DC in the spleen. Regulatory T-cells (T-reg) and the maturation of DC may modulate tumorigenesis. An increase in the FoxP3(+)T-reg cells in C. parvum–treated p53−/−NOS2+/+ mice indicates a role of NO• in the regulation of T-reg cells that may contribute to a protumor shift of the immune environment favoring an accelerated tumor development. These data provide genetic and mechanistic evidence that an inflammatory microenvironment and an increased level of NO• can accelerate tumor development. [Cancer Res 2008;68(17):7130–6]
ATM Acts Downstream of ATR in the DNA Damage Response Signaling of Bystander Cells
Authors: Burdak-Rothkamm Susanne , Rothkamm Kai , Prise Kevin M. 
Published: August 2008

Abstract
This study identifies ataxia-telangiectasia mutated (ATM) as a further component of the complex signaling network of radiation-induced DNA damage in nontargeted bystander cells downstream of ataxia-telangiectasia and Rad3-related (ATR) and provides a rationale for molecular targeted modulation of these effects. In directly irradiated cells, ATR, ATM, and DNA-dependent protein kinase (DNA-PK) deficiency resulted in reduced cell survival as predicted by the known important role of these proteins in sensing DNA damage. A decrease in clonogenic survival was also observed in ATR/ATM/DNA-PK–proficient, nonirradiated bystander cells, but this effect was completely abrogated in ATR and ATM but not DNA-PK–deficient bystander cells. ATM activation in bystander cells was found to be dependent on ATR function. Furthermore, the induction and colocalization of ATR, 53BP1, ATM-S1981P, p21, and BRCA1 foci in nontargeted cells was shown, suggesting their involvement in bystander DNA damage signaling and providing additional potential targets for its modulation. 53BP1 bystander foci were induced in an ATR-dependent manner predominantly in S-phase cells, similar to γH2AX foci induction. In conclusion, these results provide a rationale for the differential modulation of targeted and nontargeted effects of radiation. [Cancer Res 2008;68(17):7059–65]
Functional Genetic Variations in Cytotoxic T-Lymphocyte Antigen 4 and Susceptibility to Multiple Types of Cancer
Authors: Sun Tong , Zhou Yifeng , Yang Ming , Hu Zhibin , Tan Wen , Han Xiaohong , Shi Yuankai , Yao Jiarui , Guo Yongli , Yu Dianke , Tian Tian , Zhou Xiaoyi , Shen Hongbing , Lin Dongxin 
Published: August 2008

Abstract
Antitumor T lymphocytes play a pivotal role in immunosurveillance of malignancy. The CTL antigen 4 (CTLA-4) is a vital negative regulator of T-cell activation and proliferation. This study examined whether genetic polymorphisms in CTLA-4 are associated with cancer susceptibility. A two-stage investigation using haplotype-tagging single nucleotide polymorphism approach and multiple independent case-control analyses was performed to assess the association between CTLA-4 genotypes and cancer risk. Functional relevance of the polymorphisms was examined by biochemical assays. We found that the 49G&gt;A polymorphism in the CTLA-4 leading sequence causing 17Ala to 17Thr amino acid substitution is associated with increased susceptibility to multiple cancers, including lung, breast, esophagus, and gastric cardia cancers. Genotyping in 5,832 individuals with cancer and 5,831 control subjects in northern and southern Chinese populations showed that the CTLA-4 49AA genotype had an odds ratio of 1.72 (95% confidence interval, 1.50−2.10; P = 3.4 × 10−7) for developing cancer compared with the 49GG genotype. Biochemical analyses showed that CTLA-4−17Thr had higher capability to bind B7.1 and stronger inhibitory effect on T-cell activation compared with CTLA-4−17Ala. T cells carrying the 49AA genotype had significantly lower activation and proliferation rates compared with T cells carrying the 49GG genotype upon stimulation. These results are consistent with our hypothesis and indicate that genetic polymorphisms influencing T-cell activation modify cancer susceptibility. [Cancer Res 2008;68(17):7025–34]
PTEN Acetylation Modulates Its Interaction with PDZ Domain
Authors: Ikenoue Tsuneo , Inoki Ken , Zhao Bin , Guan Kun-Liang 
Published: August 2008

Abstract
The PTEN tumor suppressor gene is frequently inactivated in human cancer. As a major tumor suppressor, PTEN function must be tightly regulated. Both phosphorylation and membrane association have been reported to regulate PTEN activity. In addition, the COOH terminus of PTEN has a typical PDZ domain-binding motif that interacts with several PDZ domain-containing proteins. In this report, we show that PTEN is acetylated on Lys402, which is in the COOH-terminal PDZ domain-binding motif. We show that CBP plays a major role in PTEN acetylation, whereas the SIRT1 deacetylase is mainly responsible for PTEN deacetylation. Interestingly, Lys402 acetylation modulates PTEN interaction with PDZ domain-containing proteins, indicating a potential role of acetylation in regulating PTEN function. [Cancer Res 2008;68(17):6908–12]
Whole Chromosome Alterations Predict Survival in High-Risk Neuroblastoma without MYCN Amplification
Authors: Bilke Sven , Chen Qing-Rong , Wei Jun S. , Khan Javed 
Published: September 2008

Abstract
Purpose: Patients with stage IV neuroblastoma over the age of 500 days without MYCN amplification have a survival rate of &lt;30% and there are currently no reliable means of predicting which of these patients will survive or succumb to the disease. The goal of this study is to develop a DNA copy number–based prognostic profile for these patients.
Experimental Design: We have used comparative genomic hybridization to identify genome copy number changes that can predict outcome in patients with stage IV neuroblastoma without MYCN amplification.
Results: A strong correlation of patient survival with the presence of whole chromosome changes (WCC ≥2) was observed, even in the group of patients older than 500 days at time of diagnosis. This novel prognostic marker showed a significant dependence on the date of diagnosis; patients with WCC ≥2 diagnosed after 1998 had a significantly higher probability of survival compared with those diagnosed earlier. At the same time, no such time dependence was found among the samples with WCC &lt;2, suggesting that medical progress patients in recent years has particularly benefited those patients with a stage IV non–MYCN-amplified disease if WCC ≥2 were present.
Conclusions: In this pilot study, we present a novel prognostic marker for survival of high-risk neuroblastoma patients over the age of 500 days without MYCN amplification and diagnosed after 1998. Further validation study is required to establish this risk stratification for these patients.
A Phase I Study of Bexarotene, a Retinoic X Receptor Agonist, in Non-M3 Acute Myeloid Leukemia
Authors: Tsai Donald E. , Luger Selina M. , Andreadis Charalambos , Vogl Dan T. , Kemner Allison , Potuzak Melissa , Goradia Ami , Loren Alison W. , Perl Alexander E. , Schuster Stephen J. , Porter David L. , Stadtmauer Edward A. , Goldstein Steven C. , Thompson James E. , Swider Cezary , Bagg Adam , Mato Anthony R. , Carroll Martin 
Published: September 2008

Abstract
Purpose: Bexarotene is a retinoic X receptor agonist that has been shown in vitro to inhibit growth and induce differentiation of myeloid leukemic cell lines. We therefore conducted a phase I dose escalation study to assess the maximum tolerated dose, toxicities, and activity of bexarotene in patients with non-M3 acute myeloid leukemia (AML).
Experimental Design: We enrolled patients with active non-M3 AML who had either relapsed or refractory disease or were not eligible for standard cytotoxic chemotherapy. Cohorts of three to six patients received escalating doses of daily oral bexarotene ranging from 100 to 400 mg/m2 until evidence of disease progression or unacceptable adverse events occurred.
Results: Twenty-seven patients, with median age of 69 years (range, 51-82 years), were treated. Twenty-four (89%) patients had undergone prior chemotherapy. At the highest dose level tested (400 mg/m2), three of six patients had to reduce their dose of bexarotene due to grade 3 adverse events. The maximum tolerable dose of bexarotene was determined to be 300 mg/m2. Clinical activity was manifested by 4 (15%) patients with reduction in bone marrow blasts to ≤5%, 11 (41%) patients with improved platelet counts, and 7 (26%) patients with improved neutrophil counts. Three patients with relapsed AML survived &gt;1 year while taking bexarotene. Leukemic blast differentiation was suggested by the presence of the leukemic cytogenetic abnormality in mature circulating granulocytes and the occurrence of differentiation syndrome.
Conclusions: The recommended dose of bexarotene for future studies is 300 mg/m2/d. Bexarotene is well tolerated in patients with non-M3 AML and has evidence of antileukemic activity.
Thymidine Selectively Enhances Growth Suppressive Effects of Camptothecin/Irinotecan in MSI+ Cells and Tumors Containing a Mutation of MRE11
Authors: Rodriguez Rene , Hansen Lasse Tengbjerg , Phear Geraldine , Scorah Jennifer , Spang-Thomsen Mogens , Cox Angela , Helleday Thomas , Meuth Mark 
Published: September 2008

Abstract
Purpose: DNA synthesis inhibitors and damaging agents are widely used in cancer therapy; however, sensitivity of tumors to such agents is highly variable. The response of tumor cells in culture to these agents is strongly influenced by the status of DNA damage response pathways. Here, we attempt to exploit the altered response of mismatch repair (MMR)-deficient colon cancer cells and tumors to camptothecin or irinotecan and thymidine by combining them to improve therapeutic response.
Experimental Design: A panel of colon cancer cell lines was assayed for response to camptothecin-thymidine combinations by measuring colony formation, cell cycle distribution, and senescence. Cell strains defective in p53, p21, or Mre11 were used in these assays to investigate the role of these cell cycle regulators. The in vivo antitumor response of xenografts to irinotecan and thymidine combinations was assessed in nude mice.
Results: Camptothecin-thymidine combinations suppress colony formation of MMR-deficient tumor cells 10- to 3,000-fold relative to that obtained with camptothecin alone and significantly reduce the concentrations of the agents required to induce late S/G2 arrest and senescence. Sensitivity is not a direct result of MMR, p53, or p21 status. However MMR-deficient cell lines containing an intronic frameshift mutation of MRE11 show greatest sensitivity to these agents. Increased sensitivity to this combination is also evident in vivo as thymidine enhances irinotecan-induced growth suppression of MMR-deficient tumors carrying the MRE11 mutation in mouse xenografts.
Conclusion: Irinotecan-thymidine combinations may be particularly effective when targeted to MSI+ tumors containing this readily detectable MRE11 mutation.
Tasigna for Chronic and Accelerated Phase Philadelphia Chromosome–Positive Chronic Myelogenous Leukemia Resistant to or Intolerant of Imatinib
Authors: Hazarika Maitreyee , Jiang Xiaoping , Liu Qi , Lee Shwu-Luan , Ramchandani Roshni , Garnett Christine , Orr Micheal S. , Sridhara Rajeshwari , Booth Brian , Leighton John K. , Timmer William , Harapanhalli Ravi , Dagher Ramzi , Justice Robert , Pazdur Richard 
Published: September 2008

Abstract
Purpose: This Food and Drug Administration (FDA) approval report describes the data and analyses leading to the approval by the FDA of nilotinib (Tasigna, AMN-107; Novartis Pharmaceuticals Corporation), an inhibitor of Bcr-Abl tyrosine kinase, for the treatment of chronic-phase (CP) and accelerated-phase (AP) chronic myelogenous leukemia (CML) resistant to or intolerant of imatinib.
Experimental Design: The FDA approval of the efficacy and safety of nilotinib was based on the results of an ongoing single-arm, open-label, phase 2 clinical trial. The primary end point for CML-CP was unconfirmed major cytogenetic response. The efficacy end point for CML-AP was confirmed hematologic response.
Results: The major cytogenetic response rate in 232 evaluable CP patients was 40% (95% confidence interval, 33%, 46%). The hematologic response rate in 105 evaluable AP patients was 26% (95% confidence interval, 18%, 35%). The median duration of response has not been reached for both CML-CP and CML-AP responding patients. In CML-CP patients, the common serious drug-related adverse reactions were thrombocytopenia and neutropenia. In CML-AP patients, the common serious drug-related adverse reactions were thrombocytopenia, neutropenia, pneumonia, febrile neutropenia, leukopenia, intracranial hemorrhage, elevated lipase, and pyrexia. Nilotinib prolongs the QT interval and sudden deaths have been reported; these risks and appropriate risk minimization strategies are described in a boxed warning on the labeling.
Conclusions: On October 29, 2007, the U.S. FDA granted accelerated approval to nilotinib (Tasigna) for use in the treatment of CP and AP Philadelphia chromosome positive CML in adult patients resistant to or intolerant of prior therapy that included imatinib.
Molecular Diagnosis of Sentinel Lymph Node Metastases in Cervical Cancer Using Squamous Cell Carcinoma Antigen
Authors: Yuan Song-Hua , Liang Xue-Fang , Jia Wei-Hua , Huang Jian-Ling , Wei Mei , Deng Ling , Liang Li-Zhi , Wang Xiao-Yun , Zeng Yi-Xin 
Published: September 2008

AbstractPurpose: To clarify the prognostic value of molecular diagnosis of SLN metastases in cervical cancer using SCCA.Experimental Design: All SLNs and primary tumors, part of non-SLNs, were harvested from 36 patients with cervical cancer. Expression levels of SCCA, cytokeratin 19 (CK19), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA in 178 samples (29 primary tumors, 5 histologic positive nodes, 60 histologic negative SLNs, 69 non-SLNs, and 15 normal nodes) were assessed by quantitative reverse transcription-PCR assay. The quantitative value of SCCA or CK19 mRNA was described as each value relative to GAPDH mRNA. The cutoff value was set at the upper limit of the quantitative value of nodes from noncancer patients, and those above this value constituted the molecular metastasis group.Results: The SCCA mRNA expression values were more than 1 × 103 in 28 primary tumors and all histologic positive nodes, and its expression levels in SLNs were higher than in non-SLNs. SLNs from patients with adverse prognostic features had higher SCCA mRNA expression levels. Four histologic negative SLNs were diagnosed molecular metastases based on SCCA mRNA. Two cases with histologically uninvolved pelvic nodes recurred. Survival analysis indicates that molecular lymphatic metastasis based on elevated SCCA mRNA level is the best predictor of recurrence. However, CK19 is not a suitable marker due to its low specificity and relative higher baseline expression in normal nodes.Conclusions: SCCA mRNA levels for molecular diagnosis of SLN metastases in cervical cancer more accurately identifies patients at risk for recurrence than the routine histology does.