bluuebunny/crossref_metadata_2025_split huggingface dataset:
AKT1 Amplification Regulates Cisplatin Resistance in Human Lung Cancer Cells through the Mammalian Target of Rapamycin/p70S6K1 Pathway
Authors: Liu Ling-Zhi , Zhou Xiang-Dong , Qian Guisheng , Shi Xianglin , Fang Jing , Jiang Bing-Hua 
Published: July 2007

Abstract
Cisplatin [cis-diaminodichloroplatinum (II) (CDDP)] is one of the most widely used and effective therapeutic agents for many kinds of cancers. However, its efficiency is limited due to development of drug resistance. In this study, we showed that CDDP resistance was associated with AKT1 overexpression and gene amplification in human lung cancer cells that acquired the drug resistance. We showed that AKT1 forced expression in the cells was sufficient to render the cells CDDP resistant, and that AKT1 inhibition by its dominant negative mutant reversed the CDDP-resistant cells to be CDDP sensitive. These results show that AKT1 activity is essential for regulating CDDP resistance in cultured lung cancer cells. To study whether these results were correlated with human lung cancer tumors, we randomly selected tumor samples from human lung cancer patients to study the correlation of AKT activation and CDDP resistance in clinical tumor samples. We showed that AKT activation was highly related to CDDP chemosensitivity in human tumor tissues. Our results further showed that AKT1 induced lung cancer cells to become resistant to CDDP through the mammalian target of the rapamycin (mTOR) signaling pathway. These studies conclude that AKT amplification and the mTOR pathway play an important role in human lung cancer cells acquiring CDDP resistance, which represents a new mechanism for acquiring CDDP resistance and a potential novel therapeutic target for overcoming CDDP resistance in human cancer in the future. [Cancer Res 2007;67(13):6325–32]
Human Neuroblastoma Cells Trigger an Immunosuppressive Program in Monocytes by Stimulating Soluble HLA-G Release
Authors: Morandi Fabio , Levreri Isabella , Bocca Paola , Galleni Barbara , Raffaghello Lizzia , Ferrone Soldano , Prigione Ignazia , Pistoia Vito 
Published: July 2007

AbstractHLA-G is overexpressed in different tumors and plays a role in immune escape. Because no information is available on HLA-G in relation to human neuroblastoma, we have investigated the expression of membrane-bound and secretion of soluble isoforms of HLA-G in neuroblastoma and functionally characterized their immunosuppressive activities. At diagnosis, serum soluble HLA-G (sHLA-G) levels were significantly higher in patients than in age-matched healthy subjects. In addition, patients who subsequently relapsed exhibited higher sHLA-G levels than those who remained in remission. Neuroblastoma patient sera selected according to high sHLA-G concentrations inhibited natural killer (NK) cell and CTL-mediated neuroblastoma cell lysis. Such lysis was partially restored by serum depletion of sHLA-G. In 6 of 12 human neuroblastoma cell lines, low HLA-G surface expression was not up-regulated by IFN-γ. Only the ACN cell line secreted constitutively sHLA-G. IFN-γ induced de novo sHLA-G secretion by LAN-5 and SHSY5Y cells and enhanced that by ACN cells. Primary tumor lesions from neuroblastoma patients tested negative for HLA-G. Neuroblastoma patients displayed a higher number of sHLA-G–secreting monocytes than healthy controls. Incubation of monocytes from normal donors with IFN-γ or pooled neuroblastoma cell line supernatants significantly increased the proportion of sHLA-G–secreting cells. In addition, tumor cell supernatants up-regulated monocyte expression of CD68, HLA-DR, CD69, and CD71 and down-regulated IL-12 production. Our conclusions are the following: (a) sHLA-G serum levels are increased in neuroblastoma patients and correlate with relapse, (b) sHLA-G is secreted by monocytes activated by tumor cells rather than by tumor cells themselves, and (c) sHLA-G dampens anti-neuroblastoma immune responses. [Cancer Res 2007;67(13):6433–41]
Lineage-Specific Dependency of Lung Adenocarcinomas on the Lung Development Regulator TTF-1
Authors: Tanaka Hisaaki , Yanagisawa Kiyoshi , Shinjo Keiko , Taguchi Ayumu , Maeno Ken , Tomida Shuta , Shimada Yukako , Osada Hirotaka , Kosaka Takayuki , Matsubara Hideo , Mitsudomi Tetsuya , Sekido Yoshitaka , Tanimoto Mitsune , Yatabe Yasushi , Takahashi Takashi 
Published: July 2007

Abstract
Emerging evidence, although currently very sparse, suggests the presence of “lineage-specific dependency” in the survival mechanisms of certain cancers. TTF-1 has a decisive role as a master regulatory transcription factor in lung development and in the maintenance of the functions of terminal respiratory unit (TRU) cells. We show that a subset of lung adenocarcinoma cell lines expressing TTF-1, which presumably represent those derived from the TRU lineage, exhibit marked dependence on the persistent expression of TTF-1. The inhibition of TTF-1 by RNA interference (RNAi) significantly and specifically induced growth inhibition and apoptosis in these adenocarcinoma cell lines. Furthermore, a fraction of TTF-1–expressing tumors and cell lines displayed an increase in the gene dosage of TTF-1 in the analysis of 214 patients with non–small-cell lung cancer, including 174 adenocarcinomas, showing a tendency of higher frequency of increased gene copies at metastatic sites than at primary sites (P = 0.07, by two-sided Fisher's exact test). These findings strongly suggest that in addition to the development and maintenance of TRU lineages in normal lung, sustained TTF-1 expression may be crucial for the survival of a subset of adenocarcinomas that express TTF-1, providing credence for the lineage-specific dependency model. [Cancer Res 2007;67(13):6007–11]
Cholesterol Sensitivity of Endogenous and Myristoylated Akt
Authors: Adam Rosalyn M. , Mukhopadhyay Nishit K. , Kim Jayoung , Di Vizio Dolores , Cinar Bekir , Boucher Kelly , Solomon Keith R. , Freeman Michael R. 
Published: July 2007

Abstract
The serine-threonine kinase, Akt, has been linked to cholesterol-sensitive signaling mechanisms, suggesting a possible means whereby cholesterol might affect tumor cell growth and survival. However, it has not been shown whether Akt itself, as distinct from upstream components of the pathway (e.g., membrane phosphoinositides), can be directly responsible for cholesterol-mediated effects. Consistent with this possibility, we identified an Akt1 subpopulation in cholesterol-rich lipid raft fractions prepared from LNCaP human prostate cancer cells. Phosphorylation of this Akt subspecies was ablated with methyl-β-cyclodextrin, a cholesterol-binding compound, under conditions where nonlipid raft-resident Akt was unaffected. A myristoylated Akt1 (MyrAkt1) fusion protein expressed in LNCaP cells was found to be highly enriched in lipid rafts, indicating that oncogenic Akt is overrepresented in cholesterol-rich membranes compared with wild-type Akt. Notably, lipid raft-resident MyrAkt1 exhibited a markedly distinct substrate preference compared with MyrAkt1 immunoprecipitated from cytosol and nonraft membrane fractions, suggesting a redirection of signal transduction when the protein is present in cholesterol-rich membranes. Expression of MyrAkt1 in LNCaP cells overcame their characteristic dependence on constitutive signaling through the phosphoinositide 3′-kinase pathway. This protective effect was substantially diminished with cyclodextrin treatment. Phosphorylation of Akt substrates in lipid raft fractions, but not in cytosol/nonraft membrane fractions, was ablated with cyclodextrin. In addition, in control (LacZ transfected) cells, lipid raft fractions were relatively enriched in phosphorylated Akt substrates. Collectively, these data show that a subpopulation of Akt is cholesterol sensitive and that the oncogenic effects conferred by myristoylation arise, in part, from the tendency of the membrane-targeted form of the protein to reside in cholesterol-rich membrane microdomains. [Cancer Res 2007;67(13):6238–46]
Nuclear and Cytoplasmic Survivin: Molecular Mechanism, Prognostic, and Therapeutic Potential
Authors: Stauber Roland H. , Mann Wolf , Knauer Shirley K. 
Published: July 2007

Abstract
Survivin's proposed dual role as an apoptosis inhibitor and a mitotic effector positioned it in the front line of cancer research. Notably, survivin is detected as a cytoplasmic and nuclear protein in cancer patients, which stimulated numerous studies to investigate and to speculate on the functional and prognostic significance of its dynamic localization. Recent evidence shows that the direct interaction of survivin with the nuclear export receptor Crm1 is critically involved in its intracellular localization and cancer-relevant functions. Here, we review our current understanding of the Crm1/survivin interface and discuss its potential prognostic and therapeutic relevance. [Cancer Res 2007;67(13):5999–6002]
MicroRNA Expression Profiling in Prostate Cancer
Authors: Porkka Kati P. , Pfeiffer Minja J. , Waltering Kati K. , Vessella Robert L. , Tammela Teuvo L.J. , Visakorpi Tapio 
Published: July 2007

Abstract
MicroRNAs (miRNA) are small, endogenously expressed noncoding RNAs that negatively regulate expression of protein-coding genes at the translational level. Accumulating evidence, such as aberrant expression of miRNAs, suggests that they are involved in the development of cancer. They have been identified in various tumor types, showing that different sets of miRNAs are usually deregulated in different cancers. To identify the miRNA signature specific for prostate cancer, miRNA expression profiling of 6 prostate cancer cell lines, 9 prostate cancer xenografts samples, 4 benign prostatic hyperplasia (BPH), and 9 prostate carcinoma samples was carried out by using an oligonucleotide array hybridization method. Differential expression of 51 individual miRNAs between benign tumors and carcinoma tumors was detected, 37 of them showing down-regulation and 14 up-regulation in carcinoma samples, thus identifying those miRNAs that could be significant in prostate cancer development and/or growth. There was a significant trend (P = 0.029) between the expression of miRNAs and miRNA locus copy number determined by array comparative genomic hybridization, indicating that genetic aberrations may target miRNAs. Hierarchical clustering of the tumor samples by their miRNA expression accurately separated the carcinomas from the BPH samples and also further classified the carcinoma tumors according to their androgen dependence (hormone naive versus hormone refractory), indicating the potential of miRNAs as a novel diagnostic and prognostic tool for prostate cancer. [Cancer Res 2007;67(13):6130–5]
Effects of Chromatin-Modifying Agents on CD34+ Cells from Patients with Idiopathic Myelofibrosis
Authors: Shi Jun , Zhao Yan , Ishii Takefumi , Hu Wenyang , Sozer Selcuk , Zhang Wei , Bruno Edward , Lindgren Valerie , Xu Mingjiang , Hoffman Ronald 
Published: July 2007

Abstract
Idiopathic myelofibrosis (IM) is likely the consequence of both the acquisition of genetic mutations and epigenetic changes that silence critical genes that control cell proliferation, differentiation, and apoptosis. We have explored the effects of the sequential treatment with the DNA methyltransferase inhibitor, decitabine [5-aza-2′-deoxycytidine (5azaD)], followed by the histone deacetylase inhibitor, trichostatin A (TSA), on the behavior of IM CD34+ cells. Unlike normal CD34+ cells where 5azaD/TSA treatment leads to the expansion of CD34+ cells and marrow-repopulating cells, treatment of IM CD34+ cells results in a reduction of the number of total cells, CD34+ cells, and assayable hematopoietic progenitor cells (HPC). In IM, HPCs are either heterozygous or homozygous for the JAK2V617F mutation or possess wild-type JAK2 in varying proportions. Exposure of IM CD34+ cells to 5azaD/TSA resulted in a reduction of the proportion of JAK2V617F-positive HPCs in 83% of the patients studied and the reduction in the proportion of homozygous HPCs in 50% of the patients. 5azaD/TSA treatment led to a dramatic reduction in the number of HPCs that contained chromosomal abnormalities in two JAK2V617F-negative IM patients. IM is characterized by constitutive mobilization of HPCs, which has been partly attributed to decreased expression of the chemokine receptor CXCR4. Treatment of IM CD34+ cells with 5azaD/TSA resulted in the up-regulation of CXCR4 expression by CD34+ cells and restoration of their migration in response to SDF-1. These data provide a rationale for sequential therapy with chromatin-modifying agents for patients with IM. [Cancer Res 2007;67(13):6417–24]
Incorporation of an Internal Ribosome Entry Site–Dependent Mechanism in Arsenic-Induced GADD45α Expression
Authors: Chang Qingshan , Bhatia Deepak , Zhang Yadong , Meighan Terry , Castranova Vince , Shi Xianglin , Chen Fei 
Published: July 2007

Abstract
We have previously shown that trivalent arsenic (arsenite, As3+) is able to induce GADD45α expression in human bronchial epithelial cells through activation of c-Jun NH2-terminal kinase and nucleolin-dependent mRNA stabilization. In the present report, we show that As3+ is capable of inducing translation of the GADD45α protein through a cap-independent, or rather, an internal ribosome entry site (IRES)–dependent mechanism. In growth-arrested cells, As3+ elevated the GADD45α protein level in a dose- and time-dependent manner which did not correlate with the GADD45α mRNA expression. Pretreatment of the cells with rapamycin, an inhibitor for the cap-dependent translation machinery through the suppression of mTOR and p70S6 kinase, failed to affect the induction of the GADD45α protein induced by As3+. Sequence analysis revealed a potential IRES element in the 5′-untranslated region of the GADD45α mRNA. This IRES element in the 5′-untranslated region of the GADD45α mRNA is functional in mediating As3+-induced translation of the GADD45α protein in a dicistronic reporter gene activity assay. Immunoprecipitation and proteomic studies suggest that As3+ impairs the assembly of the cap-dependent initiating complex for general protein translation but increases the association of human elongation factor 2 and human heterogeneous nuclear ribonucleoprotin with this complex. Thus, these results suggest that in growth-arrested cells, As3+ is still capable of inducing GADD45α expression through an IRES-dependent translational regulation. [Cancer Res 2007;67(13):6146–54]
The Role of Vascular Cell Adhesion Molecule-1 in Tumor Immune Evasion
Authors: Wu T-C. 
Published: July 2007

Abstract
Tumor immune escape is a critical trait of cancer but the mechanisms involved have yet to fully emerge. One recent study has shown that tumor cells can escape T-cell immunity by overexpressing the endothelial cell adhesion molecule vascular cell adhesion molecule-1 (VCAM-1), which normally mediates leukocyte extravasion to sites of tissue inflammation. Renal cell carcinoma (RCC) was identified as one tumor type where VCAM-1 is commonly highly overexpressed. Together, our findings suggest that RCCs might exploit VCAM-1 overexpression for immune escape. [Cancer Res 2007;67(13):6003–6]
The von Willebrand factor antagonist (GPG-290) prevents coronary thrombosis without prolongation of bleeding time
Authors: Wadanoli Michael , Sako Dianne , Shaw Gray , Schaub Robert , Wang Qin , Tchernychev Boris , Xu Jin , Porter Thomas , Huang Qinheng 
Published: July 2007

SummaryThe interaction between von Willebrand factor (VWF) and platelet glycoprotein Ibα (GPIbα) is a critical step that allows platelet adhesion, activation and subsequent thrombus formation to the injured vessel wall under high-shear conditions. In this study, we sought to investigate 1) whether GPG-290, a recombinant human GPIbα chimeric protein, would prevent thrombosis in a canine model of coronary thrombosis by blocking VWFGPIbα interaction; and 2) whether desmopressin (DDAVP), a VWF release stimulant, could reduce the prolonged bleeding time caused by a 10x efficacious dose of GPG-290. The antithrombotic efficacy of GPG-290 was evaluated by the in-vivo ability to prevent cyclic flow reductions (CFRs) and ex-vivo inhibition of platelet adhesion/aggregation reflected by prolongation of Platelet Function Analyzer (PFA-100®) collagen /ADP closure time. The anti-hemostatic effect was assessed by template bleeding time. GPG-290 at doses of 25, 50 and 100 μg/kg abolished CFRs in 67%,100% and 100% of the treated dogs without bleeding time prolongation, respectively; GPG-290 dose-dependently prolonged the ex-vivo collagen/ADP-closure time, while it had no effects on plasma VWF antigen level (VWF:Ag) and VWF-collagen binding activity (VWF:CB); the prolonged template bleeding time caused by 500 μg/kg of GPG-290 was prevented by intravenous infusion of DDAVP (0.3 μg/kg). In conclusion, GPG-290 appears to be an effective agent for treating arterial thrombosis without bleeding time prolongation.
Extra- and intracellular innate immune recognition in endothelial cells
Authors: Hippenstiel Stefan , Eitel Julia , Suttorp Norbert , Opitz Bastian 
Published: July 2007

SummaryThe innate immune system represents the principal sensor of infections in multicellular organisms and might also mediate responses to some endogenous molecules. In this context, endothelial cells are among the first cells coming into contact with microbial or endogenous (danger-associated) molecules or whole pathogens entering the bloodstream. Since many bacteria and viruses invade the endothelium, endothelial cells are equipped with both extracellular and cytosolic surveillance systems capable of sensing microbial components, and endogenous danger-associated molecules. The receptor molecules, called pattern recognition receptors (PRRs), are classified as transmembrane or cytosolic molecules. While the transmembrane PRRs recognize extracellular and membrane-enclosed foreign organisms, the cytosolic PRRs appear to sense intracellular infections. Here we focus on both PRR classes in general, and outline the current knowledge of extra- and intracellular pattern recognition in endothelial cells and its potential role in vascular diseases and sepsis.
The risk of venous and arterial thrombosis in hyperhomocysteinaemia is low and mainly depends on concomitant thrombophilic defects
Authors: Coppens Michiel , van de Poel Marlène , Middeldorp Saskia , Hamulyák Karly , Bank Ivan , Veeger Nic , Prins Martin , Büller Harry , van der Meer Jan , Lijfering Willem 
Published: July 2007

SummaryAs homocysteine-lowering treatment has not reduced the risk of recurrent thrombosis in recent clinical trials, we hypothesized that mild hyperhomocysteinaemia is an epiphenomenon or associated with a low absolute risk of thrombosis. In this retrospective study, we enrolled 478 evaluable first-degree relatives of consecutive patients with venous thrombosis or premature atherosclerosis, and hyperhomocysteinemia. Absolute risks of thrombosis and effects of concomitant thrombophilic defects were compared. Relative risks were adjusted for clustering in families, age, sex, and atherosclerotic risk factors, where appropriate. Annual incidence of venous thrombosis was 0.16% (95% confidence interval [CI], 0.08–0.30) in hyperhomocysteinemic relatives versus 0.11% (CI, 0.05–0.20) in normohomocysteinemic relatives; adjusted relative risk 1.6 (CI, 0.6–4.5). Annual incidences of arterial thrombosis were 0.34% (CI, 0.21–0.52) and 0.24% (CI, 0.15–0.37) in hyperhomocysteinemic and normohomocysteinemic relatives, respectively; adjusted relative risk 1.5 (CI, 0.6–3.5). Concomitance of multiple thrombophilic risk factors increased the risk of venous thrombosis in hyperhomocysteinemic relatives 20 fold, but a comparable effect was demonstrated in normohomocysteinemic relatives. We conclude that hyperhomocysteinaemia is associated with a low absolute risk of venous and arterial thrombosis. Concomitant thrombophilic defects are probably main determinants on the risk of venous thrombosis, rather than hyperhomocysteinaemia itself.
CREB binding to the hypoxia-inducible factor-1 responsive elements in the plasminogen activator inhibitor-1 promoter mediates the glucagon effect
Authors: Dimova Elitsa , Jakubowska Malgorzata , Kietzmann Thomas 
Published: July 2007

SummaryPlasminogen activator inhibitor-1 (PAI-1) controls the regulation of the fibrinolytic system in blood by inhibiting both urokinase-type and tissue-type plasminogen activators. Enhanced levels of PAI-1 are related to pathological conditions associated with hypoxia or hyperinsulinemia. In this study, we investigated the regulation of PAI-1 expression by glucagon and the cAMP/ PKA/CREB signalling pathway in the liver. Stimulation of the cAMP/PKA/CREB signalling cascade by starvation in vivo or glucagon in vitro induced PAI-1 gene expression in liver. Furthermore, this response was associated with enhanced phosphorylation of CREB. By using EMSAs we found that three promoter elements, the HRE2, E-box 4 and E-box 5, were able to bind CREB but only the HRE2 and E5 appeared to be functionally active. Reporter gene assays confirmed that cAMP induced PAI-1 gene transcription via the same element in both human and rat promoters. Interestingly, although the HRE2 was involved, the glucagon/cAMP pathway had no influence on hypoxia-inducible factor-1 (HIF-1) mRNA and protein levels. Thus, CREB binding to the HIF-1 responsive elements in PAI-1 promoter mediates the glucagon effect in the liver.
The Settlement of Disputes Concerning States Arising From the Application of the Statute of the International Criminal Court: Balancing Sovereignty and the Need for an Effective and Independent ICC
Authors: Ochoa S. Juan Carlos 
Published: July 2007

AbstractThe tension between State sovereignty and the need of international criminal tribunals to have sufficient powers for functioning effectively and independently permeates the provisions on the settlement of disputes contained within the ICC Statute. In contrast to the Statutes and the case-law of the ad hoc international criminal tribunals, the ICC Statute gives considerable weight to States Party's sovereignty. In particular, the power of the ICC to settle any dispute concerning its judicial functions under Article 119, paragraph 1, of its Statute is weakened in the area of States Party's cooperation where the provisions of Part 9 of the Statute of that court, in addition to grant those States several possibilities for denying requests for cooperation, remain to a large extent ambiguous as to whether the ICC can scrutinise the grounds for such denials. Yet, it is submitted that the ICC Statute as a whole provides the ICC with sufficient bases to assert such a power. This contribution also casts some light on the relationship between the ICC and States non-party to its Statute from the perspective of the rules on dispute settlement laid down in that international instrument and general international law.
A Hope for the Future? Prosecuting Crimes Against Humanity in Russia's Courts
Authors: Orlova Alexandra 
Published: July 2007

AbstractThe abuses of Chechen civilians by Russian federal forces and pro-Kremlin Chechen security forces have once again attracted international attention. This article discusses some of the legal and social difficulties that make the prosecution of disappearances and other abuses against Chechen civilians virtually impossible under the rubric of crimes against humanity in Russian domestic courts. Such prosecutions are imperative, however, if the goal is to truly "normalize" the situation in Chechnya and to prevent the spread of terrorist activity within and outside of the Chechen borders.