bluuebunny/crossref_metadata_2025 huggingface dataset:
Erythroid Inhibition by the Leukemic Fusion AML1-ETO Is Associated with Impaired Acetylation of the Major Erythroid Transcription Factor GATA-1
Authors: Choi Youngjin , Elagib Kamaleldin E. , Delehanty Lorrie L. , Goldfarb Adam N.
Published: March 2006

Human acute myeloid leukemias with the t(8;21) translocation express the AML1-ETO fusion protein in the hematopoietic stem cell compartment and show impairment in erythroid differentiation. This clinical finding is reproduced in multiple murine and cell culture model systems in which AML1-ETO specifically interferes with erythroid maturation. Using purified normal human early hematopoietic progenitor cells, we find that AML1-ETO impedes the earliest discernable steps of erythroid lineage commitment. Correspondingly, GATA-1, a central transcriptional regulator of erythroid differentiation, undergoes repression by AML1-ETO in a nonconventional histone deacetylase–independent manner. In particular, GATA-1 acetylation by its transcriptional coactivator, p300/CBP, a critical regulatory step in programming erythroid development, is efficiently blocked by AML1-ETO. Fusion of a heterologous E1A coactivator recruitment module to GATA-1 overrides the inhibitory effects of AML1-ETO on GATA-1 acetylation and transactivation. Furthermore, the E1A-GATA-1 fusion, but not wild-type GATA-1, rescues erythroid lineage commitment in primary human progenitors expressing AML1-ETO. These results ascribe a novel repressive mechanism to AML1-ETO, blockade of GATA-1 acetylation, which correlates with its inhibitory effects on primary erythroid lineage commitment. (Cancer Res 2006; 66(6): 2990-96)
EGFR Tyrosine Kinase Inhibitors Decrease VEGF Expression by Both Hypoxia-Inducible Factor (HIF)-1–Independent and HIF-1–Dependent Mechanisms
Authors: Pore Nabendu , Jiang Zibin , Gupta Anjali , Cerniglia George , Kao Gary D. , Maity Amit
Published: March 2006

Epidermal growth factor receptor (EGFR) inhibitors can decrease vascular endothelial growth factor (VEGF) expression and tumor angiogenesis. In the current study, we investigate the molecular pathways by which this occurs using two drugs that have been used in the clinic, gefitinib (Iressa) and erlotinib (Tarceva). The decrease in VEGF expression by gefitinib in SQ20B squamous cell carcinoma cells was opposed by adenoviral expression of Akt in these cells. The hypoxia-inducible factor-1 (HIF-1) binding site located at approximately −1 kbp in the VEGF promoter was not required for down-regulation of promoter activity by gefitinib under normoxia. Furthermore, the drug decreased activity of a reporter containing the −88/+54 region. In a gel shift assay, gefitinib led to decreased retardation of a labeled DNA oligonucleotide probe corresponding to the −88/−66 region of the VEGF promoter, which contains Sp1 binding sites. These effects of gefitinib on VEGF promoter activity and DNA binding were both reversed by Akt expression. Phosphorylation of Sp1 was decreased in the presence of gefitinib. Gefitinib also decreases VEGF expression by decreasing HIF-1α expression. This occurs due to decreased protein translation without any change in the level of HIF-1α mRNA. Together, these results suggest that gefitinib decreases VEGF expression both by decreasing Sp1 binding to the proximal core VEGF promoter and by down-regulating HIF-1α expression. Similar results were obtained with erlotinib in SQ20B and gefitinib in HSC3 squamous carcinoma cells. These results indicate that there are at least two separate mechanisms by which EGFR inhibitors decrease VEGF expression. (Cancer Res 2006; 66(6): 3197-204)
PRL Tyrosine Phosphatases Regulate Rho Family GTPases to Promote Invasion and Motility
Authors: Fiordalisi James J. , Keller Patricia J. , Cox Adrienne D.
Published: March 2006

Phosphatase found in regenerating liver (PRL)-1, PRL-2, and PRL-3 [also known as PTP4A1, PTP4A2, and PTP4A3, respectively] constitute a unique family of putative protein tyrosine phosphatases (PTPs) modified by farnesylation. PRL-3 is amplified and its message is up-regulated in colorectal carcinoma metastases. Its ectopic expression promotes invasive and metastatic properties, supporting a causal link between PRL-3 and late-stage cancer development. However, neither PRL phosphatase substrates nor their signaling pathways have been defined. To address possible mechanisms for the biological activity of PRL-3, we sought to identify its downstream targets, reasoning that regulators of motility and invasion, such as the Rho family of small GTPases, might be logical candidates. We found that levels of active RhoA and RhoC were increased 4- to 7-fold in SW480 colorectal carcinoma cells expressing exogenous PRL-1 and PRL-3, and that PRL-mediated motility and Matrigel invasion were blocked by pharmacologic inhibition of Rho kinase (ROCK), a key Rho effector. In contrast, the activity of Rac was reduced by PRL PTPs, whereas Cdc42 activity was unaffected. PRL-3 stimulated transcription driven by the serum response element in a Rho-dependent manner. We also confirmed that the ability of PRL PTPs to induce invasion and motility is dependent on farnesylation. Catalytic PRL-3 mutants (C104A or D72A) were impaired in PRL-3-induced invasion and Rho activation, indicating that these properties require phosphatase activity. We conclude that PRL PTPs stimulate Rho signaling pathways to promote motility and invasion. Characterization of PRL activity and regulatory pathways should enhance efforts to understand and interfere with PRL-mediated events in invasion and metastasis. (Cancer Res 2006; 66(6): 3153-61)
An Inducible Mouse Model of Melanoma Expressing a Defined Tumor Antigen
Authors: Huijbers Ivo J. , Krimpenfort Paul , Chomez Patrick , van der Valk Martin A. , Song Ji-Ying , Inderberg-Suso Else-Marit , Schmitt-Verhulst Anne-Marie , Berns Anton , Van den Eynde Benoît J.
Published: March 2006

Cancer immunotherapy based on vaccination with defined tumor antigens has not yet shown strong clinical efficacy, despite promising results in preclinical models. This discrepancy might result from the fact that available preclinical models rely on transplantable tumors, which do not recapitulate the long-term host-tumor interplay that occurs in patients during progressive tumor development and results in tumor tolerance. To create a faithful preclinical model for cancer immunotherapy, we generated a transgenic mouse strain developing autologous melanomas expressing a defined tumor antigen recognized by T cells. We chose the antigen encoded by P1A, a well-characterized murine cancer germ line gene. To transform melanocytes, we aimed at simultaneously activating the Ras pathway and inactivating tumor suppressor Ink4a/Arf, thereby reproducing two genetic events frequently observed in human melanoma. The melanomas are induced by s.c. injection of 4-OH-tamoxifen (OHT). By activating a CreER recombinase expressed from a melanocyte-specific promoter, this treatment induces the loss of the conditional Ink4a/Arf gene in melanocytes. Because the CreER gene itself is also flanked by loxP sites, the activation of CreER also induces the deletion of its own coding sequence and thereby allows melanocyte-specific expression of genes H-ras and P1A, which are located downstream on the same transgene. All melanomas induced in those mice with OHT show activation of the Ras pathway and deletion of gene Ink4a/Arf. In addition, these melanomas express P1A and are recognized by P1A-specific T lymphocytes. This model will allow to characterize the interactions between the immune system and naturally occurring tumors and thereby to optimize immunotherapy approaches targeting a defined tumor antigen. (Cancer Res 2006; 66(6): 3278-86)
Phosphorylation of Nucleotide Excision Repair Factor Xeroderma Pigmentosum Group A by Ataxia Telangiectasia Mutated and Rad3-Related–Dependent Checkpoint Pathway Promotes Cell Survival in Response to UV Irradiation
Authors: Wu Xiaoming , Shell Steven M. , Yang Zhengguan , Zou Yue
Published: March 2006

DNA damage triggers complex cellular responses in eukaryotic cells, including initiation of DNA repair and activation of cell cycle checkpoints. In addition to inducing cell cycle arrest, checkpoint also has been suggested to modulate a variety of other cellular processes in response to DNA damage. In this study, we present evidence showing that the cellular function of xeroderma pigmentosum group A (XPA), a major nucleotide excision repair (NER) factor, could be modulated by checkpoint kinase ataxia-telangiectasia mutated and Rad3-related (ATR) in response to UV irradiation. We observed the apparent interaction and colocalization of XPA with ATR in response to UV irradiation. We showed that XPA was a substrate for in vitro phosphorylation by phosphatidylinositol-3-kinase–related kinase family kinases whereas in cells XPA was phosphorylated in an ATR-dependent manner and stimulated by UV irradiation. The Ser196 of XPA was identified as a biologically significant residue to be phosphorylated in vivo. The XPA-deficient cells complemented with XPA-S196A mutant, in which Ser196 was substituted with an alanine, displayed significantly higher UV sensitivity compared with the XPA cells complemented with wild-type XPA. Moreover, substitution of Ser196 with aspartic acid for mimicking the phosphorylation of XPA increased the cell survival to UV irradiation. Taken together, our results revealed a potential physical and functional link between NER and the ATR-dependent checkpoint pathway in human cells and suggested that the ATR checkpoint pathway could modulate the cellular activity of NER through phosphorylation of XPA at Ser196 on UV irradiation. (Cancer Res 2006; 66(6): 2997-3005)
Defective p53 Response and Apoptosis Associated with an Ataxia-Telangiectasia–like Phenotype
Authors: Gueven Nuri , Becherel Olivier J. , Birrell Geoff , Chen Philip , DelSal Giannino , Carney James P. , Grattan-Smith Padraic , Lavin Martin F.
Published: March 2006

Ataxia-telangiectasia mutated (ATM), the protein defective in ataxia-telangiectasia, plays a central role in DNA damage response and signaling to cell cycle checkpoints. We describe here a cell line from a patient with an ataxia-telangiectasia–like clinical phenotype defective in the p53 response to radiation but with normal ATM activation and efficient downstream phosphorylation of other ATM substrates. No mutations were detected in ATM cDNA. A normal level of interaction between p53 and peptidyl-prolyl-isomerase Pin1 suggests that posttranslational modification was intact in these cells but operating at reduced level. Defective p53 stabilization was accompanied by defective induction of p53 effector genes and failure to induce apoptosis in response to DNA-damaging agents. Continued association between p53 and murine double minute-2 (Mdm2) occurred in irradiated ATL2ABR cells in response to DNA damage, and incubation with Mdm2 antagonists, nutlins, increased the stabilization of p53 and its transcriptional activity but failed to induce apoptosis. These results suggest that ATM-dependent stabilization of p53 and induction of apoptosis by radiation involve an additional factor(s) that is defective in ATL2ABR cells. (Cancer Res 2006; 66(6): 2907-12)
Inhibition of Interleukin-6 with CNTO328, an Anti-Interleukin-6 Monoclonal Antibody, Inhibits Conversion of Androgen-Dependent Prostate Cancer to an Androgen-Independent Phenotype in Orchiectomized Mice
Authors: Wallner Lauren , Dai Jinlu , Escara-Wilke June , Zhang Jian , Yao Zhi , Lu Yi , Trikha Mohit , Nemeth Jeffrey A. , Zaki Mohamed H. , Keller Evan T.
Published: March 2006

Initially, prostate cancer is androgen dependent. However, most cases progress to an androgen-independent state through unknown mechanisms. Interleukin-6 (IL-6) has been associated with prostate cancer progression including activation of the androgen receptor (AR). To determine if IL-6 plays a role in the conversion of prostate cancer from androgen dependent to androgen independent, we established androgen-dependent LuCaP 35 human prostate cancer xenografts in nude mice, castrated the mice, and blocked IL-6 activity using a neutralizing antibody (CNT0328) for a period of 18 weeks. IL-6 inhibition increased survival of mice and inhibited tumor growth, as reflected by decreased tumor volume and prostate-specific antigen levels, compared with that in mice receiving isotype control antibody. To test the effect of IL-6 inhibition on the conversion from androgen dependent to androgen independent, tumor cells from the treated mice were assessed for their androgen dependence both in vitro and by implanting them into sham-operated or orchiectomized mice. Tumor cells derived from the isotype-treated animals converted to androgen-independent state, whereas tumor cells from the anti-IL-6 antibody-treated mice were still androgen dependent in vitro and in vivo. Although there was no difference in AR levels between the androgen-independent and androgen-dependent tumors, IL-6 inhibition promoted both apoptosis and inhibited cell proliferation in tumors and blocked the orchiectomy-induced expression of histone acetylases, p300 and CBP, which are AR cofactors. These data show that IL-6 contributes to the development of androgen independence in prostate cancer and suggest that it mediates this effect, in part, through modulation of p300 and CBP. (Cancer Res 2006; 66(6): 3087-95)
Intrapulmonary Administration of CCL21 Gene-Modified Dendritic Cells Reduces Tumor Burden in Spontaneous Murine Bronchoalveolar Cell Carcinoma
Authors: Yang Seok-Chul , Batra Raj K. , Hillinger Sven , Reckamp Karen L. , Strieter Robert M. , Dubinett Steven M. , Sharma Sherven
Published: March 2006

The antitumor efficiency of dendritic cells transduced with an adenovirus vector expressing secondary lymphoid chemokine (CCL21) was evaluated in a murine model of spontaneous bronchoalveolar cell carcinoma. The transgenic mice (CC-10 TAg) express the SV40 large T antigen (TAg) under the Clara cell promoter, develop bilateral, multifocal, and pulmonary adenocarcinomas, and die at 4 months as a result of progressive pulmonary tumor burden. A single intratracheal administration of CCL21 gene-modified dendritic cells (DC-AdCCL21) led to a marked reduction in tumor burden with extensive mononuclear cell infiltration of the tumors. The reduction in tumor burden was accompanied by the enhanced elaboration of type 1 cytokines [IFN-γ, interleukin (IL)-12, and granulocyte macrophage colony-stimulating factor] and antiangiogenic chemokines (CXCL9 and CXCL10) but a concomitant decrease in the immunosuppressive molecules (IL-10, transforming growth factor-β, prostaglandin E2) in the tumor microenvironment. The DC-AdCCL21 therapy group revealed a significantly greater frequency of tumor-specific T cells releasing IFN-γ compared with the controls. Continuous therapy with weekly intranasal delivery of DC-AdCCL21 significantly prolonged median survival by >7 weeks in CC-10 TAg mice. Both innate natural killer and specific T-cell antitumor responses significantly increased following DC-AdCCL21 therapy. Significant reduction in tumor burden in a model in which tumors develop in an organ-specific manner provides a strong rationale for further evaluation of intrapulmonary-administered DC-AdCCL21 in regulation of tumor immunity and genetic immunotherapy for lung cancer.(Cancer Res 2006; 66(6): 3205-13)
Galectin-3 Regulates Mitochondrial Stability and Antiapoptotic Function in Response to Anticancer Drug in Prostate Cancer
Authors: Fukumori Tomoharu , Oka Natsuo , Takenaka Yukinori , Nangia-Makker Pratima , Elsamman Essam , Kasai Toshinori , Shono Masayuki , Kanayama Hiro-omi , Ellerhorst Julie , Lotan Reuben , Raz Avraham
Published: March 2006

Prostate cancer is one of the malignant tumors which exhibit resistance to anticancer drugs, at least in part due to enhanced antiapoptotic mechanisms. Therefore, the understanding of such mechanisms should improve the design of chemotherapy against prostate cancer. Galectin-3 (Gal-3), a multifunctional oncogenic protein involved in the regulation of tumor proliferation, angiogenesis, and apoptosis has shown antiapoptotic effects in certain cell types. Here, we show that the expression of exogenous Gal-3 in human prostate cancer LNCaP cells, which do not express Gal-3 constitutively, inhibits anticancer drug–induced apoptosis by stabilizing the mitochondria. Thus, Gal-3-negative cells showed 66.31% apoptosis after treatment with 50 μmol/L cis-diammine-dichloroplatinum for 48 hours, whereas two clones of Gal-3-expressing cells show only 2.92% and 1.42% apoptotic cells. Similarly, Gal-3-negative cells showed 43.8% apoptosis after treatment with 300 μmol/L etoposide for 48 hours, whereas only 15.38% and 14.51% of Gal-3-expressing LNCaP cells were apoptotic. The expression of Gal-3 stimulated the phosphorylation of Ser112 of Bcl-2-associated death (Bad) protein and down-regulated Bad expression after treatment with cis-diammine-dichloroplatinum. Gal-3 also inhibited mitochondrial depolarization and damage after translocation from the nuclei to the cytoplasm, resulting in inhibition of cytochrome c release and caspase-3 activation. These findings indicate that Gal-3 inhibits anticancer drug–induced apoptosis through regulation of Bad protein and suppression of the mitochondrial apoptosis pathway. Therefore, targeting Gal-3 could improve the efficacy of anticancer drug chemotherapy in prostate cancer. (Cancer Res 2006; 66(6): 3114-9)
Signal Transducer and Activator of Transcription 3 Is Required for the Oncogenic Effects of Non–Small-Cell Lung Cancer–Associated Mutations of the Epidermal Growth Factor Receptor
Authors: Alvarez James V. , Greulich Heidi , Sellers William R. , Meyerson Matthew , Frank David A.
Published: March 2006

Somatic mutations in the epidermal growth factor receptor (EGFR) occur frequently in lung cancer and confer sensitivity to EGFR kinase inhibitors gefitinib and erlotinib. These mutations, which occur in the kinase domain of the protein, also render EGFR constitutively active and transforming. Signal transducers and activators of transcription 3 (STAT3) transduces signals from a number of oncogenic tyrosine kinases and contributes to a wide spectrum of human malignancies. Here, we show that STAT3 is activated by mutant EGFRs and is necessary for its downstream phenotypic effects. Inhibiting STAT3 function in fibroblasts abrogates transformation by mutant EGFR. In non–small-cell lung cancer cells, STAT3 activity is regulated by EGFR through modulation of STAT3 serine phosphorylation. Inhibiting STAT3 function increases apoptosis of these cells, suggesting that STAT3 is necessary for their survival. Finally, a group of genes constituting a STAT3 signature is enriched in lung tumors with EGFR mutations. Thus, STAT3 is a critical mediator of the oncogenic effects of somatic EGFR mutations and targeting STAT3 may be an effective strategy for treating tumors characterized by these mutations. (Cancer Res 2006; 66(6): 3162-8)
Identification of 14-3-3σ as a Contributor to Drug Resistance in Human Breast Cancer Cells Using Functional Proteomic Analysis
Authors: Liu Yang , Liu Hailan , Han Baoguang , Zhang Jian-Ting
Published: March 2006

Multidrug resistance (MDR) is a major obstacle to successful cancer treatment. To understand the mechanism of MDR, many cancer cell lines have been established, and various mechanisms of resistance, such as ATP-binding cassette (ABC) transporter–mediated drug efflux, have been discovered. Previously, a MDR cell line MCF7/AdVp3000 was selected from breast cancer cell line MCF7 against Adriamycin, and overexpression of ABCG2 was thought to cause MDR in this derivative cell line. However, ectopic overexpression of ABCG2 in MCF7 cells could not explain the extremely high drug resistance level of the selected MCF7/AdVp3000 cells. We hypothesized that MCF7/AdVp3000 cells must have other resistance mechanisms selected by Adriamycin. To test this hypothesis, we compared the global protein profiles between MCF7 and MCF7/AdVp3000 cells. Following two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization-time of flight mass spectrometry analysis, 17 protein spots with differential levels between the two cell lines were identified. Although 14-3-3σ, keratin 18, keratin 19, ATP synthase β, protein disulfide isomerase, heat shock protein 27, cathepsin D, triose-phosphate isomerase, peroxiredoxin 6, and electron transfer flavoprotein were increased, nm23/H1, peroxiredoxin 2, nucleophosmin 1/B23, and inorganic pyrophosphatase were decreased in MCF7/AdVp3000 cells. The differential levels of these proteins were validated using Western blot. Furthermore, functional validation showed that the elevated 14-3-3σ expression contributes considerably to the observed drug resistance in MCF7/AdVp3000 cells. We, thus, conclude that these proteins likely contribute to the resistance selected in the MCF7/AdVp3000 cells, and their altered expression in tumors may cause clinical resistance to chemotherapy. (Cancer Res 2006; 66(6): 3248-55)
Antiangiogenic Concentrations of Vinflunine Increase the Interphase Microtubule Dynamics and Decrease the Motility of Endothelial Cells
Authors: Pourroy Bertrand , Honoré Stéphane , Pasquier Eddy , Bourgarel-Rey Véronique , Kruczynski Anna , Briand Claudette , Braguer Diane
Published: March 2006

Angiogenesis is a key event in tumor progression and metastasis. This complex process, which constitutes a potent target for cancer therapy, is inhibited by very low concentrations of microtubule-targeting drugs (MTD). However, the intimate mechanisms of the antiangiogenic activity of MTDs remain unclear. Recently, we have shown that low antiangiogenic and noncytotoxic concentrations of paclitaxel induced an unexpected increase in microtubule dynamics in endothelial cells. In this study, we showed that vinflunine, the newest Vinca alkaloid, increased microtubule dynamic instability in human endothelial cells after 4-hour incubation at low concentrations (29% and 54% at 0.1 and 2 nmol/L). The growth and shortening rates were increased, and the percentage of time spent in pause and the mean duration of pauses were decreased, as previously observed with paclitaxel. As opposed to paclitaxel, the transition frequencies were not significantly disturbed by vinflunine. Moreover, low concentrations of vinflunine did not affect mitotic index and anaphase/metaphase ratio. Interestingly, these low vinflunine concentrations that increased microtubule dynamics exhibited an antiangiogenic effect through the inhibition of both morphogenesis and random motility. Capillary tube formation on Matrigel was decreased up to 44%. The cell speed and the random motility coefficient were decreased (13% and 19% and 13% and 33% at 0.1 and 2 nmol/L, respectively) and the persistent time was statistically increased. Altogether, our results confirm that the increase in microtubule dynamics is involved in MTD antiangiogenic activity and highlight the crucial role of interphase microtubule dynamics in angiogenesis. (Cancer Res 2006; 66(6): 3256-63)
Development of a Highly Active Nanoliposomal Irinotecan Using a Novel Intraliposomal Stabilization Strategy
Authors: Drummond Daryl C. , Noble Charles O. , Guo Zexiong , Hong Keelung , Park John W. , Kirpotin Dmitri B.
Published: March 2006

Liposome formulations of camptothecins have been actively pursued because of the potential for significant pharmacologic advantages from successful drug delivery of this important class of anticancer drugs. We describe nanoliposomal CPT-11, a novel nanoparticle/liposome construct containing CPT-11 (irinotecan) with unprecedented drug loading efficiency and in vivo drug retention. Using a modified gradient loading method featuring a sterically hindered amine with highly charged, multivalent anionic trapping agents, either polymeric (polyphosphate) or nonpolymeric (sucrose octasulfate), liposomes were capable of entrapping CPT-11 at extremely high drug-to-lipid ratios (>800 g CPT-11/mol phospholipid) and retaining encapsulated drug in vivo with a half-life of drug release in the circulation of 56.8 hours. CPT-11 was also protected from hydrolysis to the inactive carboxylate form and from metabolic conversion to SN-38 while circulating. The maximum tolerated dose in normal mice was determined to be 80 mg/kg for free CPT-11 and >320 mg/kg for nanoliposomal CPT-11. Nanoliposomal CPT-11 showed markedly superior efficacy when compared with free CPT-11 in human breast (BT474) and colon (HT29) cancer xenograft models. This study shows that intraliposomal stabilization of CPT-11 using a polymeric or highly charged, nonpolymeric polyanionic trapping agent results in a markedly active antitumor agent with low toxicity. (Cancer Res 2006; 66(6): 3271-7)
αβ T-Cell Receptor Engineered γδ T Cells Mediate Effective Antileukemic Reactivity
Authors: van der Veken Lars T. , Hagedoorn Renate S. , van Loenen Marleen M. , Willemze Roel , Falkenburg J.H. Frederik , Heemskerk Mirjam H.M.
Published: March 2006

Retroviral transfer of T-cell receptors (TCR) to peripheral blood–derived T cells generates large numbers of T cells with the same antigen specificity, potentially useful for adoptive immunotherapy. One drawback of this procedure is the formation of mixed TCR dimers with unknown specificities due to pairing of endogenous and introduced TCR chains. We investigated whether γδ T cells can be an alternative effector population for TCR gene transfer because the γδTCR is not able to form dimers with the αβTCR. Peripheral blood–derived γδ T cells were transduced with human leukocyte antigen (HLA) class I– or HLA class II–restricted minor histocompatibility antigen (mHag) or virus-specific TCRs. Because most γδ T cells do not express CD4 and CD8, we subsequently transferred these coreceptors. The TCR-transduced γδ T cells exerted high levels of antigen-specific cytotoxicity and produced IFN-γ and IL-4, particularly in the presence of the relevant coreceptor. γδ T cells transferred with a TCR specific for the hematopoiesis-specific mHag HA-2 in combination with CD8 displayed high antileukemic reactivity against HA-2–expressing leukemic cells. These data show that transfer of αβTCRs to γδ T cells generated potent effector cells for immunotherapy of leukemia, without the expression of potentially hazardous mixed TCR dimers. (Cancer Res 2006; 66(6): 3331-7)
Nucleophosmin Mutations in De novo Acute Myeloid Leukemia: The Age-Dependent Incidences and the Stability during Disease Evolution
Authors: Chou Wen-Chien , Tang Jih-Luh , Lin Liang-In , Yao Ming , Tsay Woei , Chen Chien-Yuan , Wu Shang-Ju , Huang Chi-Fei , Chiou Rong-Jing , Tseng Mei-Hsuan , Lin Dong-Tsamn , Lin Kai-Hsin , Chen Yao-Chang , Tien Hwei-Fang
Published: March 2006

Nucleophosmin (NPM) mutations have been found in a significant proportion of adults with de novo acute myeloid leukemia (AML), especially in those of a normal karyotype. These results provide a basis for studies of the pathogenesis in this specific subgroup of AML. In this study, NPM mutations were analyzed in 173 Chinese patients of de novo AML, including adults and children. We found that NPM mutations were present in 19.1% of the overall population and 40.3% of those with a normal karyotype. Adults had a significantly higher incidence of NPM mutations than children [32 of 126 (25.4%) versus 1 of 47 (2.1%), P < 0.001]. NPM mutations were closely associated with normal karyotype (P < 0.001) and internal tandem duplication of FLT3 (P = 0.002), but negatively associated with CEBPA mutations (P = 0.032) and expression of CD34 (P < 0.001) and HLA-DR (P = 0.003). Serial analyses of NPM mutations showed the mutation disappeared at complete remission, but the same mutation reappeared at relapse, except for one who lost the mutation at the second relapse, when new cytogenetic abnormalities emerged. None acquired novel mutations during the follow-up period. In conclusion, NPM mutations occur in an age-dependent fashion. Moreover, the findings that NPM mutations are stable during disease evolution and closely associated with disease status make it a potential marker for monitoring minimal residual disease. (Cancer Res 2006; 66(6): 3310-6)
The Phosphoinositide 3-Kinase/Akt1/Par-4 Axis: A Cancer-Selective Therapeutic Target
Authors: Goswami Anindya , Ranganathan Padhma , Rangnekar Vivek M.
Published: March 2006

Activation of the phosphoinositide 3-kinase (PI3K)/Akt cell survival pathway in many cancers makes it an appealing target for therapeutic development. However, because this pathway also has an important role in the survival of normal cells, tactics to achieve cancer selectivity may prove important. We recently showed that the cancer-selective proapoptotic protein Par-4 is a key target for inactivation by PI3K/Akt signaling. Additionally, we found that Par-4 participates in mediating apoptosis by PTEN, the tumor suppressor responsible for blocking PI3K/Akt signaling. As a central player in cancer cell survival, Par-4 may provide a useful focus for the development of cancer-selective therapeutics. (Cancer Res 2006; 66(6): 2889-92)
Association between Interpersonal Behaviour and Helping Alliance in Substance-Dependent Patients
Authors: De Weert-Van Oene G.H. , Jörg F. , de Jong C.A.J.
Published: March 2006

This paper focuses on exploring the association between the patient’s perception of his own interpersonal behaviour on the one hand, and that of the therapist’s behaviour and of helping alliance on the other hand. A cross-sectional study was conducted, including 83 patients from substance dependence programs in The Netherlands. They completed the Helping Alliance Questionnaire (HAQ) and the Interpersonal Check List (ICL). Results indicate that the patient’s perception of the therapeutic alliance, and his perception of his own and of the therapist’s interpersonal behaviour are three separate domains, each playing their role in the context of the therapeutic relationship. Helping Alliance scores are predicted by both the patient’s (complaisance) and the therapist’s interpersonal behaviour (dominance). We conclude that patient’s cognitions about himself and about his therapist do contribute significantly to the perception of the therapeutic relationship. Limitations to the study are discussed, as well as some clinical implications.
Determinants of Health-Related Quality of Life of Opiate Users at Entry to Low-Threshold Methadone Programs
Authors: Millson Peggy , Challacombe Laurel , Villeneuve Paul J. , Strike Carol J. , Fischer Benedikt , Myers Ted , Shore Ron , Hopkins Shaun
Published: March 2006

Objective: The aim of this study was to conduct an exploratory analysis of factors associated with poor health-related quality of life (HRQOL) among opiate users at entry to low-threshold methadone treatment. Methods: The SF-36 questionnaire was administered to 145 opiate users at enrollment into low-threshold methadone maintenance programs. ANOVA and correlational analyses were performed to investigate the determinants of poor physical and mental composite summary scales (PCS and MCS) of the SF-36 among opiate users. Stepwise regression methods were also employed to fit PCS and MCS multivariate models. Results: Age, employment status, chronic medical conditions, hospitalization, emotional abuse, sexual abuse and age at first injection episode were significantly associated with PCS. Mental health problems, sexual abuse, physical abuse, the use of sedatives, the use of cocaine, the number of days of cocaine use, sedative use and multiple substance use in the past month were significantly associated with MCS. The variances in the MCS and PCS were not readily explained by any one factor. Conclusion: The multiplicity of factors influencing HRQOL of opiate users suggests the need for a range of services within the context of a methadone program, addressing primary medical care needs as well as treatment for both mental health problems and abuse issues.
Severity Profiles of Substance-Abusing Patients in Italian Community Addiction Facilities: Influence of Psychiatric Concurrent Disorders
Authors: Carrà Giuseppe , Scioli Rosangela , Monti Maria Cristina , Marinoni Alessandra
Published: March 2006

Mental health and addiction services have traditionally evolved separately in many European countries, with policy reflecting this. Differences in severity profiles between users of the community addiction services with comorbidities of mental illness and substance misuse and those with substance misuse only were studied using a matched case-control study design, with regard to the main substance (opiates or cocaine) patients were dependent on. Patterns of substance abuse and diagnostic features were evaluated according to the Addiction Severity Index (ASI) and DSM-IV. Mentally ill substance abusers are significantly more likely to have used amphetamines, inhalants and having been polydrug users. They are particularly impaired in medical and family/social relationships ASI composite scores, but less in drug use. Severity profiles and needs of dually diagnosed patients require assessment and treatment skills that should be provided through adequate links with mental health system.
A Rare Case of Rectovaginal Endometriosis with Lymph Node Involvement
Authors: Thomakos Nikolaos , Rodolakis Alexandros , Vlachos George , Papaspirou Irene , Markaki Sophia , Antsaklis Aris
Published: March 2006

A rare case of rectovaginal endometriosis with lymph node involvement is described in a 44-year-old patient. The presence of endometrial tissue in pelvic lymph nodes is rare and has been confirmed in the literature in subjects who underwent surgery for endometriosis. Involvement of pelvic lymph nodes by endometriosis seems unlikely to arise de novo and probably suggests lymphatic spread of the disease.
Comparisons of the Peritoneal Equilibration Test and Ultrafiltration in Patients with and without Diabetes Mellitus on Continuous Ambulatory Peritoneal Dialysis
Authors: Chou Ming-Yen , Kao Min-Tsung , Lai Ming-Nan , Chung Shi-Yu
Published: March 2006

Background/Aims: To compare dialysance and ultrafiltration (UF) of peritoneum in diabetes mellitus (DM) and non-DM patients on continuous ambulatory peritoneal dialysis. Methods: A total of 162 adult patients on continuous ambulatory peritoneal dialysis (40 DM and 122 non-DM patients) were studied with the peritoneal equilibration test (PET) using 2.5% glucose dialysis solution retained for 4 h. Patients using 2,000 or 1,500 ml of infusion volume were classified into groups A (23 DM and 63 non-DM patients) and B (16 DM and 41 non-DM patients), respectively. PET results were compared between DM and non-DM patients by unpaired t test. Using Pearson’s correlation and least-square multiple regression, the most powerful predictors of UF rate were also evaluated in DM and non-DM patients. Results: There were no differences between PET parameters and UF rate between DM and non-DM patients in the whole group (WG) and group A. The only significant difference (p < 0.05) was an increased D4/D0 value in DM patients in group B. The most simple but powerful method to predict UF rate was (100 – GAP)/(D4/D0), where GAP corresponds to the glucose absorption percentage and D4/D0 is the PET 4-hour dialysate glucose level/PET 0-hour dialysate glucose level. GAP and D4/D0 were two major determinants of UF rate in the DM group, non-DM group and WG. Conclusions: Peritoneal permeability did not differ between DM and non-DM patients, and GAP and D4/D0 were two major factors predicting UF rate.
Microvasculature Change and Placenta Growth Factor Expression in the Early Stage of a Rat Remnant Kidney Model
Authors: Wu Qingqing , Du Yong , Yang Niansheng , Liang Yingjie , Li Youji
Published: March 2006

Background/Aim: There is significant loss of microvasculature and impaired angiogenesis in rat remnant kidney (RK). Placenta growth factor (PlGF) is a potential angiogenic growth factor. In this study, we investigate the changes of microvasculature and expression of PlGF in the first 4 weeks of the early stage of a rat RK model. Method: RK was induced by right nephrectomy and ligation of two of the three branches of the left renal arteries (equivalent to 5/6 subtotal nephrectomy). Blood urea nitrogen (BUN), serum creatinine (Scr), and blood pressure (BP) were measured. Proliferation of endothelial cells was identified by double staining of two antibodies, anti-rat endothelial cell (RECA-1) and antiproliferating cell nuclear antigen (PCNA). RT-PCR and Western blot were used for PlGF analysis. Results: BUN, Scr and BP remained stable after rising within the first week. An angiogenic response occurred in RKs, with an increase in the proliferation of peritubular and glomerular endothelial cells. Both PlGF protein and mRNA expression were significantly upregulated 2- to 3-fold in RK at week 1 and week 2, compared to the sham-operated group (p < 0.05). Conclusion: The expression of PlGF is upregulated and coincident with an early angiogenic response in rat RK, suggesting that PlGF may be involved in angiogenesis in progressive renal injury.
A Comparison of Dosing Regimens of Paricalcitol Capsule for the Treatment of Secondary Hyperparathyroidism in CKD Stages 3 and 4
Authors: Abboud Hanna , Coyne Daniel , Smolenski Olgierd , Anger Michael , Lunde Norman , Qiu Ping , Hippensteel Rich , Pradhan Rajendra S. , Palaparthy Rameshraja V. , Kavanaugh Anne , Melnick Joel Z. , Williams Laura A. , Batlle Daniel
Published: March 2006

Background: Intermittent dosing of calcitriol for secondary hyperparathyroidism (SHPT) has been associated with greater parathyroid hormone (PTH) reduction with fewer calcemic and phosphatemic effects than daily (QD) dosing. Methods: Secondary analyses of three randomized, double-blind, placebo-controlled multicenter studies in stage 3 and 4 chronic kidney disease (CKD) patients with SHPT were performed to compare three times per week (TIW) with QD dosing of paricalcitol. The pharmacokinetics of TIW and QD dosing of paricalcitol capsules were assessed in a separate group of healthy subjects. Results: Pharmacokinetics revealed similar steady state paricalcitol exposure between dosing regimens. In CKD patients, baseline data were similar between the TIW studies (n = 72, paricalcitol; n = 73, placebo) and QD studies (n = 35, paricalcitol; n = 40, placebo). Both dosing regimens resulted in similar efficacy (91%) for the primary end point of two consecutive ≧30% decreases in intact PTH from baseline, but the QD regimen resulted in a greater percent reduction in intact PTH from baseline. The chances for developing increased serum calcium and phosphorus levels or Ca × P product were similar between paricalcitol and placebo groups for both treatment regimens. Furthermore, no difference in the risk for these elevations was detected between the TIW and QD regimens. Conclusions: QD dosing of paricalcitol capsules is as efficacious as TIW dosing in achieving the primary end point (2 consecutive ≧30% reductions in PTH) in stage 3 and 4 CKD patients with SHPT. Moreover, the QD regimen had no significant effect on hypercalcemia, hyperphosphatemia or Ca × P product as compared with placebo or intermittent dosing.
Usefulness of 23S rRNA Amplification by PCR in the Detection of Bacteria in CAPD Peritonitis
Authors: Yoo Tae-Hyun , Chang Kyung Hee , Ryu Dong-Ryeol , Kim Ju Sung , Choi Hoon Young , Park Hyeong Cheon , Kang Shin-Wook , Choi Kyu Hun , Kim June Myung , Ha Sung Kyu , Han Dae Suk , Lee Ho Yung
Published: March 2006

Background: Peritonitis is the most common complication of continuous ambulatory peritoneal dialysis (CAPD), and the spectrum of organisms causing CAPD peritonitis is broad. Polymerase chain reaction (PCR) has recently broadened its diagnostic capabilities in infectious diseases. PCR can provide a sensitive method for identifying causative infectious organisms. Methods: To evaluate the usefulness of 23S bacterial ribosomal RNA amplification and direct sequencing for the detection of infectious organisms, we compared PCR with bacteriological culture for the analysis of dialysates from CAPD peritonitis patients. Thirty-two samples from CAPD peritonitis patients with current antibiotic use and control samples from 30 CAPD patients without peritonitis were examined by PCR with sequencing analysis and by conventional bacteriological culture. In addition, 95 culture-positive samples and 39 culture-negative samples from CAPD peritonitis patients before antibiotic treatment were analyzed by PCR assay. Results: In the control samples from patients without CAPD peritonitis, false-positive rates were relatively rare: 3 of 30 in the PCR study and 2 of 30 in the culture study. Of the 134 CAPD peritonitis samples collected before antibiotic therapy, positive cultures were obtained in 70.9% (95/134) of them. In 75 of the culture-positive samples, the same microorganisms were confirmed by PCR assay, and the others showed discrepant results as compared with culture study. In 30 of the 39 culture-negative samples, microbial organisms were detected by PCR assay. Of the 32 samples from patients who developed CAPD peritonitis during antibiotic treatment, 17 (53.1%) were positive by PCR assay, and 5 (15.6%) were positive by culture. Conclusion: Our study suggests that broad-spectrum PCR with RNA sequencing can complement culture methods in the diagnosis of CAPD peritonitis, especially in patients with previous or current antibiotic use.
Lysophosphatidylcholine Augments Cav3.2 but Not Cav3.1 T-Type Ca2+ Channel Current Expressed in HEK-293 Cells
Authors: Zheng Mingqi , Uchino Tomoko , Kaku Toshihiko , Kang Lin , Wang Yan , Takebayashi Satoshi , Ono Katsushige
Published: March 2006

Lysophosphatidylcholine (LPC) has been shown to induce electrophysiological disturbances to arrhythmogenesis. However, the effects of LPC on the low-voltage-activated T-type Ca2+ channels in the heart are not understood yet. We found that LPC increases the T-type Ca2+ channel current (ICa.T) in neonatal rat cardiomyocytes. To further investigate the underlying modulatory mechanism of LPC on T-type Ca2+ channels, we utilized HEK-293 cells stably expressing α1G and α1H subunits (HEK-293/α1G and HEK-293/α1H), by use of patch-clamp techniques. A low concentration of LPC (10 µmol/l) significantly increased Cav3.2 ICa.T (α1H) that were similar to those observed in neonatal rat cardiomyocytes. Activation and steady-state inactivation curves were shifted in the hyperpolarized direction by 5.1 ± 0.2 and 4.6 ± 0.4 mV, respectively, by application of 10 µmol/l LPC. The pretreatment of cells with a protein kinase C inhibitor (chelerythrine) attenuated the effects of LPC on ICa.T (α1H). However, the application of LPC failed to modify Cav3.1 (α1G) ICa.T at concentrations of 10–50 µmol/l. In conclusion, these data demonstrate that extracellularly applied LPC augments Cav3.2 ICa.T (α1H) but not Cav3.1 ICa.T (α1G) in a heterologous expression system, possibly by modulating protein kinase C signaling.
Babylonian Royal Land Grants, Memorials of Financial Interest, and Invocation of the Divine
Authors:   Brinkman
Published: March 2006

From the fourteenth to the seventh centuries B.C., Babylonian royal land grants and related documents were often engraved on stone stelae, which were decorated with divine symbols, inscribed with elaborate curses against offenders, and placed in a temple. These stone memorials (traditionally called kudurrus) throw light on contemporary legal and economic practices with individual cases involving property rights, royal patronage, family disputes, overzealous functionaries, temple offices and income, and taxation woes. This article assesses a new book which discusses the form and function of these stelae. Du XIVe au VIIe s. av. J.-C., les textes d'attribution de terrain par les rois babyloniens et certains documents similaires étaient gravés sur des stèles en pierre, décorées de symboles divins, munies de malédictions contre ceux qui ne les respecteraient pas, et installées dans un temple. Ces mémoriaux en pierre (appelés traditionellement kudurrus) éclairent les systèmes juridiques et économiques contemporains en citant des cas particuliers: ceux-ci documentent le droit de la propriété foncière, la faveur royale, les fonctionnaires trop exigeants, les disputes familiales, les bénéfices et revenus du temple, et les problèmes fiscaux. Dans cet article, on rend compte d'un livre récemment publié concernant la forme et la fonction de ces stèles.
Zebrafish G protein γ2 is required for VEGF signaling during angiogenesis
Authors: Leung TinChung , Chen Hui , Stauffer Anna M. , Giger Kathryn E. , Sinha Soniya , Horstick Eric J. , Humbert Jasper E. , Hansen Carl A. , Robishaw Janet D.
Published: March 2006

Vascular endothelial growth factor (VEGF) is a major mediator of pathologic angiogenesis, a process necessary for the formation of new blood vessels to support tumor growth. Historically, VEGF has been thought to signal via receptor tyrosine kinases, which are not typically considered to be G protein dependent. Here, we show that targeted knockdown of the G protein gng2 gene (Gγ2) blocks the normal angiogenic process in developing zebrafish embryos. Moreover, loss of gng2 function inhibits the ability of VEGF to promote the angiogenic sprouting of blood vessels by attenuating VEGF induced phosphorylation of phospholipase C-gamma1 (PLCγ1) and serine/threonine kinase (AKT). Collectively, these results demonstrate a novel interaction between Gγ2- and VEGF-dependent pathways to regulate the angiogenic process in a whole-animal model. Blocking VEGF function using a humanized anti-VEGF antibody has emerged as a promising treatment for colorectal, non-small lung cell, and breast cancers. However, this treatment may cause considerable side effects. Our findings provide a new opportunity for cotargeting G protein- and VEGF-dependent pathways to synergistically block pathologic angiogenesis, which may lead to a safer and more efficacious therapeutic regimen to fight cancer. (Blood. 2006;108:160-166)
Ethnicity and survival in childhood acute myeloid leukemia: a report from the Children's Oncology Group
Authors: Aplenc Richard , Alonzo Todd A. , Gerbing Robert B. , Smith Franklin O. , Meshinchi Soheil , Ross Julie A. , Perentesis John , Woods William G. , Lange Beverly J. , Davies Stella M.
Published: March 2006

We evaluated differences in outcome by ethnicity among children with acute myeloid leukemia (AML). We analyzed 791 children in the CCG 2891 trial and confirmed positive findings in 850 children in the CCG 2961 trial. Hispanic and black children treated with chemotherapy in CCG 2891 had significantly inferior overall survival (OS) from study entry compared with white children (37%± 9% vs 48%± 4% [P = .016] and 34% ± 10% vs 48% ± 4%, [P = .007], respectively). Significantly fewer black children had related donors. Analyses of CCG 2961 confirmed that black children had significantly decreased OS rates compared with white children (45% ± 12% vs 60% ± 4%; P = .007) The difference in OS rates between Hispanic and white children approached statistical significance (51% ± 8% vs 60% ± 4%; P = .065) Only 7.5% of black children on CCG 2961 had an available family donor. In conclusion, Hispanic and black children with AML have worse survival than white children. Access to chemotherapy, differences in supportive care or leukemia phenotype, and reduced compliance are unlikely explanations for this difference because therapy was given intravenously according to CCG protocols. Fewer black children than expected had an available family marrow donor. (Blood. 2006;108:74-80)