bluuebunny/crossref_metadata_2025_split huggingface dataset:
The DNAN-Glycosylase MED1 Exhibits Preference for Halogenated Pyrimidines and Is Involved in the Cytotoxicity of 5-Iododeoxyuridine
Authors: Turner David P. , Cortellino Salvatore , Schupp Jane E. , Caretti Elena , Loh Tamalette , Kinsella Timothy J. , Bellacosa Alfonso 
Published: August 2006

AbstractThe base excision repair protein MED1 (also known as MBD4), an interactor with the mismatch repair protein MLH1, has a central role in the maintenance of genomic stability with dual functions in DNA damage response and repair. MED1 acts as a thymine and uracil DNA N-glycosylase on T:G and U:G mismatches that occur at cytosine-phosphate-guanine (CpG) methylation sites due to spontaneous deamination of 5-methylcytosine and cytosine, respectively. To elucidate the mechanisms that underlie sequence discrimination by MED1, we did single-turnover kinetics with the isolated, recombinant glycosylase domain of MED1. Quantification of MED1 substrate hierarchy confirmed MED1 preference for mismatches within a CpG context and showed preference for hemimethylated base mismatches. Furthermore, the kst values obtained with the uracil analogues 5-fluorouracil and 5-iodouracil were over 20- to 30-fold higher than those obtained with uracil, indicating substantially higher affinity for halogenated bases. A 5-iodouracil precursor is the halogenated nucleotide 5-iododeoxyuridine (5IdU), a cytotoxic and radiosensitizing agent. Cultures of mouse embryo fibroblasts (MEF) with different Med1 genotype derived from mice with targeted inactivation of the gene were evaluated for sensitivity to 5IdU. The results revealed that Med1-null MEFs are more sensitive to 5IdU than wild-type MEFs in both 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony formation assays. Furthermore, high-performance liquid chromatography analyses revealed that Med1-null cells exhibit increased levels of 5IdU in their DNA due to increased incorporation or reduced removal. These findings establish MED1 as a bona fide repair activity for the removal of halogenated bases and indicate that MED1 may play a significant role in 5IdU cytotoxicity. (Cancer Res 2006; 66(15): 7686-93)
Adenosine-Mediated Inhibition of the Cytotoxic Activity and Cytokine Production by Activated Natural Killer Cells
Authors: Lokshin Anna , Raskovalova Tatiana , Huang Xiaojun , Zacharia Lefteris C. , Jackson Edwin K. , Gorelik Elieser 
Published: August 2006

AbstractAdenosine is an important signaling molecule that regulates multiple physiologic processes and exerts major anti-inflammatory actions. Tumors have high concentrations of adenosine, which could inhibit the function of tumor-infiltrating lymphoid cells. We investigated the ability of adenosine and its stable analogue 2-chloroadenosine (CADO) to inhibit cytokine production and cytotoxic activity of lymphokine-activated killer (LAK) cells and determined whether both these effects are initiated via a common pathway. CADO strongly inhibited cytotoxic activity of LAK cells and attenuated the production of IFN-γ, granulocyte macrophage colony-stimulating factor, tumor necrosis factor α, and macrophage inflammatory protein-1α by LAK cells stimulated by cross-linking of the Ly49D receptor. These inhibitory effects were associated with the ability of CADO to stimulate cyclic AMP (cAMP) production and activate protein kinase A (PKA). Using cAMP analogues with different affinities for the A and B sites of the regulatory subunits of PKA types I and II, we found that activation of PKA I, but not PKA II, mimicked the inhibitory effects of CADO on LAK cell cytotoxic activity and cytokine production. Inhibitors of the PKA catalytic subunits (H89 and PKI14-22 peptide) failed to abrogate the inhibitory effects of CADO whereas Rp-8-Br-cAMPS, an antagonist of the RI subunit, blocked the inhibitory effects of CADO. We conclude that the inhibitory effects of adenosine are probably mediated via cAMP-dependent activation of the RI subunits of PKA I but are independent of the catalytic activity of PKA. Tumor-produced adenosine could be a potent tumor microenvironmental factor inhibiting the functional activity of tumor-infiltrating immune cells. (Cancer Res 2006; 66(15): 7758-65)
High-Grade Glioma Formation Results from Postnatal Pten Loss or Mutant Epidermal Growth Factor Receptor Expression in a Transgenic Mouse Glioma Model
Authors: Wei Qingxia , Clarke Laura , Scheidenhelm Danielle K. , Qian Baoping , Tong Amanda , Sabha Nesrin , Karim Zia , Bock Nicholas A. , Reti Robert , Swoboda Rolf , Purev Enkhtsetseg , Lavoie Jean-Francois , Bajenaru M. Livia , Shannon Patrick , Herlyn Dorothee , Kaplan David , Henkelman R. Mark , Gutmann David H. , Guha Abhijit 
Published: August 2006

Abstract
High-grade gliomas are devastating brain tumors associated with a mean survival of &lt;50 weeks. Two of the most common genetic changes observed in these tumors are overexpression/mutation of the epidermal growth factor receptor (EGFR) vIII and loss of PTEN/MMAC1 expression. To determine whether somatically acquired EGFRvIII expression or Pten loss accelerates high-grade glioma development, we used a previously characterized RasB8 glioma-prone mouse strain, in which these specific genetic changes were focally introduced at 4 weeks of age. We show that both postnatal EGFRvIII expression and Pten inactivation in RasB8 mice potentiate high-grade glioma development. Moreover, we observe a concordant loss of Pten and EGFR overexpression in nearly all high-grade gliomas induced by either EGFRvIII introduction or Pten inactivation. This novel preclinical model of high-grade glioma will be useful in evaluating brain tumor therapies targeted to the pathways specifically dysregulated by EGFR expression or Pten loss. (Cancer Res 2006; 66(15): 7429-37)
MicroRNA-Cancer Connection: The Beginning of a New Tale
Authors: Calin George Adrian , Croce Carlo Maria 
Published: August 2006

Abstract
Cancer initiation and progression can involve microRNAs (miRNA), which are small noncoding RNAs that can regulate gene expression. Their expression profiles can be used for the classification, diagnosis, and prognosis of human malignancies. Loss or amplification of miRNA genes has been reported in a variety of cancers, and altered patterns of miRNA expression may affect cell cycle and survival programs. Germ-line and somatic mutations in miRNAs or polymorphisms in the mRNAs targeted by miRNAs may also contribute to cancer predisposition and progression. We propose that alterations in miRNA genes play a critical role in the pathophysiology of many, perhaps all, human cancers. (Cancer Res 2006; 66(15): 7390-4)
Notch Pathway Inhibition Depletes Stem-like Cells and Blocks Engraftment in Embryonal Brain Tumors
Authors: Fan Xing , Matsui William , Khaki Leila , Stearns Duncan , Chun Jiong , Li Yue-Ming , Eberhart Charles G. 
Published: August 2006

Abstract
The Notch signaling pathway is required in both nonneoplastic neural stem cells and embryonal brain tumors, such as medulloblastoma, which are derived from such cells. We investigated the effects of Notch pathway inhibition on medulloblastoma growth using pharmacologic inhibitors of γ-secretase. Notch blockade suppressed expression of the pathway target Hes1 and caused cell cycle exit, apoptosis, and differentiation in medulloblastoma cell lines. Interestingly, viable populations of better-differentiated cells continued to grow when Notch activation was inhibited but were unable to efficiently form soft-agar colonies or tumor xenografts, suggesting that a cell fraction required for tumor propagation had been depleted. It has recently been hypothesized that a small population of stem-like cells within brain tumors is required for the long-term propagation of neoplastic growth and that CD133 expression and Hoechst dye exclusion (side population) can be used to prospectively identify such tumor-forming cells. We found that Notch blockade reduced the CD133-positive cell fraction almost 5-fold and totally abolished the side population, suggesting that the loss of tumor-forming capacity could be due to the depletion of stem-like cells. Notch signaling levels were higher in the stem-like cell fraction, providing a potential mechanism for their increased sensitivity to inhibition of this pathway. We also observed that apoptotic rates following Notch blockade were almost 10-fold higher in primitive nestin-positive cells as compared with nestin-negative ones. Stem-like cells in brain tumors thus seem to be selectively vulnerable to agents inhibiting the Notch pathway. (Cancer Res 2006; 66(15): 7445-52)
Responses of Human Colorectal Tumor Cells to Treatment with the Anti–Epidermal Growth Factor Receptor Monoclonal Antibody ICR62 Used Alone and in Combination with the EGFR Tyrosine Kinase Inhibitor Gefitinib
Authors: Cunningham Matthew P. , Thomas Hilary , Fan Zhen , Modjtahedi Helmout 
Published: August 2006

Abstract
The anti–epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab has been approved for the treatment of patients with metastatic colorectal cancer. However, there is currently no reliable marker for response to therapy with the EGFR inhibitors. In this study, we investigated the sensitivity of 10 human colorectal tumor cell lines (DiFi, CCL218, CCL221, CCL225, CCL227, CCL228, CCL231, CCL235, CCL244, and HCT-116) to treatment with our anti-EGFR monoclonal antibody, ICR62, and/or the EGFR tyrosine kinase inhibitor, gefitinib. Of the cells examined, only DiFi contained high levels of constitutively active EGFR and were highly sensitive to treatment with both ICR62 (IC50 = 0.52 nmol/L) and gefitinib (IC50 = 27.5 nmol/L). In contrast, the growth of other tumor cell lines, which contained low levels of the EGFR, HER-2, and pAkt but comparable or even higher basal levels of phosphorylated mitogen-activated protein kinase (pMAPK), were relatively resistant to treatment with both inhibitors. Both ICR62 and gefitinib induced EGFR down-regulation, reduced the basal levels of pEGFR at five known tyrosine residues, pMAPK, and pAkt, and increased the sub-G1 population in DiFi cells. However, treatment with a combination of ICR62 and gefitinib neither sensitized colorectal tumor cells that were insensitive to treatment with the single agent nor enhanced the growth-inhibitory effect of the single agent in DiFi cells. These results indicate that basal levels of pMAPK and pAkt are not good indicators of response to the EGFR inhibitors in colorectal cancer cells and dual targeting of the EGFR by a combination of ICR62 and gefitinib is not superior to treatment with a single agent. (Cancer Res 2006; 66(15): 7708-15)
Gene Expression Signatures for Predicting Prognosis of Squamous Cell and Adenocarcinomas of the Lung
Authors: Raponi Mitch , Zhang Yi , Yu Jack , Chen Guoan , Lee Grace , Taylor Jeremy M.G. , MacDonald James , Thomas Dafydd , Moskaluk Christopher , Wang Yixin , Beer David G. 
Published: August 2006

Abstract
Non–small-cell lung cancers (NSCLC) compose 80% of all lung carcinomas with squamous cell carcinomas (SCC) and adenocarcinoma representing the majority of these tumors. Although patients with early-stage NSCLC typically have a better outcome, 35% to 50% will relapse within 5 years after surgical treatment. We have profiled primary squamous cell lung carcinomas from 129 patients using Affymetrix U133A gene chips. Unsupervised analysis revealed two clusters of SCC that had no correlation with tumor stage but had significantly different overall patient survival (P = 0.036). The high-risk cluster was most significantly associated with down-regulation of epidermal development genes. Cox proportional hazard models identified an optimal set of 50 prognostic mRNA transcripts using a 5-fold cross-validation procedure. Quantitative reverse transcription-PCR and immunohistochemistry using tissue microarrays were used to validate individual gene candidates. This signature was tested in an independent set of 36 SCC samples and achieved 84% specificity and 41% sensitivity with an overall predictive accuracy of 68%. Kaplan-Meier analysis showed clear stratification of high-risk and low-risk patients [log-rank P = 0.04; hazard ratio (HR), 2.66; 95% confidence interval (95% CI), 1.01-7.05]. Finally, we combined the SCC classifier with our previously identified adenocarcinoma prognostic signature and showed that the combined classifier had a predictive accuracy of 71% in 72 NSCLC samples also showing significant differences in overall survival (log-rank P = 0.0002; HR, 3.54; 95% CI, 1.74-7.19). This prognostic signature could be used to identify patients with early-stage high-risk NSCLC who might benefit from adjuvant therapy following surgery. (Cancer Res 2006; 66(15): 7466-72)
Loss of p63 Leads to Increased Cell Migration and Up-regulation of Genes Involved in Invasion and Metastasis
Authors: Barbieri Christopher E. , Tang Luo Jia , Brown Kimberly A. , Pietenpol Jennifer A. 
Published: August 2006

Abstractp63, a homologue of the tumor suppressor p53, is critical for the development and maintenance of squamous epithelia. p63 is specifically expressed in the basal layers of stratified epithelial tissues and is considered a specific marker for cells of this type. The role of p63 in tumorigenesis remains poorly defined. Numerous studies have highlighted the oncogenic potential of the predominant p63 isoform ΔNp63α; however, data suggest that other p63 proteins can act as tumor suppressors or alter the metastatic potential of tumors. ΔNp63α can act as a transcriptional repressor, but the link between the transcriptional functions of p63 and its biological role is still unclear. In this study, we used a loss-of-function approach to investigate the transcriptional programs controlled by p63. Disruption of p63 in squamous cell lines resulted in down-regulation of transcripts specifically expressed in squamous tissues and a significant alteration of keratinocyte differentiation. Interestingly, we found that disruption of p63 led to up-regulation of markers of nonepithelial tissues (mesenchyme and neural tissue) in both primary and immortalized squamous cells. Many of these up-regulated genes are associated with increased capacity for invasion and metastasis in tumors. Furthermore, loss of p63 expression was accompanied by a shift toward mesenchymal morphology and an increase in motility in primary keratinocytes and squamous cell lines. We conclude that loss of endogenous p63 expression results in up-regulation of genes associated with invasion and metastasis, and predisposes to a loss of epithelial and acquisition of mesenchymal characteristics. These findings have implications for the role of p63 in both development and tumorigenesis. (Cancer Res 2006; 66(15): 7589-97)
The Effects of Defined Benefit Pension Incentives and Working Conditions on Teacher Retirement Decisions
Authors: Furgeson Joshua , Strauss Robert P. , Vogt William B. 
Published: August 2006

The retirement behavior of Pennsylvania public school teachers in 1997–98 and 1998–99, a period when state early retirement incentives were temporarily increased, is modeled using a choice framework that emphasizes both pecuniary and nonpecuniary factors of the retirement decision under a defined benefit retirement plan. We find each to have large and statistically significant effects on the decision to retire.The present value of inflation-adjusted pension benefits of a public defined benefit plan is found to be an important and sizable determinant of retirement. A $1,000 (or .4 percent) increase in the real present value of pension benefits is estimated to increase the probability of retirement for female teachers by .02 to .08 percentage points; this implies an elasticity of retirement for female teachers with respect to the present value of real pensions of between 2.0 to 3.5. These estimated defined benefit pension elasticities for female teachers are higher than for male teachers, whose comparable retirement elasticity was 1.9 to 2.5.A $1,000 increase in current salary is found to reduce themean probability of retirement by .1 percentage points, implying an elasticity of −1.4. Thus, substantial salary increases systematically reduce the probability of older teachers retiring.
"Fidelity to the Word ": Lonerganian Conversion Through Shakespeare's The Winter's Tale and Dante's Purgatorio
Authors: Maillet Gregory 
Published: August 2006

AbstractAmong the many elements in the thought of Bernard Lonergan, a twentieth-century Canadian Jesuit philosopher and theologian, one of the most important is his theory of authentic conversion. Lonergan himself subdivided this topic into intellectual, moral, and religious conversion, but his writings on the arts may also justify a further category, aesthetic conversion. The present essay demonstrates that all four elements of Lonerganian conversion, in diverse ways and in varying degrees, can be explored through the study of two classic works of literature: Shakespeare's The Winter's Tale and Dante's Purgatorio. Not only do the major characters in these texts undergo transformations, or conversions, that can be illuminated through Lonergan's concepts but, moreover, both texts as a whole use complex aesthetic methods to attempt a similar transformation in their readers. As such, from a Lonerganian standpoint, these works of literature both illuminate the meaning of authentic conversion and seek to enact its effects.
An Aryan in Išuwa
Authors: Kosyan Aram 
Published: August 2006

AbstractThe paper deals with an Aryan onomastic evidence in a Hittite cuneiform text concerning Išuwa, hitherto unnoticed. The author assumes the possibility of a mixed Hurrian-Aryan coexistence in this area, like in Mitanni, Kizzuwatna, and Syria-Palestine.
Calibrating Differential Reflectivity on the WSR-88D
Authors: Zrnic Dusan S. , Melnikov Valery M. , Carter John K. 
Published: August 2006

Abstract
A calibration procedure of differential reflectivity on the Weather Surveillance Radar-1988 Doppler (WSR-88D) is described. It has been tested on NOAA's modified WSR-88D research and development polarimetric radar and is directly applicable to radars that simultaneously transmit and receive waves having horizontal and vertical polarization.
Phase 1/2 study of the combination of 5-aza-2′-deoxycytidine with valproic acid in patients with leukemia
Authors: Garcia-Manero Guillermo , Kantarjian Hagop M. , Sanchez-Gonzalez Blanca , Yang Hui , Rosner Gary , Verstovsek Srdan , Rytting Michael , Wierda William G. , Ravandi Farhad , Koller Charles , Xiao Lianchun , Faderl Stefan , Estrov Zeev , Cortes Jorge , O'Brien Susan , Estey Elihu , Bueso-Ramos Carlos , Fiorentino Jackie , Jabbour Elias , Issa Jean-Pierre 
Published: August 2006

AbstractWe conducted a phase 1/2 study of the combination of 5-aza-2′-deoxycytidine (decitabine) and the histone deacetylase inhibitor valproic acid (VPA) in patients with advanced leukemia, including older untreated patients. A group of 54 patients were treated with a fixed dose of decitabine (15 mg/m2 by IV daily for 10 days) administered concomitantly with escalating doses of VPA orally for 10 days. A 50 mg/kg daily dose of VPA was found to be safe. Twelve (22%) patients had objective response, including 10 (19%) complete remissions (CRs), and 2 (3%) CRs with incomplete platelet recovery (CRp). Among 10 elderly patients with acute myelogenous leukemia or myelodysplastic syndrome, 5 (50%) had a response (4CRs, 1CRp's). Induction mortality was observed in 1 (2%) patient. Major cytogenetic response was documented in 6 of 8 responders. Remission duration was 7.2 months (range, 1.3-12.6+ months). Overall survival was 15.3 months (range, 4.6-20.2+ months) in responders. Transient DNA hypomethylation and global histone H3 and H4 acetylation were induced, and were associated with p15 reactivation. Patients with lower pretreatment levels of p15 methylation had a significantly higher response rate. In summary, this combination of epigenetic therapy in leukemia was safe and active, and was associated with transient reversal of aberrant epigenetic marks. This trial was registered at www.clinicaltrials.gov as #NCT00075010.
Respiratory-related evoked potential elicited in tracheostomised lung transplant patients
Authors: Davenport P. W. , Martin A. D. , Chou Y-L. , Alexander-Miller S. 
Published: August 2006

The present study investigated the role of removal of upper airway and lung vagal afferents in the respiratory-related evoked potential (RREP) response to inspiratory occlusions in two patients with a tracheostomy, who had undergone double lung transplantation (DLT).The patients were 1.5 and 3 months post-DLT and surgical placement of the tracheostomy. RREP recordings in response to inspiratory occlusions were obtained under four conditions: mouth breathing ignore trial; mouth breathing attend trial; tracheostomy breathing attend trial; and tracheostomy breathing ignore trial.The RREP peak components, Nf, P1and N1, were present in both mouth and tracheostomy ignore breathing trials. The P300was present in both mouth and tracheostomy attend trials. RREP peak latencies were similar between conditions. The peak amplitudes were greater with mouth breathing due to greater occlusion-related inspiratory pressure.These results demonstrate that the respiratory-related evoked potential can be elicited with inspiratory occlusion in the absence of mouth, upper airway and lung vagal afferent input. This suggests that inspiratory occlusion can elicit cortical activity with activation of inspiratory pump mechanoreceptors.
Evidence for association between the HLA-DQA locus and abdominal aortic aneurysms in the Belgian population: a case control study
Authors: Ogata Toru , Gregoire Lucie , Goddard Katrina AB , Skunca Magdalena , Tromp Gerard , Lancaster Wayne D , Parrado Antonio R , Lu Qing , Shibamura Hidenori , Sakalihasan Natzi , Limet Raymond , MacKean Gerald L , Arthur Claudette , Sueda Taijiro , Kuivaniemi Helena 
Published: August 2006

Abstract

Background
Chronic inflammation and autoimmunity likely contribute to the pathogenesis of abdominal aortic aneurysms (AAAs). The aim of this study was to investigate the role of autoimmunity in the etiology of AAAs using a genetic association study approach with HLA polymorphisms.

Methods
HLA-DQA1, -DQB1, -DRB1 and -DRB3-5 alleles were determined in 387 AAA cases (180 Belgian and 207 Canadian) and 426 controls (269 Belgian and 157 Canadian) by a PCR and single-strand oligonucleotide probe hybridization assay.

Results
We observed a potential association with the HLA-DQA1 locus among Belgian males (empirical p = 0.027, asymptotic p = 0.071). Specifically, there was a significant difference in the HLA-DQA1*0102 allele frequencies between AAA cases (67/322 alleles, 20.8%) and controls (44/356 alleles, 12.4%) in Belgian males (empirical p = 0.019, asymptotic p = 0.003). In haplotype analyses, marginally significant association was found between AAA and haplotype HLA-DQA1-DRB1 (p = 0.049 with global score statistics and p = 0.002 with haplotype-specific score statistics).

Conclusion
This study showed potential evidence that the HLA-DQA1 locus harbors a genetic risk factor for AAAs suggesting that autoimmunity plays a role in the pathogenesis of AAAs.