bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interactions between CdsD, CdsQ, and CdsL, Three PutativeChlamydophila pneumoniaeType III Secretion Proteins
Authors: Johnson Dustin L. , Stone Chris B. , Mahony James B. 
Published: February 2008

ABSTRACTChlamydophila pneumoniaeis a gram-negative obligate intracellular bacterial pathogen that causes pneumonia and bronchitis and may contribute to atherosclerosis. The developmental cycle ofC. pneumoniaeincludes a morphological transition from an infectious extracellular elementary body (EB) to a noninfectious intracellular reticulate body (RB) that divides by binary fission. TheC. pneumoniaegenome encodes a type III secretion (T3S) apparatus that may be used to infect eukaryotic cells and to evade the host immune response. In the present study, Cpn0712 (CdsD), Cpn0704 (CdsQ), and Cpn0826 (CdsL), threeC. pneumoniaegenes encoding yersiniae T3S YscD, YscQ, and YscL homologs, respectively, were cloned and expressed as histidine- and glutathioneS-transferase (GST)-tagged proteins inEscherichia coli. Purified recombinant proteins were used to raise hyper-immune polyclonal antiserum and were used in GST pull-down and copurification assays to identify protein-protein interactions. CdsD was detected in both EB and RB lysates by Western blot analyses, and immunofluorescent staining demonstrated the presence of CdsD within inclusions. Triton X-114 solubilization and phase separation of chlamydial EB proteins indicated that CdsD partitions with cytoplasmic proteins, suggesting it is not an integral membrane protein. GST pull-down assays indicated that recombinant CdsD interacts with CdsQ and CdsL, and copurification assays with chlamydial lysates confirmed that native CdsD interacts with CdsQ and CdsL. To the best of our knowledge, this is the first report demonstrating interactions between YscD, YscQ, and YscL homologs of bacterial T3S systems. These novel protein interactions may play important roles in the assembly or function of the chlamydial T3S apparatus.
A Retroinhibition Approach Reveals a Tumor Cell–Autonomous Response to Rapamycin in Head and Neck Cancer
Authors: Amornphimoltham Panomwat , Patel Vyomesh , Leelahavanichkul Kantima , Abraham Robert T. , Gutkind J. Silvio 
Published: February 2008

Abstract
Emerging evidence supporting the activation of the Akt-mammalian target of rapamycin (mTOR) signaling network in head and neck squamous cell carcinoma (HNSCC) progression has provided the rationale for exploring the therapeutic potential of inhibiting this pathway for HNSCC treatment. Indeed, rapamycin, a clinically relevant mTOR inhibitor, promotes the rapid regression of HNSCC-tumor xenografts in mice. However, rapamycin does not affect the growth of HNSCC cells in vitro, thus raising the possibility that, as for other cancer types, rapamycin may not target cancer cells directly but may instead act on a component of the tumor microenvironment, such as tumor-associated vasculature. Here, we used a retroinhibition approach to assess the contribution of cancer cell–autonomous actions of rapamycin to its antitumor activity in HNSCC. A rapamycin-resistant form of mTOR (mTOR-RR) was expressed in HNSCC cells while retaining the wild-type (rapamycin-sensitive) mTOR (mTOR-WT) alleles in host-derived endothelial and stromal cells. Expression of mTOR-RR prevented the decrease in phospho-S6 levels caused by rapamycin through mTOR in HNSCC cells but not in stromal cells, and rendered HNSCC xenografts completely resistant to the antitumoral activity of rapamycin. This reverse pharmacology strategy also enabled monitoring the direct consequences of inhibiting mTOR in cancer cells within the complex tumor microenvironment, which revealed that mTOR controls the accumulation of hypoxia-inducible factor-1α (HIF-1α) and the consequent expression of vascular endothelial growth factor and a glucose transporter, Glut-1, in HNSCC cells. These findings indicate that HNSCC cells are the primary target of rapamycin in vivo, and provide evidence that its antiangiogenic effects may represent a downstream consequence of mTOR inhibition in HNSCC cells. [Cancer Res 2008;68(4):1144–53]
Nucleolin StabilizesBcl-XLMessenger RNA in Response to UVA Irradiation
Authors: Zhang Jack , Tsaprailis George , Bowden G. Tim 
Published: February 2008

AbstractOur laboratory has previously reported that UVA irradiation can increase the expression of Bcl-XL, an antiapoptotic molecule, by stabilizing its mRNA in cultured immortalized human keratinocytes. To understand the mechanism by which the Bcl-XL message is stabilized, we used a synthetic Bcl-XL 3′-untranslated region (UTR) to capture RNA-binding proteins. Nucleolin was identified as one of the binding proteins as determined by tandem mass spectrometry coupled to liquid chromatography analysis. Further study showed that nucleolin specifically recognized the AU-rich elements (AUUUA) in the 3′-UTR of the Bcl-XL mRNA and could stabilize the mRNA in vitro. Furthermore, overexpression of nucleolin stabilizes the Bcl-XL mRNA in HeLa cells, whereas reducing nucleolin by small interfering RNA shortens the Bcl-XL mRNA half-life. Interestingly, nucleolin physically interacted with polyadenylate [poly(A)]–binding protein through it RGG motifs. Its stabilizing effect on the Bcl-XL mRNA was dependent upon the presence of poly(A) tail. Based on these data, we propose a model in which nucleolin protects the Bcl-XL mRNA from nuclease degradation by enhancing the stability of the ribonucleoprotein loop structure. [Cancer Res 2008;68(4):1046–54]
A Phase I and Pharmacokinetic Trial of Erlotinib in Combination with Weekly Docetaxel in Patients with Taxane-Naive Malignancies
Authors: Chiorean E. Gabriela , Porter Jennifer M. , Foster Anne E. , Al Omari Amal S.H. , Yoder Christy A. , Fife Karen L. , Strother R. Matthew , Murry Daryl J. , Yu Menggang , Jones David R. , Sweeney Christopher J. 
Published: February 2008

Abstract
Purpose: This study aimed to define the maximum tolerated dose of weekly docetaxel combined with daily erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor.
Experimental Design: Patients with any solid tumor received 150 mg erlotinib with escalating doses of docetaxel (20, 25, 30, and 35 mg/m2) on days 1, 8, and 15 every 28 days. The pharmacokinetics of docetaxel and erlotinib was determined on cycle 2, day 1. Erlotinib was given for a maximum of 12 cycles and docetaxel was given for up to 6 cycles.
Results: Twenty-five patients (17 males and 8 females) were enrolled with a median age of 56 years (range, 34-76); Eastern Cooperative Oncology Group performance status of 0/1 was 20/5. One patient had a dose-limiting toxicity in cycle 1 at the 25 mg/m2 level (grade 3 enterocolitis). At 35 mg/m2 docetaxel dose level, 6 of 10 patients required dose reductions to 30 mg/m2 beyond cycle 1 due to neutropenia (3 patients) and mucositis, increased bilirubin, and diarrhea (1 patient each). The clearance of docetaxel and erlotinib of 61.7 and 8.16 L/h, respectively, did not seem to differ from historical controls. Responses were seen in non–small cell lung cancer, prostate cancer, and hepatobiliary cancers, including a complete response lasting 36+ months in a patient with hepatocellular carcinoma.
Conclusion: Although no maximum tolerated dose was reached in cycle 1 with 35 mg/m2 docetaxel, repetitive dosing proved intolerable in a substantial number of patients; thus, the recommended phase II dose of weekly docetaxel is 30 mg/m2 when combined with 150 mg of daily erlotinib.
Nuclear Factor-Y and Epstein Barr Virus in Nasopharyngeal Cancer
Authors: Chia Marie C. , Leung Abby , Krushel Tiffany , Alajez Nehad M. , Lo Kwok W. , Busson Pierre , Klamut Henry J. , Bastianutto Carlo , Liu Fei-Fei 
Published: February 2008

Abstract
Purpose: The Epstein Barr virus (EBV) is intimately associated with nasopharyngeal cancer (NPC) in a latent state expressing a limited number of genes. The process of switching from latency to replication is not well understood, particularly in response to DNA stress; hence, the focus of this study is on an EBV-positive NPC model.
Experimental Design: C666-1 cells were exposed to radiation (2-15 Gy) or cisplatin (0.1-50 μg/mL) assayed subsequently for relative EBV copy number (BamHI) and lytic gene expression (BRLF1 and BZLF1) using quantitative real-time PCR. Chromatin immunoprecipitation was conducted to assess the interaction of the transcription factor nuclear factor-Y (NF-Y) with promoter sequences.
Results: Radiation-induced and cisplatin-induced BamHI expression, along with increased levels of BRLF1 and BZLF1 in a dose-dependent and time-dependent manner, associated with the immediate nuclear transactivation of the transcription factor NF-Y and its own increased transcription of NF-Y subunits 8 h posttreatment. In silico analysis revealed three putative NF-Y consensus-binding sequences in the promoter region of BRLF1, which all interacted with NF-Y in response to radiation and cisplatin, confirmed using chromatin immunoprecipitation. Introduction of dominant-negative NF-YA reduced BRLF1 expression after radiation and cisplatin by 2.8-fold; in turn, overexpression of NF-YA resulted in a 2-fold increase in both BRLF1 and BZLF1 expression.
Conclusions: These results show that NF-Y is an important mediator of EBV stress response in switching from a latent to lytic state. This novel insight could provide a potential therapeutic strategy to enhance NPC response to radiation and cisplatin.
Epidermal Growth Factor Receptor Inhibitors in Neuro-oncology: Hopes and Disappointments
Authors: Brandes Alba A. , Franceschi Enrico , Tosoni Alicia , Hegi Monika E. , Stupp Roger 
Published: February 2008

Abstract
Despite advances in diagnosis and treatment made over the past two decades, high-grade gliomas are still incurable neoplasms. Moreover, after failing adjuvant therapy, few active treatments are available. In this setting, novel agents, such as new chemotherapy compounds and anticancer agents against specific molecular targets, have therefore been investigated. Epidermal growth factor receptor (EGFR) is an intriguing target in high-grade gliomas because it is frequently overexpressed due to amplification of the EGFR gene. Gefitinib and erlotinib act as ATP mimetic agents, binding to the cytoplasmic ATP pocket domain and blocking receptor phosphorylations and, thereby, EGFR-mediated activation of downstream pathways. These drugs have been evaluated in several clinical trials treating recurrent high-grade gliomas with contrasting results. Retrospective correlative analyses generated a plethora of putative predictive factors of activity of EGFR tyrosine kinase inhibitors. The first generations of studies on EGFR inhibitors have not found significant activity of these agents in high-grade gliomas. Furthermore, no clear molecular or clinical predictors have been identified. As with other targeted agents, prospective trials using specific criteria and standardized methods to evaluate tissue biomarkers are required to find predictors of EGFR inhibitors activity in high-grade glioma patients.
Honokiol, a Constituent of Oriental Medicinal Herb Magnolia officinalis, Inhibits Growth of PC-3 Xenografts In vivo in Association with Apoptosis Induction
Authors: Hahm Eun-Ryeong , Arlotti Julie A. , Marynowski Stanley W. , Singh Shivendra V. 
Published: February 2008

Abstract
Purpose: This study was undertaken to determine the efficacy of honokiol, a constituent of oriental medicinal herb Magnolia officinalis, against human prostate cancer cells in culture and in vivo.
Experimental Design: Honokiol-mediated apoptosis was assessed by analysis of cytoplasmic histone-associated DNA fragmentation. Knockdown of Bax and Bak proteins was achieved by transient transfection using siRNA. Honokiol was administered by oral gavage to male nude mice s.c. implanted with PC-3 cells. Tumor sections from control and honokiol-treated mice were examined for apoptotic bodies (terminal deoxyribonucleotidyl transferase–mediated dUTP nick end labeling assay), proliferation index (proliferating cell nuclear antigen staining), and neovascularization (CD31 staining). Levels of Bcl-2 family proteins in cell lysates and tumor supernatants were determined by immunoblotting.
Results: Exposure of human prostate cancer cells (PC-3, LNCaP, and C4-2) to honokiol resulted in apoptotic DNA fragmentation in a concentration- and time-dependent manner irrespective of their androgen responsiveness or p53 status. Honokiol-induced apoptosis correlated with induction of Bax, Bak, and Bad and a decrease in Bcl-xL and Mcl-1 protein levels. Transient transfection of PC-3 cells with Bak- and Bax-targeted siRNAs and Bcl-xL plasmid conferred partial yet significant protection against honokiol-induced apoptosis. Oral gavage of 2 mg honokiol/mouse (thrice a week) significantly retarded growth of PC-3 xenografts without causing weight loss. Tumors from honokiol-treated mice exhibited markedly higher count of apoptotic bodies and reduced proliferation index and neovascularization compared with control tumors.
Conclusion: Our data suggest that honokiol, which is used in traditional oriental medicine for the treatment of various ailments, may be an attractive agent for treatment and/or prevention of human prostate cancers.
Molecular Risk Assessment for Breast Cancer Development in Patients with Ductal Hyperplasias
Authors: Poola Indira , Abraham Jessy , Marshalleck Josephine J. , Yue Qingqi , Lokeshwar Vinatha B. , Bonney George , DeWitty Robert L. 
Published: February 2008

Abstract
Purpose: It has been reported that approximately a million women are diagnosed with benign breast lesions that include ductal hyperplasias per year in the United States. Recent studies that followed women with benign lesions have established that about 8% to 9% of them will subsequently develop invasive breast cancer (IBC). However, currently, there are no means of identifying a subclass of “true precancerous tissues” in women with ductal hyperplasias who will subsequently develop cancer. The purpose of this study is to investigate whether expression of hyaluronoglucosaminidase 1 (HYAL1), a known tumor promoter, in hyperplastic tissues identifies a “true precancerous stage” and predicts subsequent IBC development.
Experimental Design: A retrospective study was conducted with archival benign tissues of various histologic types and clinical information on development/nondevelopment of IBC. The control group was hyperplastic tissues from women who had no prior history of IBC and did not develop cancer in 5 to 7 years after diagnosis (n = 81). The test group was hyperplastic tissues from patients who developed cancer (n = 82). HYAL1 expression was studied by immunohistochemistry, and the results were statistically analyzed for significant association to develop cancer (P value), specificity, sensitivity, positive predictive value, and negative predictive value.
Results: Statistical analysis of HYAL1 expression data showed very highly significant association between its expression and subsequent cancer development (P = 0) and very high sensitivity (0.83), specificity (0.84), positive predictive value (0.84), and negative predictive value (0.83).
Conclusions: The expression of HYAL1 in ductal hyperplastic tissues is a strong predictor of subsequent development of IBC; therefore, it can be applied as a diagnostic marker either singly or in combination with other marker(s) to screen benign tissues to predict subsequent development of IBC. Detection at the precancerous stage and treatment could drastically cut down breast cancer incidence and deaths from it.
Induction of growth arrest and apoptosis in human breast cancer cells by 3,3-diindolylmethane is associated with induction and nuclear localization of p27kip
Authors: Wang Zhiwei , Yu Bennett W. , Rahman KM Wahidur , Ahmad Fakhara , Sarkar Fazlul H. 
Published: February 2008

Abstract3,3′-Diindolylmethane (DIM) is a stable condensation product of indole-3-carbanol, a potential breast cancer chemoprevention agent. Human breast cancer cell lines were studied to better understand its mechanisms. In vitro experiments were done in MCF-7, T47D, BT-20 and BT-474 cells using MTT, ELISA, immunoblotting assays, reverse transcription-PCR, protein half-life, confocal microscopy, cell fractionation, and immunoprecipitation assays. We found that DIM inhibited the growth of all four breast cancer cell lines (IC50s, 25-56 μmol/L). Because BT-20 and BT-474 overexpressed Her-2 and activated Akt, and BT-20 lacks estrogen receptor, these were studied further. In both cell lines, DIM appeared to induce expression of p27kip protein before the loss of cell viability and apoptosis. In BT-20 cells, DIM also inhibited expression of activated Akt, but this appeared after p27kip induction. In both cell lines, DIM induced p27kip transcript expression within 6 h. DIM prolonged the p27kip protein half-life in BT-20 but not BT-474 cells. We also showed, for the first time, that DIM induced nuclear localization of p27kip in both cell lines. Moreover, in BT-20 cells, DIM induced a decrease in p27kip phosphorylation at Thr187, and its association with the 14-3-3 protein, which helped to explain the protein half-life increase and nuclear localization, respectively. DIM modulates p27kip through transcription, prolongation of protein half-life, and nuclear localization. These effects appear to be independent of Her-2, Akt, or estrogen receptor status and should support further study for its chemoprevention potential in breast cancer. [Mol Cancer Ther 2008;7(2):341–9]
Russia Adapts the Model of the Finnish Legal Aid System
Authors: Venäläinen Marina 
Published: February 2008

AbstractIn this article, the author discusses the recent experiences of cooperation between the Ministry of Justice of Finland and the Ministry of Justice of the Russian Federation and the Federal Registry Service regarding the development of a free state legal aid system in Russia. These experiences stem from a pilot project initiated and implemented by the Ministry of Justice in the Russian Federation and associated with the Ministry of Justice of Finland during 2006-2007. The article first addresses the key laws within the Russian legislative system concerning legal aid that had been enacted prior to and during the pilot project, and presents the authorities that are responsible for the provision of legal aid services in Russia. Secondly, it presents some preliminary descriptive results obtained by the year 2006 on the socio-demographic profile of users of the legal aid system that was established for piloting in Russia and on the legal cases addressed during the project. The examples provided in the article are particularly based on the statistics of the State Bureau of Legal Aid of the Republic of Karelia—one of the pilot regions. The article also discusses the experiences of the Finnish experts who were involved in the project and addresses some of the specific problems that were noticed during the pilot work in the Russian legal aid system. The author concludes by identifying a number of subjects that need specific attention and practical implementation, in order to further develop the system of free state-provisioned legal aid in Russia.
The Place of aporia in Plato's Charmides
Authors: Politis Vasilis 
Published: February 2008

AbstractThe aim of the paper is twofold: to examine the argument in response to Socrates' question whether or not reflexive knowledge is, first, possible, and, second, beneficial; and by doing so, to examine the method of Plato's argument. What is distinctive of the method of argument, I want to show, is that Socrates argues on both sides of these questions (the question of possibility and the question of benefit). This, I argue, is why he describes these questions as a source of aporia. Socrates can argue, without contradiction, on both sides of these questions because the arguments against the possibility and benefit of reflexive knowledge are premised on the supposition, defended by Critias, that this knowledge is only of one's knowledge and lack of knowledge, whereas the arguments for its possibility and benefit are not committed to this supposition.
Aristotle on Ontological Dependence
Authors: Corkum Phil 
Published: February 2008

AbstractAristotle holds that individual substances are ontologically independent from non-substances and universal substances but that non-substances and universal substances are ontologically dependent on substances. There is then an asymmetry between individual substances and other kinds of beings with respect to ontological dependence. Under what could plausibly be called the standard interpretation, the ontological independence ascribed to individual substances and denied of non-substances and universal substances is a capacity for independent existence. There is, however, a tension between this interpretation and the asymmetry between individual substances and the other kinds of entities with respect to ontological independence. I will propose an alternative interpretation: to weaken the relevant notion of ontological independence from a capacity for independent existence to the independent possession of a certain ontological status.
The Christian lapsi in Smyrna, 250 A.D. (Martyrium Pionii 12-14)
Authors: Ameling Walter 
Published: February 2008

AbstractPionios died as a martyr in Smyrna during the Decian persecution. The Martyrium Pionii is one of the most interesting examples of the acta martyrum, possibly partly based on texts written by the martyr himself. There are two speeches by Pionios, the second and longer one held in prison. It is usually thought that Pionios addresses two different audiences in this speech, but it can be shown that the whole speech is directed at Christians lapsi, who had sacrificed or were forced to sacrifice in the course of the persecution. Since we know almost nothing about Decian lapsi in Asia Minor, this alone is already of some importance, but we get also some glimpses of the discussions in the Christian community and can re-assess the mention of the Jewish community in Smyrna and it's role during the persecution.
On the Proper Order of Markov Chain Model for Daily Precipitation Occurrence in the Contiguous United States
Authors: Schoof J. T. , Pryor S. C. 
Published: February 2008

Abstract
Markov chains are widely used tools for modeling daily precipitation occurrence. Given the assumption that the Markov chain model is the right model for daily precipitation occurrence, the choice of Markov model order was examined on a monthly basis for 831 stations in the contiguous United States using long-term data. The model order was first identified using the Bayesian information criteria (BIC). The maximum-likelihood estimates of the Markov transition probabilities were computed from 100 bootstrapped samples and were then used to generate 50-yr precipitation occurrence series. The distributions of dry- and wet-spell lengths in the resulting series were then compared with observations using a two-sample Kolmogorov–Smirnov (K-S) test. The results suggest that the most parsimonious model, as identified by the BIC, usually (in approximately 68% of the cases) reproduced the wet- and dry-spell length distributions. However, the K-S test often indicated a second-order model when the BIC indicated a first-order model. In a smaller number of cases, the BIC indicated a higher-order model than the K-S test. In both cases, the differences were found to be due to the distribution of wet spells rather than dry spells. It is concluded that models chosen on the basis of the BIC may not adequately reproduce the distributions of wet and dry spells for some locations and times of year.