bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome of Crocodilepox Virus
Authors: Afonso C. L. , Tulman E. R. , Delhon G. , Lu Z. , Viljoen G. J. , Wallace D. B. , Kutish G. F. , Rock D. L. 
Published: April 2006

ABSTRACT

Here, we present the genome sequence, with analysis, of a poxvirus infecting Nile crocodiles (
Crocodylus niloticus
) (crocodilepox virus; CRV). The genome is 190,054 bp (62% G+C) and predicted to contain 173 genes encoding proteins of 53 to 1,941 amino acids. The central genomic region contains genes conserved and generally colinear with those of other chordopoxviruses (ChPVs). CRV is distinct, as the terminal 33-kbp (left) and 13-kbp (right) genomic regions are largely CRV specific, containing 48 unique genes which lack similarity to other poxvirus genes. Notably, CRV also contains 14 unique genes which disrupt ChPV gene colinearity within the central genomic region, including 7 genes encoding GyrB-like ATPase domains similar to those in cellular type IIA DNA topoisomerases, suggestive of novel ATP-dependent functions. The presence of 10 CRV proteins with similarity to components of cellular multisubunit E3 ubiquitin-protein ligase complexes, including 9 proteins containing F-box motifs and F-box-associated regions and a homologue of cellular anaphase-promoting complex subunit 11 (Apc11), suggests that modification of host ubiquitination pathways may be significant for CRV-host cell interaction. CRV encodes a novel complement of proteins potentially involved in DNA replication, including a NAD
+
-dependent DNA ligase and a protein with similarity to both vaccinia virus F16L and prokaryotic serine site-specific resolvase-invertases. CRV lacks genes encoding proteins for nucleotide metabolism. CRV shares notable genomic similarities with molluscum contagiosum virus, including genes found only in these two viruses. Phylogenetic analysis indicates that CRV is quite distinct from other ChPVs, representing a new genus within the subfamily
Chordopoxvirinae
, and it lacks recognizable homologues of most ChPV genes involved in virulence and host range, including those involving interferon response, intracellular signaling, and host immune response modulation. These data reveal the unique nature of CRV and suggest mechanisms of virus-reptile host interaction.
The Unique IR2 Protein of Equine Herpesvirus 1 Negatively Regulates Viral Gene Expression
Authors: Kim Seong K. , Ahn Byung C. , Albrecht Randy A. , O'Callaghan Dennis J. 
Published: April 2006

ABSTRACT

The IR2 protein (IR2P) is a truncated form of the immediate-early protein (IEP) lacking the essential acidic transcriptional activation domain (TAD) and serine-rich tract and yet retaining binding domains for DNA and TFIIB and nuclear localization signal (NLS). Analysis of the
IR2
promoter indicated that the
IR2
promoter was upregulated by the EICP0P. The IR2P was first detected in the nucleus at 5 h postinfection in equine herpesvirus 1 (EHV-1)-infected HeLa and equine NBL6 cells. Transient-transfection assays revealed that (i) the IR2P by itself downregulated EHV-1 early promoters (
EICP0
,
TK
,
EICP22
, and
EICP27
) in a dose-dependent manner; (ii) the IR2P abrogated the IEP and the EICP27P (UL5) mediated transactivation of viral promoters in a dose-dependent manner; and (iii) the IR2P, like the IEP itself, also downregulated the
IE
promoter, indicating that the IEP TAD is not necessary to downregulate the
IE
promoter. In vitro interaction assays revealed that the IR2P interacts with TATA box-binding protein (TBP). The essential domain(s) of the IR2P that mediate negative regulation were mapped to amino acid residues 1 to 706, indicating that the DNA-binding domain and the NLS of the IR2P may be important for the downregulation. In transient-transfection and virus growth assays, the IR2P reduced EHV-1 production by 23-fold compared to virus titers achieved in cells transfected with the empty vector. Overall, these studies suggest that the IR2P downregulates viral gene expression by acting as a dominant-negative protein that blocks IEP-binding to viral promoters and/or squelching the limited supplies of TFIIB and TBP.
X-Ray Crystallographic Structure of the Norwalk Virus Protease at 1.5-Å Resolution
Authors: Zeitler Corinne E. , Estes Mary K. , Venkataram Prasad B. V. 
Published: April 2006

ABSTRACT

Norwalk virus (NV), a member of the
Caliciviridae
family, is the major cause of acute, epidemic, viral gastroenteritis. The NV genome is a positive sense, single-stranded RNA that encodes three open reading frames (ORFs). The first ORF produces a polyprotein that is processed by the viral cysteine protease into six nonstructural proteins. We have determined the structure of the NV protease to 1.5 and 2.2 Å from crystals grown in the absence or presence, respectively, of the protease inhibitor AEBSF [4-(2-aminoethyl)-benzenesulfonyl fluoride]. The protease, which crystallizes as a stable dimer, exhibits a two-domain structure similar to those of other viral cysteine proteases with a catalytic triad composed of His 30, Glu 54, and Cys 139. The native structure of the protease reveals strong hydrogen bond interactions between His 30 and Glu 54, in the favorable
syn
configuration, indicating a role of Glu 54 during proteolysis. Mutation of this residue to Ala abolished the protease activity, in a fluorogenic peptide substrate assay, further substantiating the role of Glu 54 during proteolysis. These observations contrast with the suggestion, from a previous study of another norovirus protease, that this residue may not have a prominent role in proteolysis (K. Nakamura, Y. Someya, T. Kumasaka, G. Ueno, M. Yamamoto, T. Sato, N. Takeda, T. Miyamura, and N. Tanaka, J. Virol. 79:13685-13693, 2005). In the structure from crystals grown in the presence of AEBSF, Glu 54 undergoes a conformational change leading to disruption of the hydrogen bond interactions with His 30. Since AEBSF was not apparent in the electron density map, it is possible that these conformational changes are due to subtle changes in pH caused by its addition during crystallization.
The Epstein-Barr Virus BMRF1 Gene Is Essential for Lytic Virus Replication
Authors: Neuhierl Bernhard , Delecluse Henri-Jacques 
Published: April 2006

ABSTRACT

The Epstein-Barr virus (EBV) BMRF1 protein is a DNA polymerase processivity factor. We have deleted the BMRF1 open reading frame from the EBV genome and assessed the ΔBMRF1 EBV phenotype. ΔBMRF1 viruses were replication deficient, but the wild-type phenotype could be restored by BMRF1
trans
-complementation. The replication-deficient phenotype included impaired lytic DNA replication and late protein expression. ΔBMRF1 and wild-type viruses were undistinguishable in terms of their ability to transform primary B cells. Our results provide genetic evidence that BMRF1 is essential for lytic replication of the EBV genome.
Identification and Characterization of Novel Adeno-Associated Virus Isolates in ATCC Virus Stocks
Authors: Schmidt Michael , Grot Emmanuelle , Cervenka Peter , Wainer Sandra , Buck Charles , Chiorini John A. 
Published: April 2006

ABSTRACT
Adeno-associated viruses (AAVs) depend on a helper virus for efficient replication. To identify novel AAV isolates, we screened a diverse set of virus isolates for the presence of AAV DNA. AAVs found in 10 simian adenovirus isolates showed greater than 96% homology to AAV1 and AAV6 but had distinct biological properties. Two representatives of this group, AAV(VR-195) and AAV(VR-355), were studied in more detail. While the novel AAVs had high sequence homologies and required sialic acid for cell binding and transduction, differences were observed in lectin competition, resulting in distinct tropisms in human cancer cell lines.
Weak Expression of Focal Adhesion Kinase (pp125FAK) in Patients with Cervical Cancer Is Associated with Poor Disease Outcome
Authors: Gabriel Boris , zur Hausen Axel , Stickeler Elmar , Dietz Carola , Gitsch Gerald , Fischer Dagmar-C. , Bouda Jiri , Tempfer Clemens , Hasenburg Annette 
Published: April 2006

Abstract
Purpose: The pp125 focal adhesion kinase (FAK) plays a pivotal role in tumor cell signaling. FAK expression has been linked to tumor cell invasion and metastasis, but data on cervical cancer are inconclusive. Our goal was to investigate FAK expression in cervical cancer and to assess whether its expression correlates with prognosis.
Experimental Design: FAK expression was examined using immunohistochemistry with sections from 162 resected cervical cancer specimens. Kaplan-Meier survival curves were used to determine the significance of FAK expression in the prognosis of cervical cancer patients.
Results: Specific FAK expression was found in the tumor cells, whereas normal cervical epithelium showed barely any FAK expression. Of 162 invasive cervical cancer specimens, 55 (34%) revealed weak expression of FAK, whereas moderate and strong expression was found in 63 (39%) and 44 (27%) tumors, respectively. Patients with tumors expressing weak amounts of FAK were characterized by a significantly poorer overall survival compared with those with moderate and high intratumoral FAK expression (P = 0.002). Weak expression of FAK correlated with pelvic lymph node metastasis (P = 0.026) and recurrent disease (P = 0.013). Multivariate Cox regression analysis revealed decreased FAK expression and pelvic lymph node metastasis to be significant independent factors predictive of poor disease outcome (hazard ratio, 0.36; P = 0.005; hazard ratio, 2.38; P = 0.018, respectively).
Conclusions: Weak expression of FAK in invasive cervical cancer is a strong independent predictor of poor patient outcome. Further studies are warranted to elucidate whether FAK expression analysis is a suitable tool identifying patients at high risk even at an early clinical stage.
Human Melanoma Metastases Express Functional CXCR4
Authors: Scala Stefania , Giuliano Paola , Ascierto Paolo A. , Ieranò Caterina , Franco Renato , Napolitano Maria , Ottaiano Alessandro , Lombardi Maria L. , Luongo Monica , Simeone Ester , Castiglia Daniele , Mauro Francesca , De Michele Ileana , Calemma Rosa , Botti Gerardo , Caracò Corrado , Nicoletti Gianfranco , Satriano Rocco A. , Castello Giuseppe 
Published: April 2006

Abstract
Purpose: The chemokine receptor CXCR4 was identified as an independent predictor of poor prognosis in primary melanoma. The aim of the study was to investigate the role of CXCR4 in human melanoma metastases.
Experimental Design: CXCR4 expression was evaluated in melanoma metastases and in metastatic cell lines through immunohistochemistry, immunoblotting, immunofluorescence, and reverse transcription-PCR. The function of CXCR4 was tested in the presence of the ligand, CXCL12, through induction of extracellular signal-regulated kinase-1 and -2 (Erk-1 and -2) phosphorylation, proliferation, apoptosis, and migration capabilities.
Results: CXCR4 expression was detected in 33 out of 63 (52.4%) metastases from cutaneous melanomas. Metastatic melanoma cell lines expressed cell surface CXCR4; PES 43, Alo 40, and COPA cell lines showed the highest levels of CXCR4 (&gt;90% of positive cells); PES 41, Alo 39, PES 47, POAG, and CIMA cell lines showed low to moderate degrees of expression (5-65% of positive cells). Other chemokine receptors, CCR7 and CCR10, were detected on the melanoma cell lines; CXCL12 activated Erk-1 and Erk-2, the whose induction was specifically inhibited by AMD3100 treatment. CXCL12 increased the growth in PES 41, PES 43, and PES 47 cells under suboptimal (1% serum) and serum-free culture conditions; AMD3100 (1 μmol/L) inhibited the spontaneous and CXCL12-induced proliferation. No rescue from apoptosis was shown but PES 41, PES 43, and PES 47 cells migrate toward CXCL12.
Conclusions: These findings indicate that CXCR4 is expressed and active in human melanoma metastases, suggesting that active inhibitors such as AMD3100 may be experienced in human melanoma.
New Intra-arterial Drug Delivery System for the Treatment of Liver Cancer: Preclinical Assessment in a Rabbit Model of Liver Cancer
Authors: Hong Kelvin , Khwaja Afsheen , Liapi Eleni , Torbenson Michael S. , Georgiades Cristos S. , Geschwind Jean-Francois H. 
Published: April 2006

Abstract
Background: In the fight against cancer, new drug delivery systems are attractive to improve drug targeting of tumors, maximize drug potency, and minimize systemic toxicity. We studied a new drug delivery system comprising microspheres, with unique properties allowing delivery of large amounts of drugs to tumors for a prolonged time, thereby decreasing plasma levels. Liver tumors, unlike nontumorous liver, draw most of their blood supply from the hepatic artery. Exploiting this property, we delivered drug-eluting microspheres/beads (DEB) loaded with doxorubicin, intra-arterially, in an animal model of liver cancer (Vx-2).
Purpose: The purpose of our study was to determine the pharmacokinetics and tumor-killing efficacy of DEB.
Results: Our results show that plasma concentration of doxorubicin was minimal in the animals treated with DEB at all time points (0.009-0.05 μmol/L), suggesting high tumor retention of doxorubicin. This was significantly lower (70-85% decrease in plasma concentration) than control animals treated with doxorubicin intra-arterially. Within the tumor, doxorubicin concentration peaked at 3 days (413.5 nmol/g), remaining high to 7 days (116.7 nmol/g) before declining at 14 days (41.76 nmol/g), indicating continuous doxorubicin elution from beads. In control animals, peak tumor concentration of doxorubicin was 0.09 nmol/g. Tumor necrosis (approaching 100%) was greatest at 7 days, with minimal adverse local side effects reflected in liver function tests results. The plasma concentration of doxorubicinol (doxorubicin main metabolite) was minimal.
Conclusions: Our results support the concept of DEBs as an effective way to deliver drugs to tumor. This new technology may prove to be a useful weapon against liver cancer.
Potential and Toxicity of Intravesical Pemetrexed: a Preclinical Study in Pigs
Authors: Hendricksen Kees , Moonen Paula M.J. , van der Heijden Antoine G. , Molkenboer-Kuenen Janneke , Hulsbergen-van de Kaa Christina A. , Witjes J. Alfred 
Published: April 2006

Abstract
Purpose: In search for a new drug for intravesical use in superficial urothelial cell carcinoma of the bladder, a pig model is used for pharmacokinetics and toxicity measurements after intravesically administered pemetrexed.
Experimental Design: In the dose escalation phase, two groups of two pigs received 5 and 10 mg/kg pemetrexed intravesically; four groups of three pigs received 15, 20, 25, and 30 mg/kg, respectively. The well-being of the animals was monitored. Blood was studied for pharmacokinetic analysis and signs of myelosuppression. Posttreatment urine samples were collected to measure the concentration of pemetrexed after instillation. Twenty-four hours posttreatment, the animals were cystectomized and sacrificed. Histopathologic examination of the bladder wall was done. In the second study phase, five pigs were instilled weekly with the maximum tested dose for 6 weeks. The same methods were applied.
Results: All doses (5-30 mg/kg) in the first study phase were well tolerated, enabling the use of 30 mg/kg in the second study phase. In both study phases, the pigs' well-being was not influenced. Full blood counts showed no sign of myelosuppression. Systemic absorption was not observed. Urine pemetrexed concentrations remained almost unchanged. Histopathologic examination of the bladder wall did not reveal significant abnormalities. Bladder mucosa remained intact at any time, without hemorrhage.
Conclusions: Intravesically administered pemetrexed in pigs is well tolerated, not absorbed systemically, and causes no bladder wall toxicity.
Immunohistochemical and Genetic Evaluation of Deoxycytidine Kinase in Pancreatic Cancer: Relationship to Molecular Mechanisms of Gemcitabine Resistance and Survival
Authors: Sebastiani Valeria , Ricci Francesca , Rubio-Viquiera Belen , Kulesza Piotr , Yeo Charles J. , Hidalgo Manuel , Klein Alison , Laheru Daniel , Iacobuzio-Donahue Christine A. 
Published: April 2006

AbstractGemcitabine is considered the standard first-line therapy for patients with advanced pancreatic cancer. More recent strategies have focused on improving the efficacy of gemcitabine by either improving the method of delivery or by combining gemcitabine with other non-cross-resistant chemotherapy agents or with small-molecule drugs. However, the clinical benefits, response rates, and duration of responses have been modest. Deoxycytidine kinase (dCK) is the rate-limiting enzyme involved in the metabolism of gemcitabine. The expression of dCK has been postulated to be correlative of gemcitabine resistance. We determined the relationship of dCK immunohistochemical protein expression and/or genetic status of dCK in a panel of human pancreatic cancer tissues and pancreatic cancer cell lines and determined the relationship of these variables to the clinical outcome of patients treated with gemcitabine. We report that dCK protein expression is expressed in the majority of pancreatic cancers analyzed (40 of 44 cases, 91%) and showed a range of labeling intensities ranging from 1+ (labeling weaker in intensity than normal lymphocytes present in same section) to 3+ (labeling greater in intensity than normal lymphocytes present in same section). When labeling intensity was compared with survival, low dCK expression (1+ labeling) was correlated with both overall survival (P &lt; 0.009) and progression-free survival following gemcitabine treatment (P &lt; 0.04). Low dCK labeling intensity was also significantly correlated with patient age (70.3 ± 8.1 versus 59.8 ± 7.4 years; P &lt; 0.0006), suggesting that age-related methylation of the dCK gene may account in part for the observed differences. Sequencing of the entire dCK coding sequence in 17 cell lines and 9 patients' cancer tissues with disease progression while on gemcitabine did not identify any mutations, suggesting that genetic alterations of dCK are not a common mechanism of resistance to gemcitabine for this tumor type. Moreover, dCK labeling showed similar patterns and intensities of labeling among matched pretreatment and post-treatment tissues. In summary, pretreatment levels of dCK protein are most correlated with overall survival following gemcitabine treatment and are stable even after resistance to gemcitabine is clinically documented.
Association of DNA Repair and Steroid Metabolism Gene Polymorphisms with Clinical Late Toxicity in Patients Treated with Conformal Radiotherapy for Prostate Cancer
Authors: Damaraju Sambasivarao , Murray David , Dufour Jennifer , Carandang Diana , Myrehaug Sten , Fallone Gino , Field Colin , Greiner Russell , Hanson John , Cass Carol E. , Parliament Matthew 
Published: April 2006

Abstract
Objective: To explore the possible relationship between single nucleotide polymorphisms (SNP) in candidate genes encoding DNA damage recognition/repair/response and steroid metabolism proteins with respect to clinical radiation toxicity in a retrospective cohort of patients previously treated with three-dimensional conformal radiotherapy (3-DCRT) for prostate cancer.
Experimental Design: One hundred twenty-four patients with prostate cancer underwent 3-DCRT at our institution between September 1996 and December 2000. Of these, 83 consented for follow-up of blood sampling and SNP analysis. Twenty-eight patients were documented as having experienced grade ≥2 late bladder or rectal toxicity (scoring system of Radiation Therapy Oncology Group) on at least one follow-up visit. We analyzed 49 SNPs in BRCA1, BRCA2, ESR1, XRCC1, XRCC2, XRCC3, NBN, RAD51, RAD52, LIG4, ATM, BCL2, TGFB1, MSH6, ERCC2, XPF, NR3C1, CYP1A1, CYP2C9, CYP2C19, CYP3A5, CYP2D6, CYP11B2, and CYP17A1 genes using the Pyrosequencing technique.
Results: Significant univariate associations with late rectal or bladder toxicity (grade ≥2) were found for XRCC3 (A&gt;G 5′ untranslated region NT 4541), LIG4 (T&gt;C Asp568Asp), MLH1 (C&gt;T, Val219Ile), CYP2D6*4 (G&gt;A splicing defect), mean rectal and bladder dose, dose to 30% of rectum or bladder, and age &lt;60 years. On Cox multivariate analysis, significant associations with toxicity were found for LIG4 (T&gt;C, Asp568Asp), ERCC2 (G&gt;A, Asp711Asp), CYP2D6*4 (G&gt;A, splicing defect), mean bladder dose &gt;60 Gy, and dose to 30% of rectal volume &gt;75 Gy.
Conclusions: In this study, we identified SNPs in LIG4, ERCC2, and CYP2D6 genes as putative markers to predict individuals at risk for complications arising from radiation therapy in prostate cancer.
Discrepancies between Different Northern Hemisphere Summer Atmospheric Data Products
Authors: Greatbatch Richard J. , Rong Ping-ping 
Published: April 2006

AbstractNorthern Hemisphere summer (July–August) data from the NCEP–NCAR and ECMWF 40-yr Re-Analysis (ERA-40) reanalyses are compared with each other and with Trenberth's sea level pressure (SLP) dataset. Discrepancies in SLP and 500 hPa are mostly confined to a band connecting North Africa and Asia. In the NCEP–NCAR reanalysis, there is a negative offset in SLP over North Africa and Asia prior to the late 1960s, together with a similar problem in 500-hPa height, and in Trenberth's data there is a negative offset in SLP over Asia prior to the early 1990s. Both these offsets magnify the linear trend from 1958 to 2002 over North Africa and Asia in the NCEP–NCAR and Trenberth datasets. On the other hand, the interannual variability in the three datasets is highly correlated during the periods between these offsets. Compared to SLP and 500-hPa height, there is a more extensive area of discrepancy in 2-m temperature that extends eastward from North Africa across the subtropics into the Pacific, with an additional area of discrepancy over the Arctic and parts of the American continent. At 500 and 100 hPa, the biggest differences in the temperature time series are found in the Tropics, with a marked jump being evident in the late 1970s in the NCEP–NCAR, but not in the ERA-40, reanalysis that is almost certainly associated with the introduction of satellite data. On the other hand, all three datasets agree well over Europe. The summer North Atlantic Oscillation (NAO), defined here as the first EOF of summer mean SLP over the Euro-Atlantic sector, agrees well between the different datasets. The results indicate that the upward trend in the summer index in the 1960s is part of a longer-period interdecadal cycle, with relatively high index values also being found during the 1930s. The running cross correlation between the central England temperature record and the summer NAO shows a strong correlation throughout the last half of the twentieth century, but much reduced correlation in the early part of the twentieth century. It is not clear whether the change in correlation is real, or a data artifact, a topic that requires further research.