bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhanced Antibody Responses Elicited by a CpG Adjuvant Do Not Improve the Protective Effect of an Aldrithiol-2-Inactivated Simian Immunodeficiency Virus Therapeutic AIDS Vaccine
Authors: Wang Yichuan , Blozis Shelley A. , Lederman Michael , Krieg Arthur , Landay Alan , Miller Christopher J. 
Published: February 2009

ABSTRACTThe potential benefit of using unmethylated CpG oligoribodeoxynucleotides (ODN) as an adjuvant in a therapeutic simian immunodeficiency virus (SIV) vaccine consisting of AT2-inactivated SIVmac239 was evaluated in SIV-infected rhesus macaques receiving antiretroviral therapy (ART). We hypothesized that using CpG ODN as an adjuvant in therapeutic vaccination would enhance SIV-specific immune responses and suppress SIV replication after ART was stopped. To test our hypothesis, we immunized chronically SIV-infected rhesus macaques receiving ART with one of the following therapeutic vaccines: (i) AT2-inactivated SIVmac239, (ii) CpG10103 plus AT2-inactivated SIVmac239, (iii) CpG10103, and (iv) saline. While immunization with CpG plus AT2-SIVmac239 significantly increased SIV-specific immunoglobulin G (IgG) antibody titers, the mean plasma viral RNA (vRNA) level in these animals after ART did not differ from those of saline-treated animals. The AT2-inactivated SIVmac239-immunized animal group had a significantly higher mean SIV-specific gamma interferon T-cell response after three immunizations and lower plasma vRNA levels for 6 weeks after ART was withdrawn compared to the saline-treated animal group. Compared to the saline control group, the animal group treated with CpG alone had a significantly higher mean SIV-specific lymphocyte proliferation index and a higher rate of plasma vRNA rebound after ART. These results demonstrate that while the use of CpG as an adjuvant enhances SIV-specific antibody responses, this does not improve the control of SIV replication after ART is stopped. The lack of benefit may be related to the high levels of SIV-specific lymphocyte proliferation in the CpG adjuvant group.
A New Flavivirus and a New Vector: Characterization of a Novel Flavivirus Isolated from
Uranotaenia
Mosquitoes from a Tropical Rain Forest
Authors: Junglen Sandra , Kopp Anne , Kurth Andreas , Pauli Georg , Ellerbrok Heinz , Leendertz Fabian H. 
Published: February 2009

ABSTRACT

A novel flavivirus was isolated from
Uranotaenia mashonaensis
, a mosquito genus not previously known to harbor flaviviruses. Mosquitoes were caught in the primary rain forest of the Taï National Park, Côte d'Ivoire. The novel virus, termed nounané virus (NOUV), seemed to grow only on C6/36 insect cells and not on vertebrate cells. Typical enveloped flavivirus-like particles of 60 to 65 nm in diameter were detected by electron microscopy in the cell culture supernatant of infected cells. The full genome was sequenced, and potential cleavage and glycosylation sites and cysteine residues were identified, suggesting that the processing of the NOUV polyprotein is similar to that of other flaviviruses. Phylogenetic analyses of the whole polyprotein and the NS3 protein showed that the virus forms a distinct cluster within the clade of mosquito-borne flaviviruses. Only a distant relationship to other known flaviviruses was found, indicating that NOUV is a novel lineage within the
Flaviviridae
.
Persistent West Nile Virus Associated with a Neurological Sequela in Hamsters Identified by Motor Unit Number Estimation
Authors: Siddharthan Venkatraman , Wang Hong , Motter Neil E. , Hall Jeffery O. , Skinner Robert D. , Skirpstunas Ramona T. , Morrey John D. 
Published: February 2009

ABSTRACT

To investigate the hypothesis that neurological sequelae are associated with persistent West Nile virus (WNV) and neuropathology, we developed an electrophysiological motor unit number estimation (MUNE) assay to measure the health of motor neurons temporally in hamsters. The MUNE assay was successful in identifying chronic neuropathology in the spinal cords of infected hamsters. MUNE was suppressed at days 9 to 92 in hamsters injected subcutaneously with WNV, thereby establishing that a long-term neurological sequela does occur in the hamster model. MUNE suppression at day 10 correlated with the loss of neuronal function as indicated by reduced choline acetyltransferase staining (
R
2
= 0.91). Between days 10 and 26, some α-motor neurons had died, but further neuronal death was not detected beyond day 26. MUNE correlated with disease phenotype, because the lowest MUNE values were detected in paralyzed limbs. Persistent WNV RNA and foci of WNV envelope-positive cells were identified in the central nervous systems of all hamsters tested from 28 to 86 days. WNV-positive staining colocalized with the neuropathology, which suggested that persistent WNV or its products contributed to neuropathogenesis. These results established that persistent WNV product or its proteins cause dysfunction, that WNV is associated with chronic neuropathological lesions, and that this neurological sequela is effectively detected by MUNE. Inasmuch as WNV-infected humans can also experience a poliomyelitis-like disease where motor neurons are damaged, MUNE may also be a sensitive clinical or therapeutic marker for those patients.
Role of Defective Oct-2 and OCA-B Expression in Immunoglobulin Production and Kaposi's Sarcoma-Associated Herpesvirus Lytic Reactivation in Primary Effusion Lymphoma
Authors: Di Bartolo Daniel L. , Hyjek Elizabeth , Keller Shannon , Guasparri Ilaria , Deng Hongyu , Sun Ren , Chadburn Amy , Knowles Daniel M. , Cesarman Ethel 
Published: February 2009

ABSTRACT
Primary effusion lymphoma (PEL) is a distinct type of B-cell non-Hodgkin lymphoma characterized by the presence of Kaposi's sarcoma-associated herpesvirus (KSHV/human herpesvirus 8). Despite having a genotype and gene expression signature of highly differentiated B cells, PEL does not usually express surface or cytoplasmic immunoglobulin (Ig). We show the lack of Oct-2 and OCA-B transcription factors to be responsible, at least in part, for this defect in Ig production. Like Ig genes, ORF50, the key regulator of the switch from latency to lytic reactivation, contains an octamer motif within its promoter. We therefore examined the impact of Oct-2 and OCA-B on ORF50 activation. The binding of Oct-1 to the ORF50 promoter has been shown to significantly enhance ORF50 transactivation. We found that Oct-2, on the other hand, inhibited ORF50 expression and consequently lytic reactivation by competing with Oct-1 for the octamer motif in the ORF50 promoter. Our data suggest that Oct-2 downregulation in infected cells would be favorable to KSHV in allowing for efficient viral reactivation.
Relaxed Selection and the Evolution of RNA Virus Mucin-Like Pathogenicity Factors
Authors: Wertheim Joel O. , Worobey Michael 
Published: February 2009

ABSTRACT
Mucin-like regions contribute to pathogenicity in a variety of negative-stranded RNA viruses. These regions are characterized by a preponderance of O-linked glycosylation. They evolve exceptionally rapidly yet maintain their function as pathogenicity factors. Two hypotheses have been proposed to explain this evolutionary conundrum of phenotypic stability in the face of extreme genetic divergence: strong positive selection and relaxation of purifying selection. We determined the strength and direction of selection codon by codon across genes containing these regions and found that purifying selection is relaxed over the mucin-like regions relative to the genes in which they are found. This suggests that so long as these regions maintain sufficient O-linked glycosylation, they are free to evolve rapidly without loss of function as pathogenicity factors.
Isolation and Genetic Characterization of H5N2 Influenza Viruses from Pigs in Korea
Authors: Lee Jun Han , Pascua Philippe Noriel Q. , Song Min-Suk , Baek Yun Hee , Kim Chul-Joong , Choi Hwan-Woon , Sung Moon-Hee , Webby Richard J. , Webster Robert G. , Poo Haryoung , Choi Young Ki 
Published: February 2009

ABSTRACT
Due to dual susceptibility to both human and avian influenza A viruses, pigs are believed to be effective intermediate hosts for the spread and production of new viruses with pandemic potential. In early 2008, two swine H5N2 viruses were isolated from our routine swine surveillance in Korea. The sequencing and phylogenetic analysis of surface proteins revealed that the Sw/Korea/C12/08 and Sw/Korea/C13/08 viruses were derived from avian influenza viruses of the Eurasian lineage. However, although the Sw/Korea/C12/08 isolate is an entirely avian-like virus, the Sw/Korea/C13/08 isolate is an avian-swine-like reassortant with the PB2, PA, NP, and M genes coming from a 2006 Korean swine H3N1-like virus. The molecular characterization of the two viruses indicated an absence of significant mutations that could be associated with virulence or binding affinity. However, animal experiments showed that the reassortant Sw/Korea/C13/08 virus was more adapted and was more readily transmitted than the purely avian-like virus in a swine experimental model but not in ferrets. Furthermore, seroprevalence in swine sera from 2006 to 2008 suggested that avian H5 viruses have been infecting swine since 2006. Although there are no known potential clinical implications of the avian-swine reassortant virus for pathogenicity in pigs or other species, including humans, at present, the efficient transmissibility of the swine-adapted H5N2 virus could facilitate virus spread and could be a potential model for pandemic, highly pathogenic avian influenza (e.g., H5N1 and H7N7) virus outbreaks or a pandemic strain itself.
Intersubunit Interactions Modulate pH-Induced Activation of Membrane Fusion by the Junín Virus Envelope Glycoprotein GPC
Authors: York Joanne , Nunberg Jack H. 
Published: February 2009

ABSTRACT
The mature arenavirus envelope glycoprotein GPC is a tripartite complex comprising a stable signal peptide (SSP) in addition to the receptor-binding (G1) and transmembrane fusion (G2) subunits. We have shown previously that SSP is a key element in GPC-mediated membrane fusion, and that GPC sensitivity to acidic pH is modulated in part through the lysine residue at position 33 in the ectodomain loop of SSP (J. York and J. H. Nunberg, J. Virol. 80:7775-7780, 2006). A glutamine substitution at this position stabilizes the native GPC complex and thereby prevents the induction of pH-dependent membrane fusion. In efforts to identify the intersubunit interactions of K33, we performed alanine-scanning mutagenesis at charged residues in the membrane-proximal ectodomain of G2 and determined the ability of these mutations to rescue the fusion deficiency in K33Q GPC. Four second-site mutations that specifically complement K33Q were identified (D400A, E410A, R414A, and K417A). Moreover, complementation was also observed at three hydrophobic positions in the membrane-spanning domain of G2 (F427, W428, and F438). Interestingly, all of the complementing mutations restored wild-type pH sensitivity to the K33Q mutant, while none themselves affected the pH of membrane fusion. Our studies demonstrate a specific interaction between SSP and G2 that is involved in priming the native GPC complex for pH-induced membrane fusion. Importantly, this pH-dependent interaction has been shown to be vulnerable to small-molecule compounds that stabilize the native complex and prevent the activation of membrane fusion. A detailed mechanistic understanding of the control of GPC-mediated membrane fusion will be important in guiding the development of effective therapeutics against arenaviral hemorrhagic fever.
Foreign Glycoproteins Can Be Actively Recruited to Virus Assembly Sites during Pseudotyping
Authors: Jorgenson Rebecca L. , Vogt Volker M. , Johnson Marc C. 
Published: February 2009

ABSTRACT
Retroviruses like human immunodeficiency virus type 1 (HIV-1), as well as many other enveloped viruses, can efficiently produce infectious virus in the absence of their own surface glycoprotein if a suitable glycoprotein from a foreign virus is expressed in the same cell. This process of complementation, known as pseudotyping, often can occur even when the glycoprotein is from an unrelated virus. Although pseudotyping is widely used for engineering chimeric viruses, it has remained unknown whether a virus can actively recruit foreign glycoproteins to budding sites or, alternatively, if a virus obtains the glycoproteins through a passive mechanism. We have studied the specificity of glycoprotein recruitment by immunogold labeling viral glycoproteins and imaging their distribution on the host plasma membrane using scanning electron microscopy. Expressed alone, all tested viral glycoproteins were relatively randomly distributed on the plasma membrane. However, in the presence of budding HIV-1 or Rous sarcoma virus (RSV) particles, some glycoproteins, such as those encoded by murine leukemia virus and vesicular stomatitis virus, were dramatically redistributed to viral budding sites. In contrast, the RSV Env glycoprotein was robustly recruited only to the homologous RSV budding sites. These data demonstrate that viral glycoproteins are not in preformed membrane patches prior to viral assembly but rather that glycoproteins are actively recruited to certain viral assembly sites.
Mutational Analysis of Conserved Amino Acids in the Influenza A Virus Nucleoprotein
Authors: Li Zejun , Watanabe Tokiko , Hatta Masato , Watanabe Shinji , Nanbo Asuka , Ozawa Makoto , Kakugawa Satoshi , Shimojima Masayuki , Yamada Shinya , Neumann Gabriele , Kawaoka Yoshihiro 
Published: February 2009

ABSTRACT
The nucleoprotein (NP), which has multiple functions during the virus life cycle, possesses regions that are highly conserved among influenza A, B, and C viruses. To better understand the roles of highly conserved NP amino acids in viral replication, we conducted a comprehensive mutational analysis. Using reverse genetics, we attempted to generate 74 viruses possessing mutations at conserved amino acids of NP. Of these, 48 mutant viruses were successfully rescued; 26 mutants were not viable, suggesting a critical role of the respective NP amino acids in viral replication. To identify the step(s) in the viral life cycle that is impaired by these NP mutations, we examined viral-genome replication/transcription, NP localization, and incorporation of viral-RNA segments into progeny virions. We identified 15 amino acid substitutions in NP that inhibited viral-genome replication and/or transcription, resulting in significant growth defects of viruses possessing these substitutions. We also found several NP mutations that affected the efficient incorporation of multiple viral-RNA (vRNA) segments into progeny virions even though a single vRNA segment was incorporated efficiently. The respective conserved amino acids in NP may thus be critical for the assembly and/or incorporation of sets of eight vRNA segments.
Preoperative quadriceps strength is a significant predictor of knee function two years after anterior cruciate ligament reconstruction
Authors: Eitzen I , Holm I , Risberg M A 
Published: February 2009

Objective:To identify preoperative predictive factors for knee function two years after reconstructive surgery of the anterior cruciate ligament (ACL). The main hypothesis was that preoperative quadriceps strength would be the most significant predictor for knee function two years after reconstructive surgery.Design:Cohort study.Setting:ACL injured individuals treated at a University Hospital and an outpatient clinic in Oslo, Norway.Participants:Seventy-three individuals with complete unilateral rupture of the ACL scheduled for reconstruction with a bone-patellar-bone autograft were included in the study, from where 60 were available for two-year follow up and included in the final analyses.Interventions:Not applicable.Main outcome measurements:Identification of baseline independent variables that may predict knee function assessed with the Cincinnati Knee Score as dependent variable two years after ACL reconstruction.Results:Quadriceps muscle strength, meniscus injury and the Short-Form-36 Bodily Pain sub score were identified as significant predictors for knee function assessed from the Cincinnati Knee Score two years after ACL reconstruction. Individuals with preoperative quadriceps strength deficits above 20% also had persistent significantly larger strength deficits two years after surgery.Conclusions:Preoperative quadriceps muscle strength deficits and meniscus injuries have significant negative consequences for the long-term functional outcome after ACL reconstruction. From our findings we suggest that ACL reconstruction should not be performed before quadriceps muscle strength deficits of the injured limb is less than 20% of the uninjured limb.
Bcl-2 Inhibitors: Targeting Mitochondrial Apoptotic Pathways in Cancer Therapy
Authors: Kang Min H. , Reynolds C. Patrick 
Published: February 2009

AbstractDefects in apoptotic pathways can promote cancer cell survival and also confer resistance to antineoplastic drugs. One pathway being targeted for antineoplastic therapy is the anti-apoptotic B-cell lymphoma-2 (Bcl-2) family of proteins (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, Bfl1/A-1, and Bcl-B) that bind to and inactivate BH3-domain pro-apoptotic proteins. Signals transmitted by cellular damage (including antineoplastic drugs) or cytokine deprivation can initiate apoptosis via the intrinsic apoptotic pathway. It is controversial whether some BH3-domain proteins (Bim or tBid) directly activate multidomain pro-apoptotic proteins (e.g., Bax and Bak) or act via inhibition of those anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, Bfl1/A-1, and Bcl-B) that stabilize pro-apoptotic proteins. Overexpression of anti-apoptotic Bcl-2 family members has been associated with chemotherapy resistance in various human cancers, and preclinical studies have shown that agents targeting anti-apoptotic Bcl-2 family members have preclinical activity as single agents and in combination with other antineoplastic agents. Clinical trials of several investigational drugs targeting the Bcl-2 family (oblimersen sodium, AT-101, ABT-263, GX15-070) are ongoing. Here, we review the role of the Bcl-2 family in apoptotic pathways and those agents that are known and/or designed to inhibit the anti-apoptotic Bcl-2 family of proteins.
Phase I Study of Cediranib in Combination with Oxaliplatin and Infusional 5-Fluorouracil in Patients with Advanced Colorectal Cancer
Authors: Chen Eric , Jonker Derek , Gauthier Isabelle , MacLean Martha , Wells Julie , Powers Jean , Seymour Lesley 
Published: February 2009

Abstract
Purpose: Cediranib is a potent oral inhibitor of the tyrosine kinase activity associated with all subtypes of vascular endothelial growth factor receptor. Purposes of this study were to determine the recommended phase II dose of cediranib in combination with standard doses of modified FOLFOX-6 (mFOLFOX-6), and the tolerability, safety, pharmacokinetics, and antitumor activity of this combination in patients with untreated metastatic colorectal cancer.
Experimental Design: Cediranib was administered daily orally at a starting dose of 30 mg and escalated to 45 mg daily, and mFOLFOX-6 was repeated every 14 days. Pharmacokinetic studies were done for oxaliplatin, 5-fluorouracil, and cediranib. Response was assessed by Response Evaluation Criteria in Solid Tumors every four cycles.
Results: Sixteen patients received 150 cycles of treatment (median, 6; range, 1-20 cycles). Of 9 patients enrolled at the 30-mg dose level, 1 patient experienced grade 3 diarrhea during cycle 1. No dose-limiting toxicity was observed in 7 patients at the 45-mg dose level. Common grade 3 toxicities related to cediranib included hypertension, diarrhea, fatigue, and anorexia. Of 14 patients evaluable for response, there were 6 partial responses (42.9%; 95% confidence interval, 17.7-71.1%) and 6 stable disease. The median progression-free survival was 9.3 months. There were no pharmacokinetic interactions between cediranib and 5-fluorouracil or free plasma intact oxaliplatin.
Conclusions: Toxicities of this combination were manageable and consistent with previous studies. The recommended phase II dose is cediranib at 30 mg daily continuously in combination with standard doses of mFOLFOX-6. Cediranib and mFOLFOX-6 has promising antitumor activity and this combination warrants further investigation.
Mitotic Deregulation by Survivin in ErbB2-Overexpressing Breast Cancer Cells Contributes to Taxol Resistance
Authors: Lu Jing , Tan Ming , Huang Wen-Chien , Li Ping , Guo Hua , Tseng Ling-Ming , Su Xiao-hua , Yang Wen-Tao , Treekitkarnmongkol Warapen , Andreeff Michael , Symmans Fraser , Yu Dihua 
Published: February 2009

Abstract
Purpose: Taxol resistance remains a major obstacle to improve the benefit of breast cancer patients. Here, we studied whether overexpression of ErbB2 may lead to mitotic deregulation in breast cancer cells via up-regulation of survivin that confers Taxol resistance.
Experimental Design: ErbB2-overexpressing and ErbB2-low-expressing breast cancer cell lines were used to compare their mitotic exit rate, survivin expression level, and apoptosis level in response to Taxol. Survivin was then down-regulated by antisense oligonucleotides to evaluate its contribution to mitotic exit and Taxol resistance in ErbB2-overexpressing breast cancer cells. At last, specific PI3K/Akt and Src inhibitors were used to investigate the involvement of these two pathways in ErbB2-mediated survivin up-regulation and Taxol resistance.
Results: We found that ErbB2-overexpressing cells expressed higher levels of survivin in multiple breast cancer cell lines and patient samples. ErbB2-overexpressing cells exited M phase faster than ErbB2-low-expressing cells, which correlated with the increased resistance to Taxol-induced apoptosis. Down-regulation of survivin by antisense oligonucleotide delayed mitotic exit of ErbB2-overexpressing cells and also sensitized ErbB2-overexpressing cells to Taxol-induced apoptosis. Moreover, ErbB2 up-regulated survivin at translational level and PI3K/Akt and Src activation are involved. In addition, combination treatment of Taxol with PI3K/Akt and Src inhibitor led to increased apoptosis in ErbB2-overexpressing breast cancer cells than single treatment.
Conclusions: Survivin up-regulation by ErbB2 is a critical event in ErbB2-mediated faster mitotic exit and contributes to Taxol resistance.