bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cross-Clade HIV-1 Neutralizing Antibodies Induced with V3-Scaffold Protein Immunogens following Priming with gp120 DNA
Authors: Zolla-Pazner Susan , Kong X.-P. , Jiang Xunqing , Cardozo Timothy , Nádas Arthur , Cohen Sandra , Totrov Maxim , Seaman Michael S. , Wang Shixia , Lu Shan 
Published: July 2011

ABSTRACT

The V3 epitope is a known target for HIV-1 neutralizing antibodies (NAbs), and V3-scaffold fusion proteins used as boosting immunogens after gp120 DNA priming were previously shown to induce NAbs in rabbits. Here, we evaluated whether the breadth and potency of the NAb response could be improved when boosted with rationally designed V3-scaffold immunogens. Rabbits were primed with codon-optimized clade C gp120 DNA and boosted with one of five V3-cholera toxin B fusion proteins (V3-CTBs) or with double combinations of these. The inserts in these immunogens were designed to display V3 epitopes shared by the majority of global HIV-1 isolates. Double combinations of V3-CTB immunogens generally induced more broad and potent NAbs than did boosts with single V3-CTB immunogens, with the most potent and broad NAbs elicited with the V3-CTB carrying the consensus V3 of clade C (V3
C
-CTB), or with double combinations of V3-CTB immunogens that included V3
C
-CTB. Neutralization of tier 1 and 2 pseudoviruses from clades AG, B, and C and of peripheral blood mononuclear cell (PBMC)-grown primary viruses from clades A, AG, and B was achieved, demonstrating that priming with gp120 DNA followed by boosts with V3-scaffold immunogens effectively elicits cross-clade NAbs. Focusing on the V3 region is a first step in designing a vaccine targeting protective epitopes, a strategy with potential advantages over the use of Env, a molecule that evolved to protect the virus by poorly inducing NAbs and by shielding the epitopes that are most critical for infectivity.
Identification of Nuclear and Nucleolar Localization Signals of Pseudorabies Virus (PRV) Early Protein UL54 Reveals that Its Nuclear Targeting Is Required for Efficient Production of PRV
Authors: Li Meili , Wang Shuai , Cai Mingsheng , Zheng Chunfu 
Published: July 2011

ABSTRACT

The pseudorabies virus (PRV) early protein UL54 is a homologue of herpes simplex virus 1 (HSV-1) immediate-early protein ICP27, which is a multifunctional protein that is essential for HSV-1 infection. In this study, the subcellular localization and nuclear import signals of PRV UL54 were characterized. UL54 was shown to predominantly localize to the nucleolus in transfected cells. By constructing a series of mutants, a functional nuclear localization signal (NLS) and a genuine nucleolar localization signal (NoLS) of UL54 were for the first time identified and mapped to amino acids
61
RQRRR
65
and
45
RRRRGGRGGRAAR
57
, respectively. Additionally, three recombinant viruses with mutations of the NLS and/or the NoLS in UL54 were constructed based on PRV bacterial artificial chromosome (BAC) pBecker2 to test the effect of UL54 nuclear targeting on viral replication. In comparison with the wild-type virus, a recombinant virus harboring an NLS or NoLS mutation of UL54 reduced viral production to different extents. However, mutations of both the NLS and NoLS targeted UL54 to the cytoplasm in recombinant virus-infected cells and significantly impaired viral replication, comparable to the UL54-null virus. In addition, a virus lacking the NLS or the NoLS displayed modest defects in viral gene expression and DNA synthesis. However, deletion of both the NLS and the NoLS resulted in severe defects in viral gene expression and DNA synthesis, as well as production of infectious progeny. Thus, we have identified a classical NLS and a genuine NoLS in UL54 and demonstrate that the nuclear targeting of UL54 is required for efficient production of PRV.
Creation of a Recombinant Rift Valley Fever Virus with a Two-Segmented Genome
Authors: Brennan Benjamin , Welch Stephen R. , McLees Angela , Elliott Richard M. 
Published: July 2011

ABSTRACT

Rift Valley fever virus (RVFV; family
Bunyaviridae
) is a clinically important, mosquito-borne pathogen of both livestock and humans, which is found mainly in sub-Saharan Africa and the Arabian Peninsula. RVFV has a trisegmented single-stranded RNA (ssRNA) genome. The L and M segments are negative sense and encode the L protein (viral polymerase) on the L segment and the virion glycoproteins Gn and Gc as well as two other proteins, NSm and 78K, on the M segment. The S segment uses an ambisense coding strategy to express the nucleocapsid protein, N, and the nonstructural protein, NSs. Both the NSs and NSm proteins are dispensable for virus growth in tissue culture. Using reverse genetics, we generated a recombinant virus, designated r2segMP12, containing a two-segmented genome in which the NSs coding sequence was replaced with that for the Gn and Gc precursor. Thus, r2segMP12 lacks an M segment, and although it was attenuated in comparison to the three-segmented parental virus in both mammalian and insect cell cultures, it was genetically stable over multiple passages. We further show that the virus can stably maintain an M-like RNA segment encoding the enhanced green fluorescent protein gene. The implications of these findings for RVFV genome packaging and the potential to develop multivalent live-attenuated vaccines are discussed.
Reassortment Events among Swine Influenza A Viruses in China: Implications for the Origin of the 2009 Influenza Pandemic
Authors: Lam Tommy Tsan-Yuk , Zhu Huachen , Wang Jia , Smith David K. , Holmes Edward C. , Webster Robert G. , Webby Richard , Peiris Joseph M. , Guan Yi 
Published: July 2011

ABSTRACT
That pigs may play a pivotal role in the emergence of pandemic influenza was indicated by the recent H1N1/2009 human pandemic, likely caused by a reassortant between viruses of the American triple-reassortant (TR) and Eurasian avian-like (EA) swine influenza lineages. As China has the largest human and pig populations in the world and is the only place where both TR and EA viruses have been reported to cocirculate, it is potentially the source of the H1N1/2009 pandemic virus. To examine this, the genome sequences of 405 swine influenza viruses from China were analyzed. Thirty-six TR and EA reassortant viruses were identified before and after the occurrence of the pandemic. Several of these TR-EA reassortant viruses had genotypes with most segments having the same lineage origin as the segments of the H1N1/2009 pandemic virus. However, these viruses were generated from independent reassortment events throughout our survey period and were not associated with the current pandemic. One TR-EA reassortant, which is least similar to the pandemic virus, has persisted since 2007, while all the other variants appear to be transient. Despite frequent reassortment events between TR and EA lineage viruses in China, evidence for the genesis of the 2009 pandemic virus in pigs in this region is still absent.
Circulating Monocytes Are Not a Major Reservoir of HIV-1 in Elite Suppressors
Authors: Spivak Adam M. , Salgado Maria , Rabi S. Alireza , O'Connell Karen A. , Blankson Joel N. 
Published: July 2011

ABSTRACT

Circulating HIV-1-infected monocytes have been identified in patients on highly active antiretroviral therapy and may represent an important barrier to viral eradication. The nature of these cells in HIV-1-infected patients who maintain undetectable viral loads and preserved CD4
+
T cell counts without antiretroviral therapy (known as elite controllers or elite suppressors [ES]) is unknown. We describe here infrequent recovery of proviral HIV-1 DNA from circulating monocytes relative to CD4
+
T cells in ES, despite permissiveness of these cells to HIV-1 viral entry
ex vivo
. Thus, monocytes do not appear to be a major reservoir of HIV-1 in ES.
Herpesvirus Entry Mediator and Nectin-1 Mediate Herpes Simplex Virus 1 Infection of the Murine Cornea
Authors: Karaba Andrew H. , Kopp Sarah J. , Longnecker Richard 
Published: July 2011

ABSTRACT
Herpes simplex virus 1 (HSV-1) is a ubiquitous human pathogen that enters cells by the receptor-mediated fusion of the viral envelope with a host cell membrane. The envelope glycoprotein gD of HSV must bind to one of its receptors for entry to take place. Recent studies using knockout (KO) mice demonstrated that the gD receptors herpesvirus entry mediator (HVEM) and nectin-1 are the primary entry receptors for HSV-2 in the mouse vagina and brain. Nectin-1 was most crucial for the neuronal spread of HSV-2, particularly in the brain. HVEM was dispensable for infection in these models, but when both HVEM and nectin-1 were absent, infection was completely prevented. We sought to determine the receptor requirements of HSV-1 in an ocular model of infection using knockout mice. Wild-type, HVEM KO, nectin-1 KO, and HVEM/nectin-1 double-KO mice were infected via corneal scarification and monitored for clinical signs of infection and viral replication in various tissues. We report that either HVEM or nectin-1 must be present for HSV-1 infection of the cornea. Additionally, we observed that the infection was attenuated in both HVEM KO and nectin-1 KO mice. This is in contrast to what was reported for studies of HSV-2 in vagina and brain and suggests that receptor requirements for HSV vary depending on the route of inoculation and/or serotype.
Longitudinal Analysis of the Human T Cell Response during Acute Hantavirus Infection
Authors: Lindgren Therese , Ahlm Clas , Mohamed Nahla , Evander Magnus , Ljunggren Hans-Gustaf , Björkström Niklas K. 
Published: July 2011

ABSTRACTLongitudinal studies of T cell immune responses during viral infections in humans are essential for our understanding of how effector T cell responses develop, clear infection, and provide long-lasting immunity. Here, following an outbreak of a Puumala hantavirus infection in the human population, we longitudinally analyzed the primary CD8 T cell response in infected individuals from the first onset of clinical symptoms until viral clearance. A vigorous CD8 T cell response was observed early following the onset of clinical symptoms, determined by the presence of high numbers of Ki67+CD38+HLA-DR+effector CD8 T cells. This response encompassed up to 50% of total blood CD8 T cells, and it subsequently contracted in parallel with a decrease in viral load. Expression levels of perforin and granzyme B were high throughout the initial T cell response and likewise normalized following viral clearance. When monitoring regulatory components, no induction of regulatory CD4 or CD8 T cells was observed in the patients during the infection. However, CD8 as well as CD4 T cells exhibited a distinct expression profile of inhibitory PD-1 and CTLA-4 molecules. The present results provide insight into the development of the T cell response in humans, from the very onset of clinical symptoms following a viral infection to resolution of the disease.
Speed cameras in an urban setting: a cost–benefit analysis
Authors: Mendivil Joan , García-Altés Anna , Pérez Katherine , Marí-Dell'Olmo Marc , Tobías Aurelio 
Published: July 2011

BackgroundTo perform a cost–benefit analysis of the installation of speed cameras on the beltways of Barcelona.MethodsThe analysis was performed from the society perspective over a 2-year period using a controlled before-and-after study design. The net benefit was calculated using, as benefits, the willingness to pay for the estimated number of people who avoided injury as a consequence of the intervention, subtracting costs and savings. Sensitivity analyses were performed using the maximum and minimum estimated number of people who avoided injury, assuming that there was a minimum of one death avoided, using the maximum value of a statistical life, assigning all implementation costs to the first year and assuming there was no time lost due to speed reduction.ResultsBase case results showed a net benefit of €6.8 million. Sensitivity analyses suggested that net benefits could range from €5.6 to €23.1 million over 2 years.ConclusionsThe use of speed cameras in urban areas has a favourable economic impact even when assessed using conservative assumptions.
Unmet need for effective family planning in HIV-infected individuals: results from a survey in rural Uganda
Authors: Jhangri Gian S , Heys Jennifer , Alibhai Arif , Rubaale Tom , Kipp Walter 
Published: July 2011

Background and methodologyThis study determined the unmet need for family planning among HIV-positive and HIV-negative individuals living in western Uganda. Semi-structured interviews were conducted with individuals who were randomly selected from HIV testing lists. Of those individuals, further analysis was conducted on a subset of 206 participants who did not desire more children and were not using a highly effective method of contraception. Descriptive, bivariate and multivariate methods were performed to assess the relationship between HIV status and unmet need for effective family planning.ResultsThe unmet need for effective family planning was much greater in HIV-infected individuals compared to HIV-negative individuals [75.0% vs 33.8%, adjusted odds ratio (OR) 3.97, 95% confidence interval (CI) 1.97–8.03, p<0.001]. Females were more likely to report an unmet need compared to males (69.0% vs 49.5%; adjusted OR 1.94, 95% CI 0.94–4.00, p=0.071). Other predictors of unmet need for effective family planning were older age (adjusted OR 1.08 for each year of age, 95% CI 1.00–1.16, p=0.018) and single/cohabiting vs being married (OR 2.36, 95% CI 1.16–4.80, p=0.036). Being on antiretroviral therapy was not a predictor of having a lower unmet need for effective family planning methods.Discussion and conclusionsThere is high unmet need for effective family planning in HIV-positive study participants in a region of western Uganda, which should be of concern. This suggests that HIV-infected individuals do not want to use family planning or encounter barriers to accessing and utilising family planning services. Family planning programmes and HIV care and prevention services have to work together more effectively to create services conducive to clients from both programmes.
Acceptability of self-testing for trichomoniasis increases with experience
Authors: Huppert Jill S , Hesse Elizabeth A , Bernard Molly A , Xiao Yang , Huang Bin , Gaydos Charlotte A , Kahn Jessica A 
Published: July 2011

ObjectivesSelf-testing and point-of-care (POC) tests could improve the detection of sexually transmitted infections (STIs) in adolescents. This study aimed to (1) validate a scale measuring acceptability of self-testing for trichomoniasis, (2) compare acceptability of self versus clinician testing using a POC test for trichomoniasis, (3) examine changes in acceptability after experience and review of results, and (4) examine predictors of acceptability.MethodsWomen (14–22 years old) performed the POC test and completed surveys assessing acceptability of self and clinician testing at baseline, after testing, and after discussion of results. Factor analysis examined scale structure; changes in mean scale scores were assessed with mixed models. Generalised linear models examined predictors of acceptability.ResultsOf 247 participants, 54 (22%) had a positive POC test for trichomoniasis. Factor analysis confirmed four acceptability subscales: trust of results, confidence, comfort, and effects of testing. At baseline, trust and confidence were higher, and comfort was lower, for clinician versus self testing. For self-testing, all subscale scores increased from baseline to after testing, and trust increased from after testing to after discussion. Trust of self and clinician results was not significantly different after discussion. A positive attitude towards home testing predicted higher self-test acceptability on all subscales. Tampon use was associated with increased self-test comfort at baseline. Concordance between self and clinician results predicted increased trust of self testing after discussion.ConclusionsMany young women lack confidence in their ability to self-test for trichomoniasis. Allowing women to try a POC test and review the results with a clinician increases acceptability of self-testing.
Feasibility of single‐portal access laparoscopic ovariectomy in 17 cats
Authors: Kim Y‐K. , Lee S‐Y. , Park S‐J. , Lee S‐S. , Lee H‐C. , Lee H‐J. , Yeon S‐C. 
Published: July 2011

Laparoscopic ovariectomy (LapOVE) using single‐portal access was attempted in 17 client‐owned cats of different breeds admitted for elective ovariectomy. A 12 mm umbilical portal was placed 1 cm caudal to the umbilicus with the cat in dorsal recumbency. Then, a laparoscope with an operating channel was introduced into the portal with the cat in lateral recumbency. The right ovary was pulled to the abdominal wall using grasping forceps and fixed to the abdominal wall by a transabdominal suspension suture. The ovarian vasculature, suspensory ligament and proper ligament were progressively cauterised and transected with multifunction bipolar electrocoagulation forceps. The resected right ovary was exteriorised through the umbilical portal cannula. The left ovary was then removed from the abdomen in a similar fashion. Surgical time, intraoperative haemorrhage, amount of fat in the ovarian ligament, surgical complications and postoperative pain were recorded. The mean (sd) surgical time was 23 minutes and seven seconds (five minutes and 55 seconds). Intraoperative blood loss and fat deposition of the ovarian ligament were minimal. No intra‐ and postoperative complications were encountered. No cats needed rescue analgesia within 24 hours postsurgery.
Biological Roles of the Delta Family Notch Ligand Dll4 in Tumor and Endothelial Cells in Ovarian Cancer
Authors: Hu Wei , Lu Chunhua , Dong Han Hee , Huang Jie , Shen De-yu , Stone Rebecca L. , Nick Alpa M. , Shahzad Mian M.K. , Mora Edna , Jennings Nicholas B. , Lee Sun Joo , Roh Ju-Won , Matsuo Koji , Nishimura Masato , Goodman Blake W. , Jaffe Robert B. , Langley Robert R. , Deavers Michael T. , Lopez-Berestein Gabriel , Coleman Robert L. , Sood Anil K. 
Published: July 2011

Abstract
Emerging evidence suggests that the Notch/Delta-like ligand 4 (Dll4) pathway may offer important new targets for antiangiogenesis approaches. In this study, we investigated the clinical and biological significance of Dll4 in ovarian cancer. Dll4 was overexpressed in 72% of tumors examined in which it was an independent predictor of poor survival. Patients with tumors responding to anti-VEGF therapy had lower levels of Dll4 than patients with stable or progressive disease. Under hypoxic conditions, VEGF increased Dll4 expression in the tumor vasculature. Immobilized Dll4 also downregulated VEGFR2 expression in endothelial cells directly through methylation of the VEGFR2 promoter. RNAi-mediated silencing of Dll4 in ovarian tumor cells and tumor-associated endothelial cells inhibited cell growth and angiogenesis, accompanied by induction of hypoxia in the tumor microenvironment. Combining Dll4-targeted siRNA with bevacizumab resulted in greater inhibition of tumor growth, compared with control or treatment with bevacizumab alone. Together, our findings establish that Dll4 plays a functionally important role in both the tumor and endothelial compartments of ovarian cancer and that targeting Dll4 in combination with anti-VEGF treatment might improve outcomes of ovarian cancer treatment. Cancer Res; 71(18); 6030–9. ©2011 AACR.
Phase I Study of PARP Inhibitor ABT-888 in Combination with Topotecan in Adults with Refractory Solid Tumors and Lymphomas
Authors: Kummar Shivaani , Chen Alice , Ji Jiuping , Zhang Yiping , Reid Joel M. , Ames Matthew , Jia Lee , Weil Marcie , Speranza Giovanna , Murgo Anthony J. , Kinders Robert , Wang Lihua , Parchment Ralph E. , Carter John , Stotler Howard , Rubinstein Larry , Hollingshead Melinda , Melillo Giovanni , Pommier Yves , Bonner William , Tomaszewski Joseph E. , Doroshow James H. 
Published: July 2011

Abstract
A phase I trial of ABT-888 (veliparib), a PARP inhibitor, in combination with topotecan, a topoisomerase I–targeted agent, was carried out to determine maximum tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of the combination in patients with refractory solid tumors and lymphomas. Varying schedules and doses of intravenous topotecan in combination with ABT-888 (10 mg) administered orally twice a day (BID) were evaluated. Plasma and urine pharmacokinetics were assessed and levels of poly(ADP-ribose) (PAR) and the DNA damage marker γH2AX were measured in tumor and peripheral blood mononuclear cells (PBMC). Twenty-four patients were enrolled. Significant myelosuppression limited the ability to coadminister ABT-888 with standard doses of topotecan, necessitating dose reductions. Preclinical studies using athymic mice carrying human tumor xenografts also informed schedule changes. The MTD was established as topotecan 0.6 mg/m2/d and ABT-888 10 mg BID on days one to five of 21-day cycles. Topotecan did not alter the pharmacokinetics of ABT-888. A more than 75% reduction in PAR levels was observed in 3 paired tumor biopsy samples; a greater than 50% reduction was observed in PBMCs from 19 of 23 patients with measurable levels. Increases in γH2AX response in circulating tumor cells (CTC) and PBMCs were observed in patients receiving ABT-888 with topotecan. We show a mechanistic interaction of a PARP inhibitor, ABT-888, with a topoisomerase I inhibitor, topotecan, in PBMCs, tumor, and CTCs. Results of this trial reveal that PARP inhibition can modulate the capacity to repair topoisomerase I–mediated DNA damage in the clinic. Cancer Res; 71(17); 5626–34. ©2011 AACR.
Exercise After Diagnosis of Breast Cancer in Association with Survival
Authors: Chen Xiaoli , Lu Wei , Zheng Wei , Gu Kai , Matthews Charles E. , Chen Zhi , Zheng Ying , Shu Xiao Ou 
Published: July 2011

AbstractIt has been suggested that exercise following breast cancer diagnosis is inversely associated with mortality. However, controversy exists regarding the causality of such associations. We evaluated associations of exercise after breast cancer diagnosis with total mortality and recurrence/disease-specific mortality, accounting for conditions that restrict exercise participation. The analysis included 4,826 women with stage I to III breast cancer identified 6 months after diagnosis through the population-based Shanghai Cancer Registry and recruited into the study between 2002 and 2006. Exercise was assessed approximately 6, 18, and 36 months postdiagnosis, and metabolic equivalent (MET) scores were derived. Information on medical history, cancer diagnosis, treatments, quality of life (QOL), anthropometrics, and lifestyles were obtained by in-person interviews at 6 months postdiagnosis. Medical charts were abstracted to verify clinical information. During the median follow-up of 4.3 years, 436 deaths and 450 recurrences/cancer-related deaths were documented. After adjustment for QOL, clinical prognostic factors, and other covariates, exercise during the first 36 months postdiagnosis was inversely associated with total mortality and recurrence/disease-specific mortality with HRs of 0.70 (95% CI: 0.56–0.88) and 0.60 (95% CI: 0.47–0.76), respectively. Significant dose–response relationships between total and recurrence/disease-specific mortality rates and exercise duration and MET scores were observed (all values for Ptrend &lt; 0.05). The exercise–mortality associations were not modified by menopausal status, comorbidity, QOL, or body size assessed at approximately 6 months postdiagnosis. An interaction between disease stage and hormone receptor status and total mortality was noted. Our study suggests that exercise after breast cancer diagnosis may improve overall and disease-free survival. Cancer Prev Res; 4(9); 1409–18. ©2011 AACR.