bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adjuvant Activity of the Catalytic A1 Domain of Cholera Toxin for Retroviral Antigens Delivered by GeneGun
Authors: Bagley Kenneth C. , Lewis George K. , Fouts Timothy R. 
Published: April 2011

ABSTRACTMost DNA-encoded adjuvants enhance immune responses to DNA vaccines in small animals but are less effective in primates. Here, we characterize the adjuvant activity of the catalytic A1 domain of cholera toxin (CTA1) for human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) antigens in mice and macaques delivered by GeneGun. The inclusion of CTA1 with SIVmac239 Gag dramatically enhanced anti-Gag antibody responses in mice. The adjuvant effects of CTA1 for the secreted antigen HIV gp120 were much less pronounced than those for Gag, as the responses to gp120 were high in the absence of an adjuvant. CTA1 was a stronger adjuvant for Gag than was granulocyte-macrophage colony-stimulating factor (GM-CSF), and it also displayed a wider dose range than GM-CSF in mice. In macaques, CTA1 modestly enhanced the antibody responses to SIV Gag but potently primed for a recombinant Gag protein boost. The results of this study show that CTA1 is a potent adjuvant for SIV Gag when delivered by GeneGun in mice and that CTA1 provides a potent GeneGun-mediated DNA prime for a heterologous protein boost in macaques.
Actinobaculum schaalii Causing Fournier's Gangrene
Authors: Vanden Bempt Isabelle , Van Trappen Stefanie , Cleenwerck Ilse , De Vos Paul , Camps Kim , Celens Annemie , Van De Vyvere Martine 
Published: April 2011

ABSTRACT

Actinobaculum schaalii
, which belongs to the group of Gram-positive rods, is difficult to culture. Using molecular genetics,
Actinobaculum schaalii
could be identified as a causing microorganism in a case of Fournier's gangrene.
Cytochrome
b
Gene Quantitative PCR for Diagnosing Plasmodium falciparum Infection in Travelers
Authors: Farrugia Cécile , Cabaret Odile , Botterel Françoise , Bories Christian , Foulet Françoise , Costa Jean-Marc , Bretagne Stéphane 
Published: April 2011

ABSTRACT

A cytochrome
b
(
cytb
) gene quantitative PCR (qPCR) assay was developed to diagnose malaria in travelers. First, manual and automated DNA extractions were compared and automated DNA extraction of 400 μl of blood was found to be more efficient. Sensitivity was estimated using the WHO international standard for
Plasmodium falciparum
DNA and compared to that of a previously published qPCR targeting the 18S rRNA coding gene (18S qPCR). The limit of detection of the
cytb
qPCR assay was 20 DNA copies (i.e., 1 parasite equivalent) per 400 μl of extracted whole blood and was comparable for the two qPCR assays. Both qPCR assays were used on blood samples from 265 consecutive patients seen for suspicion of malaria. There were no microscopy-positive and qPCR-negative samples. Positive
cytb
qPCR results were observed for 51 samples, and all but 1 were also 18S qPCR positive. Eight (16%) of these 51 samples were negative by microscopic examination. The 8
cytb
qPCR-positive and microscopy-negative samples were from African patients, 3 of whom had received antimalarial drugs. Three non-
P. falciparum
infections were correctly identified using an additional qPCR assay. The absence of PCR inhibitors was tested for by the use of an internal control of mouse DNA to allow reliable quantification of circulating DNA. The high analytical sensitivity of both qPCR assays combined with automated DNA extraction supports its use as a laboratory tool for diagnosis and parasitemia determination in emergencies. Whether to treat qPCR-positive and microscopy-negative patients remains to be determined.
Vitamin B12and folate deficiency and elevated plasma total homocysteine in workers with chronic exposure to chromate
Authors: Wang Tian-Cheng , Jia Guang , Zhang Ji , Ma Yan-Hui , Liu Lan-Zheng , Zhang Ning , Feng Wei-Yue , Zhou Jing-Wen , Song Yan-Shuang , Yan Lei , Du Xian-Mei 
Published: April 2011

ObjectivesChronic occupational exposure to chromium can result in a broad range of adverse effects including multiple organ damage, genotoxicity and carcinogenesis. However, the metabolic consequences of chromium exposure have not been fully investigated. This study was designed to examine vitamin B12, folate and homocysteine metabolic changes in workers chronically exposed to chromate. The potential association between metabolic alteration and renal impairment induced by chromate exposure was also assessed.MethodsThe level of chromium exposure was evaluated by measuring chromium concentrations in red blood cells (RBC-Cr) and urine (U-Cr). Renal impairment was assessed with serum cystatin C (Cys-C) and urinary β2-microglobulin (β2M). Serum vitamin B12, folate and plasma total homocysteine (tHcy) were measured and correlations analysed.ResultsSignificant increases in RBC-Cr, U-Cr, serum Cys-C, plasma tHcy and urinary β2M concentrations were observed in workers chronically exposed to chromate compared to controls. In the exposed workers, serum vitamin B12and folate levels were decreased and significantly inversely correlated with RBC-Cr concentrations, and increased plasma tHcy concentrations were mirrored by decreased serum vitamin B12and folate levels. Elevated plasma tHcy concentrations were positively related to serum Cys-C concentrations.ConclusionsHyperhomocysteinemia in chronically exposed workers was primarily induced by vitamin B12and folate deficiency. This metabolic change might be associated with renal dysfunction in chromate processing workers after long term exposure.
Working patterns and vitamin D status in mid-life: a cross-sectional study of the 1958 British birth cohort
Authors: Ward Maria , Berry Diane J , Power Chris , Hyppönen Elina 
Published: April 2011

ObjectivesTo assess the association between working patterns and vitamin D status in men and women and to determine the potential influence of related lifestyle and socioeconomic factors.MethodsThe authors used data from the 1958 British birth cohort (aged 45 years) and 6154 participants, who were in full-time work, were included in current analyses. Vitamin D status was measured by circulating concentrations of 25-hydroxyvitamin D (25(OH)D). Information on working patterns and lifestyle factors was obtained using a structured questionnaire administered at 45 years.ResultsManual social class was strongly associated with vitamin D-related lifestyle factors, with those in manual classes not only spending more time outdoors, but also spending more time watching TV/using PC, consuming less supplements and oily fish. Associations between working patterns and vitamin D-related lifestyles were less clear: night work was not strongly associated with lifestyles in either gender, while working hours were associated with time spent outside, PC/TV leisure time and use of supplements in men but not in women. In men, working patterns were not associated with lower 25(OH)D concentrations. In women, 25(OH)D concentrations were 8% lower (95% CI 15% to 2%) in night workers compared with others, while women working less than 35 h/week had 5% higher concentrations of 25(OH)D (95% CI 1% to 8%) compared with those working 35–40 h/week after adjustment for season, social class and body mass index (BMI).ConclusionsWomen working nights and longer hours may be vulnerable to deficits in vitamin D status and associated health hazards.
Nonredundant Functions for Akt Isoforms in Astrocyte Growth and Gliomagenesis in an Orthotopic Transplantation Model
Authors: Endersby Raelene , Zhu Xiaoyan , Hay Nissim , Ellison David W. , Baker Suzanne J. 
Published: April 2011

Abstract
The AKT family, comprising three highly homologous kinases, is an essential mediator of the PTEN/PI3K pathway, which is deregulated in many human cancers. A thorough understanding of the specific activities of each isoform in normal and disease tissues is lacking. We evaluated the role of each Akt isoform in gliomagenesis by using a model system driven by common glioma abnormalities, loss of function of p53 and Pten, and expression of EGFRvIII. Both Pten deletion and EGFRvIII expression accelerated the proliferation of p53-null primary murine astrocytes. All three Akt isoforms were expressed and phosphorylated in astrocytes, with significantly higher activation in Pten-null cells. Despite substantial compensation in many contexts when individual Akt isoforms were inhibited, isoform-specific effects were also identified. Specifically, loss of Akt1 or Akt2 decreased proliferation of Pten wild-type astrocytes, whereas combined loss of multiple isoforms was needed to inhibit proliferation of Pten-null astrocytes. In addition, Akt3 was required for anchorage-independent growth of transformed astrocytes and human glioma cells, and Akt3 loss inhibited invasion of transformed astrocytes. EGFRvIII expression transformed p53-null astrocytes with or without Pten deletion, causing rapid development of high-grade astrocytoma on intracranial transplantation. Furthermore, tumorigenesis of Pten;p53-null astrocytes expressing EGFRvIII was delayed by Akt1 loss and accelerated by Akt2 loss. Taken together, these results indicate context-dependent roles for individual Akt isoforms and suggest that there may be heterogeneous tumor response to isoform-specific inhibitors. Cancer Res; 71(12); 4106–16. ©2011 AACR.
Identification of Aldo-Keto Reductase AKR1B10 as a Selective Target for Modification and Inhibition by Prostaglandin A1: Implications for Antitumoral Activity
Authors: Díez-Dacal Beatriz , Gayarre Javier , Gharbi Severine , Timms John F. , Coderch Claire , Gago Federico , Pérez-Sala Dolores 
Published: April 2011

Abstract
Cyclopentenone prostaglandins (cyPG) are reactive eicosanoids that may display anti-inflammatory and antiproliferative actions, possibly offering therapeutic potential. Here we report the identification of members of the aldo-keto reductase (AKR) family as selective targets of the cyPG prostaglandin A1 (PGA1). AKR enzymes metabolize aldehydes and drugs containing carbonyl groups and are involved in inflammation and tumorigenesis. Thus, these enzymes represent a class of targets to develop small molecule inhibitors with therapeutic activity. Molecular modeling studies pointed to the covalent binding of PGA1 to Cys299, close to the active site of AKR, with His111 and Tyr49, which are highly conserved in the AKR family, playing a role in PGA1 orientation. Among AKR enzymes, AKR1B10 is considered as a tumor marker and contributes to tumor development and chemoresistance. We validated the direct modification of AKR1B10 by biotinylated PGA1 (PGA1-B) in cells, and confirmed that mutation of Cys299 abolishes PGA1-B incorporation, whereas substitution of His111 or Tyr49 reduced the interaction. Modification of AKR1B10 by PGA1 correlated with loss of enzymatic activity and both effects were increased by depletion of cellular glutathione. Moreover, in lung cancer cells PGA1 reduced tumorigenic potential and increased accumulation of the AKR substrate doxorubicin, potentiating cell-cycle arrest induced by this chemotherapeutic agent. Our findings define PGA1 as a new AKR inhibitor and they offer a framework to develop compounds that could counteract cancer chemoresistance. Cancer Res; 71(12); 4161–71. ©2011 AACR.
Preclinical Validation of Electrochemotherapy as an Effective Treatment for Brain Tumors
Authors: Agerholm-Larsen Birgit , Iversen Helle K. , Ibsen Per , Moller Jakob M. , Mahmood Faisal , Jensen Kurt Svarre , Gehl Julie 
Published: April 2011

Abstract
Electrochemotherapy represents a strategy to enhance chemotherapeutic drug uptake by delivering electrical pulses which exceed the dielectric strength of the cell membrane, causing transient formation of structures that enhance permeabilization. Here we show that brain tumors in a rat model can be eliminated by electrochemotherapy with a novel electrode device developed for use in the brain. By using this method, the cytotoxicity of bleomycin can be augmented more than 300-fold because of increased permeabilization and more direct passage of drug to the cytosol, enabling highly efficient local tumor treatment. Bleomycin was injected intracranially into male rats inoculated with rat glia-derived tumor cells 2 weeks before the application of the electrical field (32 pulses, 100 V, 0.1 ms, and 1 Hz). In this model, where presence of tumor was confirmed by magnetic resonance imaging (MRI) before treatment, we found that 9 of 13 rats (69%) receiving electrochemotherapy displayed a complete elimination of tumor, in contrast to control rats treated with bleomycin only, pulses only, or untreated where tumor progression occurred in each case. Necrosis induced by electrochemotherapy was restricted to the treated area, which MRI and histology showed to contain a fluid-filled cavity. In a long-range survival study, treatment side effects seemed to be minimal, with normal rat behavior observed after electrochemotherapy. Our findings suggest that electrochemotherapy may offer a safe and effective new tool to treat primary brain tumors and brain metastases. Cancer Res; 71(11); 3753–62. ©2011 AACR.
Quantitative Spatiotemporal Evaluation of Dynamically Downscaled MM5 Precipitation Predictions over the Tampa Bay Region, Florida
Authors: Hwang Syewoon , Graham Wendy , Hernández José L. , Martinez Chris , Jones James W. , Adams Alison 
Published: April 2011

AbstractThis research quantitatively evaluated the ability of the fifth-generation Pennsylvania State University–National Center for Atmospheric Research Mesoscale Model (MM5) to reproduce observed spatiotemporal variability of precipitation in the Tampa Bay region over the 1986–2008 period. Raw MM5 model results were positively biased; therefore, the raw model precipitation outputs were bias corrected at 53 long-term precipitation stations in the region using the cumulative distribution function (CDF) mapping approach. CDF mapping effectively removed the bias in the mean daily, monthly, and annual precipitation totals and improved the RMSE of these rainfall totals. Observed daily precipitation transition probabilities were also well predicted by the bias-corrected MM5 results. Nevertheless, significant error remained in predicting specific daily, monthly, and annual total time series. After bias correction, MM5 successfully reproduced seasonal geostatistical precipitation patterns, with higher spatial variance of daily precipitation in the wet season and lower spatial variance of daily precipitation in the dry season. Bias-corrected daily precipitation fields were kriged over the study area to produce spatiotemporally distributed precipitation fields over the dense grids needed to drive hydrologic models in the Tampa Bay region. Cross validation at the 53 long-term precipitation gauges showed that kriging reproduced observed rainfall with average RMSEs lower than the RMSEs of individually bias-corrected point predictions. Results indicate that although significant error remains in predicting actual daily precipitation at rain gauges, kriging the bias-corrected MM5 predictions over a hydrologic model grid produces distributed precipitation fields with sufficient realism in the daily, seasonal, and interannual patterns to be useful for multidecadal water resource planning in the Tampa Bay region.
Biomechanical Comparisons Between 4-Strand and Modified Larson 2-Strand Procedures for Reconstruction of the Posterolateral Corner of the Knee
Authors: Miyatake Shin , Kondo Eiji , Tsai Tsung-Yuan , Hirschmann Michael , Halewood Camilla , Jakobsen Bent W. , Yasuda Kazunori , Amis Andrew A. 
Published: April 2011

Background: The posterolateral corner (PLC) resists tibial varus angulation, external rotation, and, to a lesser extent, posterior translation. It is important that reconstructions of posterolateral knee injuries restore joint laxity and patient function, but residual laxities are often observed. Hypothesis: The knee laxity after a new 4-strand PLC reconstruction would be closer to normal than after a 2-strand “modified Larson” reconstruction. Study Design: Controlled laboratory study. Methods: Fourteen intact cadaveric knees were mounted in a 6 degrees of freedom rig and subjected to the following external loading conditions: a 90-N posterior tibial force, a 5-N·m external rotation torque, and 5-N·m varus moment. Knee kinematics were recorded with an active optical tracking system for the intact, PLC-deficient, modified Larson PLC reconstruction and 4-strand PLC reconstruction. Results: With external tibial torque, the rotational laxity in 4-strand reconstruction was significantly less than in the PLC-deficient ( P < .0001) and modified Larson reconstruction ( P = .0112) and did not differ significantly from intact laxity at any angle of flexion. In response to posterior load, posterior translation did not change in any of the tested conditions, while the coupled external rotation laxity in 4-strand PLC reconstruction was significantly less than in the PLC-deficient ( P < .0001) and modified Larson reconstruction ( P < .0486) and was not significantly different from the intact movements for both reconstructions. The varus angulation-versus-flexion curves were significantly different between the PLC-deficient and both PLC reconstructions ( P < .0001). The varus laxity was not significantly different between the modified Larson reconstruction, the 4-strand reconstruction, and the intact knee. Conclusion: This study showed that the rotational knee laxity in response to both external rotation and posterior translation load were significantly better after the 4-strand PLC reconstruction than after the modified Larson reconstruction, although significant differences were not found between the 2 procedures for varus laxity. Clinical Relevance: The 4-strand PLC reconstruction may produce a better biomechanical outcome, especially during external rotation and posterior translation tibial load. The authors suggest that this relates to load sharing among 4 graft strands crossing the joint.
A comprehensive assessment of cerebellar damage in multiple sclerosis using diffusion tractography and volumetric analysis
Authors: Anderson VM , Wheeler-Kingshott CAM , Abdel-Aziz K , Miller DH , Toosy A , Thompson AJ , Ciccarelli O 
Published: April 2011

Background: White matter (WM) and grey matter (GM) brain damage in multiple sclerosis (MS) is widespread, but the extent of cerebellar involvement and impact on disability needs to be clarified. Objective: This study aimed to assess cerebellar WM and GM atrophy and the degree of fibre coherence in the main cerebellar connections, and their contribution to disability in relapsing–remitting MS (RRMS) and primary progressive MS (PPMS). Methods: Fourteen patients with RRMS, 12 patients with PPMS and 16 healthy controls were recruited. Cerebellar WM and GM volumes and tractography-derived measures from the middle and superior cerebellar peduncles, including fractional anisotropy (FA), mean diffusivity (MD), and directional diffusivities, were quantified from magnetic resonance imaging (MRI). Patients were assessed on clinical scores, including the MS Functional Composite score subtests. Linear regression models were used to compare imaging measures between 12 RRMS, 11 PPMS and 16 controls, and investigate their association with clinical scores. Results: Patients with PPMS showed reduced FA and increased radial diffusivity in the middle cerebellar peduncle compared with controls and patients with RRMS. In PPMS, lower cerebellar WM volume was associated with worse performance on the upper limb test. In the same patient group, we found significant relationships between superior cerebellar peduncle FA and upper limb function, and between superior cerebellar peduncle FA, MD and radial diffusivity and speed of walking. Conclusion: These findings indicate reduced fibre coherence in the main cerebellar connections, and link damage in the whole cerebellar WM, and, in particular, in the superior cerebellar peduncle, to motor deficit in PPMS.
CDK6 kinase activity is required for thymocyte development
Authors: Hu Miaofen G. , Deshpande Amit , Schlichting Nicolette , Hinds Elisabeth A. , Mao Changchuin , Dose Marei , Hu Guo-fu , Van Etten Richard A. , Gounari Fotini , Hinds Philip W. 
Published: April 2011

Abstract
Cyclin-dependent kinase-6 (CDK6) is required for early thymocyte development and tumorigenesis. To mechanistically dissect the role of CDK6 in thymocyte development, we generated and analyzed mutant knock-in mice and found that mice expressing a kinase-dead Cdk6 allele (Cdk6K43M) had a pronounced reduction in thymocytes and hematopoietic stem cells and progenitor cells (Lin−Sca-1+c-Kit+ [LSK]). In contrast, mice expressing the INK4-insensitive, hyperactive Cdk6R31C allele displayed excess proliferation in LSK and thymocytes. However, this is countered at least in part by increased apoptosis, which may limit progenitor and thymocyte expansion in the absence of other genetic events. Our mechanistic studies demonstrate that CDK6 kinase activity contributes to Notch signaling because inactive CDK6 kinase disrupts Notch-dependent survival, proliferation, and differentiation of LSK, with concomitant alteration of Notch target gene expression, such as massive up-regulation of CD25. Further, knockout of CD25 in Cdk6K43M mice rescued most defects observed in young mice. These results illustrate an important role for CDK6 kinase activity in thymocyte development that operates partially through modulating Notch target gene expression. This role of CDK6 as a downstream mediator of Notch identifies CDK6 kinase activity as a potential therapeutic target in human lymphoid malignancies.
90Y-Ibritumomab tiuxetan, fludarabine, and TBI-based nonmyeloablative allogeneic transplantation conditioning for patients with persistent high-risk B-cell lymphoma
Authors: Gopal Ajay K. , Guthrie Katherine A. , Rajendran Joseph , Pagel John M. , Oliveira George , Maloney David G. , Matesan Manuela C. , Storb Rainer F. , Press Oliver W. 
Published: April 2011

Abstract
Nonmyeloablative allogeneic transplantation (NMAT) infrequently cures active chemoresistant, bulky, or aggressive B-cell lymphoma (B-cell non-Hodgkin lymphoma [B-NHL]). We hypothesized that 90Y-ibritumomab tiuxetan–based NMAT would facilitate early cytoreduction in such patients promoting improved long-term disease control by the allogeneic graft. Forty high-risk B-NHL patients with persistent disease received 0.4 mCi/kg (maximum, 32 mCi/kg) 90Y-ibritumomab tiuxetan, fludarabine, and 2 Gy total body irradiation and matched-related (15) or unrelated (25) transplantation. Baseline features included: median age, 58 years (range, 29-69 years); median prior regimens, 6 (range, 3-12); chemosensitive disease, 6 (15%); bulk > 5 cm, 17 (range, 5.2-18.6 cm, 43%); diffuse large B-cell lymphoma, 14 (35%); and comorbidity score > zero, 34 (85%). Early responses were observed in 24 (60%, 14 complete remission/complete remission unconfirmed, 10 partial response) patients, including 17 of 29 (59%) with chemotherapy-resistant disease and 10 (59%) with bulk > 5 cm. The estimated 30-month survival, progression-free survival, and nonrelapse mortality were 54.1%, 31.1%, and 15.9%, respectively. Early response, baseline platelet counts over 25 000/μL, indolent histology, and related donors were associated with improved survival. The addition of 90Y-ibritumomab tiuxetan to NMAT is safe and yields early responses and prolonged disease control in some of the highest-risk B-NHL patients. This trial was registered at www.clinicaltrials.gov as #NCT00119392.