bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cytomegalovirus UL97 Kinase Catalytic Domain Mutations That Confer Multidrug Resistance
Authors: Chou Sunwen , Ercolani Ronald J. , Marousek Gail , Bowlin Terry L. 
Published: May 2013

ABSTRACTHuman cytomegalovirus UL97 kinase mutations that commonly confer ganciclovir resistance cluster in different parts of the gene than those conferring resistance to maribavir, an experimental UL97 kinase inhibitor. The drug resistance, growth, and autophosphorylation phenotypes of several unusual UL97 mutations in the kinase catalytic domain were characterized. Mutations V466G and P521L, described in clinical specimens from ganciclovir-treated subjects, conferred a UL97 kinase knockout phenotype with no autophosphorylation, a severe growth defect, and high-level ganciclovir, cyclopropavir, and maribavir resistance, similar to mutations at the catalytic lysine residue K355. Mutations F342S and V356G, observed after propagation under cyclopropavirin vitro, showed much less growth attenuation and moderate- to high-level resistance to all three drugs while maintaining UL97 autophosphorylation competence and normal cytopathic effect in cell culture, a novel phenotype. F342S is located in the ATP-binding P-loop and is homologous to a c-Abl kinase mutation conferring resistance to imatinib. UL97 mutants with relatively preserved growth fitness and multidrug resistance are of greater concern in antiviral therapy than the severely growth-impaired UL97 knockout mutants. Current diagnostic genotyping assays are unlikely to detect F342S and V356G, and the frequency of their appearance in clinical specimens remains undefined.
Randomized Trial of the Virologic Response during up to Two Years of Entecavir-Adefovir Combination Therapy in Multiple-Drug-Refractory Chronic Hepatitis B Virus Patients
Authors: Lim Young-Suk , Lee Ji-Young , Lee Danbi , Shim Ju Hyun , Lee Han Chu , Lee Yung Sang , Suh Dong Jin 
Published: May 2013

ABSTRACTA 1-year trial with entecavir plus adefovir resulted in a rate of virological response (VR) higher than that seen with lamivudine plus adefovir in multiple-drug-refractory chronic hepatitis B (CHB) patients. This extension study enrolled 89 of 90 patients who completed a 52-week randomized trial comparing treatment with entecavir plus adefovir (EA) to treatment with lamivudine plus adefovir (LA). At the baseline of the original study, all patients had lamivudine-resistant hepatitis B virus (HBV) and serum HBV DNA > 2,000 IU/ml despite prior lamivudine plus adefovir therapy. Of the 89 enrolled patients, 45 initially randomized to receive entecavir plus adefovir and the other 44 randomized to receive lamivudine plus adefovir received entecavir plus adefovir for an additional 52 weeks (EA-EA and LA-EA, respectively). The proportions of patients with a VR (serum HBV DNA < 60 IU/ml) gradually increased in both groups and were comparable at week 104 (42.2% in the EA-EA group and 34.1% in the LA-EA group;P= 0.51). The mean reductions in serum HBV DNA from baseline in the two groups were similar (−2.8 log10IU/ml and −2.8 log10IU/ml, respectively;P= 0.87). At week 104, the number of patients who retained the preexisting HBV mutants resistant to adefovir or entecavir had decreased from 8 to 2 in the EA-EA group and from 15 to 6 in the LA-EA group (P= 0.27). Both study groups had favorable safety profiles. In conclusion, up to 104 weeks of entecavir plus adefovir treatment was associated with a progressive VR, a decrease of levels of preexisting drug-resistant mutants, and no selection for additional resistance mutants of HBV in multiple-drug-refractory CHB patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01023217.)
Discovery of a Sexual Cycle in Aspergillus lentulus, a Close Relative of A. fumigatus
Authors: Swilaiman Sameira S. , O'Gorman Céline M. , Balajee S. Arunmozhi , Dyer Paul S. 
Published: May 2013

ABSTRACTAspergillus lentuluswas described in 2005 as a new species within theA. fumigatussensu lato complex. It is an opportunistic human pathogen causing invasive aspergillosis with high mortality rates, and it has been isolated from clinical and environmental sources. The species is morphologically nearly identical toA. fumigatussensu stricto, and this similarity has resulted in their frequent misidentification. Comparative studies show thatA. lentulushas some distinguishing growth features and decreasedin vitrosusceptibility to several antifungal agents, including amphotericin B and caspofungin. Similar to the once-presumed-asexualA. fumigatus, it has only been known to reproduce mitotically. However, we now show thatA. lentulushas a heterothallic sexual breeding system. A PCR-based mating-type diagnostic detected isolates of either theMAT1-1orMAT1-2genotype, and examination of 26 worldwide clinical and environmental isolates revealed similar ratios of the two mating types (38% versus 62%, respectively).MAT1-1andMAT1-2idiomorph regions were analyzed, revealing the presence of characteristic alpha and high-mobility-group (HMG) domain genes, together with other more unusual features such as aMAT1-2-4gene. We then demonstrated thatA. lentuluspossesses a functional sexual cycle with mature cleistothecia, containing heat-resistant ascospores, being produced after 3 weeks of incubation. Recombination was confirmed using molecular markers. However, isolates ofA. lentulusfailed to cross with highly fertile strains ofA. fumigatus, demonstrating reproductive isolation between these sibling species. The discovery of theA. lentulussexual stage has significant implications for the management of drug resistance and control of invasive aspergillosis associated with this emerging fungal pathogen.
Trypanosoma brucei Tb927.2.6100 Is an Essential Protein Associated with Kinetoplast DNA
Authors: Beck Kirsten , Acestor Nathalie , Schulfer Anjelique , Anupama Atashi , Carnes Jason , Panigrahi Aswini K. , Stuart Ken 
Published: May 2013

ABSTRACT
The mitochondrial DNA of trypanosomatid protozoa consists of a complex, intercatenated network of tens of maxicircles and thousands of minicircles. This structure, called kinetoplast DNA (kDNA), requires numerous proteins and multiprotein complexes for replication, segregation, and transcription. In this study, we used a proteomic approach to identify proteins that are associated with the kDNA network. We identified a novel protein encoded by Tb927.2.6100 that was present in a fraction enriched for kDNA and colocalized the protein with kDNA by fluorescence microscopy. RNA interference (RNAi) knockdown of its expression resulted in a growth defect and changes in the proportion of kinetoplasts and nuclei in the cell population. RNAi also resulted in shrinkage and loss of the kinetoplasts, loss of maxicircle and minicircle components of kDNA at similar rates, and (perhaps secondarily) loss of edited and pre-edited mRNA. These results indicate that the Tb927.2.6100 protein is essential for the maintenance of kDNA.
GDNF–RET Signaling in ER-Positive Breast Cancers Is a Key Determinant of Response and Resistance to Aromatase Inhibitors
Authors: Morandi Andrea , Martin Lesley-Ann , Gao Qiong , Pancholi Sunil , Mackay Alan , Robertson David , Zvelebil Marketa , Dowsett Mitch , Plaza-Menacho Ivan , Isacke Clare M. 
Published: May 2013

Abstract
Most breast cancers at diagnosis are estrogen receptor-positive (ER+) and depend on estrogen for growth and survival. Blocking estrogen biosynthesis by aromatase inhibitors has therefore become a first-line endocrine therapy for postmenopausal women with ER+ breast cancers. Despite providing substantial improvements in patient outcome, aromatase inhibitor resistance remains a major clinical challenge. The receptor tyrosine kinase, RET, and its coreceptor, GFRα1, are upregulated in a subset of ER+ breast cancers, and the RET ligand, glial-derived neurotrophic factor (GDNF) is upregulated by inflammatory cytokines. Here, we report the findings of a multidisciplinary strategy to address the impact of GDNF–RET signaling in the response to aromatase inhibitor treatment. In breast cancer cells in two-dimensional and three-dimensional culture, GDNF-mediated RET signaling is enhanced in a model of aromatase inhibitor resistance. Furthermore, GDNF–RET signaling promoted the survival of aromatase inhibitor-resistant cells and elicited resistance in aromatase inhibitor-sensitive cells. Both these effects were selectively reverted by the RET kinase inhibitor, NVP-BBT594. Gene expression profiling in ER+ cancers defined a proliferation-independent GDNF response signature that prognosed poor patient outcome and, more importantly, predicted poor response to aromatase inhibitor treatment with the development of resistance. We validated these findings by showing increased RET protein expression levels in an independent cohort of aromatase inhibitor-resistant patient specimens. Together, our results establish GDNF–RET signaling as a rational therapeutic target to combat or delay the onset of aromatase inhibitor resistance in breast cancer. Cancer Res; 73(12); 3783–95. ©2013 AACR.
The Effects of Aerobic Exercise on Estrogen Metabolism in Healthy Premenopausal Women
Authors: Smith Alma J. , Phipps William R. , Thomas William , Schmitz Kathryn H. , Kurzer Mindy S. 
Published: May 2013

Abstract
Background: It is well accepted that exercise can decrease breast cancer risk. Limited clinical evidence suggests that this risk could be mediated through changes in estrogen metabolism in premenopausal women. Our objective was to investigate the effects of exercise on premenopausal estrogen metabolism pertinent to breast cancer risk.
Methods: Sedentary, healthy, young eumenorrheic women were randomized into an intervention of 30 minutes of moderate-to-vigorous aerobic exercise five times a week for approximately 16 weeks (n = 212), or into a usual-lifestyle sedentary control group (n = 179). Urinary levels of estrogens [estrone [E1], estradiol, and estriol] and nine estrogen metabolites were measured at baseline and at study end by liquid chromatography/tandem mass spectrometry. The ratios of 2-hydroxyestrone to 16α-hydroxyestrone (2-OHE1/16α-OHE1) and 2-OHE1 to 4-hydroxyestrone (2- OHE1/4-OHE1) were also calculated.
Results: The exercise intervention resulted in significant increases in aerobic fitness and lean body mass and a significant decrease in percent body fat. For exercisers who completed the study (n = 165), 2-OHE1/16α-OHE1 increased significantly (P = 0.043), whereas E1 decreased significantly (P = 0.030) in control participants (n = 153). The change from baseline in 2-OHE1/16α-OHE1 was significantly different between groups (P = 0.045), even after adjustment for baseline values.
Conclusions: The exercise intervention resulted in a significant increase in the 2-OHE1/16α-OHE1 ratio but no differences in other estrogen metabolites or ratios.
Impact: Our results suggest that changes in premenopausal estrogen metabolism may be a mechanism by which increased physical activity lowers breast cancer risk. Cancer Epidemiol Biomarkers Prev; 22(5); 756–64. ©2013 AACR.
Immunomodulatory Monoclonal Antibodies Combined with Peptide Vaccination Provide Potent Immunotherapy in an Aggressive Murine Neuroblastoma Model
Authors: Williams Emily L. , Dunn Stuart N. , James Sonya , Johnson Peter W. , Cragg Mark S. , Glennie Martin J. , Gray Juliet C. 
Published: May 2013

AbstractPurpose: Neuroblastoma is one of the commonest extracranial tumors of childhood. The majority of patients present with metastatic disease for which outcome remains poor. Immunotherapy is an attractive therapeutic approach for this disease, and a number of neuroblastoma tumor antigens have been identified. Here, we examine the therapeutic potential of combining immunomodulatory monoclonal antibodies (mAb) with peptide vaccination in murine neuroblastoma models.Experimental Design: Neuroblastoma-bearing mice were treated with mAb targeting 4-1BB, CD40, and CTLA-4 alone, or in combination with a peptide derived from the tumor antigen survivin (GWEDPPNDI). Survivin-specific immune response and therapeutic efficacy were assessed.Results: In the Neuro2a model, treatment of established tumor with anti-4-1BB, anti-CD40, or anti-CTLA-4 mAb results in tumor regression and long-term survival in 40% to 60% of mice. This is dependent on natural killer (NK) and CD8+ T cells and is associated with tumor CD8+ lymphocyte infiltrate. Successful therapy is achieved only if mAb is given to mice once tumors are established, suggesting dependence on sufficient tumor to provide antigen. In the more aggressive AgN2a and NXS2 models, single-agent mAb therapy provides ineffective therapy. However, if mAb (anti-CTLA-4) is given in conjunction with survivin peptide vaccination, then 60% long-term survival is achieved. This is associated with the generation of survivin-specific T-cell immunity, which again is only shown in the presence of tumor antigen.Conclusions: These data suggest that the combination of antigen and costimulatory mAb may provide effective immunotherapy against neuroblastoma and may be of particular use in the minimal residual disease setting. Clin Cancer Res; 19(13); 3545–55. ©2013 AACR.
Neurological Complications of Infective Endocarditis
Authors: García-Cabrera Emilio , Fernández-Hidalgo Nuria , Almirante Benito , Ivanova-Georgieva Radka , Noureddine Mariam , Plata Antonio , Lomas Jose M. , Gálvez-Acebal Juan , Hidalgo-Tenorio Carmen , Ruíz-Morales Josefa , Martínez-Marcos Francisco J. , Reguera Jose M. , de la Torre-Lima Javier , González Arístides de Alarcón 
Published: May 2013

Background—
The purpose of this study was to assess the incidence of neurological complications in patients with infective endocarditis, the risk factors for their development, their influence on the clinical outcome, and the impact of cardiac surgery.

Methods and Results—

This was a retrospective analysis of prospectively collected data on a multicenter cohort of 1345 consecutive episodes of left-sided infective endocarditis from 8 centers in Spain. Cox regression models were developed to analyze variables predictive of neurological complications and associated mortality. Three hundred forty patients (25%) experienced such complications: 192 patients (14%) had ischemic events, 86 (6%) had encephalopathy/meningitis, 60 (4%) had hemorrhages, and 2 (1%) had brain abscesses. Independent risk factors associated with all neurological complications were vegetation size ≥3 cm (hazard ratio [HR] 1.91),
Staphylococcus aureus
as a cause (HR 2.47), mitral valve involvement (HR 1.29), and anticoagulant therapy (HR 1.31). This last variable was particularly related to a greater incidence of hemorrhagic events (HR 2.71). Overall mortality was 30%, and neurological complications had a negative impact on outcome (45% of deaths versus 24% in patients without these complications;
P
<0.01), although only moderate to severe ischemic stroke (HR 1.63) and brain hemorrhage (HR 1.73) were significantly associated with a poorer prognosis. Antimicrobial treatment reduced (by 33% to 75%) the risk of neurological complications. In patients with hemorrhage, mortality was higher when surgery was performed within 4 weeks of the hemorrhagic event (75% versus 40% in later surgery).

Conclusions—
Moderate to severe ischemic stroke and brain hemorrhage were found to have a significant negative impact on the outcome of infective endocarditis. Early appropriate antimicrobial treatment is critical, and transitory discontinuation of anticoagulant therapy should be considered.
A retrospective of publications addressing suicidal behaviour in the Australian and New Zealand Journal of Psychiatry, 1967–2012
Authors: Goldney Robert D 
Published: May 2013

Objective: To review publications addressing suicidal behaviour in the Australian and New Zealand Journal of Psychiatry, 1967–2012. Method: A PubMed/MEDLINE search using the words suicide, attempted suicide (and their synonyms) and Aust NZ J Psychiatr was carried out, and an examination of all tables of contents of the journal for the years 1967–2012 was performed. Results: In 342 (7.4%) of 4599 articles there was reference to suicidal behaviour. This ratio was consistent over time, although the nature of their content changed from broader epidemiological and clinical review studies to more focused reports. Conclusions: Papers addressing suicidal behaviour have been published consistently in the Australian and New Zealand Journal of Psychiatry since its inception in 1967. Early clinical reviews remain pertinent to the present time.
Evaluation of Epiphyses in the Skeletally Immature Knee Using Magnetic Resonance Imaging
Authors: Davis Derik L. , Chen Lina , Young Stephanie T. 
Published: May 2013

Background: Questions have been raised concerning the height of the tibial epiphysis as an important factor related to the safety of intra-articular anterior cruciate ligament (ACL) reconstruction in skeletally immature knees. However, normal values for this parameter have yet to be established on cross-sectional magnetic resonance imaging (MRI). Purpose: To determine normal values for the height of the tibial epiphysis and width of the lateral femoral condylar epiphysis in children and adolescents by use of MRI. Study Design: Cross-sectional study; Level of evidence, 3. Methods: An electronic search was conducted for pediatric knee MRI examinations at the authors’ institution from August 2007 to July 2011. The height of the tibial epiphysis was determined on the sagittal T1-weighted image best containing the ACL footplate. Lateral femoral condylar width was recorded on coronal proton-density-weighted images. The intraclass correlation coefficient (ICC) was calculated to determine interobserver agreement. Knees were stratified by age into 2 groups based on potential risk of iatrogenic growth plate injury: Group 1 consisted of boys younger than 13 years (range, 7-12 years) and girls younger than 12 years (range, 10-11 years); group 2 consisted of boys between the ages of 13 and 16 years and girls between the ages of 12 and 14 years. Each cohort was further stratified by sex. Results: Group 1 consisted of 17 boys (mean age, 10.4 years) and 5 girls (mean age, 10.8 years), and group 2 contained 23 boys (mean age, 14.4 years) and 14 girls (mean age, 13.7 years). There was a total of 59 knees. No difference was found for average tibial epiphyseal height between group 1 (15.26 ± 1.25 mm) and group 2 (15.01 ± 2.14 mm). However, there was a statistically significant difference related to sex in each cohort: boys versus girls in group 1 (15.63 ± 1.15 mm vs 14.00 ± 0.62 mm, respectively; P = .007) and boys versus girls in group 2 (16.00 ± 1.88 mm vs 13.40 ± 1.47 mm, respectively; P = .0001). The average femoral condylar width for both cohorts was greater than 28 mm where femoral tunnel location would be expected. The ICC was strong (>0.7) at tibial and femoral locations where tunnel placement would be expected. Conclusion: The average height of the tibial epiphysis in both children and adolescents is 15 mm. Girls had shorter tibial epiphyses than boys, but further studies are necessary to determine whether this difference is clinically relevant. Lateral femoral condylar width in children and adolescents can be expected to be greater than 28 mm.
Use of Methylphenidate for the Management of Fatigue in Chinese Patients With Cancer
Authors: Siu Steven W. K. , Law Martin , Liu Rico K. Y. , Wong K. H. , Soong Inda S. , Kwok Annie O. L. , Ng K. H. , Lam P. T. , Leung T. W. 
Published: May 2013

Reason for the Study: Studies on methylphenidate for cancer-related fatigue showed conflicting results. This prospective study aims to determine whether methylphenidate is useful for relieving fatigue in Chinese patients with cancer. Chinese Version of Brief Fatigue Inventory (BFI-C) was administered on days 1, 8, and 29. Methylphenidate dose on day 1 was 5 mg daily then adjusted after day 8 according to response and side effects tolerance. Main Findings: Only 48% of the 25 recruited patients were on methylphenidate by day 29. Overall, no significant improvement in fatigue level was observed after methylphenidate, though benefits were shown in subgroups with age ≤ 65 and higher baseline BFI-C values. Principal Conclusions: Methylphenidate may be useful for management of cancer-related fatigue in selected Chinese patients.
Application of soft sets to diagnose the prostate cancer risk
Authors: Yuksel Saziye , Dizman Tugbahan , Yildizdan Gulnur , Sert Unal 
Published: May 2013

Abstract
In recent years the artificial intelligence has been developed rapidly since it can be applied easily to several areas like medical diagnosis, engineering and economics, among others. In this study we have devised a soft expert system (SES) as a prediction system for prostate cancer by using the prostate specific antigen (PSA), prostate volume (PV) and age factors of patients based on fuzzy sets and soft sets and have calculated the patients’ prostate cancer risk. Our data set has been provided by the Department of Urology, Meram Medical Faculty in Necmettin Erbakan University, Konya, Turkey.
Nuclear translocation and accumulation of glyceraldehyde-3-phosphate dehydrogenase involved in diclazuril-induced apoptosis in Eimeria tenella (E. tenella)
Authors: Wang Congcong , Han Chunzhou , Li Tao , Yang Dehao , Shen Xiaojiong , Fan Yinxin , Xu Yang , Zheng Wenli , Fei Chenzhong , Zhang Lifang , Xue Feiqun 
Published: May 2013

Abstract
In mammalian cells, GAPDH (glyceraldehyde-3-phosphate dehydrogenase) has recently been shown to be implicated in numerous apoptotic paradigms, especially in neuronal apoptosis, and has been demonstrated to play a vital role in some neurodegenerative disorders. However, this phenomenon has not been reported in protists. In the present study, we report for the first time that such a mechanism is involved in diclazuril-induced apoptosis in Eimeria tenella (E. tenella). We found that upon treatment of parasites with diclazuril, the expression levels of GAPDH transcript and protein were significantly increased in second-generation merozoites. Then, we examined the subcellular localization of GAPDH by fluorescence microscopy and Western blot analysis. The results show that a considerable amount of GAPDH protein appeared in the nucleus within diclazuril-treated second-generation merozoites; in contrast, the control group had very low levels of GAPDH in the nucleus. The glycolytic activity of GAPDH was kinetically analyzed in different subcellular fractions. A substantial decrease (48.5%) in glycolytic activity of GAPDH in the nucleus was displayed. Moreover, the activities of caspases-3, -9, and −8 were measured in cell extracts using specific caspase substrates. The data show significant increases in caspase-3 and caspase-9 activities in the diclazuril-treated group.
Development of human hip joint in the second and the third trimester of pregnancy; a cadaveric study
Authors: Masłoń Adrian , Sibiński Marcin , Topol Mirosław , Krajewski Karol , Grzegorzewski Andrzej 
Published: May 2013

Abstract

Background
The purpose of the study was an evaluation of fetal hip joint morphology during the second and the third trimester of pregnancy. Serial sections were performed on 23 cadaver infants.

Results
The mean lunar age was 6.6 months. Femoral shaft length (FSL) and width of the proximal and distal epiphysis were x-rayed to determine fetal age. The neck shaft angle (NSA), the femoral antetorsion angle (FAA), the acetabulum anteversion angle (AAA) and the acetabulum slope angle (ASA) were measured. Hip development ratios were plotted for all cadaveric species and revealed: flat FSL/NSA slope pattern, upward FSL/FAA slope pattern and downward slope pattern for FSL/ASA and FSL/AAA ratios. The changes, observed during the developmental period, were not statistically significant. NSA did not change during the second or the third pregnancy trimester. FAA increased during pregnancy but the changes were not statistically significant. AA, as well as ASA, showed a decreasing trend during the second and the third pregnancy trimester, however, with no correlations to age.

Conclusion
Despite an increasing depth and growing dimensions of the acetabulum in the uterus, its orientation does not change in any significant way.