bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diagnostic Accuracy and Reproducibility of WHO-Endorsed Phenotypic Drug Susceptibility Testing Methods for First-Line and Second-Line Antituberculosis Drugs
Authors: Horne David J. , Pinto Lancelot M. , Arentz Matthew , Lin S.-Y. Grace , Desmond Edward , Flores Laura L. , Steingart Karen R. , Minion Jessica 
Published: November 2012

ABSTRACT
In an effort to update and clarify policies on tuberculosis drug susceptibility testing (DST), the World Health Organization (WHO) commissioned a systematic review evaluating WHO-endorsed diagnostic tests. We report the results of this systematic review and meta-analysis of the diagnostic accuracy and reproducibility of phenotypic DST for first-line and second-line antituberculosis drugs. This review provides support for recommended critical concentrations for isoniazid and rifampin in commercial broth-based systems. Further studies are needed to evaluate critical concentrations for ethambutol and streptomycin that accurately detect susceptibility to these drugs. Evidence is limited on the performance of DST for pyrazinamide and second-line drugs.
Straightforward Selection of Broadly Neutralizing Single-Domain Antibodies Targeting the Conserved CD4 and Coreceptor Binding Sites of HIV-1 gp120
Authors: Matz Julie , Kessler Pascal , Bouchet Jérôme , Combes Olivier , Ramos Oscar Henrique Pereira , Barin Francis , Baty Daniel , Martin Loïc , Benichou Serge , Chames Patrick 
Published: November 2012

ABSTRACT
Few broadly neutralizing antibodies targeting determinants of the HIV-1 surface envelope glycoprotein (gp120) involved in sequential binding to host CD4 and chemokine receptors have been characterized. While these epitopes show low diversity among various isolates, HIV-1 employs many strategies to evade humoral immune response toward these sensitive sites, including a carbohydrate shield, low accessibility to these buried cavities, and conformational masking. Using trimeric gp140, free or bound to a CD4 mimic, as immunogens in llamas, we selected a panel of broadly neutralizing single-domain antibodies (sdAbs) that bind to either the CD4 or the coreceptor binding site (CD4BS and CoRBS, respectively). When analyzed as monomers or as homo- or heteromultimers, the best sdAb candidates could not only neutralize viruses carrying subtype B envelopes, corresponding to the Env molecule used for immunization and selection, but were also efficient in neutralizing a broad panel of envelopes from subtypes A, C, G, CRF01_AE, and CRF02_AG, including tier 3 viruses. Interestingly, sdAb multimers exhibited a broader neutralizing activity spectrum than the parental sdAb monomers. The extreme stability and high recombinant production yield combined with their broad neutralization capacity make these sdAbs new potential microbicide candidates for HIV-1 transmission prevention.
Systematic Identification of H274Y Compensatory Mutations in Influenza A Virus Neuraminidase by High-Throughput Screening
Authors: Wu Nicholas C. , Young Arthur P. , Dandekar Sugandha , Wijersuriya Hemani , Al-Mawsawi Laith Q. , Wu Ting-Ting , Sun Ren 
Published: November 2012

ABSTRACT
Compensatory mutations contribute to the appearance of the oseltamivir resistance substitution H274Y in the neuraminidase (NA) gene of H1N1 influenza viruses. Here, we describe a high-throughput screening method utilizing error-prone PCR and next-generation sequencing to comprehensively screen NA genes for H274Y compensatory mutations. We found four mutations that can either fully (R194G, E214D) or partially (L250P, F239Y) compensate for the fitness deficiency of the H274Y mutant. The compensatory effect of E214D is applicable in both seasonal influenza virus strain A/New Caledonia/20/1999 and 2009 pandemic swine influenza virus strain A/California/04/2009. The technique described here has the potential to profile a gene at the single-nucleotide level to comprehend the dynamics of mutation space and fitness and thus offers prediction power for emerging mutant species.
Alternative Serotype Adenovirus Vaccine Vectors Elicit Memory T Cells with Enhanced Anamnestic Capacity Compared to Ad5 Vectors
Authors: Penaloza-MacMaster Pablo , Provine Nicholas M. , Ra Joshua , Borducchi Erica N. , McNally Anna , Simmons Nathaniel L. , Iampietro Mark J. , Barouch Dan H. 
Published: November 2012

ABSTRACT
The failure of the adenovirus serotype 5 (Ad5) vector-based human immunodeficiency virus type 1 (HIV-1) vaccine in the STEP study has led to the development of adenovirus vectors derived from alternative serotypes, such as Ad26, Ad35, and Ad48. We have recently demonstrated that vaccines using alternative-serotype Ad vectors confer partial protection against stringent simian immunodeficiency virus (SIV) challenges in rhesus monkeys. However, phenotypic differences between the T cell responses elicited by Ad5 and those of alternative-serotype Ad vectors remain unexplored. Here, we report the magnitude, phenotype, functionality, and recall capacity of memory T cell responses elicited in mice by Ad5, Ad26, Ad35, and Ad48 vectors expressing lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP). Our data demonstrate that memory T cells elicited by Ad5 vectors were high in magnitude but exhibited functional exhaustion and decreased anamnestic potential following secondary antigen challenge compared to Ad26, Ad35, and Ad48 vectors. These data suggest that vaccination with alternative-serotype Ad vectors offers substantial immunological advantages over Ad5 vectors, in addition to circumventing high baseline Ad5-specific neutralizing antibody titers.
Cyclophilin Inhibitors Block Arterivirus Replication by Interfering with Viral RNA Synthesis
Authors: de Wilde Adriaan H. , Li Yanhua , van der Meer Yvonne , Vuagniaux Grégoire , Lysek Robert , Fang Ying , Snijder Eric J. , van Hemert Martijn J. 
Published: November 2012

ABSTRACT

Virus replication strongly depends on cellular factors, in particular, on host proteins. Here we report that the replication of the arteriviruses equine arteritis virus (EAV) and porcine reproductive and respiratory syndrome virus (PRRSV) is strongly affected by low-micromolar concentrations of cyclosporine A (CsA), an inhibitor of members of the cyclophilin (Cyp) family. In infected cells, the expression of a green fluorescent protein (GFP) reporter gene inserted into the PRRSV genome was inhibited with a half-maximal inhibitory concentration (IC
50
) of 5.2 μM, whereas the GFP expression of an EAV-GFP reporter virus was inhibited with an IC
50
of 0.95 μM. Debio-064, a CsA analog that lacks its undesirable immunosuppressive properties, inhibited EAV replication with an IC
50
that was 3-fold lower than that of CsA, whereas PRRSV-GFP replication was inhibited with an IC
50
similar to that of CsA. The addition of 4 μM CsA after infection prevented viral RNA and protein synthesis in EAV-infected cells, and CsA treatment resulted in a 2.5- to 4-log-unit reduction of PRRSV or EAV infectious progeny. A complete block of EAV RNA synthesis was also observed in an
in vitro
assay using isolated viral replication structures. The small interfering RNA-mediated knockdown of Cyp family members revealed that EAV replication strongly depends on the expression of CypA but not CypB. Furthermore, upon fractionation of intracellular membranes in density gradients, CypA was found to cosediment with membranous EAV replication structures, which could be prevented by CsA treatment. This suggests that CypA is an essential component of the viral RNA-synthesizing machinery.
Significant Reductions in Gag-Protease-Mediated HIV-1 Replication Capacity during the Course of the Epidemic in Japan
Authors: Nomura Shigeru , Hosoya Noriaki , Brumme Zabrina L. , Brockman Mark A. , Kikuchi Tadashi , Koga Michiko , Nakamura Hitomi , Koibuchi Tomohiko , Fujii Takeshi , Carlson Jonathan M. , Heckerman David , Kawana-Tachikawa Ai , Iwamoto Aikichi , Miura Toshiyuki 
Published: November 2012

ABSTRACT

Human immunodeficiency virus type 1 (HIV-1) evolves rapidly in response to host immune selection pressures. As a result, the functional properties of HIV-1 isolates from earlier in the epidemic may differ from those of isolates from later stages. However, few studies have investigated alterations in viral replication capacity (RC) over the epidemic. In the present study, we compare Gag-Protease-associated RC between early and late isolates in Japan (1994 to 2009). HIV-1 subtype B sequences from 156 antiretroviral-naïve Japanese with chronic asymptomatic infection were used to construct a chimeric NL4-3 strain encoding plasma-derived
gag-protease
. Viral replication capacity was examined by infecting a long terminal repeat-driven green fluorescent protein-reporter T cell line. We observed a reduction in the RC of chimeric NL4-3 over the epidemic, which remained significant after adjusting for the CD4
+
T cell count and plasma virus load. The same outcome was seen when limiting the analysis to a single large cluster of related sequences, indicating that our results are not due to shifts in the molecular epidemiology of the epidemic in Japan. Moreover, the change in RC was independent of genetic distance between patient-derived sequences and wild-type NL4-3, thus ruling out potential temporal bias due to genetic similarity between patient and historic viral backbone sequences. Collectively, these data indicate that Gag-Protease-associated HIV-1 replication capacity has decreased over the epidemic in Japan. Larger studies from multiple geographical regions will be required to confirm this phenomenon.
p38 and OGT Sequestration into Viral Inclusion Bodies in Cells Infected with Human Respiratory Syncytial Virus Suppresses MK2 Activities and Stress Granule Assembly
Authors: Fricke Jens , Koo Lily Y. , Brown Charles R. , Collins Peter L. 
Published: November 2012

ABSTRACT

Respiratory syncytial virus (RSV) forms cytoplasmic inclusion bodies (IBs) that are thought to be sites of nucleocapsid accumulation and viral RNA synthesis. The present study found that IBs also were the sites of major sequestration of two proteins involved in cellular signaling pathways. These are phosphorylated p38 mitogen-activated protein kinase (MAPK) (p38-P), a key regulator of cellular inflammatory and stress responses, and O-linked
N
-acetylglucosamine (OGN) transferase (OGT), an enzyme that catalyzes the posttranslational addition of OGN to protein targets to regulate cellular processes, including signal transduction, transcription, translation, and the stress response. The virus-induced sequestration of p38-P in IBs resulted in a substantial reduction in the accumulation of a downstream signaling substrate, MAPK-activated protein kinase 2 (MK2). Sequestration of OGT in IBs was associated with suppression of stress granule (SG) formation. Thus, while the RSV IBs are thought to play an essential role in viral replication, the present results show that they also play a role in suppressing the cellular response to viral infection. The sequestration of p38-P and OGT in IBs appeared to be reversible: oxidative stress resulting from arsenite treatment transformed large IBs into a scattering of smaller bodies, suggestive of partial disassembly, and this was associated with MK2 phosphorylation and OGN addition. Unexpectedly, the RSV M2-1 protein was found to localize in SGs that formed during oxidative stress. This protein was previously shown to be a viral transcription elongation factor, and the present findings provide the first evidence of possible involvement in SG activities during RSV infection.
Support systems for and barriers to diabetes management in South Asians and Whites in the UK: qualitative study of patients’ perspectives
Authors: Singh Harsimran , Cinnirella Marco , Bradley Clare 
Published: November 2012

ObjectivesTo explore experiences of UK-based South Asian and White patients with diabetes in relation to their support systems for and barriers to diabetes management.DesignQualitative study (semistructured interviews analysed using a form of Interpretative Phenomenological Analysis).Participants20 outpatients with diabetes (12 British South Asians and 8 British Whites) with either good or poor glycaemic control.SettingHillingdon Hospital, Uxbridge, UK.ResultsQualitative analysis revealed distinct themes for the two ethnic groups. For the South Asian participants, challenges surrounding diet management and social stigma attached to having diabetes were the two predominant barriers to effective diabetes management. Support from immediate family members was commonly reported as a strong support system for optimising diabetes management by the South Asian sample in addition to the perceived positive impact of religion (healing power of prayer), the valuable informational support from their diabetes-care team, patient leaflets and diabetes magazines. Similar to the South Asians, adhering to dietary recommendations was the most difficult aspect of diabetes management for the White participants followed by the inconveniences surrounding injecting insulin. The hospital diabetes-care team was considered as the most effective support system for diabetes management by the White sample and interestingly, this was the only dominant theme in their reported sources of support.ConclusionsBoth South Asian and White participants emphasised adherence to dietary recommendations as the most difficult aspect of living with diabetes. In addition, social stigma attached to diabetes was a prominent concern among South Asian participants that seemed to have a significant negative impact on their diabetes control and overall management. Given South Asian patients’ reliance on their family for the management of their condition, interventions targeting improved diabetes outcomes in this population may prove more successful if they are designed to involve significant family members.
Common Genetic Variation of the Calcium-Sensing Receptor and Lethal Prostate Cancer Risk
Authors: Shui Irene M. , Mucci Lorelei A. , Wilson Kathryn M. , Kraft Peter , Penney Kathryn L. , Stampfer Meir J. , Giovannucci Edward 
Published: November 2012

Abstract
Background: Bony metastases cause substantial morbidity and mortality from prostate cancer (PCa). The calcium-sensing receptor (CaSR) is expressed on prostate tumors and may participate in bone metastases development. We assessed whether (i) common genetic variation in CaSR was associated with PCa risk and (ii) these associations varied by calcium intake or plasma 25-hydroxyvitamin D [25(OH)D] levels.
Methods: We included 1,193 PCa cases and 1,244 controls nested in the prospective Health Professionals Follow-up Study (1993–2004). We genotyped 18 CaSR single-nucleotide polymorphism (SNPs) to capture common variation. The main outcome was risk of lethal PCa (n = 113); secondary outcomes were overall (n = 1,193) and high-grade PCa (n = 225). We used the kernel machine approach to conduct a gene-level multimarker analysis and unconditional logistic regression to compute per-allele ORs and 95% confidence intervals (CI) for individual SNPs.
Results: The joint association of SNPs in CaSR was significant for lethal PCa (P = 0.04); this association was stronger in those with low 25(OH)D (P = 0.009). No individual SNPs were associated after considering multiple testing; three SNPs were nominally associated (P &lt; 0.05) with lethal PCa with ORs (95% CI) of 0.65(0.42–0.99): rs6438705; 0.65(0.47–0.89): rs13083990; and 1.55(1.09–2.20): rs2270916. The three nonsynonymous SNPs (rs1801725, rs1042636, and rs1801726) were not significantly associated; however, the association for rs1801725 was stronger in men with low 25(OH)D [OR(95%CI): 0.54(0.31–0.95)]. There were no significant associations with overall or high-grade PCa.
Conclusions: Our findings indicate that CaSR may be involved in PCa progression.
Impact: Further studies investigating potential mechanisms for CaSR and PCa, including bone remodeling and metastases are warranted. Cancer Epidemiol Biomarkers Prev; 22(1); 118–26. ©2012 AACR.
Genetic Susceptibility Loci for Subtypes of Breast Cancer in an African American Population
Authors: Palmer Julie R. , Ruiz-Narvaez Edward A. , Rotimi Charles N. , Cupples L. Adrienne , Cozier Yvette C. , Adams-Campbell Lucile L. , Rosenberg Lynn 
Published: November 2012

Abstract
Background: Most genome-wide association studies (GWAS) have been carried out in European ancestry populations; no risk variants for breast cancer have been identified solely from African ancestry GWAS data. Few GWAS hits have replicated in African ancestry populations.
Methods: In a nested case–control study of breast cancer in the Black Women's Health Study (1,199 cases/1,948 controls), we evaluated index single-nucleotide polymorphisms (SNP) in 21 loci from GWAS of European or Asian ancestry populations, overall, in subtypes defined by estrogen receptor (ER) and progesterone receptor (PR) status (ER+/PR+, n = 336; ER−/PR−, n = 229), and in triple-negative breast cancer (TNBC, N = 81). To evaluate the contribution of genetic factors to population differences in breast cancer subtype, we also examined global percent African ancestry.
Results: Index SNPs in five loci were replicated, including three associated with ER−/PR− breast cancer (TERT rs10069690 in 5p15.33, rs704010 in 10q22.3, and rs8170 in 19p13.11): per allele ORs were 1.29 [95% confidence interval (CI) 1.04–1.59], P = 0.02, 1.52 (95% CI 1.12–2.08), P = 0.01, and 1.30 (95% CI 1.01–1.68), P = 0.04, respectively. Stronger associations were observed for TNBC. Furthermore, cases in the highest quintile of percent African ancestry were three times more likely to have TNBC than ER+/PR+ cancer.
Conclusions: These findings provide the first confirmation of the TNBC SNP rs8170 in an African ancestry population, and independent confirmation of the TERT ER− SNP. Furthermore, the risk of developing ER− breast cancer, particularly TNBC, increased with increasing proportion of global African ancestry.
Impact: The findings illustrate the importance of genetic factors in the disproportionately high occurrence of TNBC in African American women. Cancer Epidemiol Biomarkers Prev; 22(1); 127–34. ©2012 AACR.
Assessment of the Effects of Severe Obesity and Lifestyle Risk Factors On Stage of Endometrial Cancer
Authors: Bittoni Marisa A. , Fisher James L. , Fowler Jeffrey M. , Maxwell George L. , Paskett Electra D. 
Published: November 2012

Abstract
Background: Lifestyle risk factors, including obesity, have been associated with increased risk of endometrial cancer (EC). Women with higher obesity levels tend to have less aggressive EC disease stage and histology. This study further investigated associations between nonmodifiable risk factors, such as age, race, and grade, and modifiable lifestyle factors, such as diet and physical activity expenditure, in relation to severe obesity and late versus early EC stage at diagnosis.
Methods: Demographic, anthropometric, and lifestyle surveys were administered to 177 women with histologically confirmed EC. Logistic regression analyses assessed the relationship between obesity and other risk factors on EC stage at diagnosis.
Results: In multivariate models, body mass index (BMI) &lt; 35 was not significantly associated with late EC stage at diagnosis (OR = 1.67, P = 0.219) when adjusting for grade and age. Grade was significantly associated with EC stage when controlling for BMI and age (OR = 8.48, P = .000). Women more than the age of 60 had a fourfold increased risk of diagnosis at late versus early EC stage when adjusting for other risk factors. Age had a confounding effect on the obesity-EC stage association.
Conclusions: Our results corroborate those of past studies showing that BMI is not an independent risk factor for EC stage and that age may have confounded the obesity-EC stage association. Because of mixed results and implications for treatment outcomes, however, further research examining these variables is warranted.
Impact: Our results provide further insight into the obesity EC-stage association, especially the confounding effect of age. Future studies should examine modifiable lifestyle factors in larger and more diverse populations. Cancer Epidemiol Biomarkers Prev; 22(1); 76–81. ©2012 AACR.
State-Level Uterine Corpus Cancer Incidence Rates Corrected for Hysterectomy Prevalence, 2004 to 2008
Authors: Siegel Rebecca L. , Devesa Susan S. , Cokkinides Vilma , Ma Jiemin , Jemal Ahmedin 
Published: November 2012

AbstractBackground: The interpretation of uterine cancer rates is hindered by the inclusion of women whose uterus has been surgically removed in the population at risk. Hysterectomy prevalence varies widely by state and race/ethnicity, exacerbating this issue.Methods: We estimated hysterectomy-corrected, age-adjusted uterine corpus cancer incidence rates by race/ethnicity for 49 states and the District of Columbia during 2004 to 2008 using case counts obtained from population-based cancer registries; population data from the U.S. Census Bureau; and hysterectomy prevalence data from the Behavioral Risk Factor Surveillance System. Corrected and uncorrected incidence rates were compared with regard to geographic and racial/ethnic disparity patterns and the association with obesity.Results: Among non-Hispanic Whites, uterine cancer incidence rates (per 100,000 woman-years) uncorrected for hysterectomy prevalence ranged from 17.1 in Louisiana to 32.1 in New Jersey, mirrored regional hysterectomy patterns, and were not correlated with obesity prevalence (Pearson correlation coefficient, r = 0.06, two-sided P = 0.68). In comparison, hysterectomy-corrected rates were higher by a minimum of 30% (District of Columbia) to more than 100% (Mississippi, Louisiana, Alabama, and Oklahoma), displayed no discernible geographic pattern, and were moderately associated with obesity (r = 0.37, two-sided P = 0.009). For most states, hysterectomy correction diminished or reversed the Black/White deficit and accentuated the Hispanic/White deficit.Conclusion: Failure to adjust uterine cancer incidence rates for hysterectomy prevalence distorts true geographic and racial patterns and substantially underestimates the disease burden, particularly for Southern states.Impact: Correction for hysterectomy is necessary for the accurate evaluation of uterine cancer rates. Cancer Epidemiol Biomarkers Prev; 22(1); 25–31. ©2012 AACR.
Expanding the Reach of Cancer Metabolomics
Authors: Metallo Christian M. 
Published: November 2012

Abstract
Metabolism is again emerging as a key property that differentiates normal cells from neoplastic tissues. The coupling of this phenomenon with advanced bioanalytic methods may now open new avenues for diagnostics in cancer via discovery of chemical biomarkers. In this issue of Cancer Prevention Research, Montrose and colleagues apply metabolic profiling to a model of chemically induced colorectal cancer and describe the metabolomic landscape of colorectal tumors and associated biofluids in great detail. Their analysis of plasma and fecal metabolites provides inroads into the noninvasive detection of colorectal cancer using biochemical markers, as some conserved metabolic changes were altered across tumors, plasma, and feces. Meanwhile, the specific alterations identified in this study offer insights into potential metabolic drivers of colorectal cancer. For example, elevated sarcosine and 2-hydroxyglutarate were detected in these induced tumors, implicating their respective metabolic pathways and downstream interactions in colorectal cancer progression. This work highlights the potential value of cancer metabolomics for the noninvasive analysis of colorectal neoplasias while underscoring the importance of profiling diverse sample sets and metabolites in relevant cancer models to identify and validate such findings. Cancer Prev Res; 5(12); 1337–40. ©2012 AACR.