bluuebunny/crossref_metadata_2025_split huggingface dataset:
A comparative study using WHO and binary oral epithelial dysplasia grading systems in actinic cheilitis
Authors: Câmara PR , Dutra SN , Takahama Júnior A , Fontes KBFC , Azevedo RS 
Published: March 2016

ObjectiveTo evaluate comparatively the influence of histopathological features on epithelial dysplasia (ED) and the effectiveness in usage of WHO and binary grading systems in actinic cheilitis (AC).Material and methodsCytological and architectural alterations established by WHO for ED were evaluated in 107 cases of AC. Epithelial dysplasia was graded using WHO and binary systems. The comparisons were performed using kappa, chi‐square, and phi coefficient tests (P < 0.05).ResultsMost cases were classified as mild ED (44.5%) in the WHO system and as low risk for malignant transformation (64.5%) in the binary system. There was a positive correlation between WHO and binary systems (k = 0.33; P < 0.0002). Loss of basal cell polarity (P < 0.001) was associated with severity of ED grade in the WHO system. Anisonucleosis (P < 0.0001), nuclear pleomorphism (P < 0.0001), anisocytosis (P = 0.03), cell pleomorphism (P = 0.002) increased nuclear/cytoplasm ratio (P < 0.0001), increased nuclear size (P < 0.0001), increased number of mitotic figures (P = 0.0006), and dyskeratosis (P = 0.008) were associated with severity of ED grade in the binary system.ConclusionsIt seems that usage of binary ED grading system in AC may be more precise because there is correlation between many of cytological and some of architectural microscopic alterations with increased grade of ED.
Fertility Assessment in Sorraia Stallions by Sperm‐Fish and Fkbp6 Genotyping
Authors: Kjöllerström HJ , do Mar Oom M , Chowdhary BP , Raudsepp T 
Published: March 2016

ContentsThe Sorraia, a critically endangered indigenous Iberian horse breed, is characterized by low genetic variability, high rate of inbreeding, bad sperm quality and subfertility. Here, we studied 11 phenotypically normal but subfertile Sorraia stallions by karyotyping, sex chromosome sperm‐FISH and molecular analysis of FKBP6 – a susceptibility locus for impaired acrosome reaction (IAR). The stallions had normal sperm concentration (>300 million cells/ml), but the numbers of progressively motile sperm (21%) and morphologically normal sperm (28%) were invariably low. All stallions had a normal 64,XY karyotype. The majority of sperm (89%) had normal haploid sex chromosome content, although 11% of sperm carried various sex chromosome aneuploidies. No correlation was found between the percentage of sperm sex chromosome abnormalities and inbreeding, sperm morphology or stallion age. Direct sequencing of FKBP6 exon 4 for SNPs g.11040315G>A and g.11040379C>A revealed that none of the stallions had the susceptibility genotype (A/A‐A/A) for IAR. Instead, all animals had a G/G‐A/A genotype – a testimony of low genetic variability. The findings ruled out chromosomal abnormalities and genetic predisposition for IAR as contributing factors for subfertility. However, low fertility of the Sorraia stallions could be partly attributed to relatively higher rate of sex chromosome aneuploidies in the sperm.
Pre‐transplant end‐stage renal disease‐related immune risk profile in kidney transplant recipients predicts post‐transplant infections
Authors: Crepin T. , Gaiffe E. , Courivaud C. , Roubiou C. , Laheurte C. , Moulin B. , Frimat L. , Rieu P. , Mousson C. , Durrbach A. , Heng A.‐E. , Saas P. , Bamoulid J. , Ducloux D. 
Published: March 2016

AbstractBackgroundEnd‐stage renal disease (ESRD) is associated with premature aging of the T‐cell system. Nevertheless, the clinical significance of pre‐transplant ESRD‐related immune senescence is unknown.MethodsWe studied whether immune risk phenotype (IRP), a typical feature of immune senescence, may affect post‐transplant infectious complications. A total of 486 patients were prospectively studied during the first year post transplant. IRP was defined as positive cytomegalovirus serology with at least 1 of the following criteria: CD4/CD8 ratio <1 and/or CD8 T‐cell count >90th percentile.ResultsWe found that 47 patients (9.7%) had pre‐transplant IRP. IRP+ patients did not differ from IRP− patients for any clinical characteristics, but exhibited more pronounced immune senescence. Both opportunistic infections (43% vs. 6%, P < 0.001) and severe bacterial infection (SBI) (40% vs. 25%, P = 0.028) were more frequent in IRP+ patients. In multivariate analysis, IRP was predictive of both opportunistic infection (hazard ratio [HR] 2.97 [95% confidence interval {CI} 1.53–5.76], P = 0.001), and SBI (HR 2.33 [95% CI 1.34–3.92], P = 0.008). Acute rejection rates were numerically much lower in IRP+ patients. A total of 418 patients (86%) had biological evaluation 1 year post transplant. Among 41 IRP+ patients, 35 (85%) remained IRP+ 1 year post transplant.ConclusionPre‐transplant IRP is associated with an increased risk of post‐transplant infection.
Blood vessel occlusion in peri‐burn tissue is secondary to erythrocyte aggregation and mitigated by a fibronectin‐derived peptide that limits burn injury progression
Authors: Asif Bilal , Rahim Abdul , Fenner Justine , Lin Fubao , Hirth Douglas , Hassani John , McClain Steven A. , Singer Adam J. , Tonnesen Marcia G. , Clark Richard A.F. 
Published: March 2016

AbstractAlthough vascular occlusion has long been noted in peri‐burn tissue, the literature is inconsistent regarding the nature of the occlusion, with articles in the 1940s claiming that erythrocytes were the culprit and in the 1980s–1990s that microthrombi were responsible. To better define the nature of vessel occlusion, we studied two porcine burn models, a hot comb horizontal injury model and a vertical injury progression model. In both cases, tissue from the first two days after burn were stained with hemotoxylin and eosin, or probed for platelets or for fibrinogen/fibrin. Erythrocytes, identified as nonstained, clumped, anuclear, 5 µm cells, occluded most blood vessels (BVs) in both burn models. In contrast, platelet or fibrinogen/fibrin antibodies stained BV occlusions minimally at early time points, and only up to 16% of deep dermal BVs at 48 hours in the hot comb model and up to 7% at 24 hours in the vertical injury progression model. Treatment of animals with a fibronectin‐derived peptide (P12), which limits burn injury progression and can dilate peripheral microvasculature, reduced erythrocyte occlusion by at least 50%, speeded healing and reduced scarring. Early erythrocyte aggregation, rather than thrombosis, explains the ineffectiveness of anticoagulants to prevent burn injury progression.
Emergence of a Large-Plaque Variant in Mice Infected with Coxsackievirus B3
Authors: Wang Yao , Pfeiffer Julie K. 
Published: March 2016

ABSTRACT

Coxsackieviruses are enteric viruses that frequently infect humans. To examine coxsackievirus pathogenesis, we orally inoculated mice with the coxsackievirus B3 (CVB3) Nancy strain. Using HeLa cell plaque assays with agar overlays, we noticed that some fecal viruses generated plaques >100 times as large as inoculum viruses. These large-plaque variants emerged following viral replication in several different tissues. We identified a single amino acid change, N63Y, in the VP3 capsid protein that was sufficient to confer the large-plaque phenotype. Wild-type CVB3 and N63Y mutant CVB3 had similar plaque sizes when agarose was used in the overlay instead of agar. We determined that sulfated glycans in agar inhibited plaque formation by wild-type CVB3 but not by N63Y mutant CVB3. Furthermore, N63Y mutant CVB3 bound heparin, a sulfated glycan, less efficiently than wild-type CVB3 did. While N63Y mutant CVB3 had a growth defect in cultured cells and reduced attachment, it had enhanced replication and pathogenesis in mice. Infection with N63Y mutant CVB3 induced more severe hepatic damage than infection with wild-type CVB3, likely because N63Y mutant CVB3 disseminates more efficiently to the liver. Our data reinforce the idea that culture-adapted laboratory virus strains can have reduced fitness
in vivo
. N63Y mutant CVB3 may be useful as a platform to understand viral adaptation and pathogenesis in animal studies.

IMPORTANCE
Coxsackieviruses frequently infect humans, and although many infections are mild or asymptomatic, there can be severe outcomes, including heart inflammation. Most studies with coxsackieviruses and other viruses use laboratory-adapted viral strains because of their efficient replication in cell culture. We used a cell culture-adapted strain of CVB3, Nancy, to examine viral replication and pathogenesis in orally inoculated mice. We found that mice shed viruses distinct from input viruses because they formed extremely large plaques in cell culture. We identified a single mutation, VP3 N63Y, that was sufficient for large-plaque formation. N63Y mutant viruses have reduced glycan binding and replication in cell culture; however, they have enhanced replication and virulence in mice. We are now using N63Y mutant CVB3 as an improved system for viral pathogenesis studies.
Middle East Respiratory Syndrome Coronavirus NS4b Protein Inhibits Host RNase L Activation
Authors: Thornbrough Joshua M. , Jha Babal K. , Yount Boyd , Goldstein Stephen A. , Li Yize , Elliott Ruth , Sims Amy C. , Baric Ralph S. , Silverman Robert H. , Weiss Susan R. 
Published: March 2016

ABSTRACTMiddle East respiratory syndrome coronavirus (MERS-CoV) is the first highly pathogenic human coronavirus to emerge since severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002. Like many coronaviruses, MERS-CoV carries genes that encode multiple accessory proteins that are not required for replication of the genome but are likely involved in pathogenesis. Evasion of host innate immunity through interferon (IFN) antagonism is a critical component of viral pathogenesis. The IFN-inducible oligoadenylate synthetase (OAS)-RNase L pathway activates upon sensing of viral double-stranded RNA (dsRNA). Activated RNase L cleaves viral and host single-stranded RNA (ssRNA), which leads to translational arrest and subsequent cell death, preventing viral replication and spread. Here we report that MERS-CoV, a lineage CBetacoronavirus, and related bat CoV NS4b accessory proteins have phosphodiesterase (PDE) activity and antagonize OAS-RNase L by enzymatically degrading 2′,5′-oligoadenylate (2-5A), activators of RNase L. This is a novel function for NS4b, which has previously been reported to antagonize IFN signaling. NS4b proteins are distinct from lineage ABetacoronavirusPDEs and rotavirus gene-encoded PDEs, in having an amino-terminal nuclear localization signal (NLS) and are localized mostly to the nucleus. However, the expression level of cytoplasmic MERS-CoV NS4b protein is sufficient to prevent activation of RNase L. Finally, this is the first report of an RNase L antagonist expressed by a human or bat coronavirus and provides a specific mechanism by which this occurs. Our findings provide a potential mechanism for evasion of innate immunity by MERS-CoV while also identifying a potential target for therapeutic intervention.IMPORTANCEMiddle East respiratory syndrome coronavirus (MERS-CoV) is the first highly pathogenic human coronavirus to emerge since severe acute respiratory syndrome coronavirus (SARS-CoV). MERS-CoV, like other coronaviruses, carries genes that encode accessory proteins that antagonize the host antiviral response, often the type I interferon response, and contribute to virulence. We found that MERS-CoV NS4b and homologs from related lineage C bat betacoronaviruses BtCoV-SC2013 (SC2013) and BtCoV-HKU5 (HKU5) are members of the 2H-phosphoesterase (2H-PE) enzyme family with phosphodiesterase (PDE) activity. Like murine coronavirus NS2, a previously characterized PDE, MERS NS4b, can antagonize activation of the OAS-RNase L pathway, an interferon-induced potent antiviral activity. Furthermore, MERS-CoV mutants with deletion of genes encoding accessory proteins NS3 to NS5 or NS4b alone or inactivation of the PDE can activate RNase L during infection of Calu-3 cells. Our report may offer a potential target for therapeutic intervention if NS4b proves to be critical to pathogenesis inin vivomodels of MERS-CoV infection.
p53 Loss in MYC-Driven Neuroblastoma Leads to Metabolic Adaptations Supporting Radioresistance
Authors: Yogev Orli , Barker Karen , Sikka Arti , Almeida Gilberto S. , Hallsworth Albert , Smith Laura M. , Jamin Yann , Ruddle Ruth , Koers Alexander , Webber Hannah T. , Raynaud Florence I. , Popov Sergey , Jones Chris , Petrie Kevin , Robinson Simon P. , Keun Hector C. , Chesler Louis 
Published: March 2016

Abstract
Neuroblastoma is the most common childhood extracranial solid tumor. In high-risk cases, many of which are characterized by amplification of MYCN, outcome remains poor. Mutations in the p53 (TP53) tumor suppressor are rare at diagnosis, but evidence suggests that p53 function is often impaired in relapsed, treatment-resistant disease. To address the role of p53 loss of function in the development and pathogenesis of high-risk neuroblastoma, we generated a MYCN-driven genetically engineered mouse model in which the tamoxifen-inducible p53ERTAM fusion protein was expressed from a knock-in allele (Th-MYCN/Trp53KI). We observed no significant differences in tumor-free survival between Th-MYCN mice heterozygous for Trp53KI (n = 188) and Th-MYCN mice with wild-type p53 (n = 101). Conversely, the survival of Th-MYCN/Trp53KI/KI mice lacking functional p53 (n = 60) was greatly reduced. We found that Th-MYCN/Trp53KI/KI tumors were resistant to ionizing radiation (IR), as expected. However, restoration of functional p53ERTAM reinstated sensitivity to IR in only 50% of Th-MYCN/Trp53KI/KI tumors, indicating the acquisition of additional resistance mechanisms. Gene expression and metabolic analyses indicated that the principal acquired mechanism of resistance to IR in the absence of functional p53 was metabolic adaptation in response to chronic oxidative stress. Tumors exhibited increased antioxidant metabolites and upregulation of glutathione S-transferase pathway genes, including Gstp1 and Gstz1, which are associated with poor outcome in human neuroblastoma. Accordingly, glutathione depletion by buthionine sulfoximine together with restoration of p53 activity resensitized tumors to IR. Our findings highlight the complex pathways operating in relapsed neuroblastomas and the need for combination therapies that target the diverse resistance mechanisms at play. Cancer Res; 76(10); 3025–35. ©2016 AACR.
A CDK4/6-Dependent Epigenetic Mechanism Protects Cancer Cells from PML-induced Senescence
Authors: Acevedo Mariana , Vernier Mathieu , Mignacca Lian , Lessard Frédéric , Huot Geneviève , Moiseeva Olga , Bourdeau Véronique , Ferbeyre Gerardo 
Published: March 2016

Abstract
Promyelocytic leukemia (PML) plays a tumor suppressive role by inducing cellular senescence in response to oncogenic stress. However, tumor cell lines fail to engage in complete senescence upon PML activation. In this study, we investigated the mechanisms underlying resistance to PML-induced senescence. Here, we report that activation of the cyclin-dependent kinases CDK4 and CDK6 are essential and sufficient to impair senescence induced by PML expression. Disrupting CDK function by RNA interference or pharmacological inhibition restored senescence in tumor cells and diminished their tumorigenic potential in mouse xenograft models. Complete senescence correlated with an increase in autophagy, repression of E2F target genes, and an gene expression signature of blocked DNA methylation. Accordingly, treatment of tumor cells with inhibitors of DNA methylation reversed resistance to PML-induced senescence. Further, CDK inhibition with palbociclib promoted autophagy-dependent degradation of the DNA methyltransferase DNMT1. Lastly, we found that CDK4 interacted with and phosphorylated DNMT1 in vitro, suggesting that CDK activity is required for its stabilization. Taken together, our findings highlight a potentially valuable feature of CDK4/6 inhibitors as epigenetic modulators to facilitate activation of senescence programs in tumor cells. Cancer Res; 76(11); 3252–64. ©2016 AACR.
Membrane IL1α Inhibits the Development of Hepatocellular Carcinoma via Promoting T- and NK-cell Activation
Authors: Lin Dandan , Lei Lei , Liu Yonghao , Zhang Yinsheng , Hu Bo , Bao Guangming , Song Yuan , Jin Ziqi , Liu Chunliang , Mei Yu , Sandikin Dedy , Wu Yan , Zhao Lixiang , Yu Xiao , Liu Haiyan 
Published: March 2016

AbstractHepatocellular carcinoma is a worldwide health problem with limited treatment options and poor prognosis. Inflammation associated with liver injury and hepatocyte regeneration can lead to fibrosis, cirrhosis, and eventually, hepatocellular carcinoma. IL1α is one of the most important inflammatory cytokines involved in inflammation and tumor development. IL1α presents as multiple forms in vivo, including precursor, propiece, membrane, and secreted forms, and their functions have been thought to be different. The role of membrane IL1α in hepatocellular carcinoma tumorigenesis is still not clear. Here, we examined the functions of membrane IL1α in murine hepatocellular carcinoma models. We found that membrane IL1α potently inhibited hepatocellular carcinoma tumor growth. Further studies showed that membrane IL1α promoted T- and natural killer (NK)–cell activation in vivo. IFNγ production by CD8+ T and NK cells was also increased as a result of membrane IL1α expression. Moreover, the cytotoxicity of the CTL and NK cells was also enhanced by membrane IL1α expression. Furthermore, in vitro studies demonstrated that membrane IL1α could directly activate T cells and NK cells in a cell contact–dependent manner. Conversely, depletion of both CD8+ T and NK cells suppressed the antitumor activity of membrane IL1α. Our studies demonstrated that membrane IL1α could promote antitumor immune responses through activation of T and NK cells. Thus, our findings provide new insights of IL1α functions during hepatocellular carcinoma development. Cancer Res; 76(11); 3179–88. ©2016 AACR.
Trastuzumab, but Not Pertuzumab, Dysregulates HER2 Signaling to Mediate Inhibition of Autophagy and Increase in Reactive Oxygen Species Production in Human Cardiomyocytes
Authors: Mohan Nishant , Shen Yi , Endo Yukinori , ElZarrad M. Khair , Wu Wen Jin 
Published: March 2016

Abstract
Dysregulation of autophagy has been implicated in various cardiovascular diseases. Trastuzumab, a humanized monoclonal antibody, binds to HER2 domain IV and is approved for the treatment of HER2-positive breast cancer. Trastuzumab therapy is associated with considerable cardiotoxicity, the mechanism of which remains unclear. HER2 signaling plays a pivotal role in cardiomyocyte development and survival and is essential for the prevention of cardiomyopathy. However, a direct link has not been confirmed between trastuzumab-induced cardiomyopathy and impaired HER2 signaling. Our data reveal a novel mechanism by which trastuzumab dysregulates HER2 signaling and impairs basal autophagic process in human primary cardiomyocytes. Specifically, trastuzumab treatment leads to the phosphorylation of HER1-Y845 and HER2-Y1248 and the activation of Erk. This in turn results in upregulation of mTOR signaling pathway and subsequently inhibition of autophagy in primary cardiomyocytes and C57BL/6 mice. Trastuzumab-induced downregulation of autophagy is further supported by the fact that trastuzumab treatment reduces protein levels of autophagosome-associated signaling molecules such as Atg 5-12, Atg 7, Atg 14, and Beclin 1. We further demonstrated that trastuzumab-mediated inhibition of autophagy resulted in the increased production of reactive oxygen species (ROS) in cardiomyocytes. Pertuzumab, another anti-HER2 therapeutic mAb binding to HER2 domain II, fails to modulate HER2 signaling and is unable to inhibit autophagy and to increase ROS production in cardiomyocytes. This study provides novel mechanistic insights into trastuzumab-induced cardiotoxicity, which may assist in formulating novel approaches for clinical management of trastuzumab-induced cardiomyopathy. Mol Cancer Ther; 15(6); 1321–31. ©2016 AACR.
Prevalence of Masked Hypertension and Its Association With Subclinical Cardiovascular Disease in African Americans: Results From the Jackson Heart Study
Authors: Redmond Nicole , Booth John N. , Tanner Rikki M. , Diaz Keith M. , Abdalla Marwah , Sims Mario , Muntner Paul , Shimbo Daichi 
Published: March 2016

Background
Studies consisting mostly of whites have shown that the prevalence of masked hypertension differs by prehypertension status. Using data from the Jackson Heart Study, an exclusively African American population‐based cohort, we evaluated the association of masked hypertension and prehypertension with left ventricular mass index and common carotid intima media thickness.

Methods and Results

At the baseline visit, clinic blood pressure (
CBP
) measurement and 24‐hour ambulatory blood pressure monitoring were performed. Masked hypertension was defined as mean systolic/diastolic
CBP
<140/90 mm Hg and mean daytime systolic/diastolic ambulatory blood pressure ≥135/85 mm Hg. Clinic hypertension was defined as mean systolic/diastolic
CBP
≥140/90 mm Hg. Normal
CBP
was defined as mean systolic/diastolic
CBP
<120/80 mm Hg and prehypertension as mean systolic/diastolic
CBP
120 to 139/80 to 89 mm Hg. The analytic sample included 909 participants. Among participants with systolic/diastolic
CBP
<140/90 mm Hg, the prevalence of masked hypertension and prehypertension was 27.5% and 62.4%, respectively. The prevalence of masked hypertension among those with normal
CBP
and prehypertension was 12.9% and 36.3%, respectively. In a fully adjusted model, which included prehypertension status and antihypertensive medication use as covariates, left ventricular mass index was 7.94 g/m
2
lower among those without masked hypertension compared to participants with masked hypertension (
P
<0.001). Left ventricular mass index was also 4.77 g/m
2
lower among those with clinic hypertension, but this difference was not statistically significant (
P
=0.068). There were no significant differences in left ventricular mass index between participants with and without masked hypertension, or clinic hypertension.

Conclusions

Masked hypertension was common among African Americans with prehypertension and also normal
CBP
, and was associated with subclinical cardiovascular disease.