bluuebunny/crossref_metadata_2025_split huggingface dataset:
What Do Chaotrope-Based Avidity Assays for Antibodies to HIV-1 Envelope Glycoproteins Measure?
Authors: Alexander Marina R. , Ringe Rajesh , Sanders Rogier W. , Voss James E. , Moore John P. , Klasse Per Johan 
Published: March 2015

ABSTRACTWhen HIV-1 vaccine candidates that include soluble envelope glycoproteins (Env) are tested in humans and other species, the resulting antibody responses to Env are sifted for correlates of protection or risk. One frequently used assay measures the reduction in antibody binding to Env antigens by an added chaotrope (such as thiocyanate). Based on that assay, an avidity index was devised for assessing the affinity maturation of antibodies of unknown concentration in polyclonal sera. Since a high avidity index was linked to protection in animal models of HIV-1 infection, it has become a criterion for evaluating antibody responses to vaccine candidates. But what does the assay measure and what does an avidity index mean? Here, we have used a panel of monoclonal antibodies to well-defined epitopes on Env (gp120, gp41, and SOSIP.664 trimers) to explore how the chaotrope acts. We conclude that the chaotrope sensitivity of antibody binding to Env depends on several properties of the epitopes (continuity versus tertiary- and quaternary-structural dependence) and that the avidity index has no simple relationship to antibody affinity for functional Env spikes on virions. We show that the binding of broadly neutralizing antibodies against quaternary-structural epitopes is particularly sensitive to chaotrope treatment, whereas antibody binding to epitopes in variable loops and to nonneutralization epitopes in gp41 is generally resistant. As a result of such biases, the avidity index may at best be a mere surrogate for undefined antibody or other immune responses that correlate weakly with protection.IMPORTANCEAn effective HIV-1 vaccine is an important goal. Such a vaccine will probably need to induce antibodies that neutralize typically transmitted variants of HIV-1, preventing them from infecting target cells. Vaccine candidates have so far failed to induce such antibody responses, although some do protect weakly against infection in animals and, possibly, humans. In the search for responses associated with protection, an avidity assay based on chemical disruption is often used to measure the strength of antibody binding. We have analyzed this assay mechanistically and found that the epitope specificity of an antibody has a greater influence on the outcome than does its affinity. As a result, the avidity assay is biased toward the detection of some antibody specificities while disfavoring others. We conclude that the assay may yield merely indirect correlations with weak protection, specifically when Env vaccination has failed to induce broad neutralizing responses.
Function of the Herpes Simplex Virus 1 Small Capsid Protein VP26 Is Regulated by Phosphorylation at a Specific Site
Authors: Kobayashi Ryosuke , Kato Akihisa , Oda Shinya , Koyanagi Naoto , Oyama Masaaki , Kozuka-Hata Hiroko , Arii Jun , Kawaguchi Yasushi 
Published: March 2015

ABSTRACT

Replacement of the herpes simplex virus 1 small capsid protein VP26 phosphorylation site Thr-111 with alanine reduced viral replication and neurovirulence to levels observed with the VP26 null mutation. This mutation reduced VP26 expression and mislocalized VP26 and its binding partner, the major capsid protein VP5, in the nucleus. VP5 mislocalization was also observed with the VP26 null mutation. Thus, we postulate that phosphorylation of VP26 at Thr-111 regulates VP26 function
in vitro
and
in vivo
.
African Swine Fever Virus Georgia Isolate Harboring Deletions of MGF360 and MGF505 Genes Is Attenuated in Swine and Confers Protection against Challenge with Virulent Parental Virus
Authors: O'Donnell Vivian , Holinka Lauren G. , Gladue Douglas P. , Sanford Brenton , Krug Peter W. , Lu Xiqiang , Arzt Jonathan , Reese Bo , Carrillo Consuelo , Risatti Guillermo R. , Borca Manuel V. 
Published: March 2015

ABSTRACT

African swine fever virus (ASFV) is the etiological agent of a contagious and often lethal disease of domestic pigs that has significant economic consequences for the swine industry. The control of African swine fever (ASF) has been hampered by the unavailability of vaccines. Experimental vaccines have been developed using genetically modified live attenuated ASFVs where viral genes involved in virus virulence were removed from the genome. Multigene family 360 (MGF360) and MGF505 represent a group of genes sharing partial sequence and structural identities that have been connected with ASFV host range specificity, blocking of the host innate response, and virus virulence. Here we report the construction of a recombinant virus (ASFV-G-ΔMGF) derived from the highly virulent ASFV Georgia 2007 isolate (ASFV-G) by specifically deleting six genes belonging to MGF360 or MGF505: MGF505-1R, MGF360-12L, MGF360-13L, MGF360-14L, MGF505-2R, and MGF505-3R. ASFV-G-ΔMGF replicates as efficiently in primary swine macrophage cell cultures as the parental virus.
In vivo
, ASFV-G-ΔMGF is completely attenuated in swine, since pigs inoculated intramuscularly (i.m.) with either 10
2
or 10
4
50% hemadsorbing doses (HAD
50
) remained healthy, without signs of the disease. Importantly, when these animals were subsequently exposed to highly virulent parental ASFV-G, no signs of the disease were observed, although a proportion of these animals harbored the challenge virus. This is the first report demonstrating the role of MGF genes acting as independent determinants of ASFV virulence. Additionally, ASFV-G-ΔMGF is the first experimental vaccine reported to induce protection in pigs challenged with highly virulent and epidemiologically relevant ASFV-G.

IMPORTANCE
The main problem for controlling ASF is the lack of vaccines. Studies focusing on understanding ASFV virulence led to the production of genetically modified recombinant viruses that, while attenuated, are able to confer protection in pigs challenged with homologous viruses. Here we have produced an attenuated recombinant ASFV derived from highly virulent ASFV strain Georgia (ASFV-G) lacking only six of the multigene family 360 (MGF360) and MGF505 genes (ASFV-G-ΔMGF). It is demonstrated, by first time, that deleting specific MGF genes alone can completely attenuate a highly virulent field ASFV isolate. Recombinant virus ASFV-G-ΔMGF effectively confers protection in pigs against challenge with ASFV-G when delivered once via the intramuscular (i.m.) route. The protection against ASFV-G is highly effective by 28 days postvaccination. This is the first report of an experimental vaccine that induces solid protection against virulent ASFV-G.
What has happened to suicides during the Greek economic crisis? Findings from an ecological study of suicides and their determinants (2003–2012)
Authors: Rachiotis George , Stuckler David , McKee Martin , Hadjichristodoulou Christos 
Published: March 2015

ObjectivesThere is a controversy about the impact of economic crisis on suicide rates in Greece. We analysed recent suicide data to identify who has been most affected and the relationships to economic and labour market indicators.SettingGreece.Primary and secondary outcome measuresAge-specific and sex-specific suicide rates in Greece for the period 2003–2012 were calculated using data provided by the Hellenic Statistical Authority. We performed a join-point analysis to identify discontinuities in suicide trends between 2003 and 2010, prior to austerity, and in 2011–2012, during the period of austerity. Regression models were used to assess relationships between unemployment, Gross Domestic Product (GDP) and suicide rates for the entire period by age and sex.ResultsThe mean suicide rate overall rose by 35% between 2010 and 2012, from 3.37 to 4.56/100 000 population. The suicide mortality rate for men increased from 5.75 (2003–2010) to 7.43/100 000 (2011–2012; p<0.01). Among women, the suicide rate also rose, albeit less markedly, from 1.17 to 1.55 (p=0.03). When differentiated by age group, suicide mortality increased among both sexes in the age groups 20–59 and >60 years. We found that each additional percentage point of unemployment was associated with a 0.19/100 000 population rise in suicides (95% CI 0.11 to 0.26) among working age men.ConclusionsWe found a clear increase in suicides among persons of working age, coinciding with austerity measures. These findings corroborate concerns that increased suicide risk in Greece is a health hazard associated with austerity measures.
Recognition of the deteriorating patient
Authors: Spiers Laura , Singh Mohal Jagdeep , Pearson-Stuttard Jonathan , Greenlee Hannah , Carmichael Juliet , Busher Rebecca 
Published: March 2015

AbstractFollowing Sir Bruce Keogh’s review of 14 NHS Trusts, Buckinghamshire NHS Trust was found to have higher mortality rates than the England average. As part of a series of implementations and investigations to address this, a quality improvement project looking at clinical responses to the deteriorating patients was designed. Buckinghamshire NHS Trust utilises the National Early Warning Score (NEWS) metric for observations and escalation, and this was the standard used for the project. Episodes were eligible for inclusion if the NEWS score was increased to 5 or above. Data was collected by junior doctors from acute wards across the trust using notes and charts available. The initial cycle identified that in 57% of cases the high NEWS was escalated for review. Only half of cases were reviewed by a doctor; only a third were reviewed within an hour. In only 20% of cases were all criteria of the NEWS guidelines met. The first intervention was through education. After this, the project was completed on a monthly basis for 6 months with additional interventions introduced, including increased medical staff availability, grand round presentations, and increased outreach provision. Over this 6 month period, there was an increase to 87% of cases being reviewed by a doctor of appropriate seniority. Whilst this is a surrogate for reducing mortality and improving the clinical care given in the hospital, these results suggest successful interventions for improving clinical response to deteriorating patients across the trust. The project has recruited a new cohort of juniors to continue the quality improvement cycle.
Full-Length Semaphorin-3C Is an Inhibitor of Tumor Lymphangiogenesis and Metastasis
Authors: Mumblat Yelena , Kessler Ofra , Ilan Neta , Neufeld Gera 
Published: March 2015

Abstract
Semaphorins play important regulatory roles in diverse processes such as axon guidance, angiogenesis, and immune responses. We find that semaphorin-3C (sema3C) induces the collapse of the cytoskeleton of lymphatic endothelial cells (LEC) in a neuropilin-2-, plexin-D1-, and plexin-A1–dependent manner, while most other semaphorins, including antiangiogenic semaphorins such as sema3A do not. Sema3C is cleaved, like other class-3 semaphorins, by furin-like pro-protein convertases (FPPC). Cleaved sema3C (p65-Sema3C) was unable to induce the collapse of the cytoskeleton of LEC. FPPC are strongly upregulated in tumor cells. In order to examine the effects of full-length sema3C on tumor progression, we therefore generated an active point mutated furin cleavage-resistant sema3C (FR-sema3C). FR-sema3C inhibited potently proliferation of LEC and to a lesser extent proliferation of human umbilical vein–derived endothelial cells. FR-sema3C also inhibited VEGF-C–induced phosphorylation of VEGFR-3, ERK1/2, and AKT. Expression of recombinant FR-sema3C in metastatic, triple-negative LM2-4 breast cancer cells did not affect their migration or proliferation in vitro. However, tumors derived from FR-sema3C–expressing LM2-4 cells implanted in mammary fat pads developed at a slower rate, contained a lower concentration of blood vessels and lymph vessels, and metastasized much less effectively to lymph nodes. Interestingly, p65-Sema3C, but not FR-sema3C, rendered A549 lung cancer cells resistant to serum deprivation, suggesting that previously reported protumorigenic activities of sema3C may be due to p65-Sema3C produced by tumor cells. Our observations suggest that FR-sema3C may be further developed into a novel antitumorigenic drug. Cancer Res; 75(11); 2177–86. ©2015 AACR.
Development of Resistance to EGFR-Targeted Therapy in Malignant Glioma Can Occur through EGFR-Dependent and -Independent Mechanisms
Authors: Klingler Stefan , Guo Baofeng , Yao Jun , Yan Haiyan , Zhang Ling , Vaseva Angelina V. , Chen Sida , Canoll Peter , Horner James W. , Wang Y. Alan , Paik Ji-Hye , Ying Haoqiang , Zheng Hongwu 
Published: March 2015

Abstract
Epidermal growth factor receptor (EGFR) is highly amplified, mutated, and overexpressed in human malignant gliomas. Despite its prevalence and growth-promoting functions, therapeutic strategies to inhibit EGFR kinase activity have not been translated into profound beneficial effects in glioma clinical trials. To determine the roles of oncogenic EGFR signaling in gliomagenesis and tumor maintenance, we generated a novel glioma mouse model driven by inducible expression of a mutant EGFR (EGFR*). Using combined genetic and pharmacologic interventions, we revealed that EGFR*-driven gliomas were insensitive to EGFR tyrosine kinase inhibitors, although they could efficiently inhibit EGFR* autophosphorylation in vitro and in vivo. This is in contrast with the genetic suppression of EGFR* induction that led to significant tumor regression and prolonged animal survival. However, despite their initial response to genetic EGFR* extinction, all tumors would relapse and propagate independent of EGFR*. We further showed that EGFR*-independent tumor cells existed prior to treatment and were responsible for relapse following genetic EGFR* suppression. And, the addition of a PI3K/mTOR inhibitor could significantly delay relapse and prolong animal survival. Our findings shed mechanistic insight into EGFR drug resistance in glioma and provide a platform to test therapies targeting aberrant EGFR signaling in this setting. Cancer Res; 75(10); 2109–19. ©2015 AACR.
Identification of Rare High-Avidity, Tumor-Reactive CD8+ T Cells by Monomeric TCR–Ligand Off-Rates Measurements on Living Cells
Authors: Hebeisen Michael , Schmidt Julien , Guillaume Philippe , Baumgaertner Petra , Speiser Daniel E. , Luescher Immanuel , Rufer Nathalie 
Published: March 2015

AbstractThe avidity of the T-cell receptor (TCR) for antigenic peptides presented by the peptide–MHC (pMHC) on cells is a key parameter for cell-mediated immunity. Yet a fundamental feature of most tumor antigen-specific CD8+ T cells is that this avidity is low. In this study, we addressed the need to identify and select tumor-specific CD8+ T cells of highest avidity, which are of the greatest interest for adoptive cell therapy in patients with cancer. To identify these rare cells, we developed a peptide–MHC multimer technology, which uses reversible Ni2+-nitrilotriacetic acid histidine tags (NTAmers). NTAmers are highly stable but upon imidazole addition, they decay rapidly to pMHC monomers, allowing flow-cytometric–based measurements of monomeric TCR–pMHC dissociation rates of living CD8+ T cells on a wide avidity spectrum. We documented strong correlations between NTAmer kinetic results and those obtained by surface plasmon resonance. Using NTAmers that were deficient for CD8 binding to pMHC, we found that CD8 itself stabilized the TCR–pMHC complex, prolonging the dissociation half-life several fold. Notably, our NTAmer technology accurately predicted the function of large panels of tumor-specific T cells that were isolated prospectively from patients with cancer. Overall, our results demonstrated that NTAmers are effective tools to isolate rare high-avidity cytotoxic T cells from patients for use in adoptive therapies for cancer treatment. Cancer Res; 75(10); 1983–91. ©2015 AACR.
PLZF, a Tumor Suppressor Genetically Lost in Metastatic Castration-Resistant Prostate Cancer, Is a Mediator of Resistance to Androgen Deprivation Therapy
Authors: Hsieh Chen-Lin , Botta Ginevra , Gao Shuai , Li Tiantian , Van Allen Eliezer M. , Treacy Daniel J. , Cai Changmeng , He Housheng Hansen , Sweeney Christopher J. , Brown Myles , Balk Steven P. , Nelson Peter S. , Garraway Levi A. , Kantoff Philip W. 
Published: March 2015

Abstract
Whole-exome sequencing of metastatic castration-resistant prostate cancer (mCRPC) reveals that 5% to 7% of tumors harbor promyelocytic leukemia zinc finger (PLZF) protein homozygous deletions. PLZF is a canonical androgen-regulated putative tumor suppressor gene whose expression is inhibited by androgen deprivation therapy (ADT). Here, we demonstrate that knockdown of PLZF expression promotes a CRPC and enzalutamide-resistant phenotype in prostate cancer cells. Reintroduction of PLZF expression is sufficient to reverse androgen-independent growth mediated by PLZF depletion. PLZF loss enhances CRPC tumor growth in a xenograft model. Bioinformatic analysis of the PLZF cistrome shows that PLZF negatively regulates multiple pathways, including the MAPK pathway. Accordingly, our data support an oncogenic program activated by ADT. This acquired mechanism together with the finding of genetic loss in CRPC implicates PLZF inactivation as a mechanism promoting ADT resistance and the CRPC phenotype. Cancer Res; 75(10); 1944–8. ©2015 AACR.
Racial Variation in Breast Tumor Promoter Methylation in the Carolina Breast Cancer Study
Authors: Conway Kathleen , Edmiston Sharon N. , Tse Chiu-Kit , Bryant Christopher , Kuan Pei Fen , Hair Brionna Y. , Parrish Eloise A. , May Ryan , Swift-Scanlan Theresa 
Published: March 2015

Abstract
Background: African American (AA) women are diagnosed with more advanced breast cancers and have worse survival than white women, but a comprehensive understanding of the basis for this disparity remains unclear. Analysis of DNA methylation, an epigenetic mechanism that can regulate gene expression, could help to explain racial differences in breast tumor clinical biology and outcomes.
Methods: DNA methylation was evaluated at 1,287 CpGs in the promoters of cancer-related genes in 517 breast tumors of AA (n = 216) or non-AA (n = 301) cases in the Carolina Breast Cancer Study (CBCS).
Results: Multivariable linear regression analysis of all tumors, controlling for age, menopausal status, stage, intrinsic subtype, and multiple comparisons [false discovery rate (FDR)], identified seven CpG probes that showed significant (adjusted P &lt; 0.05) differential methylation between AAs and non-AAs. Stratified analyses detected an additional four CpG probes differing by race within hormone receptor–negative (HR−) tumors. Genes differentially methylated by race included DSC2, KCNK4, GSTM1, AXL, DNAJC15, HBII-52, TUSC3, and TES; the methylation state of several of these genes may be associated with worse survival in AAs. TCGA breast tumor data confirmed the differential methylation by race and negative correlations with expression for most of these genes. Several loci also showed racial differences in methylation in peripheral blood leukocytes (PBL) from CBCS cases, indicating that these variations were not necessarily tumor-specific.
Conclusions: Racial differences in the methylation of cancer-related genes are detectable in both tumors and PBLs from breast cancer cases.
Impact: Epigenetic variation could contribute to differences in breast tumor development and outcomes between AAs and non-AAs. Cancer Epidemiol Biomarkers Prev; 24(6); 921–30. ©2015 AACR.
Folate Pathway Gene Polymorphisms and Risk of Childhood Brain Tumors: Results from an Australian Case–Control Study
Authors: Greenop Kathryn R. , Scott Rodney J. , Attia John , Bower Carol , de Klerk Nicholas H. , Norris Murray D. , Haber Michelle , Jamieson Sarra E. , van Bockxmeer Frank M. , Gottardo Nicholas G. , Ashton Lesley J. , Armstrong Bruce K. , Milne Elizabeth 
Published: March 2015

Abstract
Background: Recent research suggests that maternal folic acid supplementation is associated with a reduced risk of childhood brain tumors (CBT); polymorphisms in folate pathway genes could modify this association or directly influence CBT risk.
Methods: Associations between risk of CBT and folate pathway polymorphisms were investigated in a population-based case–control study in Australia (2005–2010). Cases were recruited through all Australian pediatric oncology centers and controls by national random digit dialing. Data were available from 321 cases and 552 controls. Six polymorphisms were genotyped in children and parents (MTHFR 677C&gt;T, MTHFR 1298A&gt;C, MTRR 66A&gt;G, MTR 2756A&gt;G, MTR 5049C&gt;A, and CBS 2199 T&gt;C). Maternal folic acid use was ascertained via questionnaire. ORs were estimated using unconditional logistic regression. Case–parent trio analyses were also undertaken.
Results: There was weak evidence of a reduced risk of CBT for the MTRR 66GG genotype in the child or father: ORs 0.71 [95% confidence interval (CI), 0.48–1.07]; 0.54 (95% CI, 0.34–0.87), respectively. Maternal prepregnancy folic acid supplementation showed a stronger negative association with CBT risk where the child, mother, or father had the MTRR 66GG genotype (Pinteraction = 0.07, 0.10, and 0.18, respectively).
Conclusions: Evidence for an association between folate pathway genotypes and CBT is limited in this study. There was possible protection by the MTRR 66GG genotype, particularly when combined with maternal prepregnancy folic acid supplementation; these results are novel and require replication.
Impact: The possible interaction between folic acid supplementation and MTRR 66A&gt;G, if confirmed, would strengthen evidence for prepregnancy folate protection against CBT. Cancer Epidemiol Biomarkers Prev; 24(6); 931–7. ©2015 AACR.
Molecular Pathways: GLI1-Induced Drug Glucuronidation in Resistant Cancer Cells
Authors: Zahreddine Hiba Ahmad , Borden Katherine L.B. 
Published: March 2015

Abstract
Drug resistance remains a major impediment in the development of durable cancer therapies. Studies in acute myelogenous leukemia (AML) patients revealed a new form of multidrug resistance. Here, increased glioma-associated protein GLI1 leads to elevation of the UDP-glucuronosyl transferase (UGT) enzymes. UGTs add glucuronic acid to xenobiotics and metabolites. Traditionally, the loss of these enzymes is thought to contribute to cancer as a result of impaired clearance of environmental carcinogens. However, we demonstrate that overexpression of UGTs can contribute to oncogenesis by promoting drug resistance. Indeed, UGT levels in AML patients treated with ribavirin and/or cytarabine were elevated at relapse relative to diagnosis. This was reversed by GLI1 inhibition, suggesting a clinically relevant strategy to overcome drug resistance. Further, overexpression of UGTs can also lead to drug resistance in other cancers, such as certain Hsp90 inhibitors and vorinostat in colorectal and chronic lymphoblastic leukemia, respectively. Not all drugs are targets of glucuronidation, suggesting that UGT status could be relevant to treatment choice. Here, we describe several facets of UGT biology and how these could be exploited clinically. These studies demonstrate how drugs in cancer cells can be metabolized differentially than their normal counterparts. In summary, we describe a new form of drug resistance relevant to a variety of cancer contexts. Clin Cancer Res; 21(10); 2207–10. ©2015 AACR.