bluuebunny/crossref_metadata_2025_split huggingface dataset:
HIV-1 gp120 Determinants Proximal to the CD4 Binding Site Shift Protective Glycans That Are Targeted by Monoclonal Antibody 2G12
Authors: Duenas-Decamp Maria J. , Clapham Paul R. 
Published: July 2010

ABSTRACT
HIV-1 R5 envelopes vary considerably in their capacities to exploit low CD4 levels on macrophages for infection and in their sensitivities to the CD4 binding site (CD4bs) monoclonal antibody (MAb) b12 and the glycan-specific MAb 2G12. Here, we show that nonglycan determinants flanking the CD4 binding loop, which affect exposure of the CD4bs, also modulate 2G12 neutralization. Our data indicate that such residues act via a mechanism that involves shifts in the orientation of proximal glycans, thus modulating the sensitivity of 2G12 neutralization and affecting the overall presentation and structure of the glycan shield.
Different Strains of Theiler's Murine Encephalomyelitis Virus Antagonize Different Sites in the Type I Interferon Pathway
Authors: Stavrou Spyridon , Feng Zongdi , Lemon Stanley M. , Roos Raymond P. 
Published: July 2010

ABSTRACT

The DA strain of Theiler's murine encephalomyelitis virus (TMEV), a member of the
Cardiovirus
genus of the family
Picornaviridae
, causes persistent infection in susceptible mice, associated with restricted expression of viral proteins, and induces a demyelinating disease of the central nervous system. DA-induced demyelinating disease serves as a model of human multiple sclerosis because of similarities in pathology and because host immune responses contribute to pathogenesis in both disorders. In contrast, the GDVII strain of TMEV causes acute lethal encephalitis with no virus persistence. Cardiovirus L is a multifunctional protein that blocks beta interferon (IFN-β) gene transcription. We show that both DA L and GDVII L disrupt IFN-β gene transcription induction by IFN regulatory factor 3 (IRF-3) but do so at different points in the signaling pathway. DA L blocks IFN-β gene transcription downstream of mitochondrial antiviral signaling protein (MAVS) but upstream of IRF-3 activation, while GDVII L acts downstream of IRF-3 activation. Both DA L and GDVII L block IFN-β gene transcription in infected mice; however, IFN-β mRNA is expressed at low levels in the central nervous systems of mice persistently infected with DA. The particular level of IFN-β mRNA expression set by DA L as well as other factors in the IRF-3 pathway may play a role in virus persistence, inflammation, and the restricted expression of viral proteins during the late stage of demyelinating disease.
Dominant Negative Mutants of the Murine Cytomegalovirus M53 Gene Block Nuclear Egress and Inhibit Capsid Maturation
Authors: Popa Mirela , Ruzsics Zsolt , Lötzerich Mark , Dölken Lars , Buser Christopher , Walther Paul , Koszinowski Ulrich H. 
Published: July 2010

ABSTRACT

The alphaherpesvirus proteins UL31 and UL34 and their homologues in other herpesvirus subfamilies cooperate at the nuclear membrane in the export of nascent herpesvirus capsids. We studied the respective betaherpesvirus proteins M53 and M50 in mouse cytomegalovirus (MCMV). Recently, we established a random approach to identify dominant negative (DN) mutants of essential viral genes and isolated DN mutants of M50 (B. Rupp, Z. Ruzsics, C. Buser, B. Adler, P. Walther and U. H. Koszinowski, J. Virol
81:
5508-5517). Here, we report the identification and phenotypic characterization of DN alleles of its partner, M53. While mutations in the middle of the M53 open reading frame (ORF) resulted in DN mutants inhibiting MCMV replication by ∼100-fold, mutations at the C terminus resulted in up to 1,000,000-fold inhibition of virus production. C-terminal DN mutants affected nuclear distribution and steady-state levels of the nuclear egress complex and completely blocked export of viral capsids. In addition, they induced a marked maturation defect of viral capsids, resulting in the accumulation of nuclear capsids with aberrant morphology. This was associated with a two-thirds reduction in the total amount of unit length genomes, indicating an accessory role for M53 in DNA packaging.
Remarkable Lethal G-to-A Mutations in
vif-
Proficient HIV-1 Provirus by Individual APOBEC3 Proteins in Humanized Mice
Authors: Sato Kei , Izumi Taisuke , Misawa Naoko , Kobayashi Tomoko , Yamashita Yoshiki , Ohmichi Masahide , Ito Mamoru , Takaori-Kondo Akifumi , Koyanagi Yoshio 
Published: July 2010

ABSTRACT

Genomic hypermutation of RNA viruses, including human immunodeficiency virus type 1 (HIV-1), can be provoked by intrinsic and extrinsic pressures, which lead to the inhibition of viral replication and/or the progression of viral diversity. Human APOBEC3G was identified as an HIV-1 restriction factor, which edits nascent HIV-1 DNA by inducing G-to-A hypermutations and debilitates the infectivity of
vif
-deficient HIV-1. On the other hand, HIV-1 Vif protein has the robust potential to degrade APOBEC3G protein. Although subsequent investigations have revealed that lines of APOBEC3 family proteins have the capacity to mutate HIV-1 DNA, it remains unclear whether these endogenous APOBEC3s, including APOBEC3G, contribute to mutations of
vif
-proficient HIV-1 provirus
in vivo
and, if so, what is the significance of these mutations. In this study, we use a human hematopoietic stem cell-transplanted humanized mouse (NOG-hCD34 mouse) model and demonstrate the predominant accumulation of G-to-A mutations in
vif
-proficient HIV-1 provirus displaying characteristics of APOBEC3-mediated mutagenesis. Notably, the APOBEC3-associated G-to-A mutation of HIV-1 DNA that leads to the termination of translation was significantly observed. We further provide a novel insight suggesting that HIV-1 G-to-A hypermutation is independently induced by individual APOBEC3 proteins. In contrast to the prominent mutation in intracellular proviral DNA, viral RNA in plasma possessed fewer G-to-A mutations. Taken together, these results provide the evidence indicating that endogenous APOBEC3s are associated with G-to-A mutation of HIV-1 provirus
in vivo
, which can result in the abrogation of HIV-1 infection.
Role of Peroxiredoxin 1 and Peroxiredoxin 4 in Protection of Respiratory Syncytial Virus-Induced Cysteinyl Oxidation of Nuclear Cytoskeletal Proteins
Authors: Jamaluddin Mohammad , Wiktorowicz John E. , Soman Kizhake V. , Boldogh Istvan , Forbus Jeffrey D. , Spratt Heidi , Garofalo Roberto P. , Brasier Allan R. 
Published: July 2010

ABSTRACT
The respiratory epithelium plays a central role in innate immunity by secreting networks of inflammatory mediators in response to respiratory syncytial virus (RSV) infection. Previous proteomic studies focusing on the host cellular response to RSV indicated the existence of a nuclear heat shock response and cytoplasmic depletion of antioxidant proteins in model type II-like airway epithelial cells. Here, we increased the depth of nuclear proteomic interrogation by using fluorescence difference labeling followed by liquid isoelectric focusing prefractionation/two-dimensional gel electrophoresis (2-DE) to identify an additional 41 proteins affected by RSV infection. Surprisingly, we found inducible oligomers and shifts in isoelectric points for peroxiredoxin 1 (Prdx-1), Prdx-3, and Prdx-4 isoforms without changes in their total abundance, indicating that Prdxs were being oxidized in response to RSV. To address the role of Prdx-1 and Prdx-4 in RSV infection, isoforms were selectively knocked down by small interfering RNA (siRNA) transfection. Cells lacking Prdx-1, Prdx-4, or both showed increased levels of reactive oxygen species formation and a higher level of protein carbonylation in response to RSV infection. Using a novel saturation fluorescence labeling 2-DE analysis, we showed that 15 unique proteins had enhanced oxidative modifications of at least >1.2-fold in the Prdx knockdowns in response to RSV, including annexin A2 and desmoplakin. Our results suggest that Prdx-1 and Prdx-4 are essential for preventing RSV-induced oxidative damage in a subset of nuclear intermediate filament and actin binding proteins in epithelial cells.
T Cell Responses Are Required for Protection from Clinical Disease and for Virus Clearance in Severe Acute Respiratory Syndrome Coronavirus-Infected Mice
Authors: Zhao Jincun , Zhao Jingxian , Perlman Stanley 
Published: July 2010

ABSTRACTA dysregulated innate immune response and exuberant cytokine/chemokine expression are believed to be critical factors in the pathogenesis of severe acute respiratory syndrome (SARS), caused by a coronavirus (SARS-CoV). However, we recently showed that inefficient immune activation and a poor virus-specific T cell response underlie severe disease in SARS-CoV-infected mice. Here, we extend these results to show that virus-specific T cells, in the absence of activation of the innate immune response, were sufficient to significantly enhance survival and diminish clinical disease. We demonstrated that T cells are responsible for virus clearance, as intravenous adoptive transfer of SARS-CoV-immune splenocytes orin vitro-generated T cells to SCID or BALB/c mice enhanced survival and reduced virus titers in the lung. Enhancement of the number of virus-specific CD8 T cells by immunization with SARS-CoV peptide-pulsed dendritic cells also resulted in a robust T cell response, earlier virus clearance, and increased survival. These studies are the first to show that T cells play a crucial role in SARS-CoV clearance and that a suboptimal T cell response contributes to the pathological changes observed in SARS. They also provide a new approach to SARS vaccine design.
The Mitogen-Activated Protein Kinase Kinase 4 Has a Pro-Oncogenic Role in Skin Cancer
Authors: Finegan Katherine G. , Tournier Cathy 
Published: July 2010

AbstractThe mitogen-activated protein kinase (MAPK) kinase 4 (MKK4) is a nonredundant component of stress-activated MAPK signaling modules. Its function in tumorigenesis remains highly controversial with some studies indicating that MKK4 is a tumor suppressor, whereas others have reported a pro-oncogenic role. To clarify the role of MKK4 in cancer, we have created a novel mouse model to test the effect of the specific loss of MKK4 in the epidermis on the formation of papillomas caused by activated ras mutation. We have discovered that skin-specific MKK4-deficient mice are resistant to carcinogen-induced tumorigenesis. One mechanism by which MKK4 promotes cell proliferation and the formation of tumors is by increasing epidermal growth factor receptor expression through the c-Jun NH2-terminal protein kinase/c-Jun signaling pathway. Together, our results provide the first genetic demonstration that MKK4 is essential to mediate the oncogenic effect of Ras in vivo, thereby validating MKK4 as a potential drug target for cancer therapy. Cancer Res; 70(14); 5797–806. ©2010 AACR.
Transiently Entrapped Circulating Tumor Cells Interact with Neutrophils to Facilitate Lung Metastasis Development
Authors: Huh Sung Jin , Liang Shile , Sharma Arati , Dong Cheng , Robertson Gavin P. 
Published: July 2010

AbstractIt is unknown why only a minority of circulating tumor cells trapped in lung capillaries form metastases and involvement of immune cells remains uncertain. A novel model has been developed in this study showing that neutrophils regulate lung metastasis development through physical interaction and anchoring of circulating tumor cells to endothelium. Human melanoma cells were i.v. injected into nude mice leading to the entrapment of many cancer cells; however, 24 hours later, very few remained in the lungs. In contrast, injection of human neutrophils an hour after tumor cell injection increased cancer cell retention by ∼3-fold. Entrapped melanoma cells produced and secreted high levels of a cytokine called interleukin-8 (IL-8), attracting neutrophils and increasing tethering β2 integrin expression by 75% to 100%. Intercellular adhesion molecule-1 on melanoma cells and β2 integrin on neutrophils interacted, promoting anchoring to vascular endothelium. Decreasing IL-8 secretion from melanoma cells lowered extracellular levels by 20% to 50%, decreased β2 integrin on neutrophils by ∼50%, and reduced neutrophil-mediated extravasation by 25% to 60%, resulting in ∼50% fewer melanoma cells being tethered to endothelium and retained in lungs. Thus, transendothelial migration and lung metastasis development decreased by ∼50%, showing that targeting IL-8 in melanoma cells has the potential to decrease metastasis development by disrupting interaction with neutrophils. Cancer Res; 70(14); 6071–82. ©2010 AACR.
A Novel Imaging Approach for Early Detection of Prostate Cancer Based on Endogenous Zinc Sensing
Authors: Ghosh Subrata K. , Kim Pilhan , Zhang Xiao-an , Yun Seok-Hyun , Moore Anna , Lippard Stephen J. , Medarova Zdravka 
Published: July 2010

Abstract
The early detection of prostate cancer is a life-saving event in patients harboring potentially aggressive disease. With the development of malignancy, there is a dramatic reduction in the zinc content of prostate tissue associated with the inability of cancer cells to accumulate the ion. In the current study, we used endogenous zinc as an imaging biomarker for prostate cancer detection and progression monitoring. We employed a novel fluorescent sensor for mobile zinc (ZPP1) to detect and monitor the development of prostate cancer in a transgenic mouse model of prostate adenocarcinoma, using in vivo optical imaging correlated with biological fluid-based methods. We showed that the progression of prostate cancer could be monitored in vivo judging by the decreasing zinc content in the prostates of tumor-bearing mice in an age-dependent manner. In a novel quantitative assay, we determined the concentration of mobile zinc in both prostate cell lysates and mouse prostate extracts through simple titration of the ZPP1 sensor. Our findings fulfill the promise of zinc-based prostate cancer diagnostics with the prospect for immediate clinical translation. Cancer Res; 70(15); 6119–27. ©2010 AACR.
AACR Centennial Series: The Biology of Cancer Metastasis: Historical Perspective
Authors: Talmadge James E. , Fidler Isaiah J. 
Published: July 2010

AbstractMetastasis resistant to therapy is the major cause of death from cancer. Despite almost 200 years of study, the process of tumor metastasis remains controversial. Stephen Paget initially identified the role of host-tumor interactions on the basis of a review of autopsy records. His “seed and soil” hypothesis was substantiated a century later with experimental studies, and numerous reports have confirmed these seminal observations. An improved understanding of the metastatic process and the attributes of the cells selected by this process is critical for the treatment of patients with systemic disease. In many patients, metastasis has occurred by the time of diagnosis, so metastasis prevention may not be relevant. Treating systemic disease and identifying patients with early disease should be our goal. Revitalized research in the past three decades has focused on new discoveries in the biology of metastasis. Even though our understanding of molecular events that regulate metastasis has improved, the contributions and timing of molecular lesion(s) involved in metastasis pathogenesis remain unclear. Review of the history of pioneering observations and discussion of current controversies should increase understanding of the complex and multifactorial interactions between the host and selected tumor cells that contribute to fatal metastasis and should lead to the design of successful therapy. Cancer Res; 70(14); 5649–69. ©2010 AACR.
Variation in Blame Attributions across Different Cancer Types
Authors: Marlow Laura A.V. , Waller Jo , Wardle Jane 
Published: July 2010

Abstract
Background: Cancer communication has begun to focus on prevention through lifestyle change. One possible consequence of this is that attitudes towards people with certain types of cancer could become increasingly negative. In this study, we assessed attributions of blame for five common cancers.
Methods: Data were collected as part of a population-based survey of women's attitudes to cancer. A sample of 1,620 women rated how much they would blame someone who had a diagnosis of breast cancer, cervical cancer, bowel cancer, lung cancer, and leukemia, as well as chlamydia and obesity.
Results: Few women attributed any blame for someone with leukemia or breast cancer (9% and 15%). The proportions attributing some blame for bowel cancer and cervical cancer were slightly higher (23% and 37%). Patients with lung cancer were considered at least partly to blame by 70% of respondents, approaching chlamydia (87%) and obesity (96%). Attributions of blame for bowel, cervical, and lung cancer were most common among those with more qualifications, and women who knew that cervical cancer was linked to sexual activity were more likely to attribute blame to it (48% versus 32%).
Conclusions: Cancers are not generally seen as a matter of personal responsibility, but lung cancer, and to a lesser extent, cervical and bowel cancer do attract blame attributions. Knowledge of the preventability of cancer seems to be associated with perceived responsibility.
Impact: Increasing awareness of the preventable nature of some cancers might affect blame attributions. Additional research is needed to explore the implications of these findings. Cancer Epidemiol Biomarkers Prev; 19(7); 1799–805. ©2010 AACR.
Fecal MicroRNAs as Novel Biomarkers for Colon Cancer Screening
Authors: Link Alexander , Balaguer Francesc , Shen Yan , Nagasaka Takeshi , Lozano Juan José , Boland C. Richard , Goel Ajay 
Published: July 2010

Abstract
Introduction: Colorectal cancer (CRC) is the second leading cause of cancer-related deaths, but currently available noninvasive screening programs have achieved only a modest decrease in mortality. MicroRNAs (miRNA) play an important role in a wide array of biological processes and are commonly dysregulated in neoplasia. We aimed to evaluate the feasibility of fecal miRNAs as biomarkers for colorectal neoplasia screening.
Materials and Methods: Total RNA was extracted from freshly collected stool samples from 8 healthy volunteers and 29 samples collected via fecal occult blood testing from subjects with normal colonoscopies, colon adenomas, and CRCs. miRNA expression analyses were done with TaqMan quantitative reverse transcription-PCR for a subset of miRNAs. Illumina miRNA microarray profiling was done to evaluate the differences in expression patterns between normal colonic mucosa tissues and stool samples from healthy subjects.
Results: We efficiently extracted miRNAs from stool specimens using our developed protocol. Data from independent experiments showed high reproducibility for miRNA extraction and expression. miRNA expression patterns were similar in stool specimens among healthy volunteers, and reproducible in stool samples that were collected serially in time from the same individuals. miRNA expression profiles from 29 patients showed higher expression of miR-21 and miR-106a in patients with adenomas and CRCs compared with individuals free of colorectal neoplasia.
Conclusion: Our data indicate that miRNAs could be extracted from stool easily and reproducibly. The stools of patients with colorectal neoplasms have unique and identifiable patterns of miRNA expression.
Impact: Fecal miRNAs may be an excellent candidate for the development of a noninvasive screening test for colorectal neoplasms. Cancer Epidemiol Biomarkers Prev; 19(7); 1766–74. ©2010 AACR.
Comparative Biomarker Expression and RNA Integrity in Biospecimens Derived from Radical Retropubic and Robot-Assisted Laparoscopic Prostatectomies
Authors: Ricciardelli Carmela , Bianco-Miotto Tina , Jindal Shalini , Dodd Thomas J. , Cohen Penelope A. , Marshall Villis R. , Sutherland Peter D. , Samaratunga Hemamali , Kench James G. , Dong Ying , Wang Hong , Clements Judith A. , Risbridger Gail P. , Sutherland Robert L. , Tilley Wayne D. , Horsfall David J. 
Published: July 2010

Abstract
Background: Knowledge of preanalytic conditions that biospecimens are subjected to is critically important because novel surgical procedures, tissue sampling, handling, and storage might affect biomarker expression or invalidate tissue samples as analytes for some technologies.
Methods: We investigated differences in RNA quality, gene expression by quantitative real-time PCR, and immunoreactive protein expression of selected prostate cancer biomarkers between tissues from retropubic radical prostatectomy (RRP) and robot-assisted laparoscopic prostatectomy (RALP). Sections of tissue microarray of 23 RALP and 22 RRP samples were stained with antibodies to androgen receptor (AR) and prostate-specific antigen (PSA) as intersite controls, and 14 other candidate biomarkers of research interest to three laboratories within the Australian Prostate Cancer BioResource tissue banking network. Quantitative real-time PCR was done for AR, PSA (KLK3), KLK2, KLK4, and HIF1A on RNA extracted from five RALP and five RRP frozen tissue cores.
Results: No histologic differences were observed between RALP and RRP tissue. Biomarker staining grouped these samples into those with increased (PSA, CK8/18, CKHMW, KLK4), decreased (KLK2, KLK14), or no change in expression (AR, ghrelin, Ki67, PCNA, VEGF-C, PAR2, YB1, p63, versican, and chondroitin 0-sulfate) in RALP compared with RRP tissue. No difference in RNA quality or gene expression was detected between RALP and RRP tissue.
Conclusions: Changes in biomarker expression between RALP and RRP tissue exist at the immunoreactive protein level, but the etiology is unclear.
Impact: Future studies should account for changes in biomarker expression when using RALP tissues, and mixed cohorts of RALP and RRP tissue should be avoided. Cancer Epidemiol Biomarkers Prev; 19(7); 1755–65. ©2010 AACR.
Knowledge and Attitudes about Vitamin D and Impact on Sun Protection Practices among Urban Office Workers in Brisbane, Australia
Authors: Vu Lan H. , van der Pols Jolieke C. , Whiteman David C. , Kimlin Michael G. , Neale Rachel E. 
Published: July 2010

Abstract
Background: Sun exposure is the main source of vitamin D. Increasing scientific and media attention to the potential health benefits of sun exposure may lead to changes in sun exposure behaviors.
Methods: To provide data that might help frame public health messages, we conducted an online survey among office workers in Brisbane, Australia, to determine knowledge and attitudes about vitamin D and associations of these with sun protection practices. Of the 4,709 people invited to participate, 2,867 (61%) completed the questionnaire. This analysis included 1,971 (69%) participants who indicated that they had heard about vitamin D.
Results: Lack of knowledge about vitamin D was apparent. Eighteen percent of people were unaware of the bone benefits of vitamin D but 40% listed currently unconfirmed benefits. Over half of the participants indicated that more than 10 minutes in the sun was needed to attain enough vitamin D in summer, and 28% indicated more than 20 minutes in winter. This was significantly associated with increased time outdoors and decreased sunscreen use. People believing sun protection might cause vitamin D deficiency (11%) were less likely to be frequent sunscreen users (summer odds ratio, 0.63; 95% confidence interval, 0.52-0.75).
Conclusions: Our findings suggest that there is some confusion about sun exposure and vitamin D, and that this may result in reduced sun-protective behavior.
Impact: More information is needed about vitamin D production in the skin. In the interim, education campaigns need to specifically address the vitamin D issue to ensure that skin cancer incidence does not increase. Cancer Epidemiol Biomarkers Prev; 19(7); 1784–9. ©2010 AACR.