bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Mouse Monoclonal Antibody against Dengue Virus Type 1 Mochizuki Strain Targeting Envelope Protein Domain II and Displaying Strongly Neutralizing but Not Enhancing Activity
Authors: Yamanaka Atsushi , Kotaki Tomohiro , Konishi Eiji 
Published: September 2013

ABSTRACTDengue fever and its more severe form, dengue hemorrhagic fever, are major global concerns. Infection-enhancing antibodies are major factors hypothetically contributing to increased disease severity. In this study, we generated 26 monoclonal antibodies (MAbs) against the dengue virus type 1 Mochizuki strain. We selected this strain because a relatively large number of unique and rare amino acids were found on its envelope protein. Although most MAbs showing neutralizing activities exhibited enhancing activities at subneutralizing doses, one MAb (D1-IV-7F4 [7F4]) displayed neutralizing activities without showing enhancing activities at lower concentrations. In contrast, another MAb (D1-V-3H12 [3H12]) exhibited only enhancing activities, which were suppressed by pretreatment of cells with anti-FcγRIIa. Although antibody engineering revealed that antibody subclass significantly affected 7F4 (IgG3) and 3H12 (IgG1) activities, neutralizing/enhancing activities were also dependent on the epitope targeted by the antibody. 7F4 recognized an epitope on the envelope protein containing E118 (domain II) and had a neutralizing activity 10- to 1,000-fold stronger than the neutralizing activity of previously reported human or humanized neutralizing MAbs targeting domain I and/or domain II. An epitope-blocking enzyme-linked immunosorbent assay (ELISA) indicated that a dengue virus-immune population possessed antibodies sharing an epitope with 7F4. Our results demonstrating induction of these antibody species (7F4 and 3H12) in Mochizuki-immunized mice may have implications for dengue vaccine strategies designed to minimize induction of enhancing antibodies in vaccinated humans.
An HIV-1 Replication Pathway Utilizing Reverse Transcription Products That Fail To Integrate
Authors: Trinité Benjamin , Ohlson Eric C. , Voznesensky Igor , Rana Shashank P. , Chan Chi N. , Mahajan Saurabh , Alster Jason , Burke Sean A. , Wodarz Dominik , Levy David N. 
Published: September 2013

ABSTRACTIntegration is a central event in the replication of retroviruses, yet ≥90% of HIV-1 reverse transcripts fail to integrate, resulting in accumulation of unintegrated viral DNA in cells. However, understanding what role, if any, unintegrated viral DNA plays in the natural history of HIV-1 has remained elusive. Unintegrated HIV-1 DNA is reported to possess a limited capacity for gene expression restricted to early gene products and is considered a replicative dead end. Although the majority of peripheral blood CD4+T cells are refractory to infection, nonactivated CD4 T cells present in lymphoid and mucosal tissues are major targets for infection. Treatment with cytokine interleukin-2 (IL-2), IL-4, IL-7, or IL-15 renders CD4+T cells permissive to HIV-1 infection in the absence of cell activation and proliferation and provides a useful model for infection of resting CD4+T cells. We found that infection of cytokine-treated resting CD4+T cells in the presence of raltegravir or with integrase active-site mutant HIV-1 yieldedde novovirus production following subsequent T cell activation. Infection with integration-competent HIV-1 naturally generated a population of cells generating virus from unintegrated DNA. Latent infection persisted for several weeks and could be activated to virus production by a combination of a histone deacetylase inhibitor and a protein kinase C activator or by T cell activation. HIV-1 Vpr was essential for unintegrated HIV-1 gene expression andde novovirus production in this system. Bypassing integration by this mechanism may allow the preservation of genetic information that otherwise would be lost.
Bromo- and Extraterminal Domain Chromatin Regulators Serve as Cofactors for Murine Leukemia Virus Integration
Authors: Gupta Saumya Shree , Maetzig Tobias , Maertens Goedele N. , Sharif Azar , Rothe Michael , Weidner-Glunde Magdalena , Galla Melanie , Schambach Axel , Cherepanov Peter , Schulz Thomas F. 
Published: September 2013

ABSTRACT

Retroviral integrase (IN) proteins catalyze the permanent integration of proviral genomes into host DNA with the help of cellular cofactors. Lens epithelium-derived growth factor (LEDGF) is a cofactor for lentiviruses, including human immunodeficiency virus type 1 (HIV-1), and targets lentiviral integration toward active transcription units in the host genome. In contrast to lentiviruses, murine leukemia virus (MLV), a gammaretrovirus, tends to integrate near transcription start sites. Here, we show that the bromodomain and extraterminal domain (BET) proteins BRD2, BRD3, and BRD4 interact with gammaretroviral INs and stimulate the catalytic activity of MLV IN
in vitro
. We mapped the interaction site to a characteristic structural feature within the BET protein extraterminal (ET) domain and to three amino acids in MLV IN. The ET domains of different BET proteins stimulate MLV integration
in vitro
and, in the case of BRD2, also
in vivo
. Furthermore, two small-molecule BET inhibitors, JQ1 and I-BET, decrease MLV integration and shift it away from transcription start sites. Our data suggest that BET proteins might act as chromatin-bound acceptors for the MLV preintegration complex. These results could pave a way to redirecting MLV DNA integration as a basis for creating safer retroviral vectors.
The Human Interferon-Induced MxA Protein Inhibits Early Stages of Influenza A Virus Infection by Retaining the Incoming Viral Genome in the Cytoplasm
Authors: Xiao Han , Killip Marian J. , Staeheli Peter , Randall Richard E. , Jackson David 
Published: September 2013

ABSTRACT
The induction of an interferon-induced antiviral state is a powerful cellular response against viral infection that limits viral spread. Here, we show that a preexisting antiviral state inhibits the replication of influenza A viruses in human A549 cells by preventing transport of the viral genome to the nucleus and that the interferon-induced MxA protein is necessary but not sufficient for this process. This represents a previously unreported antiviral function of MxA against influenza A virus infection.
Human Parvovirus B19 Infection Causes Cell Cycle Arrest of Human Erythroid Progenitors at Late S Phase That Favors Viral DNA Replication
Authors: Luo Yong , Kleiboeker Steve , Deng Xuefeng , Qiu Jianming 
Published: September 2013

ABSTRACT

Human parvovirus B19 (B19V) infection has a unique tropism to human erythroid progenitor cells (EPCs) in human bone marrow and the fetal liver. It has been reported that both B19V infection and expression of the large nonstructural protein NS1 arrested EPCs at a cell cycle status with a 4 N DNA content, which was previously claimed to be “G
2
/M arrest.” However, a B19V mutant infectious DNA (M20
mTAD2
) replicated well in B19V-semipermissive UT7/Epo-S1 cells but did not induce G
2
/M arrest (S. Lou, Y. Luo, F. Cheng, Q. Huang, W. Shen, S. Kleiboeker, J. F. Tisdale, Z. Liu, and J. Qiu, J. Virol.
86:
10748–10758, 2012). To further characterize cell cycle arrest during B19V infection of EPCs, we analyzed the cell cycle change using 5-bromo-2′-deoxyuridine (BrdU) pulse-labeling and DAPI (4′,6-diamidino-2-phenylindole) staining, which precisely establishes the cell cycle pattern based on both cellular DNA replication and nuclear DNA content. We found that although both B19V NS1 transduction and infection immediately arrested cells at a status of 4 N DNA content, B19V-infected 4 N cells still incorporated BrdU, indicating active DNA synthesis. Notably, the BrdU incorporation was caused neither by viral DNA replication nor by cellular DNA repair that could be initiated by B19V infection-induced cellular DNA damage. Moreover, several S phase regulators were abundantly expressed and colocalized within the B19V replication centers. More importantly, replication of the B19V wild-type infectious DNA, as well as the M20
mTAD2
mutant, arrested cells at S phase. Taken together, our results confirmed that B19V infection triggers late S phase arrest, which presumably provides cellular S phase factors for viral DNA replication.
European Public Assessment Report (EPAR) summaries for the public: are they fit for purpose? A user-testing study
Authors: Raynor David K , Bryant David 
Published: September 2013

ObjectivesApply ‘user testing’ methodology to test the readability of a European Public Assessment Report (EPAR) summary—which describes how the decision was made by the European Medicines Agency to approve a medicine.DesignUser testing uses mixed methods (questionnaire and semistructured interview), applied iteratively, to assess document performance—can people find and understand key points of information.Setting and participantsTesting was undertaken with 40 members of the public in four consecutive rounds of 10. Inclusion criteria, matched across rounds, included range of ages and educational attainment.Tested documentsIn round 1 we tested 19 key points of information in a printed version of the EPAR summary for Bondronat (a cancer medicine). This was then revised to address the findings, and tested in round 2. In round 3 we tested the summary on-screen, and in round 4, tested a revised on-screen version, after addressing findings from both rounds 1 and 3.Primary outcome measureThe target followed European guidance for medicine leaflets: for each point of information 90% of participants should be able to find, and of those, 90% able to show understanding of the point.ResultsFor the original EPAR summary, 6 of the 19 points of information reached the target (both paper-based and on-screen). After revisions to format and content, using good practice in information writing and design, 14 and 16 points, respectively, met the target. The problems related to both finding (dependent on layout, headings and design) and understanding (words and sentences used, as well as design). We devised a new heading structure, increased use of bullet points, replaced difficult and technical words and divided long sentences.ConclusionsPeople had difficulty finding and understanding key messages in the summary, but user testing identified the problems, and application of good practice resulted in a revised format which performed well.
An economic evaluation of anonymised information sharing in a partnership between health services, police and local government for preventing violence-related injury
Authors: Florence Curtis , Shepherd Jonathan , Brennan Iain , Simon Thomas R 
Published: September 2013

ObjectiveTo assess the costs and benefits of a partnership between health services, police and local government shown to reduce violence-related injury.MethodsBenefit-cost analysis.ResultsAnonymised information sharing and use led to a reduction in wounding recorded by the police that reduced the economic and social costs of violence by £6.9 million in 2007 compared with the costs the intervention city, Cardiff UK, would have experienced in the absence of the programme. This includes a gross cost reduction of £1.25 million to the health service and £1.62 million to the criminal justice system in 2007. By contrast, the costs associated with the programme were modest: setup costs of software modifications and prevention strategies were £107 769, while the annual operating costs of the system were estimated as £210 433 (2003 UK pound). The cumulative social benefit-cost ratio of the programme from 2003 to 2007 was £82 in benefits for each pound spent on the programme, including a benefit-cost ratio of 14.80 for the health service and 19.1 for the criminal justice system. Each of these benefit-cost ratios is above 1 across a wide range of sensitivity analyses.ConclusionsAn effective information-sharing partnership between health services, police and local government in Cardiff, UK, led to substantial cost savings for the health service and the criminal justice system compared with 14 other cities in England and Wales designated as similar by the UK government where this intervention was not implemented.
Adjuvants That Improve the Ratio of Antigen-Specific Effector to Regulatory T Cells Enhance Tumor Immunity
Authors: Perret Rachel , Sierro Sophie R. , Botelho Natalia K. , Corgnac Stéphanie , Donda Alena , Romero Pedro 
Published: September 2013

Abstract
Antitumor immunity is strongly influenced by the balance of tumor antigen-specific effector T cells (Teff) and regulatory T cells (Treg). However, the impact that vaccine adjuvants have in regulating the balance of antigen-specific T-cell populations is not well understood. We found that antigen-specific Tregs were induced following subcutaneous vaccination with either OVA or melanoma-derived peptides, with a restricted expansion of Teffs. Addition of the adjuvants CpG-ODN or Poly(I:C) preferentially amplified Teffs over Tregs, dramatically increasing the antigen-specific Teff:Treg ratios and inducing polyfunctional effector cells. In contrast, two other adjuvants, imiquimod and Quil A saponin, favored an expansion of antigen-specific Tregs and failed to increase Teff:Treg ratios. Following therapeutic vaccination of tumor-bearing mice, high ratios of tumor-specific Teffs:Tregs in draining lymph nodes were associated with enhanced CD8+ T-cell infiltration at the tumor site and a durable rejection of tumors. Vaccine formulations of peptide+CpG-ODN or Poly(I:C) induced selective production of proinflammatory type I cytokines early after vaccination. This environment promoted CD8+ and CD4+ Teff expansion over that of antigen-specific Tregs, tipping the Teff to Treg balance to favor effector cells. Our findings advance understanding of the influence of different adjuvants on T-cell populations, facilitating the rational design of more effective cancer vaccines. Cancer Res; 73(22); 6597–608. ©2013 AACR.
Risk of Colorectal Cancer in Patients with Acute Myocardial Infarction and Stroke: A Nationwide Cohort Study
Authors: Erichsen Rune , Sværke Claus , Sørensen Henrik T. , Sandler Robert S. , Baron John A. 
Published: September 2013

Abstract
Background: An association between colorectal cancer and acute myocardial infarction (AMI) and stroke has been suggested, but evidence is conflicting.
Method: We conducted a population-based cohort study (1978–2010) of the association between AMI/stroke and colorectal cancer by linking nationwide Danish registries. We calculated standardized incidence ratios (SIR) of colorectal cancer after AMI/stroke as the ratios of observed to expected incidence.
Results: A total of 297,523 patients with AMI (median age, 69.4 years; 64% men) were followed for a median of 3.1 years (range, 0–33 years) and 4,387 developed colorectal cancer [SIR, 1.08; 95% confidence interval (CI), 1.05–1.11; P &lt; 0.001]. In the first year of follow-up, the SIR was 1.85 (95% CI, 1.73–1.98; P &lt; 0.001), whereas it was 0.98 (95% CI, 0.95–1.02; P = 0.318) in the second and subsequent years. We followed 246,998 patients with stroke (median age, 72.4 years; 52% men) for a median of 2.9 years (range, 0–33 years) and 3,035 developed colorectal cancer (SIR, 1.04; 95% CI, 1.00–1.07; P = 0.053). In the first year of follow-up, the SIR was 1.42 (95% CI, 1.31–1.53; P &lt; 0.001), whereas it was 0.96 (95% CI, 0.93–1.00; P = 0.072) thereafter. We found no difference between the SIRs for ischemic and hemorrhagic stroke. The increased one-year relative risks for AMI and stroke corresponded to a 0.3% absolute risk.
Conclusions: Our findings reflect detection of occult cancer at the time of the vascular event. The lack of increased risk after one year suggests that an association based on shared risk factors or chronic inflammation is unlikely.
Impact: In patients with AMI/stroke, the diagnostic workup including screening for colorectal cancer should follow that of the general population. Cancer Epidemiol Biomarkers Prev; 22(11); 1994–9. ©2013 AACR.
Monoclonal Antibody against Cell Surface GRP78 as a Novel Agent in Suppressing PI3K/AKT Signaling, Tumor Growth, and Metastasis
Authors: Liu Ren , Li Xiuqing , Gao Wenming , Zhou Yue , Wey Shiuan , Mitra Satyajit K. , Krasnoperov Valery , Dong Dezheng , Liu Shuanglong , Li Dan , Zhu Genyuan , Louie Stan , Conti Peter S. , Li Zibo , Lee Amy S. , Gill Parkash S. 
Published: September 2013

AbstractPurpose: The ER chaperone GRP78 translocates to the surface of tumor cells and promotes survival, metastasis, and resistance to therapy. An oncogenic function of cell surface GRP78 has been attributed to the activation of the phosphoinositide 3-kinase (PI3K) pathway. We intend to use a novel anti-GRP78 monoclonal antibody (MAb159) to attenuate PI3K signaling and inhibit tumor growth and metastasis.Experimental Design: MAb159 was characterized biochemically. Antitumor activity was tested in cancer cell culture, tumor xenograft models, tumor metastasis models, and spontaneous tumor models. Cancer cells and tumor tissues were analyzed for PI3K activity. MAb159 was humanized and validated for diagnostic and therapeutic application.Results: MAb159 specifically recognized surface GRP78, triggered GRP78 endocytosis, and localized to tumors but not to normal organs in vivo. MAb159 inhibited tumor cell proliferation and enhanced tumor cell death both in vitro and in vivo. In MAb159-treated tumors, PI3K signaling was inhibited without compensatory MAPK pathway activation. Furthermore, MAb159 halted or reversed tumor progression in the spontaneous PTEN–loss-driven prostate and leukemia tumor models, and inhibited tumor growth and metastasis in xenograft models. Humanized MAb159, which retains high affinity, tumor specific localization, and the antitumor activity, was nontoxic in mice, and had desirable pharmacokinetics.Conclusions: GRP78-specific antibody MAb159 modulates the PI3K pathway and inhibits tumor growth and metastasis. Humanized MAb159 will enter human trials shortly. Clin Cancer Res; 19(24); 6802–11. ©2013 AACR.
MTI-101 (Cyclized HYD1) Binds a CD44 Containing Complex and Induces Necrotic Cell Death in Multiple Myeloma
Authors: Gebhard Anthony W. , Jain Priyesh , Nair Rajesh R. , Emmons Michael F. , Argilagos Raul F. , Koomen John M. , McLaughlin Mark L. , Hazlehurst Lori A. 
Published: September 2013

AbstractOur laboratory recently reported that treatment with the d-amino acid containing peptide HYD1 induces necrotic cell death in multiple myeloma cell lines. Because of the intriguing biological activity and promising in vivo activity of HYD1, we pursued strategies for increasing the therapeutic efficacy of the linear peptide. These efforts led to a cyclized peptidomimetic, MTI-101, with increased in vitro activity and robust in vivo activity as a single agent using two myeloma models that consider the bone marrow microenvironment. MTI-101 treatment similar to HYD1 induced reactive oxygen species, depleted ATP levels, and failed to activate caspase-3. Moreover, MTI-101 is cross-resistant in H929 cells selected for acquired resistance to HYD1. Here, we pursued an unbiased chemical biology approach using biotinylated peptide affinity purification and liquid chromatography/tandem mass spectrometry analysis to identify binding partners of MTI-101. Using this approach, CD44 was identified as a predominant binding partner. Reducing the expression of CD44 was sufficient to induce cell death in multiple myeloma cell lines, indicating that multiple myeloma cells require CD44 expression for survival. Ectopic expression of CD44s correlated with increased binding of the FAM-conjugated peptide. However, ectopic expression of CD44s was not sufficient to increase the sensitivity to MTI-101–induced cell death. Mechanistically, we show that MTI-101–induced cell death occurs via a Rip1-, Rip3-, or Drp1-dependent and -independent pathway. Finally, we show that MTI-101 has robust activity as a single agent in the SCID-Hu bone implant and 5TGM1 in vivo model of multiple myeloma. Mol Cancer Ther; 12(11); 2446–58. ©2013 AACR.
PHD4 Stimulates Tumor Angiogenesis in Osteosarcoma Cells via TGF-α
Authors: Klotzsche-von Ameln Anne , Prade Ina , Grosser Marianne , Kettelhake Antje , Rezaei Maryam , Chavakis Triantafyllos , Flamme Ingo , Wielockx Ben , Breier Georg 
Published: September 2013

Abstract
Solid tumor growth is intimately associated with angiogenesis, a process that is efficiently triggered by hypoxia. Therefore, oxygen-sensitive signaling pathways are thought to play a critical role in tumor angiogenesis and progression. Here, the function of prolyl hydroxylase-4 (PHD4), a relative of the prolyl hydroxylase domain proteins 1–3 that promote the degradation of hypoxia-inducible factors (HIF), was interrogated. To test the hypothesis that PHD4 might inhibit tumor angiogenesis, it was overexpressed in osteosarcoma cells, and unexpectedly, this manipulation led to increased tumor blood vessel density. However, the newly formed blood vessels were smaller than normal and appeared to be partially nonfunctional, as indicated by poor vessel perfusion. PHD4 overexpression in tumor cells stimulated the expression of TGF-α, which was necessary and sufficient to promote angiogenic sprouting of endothelial cells. On the other hand, PHD4 overexpression reduced HIF-2α protein levels, which in turn inhibited in vivo tumor growth. Combined, elevated PHD4 levels deregulate angiogenesis via increased TGF-α expression in vitro and in vivo. These data support the hypothesis that tumor growth can be uncoupled from vessel density and that the individual PHD family members exert distinct functions in tumors.
Implications: PHD4 influences tumor growth and vascularization through discrete mechanisms and molecular pathways that likely have therapeutic potential. Mol Cancer Res; 11(11); 1337–48. ©2013 AACR.
Physical Activity Is Associated with Reduced Risk of Gastric Cancer: A Systematic Review and Meta-analysis
Authors: Singh Siddharth , Varayil Jithinraj Edakkanambeth , Devanna Swapna , Murad Mohammad Hassan , Iyer Prasad G. 
Published: September 2013

Abstract
Physical activity may be associated with reduced risk of gastric cancer. We performed a systematic review and meta-analysis to evaluate the magnitude of the association and the quality of supporting evidence. After a comprehensive search of bibliographic databases and conference proceedings through February 2013 for observational studies that examined associations between recreational and/or occupational physical activity and gastric cancer risk, we identified 16 studies (seven cohort, nine case control) reporting 11,111 cases of gastric cancer among 1,606,760 patients. Summary adjusted-OR estimates with 95% confidence intervals (CI) were estimated using the random-effects model. Meta-analysis demonstrated that the risk of gastric cancer was 21% lower among the most physically active people as compared with the least physically active people (OR = 0.79; 95% CI, 0.71–0.87) with moderate heterogeneity among studies (I2 = 55%). This protective effect was seen for gastric cancers in the cardia (four studies; OR = 0.80; 95% CI, 0.63–1.00) and distal stomach (five studies; OR = 0.63; 95% CI, 0.52–0.76). The effect size was significantly smaller in high-quality studies (six studies; OR = 0.86; 95% CI, 0.75–0.99), as compared with low-quality studies (10 studies; OR = 0.74; 95% CI, 0.69–0.81). The results were consistent across sex, study quality, study design, and geographic location. In conclusion, meta-analysis of published observational studies indicates that physical activity is associated with reduced risk of gastric cancer. Lifestyle interventions focusing on increasing physical activity may decrease the global burden of gastric cancer, in addition to a myriad of other health benefits. Cancer Prev Res; 7(1); 12–22. ©2013 AACR.