bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effective Antiviral Treatment of Systemic Orthopoxvirus Disease: ST-246 Treatment of Prairie Dogs Infected with Monkeypox Virus
Authors: Smith Scott K. , Self Josh , Weiss Sonja , Carroll Darin , Braden Zach , Regnery Russell L. , Davidson Whitni , Jordan Robert , Hruby Dennis E. , Damon Inger K. 
Published: June 2011

ABSTRACTSmallpox preparedness research has led to development of antiviral therapies for treatment of serious orthopoxvirus infections. Monkeypox virus is an emerging, zoonotic orthopoxvirus which can cause severe and transmissible disease in humans, generating concerns for public health. Monkeypox virus infection results in a systemic, febrile-rash illness closely resembling smallpox. Currently, there are no small-molecule antiviral therapeutics approved to treat orthopoxvirus infections of humans. The prairie dog, using monkeypox virus as a challenge virus, has provided a valuable nonhuman animal model in which monkeypox virus infection closely resembles human systemic orthopoxvirus illness. Here, we assess the efficacy of the antiorthopoxvirus compound ST-246 in prairie dogs against a monkeypox virus challenge of 65 times the 50% lethal dose (LD50). Animals were infected intranasally and administered ST-246 for 14 days, beginning on days 0, 3, or after rash onset. Swab and blood samples were collected every 2 days and analyzed for presence of viral DNA by real-time PCR and for viable virus by tissue culture. Seventy-five percent of infected animals that received vehicle alone succumbed to infection. One hundred percent of animals that received ST-246 survived challenge, and animals that received treatment before symptom onset remained largely asymptomatic. Viable virus and viral DNA were undetected or at greatly reduced levels in animals that began treatment on 0 or 3 days postinfection, compared to control animals or animals treated post-rash onset. Animals treated after rash onset manifested illness, but all recovered. Our results indicate that ST-246 can be used therapeutically, following onset of rash illness, to treat systemic orthopoxvirus infections.
Cutaneous Human Papillomavirus Type 38 E7 Regulates Actin Cytoskeleton Structure for Increasing Cell Proliferation through CK2 and the Eukaryotic Elongation Factor 1A
Authors: Yue Jiping , Shukla Ruchi , Accardi Rosita , Zanella-Cleon Isabelle , Siouda Maha , Cros Marie-Pierre , Krutovskikh Vladimir , Hussain Ishraq , Niu Yamei , Hu Shiqiong , Becchi Michel , Jurdic Pierre , Tommasino Massimo , Sylla Bakary S. 
Published: June 2011

ABSTRACT

We previously reported that the oncoproteins E6 and E7 from cutaneous human papillomavirus type 38 (HPV38) can immortalize primary human keratinocytes
in vitro
and sensitize transgenic mice to develop skin cancer
in vivo
. Immunofluorescence staining revealed that human keratinocytes immortalized by HPV38 E6 and E7 display fewer actin stress fibers than do control primary keratinocyte cells, raising the possibility of a role of the viral oncoproteins in the remodeling of the actin cytoskeleton. In this study, we show that HPV38 E7 induces actin stress fiber disruption and that this phenomenon correlates with its ability to downregulate Rho activity. The downregulation of Rho activity by HPV38 E7 is mediated through the activation of the CK2–MEK–extracellular signal-regulated kinase (ERK) pathway. In addition, HPV38 E7 is able to induce actin fiber disruption by binding directly to eukaryotic elongation factor 1A (eEF1A) and abolishing its effects on actin fiber formation. Finally, we found that the downregulation of Rho activity by HPV38 E7 through the CK2-MEK-ERK pathway facilitates cell growth proliferation. Taken together, our data support the conclusion that HPV38 E7 promotes keratinocyte proliferation in part by negatively regulating actin cytoskeleton fiber formation through the CK2-MEK-ERK-Rho pathway and by binding to eEF1A and inhibiting its effects on actin cytoskeleton remodeling.
Ebolavirus Δ-Peptide Immunoadhesins Inhibit Marburgvirus and Ebolavirus Cell Entry
Authors: Radoshitzky Sheli R. , Warfield Kelly L. , Chi Xiaoli , Dong Lian , Kota Krishna , Bradfute Steven B. , Gearhart Jacqueline D. , Retterer Cary , Kranzusch Philip J. , Misasi John N. , Hogenbirk Marc A. , Wahl-Jensen Victoria , Volchkov Viktor E. , Cunningham James M. , Jahrling Peter B. , Aman M. Javad , Bavari Sina , Farzan Michael , Kuhn Jens H. 
Published: June 2011

ABSTRACT

With the exception of Reston and Lloviu viruses, filoviruses (marburgviruses, ebolaviruses, and “cuevaviruses”) cause severe viral hemorrhagic fevers in humans. Filoviruses use a class I fusion protein, GP
1,2
, to bind to an unknown, but shared, cell surface receptor to initiate virus-cell fusion. In addition to GP
1,2
, ebolaviruses and cuevaviruses, but not marburgviruses, express two secreted glycoproteins, soluble GP (sGP) and small soluble GP (ssGP). All three glycoproteins have identical N termini that include the receptor-binding region (RBR) but differ in their C termini. We evaluated the effect of the secreted ebolavirus glycoproteins on marburgvirus and ebolavirus cell entry, using Fc-tagged recombinant proteins. Neither sGP-Fc nor ssGP-Fc bound to filovirus-permissive cells or inhibited GP
1,2
-mediated cell entry of pseudotyped retroviruses. Surprisingly, several Fc-tagged Δ-peptides, which are small C-terminal cleavage products of sGP secreted by ebolavirus-infected cells, inhibited entry of retroviruses pseudotyped with Marburg virus GP
1,2
, as well as Marburg virus and Ebola virus infection in a dose-dependent manner and at low molarity despite absence of sequence similarity to filovirus RBRs. Fc-tagged Δ-peptides from three ebolaviruses (Ebola virus, Sudan virus, and Taï Forest virus) inhibited GP
1,2
-mediated entry and infection of viruses comparably to or better than the Fc-tagged RBRs, whereas the Δ-peptide-Fc of an ebolavirus nonpathogenic for humans (Reston virus) and that of an ebolavirus with lower lethality for humans (Bundibugyo virus) had little effect. These data indicate that Δ-peptides are functional components of ebolavirus proteomes. They join cathepsins and integrins as novel modulators of filovirus cell entry, might play important roles in pathogenesis, and could be exploited for the synthesis of powerful new antivirals.
Binding of the Mannose-Specific Lectin, Griffithsin, to HIV-1 gp120 Exposes the CD4-Binding Site
Authors: Alexandre Kabamba Bankoledi , Gray Elin S. , Pantophlet Ralph , Moore Penny L. , McMahon James B. , Chakauya Ereck , O'Keefe Barry R. , Chikwamba Rachel , Morris Lynn 
Published: June 2011

ABSTRACT
The glycans on HIV-1 gp120 play an important role in shielding neutralization-sensitive epitopes from antibody recognition. They also serve as targets for lectins that bind mannose-rich glycans. In this study, we investigated the interaction of the lectin griffithsin (GRFT) with HIV-1 gp120 and its effects on exposure of the CD4-binding site (CD4bs). We found that GRFT enhanced the binding of HIV-1 to plates coated with anti-CD4bs antibodies b12 and b6 or the CD4 receptor mimetic CD4-IgG2. The average enhancement of b12 or b6 binding was higher for subtype B viruses than for subtype C, while for CD4-IgG2, it was similar for both subtypes, although lower than observed with antibodies. This GRFT-mediated enhancement of HIV-1 binding to b12 was reflected in synergistic neutralization for 2 of the 4 viruses tested. The glycan at position 386, which shields the CD4bs, was involved in both GRFT-mediated enhancement of binding and neutralization synergism between GRFT and b12. Although GRFT enhanced CD4bs exposure, it simultaneously inhibited ligand binding to the coreceptor binding site, suggesting that GRFT-dependent enhancement and neutralization utilize independent mechanisms. This study shows for the first time that GRFT interaction with gp120 exposes the CD4bs through binding the glycan at position 386, which may have implications for how to access this conserved site.
Mutational Analysis of the Zippering Reaction during Flavivirus Membrane Fusion
Authors: Pangerl Karen , Heinz Franz X. , Stiasny Karin 
Published: June 2011

ABSTRACT

The current model of flavivirus membrane fusion is based on atomic structures of truncated forms of the viral fusion protein E in its dimeric prefusion and trimeric postfusion conformations. These structures lack the two transmembrane domains (TMDs) of E as well as the so-called stem, believed to be involved in an intra- and intermolecular zippering reaction within the E trimer during the fusion process. In order to gain experimental evidence for the functional role of the stem in flavivirus membrane fusion, we performed a mutagenesis study with recombinant subviral particles (RSPs) of tick-borne encephalitis virus, which have fusion properties similar to those of whole infectious virions and are an established model for viral fusion. Mutations were introduced into the stem as well as that part of E predicted to interact with the stem during zippering, and the effect of these mutations was analyzed with respect to fusion peptide interactions with target cells, E protein trimerization, trimer stability, and membrane fusion in an
in vitro
liposome fusion assay. Our data provide evidence for a molecular interaction between a conserved phenylalanine at the N-terminal end of the stem and a pocket in domain II of E, which appears to be essential for the positioning of the stem in an orientation that allows zippering and the formation of a structure in which the TMDs can interact as required for efficient fusion.
Current practice patterns among pathologists in the assessment of venous invasion in colorectal cancer
Authors: Messenger David E , Driman David K , McLeod Robin S , Riddell Robert H , Kirsch Richard 
Published: June 2011

AimsVenous invasion (VI) is a known independent prognostic indicator of recurrence and survival in colorectal cancer. The guidelines of the Royal College of Pathologists (RCPath) state that, in a series of resections, extramural VI should be detected in at least 25% of specimens. However, there is widespread variability in the reported incidence, and this may affect patient access to adjuvant therapy. This study aims to clarify the current practice patterns of pathologists regarding the assessment of VI and to identify factors associated with an increased self-reported VI detection rate.MethodsA population-based survey was mailed to 361 pathologists in the province of Ontario, Canada.ResultsThe overall response rate was 64.9%. Most pathologists were practicing in community-based centres (66.2%) and approximately half had been in practice for over 15 years (53.5%). A subspecialist interest in gastrointestinal (GI) pathology was declared by 27.3% of pathologists. The majority of pathologists (70.2%) reported that they detected VI in less than 10% of resection specimens, with only 9.1% reporting VI detection rates above 20%. Standardised reporting criteria were applied by 62.1%. Special stains were employed by 57.6% if VI was suspected on H&E-stained sections. Practice in a university-affiliated centre, a subspecialist interest in GI pathology and the acceptance of the ‘orphan arteriole’ sign were all independently associated with a self-reported VI detection rate above 10% on multivariate analysis.ConclusionsSelf-reported VI detection rates are low among most pathologists. Even among specialist GI pathologists practicing in university-affiliated centres, few reported a detection rate close to that recommended by the RCPath. Strategies to increase the detection of VI may be required.
ADP-Ribosylarginine Hydrolase Regulates Cell Proliferation and Tumorigenesis
Authors: Kato Jiro , Zhu Jianfeng , Liu Chengyu , Stylianou Mario , Hoffmann Victoria , Lizak Martin J. , Glasgow Connie G. , Moss Joel 
Published: June 2011

AbstractProtein ADP-ribosylation is a reversible posttranslational modification of uncertain significance in cancer. In this study, we evaluated the consequences for cancer susceptibility in the mouse of a genetic deletion of the enzyme responsible for removing mono-ADP–ribose moieties from arginines in cellular proteins. Specifically, we analyzed cancer susceptibility in animals lacking the ADP-ribosylarginine hydrolase (ARH1) that cleaves the ADP ribose–protein bond. ARH1−/− cells or ARH1−/− cells overexpressing an inactive mutant ARH1 protein (ARH1−/−+dm) had higher proliferation rates than either wild-type ARH1+/+ cells or ARH1−/− cells engineered to express the wild-type ARH1 enzyme. More significantly, ARH1−/− and ARH1+/− mice spontaneously developed lymphomas, adenocarcinomas, and metastases more frequently than wild-type ARH1+/+ mice. In ARH1+/− mice, we documented in all arising tumors mutation of the remaining wild-type allele (or loss of heterozygosity), illustrating the strict correlation that existed between tumor formation and absence of ARH1 gene function. Our findings show that proper control of protein ADP-ribosylation levels affected by ARH1 is essential for cancer suppression. Cancer Res; 71(15); 5327–35. ©2011 AACR.
Api6/AIM/Spα/CD5L Overexpression in Alveolar Type II Epithelial Cells Induces Spontaneous Lung Adenocarcinoma
Authors: Li Yuan , Qu Peng , Wu Lingyan , Li Beilin , Du Hong , Yan Cong 
Published: June 2011

Abstract
Chronic inflammation is an important contributor to the development of lung cancers, one of the most common malignancies worldwide, but the underlying molecular mechanisms of inflammation that specifically cue cancer risk remain poorly understood. Apoptosis inhibitor 6 (Api6, also known as AIM, Sp-α, and CD5L) is a downstream target gene of neutral lipids and peroxisome proliferator–activated receptor gamma in lung alveolar type II (AT II) epithelial cells. An association among increased expression of Api6 in certain settings of pathogenic lung inflammation in mice prompted us to hypothesize a possible role in cancer. Here, we report that Api6 promotes malignant transformation by limiting lung epithelial cell apoptosis and promoting immune escape. The specific function of Api6 in AT II cells was determined by using a doxycycline-inducible Api6 mouse model. Api6 overexpression inhibited apoptosis and activated oncogenic signaling in AT II lung epithelial cells, inducing emphysema and adenocarcinoma. In addition, Api6 overexpression in AT II cells increased the concentrations of proinflammatory cytokines/chemokines in bronchoalveolar lavage fluid and serum, promoting expansion of myeloid-derived suppressor cells (MDSC) in lung and blood but not in bone marrow or spleen. Lung MDSCs suppressed T-cell proliferation and activity in vitro and reduced levels of T cells in vivo following doxycycline treatment to activate Api6. Together, our findings establish that Api6 promotes lung tumorigenesis by blocking a mechanism of epithelial apoptosis that would normally support immunosurveillance. Cancer Res; 71(16); 5488–99. ©2011 AACR.
Discovery of a Small Molecule Targeting IRA2 Deletion in Budding Yeast and Neurofibromin Loss in Malignant Peripheral Nerve Sheath Tumor Cells
Authors: Wood Matthew , Rawe Melissa , Johansson Gunnar , Pang Shu , Soderquist Ryan S. , Patel Ami V. , Nelson Sandra , Seibel William , Ratner Nancy , Sanchez Yolanda 
Published: June 2011

Abstract
Malignant peripheral nerve sheath tumor (MPNST) is a life-threatening complication of neurofibromatosis type 1 (NF1). NF1 is caused by mutation in the gene encoding neurofibromin, a negative regulator of Ras signaling. There are no effective pharmacologic therapies for MPNST. To identify new therapeutic approaches targeting this dangerous malignancy, we developed assays in NF1+/+ and NF1−/− MPNST cell lines and in budding yeast lacking the NF1 homologue IRA2 (ira2Δ). Here, we describe UC1, a small molecule that targets NF1−/− cell lines and ira2Δ budding yeast. By using yeast genetics, we identified NAB3 as a high-copy suppressor of UC1 sensitivity. NAB3 encodes an RNA binding protein that associates with the C-terminal domain of RNA Pol II and plays a role in the termination of nonpolyadenylated RNA transcripts. Strains with deletion of IRA2 are sensitive to genetic inactivation of NAB3, suggesting an interaction between Ras signaling and Nab3-dependent transcript termination. This work identifies a lead compound and a possible target pathway for NF1-associated MPNST, and shows a novel model system approach to identify and validate target pathways for cancer cells in which NF1 loss drives tumor formation. Mol Cancer Ther; 10(9); 1740–50. ©2011 AACR.
EZH2 Promotes Malignant Phenotypes and Is a Predictor of Oral Cancer Development in Patients with Oral Leukoplakia
Authors: Cao Wei , Younis Rania H. , Li Jiang , Chen Haiyan , Xia Ronghui , Mao Li , Chen Wantao , Ren Hening 
Published: June 2011

Abstract
Oral leukoplakia (OL) is the most common premalignancy in the oral cavity. A small proportion of OLs progresses to oral squamous cell carcinoma (OSCC). To assess OSCC risk of OLs, we investigated the role of the transcriptional repressor enhancer of zeste homolog 2 (EZH2) in oral tumorigenesis and its clinical implication as an OSCC risk predictor. Immunohistochemistry was used to measure EZH2 expression in OLs from 76 patients, including 37 who later developed OSCC and 39 who did not. EZH2 expression was associated with clinicopathologic parameters and clinical outcomes. To determine the biological role of EZH2 in OL, EZH2 level was reduced using EZH2 siRNAs in Leuk-1 cells, its impact on cell cycle, anchorage-dependent/independent growth, and invasion was assessed. We observed strong EZH2 expression in 34 (45%), moderate expression in 26 (34%), and weak/no expression in 16 (21%) of the OLs. The higher EZH2 levels were strongly associated with dysplasia (P &lt; 0.001) and OSCC development (P &lt; 0.0001). Multivariate analysis indicated that EZH2 expression was the only independent factor for OSCC development (P &lt; 0.0001). At 5 years after diagnosis, 80% of patients whose OLs expressed strong EZH2 developed OSCC whereas only 24% patients with moderate and none with weak/no EZH2 expression did so (P &lt; 0.0001). In Leuk-1 cells, EZH2 downregulation resulted in G1 arrest; decreased invasion capability, decreased anchorage-independent growth; downregulation of cyclin D1 and upregulation of p15INK4B. Our data suggest that EZH2 plays an important role in OL malignant transformation and may be a biomarker in predicting OSCC development in patients with OLs. Cancer Prev Res; 4(11); 1816–24. ©2011 AACR.
Metabolic Syndrome and Risks of Colon and Rectal Cancer: The European Prospective Investigation into Cancer and Nutrition Study
Authors: Aleksandrova Krasimira , Boeing Heiner , Jenab Mazda , Bas Bueno-de-Mesquita H. , Jansen Eugene , van Duijnhoven Fränzel J.B. , Fedirko Veronika , Rinaldi Sabina , Romieu Isabelle , Riboli Elio , Romaguera Dora , Overvad Kim , Østergaard Jane Nautrup , Olsen Anja , Tjønneland Anne , Boutron-Ruault Marie-Christine , Clavel-Chapelon Françoise , Morois Sophie , Masala Giovanna , Agnoli Claudia , Panico Salvatore , Tumino Rosario , Vineis Paolo , Kaaks Rudolf , Lukanova Annekatrin , Trichopoulou Antonia , Naska Androniki , Bamia Christina , Peeters Petra H. , Rodríguez Laudina , Buckland Genevieve , Sánchez María-José , Dorronsoro Miren , Huerta Jose-María , Barricarte Aurelio , Hallmans Göran , Palmqvist Richard , Khaw Kay-Tee , Wareham Nicholas , Allen Naomi E. , Tsilidis Konstantinos K , Pischon Tobias 
Published: June 2011

Abstract
Metabolic syndrome (MetS) is purportedly related to risk of developing colorectal cancer; however, the association of MetS, as defined according to recent international criteria, and colorectal cancer has not been yet evaluated. In particular, it remains unclear to what extent the MetS components individually account for such an association. We addressed these issues in a nested case–control study that included 1,093 incident cases matched (1:1) to controls by using incidence density sampling. Conditional logistic regression was used to estimate relative risks (RR) and 95% CIs. MetS was defined according to the criteria of the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATPIII), the International Diabetes Federation (IDF), and the 2009 harmonized definition. Among individual components, abdominal obesity (RR = 1.51; 95% CI: 1.16–1.96) was associated with colon cancer, whereas abnormal glucose metabolism was associated with both colon (RR = 2.05; 95% CI: 1.57–2.68) and rectal cancer (RR = 2.07; 95% CI: 1.45–2.96). MetS, as defined by each of the definitions, was similarly associated with colon cancer (e.g., RR = 1.91; 95% CI: 1.47–2.42 for MetS by NCEP/ATPIII), whereas MetS by NCEP/ATPIII, but not IDF or harmonized definition, was associated with rectal cancer (RR = 1.45; 95% CI: 1.02–2.06). Overall, these associations were stronger in women than in men. However, the association between MetS and colorectal
cancer was accounted for by abdominal obesity and abnormal glucose metabolism such that MetS did not provide risk information beyond these components (likelihood ratio test P = 0.10 for MetS by NCEP/ATPIII). These data suggest that simple assessment of abnormal glucose metabolism and/or abdominal obesity to identify individuals at colorectal cancer risk may have higher clinical utility than applying more complex MetS definitions. Cancer Prev Res; 4(11); 1873–83. ©2011 AACR.
Similarities between Optimal Precursors that Trigger the Onset of Blocking Events and Optimally Growing Initial Errors in Onset Prediction
Authors: Mu Mu , Jiang Zhina 
Published: June 2011

AbstractA triangular T21, three-level, quasigeostrophic global spectral model was used to investigate how precursors relate to the predictability of blocking onset when a conditional nonlinear optimal perturbation approach is used. Here the authors focused on links between the optimal precursor to blocking onset and the optimally growing initial error in onset prediction.Numerical results have shown that during the prediction of blocking events, a type-1 optimally growing initial error, which causes an overprediction of blocking onset, bears the greatest resemblance to the optimal precursor, and both are distributed primarily over the blocking and its upstream regions. A type-2 optimally growing initial error is also characterized by a similar pattern, but with the opposite sign. Further analysis reveals that a type-1 optimally growing initial error has a similar growth behavior to that of the optimal precursor, and both develop into a dipole blocking anomaly pattern with a strong positive anomaly in the north and a weak negative anomaly to the south. The evolutionary mechanism of a type-1 optimally growing initial error during blocking onset can be explained in the same manner as that of an optimal precursor triggering blocking onset. This similarity between an optimal precursor and an optimally growing initial error also suggests that targeted observations over sensitive areas may be carried out in advance to eliminate optimally growing errors (as many as possible) in the prediction of blocking onset. Thus, the improved observation network will help to better capture the spatial structure of precursors that trigger blocking onset and will increase the ability to predict blocking events.