bluuebunny/crossref_metadata_2025_split huggingface dataset:
Residues Arg703, Asp777, and Arg781 of the RNase H Domain of Hepatitis B Virus Polymerase Are Critical for Viral DNA Synthesis
Authors: Ko Chunkyu , Shin Youn-Chul , Park Woo-Jin , Kim Seungtaek , Kim Jonghwa , Ryu Wang-Shick 
Published: October 2013

ABSTRACT
Hepatitis B virus (HBV) synthesizes its DNA genome through reverse transcription, which is catalyzed by viral polymerase (Pol). Previous studies suggested that the RNase H domain of hepadnaviral Pol may contribute to multiple steps of the viral genome replication, such as RNA encapsidation and viral DNA synthesis. However, specific residues of the RNase H domain that contribute to viral reverse transcription have not been determined. Therefore, we employed charged-to-alanine scanning mutagenesis to generate a set of single-substitution mutants of the RNase H domain and then analyzed their ability to support viral reverse transcription. Southern blot analysis showed that three mutants (R703A, D777A, and R781A mutants) yielded significantly reduced amounts of viral DNAs. However, none of these mutants were defective in RNA encapsidation. The data indicated that in the R703A and D777A mutants, minus-strand DNA synthesis was incomplete due to loss of catalytic activity of RNase H. In contrast, in the R781A mutant, the minus-strand DNA synthesis was near complete to some extent, while the plus-strand DNA synthesis (i.e., relaxed circular DNA) was severely impaired due to the defect in RNase H activity. Overall, our analysis revealed that three charged residues of the HBV Pol RNase H domain contribute to the catalysis of RNase H in removing the RNA template, but not in the RNA encapsidation.
Both HLA-B*57 and Plasma HIV RNA Levels Contribute to the HIV-Specific CD8
+
T Cell Response in HIV Controllers
Authors: Lécuroux Camille , Sáez-Cirión Asier , Girault Isabelle , Versmisse Pierre , Boufassa Faroudy , Avettand-Fenoël Véronique , Rouzioux Christine , Meyer Laurence , Pancino Gianfranco , Lambotte Olivier , Sinet Martine , Venet Alain 
Published: October 2013

ABSTRACT

CD8
+
T cell responses are thought to play an important role during HIV infection, particularly in HIV controllers (HIC) in whom viral replication is spontaneously controlled without any treatment. We have demonstrated that CD8
+
T cells from these subjects are able to suppress viral replication
in vitro
. In parallel, HIV-specific CD8
+
responses were shown to be strong and of high quality, with proliferative abilities and cytotoxic capacities, in HIC. The HLA-B*57 allele, which is associated with a better clinical outcome in HIV infection, is overrepresented in HIC. However, we showed that these patients constitute a heterogeneous group that includes subjects who present weak suppression of viral replication
in vitro
and HIV-specific responses. We performed an extensive study of 101 HIC (49 HLA-B*57
+
and 52 HLA-B*57
−
) to determine the impact of HLA-B*57 on the HIV-specific CD8
+
response. The HLA-B*57-restricted response displayed better qualitative features, such as higher functional avidity, higher proliferation capacity, and a higher level of cytokine production, than responses not restricted by HLA-B*57. However, the highest frequencies of HIV-specific CD8
+
T cells were observed only in a subset of HLA-B*57
+
subjects. They were tightly associated with the ability to suppress viral replication
in vitro
. In contrast, the subset of HLA-B*57
+
subjects with a weak ability to suppress viral replication had significantly lower ultrasensitive viral loads than all the other groups of controllers. In conclusion, both HLA-B*57 and the amount of ultrasensitive viral load seem to play a role in HIV-specific CD8
+
T cell responses in HIC.
Patient-initiated questions: How can doctors encourage them and improve the consultation process? A qualitative study
Authors: Murtagh G M , Furber L , Thomas A L 
Published: October 2013

ObjectiveTo investigate the circumstances under which patients initiate direct questions in oncology consultations.DesignConversation analysis of 47 consultations between oncologists and patients with cancer.SettingAn oncology clinic at a teaching hospital in the East Midlands.Participants16 Oncologists and 67 cancer patients.Outcome measurePatient initiated direct questions.ResultsOn the whole patients’ direct questions are designed to seek specific information regarding, the cancer itself, treatment options or their experience of symptoms. When patients do ask direct questions they typically follow the announcement of test results where some reference to the details of those results, is provided. More specifically, there seems to be a relation between showing the patient their scan/X-ray results, patient involvement and patient-initiated direct questions. Higher levels of patient-initiated direct questions were clustered around occasions where doctors provided information and explanations of test results (12 consultations) sometimes with direct reference to scan or X-ray results (7 consultations).ConclusionsThis study highlights the importance of careful explanation of diagnostic evidence as a factor contributing to increased patient involvement. More specifically, the findings suggest that, when appropriate, invoking diagnostic evidence (eg, scan or X-ray results) is an effective way of increasing levels of patient question asking. Doctors need to be able to encourage patient question asking to ensure that patients have at their disposal an important means through which they can determine their information needs. Although these results come from a study of oncology consultations, the findings may be transferable to other clinical contexts.
Social influence analysis and application on multimedia sharing websites
Authors: Sang Jitao , Xu Changsheng 
Published: October 2013

Social media is becoming popular these days, where users necessarily interact with each other to form social networks. Influence network, as one special case of social network, has been recognized as significantly impacting social activities and user decisions. We emphasize in this article that the inter-user influence is essentially topic-sensitive, as for different tasks users tend to trust different influencers and be influenced most by them. While existing research focuses on global influence modeling and applies to text-based networks, this work investigates the problem of topic-sensitive influence modeling in the multimedia domain.
According to temporal data justification, we propose a multimodal probabilistic model, considering both users' textual annotation and uploaded visual images. This model is capable of simultaneously extracting user topic distributions and topic-sensitive influence strengths. By identifying the topic-sensitive influencer, we are able to conduct applications, like collective search and collaborative recommendation. A risk minimization-based general framework for personalized image search is further presented, where the image search task is transferred to measure the distance of image and personalized query language models. The framework considers the noisy tag issue and enables easy incorporation of social influence. We have conducted experiments on a large-scale Flickr dataset. Qualitative as well as quantitative evaluation results have validated the effectiveness of the topic-sensitive influencer mining model, and demonstrated the advantage of incorporating topic-sensitive influence in personalized image search and topic-based image recommendation.
Understanding the role of phase function in translucent appearance
Authors: Gkioulekas Ioannis , Xiao Bei , Zhao Shuang , Adelson Edward H. , Zickler Todd , Bala Kavita 
Published: October 2013

Multiple scattering contributes critically to the characteristic translucent appearance of food, liquids, skin, and crystals; but little is known about how it is perceived by human observers. This article explores the perception of translucency by studying the image effects of variations in one factor of multiple scattering: the phase function. We consider an expanded space of phase functions created by linear combinations of Henyey-Greenstein and von Mises-Fisher lobes, and we study this physical parameter space using computational data analysis and psychophysics.
Our study identifies a two-dimensional embedding of the physical scattering parameters in a perceptually meaningful appearance space. Through our analysis of this space, we find uniform parameterizations of its two axes by analytical expressions of moments of the phase function, and provide an intuitive characterization of the visual effects that can be achieved at different parts of it. We show that our expansion of the space of phase functions enlarges the range of achievable translucent appearance compared to traditional single-parameter phase function models. Our findings highlight the important role phase function can have in controlling translucent appearance, and provide tools for manipulating its effect in material design applications.
Path exploration based on symbolic output
Authors: Qi Dawei , Nguyen Hoang D. T. , Roychoudhury Abhik 
Published: October 2013

Efficient program path exploration is important for many software engineering activities such as testing, debugging, and verification. However, enumerating all paths of a program is prohibitively expensive. In this article, we develop a partitioning of program paths based on the program output. Two program paths are placed in the same partition if they derive the output similarly, that is, the symbolic expression connecting the output with the inputs is the same in both paths. Our grouping of paths is gradually created by a smart path exploration. Our experiments show the benefits of the proposed path exploration in test-suite construction.
Our path partitioning produces a semantic signature of a program—describing all the different symbolic expressions that the output can assume along different program paths. To reason about changes between program versions, we can therefore analyze their semantic signatures. In particular, we demonstrate the applications of our path partitioning in testing and debugging of software regressions.
A Dose-Escalation Study of SAR3419, an Anti-CD19 Antibody Maytansinoid Conjugate, Administered by Intravenous Infusion Once Weekly in Patients with Relapsed/Refractory B-cell Non-Hodgkin Lymphoma
Authors: Ribrag Vincent , Dupuis Jehan , Tilly Herve , Morschhauser Franck , Laine Fabrice , Houot Roch , Haioun Corinne , Copie Christiane , Varga Andrea , Lambert John , Hatteville Laurence , Ziti-Ljajic Samira , Caron Anne , Payrard Sandrine , Coiffier Bertrand 
Published: October 2013

AbstractPurpose: To determine recommended dose, dose-limiting toxicity, safety profile, pharmacokinetics, preliminary antitumor activity, and exploratory pharmacodynamics of SAR3419, an antibody–drug conjugate targeting CD19, administered alone by intravenous infusion weekly (qw), in a dose-escalation phase I study in patients with refractory/relapsed (R/R) non-Hodgkin lymphoma (NHL).Experimental Design: Patients with R/R CD19+ B-NHL were treated with escalating doses of SAR3419 repeated qw for eight to 12 doses. On the basis of clinical evidence of late or cumulative toxicities, the study protocol was amended to test an “optimized” administration schedule consisting of four qw doses followed by four biweekly (q2w) doses (qw/q2w) at the recommended dose with the intent of reducing drug accumulation.Results: Forty-four patients were treated on seven dose levels ranging from 5 to 70 mg/m2. SAR3419 recommended dose was determined as 55 mg/m2 qw. Twenty-five patients received the qw/q2w schedule at 55 mg/m2, which showed an improved safety profile compared with the qw schedule. Antilymphoma activity was observed with both schedules in around 30% of patients with either indolent or aggressive diseases. SAR3419 displayed a long terminal half-life (approximately 7 days) and a low clearance (approximately 0.6 L/d), with no dose effect. The qw/q2w schedule allowed limiting accumulation with a decrease in SAR3419 plasma trough and average concentrations by around 1.4-fold compared with the qw schedule.Conclusion: While administered weekly, SAR3419 is well tolerated and active. The qw/q2w schedule that shows an improved safety profile and preserves antilymphoma activity is selected for clinical phase II studies. Clin Cancer Res; 20(1); 213–20. ©2013 AACR.
Loss of PTEN Expression Is Associated with Poor Prognosis in Patients with Intraductal Papillary Mucinous Neoplasms of the Pancreas
Authors: Garcia-Carracedo Dario , Turk Andrew T. , Fine Stuart A. , Akhavan Nathan , Tweel Benjamin C. , Parsons Ramon , Chabot John A. , Allendorf John D. , Genkinger Jeanine M. , Remotti Helen E. , Su Gloria H. 
Published: October 2013

Abstract
Purpose: Previously, we reported PIK3CA gene mutations in high-grade intraductal papillary mucinous neoplasms (IPMN). However, the contribution of phosphatidylinositol-3 kinase pathway (PI3K) dysregulation to pancreatic carcinogenesis is not fully understood and its prognostic value unknown. We investigated the dysregulation of the PI3K signaling pathway in IPMN and its clinical implication.
Experimental Design: Thirty-six IPMN specimens were examined by novel mutant-enriched sequencing methods for hot-spot mutations in the PIK3CA and AKT1 genes. PIK3CA and AKT1 gene amplifications and loss of heterozygosity at the PTEN locus were also evaluated. In addition, the expression levels of PDPK1/PDK1, PTEN, and Ki67 were analyzed by immunohistochemistry.
Results: Three cases carrying the E17K mutation in the AKT1 gene and one case harboring the H1047R mutation in the PIK3CA gene were detected among the 36 cases. PDK1 was significantly overexpressed in the high-grade IPMN versus low-grade IPMN (P = 0.034) and in pancreatic and intestinal-type of IPMN versus gastric-type of IPMN (P = 0.020). Loss of PTEN expression was strongly associated with presence of invasive carcinoma and poor survival in these IPMN patients (P = 0.014).
Conclusion: This is the first report of AKT1 mutations in IPMN. Our data indicate that oncogenic activation of the PI3K pathway can contribute to the progression of IPMN, in particular loss of PTEN expression. This finding suggests the potential employment of PI3K pathway-targeted therapies for IPMN patients. The incorporation of PTEN expression status in making surgical decisions may also benefit IPMN patients and should warrant further investigation. Clin Cancer Res; 19(24); 6830–41. ©2013 AACR.
Development, Characterization, and Reversal of Acquired Resistance to the MEK1 Inhibitor Selumetinib (AZD6244) in an In Vivo Model of Childhood Astrocytoma
Authors: Bid Hemant K. , Kibler Aaron , Phelps Doris A. , Manap Sagymbek , Xiao Linlin , Lin Jiayuh , Capper David , Oswald Duane , Geier Brian , DeWire Mariko , Smith Paul D. , Kurmasheva Raushan T. , Mo Xiaokui , Fernandez Soledad , Houghton Peter J. 
Published: October 2013

Abstract
Purpose: The BT-40 low-grade childhood astrocytoma xenograft model expresses mutated BRAFV600E and is highly sensitive to the MEK inhibitor selumetinib (AZD6244). In this study, we developed and characterized selumetinib resistance and explored approaches to circumventing the mechanisms of acquired resistance.
Experimental Design: BT-40 xenografts were selected in vivo for selumetinib resistance. Resistant tumors were obtained and characterized, as were tumors that reverted to sensitivity. Characterization included expression profiling, assessment of MEK signature and compensatory pathways, MEK inhibition, BRAF expression, and cytokine levels. Combination treatment of BT-40/AZD–resistant tumors with the MEK inhibitor and a STAT3 inhibitor (LLL12) was assessed.
Results: Resistance was unstable, tumors reverting to selumetinib sensitivity when passaged in untreated mice, and MEK was equally inhibited in sensitive and resistant tumors by selumetinib. Drug resistance was associated with an enhanced MEK signature and increased interleukin (IL)-6 and IL-8 expression. Selumetinib treatment induced phosphorylation of STAT3 (Y705) only in resistant xenografts, and similar results were observed in BRAFV600E astrocytic cell lines intrinsically resistant to selumetinib. Treatment of BT-40–resistant tumors with selumetinib or LLL12 had no significant effect, whereas combined treatment induced complete regressions of BT-40/AZD–resistant xenografts.
Conclusions: Resistance to selumetinib selected in vivo in BT-40 tumor xenografts was unstable. In resistant tumors, selumetinib activated STAT3, and combined treatment with selumetinib and LLL12 induced complete responses in resistant BT-40 tumors. These results suggest dual targeting BRAF (V600E) signaling and STAT3 signaling may be effective in selumetinib-resistant tumors or may retard or prevent onset of resistance. Clin Cancer Res; 19(24); 6716–29. ©2013 AACR.
αB-Crystallin: A Novel Regulator of Breast Cancer Metastasis to the Brain
Authors: Malin Dmitry , Strekalova Elena , Petrovic Vladimir , Deal Allison M. , Al Ahmad Abraham , Adamo Barbara , Miller C. Ryan , Ugolkov Andrey , Livasy Chad , Fritchie Karen , Hamilton Erika , Blackwell Kimberly , Geradts Joseph , Ewend Matt , Carey Lisa , Shusta Eric V. , Anders Carey K. , Cryns Vincent L. 
Published: October 2013

Abstract
Purpose: Basal-like breast tumors are typically (ER/PR/HER2) triple-negative and are associated with a high incidence of brain metastases and poor clinical outcomes. The molecular chaperone αB-crystallin is predominantly expressed in triple-negative breast cancer (TNBC) and contributes to an aggressive tumor phenotype in preclinical models. We investigated the potential role of αB-crystallin in brain metastasis in TNBCs.
Experimental Design: αB-crystallin expression in primary breast carcinomas and brain metastases was analyzed by immunohistochemistry among patients with breast cancer with brain metastases. αB-crystallin was overexpressed or silenced in two different TNBC cell lines. The effects on cell adhesion to human brain microvascular endothelial cells (HBMEC) or extracellular matrix proteins, transendothelial migration, and transmigration across a HBMEC/astrocyte coculture blood–brain barrier (BBB) model were examined. In addition, the effects of overexpressing or silencing αB-crystallin on brain metastasis in vivo were investigated using orthotopic TNBC models.
Results: In a cohort of women with breast cancer brain metastasis, αB-crystallin expression in primary breast carcinomas was associated with poor overall survival and poor survival after brain metastasis, even among patients with TNBC. Stable overexpression of αB-crystallin in TNBC cells enhanced adhesion to HBMECs, transendothelial migration, and BBB transmigration in vitro, whereas silencing αB-crystallin inhibited these events. αB-crystallin promoted adhesion of TNBC cells to HBMECs, at least in part, through an α3β1 integrin–dependent mechanism. αB-crystallin overexpression promoted brain metastasis, whereas silencing αB-crystallin inhibited brain metastasis in orthotopic TNBC models.
Conclusion: αB-crystallin is a novel regulator of brain metastasis in TNBC and represents a potential biomarker and drug target for this aggressive disease. Clin Cancer Res; 20(1); 56–67. ©2013 AACR.
Intracellular matrix metalloproteinase-2 (MMP-2) regulates human platelet activation via hydrolysis of talin
Authors: Mason Christopher , Lynch Stephen , Benjamin James , Ashak Dani , Prakash Jamunabai M. , Moore Andrew , Bagsiyao Pamela , Albert Trevine , Mathew Lynn M. , Jost Monika , Soslau Gerald 
Published: October 2013

SummaryMatrix metalloproteinase (MMP) activity is generally associated with normal or pathological extracellular processes such as tissue remodeling in growth and development or in tumor metastasis and angiogenesis. Platelets contain at least three MMPs, 1, 2 and 9 that have been reported to stimulate or inhibit agonist-induced platelet aggregation via extracellular signals. The non-selective Zn+2 chelating MMP inhibitor, 1,10-phenanthroline, and the serine protease inhibitor, AEBSF, were found to inhibit all tested agonist-induced platelet aggregation reactions. In vitro analysis demonstrated that 1,10-phenanthroline completely inhibited MMP-1,2,and 9 but had little to no effect on calpain activity while the converse was true with AEBSF. We now demonstrate that MMP-2 functions intracellularly to regulate agonistinduced platelet aggregations via the hydrolytic activation of talin, the presumed final activating factor of glycoprotein (GP)IIb/IIIa integrin (the inside-out signal). Once activated GPIIb/IIIa binds the dimeric fibrinogen molecule required for platelet aggregation. The active intracellular MMP-2 molecule is complexed with JAK 2/STAT 3, as demonstrated by the fact that all three proteins are co-immunoprecipitated with either anti-JAK 2, or anti-STAT 3 antibodies and by immunofluorescence studies. The MMP-2 platelet activation pathway can be synergistically inhibited with the non-selective MMP inhibitor, 1,10-phenanthroline, plus a JAK 2 inhibitor. This activation pathway is distinct from the previously reported calpain-talin activating pathway. The identification of a new central pathway for platelet aggregation presents new potential targets for drug regulation and furthers our understanding of the complexity of platelet activation mechanisms.
Reversing the new oral anticoagulants with prothrombin complex concentrates (PCCs): what is the evidence?
Authors: Hoffman Maureane , Dickneite Gerhard 
Published: October 2013

SummaryNewer oral anticoagulants offer several advantages over traditional agents (e.g. warfarin), but they are still associated with a bleeding risk and currently there is no validated reversal treatment for them. While there is little support for the use of fresh frozen plasma, and limited data available on the effects of activated recombinant factor VII, preclinical data suggest that prothrombin complex concentrates (PCCs) may have potential in this setting. PCCs are currently used to successfully reverse warfarin-induced anticoagulation; however, clinical evidence for their use with new oral anticoagulants is lacking, with most of the available data coming from preclinical animal studies. Furthermore, there appears to be variation in the ability of different PCCs to reverse the coagulopathy induced by the new anticoagulants, and a lack of correlation between the reversal of laboratory test results and the reversal of anticoagulant-induced bleeding. Although there have been encouraging results, care must be taken in generalising findings from animal models and nonbleeding human subjects to the situation in bleeding patients. Ultimately, more evidence supporting anticoagulation reversal for new anticoagulants is needed, particularly regarding the treatment of bleeding in human patients in a clinical setting. According to the current evidence, use of PCCs may be considered a reasonable approach in dire clinical situations; however, a consensus has not yet been reached regarding PCC use or dosing, due to lack of clinical data.