bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dengue Virus Infection with Highly Neutralizing Levels of Cross-Reactive Antibodies Causes Acute Lethal Small Intestinal Pathology without a High Level of Viremia in Mice
Authors: Watanabe Satoru , Chan Kitti Wing Ki , Wang Jiaqi , Rivino Laura , Lok Shee-Mei , Vasudevan Subhash G. 
Published: March 2015

ABSTRACT

Severe dengue virus (DENV)-associated diseases can occur in patients who have preexisting DENV antibodies (Abs) through antibody-dependent enhancement (ADE) of infection. It is well established that during ADE, DENV-antibody immune complexes (ICs) infect Fcγ receptor-bearing cells and increase the systemic viral burden that can be measured in the blood. For protection against infection with DENV serotypes 1 to 4, strongly neutralizing Abs must be elicited to overcome the effect of ADE. Clinical observations in infants who have maternal DENV Abs or recent phase II/III clinical trials with a leading tetravalent dengue vaccine suggested a lack of correlation between Ab neutralization and
in vivo
disease prevention. In addressing this gap in knowledge, we found that inoculation of ICs formed with serotype cross-reactive Abs that are more than 98% neutralized
in vitro
promotes high mortality in AG129 mice even though peak viremia was lower than that in direct virus infection. This suggests that the serum viremia level is not always correlated with disease severity. We further demonstrated that infection with the ICs resulted in increased vascular permeability, specifically in the small intestine, accompanied with increased tissue viral load and cytokine production, which can be suppressed by anti-tumor necrosis factor alpha (anti-TNF-α) Abs. Flow cytometric analysis identified increased infection in CD11b
int
CD11c
int/hi
CD103
−
antigen-presenting cells by IC inoculation, suggesting that these infected cells may be responsible for the increase in TNF-α production and vascular permeability in the small intestine that lead to mortality in mice. Our findings may have important implications for the development of dengue therapeutics.

IMPORTANCE
We examined the relationship between the neutralizing level of Abs at the time of infection and subsequent disease progression in a mouse model in order to understand why patients who are shown to have a neutralizing quantity of Abs still allow sufficient DENV replication to induce severe dengue manifestations, which sometimes do not correlate with viremia level. Strikingly, we found that high mortality was induced in AG129 mice by the increase in TNF-α-induced vascular permeability accompanied by an increased viral load, specifically in the small intestine, even when the initial infection level is suppressed to less than 5% and the peak viremia level is not enhanced. This suggests that ADE overcomes the protective efficacy of Abs in a tissue-dependent manner that leads to severe small intestinal pathology. Our findings may serve to address the pathogenic role of Abs on severe dengue disease and also help to develop safe Ab-based therapeutic strategies.
Receptor Usage and Cell Entry of Porcine Epidemic Diarrhea Coronavirus
Authors: Liu Chang , Tang Jian , Ma Yuanmei , Liang Xueya , Yang Yang , Peng Guiqing , Qi Qianqian , Jiang Shibo , Li Jianrong , Du Lanying , Li Fang 
Published: March 2015

ABSTRACT

Porcine epidemic diarrhea coronavirus (PEDV) has significantly damaged America's pork industry. Here we investigate the receptor usage and cell entry of PEDV. PEDV recognizes protein receptor aminopeptidase N from pig and human and sugar coreceptor
N
-acetylneuraminic acid. Moreover, PEDV infects cells from pig, human, monkey, and bat. These results support the idea of bats as an evolutionary origin for PEDV, implicate PEDV as a potential threat to other species, and suggest antiviral strategies to control its spread.
Emergence of Highly Pathogenic Avian Influenza A(H5N1) Virus PB1-F2 Variants and Their Virulence in BALB/c Mice
Authors: Kamal Ram P. , Kumar Amrita , Davis Charles T. , Tzeng Wen-Pin , Nguyen Tung , Donis Ruben O. , Katz Jacqueline M. , York Ian A. 
Published: March 2015

ABSTRACT

Influenza A viruses (IAVs) express the PB1-F2 protein from an alternate reading frame within the PB1 gene segment. The roles of PB1-F2 are not well understood but appear to involve modulation of host cell responses. As shown in previous studies, we find that PB1-F2 proteins of mammalian IAVs frequently have premature stop codons that are expected to cause truncations of the protein, whereas avian IAVs usually express a full-length 90-amino-acid PB1-F2. However, in contrast to other avian IAVs, recent isolates of highly pathogenic H5N1 influenza viruses had a high proportion of PB1-F2 truncations (15% since 2010; 61% of isolates in 2013) due to several independent mutations that have persisted and expanded in circulating viruses. One natural H5N1 IAV containing a mutated PB1-F2 start codon (i.e., lacking ATG) was 1,000-fold more virulent for BALB/c mice than a closely related H5N1 containing intact PB1-F2.
In vitro
, we detected expression of an in-frame protein (C-terminal PB1-F2) from downstream ATGs in PB1-F2 plasmids lacking the well-conserved ATG start codon. Transient expression of full-length PB1-F2, truncated (24-amino-acid) PB1-F2, and PB1-F2 lacking the initiating ATG in mammalian and avian cells had no effect on cell apoptosis or interferon expression in human lung epithelial cells. Full-length and C-terminal PB1-F2 mutants colocalized with mitochondria in A549 cells. Close monitoring of alterations of PB1-F2 and their frequency in contemporary avian H5N1 viruses should continue, as such changes may be markers for mammalian virulence.

IMPORTANCE
Although most avian influenza viruses are harmless for humans, some (such as highly pathogenic H5N1 avian influenza viruses) are capable of infecting humans and causing severe disease with a high mortality rate. A number of risk factors potentially associated with adaptation to mammalian infection have been noted. Here we demonstrate that the protein PB1-F2 is frequently truncated in recent isolates of highly pathogenic H5N1 viruses. Truncation of PB1-F2 has been proposed to act as an adaptation to mammalian infection. We show that some forms of truncation of PB1-F2 may be associated with increased virulence in mammals. Our data support the assessment of PB1-F2 truncations for genomic surveillance of influenza viruses.
How does tolerability of double balloon enteroscopy compare to other forms of endoscopy?
Authors: Irvine Andrew J , Sanders David S , Hopper Andrew , Kurien Matthew , Sidhu Reena 
Published: March 2015

Background and aimsGastrointestinal endoscopy can be difficult for patients to tolerate. Studies on endoscopic tolerability mainly focus on gastroscopy or colonoscopy with a paucity of data on double balloon enteroscopy (DBE). We aimed to prospectively evaluate tolerability in patients undergoing several forms of endoscopy including DBE.MethodsConsecutive patients undergoing colonoscopy, flexible sigmoidoscopy, gastroscopy, endoscopic retrograde pancreatography (ERCP), capsule endoscopy (CE) and DBE were prospectively recruited. A questionnaire recorded demographics, procedural data, patient tolerability (pain, discomfort and distress recorded on numerical rating scales) and the Hospital Anxiety and Depression Scale (HADS).Results956 patients were recruited (512 women; median age 57 years). The median pain score for DBE was poor with a score of 5 compared with 1 and 0 for oesophagogastroduodenoscopy and ERCP, respectively (p<0.001). Colonoscopy and retrograde DBE scores were not dissimilar. CE was well tolerated with a median pain score of 0. Patients with DBE required significantly higher doses of sedation and analgesia than other patients. The HADS Anxiety Score was also associated with poorer tolerability.ConclusionsDBE is poorly tolerated when compared with other forms of endoscopy despite higher doses of sedation. Increasing demand to improve tolerability of DBE in the UK may be addressed with the use of propofol.
Inadequacy of different methods of assessing the correct dosages during the preparation of air-hardening lime mortars
Authors: Arizzi A. , Cultrone G. 
Published: March 2015

Abstract
This work highlights the importance of applying suitable methods for the design of air-hardening lime mortars with the correct water dosage and binder-to-aggregate ratios. To this end, the recently developed ‘wet packing method’ has been used to assess the optimum water-to-binder ratio at which the packing density is achieved in lime mortars with different binder-to-aggregate proportions. To support the validity of this method, it has been compared with other standardized methods of determining the bulk density of the dry granular components and the consistency of the mortar pastes. The reliability of the wet packing method has then been verified by studying the mineralogical, textural and mechanical properties of mortars after 2 and 6 months of carbonation. Results showed that although the wet packing method seems to be more realistic than the majority of standards used for the determination of the packing density and workability in granular mixtures, it is not totally suitable for the preparation of air-hardening lime mortars with good performances in the fresh and hardened state.
Repair rendering mortars for the restoration of the Vargas Palace in Granada (Spain): a comparative study of the mortar behaviour in the laboratory and on site
Authors: Arizzi A. , Molina E. , Cultrone G. 
Published: March 2015

Abstract
This study gives an example of the steps that a repair work must include to be successful. It deals with a specific building, repair material (lime mortar) and application (render), but also with the study of the repair mortar in the laboratory and on site. Firstly, the original materials of the wall were characterized to ensure compatibility with the new repair mortars. Secondly, the suitability of different mortar mixes, made with lime and calcareous aggregate, was assessed by characterizing their properties after 15 months. At the same time, the repair mortars were applied in testing panels, and their behaviour under environmental conditions was studied and compared with that of the laboratory mortars. Mortar properties (shrinkage, adhesion, mineralogy, microstructure and texture) developed differently according to the curing conditions. The carbonation degree was higher in mortars cured on site (especially those with higher aggregate content), although in both cases it depended on mortar porosity. Testing the type of application on site was helpful to define the best performance of the designed mixes and to choose the most suitable one among them, which was found to be the 1:6 binder-to-sand ratio mortar applied in both layers of the render.
Cell Membrane Fluid–Mosaic Structure and Cancer Metastasis
Authors: Nicolson Garth L. 
Published: March 2015

Abstract
Cancer cells are surrounded by a fluid–mosaic membrane that provides a highly dynamic structural barrier with the microenvironment, communication filter and transport, receptor and enzyme platform. This structure forms because of the physical properties of its constituents, which can move laterally and selectively within the membrane plane and associate with similar or different constituents, forming specific, functional domains. Over the years, data have accumulated on the amounts, structures, and mobilities of membrane constituents after transformation and during progression and metastasis. More recent information has shown the importance of specialized membrane domains, such as lipid rafts, protein–lipid complexes, receptor complexes, invadopodia, and other cellular structures in the malignant process. In describing the macrostructure and dynamics of plasma membranes, membrane-associated cytoskeletal structures and extracellular matrix are also important, constraining the motion of membrane components and acting as traction points for cell motility. These associations may be altered in malignant cells, and probably also in surrounding normal cells, promoting invasion and metastatic colonization. In addition, components can be released from cells as secretory molecules, enzymes, receptors, large macromolecular complexes, membrane vesicles, and exosomes that can modify the microenvironment, provide specific cross-talk, and facilitate invasion, survival, and growth of malignant cells. Cancer Res; 75(7); 1169–76. ©2015 AACR.
Prognostic Significance of Tryptophan Catabolism in Adult T-cell Leukemia/Lymphoma
Authors: Masaki Ayako , Ishida Takashi , Maeda Yasuhiro , Suzuki Susumu , Ito Asahi , Takino Hisashi , Ogura Hiroka , Totani Haruhito , Yoshida Takashi , Kinoshita Shiori , Narita Tomoko , Ri Masaki , Kusumoto Shigeru , Inagaki Atsushi , Komatsu Hirokazu , Niimi Akio , Ueda Ryuzo , Utsunomiya Atae , Inagaki Hiroshi , Iida Shinsuke 
Published: March 2015

Abstract
Purpose: Indoleamine 2,3-dioxygenase 1 (IDO1: IDO), an enzyme catabolizing tryptophan (Trp) into the kynurenine (Kyn) pathway, is increasingly being recognized as an important microenvironmental factor suppressing antitumor immune responses. The purpose of the present study was to determine the prognostic significance of Trp catabolism in adult T-cell leukemia/lymphoma (ATL).
Experimental Design: We quantified serum Trp and Kyn in 96 ATL patients, 38 human T-cell lymphotropic virus type-1 asymptomatic carriers (HTLV-1 ACs), and 40 healthy adult volunteer controls. The relationships between various clinical parameters including overall survival were analyzed. IDO expression was evaluated in the affected lymph nodes of ATL patients.
Results: Serum Kyn concentrations and Kyn/Trp ratios were significantly higher in HTLV-1 ACs than healthy controls. Both increased significantly with progression from HTLV-1 AC to ATL. However, there were no significant differences in the serum Trp concentrations between ATL patients, HTLV-1 ACs, and controls. IDO was possibly produced by ATL and/or cells of the microenvironment. Multivariate analyses demonstrated that a high serum Kyn/Trp ratio and high Kyn level, but not a high Trp level, were significantly independent detrimental prognostic factors in ATL, as well as in that subset of patients with aggressive variant ATL.
Conclusions: Quantification of serum Kyn and Trp is useful for predicting prognosis of an individual ATL patient. Furthermore, ATL, especially in patients with a high serum Kyn/Trp ratio, is an appropriate disease for testing novel cancer immunotherapies targeting IDO. Clin Cancer Res; 21(12); 2830–9. ©2015 AACR.
Identification of a Candidate Gene Panel for the Early Diagnosis of Prostate Cancer
Authors: Leyten Gisele H.J.M. , Hessels Daphne , Smit Frank P. , Jannink Sander A. , de Jong Hans , Melchers Willem J.G. , Cornel Erik B. , de Reijke Theo M. , Vergunst Henk , Kil Paul , Knipscheer Ben C. , Hulsbergen-van de Kaa Christina A. , Mulders Peter F.A. , van Oort Inge M. , Schalken Jack A. 
Published: March 2015

Abstract
Purpose: Serum PSA (sPSA) testing has led to the identification of patients with indolent prostate cancer, and inevitably overtreatment has become a concern. Progensa PCA3 urine testing was shown to improve the diagnosis of prostate cancer, but its diagnostic value for aggressive prostate cancer is limited. Therefore, urinary biomarkers that can be used for prediction of Gleason score ≥7 prostate cancer in biopsies are urgently needed.
Experimental Design: Using gene expression profiling data, 39 prostate cancer biomarkers were identified. After quantitative PCR analysis on tissue specimens and urinary sediments, eight promising biomarkers for the urinary detection of prostate cancer were selected (ONECUT2, HOXC4, HOXC6, DLX1, TDRD1, NKAIN1, MS4A8B, PPFIA2). The hypothesis that biomarker combinations improve the diagnostic value for aggressive prostate cancer was tested on 358 urinary sediments of an intention-to-treat cohort.
Results: A urinary three-gene panel (HOXC6, TDRD1, and DLX1) had higher accuracy [area under the curve (AUC), 0.77; 95% confidence interval (CI), 0.71–0.83] to predict Gleason score ≥7 prostate cancer in biopsies compared with Progensa PCA3 (AUC, 0.68; 95% CI, 0.62–0.75) or sPSA (AUC, 0.72; 95% CI, 0.65–0.78). Combining the three-gene panel with sPSA further improved the predictive accuracy (AUC, 0.81; 95% CI, 0.75–0.86). The accuracy of the three-gene predictive model was maintained in subgroups with low sPSA concentrations.
Conclusions: The urinary three-gene panel (HOXC6, TDRD1, and DLX1) represents a promising tool to identify patients with aggressive prostate cancer, also in those with low sPSA values. The combination of the urinary three-gene panel with sPSA bears great potential for the early diagnosis of patients with clinically significant prostate cancer. Clin Cancer Res; 21(13); 3061–70. ©2015 AACR.
A Phase I/II Trial of BNC105P with Everolimus in Metastatic Renal Cell Carcinoma
Authors: Pal Sumanta , Azad Arun , Bhatia Shailender , Drabkin Harry , Costello Brian , Sarantopoulos John , Kanesvaran Ravindran , Lauer Richard , Starodub Alexander , Hauke Ralph , Sweeney Christopher J. , Hahn Noah M. , Sonpavde Guru , Richey Stephen , Breen Timothy , Kremmidiotis Gabriel , Leske Annabell , Doolin Elizabeth , Bibby David C. , Simpson Jeremy , Iglesias Jose , Hutson Thomas 
Published: March 2015

Abstract
Purpose: BNC105P inhibits tubulin polymerization, and preclinical studies suggest possible synergy with everolimus. In this phase I/II study, efficacy and safety of the combination were explored in patients with metastatic renal cell carcinoma (mRCC).
Experimental Design: A phase I study in patients with clear cell mRCC and any prior number of therapies was conducted using a classical 3 + 3 design to evaluate standard doses of everolimus with increasing doses of BNC105P. At the recommended phase II dose (RP2D), patients with clear cell mRCC and one to two prior therapies (including ≥ 1 VEGF-TKI) were randomized to BNC105P with everolimus (arm A) or everolimus alone (arm B). The primary endpoint of the study was 6-month progression-free survival (6MPFS). Secondary endpoints included response rate, PFS, overall survival, and exploratory biomarker analyses.
Results: In the phase I study (N = 15), a dose of BNC105P at 16 mg/m2 with everolimus at 10 mg daily was identified as the RP2D. In the phase II study, 139 patients were randomized, with 69 and 67 evaluable patients in arms A and B, respectively. 6MPFS was similar in the treatment arms (arm A: 33.82% vs. arm B: 30.30%, P = 0.66) and no difference in median PFS was observed (arm A: 4.7 mos vs. arm B: 4.1 mos; P = 0.49). Changes in matrix metalloproteinase-9, stem cell factor, sex hormone-binding globulin, and serum amyloid A protein were associated with clinical outcome with BNC105P.
Conclusions: Although the primary endpoint was not met in an unselected population, correlative studies suggest several biomarkers that warrant further prospective evaluation. Clin Cancer Res; 21(15); 3420–7. ©2015 AACR.
DNA, histones and neutrophil extracellular traps exert anti-fibrinolytic effects in a plasma environment
Authors: Varjú Imre , Longstaff Colin , Szabó László , Farkas Ádám Zoltán , Varga-Szabó Veronika Judit , Tanka-Salamon Anna , Machovich Raymund , Kolev Krasimir 
Published: March 2015

SummaryIn response to various inflammatory stimuli, neutrophils secrete neutrophil extracellular traps (NETs), web-like meshworks of DNA, histones and granular components forming supplementary scaffolds in venous and arterial thrombi. Isolated DNA and histones are known to promote thrombus formation and render fibrin clots more resistant to mechanical forces and tissue-type plasminogen activator (tPA)-induced enzymatic digestion. The present study extends our earlier observations to a physiologically more relevant environment including plasma clots and NET-forming neutrophils. A range of techniques was employed including imaging (scanning electron microscopy (SEM), confocal laser microscopy, and photoscanning of macroscopic lysis fronts), clot permeability measurements, turbidimetric lysis and enzyme inactivation assays. Addition of DNA and histones increased the median fibre diameter of plasma clots formed with 16 nM thrombin from 108 to 121 and 119 nm, respectively, and decreased their permeability constant from 6.4 to 3.1 and 3.7×10−9 cm2. Histones effectively protected thrombin from antithrombin-induced inactivation, while DNA inhibited plasminogen activation on the surface of plasma clots and their plasmin-induced resolution by 20 and 40 %, respectively. DNA and histones, as well as NETs secreted by phorbol-myristate-acetate-activated neutrophils, slowed down the tPA-driven lysis of plasma clots and the latter effect could be reversed by the addition of DNase (streptodornase). SEM images taken after complete digestion of fibrin in NET-containing plasma clots evidenced retained NET scaffold that was absent in DNase-treated clots. Our results show that DNA and histones alter the fibrin architecture in plasma clots, while NETs contribute to a decreased lytic susceptibility that can be overcome by DNase.
ApoA-I/HDL-C levels are inversely associated with abdominal aortic aneurysm progression
Authors: Molina-Sánchez Pedro , Jorge Inmaculada , Martinez-Pinna Roxana , Blanco-Colio Luis Miguel , Tarin Carlos , Torres-Fonseca Monica Maria , Esteban Margarita , Laustsen Jesper , Ramos-Mozo Priscila , Calvo Enrique , Lopez Juan Antonio , Ceniga Melina Vega de , Michel Jean-Baptiste , Egido Jesus , Andrés Vicente , Vazquéz Jesús , Meilhac Olivier , Burillo Elena , Lindholt Jes S. , Martin-Ventura Jose Luis 
Published: March 2015

SummaryAbdominal aortic aneurysm (AAA) evolution is unpredictable, and there is no therapy except surgery for patients with an aortic size > 5 cm (large AAA). We aimed to identify new potential biomarkers that could facilitate prognosis and treatment of patients with AAA. A differential quantitative proteomic analysis of plasma proteins was performed in AAA patients at different stages of evolution [small AAA (aortic size=3�5cm) vs large AAA] using iTRAQ labelling, highthroughput nano-LC-MS/MS and a novel multi-layered statistical model. Among the proteins identified, ApoA-I was decreased in patients with large AAA compared to those with small AAA. These results were validated by ELISA on plasma samples from small (n=90) and large AAA (n=26) patients (150 ± 3 vs 133 ± 5 mg/dl, respectively, p< 0.001). ApoA-I levels strongly correlated with HDL-Cholesterol (HDL-C) concentration (r=0.9, p< 0.001) and showed a negative correlation with aortic size (r=-0.4, p< 0.01) and thrombus volume (r=-0.3, p< 0.01), which remained significant after adjusting for traditional risk factors. In a prospective study, HDL-C independently predicted aneurysmal growth rate in multiple linear regression analysis (n=122, p=0.008) and was inversely associated with need for surgical repair (Adjusted hazard ratio: 0.18, 95 % confidence interval: 0.04�0.74, p=0.018). In a nation-wide Danish registry, we found lower mean HDL-C concentration in large AAA patients (n=6,560) compared with patients with aorto-iliac occlusive disease (n=23,496) (0.89 ± 2.99 vs 1.59 ± 5.74 mmol/l, p< 0.001). Finally, reduced mean aortic AAA diameter was observed in AngII-infused mice treated with ApoA-I mimetic peptide compared with saline-injected controls. In conclusion, ApoAI/ HDL-C systemic levels are negatively associated with AAA evolution. Therapies targeting HDL functionality could halt AAA formation.