bluuebunny/crossref_metadata_2025_split huggingface dataset:
Morbillivirus Control of the Interferon Response: Relevance of STAT2 and mda5 but Not STAT1 for Canine Distemper Virus Virulence in Ferrets
Authors: Svitek Nicholas , Gerhauser Ingo , Goncalves Christophe , Grabski Elena , Döring Marius , Kalinke Ulrich , Anderson Danielle E. , Cattaneo Roberto , von Messling Veronika 
Published: December 2013

ABSTRACT

The V proteins of paramyxoviruses control the innate immune response. In particular, the V protein of the genus
Morbillivirus
interferes with the signal transducer and activator of transcription 1 (STAT1), STAT2, and melanoma differentiation-associated protein 5 (mda5) signaling pathways. To characterize the contributions of these pathways to canine distemper virus (CDV) pathogenesis, we took advantage of the knowledge about the mechanisms of interaction between the measles virus V protein with these key regulators of innate immunity. We generated recombinant CDVs with V proteins unable to properly interact with STAT1, STAT2, or mda5. A virus with combined STAT2 and mda5 deficiencies was also generated, and available wild-type and V-protein-knockout viruses were used as controls. Ferrets infected with wild-type and STAT1-blind viruses developed severe leukopenia and loss of lymphocyte proliferation activity and succumbed to the disease within 14 days. In contrast, animals infected with viruses with STAT2 or mda5 defect or both STAT2 and mda5 defects developed a mild self-limiting disease similar to that associated with the V-knockout virus. This study demonstrates the importance of interference with STAT2 and mda5 signaling for CDV immune evasion and provides a starting point for the development of morbillivirus vectors with reduced immunosuppressive properties.

IMPORTANCE
The V proteins of paramyxoviruses interfere with the recognition of the virus by the immune system of the host. For morbilliviruses, the V protein is known to interact with the signal transducer and activator of transcription 1 (STAT1) and STAT2 and the melanoma differentiation-associated protein 5 (mda5), which are involved in interferon signaling. Here, we examined the contribution of each of these signaling pathways to the pathogenesis of the carnivore morbillivirus canine distemper virus. Using viruses selectively unable to interfere with the respective signaling pathway to infect ferrets, we found that inhibition of STAT2 and mda5 signaling was critical for lethal disease. Our findings provide new insights in the mechanisms of morbillivirus immune evasion and may lead to the development of new vaccines and oncolytic vectors.
A proposed model for prediction of survival based on a follow-up study in unresectable pancreatic cancer
Authors: Forssell Henrik , Wester Michael , Åkesson Katrin , Johansson Sigrid 
Published: December 2013

ObjectivesTo define an easy-to-use model for prediction of survival time in patients with unresectable pancreatic cancer in order to optimise patient' care.DesignAn observational retrospective study on patients with unresectable pancreatic cancer. The initial radiographs at presentation of symptoms were reviewed and the maximum diameter of the primary tumour was determined. The occurrence of liver metastases and performance status that determines initiation of chemotherapy was also used in the regression analysis to identify prognostic subgroups.SettingCounty hospital in south-east of Sweden.PopulationConsecutive patients with unresectable pancreatic cancer who were diagnosed between January 2003 and May 2010 (n=132).Main outcome measuresStatistical analyses were performed using Stata V.13. Survival time was assessed with Kaplan-Meier analysis, log-rank test for equality of survivor functions and Cox regression for calculation of individual hazard based on tumour diameter, presence of liver metastases and initiation of chemotherapy treatment according to patient performance status.ResultsThe individual hazard was log h=0.357 tumour size+1.181 liver metastases−0.989 performance status/chemotherapy. Three prognostic groups could be defined: a low-risk group with a median survival time of 6.7 (IQR 9.7) months, a medium-risk group with a median survival time of 4.5 (IQR 4.5) months and a high-risk group with a median survival time of 1.2 (IQR 1.7) months.ConclusionsThe maximum diameter of the primary tumour and the presence of liver metastases found at the X-ray examination of patients with pancreatic cancer, in conjunction with whether or not chemotherapy is initiated according to performance status, predict the survival time for patients who do not undergo surgical resection. The findings result in an easy-to-use model for predicting the survival time.
WEIGHTED AUTOMATA AS COALGEBRAS IN CATEGORIES OF MATRICES
Authors: OLIVEIRA JOSÉ N. 
Published: December 2013

The evolution from non-deterministic to weighted automata represents a shift from qualitative to quantitative methods in computer science. The trend calls for a language able to reconcile quantitative reasoning with formal logic and set theory, which have for so many years supported qualitative reasoning. Such a lingua franca should be typed, polymorphic, diagrammatic, calculational and easy to blend with conventional notation. This paper puts forward typed linear algebra as a candidate notation for such a unifying role. This notation, which emerges from regarding matrices as morphisms of suitable categories, is put at work in describing weighted automata as coalgebras in such categories. Some attention is paid to the interface between the index-free (categorial) language of matrix algebra and the corresponding index-wise, set-theoretic notation.
Accumulation of Cytosolic Calcium Induces Necroptotic Cell Death in Human Neuroblastoma
Authors: Nomura Motonari , Ueno Ayumi , Saga Kotaro , Fukuzawa Masahiro , Kaneda Yasufumi 
Published: December 2013

Abstract
Necrosis has been studied extensively since the early days of medicine, with some patterns of necrosis found to be programmed like apoptotic cell death. However, mechanisms of programmed necrosis (necroptosis) are yet to be fully elucidated. In this study, we investigated how the hemagglutinating virus of Japan-envelope (HVJ-E) induces necrosis in mouse xenografts of human neuroblastoma cells. HVJ-E–induced necrosis in this system was found to depend on phosphorylation of the death receptor kinase receptor interacting protein kinase 1 (RIP1) and on the production of reactive oxygen species. This process was interpreted as necroptosis, based on its suppression by the small molecule necrostatin-1, and it did not involve the TNF-α receptor pathway. We also demonstrated that increased concentrations of cytoplasmic calcium triggered necroptosis by activating calcium-calmodulin kinase (CaMK) II. Finally, we determined that RIP1 phosphorylation was mediated by CaMK II activation. Together, our results define an upstream pathway for the activation of necroptosis in neuroblastoma cells, with potential therapeutic implications. Cancer Res; 74(4); 1056–66. ©2013 AACR.
Phosphorylation at Ser-181 of Oncogenic KRAS Is Required for Tumor Growth
Authors: Barceló Carles , Paco Noelia , Morell Mireia , Alvarez-Moya Blanca , Bota-Rabassedas Neus , Jaumot Montserrat , Vilardell Felip , Capella Gabriel , Agell Neus 
Published: December 2013

Abstract
KRAS phosphorylation has been reported recently to modulate the activity of mutant KRAS protein in vitro. In this study, we defined S181 as a specific phosphorylation site required to license the oncogenic function of mutant KRAS in vivo. The phosphomutant S181A failed to induce tumors in mice, whereas the phosphomimetic mutant S181D exhibited an enhanced tumor formation capacity, compared with the wild-type KRAS protein. Reduced growth of tumors composed of cells expressing the nonphosphorylatable KRAS S181A mutant was correlated with increased apoptosis. Conversely, increased growth of tumors composed of cells expressing the phosphomimetic KRAS S181D mutant was correlated with increased activation of AKT and ERK, two major downstream effectors of KRAS. Pharmacologic treatment with PKC inhibitors impaired tumor growth associated with reduced levels of phosphorylated KRAS and reduced effector activation. In a panel of human tumor cell lines expressing various KRAS isoforms, we showed that KRAS phosphorylation was essential for survival and tumorigenic activity. Furthermore, we identified phosphorylated KRAS in a panel of primary human pancreatic tumors. Taken together, our findings establish that KRAS requires S181 phosphorylation to manifest its oncogenic properties, implying that its inhibition represents a relevant target to attack KRAS-driven tumors. Cancer Res; 74(4); 1190–9. ©2013 AACR.
An Antibody–Drug Conjugate That Targets Tissue Factor Exhibits Potent Therapeutic Activity against a Broad Range of Solid Tumors
Authors: Breij Esther C.W. , de Goeij Bart E.C.G. , Verploegen Sandra , Schuurhuis Danita H. , Amirkhosravi Ali , Francis John , Miller Vibeke Breinholt , Houtkamp Mischa , Bleeker Wim K. , Satijn David , Parren Paul W.H.I. 
Published: December 2013

Abstract
Tissue factor (TF) is aberrantly expressed in solid cancers and is thought to contribute to disease progression through its procoagulant activity and its capacity to induce intracellular signaling in complex with factor VIIa (FVIIa). To explore the possibility of using tissue factor as a target for an antibody-drug conjugate (ADC), a panel of human tissue factor–specific antibodies (TF HuMab) was generated. Three tissue factor HuMab, that induced efficient inhibition of TF:FVIIa-dependent intracellular signaling, antibody-dependent cell-mediated cytotoxicity, and rapid target internalization, but had minimal impact on tissue factor procoagulant activity in vitro, were conjugated with the cytotoxic agents monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF). Tissue factor–specific ADCs showed potent cytotoxicity in vitro and in vivo, which was dependent on tissue factor expression. TF-011-MMAE (HuMax-TF-ADC) was the most potent ADC, and the dominant mechanism of action in vivo was auristatin-mediated tumor cell killing. Importantly, TF-011-MMAE showed excellent antitumor activity in patient-derived xenograft (PDX) models with variable levels of tissue factor expression, derived from seven different solid cancers. Complete tumor regression was observed in all PDX models, including models that showed tissue factor expression in only 25% to 50% of the tumor cells. In conclusion, TF-011-MMAE is a promising novel antitumor agent with potent activity in xenograft models that represent the heterogeneity of human tumors, including heterogeneous target expression. Cancer Res; 74(4); 1214–26. ©2013 AACR.
Interactions between MUC1 and p120 Catenin Regulate Dynamic Features of Cell Adhesion, Motility, and Metastasis
Authors: Liu Xiang , Yi Chunhui , Wen Yunfei , Radhakrishnan Prakash , Tremayne Jarrod R. , Dao Thongtan , Johnson Keith R. , Hollingsworth Michael A. 
Published: December 2013

Abstract
The mechanisms by which MUC1 and p120 catenin contribute to progression of cancers from early transformation to metastasis are poorly understood. Here we show that p120 catenin ARM domains 1, 3–5, and 8 mediate interactions between p120 catenin and MUC1, and that these interactions modulate dynamic properties of cell adhesion, motility, and metastasis of pancreatic cancer cells. We also show that different isoforms of p120 catenin, when coexpressed with MUC1, create cells that exhibit distinct patterns of motility in culture (motility independent of cell adhesion, motility within a monolayer while exchanging contacts with other cells, and unified motility while maintaining static epithelial contacts) and patterns of metastasis. The results provide new insight into the dynamic interplay between cell adhesion and motility and the relationship of these to the metastatic process. Cancer Res; 74(5); 1609–20. ©2013 AACR.
Platelets Mediate Oxidized Low-Density Lipoprotein–Induced Monocyte Extravasation and Foam Cell Formation
Authors: Badrnya Sigrun , Schrottmaier Waltraud C. , Kral Julia B. , Yaiw Koon-Chu , Volf Ivo , Schabbauer Gernot , Söderberg-Nauclér Cecilia , Assinger Alice 
Published: December 2013

Objective—
A growing body of evidence indicates that platelets contribute to the onset and progression of atherosclerosis by modulating immune responses. We aimed to elucidate the effects of oxidized low-density lipoprotein (OxLDL) on platelet–monocyte interactions and the consequences of these interactions on platelet phagocytosis, chemokine release, monocyte extravasation, and foam cell formation.

Approach and Results—

Confocal microscopy and flow cytometric analysis revealed that in vitro and in vivo stimulation with OxLDL resulted in rapid formation of platelet–monocyte aggregates, with a preference for CD16+ monocyte subsets. This platelet–monocyte interaction facilitated OxLDL uptake by monocytes, in a process that involved platelet CD36–OxLDL interaction, release of chemokines, such as CXC motif ligand 4, direct platelet–monocyte interaction, and phagocytosis of platelets. Inhibition of cyclooxygenase with acetylsalicylic acid and antagonists of ADP receptors, P2Y1 and P2Y12, partly abrogated OxLDL-induced platelet–monocyte aggregates and platelet-mediated lipid uptake in monocytes. Platelets also enhanced OxLDL-induced monocyte transmigration across an endothelial monolayer via direct interaction with monocytes in a transwell assay. Importantly, in LDLR
−/−
mice, platelet depletion resulted in a significant decrease of peritoneal macrophage recruitment and foam cell formation in a thioglycollate-elicited peritonitis model. In platelet-depleted wild-type mice, transfusion of ex vivo OxLDL-stimulated platelets induced monocyte extravasation to a higher extent when compared with resting platelets.

Conclusions—
Our results on OxLDL-mediated platelet–monocyte aggregate formation, which promoted phenotypic changes in monocytes, monocyte extravasation and enhanced foam cell formation in vitro and in vivo, provide a novel mechanism for how platelets potentiate key steps of atherosclerotic plaque development and plaque destabilization.
Decreased Serum Bilirubin Is Associated With Silent Cerebral Infarction
Authors: Li Rui-Yan , Cao Zhi-Gang , Zhang Ji-Rong , Li Ying , Wang Rui-Tao 
Published: December 2013

Objective—
The presence of silent cerebral infarction (SCI) increases the risk of transient ischemia attack, symptomatic stroke, cardiovascular disease, and dementia. Total bilirubin (TB) levels were demonstrated to be decreased in carotid intima–media thickness, cardiovascular disease, stroke, and peripheral arterial disease. However, little information is available concerning the correlation between TB and SCI.

Approach and Results—

A cross-sectional study was conducted to evaluate the association between TB and SCI in 2865 subjects (1831 men and 1034 women) undergoing medical checkup. The participants with SCI had lower TB levels than those without SCI. The subjects with a low TB had a higher prevalence of SCI. Moreover, partial correlation showed that TB levels were tightly correlated with brachial-ankle pulse wave velocity after adjusting for confounding covariates (
r
=−0.149;
P
<0.001). Multivariate logistic regression analysis revealed that higher TB was associated with a lower risk of SCI (odds ratio, 0.925; 95% confidence interval, 0.897–0.954;
P
<0.001).

Conclusions—
TB is a novel biochemical indicator for SCI regardless of classical cardiovascular risk factors. Early measurement of TB may be useful to assess the risk of SCI.
Predictors of Death and Prolonged Renal Insufficiency in Ethylene Glycol Poisoning
Authors: Lung Derrick D. , Kearney Thomas E. , Brasiel James A. , Olson Kent R. 
Published: December 2013

Background: We assessed the predictive value of selected factors on the outcomes of death and prolonged renal insufficiency (RI) from ethylene glycol poisoning. Methods: Retrospective, observational California Poison Control System study, over a 10-year period (1999-2008). We compared 2 groups. The first group (D/RI) included 59 patients who died (9 patients) or had prolonged RI (50 patients). Prolonged RI was defined as kidney injury in which dialysis was required for greater than 3 days after presentation. The second group (RECOV) of 62 patients had an uncomplicated recovery. Secondarily, we evaluated the association of time to antidote (ethanol and/or fomepizole) and time to dialysis with these outcomes. Results: The D/RI group was more likely than the RECOV group to present comatose, have seizures, and require intubation. The D/RI group had a lower mean initial arterial pH of 7.03 (standard deviation [SD] 0.20), compared to 7.27 (SD 0.14) for the RECOV group. The D/RI group had a higher initial creatinine (1.7 mg/dL, SD 0.71) than that of the RECOV group (1.0 mg/dL, SD 0.33). Patients with a time to antidote greater than 6 hours had a higher odds of dying or having prolonged RI (OR 3.34, 95% CI : 1.21-9.26) Patients with a time to dialysis greater than 6 hours had a lower odds of dying or having prolonged RI (OR 0.36, 95% CI : 0.15-0.87). Conclusion: Compared to survivors with an uncomplicated recovery, patients poisoned with ethylene glycol who died or had prolonged RI were more likely to exhibit clinical signs such as coma, seizures, and acidosis. Antidote administration within 6 hours is associated with better outcomes, unlike earlier time to dialysis.
Geometry of the Lateral Sliding, Closing Wedge Calcaneal Osteotomy
Authors: Kraus Jonathan C. , Fischer Mark T. , McCormick Jeremy J. , Klein Sandra E. , Johnson Jeffrey E. 
Published: December 2013

Background: A lateral closing wedge osteotomy is used for correction of varus hindfoot deformities. Since its original description, different techniques and geometries of the calcaneal bone wedge resection have been described. Even though the techniques seem similar, very different final bone architectures result from each technique, the effects of which are not known. This paper explores several of these techniques and the implications in deformity correction as well as the secondary effects of calcaneal shortening. Methods: Mathematical and geometric analysis is performed in 2-dimensions for several hypothetical calcaneal osteotomies as described by the original authors. The resulting changes are calculated and compared. Results: The shape of the bone resection for the lateral closing wedge osteotomy does not result in significantly different final calcaneal architectures. Both techniques studied result in the same amount of calcaneal shortening and deformity correction. However, when lateral calcaneal wedge resection is combined with lateral translation of the tuberosity for additional deformity correction, more calcaneal shortening is seen with posteriorly directed osteotomies than those that are transverse. Conclusion: The lateral closing wedge osteotomy of the calcaneus results in correction of varus hindfoot deformity at the expense of some calcaneal shortening. Lateral translation of the tuberosity may result in additional calcaneal. The clinical effects of calcaneal shortening or medial soft tissue or nerve tethering from these different techniques are unknown and deserve further investigation. Level of Evidence: Level V, expert opinion.
Observation of Social Behavior in Frontotemporal Dementia
Authors: Mendez Mario F. , Fong Sylvia S. , Shapira Jill S. , Jimenez Elvira E. , Kaiser Natalie C. , Kremen Sarah A. , Tsai Po-Heng 
Published: December 2013

Background: The most characteristic manifestations of behavioral variant frontotemporal dementia (bvFTD) are abnormalities in social behavior. However, distinguishing bvFTD based on social behavior can be difficult in structured clinical settings. Methods: Using a Social Observation Inventory, 10 patients with bvFTD and 10 patients with Alzheimer’s disease (AD) were compared to their caregiver interlocutors on 1-hour mealtime, in-home videotaped segments. Results: Compared to caregivers and patients with AD, patients with bvFTD were significantly disturbed in social behavior. In contrast, patients with AD were indistinguishable from their caregivers. The lack of “you” comments and decreased tact and manners distinguished 92.6% of the patients with bvFTD from patients with AD and caregivers. The Social Observation Inventory scores correlated with scores on frontal-executive tests and socioemotional scales. Conclusions: The systematic observation of social behavior during routine activities may be one of the best ways to distinguish patients with bvFTD from normal individuals and from patients with other dementias.
Genome wide association studies in presence of misclassified binary responses
Authors: Smith Shannon , Hay El Hamidi , Farhat Nourhene , Rekaya Romdhane 
Published: December 2013

Abstract

Background
Misclassification has been shown to have a high prevalence in binary responses in both livestock and human populations. Leaving these errors uncorrected before analyses will have a negative impact on the overall goal of genome-wide association studies (GWAS) including reducing predictive power. A liability threshold model that contemplates misclassification was developed to assess the effects of mis-diagnostic errors on GWAS. Four simulated scenarios of case–control datasets were generated. Each dataset consisted of 2000 individuals and was analyzed with varying odds ratios of the influential SNPs and misclassification rates of 5% and 10%.

Results
Analyses of binary responses subject to misclassification resulted in underestimation of influential SNPs and failed to estimate the true magnitude and direction of the effects. Once the misclassification algorithm was applied there was a 12% to 29% increase in accuracy, and a substantial reduction in bias. The proposed method was able to capture the majority of the most significant SNPs that were not identified in the analysis of the misclassified data. In fact, in one of the simulation scenarios, 33% of the influential SNPs were not identified using the misclassified data, compared with the analysis using the data without misclassification. However, using the proposed method, only 13% were not identified. Furthermore, the proposed method was able to identify with high probability a large portion of the truly misclassified observations.

Conclusions
The proposed model provides a statistical tool to correct or at least attenuate the negative effects of misclassified binary responses in GWAS. Across different levels of misclassification probability as well as odds ratios of significant SNPs, the model proved to be robust. In fact, SNP effects, and misclassification probability were accurately estimated and the truly misclassified observations were identified with high probabilities compared to non-misclassified responses. This study was limited to situations where the misclassification probability was assumed to be the same in cases and controls which is not always the case based on real human disease data. Thus, it is of interest to evaluate the performance of the proposed model in that situation which is the current focus of our research.