bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Development of Immunostimulatory Monoclonal Antibodies and Opportunities for Combination
Authors: Melero Ignacio , Grimaldi Antonio M. , Perez-Gracia Jose L. , Ascierto Paolo A. 
Published: March 2013

AbstractImmune system responses are under the control of extracellular biomolecules, which express functions in receptors present on the surface of cells of the immune system, and thus are amenable to be functionally modulated by monoclonal antibodies. Some of these mechanisms are activating and dictate whether the response ensues, while others play the role of powerful repressors. Antagonist antibodies acting on such repressors result in enhanced immune responses, a goal that is also achieved with agonist antibodies acting on the activating receptors. With these simple logics, a series of therapeutic agents are under clinical development and one of them directed at the CTL-associated antigen 4 (CTLA-4) inhibitory receptor (ipilimumab) has been approved for the treatment of metastatic melanoma. The list of antagonist agents acting on repressors under development includes anti–CTLA-4, anti–PD-1, anti–PD-L1 (B7-H1), anti-KIR, and anti–TGF-β. Agonist antibodies currently being investigated in clinical trials target CD40, CD137 (4-1BB), CD134 (OX40), and glucocorticoid-induced TNF receptor (GITR). A blossoming preclinical pipeline suggests that other active targets will also be tested in patients in the near future. All of these antibodies are being developed as conventional monoclonal immunoglobulins, but other engineered antibody formats or RNA aptamers are under preclinical scrutiny. The “dark side” of these immune interventions is that they elicit autoimmune/inflammatory reactions that can be severe in some patients. A critical and, largely, pending subject is to identify reliable predictive biomarkers both for efficacy and immune toxicity. Preclinical and early clinical studies indicate a tremendous potential to further improve efficacy, using combinations from among these new agents that frequently act in a synergistic fashion. Combinations with other more conventional means of treatment such as radiotherapy, chemotherapy, or cancer vaccines also hold much promise. Clin Cancer Res; 19(5); 997–1008. ©2013 AACR.
Biomarkers for Immunostimulatory Monoclonal Antibodies in Combination Strategies for Melanoma and Other Tumor Types
Authors: Ascierto Paolo A. , Kalos Michael , Schaer David A. , Callahan Margaret K. , Wolchok Jedd D. 
Published: March 2013

Abstract
Modulation of the immune system by targeting coinhibitory and costimulatory receptors has become a promising new approach of immunotherapy for cancer. The recent approval of the CTLA-4–blocking antibody ipilimumab for the treatment of melanoma was a watershed event, opening up a new era in the field of immunotherapy. Ipilimumab was the first treatment to ever show enhanced overall survival (OS) for patients with stage IV melanoma. However, measuring response rates using standard Response Evaluation Criteria in Solid Tumors (RECIST) or modified World Health Organization criteria or progression-free survival does not accurately capture the potential for clinical benefit for ipilimumab-treated patients. As immunotherapy approaches are translated into more tumor types, it is important to study biomarkers, which may be more predictive of OS to identify the patients most likely to have clinical benefit. Ipilimumab is the first-in-class of a series of immunomodulating antibodies that are in clinical development. Anti-PD1 (nivolumab and MK-3475), anti-PD-L1 (BMS-936 559, RG7446, and MEDI4736), anti-CD137 (urelumab), anti-OX40, anti-GITR, and anti-CD40 monoclonal antibodies are just some of the agents that are being actively investigated in clinical trials, each having the potential for combination with the ipilimumab to enhance its effectiveness. Development of rational combinations of immunomodulatory antibodies with small-molecule pathway inhibitor therapies such as vemurafenib makes the discovery of predictive biomarkers even more important. Identifying reliable biomarkers is a necessary step in personalizing the treatment of each patient's cancer through a baseline assessment of tumor gene expression and/or immune profile to optimize therapy for the best chance of therapeutic success. Clin Cancer Res; 19(5); 1009–20. ©2013 AACR.
Direct Numerical Simulation of Evaporative Cooling at the Lateral Boundary of Shallow Cumulus Clouds
Authors: Abma Dick , Heus Thijs , Mellado Juan Pedro 
Published: March 2013

Abstract
This study investigates the dynamics of the subsiding shell at the lateral boundary of cumulus clouds, focusing on the role of evaporative cooling. Since the size of this shell is well below what large-eddy simulations can resolve, the authors have performed direct numerical simulations of an idealized subsiding shell. The system develops a self-similar, Reynolds number–independent flow that allows for the determination of explicit scaling laws relating the characteristic length, time, and velocity scales of the shell. It is found that the shell width grows quadratically in time, linearly with the traveled distance. The magnitude of these growth rates shows that evaporative cooling, in its most idealized form, is capable of producing a fast-growing shell with numbers that are consistent with observations of the subsiding shell around real shallow cumulus clouds: for typical thermodynamic conditions in cumulus clouds, a velocity on the order of 1 m s−1 and a thickness on the order of 10 m are established in about 2 min. This fits well within the typical cloud lifetime, suggesting that this idealization is an adequate framework for the analysis of relevant aspects in the subsiding shell associated with buoyancy reversal. It also indicates that the scaling laws derived here can be used to estimate the potential strength of a subsiding shell and the mean lateral entrainment associated with it, once an estimate of the local thermodynamical state of the cloud boundary is provided. It is shown that the dominant parameter of this system is the saturation buoyancy, whereas the effect of the saturation mixing fraction is minor.
The Key Role of Heavy Precipitation Events in Climate Model Disagreements of Future Annual Precipitation Changes in California
Authors: Pierce David W. , Cayan Daniel R. , Das Tapash , Maurer Edwin P. , Miller Norman L. , Bao Yan , Kanamitsu M. , Yoshimura Kei , Snyder Mark A. , Sloan Lisa C. , Franco Guido , Tyree Mary 
Published: March 2013

Abstract
Climate model simulations disagree on whether future precipitation will increase or decrease over California, which has impeded efforts to anticipate and adapt to human-induced climate change. This disagreement is explored in terms of daily precipitation frequency and intensity. It is found that divergent model projections of changes in the incidence of rare heavy (&gt;60 mm day−1) daily precipitation events explain much of the model disagreement on annual time scales, yet represent only 0.3% of precipitating days and 9% of annual precipitation volume. Of the 25 downscaled model projections examined here, 21 agree that precipitation frequency will decrease by the 2060s, with a mean reduction of 6–14 days yr−1. This reduces California's mean annual precipitation by about 5.7%. Partly offsetting this, 16 of the 25 projections agree that daily precipitation intensity will increase, which accounts for a model average 5.3% increase in annual precipitation. Between these conflicting tendencies, 12 projections show drier annual conditions by the 2060s and 13 show wetter. These results are obtained from 16 global general circulation models downscaled with different combinations of dynamical methods [Weather Research and Forecasting (WRF), Regional Spectral Model (RSM), and version 3 of the Regional Climate Model (RegCM3)] and statistical methods [bias correction with spatial disaggregation (BCSD) and bias correction with constructed analogs (BCCA)], although not all downscaling methods were applied to each global model. Model disagreements in the projected change in occurrence of the heaviest precipitation days (&gt;60 mm day−1) account for the majority of disagreement in the projected change in annual precipitation, and occur preferentially over the Sierra Nevada and Northern California. When such events are excluded, nearly twice as many projections show drier future conditions.
Seasonal Tropical Cyclone Rain Volumes over Australia
Authors: Dare Richard A. 
Published: March 2013

Abstract
For a continent as dry as Australia, where water is a valuable resource, it is important to understand the sources of rainfall. The volume of water contributed by tropical cyclones (TCs) during the November–April season is investigated using 42 seasons of TC and rainfall data. The seasonal total TC rain volume (SRV) ranges from a minimum of 34.2 km3 in 1987/88 to a maximum of 564.4 km3 in 2000/01, with a long-term mean of 198.6 ± 107.4 km3. In terms of mean percentage, TCs contribute 7.6% to the seasonal total rain volume over Australia. The number of landfalling TCs and the number of TCs that individually produce more than the mean individual TC rain volume (25.7 km3) during a season are significant influences on the SRV. The TCs passing near the coast without landfalling have little impact on the SRV. The two parameters that correlate best with SRV are the total time spent over land by TCs during a season and the total land area covered by TCs during a season (correlation coefficients of 0.79 and 0.84, respectively). Although the highest SRVs occur almost exclusively during La Niña and neutral seasons, there is a mixture of ENSO seasons corresponding to the lowest SRVs. In general, the large interannual variability, even within a particular ENSO class, indicates that caution should be used when attempting to relate SRV to the phase of ENSO.
Antarctic Bottom Water Warming and Freshening: Contributions to Sea Level Rise, Ocean Freshwater Budgets, and Global Heat Gain*
Authors: Purkey Sarah G. , Johnson Gregory C. 
Published: March 2013

Abstract
Freshening and warming of Antarctic Bottom Water (AABW) between the 1980s and 2000s are quantified, assessing the relative contributions of water-mass changes and isotherm heave. The analysis uses highly accurate, full-depth, ship-based, conductivity–temperature–depth measurements taken along repeated oceanographic sections around the Southern Ocean. Fresher varieties of AABW are present within the South Pacific and south Indian Oceans in the 2000s compared to the 1990s, with the strongest freshening in the newest waters adjacent to the Antarctic continental slope and rise indicating a recent shift in the salinity of AABW produced in this region. Bottom waters in the Weddell Sea exhibit significantly less water-mass freshening than those in the other two southern basins. However, a decrease in the volume of the coldest, deepest waters is observed throughout the entire Southern Ocean. This isotherm heave causes a salinification and warming on isobaths from the bottom up to the shallow potential temperature maximum. The water-mass freshening of AABW in the Indian and Pacific Ocean sectors is equivalent to a freshwater flux of 73 ± 26 Gt yr−1, roughly half of the estimated recent mass loss of the West Antarctic Ice Sheet. Isotherm heave integrated below 2000 m and south of 30°S equates to a net heat uptake of 34 ± 14 TW of excess energy entering the deep ocean from deep volume loss of AABW and 0.37 ± 0.15 mm yr−1 of sea level rise from associated thermal expansion.
Using Evolutionary Programming to Generate Skillful Extreme Value Probabilistic Forecasts
Authors: Roebber Paul J. 
Published: March 2013

Abstract
A new method for producing large member ensemble forecasts, using a variation of evolutionary programming (EP), is presented. A series of increasingly complex datasets are used to demonstrate the method and its potential utility. First, EP performance is considered using training and test “atmospheric” data derived from the Lorenz low-order dynamical system. Next, a modified form of the intermediate-order Lorenz model representing 500-hPa height is used. Finally, EP performance is evaluated using real 500-hPa data and day-3 forecasts of the reforecast model. As expected, short observational records limit the potential of the EP method by preventing proper training. A kind of perfect-prog approach, in which the EP ensemble is trained using a large “observational” sample constructed from the imperfect model, is shown to be a potentially viable means of counteracting limits to the observed record. The EP ensembles are shown to outperform dynamical model ensembles at the extremes, and to be competitive with dynamical models across a wide range of values of the variables of interest. In particular, the EP ensembles improve resolution compared to dynamical model ensembles, which suggests that further skill might be obtainable by also improving reliability using additional postprocessing. Future applications of the ensemble EP method are briefly discussed.
Design of, and first data from, PATRO Children, a multicentre, noninterventional study of the long-term efficacy and safety of Omnitrope® in children requiring growth hormone treatment
Authors: Pfäffle Roland , Schwab Karl Otfried , Marginean Otilia , Walczak Mieczyslaw , Szalecki Mieczyslaw , Schuck Ellen , Zabransky Markus , Zucchini Stefano 
Published: March 2013

Objective: To describe the rationale, design and first data from PATRO Children, a postmarketing surveillance of the long-term efficacy and safety of somatropin (Omnitrope®) for the treatment of children requiring growth hormone treatment. Methods: PATRO Children is a multicentre, open, longitudinal, noninterventional study being conducted in children’s hospitals and specialised endocrinology clinics. The primary objective is to assess the long-term safety of Omnitrope® in routine clinical practice. Eligible patients are infants, children and adolescents (male or female) who are receiving treatment with Omnitrope® and who have provided informed consent. Patients who have been treated with another recombinant human growth hormone (rhGH) product before starting Omnitrope® are eligible for inclusion. All adverse events (AEs) are monitored and recorded, with particular emphasis on: long-term safety; the recording of malignancies; the occurrence and clinical impact of anti-hGH antibodies; the development of diabetes during Omnitrope® treatment in children short for gestational age (SGA); safety issues in patients with Prader–Willi syndrome (PWS). Efficacy assessments include auxological parameters, plus insulin-like growth factor-1 and insulin-like growth factor binding protein-3. Results: As of September 2012, 1837 patients were enrolled in the study from 184 sites in 10 European countries. To date, efficacy data are reassuring and consistent with previous studies. In addition, there have been no confirmed cases of diabetes occurring under Omnitrope® treatment, no reports of malignancy and no safety issues in PWS patients. Conclusions: The efficacy and safety profile of Omnitrope® in the PATRO Children study so far are as expected. The ongoing study will extend the safety database for Omnitrope®, and rhGH products more generally, in paediatric indications. Of particular interest, PATRO Children will add important information on the diabetogenic potential of rhGH in children born SGA, the risk of malignancies in children receiving rhGH, and AEs with a possible causal relationship to rhGH treatment in children with PWS.
Mast cells contribute to double-stranded RNA-induced augmentation of airway eosinophilia in a murine model of asthma
Authors: Kan-o Keiko , Matsunaga Yuko , Fukuyama Satoru , Moriwaki Atsushi , Hirai-Kitajima Hiroko , Yokomizo Takehiko , Aritake Kosuke , Urade Yoshihiro , Nakanishi Yoichi , Inoue Hiromasa , Matsumoto Koichiro 
Published: March 2013

Abstract

Background
Clinical studies showed the contribution of viral infection to the development of asthma. Although mast cells have multiple roles in the pathogenesis of allergic asthma, their role of in the virus-associated pathogenesis of asthma remains unknown. Most respiratory viruses generate double-stranded (ds) RNA during their replication. dsRNA provokes innate immune responses. We recently showed that an administration of polyinocinic polycytidilic acid (poly IC), a mimetic of viral dsRNA, during allergen sensitization augments airway eosinophilia and hyperresponsiveness in mice via enhanced production of IL-13.

Methods
The effect of poly IC on allergen-induced airway eosinophilia was investigated for mast cell-conserved Kit+/+ mice and -deficient KitW/KitW-v mice. The outcome of mast cell reconstitution was further investigated.

Results
Airway eosinophilia and IL-13 production were augmented by poly IC in Kit+/+ mice but not in KitW/KitW-v mice. When KitW/KitW-v mice were reconstituted with bone marrow-derived mast cells (BMMCs), the augmentation was restored. The augmentation was not induced in the mice systemically deficient for TIR domain-containing adaptor-inducing IFN-β (TRIF) or interferon regulatory factor (IRF)-3, both mediate dsRNA-triggered innate immune responses. The augmentation was, however, restored in KitW/KitW-v mice reconstituted with TRIF-deficient or IRF-3-deficient BMMCs. Although leukotriene B4 and prostaglandin D2 are major lipid mediators released from activated mast cells, no their contribution was shown to the dsRNA-induced augmentation of airway eosinophilia.

Conclusions
We conclude that mast cells contribute to dsRNA-induced augmentation of allergic airway inflammation without requiring direct activation of mast cells with dsRNA or involvement of leukotriene B4 or prostaglandin D2.
The ArabidopsisAt1g30680 gene encodes a homologue to the phage T7 gp4 protein that has both DNA primase and DNA helicase activities
Authors: Diray-Arce Joann , Liu Bin , Cupp John D , Hunt Travis , Nielsen Brent L 
Published: March 2013

Abstract

Background
The Arabidopsis thaliana genome encodes a homologue of the full-length bacteriophage T7 gp4 protein, which is also homologous to the eukaryotic Twinkle protein. While the phage protein has both DNA primase and DNA helicase activities, in animal cells Twinkle is localized to mitochondria and has only DNA helicase activity due to sequence changes in the DNA primase domain. However, Arabidopsis and other plant Twinkle homologues retain sequence homology for both functional domains of the phage protein. The Arabidopsis Twinkle homologue has been shown by others to be dual targeted to mitochondria and chloroplasts.

Results
To determine the functional activity of the Arabidopsis protein we obtained the gene for the full-length Arabidopsis protein and expressed it in bacteria. The purified protein was shown to have both DNA primase and DNA helicase activities. Western blot and qRT-PCR analysis indicated that the Arabidopsis gene is expressed most abundantly in young leaves and shoot apex tissue, as expected if this protein plays a role in organelle DNA replication. This expression is closely correlated with the expression of organelle-localized DNA polymerase in the same tissues. Homologues from other plant species show close similarity by phylogenetic analysis.

Conclusions
The results presented here indicate that the Arabidopsis phage T7 gp4/Twinkle homologue has both DNA primase and DNA helicase activities and may provide these functions for organelle DNA replication.
The personal and national costs of lost labour force participation due to arthritis: an economic study
Authors: Schofield Deborah J , Shrestha Rupendra N , Percival Richard , Passey Megan E , Callander Emily J , Kelly Simon J 
Published: March 2013

Abstract

Background
The costs of arthritis to the individuals and the state are considerable.

Methods
Cross-sectional analysis of the base population of Health&WealthMOD, a microsimulation model of 45 to 64 year old Australians built on data from the Australian Bureau of Statistics’ Survey of Disability, Ageing and Carers and STINMOD, an income and savings microsimulation model.

Results
Individuals aged 45 to 64 years who had retired early due to arthritis had a median value of AU$260 in total weekly income whereas those who were employed full time were likely to average more than five times this. The large national aggregate impact of early retirement due to arthritis includes AU$9.4 billion in lost GDP, attributable to arthritis through its impact on labour force participation.
When looking at the ongoing impact of being out of the labour force those who retired from the labour force early due to arthritis were estimated to have a median value of total savings by the time they are 65 of as little as $300 (for males aged 45–54). This is far lower than the median value of savings for those males aged 45–54 who remained in the labour force full time, who would have an estimated $339 100 of savings at age 65.

Conclusions
The costs of arthritis to the individuals and the state are considerable. The impacts on the state include loss of productivity from reduced workforce participation, lost income taxation revenue, and increased government support payments – in addition to direct health care costs. Individuals bear the economic costs of lost income and the reduction of their savings over the long term.
Differential expression of beta-catenin and dickkopf-1 in the third trimester placentas from normal and preeclamptic pregnancies: a comparative study
Authors: Zhang Zhan , Li He , Zhang Linlin , Jia Liting , Wang Peng 
Published: March 2013

Abstract

Background
Beta-catenin is a key nuclear effector of Wnt signaling which could be antagonized by dickkopf-1(DKK1). Beta-catenin and DKK1 are involved in a variety of biological processes; however, their expression in the placenta with severe preeclampsia (PE) has not been elucidated. This study was aimed to detect the localization and compare the expression of beta-catenin and DKK1 in normal and preeclamptic placenta.

Methods
Sixty pregnant women who underwent cesarean section were enrolled in this study, including 30 healthy pregnant women in the control group and 30 preeclamptic women in the severe PE group. Real-time polymerase chain reaction (real-time-PCR) and western blot were employed to detect the beta-catenin and DKK1 mRNA and protein expression levels, respectively, and their locations were evaluated by immunohistochemistry (IHC).

Results
Our results indicated that beta-catenin and DKK1 were expressed predominantly in the syncytiotrophoblast and the extravillous trophoblast (EVT). The beta-catenin mRNA and protein expressions were significantly decreased, whereas the DKK1 significantly increased in preeclamptic placental tissues compared to normal placental controls.

Conclusions
In conclusion, decreased beta-catenin expression, as well as DKK1 over-expression might be associated with the process of the pathogenesis of PE. Further studies would elucidate their exact roles in the pathogenesis of PE.