The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network

Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Methods and Findings: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects

Antigen-expressing immunostimulatory liposomes as a genetically programmable synthetic vaccine

Liposomes are versatile (sub)micron-sized membrane vesicles that can be used for a variety of applications, including drug delivery and in vivo imaging but they also represent excellent models for artificial membranes or cells. Several studies have demonstrated that in vitro transcription and translation can take place inside liposomes to obtain compartmentalized production of functional proteins within the liposomes (Kita et al. in Chembiochem 9(15):2403–2410, 2008; Moritani et al.in FEBS J, 2010; Kuruma et al. in Methods Mol Biol 607:161–171, 2010; Murtas et al. in Biochem Biophys Res Commun 363(1):12–17, 2007; Sunami et al. in Anal Biochem 357(1):128–136, 2006; Ishikawa et al. in FEBS Lett 576(3):387–390, 2004; Oberholzer et al. in Biochem Biophys Res Commun 261(2):238–241, 1999). Such a minimal artificial cell-based model is ideal for synthetic biology based applications. In this study, we propose the use of liposomes as artificial microbes for vaccination. These artificial microbes can be genetically programmed to produce specific antigens at will. To show proof-of-concept for this artificial cell-based platform, a bacterial in vitro transcription and translation system together with a gene construct encoding the model antigen β-galactosidase were entrapped inside multilamellar liposomes. Vaccination studies in mice showed that such antigen-expressing immunostimulatory liposomes (AnExILs) elicited higher specific humoral immune responses against the produced antigen (β-galactosidase) than control vaccines (i.e. AnExILs without genetic input, liposomal β-galactosidase or pDNA encoding β-galactosidase). In conclusion, AnExILs present a new platform for DNA-based vaccines which combines antigen production, adjuvanticity and delivery in one system and which offer several advantages over existing vaccine formulations

Improved representation of the diurnal variation of warm season precipitation by an atmospheric general circulation model at a 10 km horizontal resolution

This study investigates the diurnal variation of the warm season precipitation simulated by the Goddard Earth Observing System version 5 atmospheric general circulation model for 2??years (2005???2006) at a horizontal resolution of 10??km. The simulation was validated with the satellite-derived Tropical Rainfall Measuring Mission (TRMM) 3B42 precipitation data and the Modern-Era Retrospective analysis for Research and Applications atmospheric reanalysis for atmospheric winds and moisture. The simulation is compared with the coarse-resolution run in 50??km to examine the impacts driven by resolution change. Overall, the 10??km model tends to reproduce the important features of the observed diurnal variation, such as the amplitude and phase at which precipitation peaks in the evening on land and in the morning over the ocean, despite an excessive amplitude bias over land. The model also reproduces the realistic propagation patterns of precipitation in the vicinity of ocean coasts and major mountains. The regional characteristics of the diurnal precipitation over two regions, the Bay of Bengal and the Great Plains in North America, are examined in detail, where the observed diurnal cycle exhibits a systematic transition in the peak phase due to the development and propagation of regional-scale convective systems. The model is able to reproduce this pattern as well as the diurnal variation of low-level wind and moisture convergence; however, it is less effective at representing the nocturnal peak of precipitation over the Great Plains. The model results suggest that increasing the horizontal resolution of the model to 10??km substantially improves the representation of the diurnal precipitation cycle. However, intrinsic model deficiencies in topographical precipitation and the accurate representation of mesoscale convective systems remain a challenge

Extremely Low Genetic Diversity Indicating the Endangered Status of Ranodon sibiricus (Amphibia: Caudata) and Implications for Phylogeography

Background: The Siberian salamander (Ranodon sibiricus), distributed in geographically isolated areas of Central Asia, is an ideal alpine species for studies of conservation and phylogeography. However, there are few data regarding the genetic diversity in R. sibiricus populations. Methodology/Principal Findings: We used two genetic markers (mtDNA and microsatellites) to survey all six populations of R. sibiricus in China. Both of the markers revealed extreme genetic uniformity among these populations. There were only three haplotypes in the mtDNA, and the overall nucleotide diversity in the mtDNA was 0.00064, ranging from 0.00000 to 0.00091 for the six populations. Although we recovered 70 sequences containing microsatellite repeats, there were only two loci that displayed polymorphism. We used the approximate Bayesian computation (ABC) method to study the demographic history of the populations. This analysis suggested that the extant populations diverged from the ancestral population approximately 120 years ago and that the historical population size was much larger than the present population size; i.e., R. sibiricus has experienced dramatic population declines. Conclusion/Significance: Our findings suggest that the genetic diversity in the R. sibiricus populations is the lowest among all investigated amphibians. We conclude that the isolation of R. sibiricus populations occurred recently and was a result of recent human activity and/or climatic changes. The Pleistocene glaciation oscillations may have facilitated intraspecie

Reactivity of He with ionic compounds under high pressure

Helium was long thought to be unable to form stable solid compounds, until a recent discovery that helium reacts with sodium at high pressure. Here, the authors demonstrate the driving force for helium reactivity, showing that it can form new compounds under pressure without forming any local chemical bonds