The clinicopathological and gene expression patterns associated with ulceration of primary melanoma

Ulceration of primary melanomas is associated with poor prognosis yet is reported to predict benefit from adjuvant interferon. To better understand the biological processes involved, clinicopathological factors associated with ulceration were determined in 1804 patients. From this cohort, 348 primary tumor blocks were sampled to generate gene expression data using a 502‐gene cancer panel and 195 blocks were used for immunohistochemistry to detect macrophage infiltration and vessel density. Gene expression results were validated using a whole genome array in two independent sample sets. Ulceration of primary melanomas was associated with more proliferative tumors, tumor vessel invasion, and increased microvessel density. Infiltration of tumors with greater number of macrophages and gene expression pathways associated with wound healing and up‐regulation of pro‐inflammatory cytokines suggests that ulceration is associated with tumor‐related inflammation. The relative benefit from interferon reported in patients with ulcerated tumors may reflect modification of signaling pathways involved in inflammation.     

Fitness reduction and potential extinction of wild populations of Atlantic salmon, Salmo salar, as a result of interactions with escaped farm salmon

The high level of escapes from Atlantic salmon farms, up to two million fishes per year in the North Atlantic, has raised concern about the potential impact on wild populations. We report on a two-generation experiment examining the estimated lifetime successes, relative to wild natives, of farm, F(1) and F(2) hybrids and BC(1) backcrosses to wild and farm salmon. Offspring of farm and "hybrids" (i.e. all F(1), F(2) and BC(1) groups) showed reduced survival compared with wild salmon but grew faster as juveniles and displaced wild parr, which as a group were significantly smaller. Where suitable habitat for these emigrant parr is absent, this competition would result in reduced wild smolt production. In the experimental conditions, where emigrants survived downstream, the relative estimated lifetime success ranged from 2% (farm) to 89% (BC(1) wild) of that of wild salmon, indicating additive genetic variation for survival. Wild salmon primarily returned to fresh water after one sea winter (1SW) but farm and 'hybrids' produced proportionately more 2SW salmon. However, lower overall survival means that this would result in reduced recruitment despite increased 2SW fecundity. We thus demonstrate that interaction of farm with wild salmon results in lowered fitness, with repeated escapes causing cumulative fitness depression and potentially an extinction vortex in vulnerable populations.     

Late‐moulting Black‐necked Grebes Podiceps nigricollis show greater body mass in the face of failing food supply

From August to December, thousands of Black‐necked Grebes Podiceps nigricollis concentrate during the flightless moult period in salt ponds in the Odiel Marshes, southern Spain, where they feed on the brine shrimp Artemia parthenogenetica. We predicted that because Black‐necked Grebes moulted in a food‐rich, predator‐free environment, there would be no net loss of body mass caused by the use of fat stored to meet energy needs during remigial feather replacement (as is the case for some other diving waterbirds). However, because the food resource disappears in winter, we predicted that grebes moulting later in the season would put on more body mass prior to moult because of the increasing risk of an Artemia population crash before the moult period is completed. Body mass determinations of thousands of birds captured during 2000–2010 showed that grebes in active wing‐moult showed greater mass with date of capture. Early‐moulting grebes were significantly lighter at all stages than late‐moulting birds. Grebes captured with new feathers post‐moult were significantly lighter than those in moult. This is the first study to support the hypothesis that individual waterbirds adopt different strategies in body mass accumulation according to timing of moult: early‐season grebes were able to acquire an excess of energy over expenditure and accumulate fat stores while moulting. Delayed moulters acquired greater fat stores in advance of moult to contribute to energy expenditure for feather replacement and retained extra stores later, most likely as a bet hedge against the increasing probability of failing food supply and higher thermoregulatory demands late in the season. An alternative hypothesis, that mass change is affected by a trophically transmitted cestode using brine shrimps as an intermediate host and Black‐necked Grebes as final host, was not supported by the data.     

Enhanced regional terrestrial carbon uptake over Korea revealed by atmospheric CO2 measurements from 1999 to 2017

Understanding changes in terrestrial carbon balance is important to improve our knowledge of the regional carbon cycle and climate change. However, evaluating regional changes in the terrestrial carbon balance is challenging due to the lack of surface flux measurements. This study reveals that the terrestrial carbon uptake over the Republic of Korea has been enhanced from 1999 to 2017 by analyzing long‐term atmospheric CO₂ concentration measurements at the Anmyeondo Station (36.53°N, 126.32°E) located in the western coast. The influence of terrestrial carbon flux on atmospheric CO₂ concentrations (ΔCO₂) is estimated from the difference of CO₂ concentrations that were influenced by the land sector (through easterly winds) and the Yellow Sea sector (through westerly winds). We find a significant trend in ΔCO₂ of ?4.75 ppm per decade (p < .05) during the vegetation growing season (May through October), suggesting that the regional terrestrial carbon uptake has increased relative to the surrounding ocean areas. Combined analysis with satellite measured normalized difference vegetation index and gross primary production shows that the enhanced carbon uptake is associated with significant nationwide increases in vegetation and its production. Process‐based terrestrial model and inverse model simulations estimate that regional terrestrial carbon uptake increases by up to 18.9 and 8.0 Tg C for the study period, accounting for 13.4% and 5.7% of the average annual domestic carbon emissions, respectively. Atmospheric chemical transport model simulations indicate that the enhanced terrestrial carbon sink is the primary reason for the observed ΔCO₂ trend rather than anthropogenic emissions and atmospheric circulation changes. Our results highlight the fact that atmospheric CO₂ measurements could open up the possibility of detecting regional changes in the terrestrial carbon cycle even where anthropogenic emissions are not negligible.     

[Zn(phen)(O,N,O)(H2O)] and [Zn(phen)(O,N)(H2O)] with O,N,O?is?2,6-dipicolinate and N,O?is?l-threoninate: synthesis, characterization, and biomedical properties

Two ternary Zn(II) complexes, with 1,10-phenanthroline (phen) as the main ligand and a carboxylate-containing ligand [dipicolinate (dipico) or L-threoninate (L-Thr)] as the subsidiary ligand, were prepared and characterized by elemental analysis, Fourier transform IR, UV, and fluorescence spectroscopy, X-ray diffraction, molar conductivity, and electrospray ionization mass spectrometry. X-ray structure analysis shows that both [Zn(phen)(dipico)(H(2)O)]·H(2)O (1) and [Zn(phen)(L-Thr)(H(2)O)Cl]·2H(2)O (2) have octahedral geometry about the Zn(II) atom. Both complexes can inhibit topoisomerase I, and have better anticancer activity than cisplatin against nasopharyngeal cancer cell lines, HK1 and HONE-1, with concentrations causing 50?% inhibition of cell proliferation (IC(50)) in the low micromolar range. Complex 2 has the highest therapeutic index for HK1. Both Zn(II) complexes can induce cell death by apoptosis. Changing the subsidiary ligand in the Zn(II) complexes affects the UV-fluorescence spectral properties of the coordinated phen ligand, the binding affinity for some DNA sequences, nucleobase sequence-selective binding, the phase at which cell cycle progression was arrested for treated cancer cells, and their therapeutic index.     

Comparative study of myocytes from normal and mdx mice iPS cells

Recently, induced pluripotent stem cells (iPS cells) have been derived from various techniques and show great potential for therapy of human diseases. Furthermore, the iPS technique can be used to provide cell models to explore pathological mechanisms of many human diseases in vitro, such as Duchenne muscular dystrophy (DMD), which is a severe recessive X-linked form of muscular dystrophy without effective treatment. In this study, we try to determine whether there are different characteristics of myocytes from mdx iPS cells and C57BL/10 iPS cells. Our results showed that both of mdx and C57BL/10 cells could be induced into iPS cells in vitro, whereas colony-forming ability of mdx iPS cells was much weaker than that of C57BL/10 iPS cells. Meanwhile, mdx iPS cells could be induced to differentiate into myocytes, whereas their differentiation efficiency was much lower than that of C57BL/10 iPS cells. And, the number of apoptotic cells in differentiated myocytes from mdx iPS cells was significantly higher than that from C57BL/10 iPS cells. More importantly, treatment of a pan-caspase inhibitor (Z-VAD) produced a significant decrease in apoptotic cells. This study might add some insight to the biology study of dystrophin gene.     

Atlas versus range maps: robustness of chorological relationships to distribution data types in European mammals

Aim Chorological relationships describe the patterns of distributional overlap among species. In addition to revealing biogeographical structure, the resulting clusters of species with similar geographical distributions can serve as natural units in conservation planning. Here, we assess the extent to which temporal, methodological and taxonomical differences in the source of species’ distribution data can affect the relationships that are found. Location Western Europe. Methods We used two data sets – the Atlas of European mammals and polygon range maps from the IUCN Global Mammal Assessment – both as presence–absence data for UTM 50 km × 50 km squares. We performed pairwise comparisons among 156 species for each data set to build matrices of the similarity in distribution across species, using both Jaccard’s and Baroni‐Urbani & Buser’s indices. We then compared these similarity matrices (chorological relationships), as well as the species richness and occurrence patterns from the two data sets. Results As expected, range maps increased both the mean prevalence per species and mean species richness per grid cell in comparison to atlas data, reflecting the general view that these data types respectively over‐ and underestimate species occurrence. However, species richness and occurrence patterns in atlas and range map data were positively associated and, most importantly, the chorological relationships underlying the two data sets were highly similar. Main conclusions Despite many methodological, temporal and taxonomical differences between atlas data and range maps, the chorological relationships encountered between species were similar for both data sets. Chorological analyses can thus be robust to the data source used and provide a solid basis for analytical biogeographical studies, even over broad spatial scales.     

The stratigraphy of the Middle Stone Age sediments at Pinnacle Point Cave 13B (Mossel Bay, Western Cape Province, South Africa)

Pinnacle Point Cave 13B (PP13B) has provided the earliest archaeological evidence for the exploitation of marine shellfish, along with very early evidence for use and modification of pigments and the production of bladelets, all dated to approximately 164?ka (Marean et?al., 2007). This makes PP13B a key site in studies of the origins of modern humans, one of a handful of sites in Africa dating to Marine Isotope Stage 6 (MIS 6), and the only site on the coast of South Africa with human occupation confidently dated to MIS 6. Along with this MIS 6 occupation there are rich archaeological sediments dated to MIS 5, and together these sediments are differentially preserved in three different areas of the cave. The sediments represent a complex palimpsest of geogenic, biogenic, and anthropogenic input and alteration that are described and interpreted through the use of a variety of macrostratigraphic, micromorphologic, and geochemical techniques. Three independent dating techniques allow us to constrain the age range of these sediments and together provide the stratigraphic context for the analyses of the material that follow in this special issue.     

Good Manufacturing Practices (GMP) manufacturing of advanced therapy medicinal products: a novel tailored model for optimizing performance and estimating costs

Background aimsAdvanced therapy medicinal products (ATMP) have gained considerable attention in academia due to their therapeutic potential. Good Manufacturing Practice (GMP) principles ensure the quality and sterility of manufacturing these products. We developed a model for estimating the manufacturing costs of cell therapy products and optimizing the performance of academic GMP-facilities.MethodsThe “Clean-Room Technology Assessment Technique” (CTAT) was tested prospectively in the GMP facility of BCRT, Berlin, Germany, then retrospectively in the GMP facility of the University of California-Davis, California, USA. CTAT is a two-level model: level one identifies operational (core) processes and measures their fixed costs; level two identifies production (supporting) processes and measures their variable costs. The model comprises several tools to measure and optimize performance of these processes. Manufacturing costs were itemized using adjusted micro-costing system.ResultsCTAT identified GMP activities with strong correlation to the manufacturing process of cell-based products. Building best practice standards allowed for performance improvement and elimination of human errors. The model also demonstrated the unidirectional dependencies that may exist among the core GMP activities. When compared to traditional business models, the CTAT assessment resulted in a more accurate allocation of annual expenses. The estimated expenses were used to set a fee structure for both GMP facilities. A mathematical equation was also developed to provide the final product cost.ConclusionsCTAT can be a useful tool in estimating accurate costs for the ATMPs manufactured in an optimized GMP process. These estimates are useful when analyzing the cost-effectiveness of these novel interventions.