Genetic studies of Neolithic and Bronze Age skeletons from Europe have provided evidence for strong population genetic changes at the beginning and the end of the Neolithic period. To further ...understand the implications of these in Southern Central Europe, we analyze 96 ancient genomes from Switzerland, Southern Germany, and the Alsace region in France, covering the Middle/Late Neolithic to Early Bronze Age. Similar to previously described genetic changes in other parts of Europe from the early 3rd millennium BCE, we detect an arrival of ancestry related to Late Neolithic pastoralists from the Pontic-Caspian steppe in Switzerland as early as 2860-2460 calBCE. Our analyses suggest that this genetic turnover was a complex process lasting almost 1000 years and involved highly genetically structured populations in this region.
Metastatic castration-resistant prostate cancer (mCRPC) remains a disease with high unmet medical need, as most patients do not achieve durable response with available treatments. Prostate-specific ...membrane antigen (PSMA) is a compelling target for mCRPC. It is highly expressed by primary and metastatic prostate cancer cells, with increased expression after progression on androgen deprivation therapy.
We developed AMG 160, a half-life extended, bispecific T-cell engager immuno-oncology therapy that binds PSMA on prostate cancer cells and cluster of differentiation 3 on T cells for treatment of mCRPC. AMG 160 was evaluated
and in mCRPC xenograft models. AMG 160 tolerability was assessed in nonhuman primates (NHP). AMG 160 activity as monotherapy and in combination with a PSMA-imaging agent, novel hormonal therapy, and immune checkpoint blockade was evaluated.
AMG 160 induces potent, specific killing of PSMA-expressing prostate cancer cell lines
, with half-maximal lysis of 6-42 pmol/L.
, AMG 160 administered weekly at 0.2 mg/kg engages T cells administered systemically and promotes regression of established 22Rv-1 mCRPC xenograft tumors. AMG 160 is compatible with the imaging agent gallium 68-labeled PSMA-11, and shows enhanced cytotoxic activity when combined with enzalutamide or an anti-programmed death-1 antibody. AMG 160 exhibits an extended half-life and has an acceptable safety profile in NHPs.
The preclinical characterization of AMG 160 highlights its potent antitumor activity
and
, and its potential for use with known diagnostic or therapeutic agents in mCRPC. These data support the ongoing clinical evaluation of AMG 160 in patients with mCRPC.
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Previous research found sexual dimorphism in the bony labyrinth of a Greek population sample (Osipov et al.
2013
). This study intends to investigate the nature of this structure’s sexual dimorphism ...across populations of diverse geographic origin and to identify the effect of inter-population variation on the accuracy of determining sex using the bony labyrinth. Three population samples of known sex were analyzed originating from Europe (
n
= 30), Africa (
n
= 38), and North America (
n
= 30). The discriminant function developed in Osipov et al. (
2013
) was applied, and new function equations for sex estimation were developed. In addition, we used principal component analyses for investigating population differences, while bivariate tests were used to compare across population samples, sexes, and anatomical sides. A significant level of sexual dimorphism was found in all population samples, being driven by both size and shape differences. Discriminant functions for sex estimation were developed for all three population samples combined (71.4% accuracy) as well as separately (70–80% accuracy). The German sample was the least sexually dimorphic, whereas the North American sample exhibited the greatest sexual dimorphism. The size and shape of the bony labyrinth also significantly differed across population samples. The bony labyrinth is found to be sexually dimorphic across distinct population groups. Due to significant differences across our population samples, the accuracy of the previously proposed method for sex determination (Osipov et al.,
2013
) was relatively low. For this purpose, this study presented new functions, whose accuracy was tested in three distinct population samples.
Community differentiation is a fundamental topic of the social sciences, and its prehistoric origins in Europe are typically assumed to lie among the complex, densely populated societies that ...developed millennia after their Neolithic predecessors. Here we present the earliest, statistically significant evidence for such differentiation among the first farmers of Neolithic Europe. By using strontium isotopic data from more than 300 early Neolithic human skeletons, we find significantly less variance in geographic signatures among males than we find among females, and less variance among burials with ground stone adzes than burials without such adzes. From this, in context with other available evidence, we infer differential land use in early Neolithic central Europe within a patrilocal kinship system.
The pathogen landscape in the Early European Middle Ages remains largely unexplored. Here, we perform a systematic pathogen screening of the rural community Lauchheim "Mittelhofen," in present-day ...Germany, dated to the Merovingian period, between fifth and eighth century CE. Skeletal remains of individuals were subjected to an ancient DNA metagenomic analysis. Genomes of the detected pathogens were reconstructed and analyzed phylogenetically.
Over 30% of the individuals exhibit molecular signs of infection with hepatitis B virus (HBV), parvovirus B19, variola virus (VARV), and Mycobacterium leprae. Seven double and one triple infection were detected. We reconstructed four HBV genomes and one genome each of B19, VARV, and M. leprae. All HBV genomes are of genotype D4 which is rare in Europe today. The VARV strain exhibits a unique pattern of gene loss indicating that viruses with different gene compositions were circulating in the Early Middle Ages. The M. leprae strain clustered in branch 3 together with the oldest to-date genome from the UK.
The high burden of infectious disease, together with osteological markers of physiological stress, reflect a poor health status of the community. This could have been an indirect result of the climate decline in Europe at the time, caused by the Late Antique Little Ice Age (LALIA). Our findings suggest that LALIA may have created an ecological context in which persistent outbreaks set the stage for major epidemics of severe diseases such as leprosy and smallpox hundreds of years later.
•Amino acid based ionic liquids with different proteinogenic l-amino acids were prepared and tested as background electrolyte additives for the separation of phenethylamine enantiomers.•A design of ...experiments approach was performed for the optimization of buffer pH and ionic liquid concentration.•Best separations were achieved using tetrabutylammonium l-argininate in a phosphate buffer containing β-cyclodextrin.•A synergistic effect between β-CD and l-Arg on the separation of phenethylamine enantiomers was observed.
In recent years increasing interest was drawn towards ionic liquids in analytical separation science, such as capillary electrophoresis. Ionic liquids combining tetrabutylammonium cations with chiral amino acid based anions were prepared and investigated as capillary electrophoresis background electrolyte additives for the enantioseparation of ephedrine, pseudoephedrine, and methylephedrine isomers. For the optimization of buffer pH and ionic liquid concentration a design of experiments approach was performed. The best results for the separation of all enantiomers were achieved using 125mmol/L tetrabutylammonium l-argininate in a 75mmol/L phosphate buffer pH 1.5 containing 30mmol/L β-cyclodextrin.
Sympathoadrenergic progenitor cells (SAPs) of the peripheral nervous system (PNS) are important for normal development of the sympathetic PNS and for the genesis of neuroblastoma, the most common and ...often lethal extracranial solid tumor in childhood. However, it remains difficult to isolate sufficient numbers of SAPs for investigations. We therefore set out to improve generation of SAPs by using two complementary approaches, differentiation from murine embryonic stem cells (ESCs) and isolation from postnatal murine adrenal glands. We provide evidence that selecting for GD2 expression enriches for ESC-derived SAP-like cells and that proliferating SAP-like cells can be isolated from postnatal adrenal glands of mice. These advances may facilitate investigations about the development and malignant transformation of the sympathetic PNS.
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