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The case describes the coincidental mRNA vaccination and SARS-CoV-2 infection of a 31-year-old physician addressing the theoretical considerations and recommendations for further actions in such a particular constellation that we will expect more often in the near future.

Background Most current approaches in forest science and practice require information about structure and growth of individual trees rather than - or in addition to - sum and mean values of growth and yield at forest stand level as provided by classic experimental designs. By inventing the wheel design, Nelder provided the possibility to turn to the individual tree as basic information unit. Such trials provide valuable insights into the dependency of growth on stand density at particular sites. Methods Here, we present an extension of the original design and evaluation by Nelder. (i) We established Nelder wheels along an environmental gradient through Europe in atlantic climate in Belgium and Germany, Mediterranean climate in Italy, continental climate in Hungary as well as on high land climate in Mexico. Such disjunct Nelder wheels along an environmental gradient can be regarded and analysed as a two-factor design with the factors of site condition and stand density. (ii) We present an advanced statistical approach to evaluate density dependent growth dynamics of trees planted in form of the Nelder design, which considers spatio-temporal autocorrelation. (iii) We prove the usefulness of the methods in improving ecological theory concerning density related productivity, trade-offs between facilitation and competition, and allometric relations between size variables. Results First evaluations based on remeasured Nelder wheels in oak ( Quercus robur L. ) show a size growth differentiation during the first observation period. In particular, height growth is accelerated under higher competition indicating facilitation effects. We detect furthermore a high variability in allometric relations. Conclusions The proposed design, methods, and results are discussed regarding their impact on forest practice, model building, and ecological theory. We conclude that the extended Nelder approach is highly efficient in providing currently lacking individual tree level information.

ERBB2 is a ligand-less tyrosine kinase receptor expressed at very low levels in normal tissues; when overexpressed, it is involved in malignant transformation and tumorigenesis in several carcinomas. In cancer cells, ERBB2 represents the preferred partner of other members of the ERBB receptor family, leading to stronger oncogenic signals, by promoting both ERK and AKT activation. The identification of the specific signaling downstream of ERBB2 has been impaired by the lack of a ligand and of an efficient way to selectively activate the receptor. In this paper, we found that antibodies (Abs) targeting different epitopes on the ERBB2 extracellular domain foster the activation of ERBB2 homodimers, and surprisingly induce a unique cytostatic signaling cascade promoting an ERK-dependent ERBB2 Thr 701 phosphorylation, leading to AKT de-phosphorylation, via PP2A Ser/Thr phosphatases. Furthermore, the immunophilin Cyclophilin A plays a crucial role in this pathway, acting as a negative modulator of AKT de-phosphorylation, possibly by competing with Ser/Thr phosphatases for binding to AKT. Altogether, our data show that Ab recognizing ERBB2 extracellular domain function as receptor agonists, promoting ERBB2 homodimer activation, leading to an anti-proliferative signaling. Thus, the ultimate outcome of ERBB2 activity might depend on the dimerization status: pro-oncogenic in the hetero-, and anti-oncogenic in the homo-dimeric form.

ERBB2 is a ligand-less tyrosine kinase receptor expressed at very low levels in normal tissues; when overexpressed, it is involved in malignant transformation and tumorigenesis in several carcinomas. In cancer cells, ERBB2 represents the preferred partner of other members of the ERBB receptor family, leading to stronger oncogenic signals, by promoting both ERK and AKT activation. The identification of the specific signaling downstream of ERBB2 has been impaired by the lack of a ligand and of an efficient way to selectively activate the receptor. In this paper, we found that antibodies (Abs) targeting different epitopes on the ERBB2 extracellular domain foster the activation of ERBB2 homodimers, and surprisingly induce a unique cytostatic signaling cascade promoting an ERK-dependent ERBB2 Thr phosphorylation, leading to AKT de-phosphorylation, via PP2A Ser/Thr phosphatases. Furthermore, the immunophilin Cyclophilin A plays a crucial role in this pathway, acting as a negative modulator of AKT de-phosphorylation, possibly by competing with Ser/Thr phosphatases for binding to AKT. Altogether, our data show that Ab recognizing ERBB2 extracellular domain function as receptor agonists, promoting ERBB2 homodimer activation, leading to an anti-proliferative signaling. Thus, the ultimate outcome of ERBB2 activity might depend on the dimerization status: pro-oncogenic in the hetero-, and anti-oncogenic in the homo-dimeric form.

The emergence of next generation DNA sequencing technology is enabling high-resolution cancer genome analysis. Large-scale projects like the International Cancer Genome Consortium (ICGC) are systematically scanning cancer genomes to identify recurrent somatic mutations. Second generation DNA sequencing, however, is still an evolving technology and procedures, both experimental and analytical, are constantly changing. Thus the research community is still defining a set of best practices for cancer genome data analysis, with no single protocol emerging to fulfil this role. Here we describe an extensive benchmark exercise to identify and resolve issues of somatic mutation calling. Whole genome sequence datasets comprising tumor-normal pairs from two different types of cancer, chronic lymphocytic leukaemia and medulloblastoma, were shared within the ICGC and submissions of somatic mutation calls were compared to verified mutations and to each other. Varying strategies to call mutations, incomplete awareness of sources of artefacts, and even lack of agreement on what constitutes an artefact or real mutation manifested in widely varying mutation call rates and somewhat low concordance among submissions. We conclude that somatic mutation calling remains an unsolved problem. However, we have identified many issues that are easy to remedy that are presented here. Our study highlights critical issues that need to be addressed before this valuable technology can be routinely used to inform clinical decision-making.

As next-generation sequencing becomes a clinical tool, a full understanding of the variables affecting sequencing analysis output is required. Through the International Cancer Genome Consortium (ICGC), we compared sequencing pipelines at five independent centers (CNAG, DKFZ, OICR, RIKEN and WTSI) using a single tumor-blood DNA pair. Analyses by each center and with one standardized algorithm revealed significant discrepancies. Although most pipelines performed well for coding mutations, library preparation methods and sequencing coverage metrics clearly influenced downstream results. PCR-free methods showed reduced GC-bias and more even coverage. Increasing sequencing depth to ~100x (two- to three-fold higher than current standards) showed a benefit, as long as the tumor:control coverage ratio remained balanced. To become part of routine clinical care, high-throughput sequencing must be globally compatible and comparable. This benchmarking exercise has highlighted several fundamental parameters to consider in this regard, which will allow for better optimization and planning of both basic and translational studies.