PALLD mutation in a European family conveys a stromal predisposition for familial pancreatic cancer.

BACKGROUNDPancreatic cancer is one of the deadliest cancers, with low long-term survival rates. Despite recent advances in treatment, it is important to identify and screen high-risk individuals for cancer prevention. Familial pancreatic cancer (FPC) accounts for 4%-10% of pancreatic cancers. Several germline mutations are related to an increased risk and might offer screening and therapy options. In this study, we aimed to identity of a susceptibility gene in a family with FPC.METHODSWhole exome sequencing and PCR confirmation was performed on the surgical specimen and peripheral blood of an index patient and her sister in a family with high incidence of pancreatic cancer, to identify somatic and germline mutations associated with familial pancreatic cancer. Compartment-specific gene expression data and immunohistochemistry were also queried.RESULTSThe identical germline mutation of the PALLD gene (NM_001166108.1:c.G154A:p.D52N) was detected in the index patient with pancreatic cancer and the tumor tissue of her sister. Whole genome sequencing showed similar somatic mutation patterns between the 2 sisters. Apart from the PALLD mutation, commonly mutated genes that characterize pancreatic ductal adenocarcinoma were found in both tumor samples. However, the 2 patients harbored different somatic KRAS mutations (G12D and G12V). Healthy siblings did not have the PALLD mutation, indicating a disease-specific impact. Compartment-specific gene expression data and IHC showed expression in cancer-associated fibroblasts (CAFs).CONCLUSIONWe identified a germline mutation of the palladin (PALLD) gene in 2 siblings in Europe, affected by familial pancreatic cancer, with a significant overexpression in CAFs, suggesting that stromal palladin could play a role in the development, maintenance, and/or progression of pancreatic cancer.FUNDINGDFG SFB 1321.

Multistate design of influenza antibodies improves affinity and breadth against seasonal viruses.

Influenza is a yearly threat to global public health. Rapid changes in influenza surface proteins resulting from antigenic drift and shift events make it difficult to readily identify antibodies with broadly neutralizing activity against different influenza subtypes with high frequency, specifically antibodies targeting the receptor binding domain (RBD) on influenza HA protein. We developed an optimized computational design method that is able to optimize an antibody for recognition of large panels of antigens. To demonstrate the utility of this multistate design method, we used it to redesign an antiinfluenza antibody against a large panel of more than 500 seasonal HA antigens of the H1 subtype. As a proof of concept, we tested this method on a variety of known antiinfluenza antibodies and identified those that could be improved computationally. We generated redesigned variants of antibody C05 to the HA RBD and experimentally characterized variants that exhibited improved breadth and affinity against our panel. C05 mutants exhibited improved affinity for three of the subtypes used in design by stabilizing the CDRH3 loop and creating favorable electrostatic interactions with the antigen. These mutants possess increased breadth and affinity of binding while maintaining high-affinity binding to existing targets, surpassing a major limitation up to this point.

Action-effect binding and agency.

The sense of agency is a pervasive phenomenon that accompanies conscious acting and extends to the consequences of one's actions in the environment. Subjective feelings of agency are typically explained in terms of predictive processes, based on internal forward models inherent to the sensorimotor system, and postdictive processes, i.e., explicit, retrospective judgments by the agent. Only recently, research has begun to elucidate the link between sense of agency and more basic processes of human action control. The present study was conducted in this spirit and explored the relation between short-term action-effect binding and explicit agency judgments. We found evidence for such a link in that the participants' short-term action-effect binding predicted subsequent agency ratings. This offers a new perspective on the sense of agency, providing an additional mechanism (together with predictive and postdictive processes) that may underlie its formation.

Software design and implementation concepts for an interoperable medical communication framework.

The new IEEE 11073 service-oriented device connectivity (SDC) standard proposals for networked point-of-care and surgical devices constitutes the basis for improved interoperability due to its independence of vendors. To accelerate the distribution of the standard a reference implementation is indispensable. However, the implementation of such a framework has to overcome several non-trivial challenges. First, the high level of complexity of the underlying standard must be reflected in the software design. An efficient implementation has to consider the limited resources of the underlying hardware. Moreover, the frameworks purpose of realizing a distributed system demands a high degree of reliability of the framework itself and its internal mechanisms. Additionally, a framework must provide an easy-to-use and fail-safe application programming interface (API). In this work, we address these challenges by discussing suitable software engineering principles and practical coding guidelines. A descriptive model is developed that identifies key strategies. General feasibility is shown by outlining environments in which our implementation has been utilized.