Patient characteristics and clinical outcomes following initial surgical intervention for MEN1 associated pancreatic neuroendocrine tumours: A systematic review and exploratory meta-analysis of the literature

Background

This systematic review aimed to define the outcomes of different pancreatic resection procedures for multiple endocrine neoplasia type 1 (MEN1) associated pancreatic neuroendocrine neoplasms (pNENs).

Personalized treatment selection using data from crossover designs with carry-over effects

In this work, we propose a semiparametric method for estimating the optimal treatment for a given patient based on individual covariate information for that patient when data from a crossover design are available. Here, we assume there are carry-over effects for patients switching from one treatment to another. For the K treatment (K ≥ 2) scenario, we show that nonparametric estimation of carry-over effects can have the undesirable property that comparison of treatment means can only be done using independent outcome measurements from different groups of patients rather than using available joint measurements for each patient. To overcome this barrier, we compare probabilities of outcome variable of each treatment dominating outcome variables for all other treatments conditional on patient-specific scores constructed from patient covariates. We suggest single-index models as appropriate models connecting outcome variables to covariates and our empirical investigations show that frequencies of correct treatment assignments are highly accurate. The proposed method is also rather robust against departures from a single-index model structure. We also conduct a real data analysis to show the applicability of the proposed procedure.     

Pre-exposure Prophylaxis Therapy and the Blood-Brain Barrier: Is PrEP Neuroprotective?

Journal of Neuroimmune Pharmacology -     

Structural Investigation of Orf Virus Bcl-2 Homolog ORFV125 Interactions with BH3-Motifs from BH3-Only Proteins Puma and Hrk

Numerous viruses have evolved sophisticated countermeasures to hijack the early programmed cell death of host cells in response to infection, including the use of proteins homologous in sequence or structure to Bcl-2. Orf virus, a member of the parapoxviridae, encodes for the Bcl-2 homolog ORFV125, a potent inhibitor of Bcl-2-mediated apoptosis in the host. ORFV125 acts by directly engaging host proapoptotic Bcl-2 proteins including Bak and Bax as well as the BH3-only proteins Hrk and Puma. Here, we determined the crystal structures of ORFV125 bound to the BH3 motif of proapoptotic proteins Puma and Hrk. The structures reveal that ORFV125 engages proapoptotic BH3 motif peptides using the canonical ligand binding groove. An Arg located in the structurally equivalent BH1 region of ORFV125 forms an ionic interaction with the conserved Asp in the BH3 motif in a manner that mimics the canonical ionic interaction seen in host Bcl-2:BH3 motif complexes. These findings provide a structural basis for Orf virus-mediated inhibition of host cell apoptosis and reveal the flexibility of virus encoded Bcl-2 proteins to mimic key interactions from endogenous host signalling pathways.