Suchergebnisse

Identification of medical countermeasures (MCM) to mitigate radiation damage and/or protect first responders is a compelling unmet medical need. The prostaglandin E(2) (PGE(2)) analog, 16,16 dimethyl-PGE(2) (dmPGE(2)), has shown efficacy as a radioprotectant and radiomitigator that can enhance hematopoiesis and ameliorate intestinal mucosal cell damage. In this study, we optimized the time of administration of dmPGE(2) for protection and mitigation against mortality from the hematopoietic acute radiation syndrome (H-ARS) in young adult mice, evaluated its activity in pediatric and geriatric populations, and investigated potential mechanisms of action. Windows of 30-day survival efficacy for single administration of dmPGE(2) were defined as within 3 h prior to and 6–30 h after total-body γ irradiation (TBI). Radioprotective and radio-mitigating efficacy was also observed in 2-year-old geriatric mice and 6-week-old pediatric mice. PGE(2) receptor agonist studies suggest that signaling through EP4 is primarily responsible for the radioprotective effects. DmPGE(2) administration prior to TBI attenuated the drop in red blood cells and platelets, accelerated recovery of all peripheral blood cell types, and resulted in higher hematopoietic and mesenchymal stem cells in survivor bone marrow. Multiplex analysis of bone marrow cytokines together with RNA sequencing of hematopoietic stem cells indicated a pro-hematopoiesis cytokine milieu induced by dmPGE(2), with IL-6 and G-CSF strongly implicated in dmPGE(2)-mediated radioprotective activity. In summary, we have identified windows of administration for significant radio-mitigation and radioprotection by dmPGE(2) in H-ARS, demonstrated survival efficacy in special populations, and gained insight into radioprotective mechanisms, information useful towards development of dmPGE(2) as a MCM for first responders, military personnel, and civilians facing radiation threats.

Background: Duct to mucosa Pancreatico-gastrostomy (DMPG) is a method for reconstruction of pancreatic mass
following pancreaticoduodenectomy (PD). There are still controversies about the benefits of this surgical technique compared to
the old ones. Objectives: This study aimed to evaluate the long-term outcomes of DMPG reconstruction following PD operation.
Method: Through a prospective observational setting, 164 patients, undergoing PD surgery, with diagnosed pancreatic head or
peri-ampullary cancer, were enrolled. A pylorus-preserving PD and DMPG were done for all patients to reconstruct the pancreatic
mass. Patients were followed up to a mean of 21.06±14.12 months. Demographic data, risk factors, tumoral staging, and
postoperative follow-up data were collected for the analytic study. Results: The mean survival of the patients was 21.06±14.23
months after surgery. DGE (delayed gastric emptying) (34.75%), pancreatic fistula (21.34%), bile duct fistula (7.31%), and
hemorrhage (5.5%) were recorded as the most important complication in patients. Some post-operative complications were
significantly observed in patients with diabetes mellitus (pancreatic fistula, increased amylase, and DGE), Smokers (bile duct
fistula, hemorrhage, and increased Amylase), and the elders (bile duct fistula) (p-value 0.05). Conclusions: Although our results
indicate that DMPG reconstruction is a safe technique, our findings did not confirm the priority of this method over the older
techniques.

Silk fibroin (SF) hydrogels can be obtained via self‐assembly, but this process takes several days or weeks, being unfeasible to produce cell carrier hydrogels. In this work, a phospholipid, namely, 1,2‐dimyristoyl‐sn‐glycero‐3‐phospho‐(1′‐rac‐glycerol) sodium salt (DMPG), was used to induce and accelerate the gelation process of SF solutions. Due to the amphipathic nature and negative charge of DMPG, electrostatic and hydrophobic interactions between the phospholipids and SF chains will occur, inducing the structural transition of SF chains to the beta sheet and consequently a rapid gel formation is observed (less than 50 min). Moreover, the gelation time can be controlled by varying the lipid concentration. To assess the potential of the hydrogels as cell carriers, several mammalian cell lines, including L929, NIH/3T3, SaOS‐2, and CaSki, were encapsulated into the hydrogel. The silk‐based hydrogels supported the normal growth of fibroblasts, corroborating their cytocompatibility. Interestingly, an inhibition in the growth of cancer‐derived cell lines was observed. Therefore, DMPG‐induced SF hydrogels can be successfully used as a 3D platform for in situ cell encapsulation, opening promising opportunities in biomedical applications, such as in cell therapies and tissue regeneration. ; This paper was supported by the REMIX Project, funded by the European Union's Horizon 2020 Research and Innovation programme under the Maria Sklodowska‐Curie Grant agreement n. 778078. Financial support is acknowledged from Chulalongkorn Academic Advancement into Its 2nd Century (CUAASC), SPARTAN project (PTDC/CTM‐BIO/4388/2014), and NORTE 2020 Structured Project within the R&D&I Structured Project, cofunded by Norte2020—Programa Operacional Regional do Norte. Chavee Laomeephol was awarded with The 100th Anniversary Chulalongkorn University Fund for his Doctoral Scholarship and The 90th Anniversary Chulalongkorn University Fund (Ratchadaphiseksomphot Endowment Fund). Marta Guedes acknowledges the Portuguese Foundation for ...

A series of β-amino alcohols were prepared by the reaction of eugenol epoxide with aliphatic and aromatic amine nucleophiles. The synthesized compounds were fully characterized and evaluated as potential insecticides through the assessment of their biological activity against Sf9 insect cells, compared with a commercial synthetic pesticide (chlorpyrifos, CHPY). Three derivatives bearing a terminal benzene ring, either substituted or unsubstituted, were identified as the most potent molecules, two of them displaying higher toxicity to insect cells than CHPY. In addition, the most promising molecules were able to increase the activity of serine proteases (caspases) pivotal to apoptosis and were more toxic to insect cells than human cells. Structure-based inverted virtual screening and molecular dynamics simulations demonstrate that these molecules likely target acetylcholinesterase and/or the insect odorant-binding proteins and are able to form stable complexes with these proteins. Encapsulation assays in liposomes of DMPG and DPPC/DMPG (1:1) were performed for the most active compound, and high encapsulation efficiencies were obtained. A thermosensitive formulation was achieved with the compound release being more efficient at higher temperatures. ; This research was funded by project PTDC/ASP-AGR/30154/2017 (POCI-01-0145-FEDER-030154) of the COMPETE 2020 program, co-financed by the FEDER and the European Union. The authors acknowledge also the Foundation for Science and Technology (FCT, Portugal) and FEDER-COMPETE-QREN-EU for financial support to the research centers CQ-UM (UID/QUI/00686/2020), CF-UM-UP (UIDB/04650/2020) and REQUIMTE (UIDB/50006/2020). The NMR spectrometer Bruker Avance III 400 is part of the National NMR Network and was purchased within the framework of the National Program for Scientific Re-equipment, contract REDE/1517/RMN/2005 with funds from POCI 2010 (FEDER) and ...