Citations

Pancreatic cancer, mostly pancreatic ductal adenocarcinoma (PDAC), is one of the most lethal cancer types, with an estimated 44,330 death in 2018 in the US alone. While targeted therapies and immune checkpoint inhibitors have significantly improved treatment options for patients with lung cancer and renal cell carcinomas, little progress has been made in pancreatic cancer, with a dismal 5-year survival rate currently at ~8%. Upon diagnosis, the majority of pancreatic cancer cases (~80%) are already metastatic. Thus, identifying ways to reduce pancreatic cancer metastasis is an unmet medical need. Furthermore, pancreatic cancer is notorious resistant to chemotherapy. While Kirsten RAt Sarcoma virus oncogene (K-RAS) mutation is the major driver for pancreatic cancer, specific inhibition of RAS signaling has been very challenging, and combination therapy is thought to be promising. In this study, we report that combination of hedgehog (Hh) and Mitogen-activated Protein/Extracellular Signal-regulated Kinase Kinase (MEK) signaling inhibitors reduces pancreatic cancer metastasis in mouse models. In mouse models of pancreatic cancer metastasis using human pancreatic cancer cells, we found that Hh target gene Gli1 is up-regulated during pancreatic cancer metastasis. Specific inhibition of smoothened signaling significantly altered the gene expression profile of the tumor microenvironment but had no significant effects on cancer metastasis. By combining Hh signaling inhibitor BMS833923 with RAS downstream MEK signaling inhibitor AZD6244, we observed reduced number of metastatic nodules in several mouse models for pancreatic cancer metastasis. These two inhibitors also decreased cell proliferation significantly and reduced CD45+ cells (particularly Ly6G+CD11b+ cells). We demonstrated that depleting Ly6G+ CD11b+ cells is sufficient to reduce cancer cell proliferation and the number of metastatic nodules. In vitro, Ly6G+ CD11b+ cells can stimulate cancer cell proliferation, and this effect is sensitive to MEK and Hh inhibition. Our studies may help design novel therapeutic strategies to mitigate pancreatic cancer metastasis.

AbstractObjectivesThe aim of this review was to determine the clinical performance of dental implants that are intentionally tilted when compared with implants that are placed following the long axis of the residual alveolar ridge.Materials and methodsA systematic review of the scientific literature using a predefined research question (PICO) and search strategy was undertaken. This search included five electronic databases. Two independent reviewers examined electronic databases and performed a manual review following search strategy to accomplish the item generation and reduction. Included articles were evaluated to determine the level of evidence. Data were extracted only from level I and level II studies, based on the Oxford Centre for Evidence‐based Medicine—Levels of Evidence (March 2009). If included studies were homogeneous in nature, data were to be accumulated. However, if included studies were heterogeneous in nature, only descriptive data would be reviewed and analyzed.ResultsA total of 811 articles were identified through the PICO question and search strategy. Detailed review of the abstracts and articles resulted in further item reduction, and 46 articles were included for full‐text review. A total of 42 articles were then selected for inclusion in the systematic review. The identified articles included two level I and 20 level II studies. In addition, 15 level IV, one gray literature, and four previous systematic reviews with meta‐analyses were also used in the study. The extracted data from the included studies demonstrated heterogeneity that prevented quantitative assessment, and only one level II study directly compared tilted and axially placed implants. Assessment of the descriptive data demonstrated no differences in implant survival, marginal bone loss, prosthesis survival, or patient‐reported outcome measures (PROMs) whether implants are placed axially or with intentional inclination of the coronal aspect of the implant toward the distal aspect of edentulous jaws.ConclusionsBased upon the systematic review of the literature, an analysis of the descriptive data suggested no differences in clinical performance between implants that are placed in an axial position relative to the residual alveolar ridge when compared with implants that are intentionally tilted toward the distal aspect of edentulous jaws.

Abstract Objectives Working Group 2 was convened to address topics relevant to prosthodontics and dental implants. Systematic reviews were developed according to focused questions addressing (a) the number of implants required to support fixed full‐arch restorations, (b) the influence of intentionally tilted implants compared to axial positioned implants when supporting fixed dental prostheses ( FDP s), (c) implant placement and loading protocols, (d) zirconia dental implants, (e) zirconia and metal ceramic implant supported single crowns and (f) zirconia and metal ceramic implant supported FDP s. Materials and methods Group 2 considered and discussed information gathered in six systematic reviews. Group participants discussed statements developed by the authors and developed consensus. The group developed and found consensus for clinical recommendations based on both the statements and the experience of the group. The consensus statements and clinical recommendations were presented to the plenary (gathering of all conference attendees) and discussed. Final versions were developed after consensus was reached. Results A total of 27 consensus statements were developed from the systematic reviews. Additionally, the group developed 24 clinical recommendations based on the combined expertise of the participants and the developed consensus statements. Conclusions The literature supports the use of various implant numbers to support full‐arch fixed prostheses. The use of intentionally tilted dental implants is indicated when appropriate conditions exist. Implant placement and loading protocols should be considered together when planning and treating patients. One‐piece zirconia dental implants can be recommended when appropriate clinical conditions exist although two‐piece zirconia implants should be used with caution as a result of insufficient data. Clinical performance of zirconia and metal ceramic single implant supported crowns is similar and each demonstrates significant, though different, complications. Zirconia ceramic FDP s are less reliable than metal ceramic. Implant supported monolithic zirconia prostheses may be a future option with more supporting evidence.

Background: The human Monoamine Transporters (hMATs), primarily including hSERT, hNET and hDAT, are important targets for the treatment of depression and other behavioral disorders with more than the availability of 30 approved drugs. Objective: This paper is to review the recent progress in the binding mode and inhibitory mechanism of hMATs inhibitors with the central or allosteric binding sites, for the benefit of future hMATs inhibitor design and discovery. The Structure-Activity Relationship (SAR) and the selectivity for hit/lead compounds to hMATs that are evaluated by in vitro and in vivo experiments will be highlighted. Methods: PubMed and Web of Science databases were searched for protein-ligand interaction, novel inhibitors design and synthesis studies related to hMATs. Results: Literature data indicate that since the first crystal structure determinations of the homologous bacterial Leucine Transporter (LeuT) complexed with clomipramine, a sizable database of over 100 experimental structures or computational models has been accumulated that now defines a substantial degree of structural variability hMATs-ligands recognition. In the meanwhile, a number of novel hMATs inhibitors have been discovered by medicinal chemistry with significant help from computational models. Conclusion: The reported new compounds act on hMATs as well as the structures of the transporters complexed with diverse ligands by either experiment or computational modeling have shed light on the poly-pharmacology, multimodal and allosteric regulation of the drugs to transporters. All of the studies will greatly promote the Structure-Based Drug Design (SBDD) of structurally novel scaffolds with high activity and selectivity for hMATs.

Arthroscopic dorsal wrist ganglionectomy is demonstrably a safe procedure with recurrence rates comparable to open surgery. We present a patient with wrist pain following arthroscopic ganglion excision. MRI and arthroscopic findings showed a large dorsal capsular defect, synovial fistula to the fourth extensor compartment, and dorsal radiocarpal ligament resection. Ligament reconstruction and capsular imbrication resolved her symptoms. We postulate that this complication resulted from a large capsular resection. Because we feel that it can be difficult to judge the size of the debridement through an arthroscope, the need for adequate capsular resection in dorsal wrist ganglionectomy needs to be balanced by consideration of potential complications from more aggressive capsular debridement, and thus we feel that capsular resection should be limited to no more than 1 cm2.

AbstractParenteral nutrition (PN) is a complex therapeutic modality provided to neonates, children, and adults for various indications. Surveys have shown that current electronic health record (EHR) systems are in need of functionality enhancement for safe and optimal delivery of PN. This is a consensus statement from the American Society for Parenteral and Enteral Nutrition, the Academy of Nutrition and Dietetics, and the American Society of Health‐System Pharmacists outlining some of the key challenges to prescribing, order review/verification, compounding, and administration of PN using EHRs today and is a call to action for clinicians and vendors to optimize their EHRs regarding the PN build and workflow.