Synthesis and PI 3-Kinase Inhibition Activity of Some Novel 2,4,6-Trisubstituted 1,3,5-Triazines.

A number of new trisubstituted triazine phosphatidylinositol 3-kinase (PI3K) inhibitors were prepared via a three-step procedure utilizing sequential nucleophilic aromatic substitution and cross-coupling reactions. All were screened as PI3K inhibitors relative to the well-characterized PI3K inhibitor, ZSTK474. The most active inhibitors prepared here were 2⁻4 times more potent than ZSTK474. A leucine linker was attached to the most active inhibitor since it would remain on any peptide-containing prodrug after cleavage by a prostate-specific antigen, and it did not prevent inhibition of protein kinase B (Akt) phosphorylation, and hence, the inhibition of PI3K by the modified inhibitor.

Synthesis and PI3 Kinase Inhibition Activity of Some Novel Trisubstituted Morpholinopyrimidines.

A number of new substituted morpholinopyrimidines were prepared utilizing sequential nucleophilic aromatic substitution and cross-coupling reactions. One of the disubstituted pyrimidines was converted into two trisubstituted compounds which were screened as PI3K inhibitors relative to the well-characterized PI3K inhibitor ZSTK474, and were found to be 1.5⁻3-times more potent. A leucine linker was attached to the most active inhibitor since it would remain on any peptide-containing prodrug after cleavage by prostate-specific antigen, and it did not prevent inhibition of AKT phosphorylation and hence the inhibition of PI3K by the modified inhibitor.

Engineered Gold and Silica Nanoparticle-Incorporated Hydrogel Scaffolds for Human Stem Cell-Derived Cardiac Tissue Engineering.

Electrically conductive biomaterials and nanomaterials have demonstrated great potential in the development of functional and mature cardiac tissues. In particular, gold nanomaterials have emerged as promising candidates due to their biocompatibility and ease of fabrication for cardiac tissue engineering utilizing rat- or stem cell-derived cardiomyocytes (CMs). However, despite significant advancements, it is still not clear whether the enhancement in cardiac tissue function is primarily due to the electroconductivity features of gold nanoparticles or the structural changes of the scaffold resulting from the addition of these nanoparticles. To address this question, we developed nanoengineered hydrogel scaffolds comprising gelatin methacrylate (GelMA) embedded with either electrically conductive gold nanorods (GNRs) or nonconductive silica nanoparticles (SNPs). This enabled us to simultaneously assess the roles of electrically conductive and nonconductive nanomaterials in the functionality and fate of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Our studies revealed that both GNR- and SNP-incorporated hydrogel scaffolds exhibited excellent biocompatibility and similar cardiac cell attachment. Although the expression of sarcomere alpha-actinin did not significantly differ among the conditions, a more organized sarcomere structure was observed within the GNR-embedded hydrogels compared to the nonconductive nanoengineered scaffolds. Furthermore, electrical coupling was notably improved in GNR-embedded scaffolds, as evidenced by the synchronous calcium flux and enhanced calcium transient intensity. While we did not observe a significant difference in the gene expression profile of human cardiac tissues formed on the conductive GNR- and nonconductive SNP-incorporated hydrogels, we noticed marginal improvements in the expression of some calcium and structural genes in the nanomaterial-embedded hydrogel groups as compared to the control condition. Given that the cardiac tissues formed atop the nonconductive SNP-based scaffolds (used as the control for conductivity) also displayed similar levels of gene expression as compared to the conductive hydrogels, it suggests that the electrical conductivity of nanomaterials (i.e., GNRs) may not be the sole factor influencing the function and fate of hiPSC-derived cardiac tissues when cells are cultured atop the scaffolds. Overall, our findings provide additional insights into the role of electrically conductive gold nanoparticles in regulating the functionalities of hiPSC-CMs.

The Wnt/ß-catenin/T-cell factor 4 pathway up-regulates high-mobility group A1 expression in colon cancer.

High-mobility group A1 (HMGA1) encodes proteins that act as mediators in viral integration, modification of chromatin structure, neoplastic transformation and metastatic progression. Because HMGA1 is overexpressed in most cancers and has transcriptional relationships with several Wnt-responsive genes, we explored the involvement of HMGA1 in Wnt/ß-catenin/TCF-4 signalling. In adenomatous polyposis coli (APC(Min/+)) mice, we observed significant up-regulation of HMGA1 mRNA and protein in intestinal tumours when compared with normal intestinal mucosa. Conversely, restoration of Wnt signalling by the zinc induction of wild-type APC resulted in HMGA1 down-regulation in HT-29 cells. Because APC mutations are associated with mobilization of the ß-catenin/TCF-4 transcriptional complex and subsequent activation of downstream oncogenic targets, we analyzed the 5'-flanking sequence of HMGA1 for putative TCF-4 binding elements. We identified two regions that specifically bind the ß-catenin/TCF-4 complex in vitro and in vivo, identifying HMGA1 as an immediate target of the ß-catenin/TCF-4 signalling pathway in colon cancer. Collectively, these findings strongly implicate Wnt/ß-catenin/TCF-4 signalling in regulating HMGA1 to further expand the extensive regulatory network affected by Wnt/ß-catenin/TCF-4 signalling.

Amnion membrane hydrogel and amnion membrane powder accelerate wound healing in a full thickness porcine skin wound model.

There is a need for effective wound treatments that retain the bioactivity of a cellular treatment, but without the high costs and complexities associated with manufacturing, storing, and applying living biological products. Previously, we developed an amnion membrane-derived hydrogel and evaluated its wound healing properties using a mouse wound model. In this study, we used a full thickness porcine skin wound model to evaluate the wound-healing efficacy of the amnion hydrogel and a less-processed amnion product comprising a lyophilized amnion membrane powder. These products were compared with commercially available amnion and nonamnion wound healing products. We found that the amnion hydrogel and amnion powder treatments demonstrated significant and rapid wound healing, driven primarily by new epithelialization versus closure by contraction. Histological analysis demonstrated that these treatments promote the formation of a mature epidermis and dermis with similar composition to healthy skin. The positive skin regenerative outcomes using amnion hydrogel and amnion powder treatments in a large animal model further demonstrate their potential translational value for human wound treatments.

Toward patient-centered outcomes for cognitive evaluations: the perspective of those affected by Parkinson's disease.

OBJECTIVE: Patient-centered outcomes research is predicated on the idea that the opinions, attitudes, and preferences of patients should help inform study design and interpretation. To date, little is known about what defines patient-centered outcomes from cognitive evaluations. The current evaluation sought to explore this issue in persons with Parkinson's disease (PwPD) and their care partners (CP). METHOD: Focus groups of 22 PwPD/CP dyads were conducted to identify potential consumer oriented endpoints from cognitive evaluations. These endpoints were utilized to create a Patient-Centered Cognitive Assessment Outcomes Scale, which was administered to a different group of 50 PwPD/CP dyads who rated the importance of each outcome and identified their top three priority outcomes. RESULTS: Three themes emerged from the focus groups: improved knowledge, advice, and planning. Both PwPD and CP rated items in all three domains as being very important outcomes. Priorities for outcomes in both groups favored treatment planning information slightly above knowledge based outcomes. CONCLUSIONS: The PwPD and CP identified improved knowledge, advice for daily activities, and knowledge they could use to plan for future eventualities as very important. This information can be used as a framework for future studies aimed at demonstrating patient-centered outcomes from neuropsychological evaluations. Implications for future research are discussed.

Penile and scrotal elephantiasis caused by indolent Chlamydia trachomatis infection.

Isolated penile and scrotal elephantiasis presents a diagnostic and therapeutic challenge. We report a case of chronic penile and scrotal elephantiasis caused by indolent Chlamydia trachomatis infection. The patient improved modestly with long-term doxycycline.