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The decellularized human umbilical artery (HUA) is considered as a promising option for small-diameter, tissue-engineered vascular grafts (TEVGs). Our previous study showed that the HUA bears a thin, watertight lining on its outermost abluminal surface. Removal of this abluminal lining layer improves efficacy of the perfusion-assisted decellularization of the HUA and increases its compliance. As stress across the wall is believed to affect growth and remodeling of the TEVG, it is imperative to mechanically characterize the HUA using thick-walled models. Combining inflation experiments and computational methods, we investigate the mechanical properties of the HUA before and after the abluminal lining removal to examine the HUA's wall mechanics. The inflation tests of five HUAs were performed to obtain the mechanical and geometrical response of the vessel wall before and after the lining layer removal. Using nonlinear hyperelastic models, the same responses are obtained computationally using the thick-walled models. The experimental data are incorporated into the computational models to estimate the mechanical and orientation parameters of the fibers and isotropic matrix of different layers in the HUAs. The parameter fitting of both thick-walled models (before and after the abluminal lining removal) results in most of the R-squared values for measuring the goodness of fitting to be over 0.90 for all samples. The compliance of the HUA increases from a mean value of 2.60% per 100 mmHg before the removal of the lining to a mean value of 4.21% per 100 mmHg after the removal. The results reveal that, although the abluminal lining is thin, it is stiff and capable of supporting majority of the high luminal pressure, and that the inner layer is far less stressed than the abluminal lining. Computational simulations also show that removal of the abluminal lining increases the circumferential wall stress by up to 280 kPa under the in vivo luminal pressure. The integrated computational and experimental approaches provide more accurate estimates of the material behaviors of HUAs employed in grafts and, in turn, the study enhances our understanding of interactions between the graft and the native vessel on vascular growth and remodeling. [ABSTRACT FROM AUTHOR]

Abstract: For the Goursat problem, we consider a triangular domain with mixed Dirichlet and impedance boundary conditions imposed on it. We develop an algorithm for its numerical solution mainly based on Runge–Kutta method and trapezoidal formula. Iterative techniques are constructed to compute some data for the nonlinear part of the differential equation and the impedance boundary condition. Error estimates are derived. Examples are presented to illustrate the effectiveness of the method. [Copyright &y& Elsevier]

Targeting mitochondrial complex I (CI) is emerging as an attractive anticancer strategy, and CI inhibitor IACS-010759 has achieved breakthrough success. However, the narrow therapeutic index of IACS-010759 seriously hinders its further application. In this study, a series of novel pyrazole amides were designed and optimized based on IACS-010759, and their potential CI inhibitory effects were biologically evaluated. Among them, the maximum tolerated dose (MTD) values of SCAL-255 (compound 5q) and SCAL-266 (compound 6f) were 68 mg/kg, which was nearly 10 times that of IACS-010759 (6 mg/kg), showing good safety. In addition, SCAL-255 and SCAL-266 significantly inhibited the proliferation of HCT116 and KG-1 cells in vitro and exerted satisfactory inhibitory activity against KG-1 cells in vivo. These results suggested that the optimized compounds might serve as promising CI inhibitors against oxidative phosphorylation (OXPHOS)-dependent cancer, which merits further study. [Display omitted] • Targeting CI is a promising approach to cancer therapy. • Pyrazole amides small molecule CI inhibitors. • Satisfactory antitumor effect and safety in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Blocking the de novo biosynthesis of pyrimidine by inhibiting human dihydroorotate dehydrogenase (h DHODH) is an effective way to suppress the proliferation of cancer cells and activated lymphocytes. Herein, eighteen teriflunomide derivatives and four ASLAN003 derivatives were designed and synthesized as novel h DHODH inhibitors based on a benzophenone scaffold. The optimal compound 7d showed a potent h DHODH inhibitory activity with an IC 50 value of 10.9 nM, and displayed promising antiproliferative activities against multiple human cancer cells with IC 50 values of 0.1–0.8 μM. Supplementation of exogenous uridine rescued the cell viability of 7d -treated Raji and HCT116 cells. Meanwhile, 7d significantly induced cell cycle S-phase arrest in Raji and HCT116 cells. Furthermore, 7d exhibited favorable safety profiles in mice and displayed effective antitumor activities with tumor growth inhibition (TGI) rates of 58.3% and 42.1% at an oral dosage of 30 mg/kg in Raji and HCT116 cells xenograft models, respectively. Taken together, these findings provide a promising h DHODH inhibitor 7d with potential activities against some tumors. [Display omitted] • Twenty-three novel h DHODH inhibitors were synthesized. • In vitro , compound 7d showed potent hDHODH inhibitory activity and promising antiproliferative activities against multiple human cancer cells. • 7d exhibited favorable safety profiles and displayed effective antitumor activity in Raji cells xenograft model. [ABSTRACT FROM AUTHOR]

Human dihydroorotate dehydrogenase (h DHODH) is a key enzyme in the de novo synthesis pathway of pyrimidine nucleotide in cells. The moderate efficiency of teriflunomide, an approved h DHODH inhibitor for the treatment of multiple sclerosis, limited its therapeutic application of malignancy. Herein, thirty-seven novel teriflunomide derivatives with a biphenyl scaffold were designed, synthesized and evaluated. As a result, the optimal compound A37 exhibited a potent h DHODH inhibitory activity with an IC 50 value of 10.2 nM, which was about 40-fold stronger than that of teriflunomide (IC 50 = 407.8 nM), and showed favorable antiproliferative activities against HCT116 cells with an IC 50 value of 0.3 μM. Meanwhile, A37 displayed an acceptable safety profile at an oral dosage of 400 mg/kg in the acute toxicity assay, and exhibited a promising antitumor effect with tumor growth inhibition rate of 54.4% at an oral dosage of 30 mg/kg in HCT116 xenograft model. These results indicate that A37 is an efficacious h DHODH inhibitor with potential in the treatment of colorectal carcinoma. [Display omitted] • Thirty-seven novel teriflunomide derivatives with a biphenyl scaffold were designed, synthesized and evaluated. • Compound A37 exhibited a potent h DHODH inhibitory activity, which was about 40-fold stronger than that of teriflunomide. • Compound A37 exhibited a promising antitumor effect with TGI rate of 54.4% at an oral dosage of 30 mg/kg in vivo. [ABSTRACT FROM AUTHOR]