Thoracic endovascular aneurysm repair in Japan: Experience with fenestrated stent grafts in the treatment of distal arch aneurysms

ObjectivesIn the West, stent grafts for endovascular repair of thoracic aortic aneurysms have been commercially available for several years, whereas in Japan, a manufactured stent graft was not approved for this application until March 2008. Nevertheless, endovascular thoracic intervention began to be performed in Japan in the early 1990s, with homemade devices used in most cases. Many researchers have continued to develop homemade devices. We have participated in joint design and assessment efforts with a stent graft manufacturer, focusing primarily on fenestrated stent grafts used in repairs at the distal arch, a site especially prone to aneurysm.MethodsFrom 1995 to February 2008, we performed about 1100 endovascular procedures to treat thoracic aortic aneurysms and 682 cases were performed at Tokyo Medical University. In 435 out of 682 the aneurysm was located in the area from the distal arch to the proximal descending aorta. Fenestrated stent grafts were inserted in 288 cases. Computed tomography scans were performed at 3, 6, and 12 months postoperatively and annually thereafter.ResultsThe initial success rate in the entire series was 95.2%. Complications included 26 cerebral infarctions (3.8%), six of which (0.9%) resulted in serious paralysis and changes in consciousness. Among patients who received fenestrated stent grafts, paraplegia occurred in 2.6%, aortic injury in 1.2%, and iliofemoral artery injury in 6.0%. No complications resulted from occlusion of aortic arch branches. At ≥2 years after intervention, aneurysm diameter was reduced in 62% of patients, 33% had no change, and 5% had a diameter enlargement. The stent graft complication rate during follow-up was 8.4%, the device fracture rate was 1.4%, and the device migration rate was 7%. The 5-year survival rate was 62.4%, with follow-up in 96.8% of the patients.ConclusionEndovascular repair has promising results in the descending thoracic aortic region, although some stent grafts and their delivery systems can still be improved. Additional commercial developments and available stent grafts designed for use in the distal arch are urgently needed

Comparison of capacities to maintain hematopoietic stem cells among different types of stem cells derived from the placenta and umbilical cord

AbstractIntroductionCord blood is utilized as a useful source of cells for hematopoietic stem cell transplantation, but this can be problematic because there is a high rate of graft failure compared to when other graft sources are used. A previous study successfully avoided graft failure by simultaneously grafting cord blood and bone marrow mesenchymal stem cells (MSCs) that are considered to function in the hematopoietic stem cell niche of the bone marrow.Organs of the fetal life support system such as the placenta and umbilical cord, which are discarded after delivery, contain an abundance of MSCs as well as cells that function in the hematopoietic stem cell niche. By identifying and collecting such cells and subsequently co-transplanting them with cord blood, an improvement in graft survival can be anticipated.MethodsThree types of stem cells, amnion epithelial stem cells (AM-Epi), amnion mesenchymal stem cells (AM-Mes), and Wharton's jelly (WJ)-MSCs, all of which can be isolated and cultured from the placenta amnion or umbilical cord WJ, were investigated for the expression of hematopoietic stem cell niche markers and for their capabilities to maintain hematopoietic stem cells when co-cultured with cord blood hematopoietic stem cells.ResultsAll types of isolated cells showed profiles that met the MSC minimal criteria according to surface marker analysis. In addition, all cell types expressed the hematopoietic stem cell niche marker stromal cell-derived factor-1 (SDF-1) (in order: AM-Epi > WJ-MSCs ≫ AM-Mes), although the expression declined with further passaging.After 5 days of co-culturing with cord blood CD34+ cells, the percentages of CD34+, CD45− cells were: AM-Epi 37.8%, AM-Mes 38.8%, WJ-MSCs 27.3%, and fibroblasts 27.4%; and the number of CFU-GM colonies were: AM-Epi 255.5 ± 21.6, AM-Mes 246.3 ± 28.5, WJ-MSCs 118.3 ± 11.8, fibroblasts 147.8 ± 19.0, and NC 121.3 ± 6.5. Statistical analyses demonstrated that AM-Epi and AM-Mes produced significantly greater numbers of CFU-GM compared to WJ-MSC, fibroblasts, or NC (p < 0.05).ConclusionsThese findings indicated that cells derived from the fetal life support system such as AM-Epi and AM-Mes can be anticipated as potential cell sources for clinical application in cell therapies for the purpose of enhancing graft survival during hematopoietic stem cell transplantation

p38 MAP kinase negatively regulates endothelial cell survival, proliferation, and differentiation in FGF-2–stimulated angiogenesis

The p38 mitogen–activated protein kinase (p38) is activated in response to environmental stress and inflammatory cytokines. Although several growth factors, including fibroblast growth factor (FGF)-2, mediate activation of p38, the consequences for growth factor–dependent cellular functions have not been well defined. We investigated the role of p38 activation in FGF-2–induced angiogenesis. In collagen gel cultures, bovine capillary endothelial cells formed tubular growth-arrested structures in response to FGF-2. In these collagen gel cultures, p38 activation was induced more potently by FGF-2 treatment compared with that in proliferating cultures. Treatment with the p38 inhibitor SB202190 enhanced FGF-2–induced tubular morphogenesis by decreasing apoptosis, increasing DNA synthesis and cell proliferation, and enhancing the kinetics of cell differentiation including increased expression of the Notch ligand Jagged1. Overexpression of dominant negative mutants of the p38-activating kinases MKK3 and MKK6 also supported FGF-2–induced tubular morphogenesis. Sustained activation of p38 by FGF-2 was identified in vascular endothelial cells in vivo in the chick chorioallantoic membrane (CAM). SB202190 treatment enhanced FGF-2–induced neovascularization in the CAM, but the vessels displayed abnormal features indicative of hyperplasia of endothelial cells. These results implicate p38 in organization of new vessels and suggest that p38 is an essential regulator of FGF-2–driven angiogenesis

S-1 mediated tumor priming enhances intratumor liposomal fate

The efficient delivery of nanocarrier-based cancer therapeutics into tumor tissue is problematic. Structural abnormalities, tumor vasculature heterogeneity, and elevated intratumor pressure impose barriers against the preferential accumulation of nanocarrier-based cancer therapeutics within tumor tissues and, consequently, compromise their therapeutic efficacy. Recently, we have reported that metronomic S-1, orally available tegafur formulation, dosing synergistically augmented the therapeutic efficacy of oxaliplatin (l-OHP)-containing PEGylated liposome without increasing the toxicity in animal model. However, the exact mechanism behind such synergistic effect was not fully elucidated. In this study, therefore, we tried to shed the light on the contributions of metronomic S-1 dosing to the enhanced accumulation and/or spatial distribution of PEGylated liposome within tumor tissue. Tumor priming with metronomic S-1 treatment induced a potent apoptotic response against both angiogenic endothelial cells and tumor cells adjacent to tumor blood vessels, resulting in enhanced tumor blood flow via transient normalization of tumor vasculature, along with alleviation of intratumor pressure. Such a change in the tumor microenvironment imparted by S-1 treatment allows efficient delivery of PEGylated liposome to tumor tissue and permits their deep penetration/distribution into the tumor mass. Such a priming effect of S-1 dosing can be exploited as a promising strategy to enhance the therapeutic efficacy of nanocarrier-based cancer therapeutics suffering from inadequate/heterogeneous delivery to tumor tissues

A Case of Right Hepatic Artery Syndrome Diagnosed by Using SpyGlassDSTM System

We report the case of a 68-year-old woman who had abdominal pain and slightly elevated biliary enzymes. Magnetic resonance cholangiopancreatography detected biliary duct stenosis, while contrast-enhanced magnetic resonance imaging showed that the right hepatic artery transversed the extrahepatic bile duct at the level of bifurcation of the bile duct. We performed endoscopic retrograde cholangiopancreatography and peroral cholangioscopy with the SpyGlass DS? system. Then, mild extrinsic pulsatile compression of the bile duct was observed at stricture level with an intact bile duct epithelium. Therefore, she was diagnosed with right hepatic artery syndrome and underwent cholecystectomy. Six months later, her biliary enzyme level decreased, and the recurrence of pain gradually decreased

CDK8/19 inhibition plays an important role in pancreatic β-cell induction from human iPSCs

サイクリン依存性キナーゼCDK8/19阻害はヒトiPS細胞からの膵島様細胞への分化誘導において重要な役割を果たす. 京都大学プレスリリース. 2023-02-27.A safer method of generating pancreatic islet-like cells from human iPS cells by inhibiting cyclin-dependent kinase CDK8/19. 京都大学プレスリリース. 2023-03-08.[Background] Transplantation of differentiated cells from human-induced pluripotent stem cells (hiPSCs) holds great promise for clinical treatments. Eliminating the risk factor of malignant cell transformation is essential for ensuring the safety of such cells. This study was aimed at assessing and mitigating mutagenicity that may arise during the cell culture process in the protocol of pancreatic islet cell (iPIC) differentiation from hiPSCs. [Methods] We evaluated the mutagenicity of differentiation factors used for hiPSC-derived pancreatic islet-like cells (iPICs). We employed Ames mutagenicity assay, flow cytometry analysis, immunostaining, time-resolved fluorescence resonance energy transfer-based (TR-FRET) cell-free dose–response assays, single-cell RNA-sequencing and in vivo efficacy study. [Results] We observed a mutagenic effect of activin receptor-like kinase 5 inhibitor II (ALK5iII). ALK5iII is a widely used β-cell inducer but no other tested ALK5 inhibitors induced β-cells. We obtained kinase inhibition profiles and found that only ALK5iII inhibited cyclin-dependent kinases 8 and 19 (CDK8/19) among all ALK5 inhibitors tested. Consistently, CDK8/19 inhibitors efficiently induced β-cells in the absence of ALK5iII. A combination treatment with non-mutagenic ALK5 inhibitor SB431542 and CDK8/19 inhibitor senexin B afforded generation of iPICs with in vitro cellular composition and in vivo efficacy comparable to those observed with ALK5iII. [Conclusion] Our findings suggest a new risk mitigation approach for cell therapy and advance our understanding of the β-cell differentiation mechanism

Cnm of Streptococcus mutans is important for cell surface structure and membrane permeability

Streptococcus mutans, a Gram-positive facultative anaerobic bacterium, is a major pathogen of dental caries. The protein Cnm of S. mutans is involved in collagen binding, but its other biological functions are unknown. In this study, a Cnm-deficient isogenic mutant and a complementation strain were generated from a Cnm-positive S. mutans strain to help determine the properties of Cnm. Initially, comparison of the cell surface structure was performed by electron microscopy, which demonstrated that Cnm appears to be localized on the cell surface and associated with a protruding cell surface structure. Deep RNA sequencing of the strains revealed that the defect in Cnm caused upregulated expression of many genes related to ABC transporters and cell-surface proteins, while a few genes were downregulated. The amount of biofilm formed by the Cnm-defective strain increased compared with the parental and complemented strains, but the biofilm structure was thinner because of elevated expression of genes encoding glucan synthesis enzymes, leading to increased production of extracellular polysaccharides. Particular antibiotics, including bacitracin and chloramphenicol, had a lower minimum inhibitory concentration for the Cnm-defective strain than particular antibiotics, including bacitracin and chloramphenicol, compared with the parental and complemented strains. Our results suggest that S. mutans Cnm is located on the cell surface, gives rise to the observed protruding cell surface, and is associated with several biological properties related to membrane permeability