Abstract: Hyaluronan（HA）is a ubiquitous glycosaminoglycan comprising N-acetylglucosamine and glucuronic acid and is involved in matrix formation and cell maintenance. 4-Methylumbelliferone（MU）exhibits anti-tumor activities by inhibiting HA synthesis. In this study, we aimed to elucidate the association between HA and numerous matrix molecules. Materials and Methods: We created HA-knock down extracellular matrix（ECM）by culturing human skin fibroblasts（HSF）in the presence of MU（0.5 mM）for 3 days after confluence. Following culture in the presence or absence of MU, the cell layer and culture medium were collected and ECM molecules were measured using enzyme-linked immunosolvent assay, and the［35S］-sulfate uptake method. Results: Proteoglycans and type I collagen were released into the medium as HA decreased. However, type I collagen, but not proteoglycans, was immediately replenished. Fibronectin and CD44 in the cell layer decreased, but were not replenished, as HA decreased. On contrary, laminin, cadherin, and vitronectin were not affected by HA decrease. Conclusions: HA knockdown by MU treatment elucidated the dynamic interactions between HA and ECM components. Our findings suggest that HA interacts with other ECM components through various ways, including strong interactions for ECM network formation and loose interactions for signal transduction.
The causes for individual relapse in children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) remain incompletely understood. Here, we performed comprehensive genetic analyses of 20 pediatric BCP-ALL paired diagnosis-relapse samples. Copy number variation analysis of IKZF1, a gene for which deletions are associated with increased relapse risk, revealed deletions at both diagnosis and at relapse (n=5). Targeted next generation sequencing showed that RAS pathway genes including KRAS (n=4), NRAS (n=2) and PTPN11 (n=2) were the most common mutations among the sequencing targets at diagnosis and/or relapse. In 7 of 20 cases (35%), mutations in PTPN11, KRAS, TP53, CTCF, NCOR1, WHSC1, TUSC3, ERG and NT5C2
were detected only at relapse. Two cases with TP53
mutations showed fatal outcomes. In two of the four cases with high hyperdiploid BCP-ALL, associated with favorable prognosis, PTPN11 mutations were detected only at relapse. Targeted RNA sequencing identified a rare subtype of BCP-ALL with a NUP214-ABL1 fusion that could benefit from tyrosine kinase inhibitors. Together with recent reports that RAS mutations confer sensitivity to MEK inhibitors, these results suggest that comprehensive genetic analysis will contribute to the optimal treatment for relapsed BCP-ALL.
Toxic amyloid-beta (Aβ) is known to generate symptoms of Alzheimer’s disease (AD); however, less is known regarding the neurotoxicity of Aβ at lower concentrations. Moreover, the neuroprotective potential of combination treatment with plant biophenols and existing drugs is not well understood. In this study, we estimated the no-observed adverse effect level (NOAEL) of Aβ 1–42 (Aβ42) against cultured human neuroblastoma SH-SY5Y cells, and examined the neuroprotective effect of combination pretreatment with 10 µM carnosic acid, 30 nM rebamipide, 10 µM edaravone, and 10 µM of resveratrol (the “CRER” blend) on weak but toxic Aβ42-treated SH-SY5Y cells. We evaluated the NOAEL of Aβ42 at 500 nM in these cells. Aβ42 at 1–8 µM reduced cell viability; however, the “CRER” blend ameliorated this Aβ42-induced decrease in viability. The “CRER” blend induced the expression of Aβ-degrading enzymes including matrix metalloproteinase-14 (MMP-14) and neprilysin, while also enhancing the expression of the inducible α-secretase TACE (tumor necrosis factor-α-converting enzyme), sirtuin 1 (SIRT1), and brain-derived neurotrophic factor (BDNF). Collectively, our results indicate that the “CRER” may aid in the prevention of Aβ toxicity by enhancing MMP-14, neprilysin, TACE, SIRT1, and BDNF. Thus, the “CRER” blend may prove to be a promising strategy for the prevention of Aβ-mediated disorders, particularly AD.
An 80-year-old man with multilevel aortic aneurysms was referred to our hospital. Enhanced computed tomography showed a 90-mm descending aortic aneurysm and a 50-mm abdominal aortic aneurysm with severe stenosis of bilateral external iliac arteries. Thoracotomy was considered a high-risk procedure because he had a long history of chronic obstructive pulmonary disease. We performed combined operation; Y-graft replacement for making access routes, followed by thoracic endovascular aortic repair for the thoracic aortic aneurysm with one de-branching bypass from the left common carotid artery to the left subclavian artery. Neither paraplegia nor infectious complications occurred postoperatively.
A high percentage of patients with a unicuspid aortic valve require cardiac surgery, because it always induces aortic stenosis or regurgitation. It is sometimes difficult to discriminate it from a bicuspid valve. Here, we report a case of a young patient with severe aortic regurgitation and aortic root enlargement caused by the unicommissural form of unicuspid aortic valve. An aortic valve-sparing operation could not be performed because of his special morphology, and it was thought that sufficient durability could not be obtained postoperatively. The Bentall operation was successfully performed with a mechanical prosthetic valve. His postoperative course was uneventful.
In recent years, anti-programmed cell death 1 (PD-1) antibody has been approved for recurrent/metastatic head and neck cancer and was reported by the phase 3 study ChackMate 141 to improve the overall survival rate of patients with recurrent/metastatic head and neck squamous cell carcinoma. With the increasing number of cases treated with anti-PD-1 antibody, the synergic interaction between cancer immunotherapy and chemotherapy has been gathering attention. Some reported that administration of chemotherapy after immunotherapy was remarkably effective for progressive non-small cell lung cancer. We examined two notable cases of recurrent/metastatic head and neck cancer in which the subsequent administration of chemotherapy after immunotherapy was markedly effective. The two cases included maxillary sinus cancer and laryngeal cancer that were treated with radiotherapy and chemotherapy as first-line treatment. Both cases developed recurrent/metastatic lesion that were treated with anti-PD-1 antibody. However, the lesions increased in size after immunotherapy. Therefore, subsequent chemotherapy with cetuximab and paclitaxel was considered and showed marked reduction of size of the recurrent/metastatic lesions. The two cases suggested that administration of salvage chemotherapy after immunotherapy is promising for recurrent/metastatic head and neck cancer.