Identification of the matricellular protein Fibulin-5 as a target molecule of glucokinase-mediated calcineurin/NFAT signaling in pancreatic islets

Glucokinase-mediated glucose signaling induces insulin secretion, proliferation, and apoptosis in pancreatic β-cells. However, the precise molecular mechanisms underlying these processes are not clearly understood. Here, we demonstrated that glucokinase activation using a glucokinase activator (GKA) significantly upregulated the expression of Fibulin-5 (Fbln5), a matricellular protein involved in matrix-cell signaling, in isolated mouse islets. The islet Fbln5 expression was induced by ambient glucose in a time- and dose-dependent manner and further enhanced by high-fat diet or the deletion of insulin receptor substrate 2 (IRS-2), whereas the GKA-induced increase in Fbln5 expression was diminished in Irs-2-deficient islets. GKA-induced Fbln5 upregulation in the islets was blunted by a glucokinase inhibitor, KATP channel opener, Ca2+ channel blocker and calcineurin inhibitor, while it was augmented by harmine, a dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) 1 A inhibitor. Although deletion of Fbln5 in mice had no significant effects on the glucose tolerance or β-cell functions, adenovirus-mediated Fbln5 overexpression increased glucose-stimulated insulin secretion in INS-1 rat insulinoma cells. Since the islet Fbln5 expression is regulated through a glucokinase/KATP channel/calcineurin/nuclear factor of activated T cells (NFAT) pathway crucial for the maintenance of β-cell functions, further investigation of Fbln5 functions in the islets is warranted

Transplantation of a human induced pluripotent stem cell-derived airway epithelial cell sheet into the middle ear of rats

[Introduction] Early postoperative regeneration of the middle ear mucosa is essential for the prevention of postoperative refractory otitis media and recurrent cholesteatoma. As a means for intractable otitis media management, we focused on human induced pluripotent stem cell (hiPSC)-derived airway epithelial cells (AECs), which have been used in upper airway mucosal regeneration and transplantation therapy. In this study, we transplanted hiPSC-derived AECs into the middle ear of immunodeficient rats. [Methods] Following the preparation of AEC sheets from hiPSCs, the bilateral middle ear mucosa of X-linked severe combined immunodeficient rats was scraped, and the AEC sheets were transplanted in the ears unilaterally. [Results] Human nuclear antigen (HNA)-positive ciliated cells were observed on the transplanted side of the middle ear cavity surface in three of six rats in the 1-week postoperative group and in three of eight rats in the 2-week postoperative group. No HNA-positive cells were found on the control side. The percentage of HNA-positive ciliated cells in the transplanted areas increased in the 2-week postoperative group compared with the 1-week group, suggesting survival of hiPSC-derived AECs. Additionally, HNA-positive ciliated cells were mainly located at sites where the original ciliated cells were localized. Immunohistochemical analysis showed that the transplanted AECs contained cytokeratin 5- and mucin 5AC-positive cells, indicating that both basal cells and goblet cells had regenerated within the middle ear cavity. [Conclusions] The results of this study are an important first step in the establishment of a novel transplantation therapy for chronic otitis media

Improvement of acid resistance of Zn-doped dentin by newly generated chemical bonds

Dental caries, the world's most prevalent infectious disease, is caused by the diffusion of hydroxyl ions into tooth structures. To prevent dental caries, the application of fluoride (F) and zinc (Zn) ions to teeth surfaces are potential effective measures. In this study, The ionic influence, especially the chemical bond of F and Zn, on the acid resistance of dentin were investigated by particle induced X-ray / gamma-ray emission, X-ray diffraction, X-ray photoelectron spectroscopy and X-ray absorption spectroscopy. The results showed Zn was distributed in the limited surface layer of dentin without altering its crystal structure. From the Zn K edge extended X-ray absorption fine structure, Zn incorporated into dentin was surrounded by oxygen and demonstrated four-fold coordination. The bond length and chemical state of Zn–O in Zn doped dentin suggested newly generated Zn–O covalent bond, which may improve acid resistance of dentin. This study showed that the atomic and molecular structures, such as the molecular distances and chemical state, influenced acid resistance of teeth, emphasizing the validity of chemical state analysis for understanding properties in biomaterials.Naito K., Kuwahara Y., Yamamoto H., et al. Improvement of acid resistance of Zn-doped dentin by newly generated chemical bonds. Materials and Design, 215, 110412. https://doi.org/10.1016/j.matdes.2022.110412

BRCAness Predicts Resistance to Taxane-Containing Regimens in Triple Negative Breast Cancer During Neoadjuvant Chemotherapy

AbstractBackgroundTo provide optimal treatment of heterogeneous triple negative breast cancer (TNBC), we need biomarkers that can predict the chemotherapy response.Patients and MethodsWe retrospectively investigated BRCAness in 73 patients with breast cancer who had been treated with taxane- and/or anthracycline-based neoadjuvant chemotherapy (NAC). Using multiplex, ligation-dependent probe amplification on formalin-fixed core needle biopsy (CNB) specimens before NAC and surgical specimens after NAC. BRCAness status was assessed with the assessor unaware of the clinical information.ResultsWe obtained 45 CNB and 60 surgical specimens from the 73 patients. Of the 45 CNB specimens, 17 had BRCAness (38.6% of all subtypes). Of the 23 TNBC CNB specimens, 14 had BRCAness (61% of TNBC cases). The clinical response rates were significantly lower for BRCAness than for non-BRCAness tumors, both for all tumors (58.8% vs. 89.3%, P = .03) and for TNBC (50% vs. 100%, P = .02). All tumors that progressed with taxane therapy had BRCAness. Of the patients with TNBC, those with non-BRCAness cancer had pathologic complete responses significantly more often than did those with BRCAness tumors (77.8% vs. 14.3%, P = .007). After NAC, the clinical response rates were significant lower for BRCAness than for non-BRCAness tumors in all subtypes (P = .002) and in TNBC cases (P = .008). After a median follow-up of 26.4 months, 6 patients—all with BRCAness—had developed recurrence. Patients with BRCAness had shorter progression-free survival than did those with non- BRCAness (P = .049).ConclusionIdentifying BRCAness can help predict the response to taxane, and changing regimens for BRCAness TNBC might improve patient survival. A larger prospective study is needed to further clarify this issue

Construction of possible integrated predictive index based on EGFR and ANXA3 polymorphisms for chemotherapy response in fluoropyrimidine-treated Japanese gastric cancer patients using a bioinformatic method

Selected genetic and clinical parameters of gastric cancer patients. (XLS 33 kb

Acute superior mesenteric venous thrombosis with advanced gastric cancer: a case report

Although the advanced stages of neoplasms have a risk of superior mesenteric venous thrombosis (MVT), an initial clinical diagnosis of MVT is sometimes difficult and it can be treated as a cancer-related pain using NSAIDs and/or opioids

Distinct Roles of α7 nAChRs in Antigen-Presenting Cells and CD4+ T Cells in the Regulation of T Cell Differentiation

It is now apparent that immune cells express a functional cholinergic system and that α7 nicotinic acetylcholine receptors (α7 nAChRs) are involved in regulating T cell differentiation and the synthesis of antigen-specific antibodies and proinflammatory cytokines. Here, we investigated the specific function α7 nAChRs on T cells and antigen presenting cells (APCs) by testing the effect of GTS-21, a selective α7 nAChR agonist, on differentiation of CD4+ T cells from ovalbumin (OVA)-specific TCR transgenic DO11.10 mice activated with OVA or OVA peptide323−339 (OVAp). GTS-21 suppressed OVA-induced antigen processing-dependent development of CD4+ regulatory T cells (Tregs) and effector T cells (Th1, Th2, and Th17). By contrast, GTS-21 up-regulated OVAp-induced antigen processing-independent development of CD4+ Tregs and effector T cells. GTS-21 also suppressed production of IL-2, IFN-γ, IL-4, IL-17, and IL-6 during OVA-induced activation but, with the exception IL-2, enhanced their production during OVAp-induced activation. In addition, during antigen-nonspecific, APC-independent anti-CD3/CD28 antibody-induced CD4+ polyclonal T cell activation in the presence of respective polarizing cytokines, GTS-21 promoted development of all lineages, which indicates that GTS-21 also acts via α7 nAChRs on T cells. These results suggest 1) that α7 nAChRs on APCs suppress CD4+ T cell activation by interfering with antigen presentation through inhibition of antigen processing; 2) that α7 nAChRs on CD4+ T cells up-regulate development of Tregs and effector T cells; and that α7 nAChR agonists and antagonists could be potentially useful agents for immune response modulation and enhancement

静止衛星データの全球合成技術の開発

Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is an X-linked genetic disorder caused by a deficiency of iduronate 2-sulfatase (IDS), and missense mutations comprising about 30% of the mutations responsible for MPS II result in heterogeneous phenotypes ranging from the severe to the attenuated form. To elucidate the basis of MPS II from the structural viewpoint, we built structural models of the wild type and mutant IDS proteins resulting from 131 missense mutations (phenotypes: 67 severe and 64 attenuated), and analyzed the influence of each amino acid substitution on the IDS structure by calculating the accessible surface area, the number of atoms affected and the root-mean-square distance. The results revealed that the amino acid substitutions causing MPS II were widely spread over the enzyme molecule and that the structural changes of the enzyme protein were generally larger in the severe group than in the attenuated one. Coloring of the atoms influenced by different amino acid substitutions at the same residue showed that the structural changes influenced the disease progression. Based on these data, we constructed a database of IDS mutations as to the structures of mutant IDS proteins

National seroepidemiological study of COVID-19 after the initial rollout of vaccines: Before and at the peak of the Omicron-dominant period in Japan

BACKGROUND: Based on routine surveillance data, Japan has been affected much less by COVID-19 compared with other countries. To validate this, we aimed to estimate SARS-CoV-2 seroprevalence and examine sociodemographic factors associated with cumulative infection in Japan. METHODS: A population-based serial cross-sectional seroepidemiological investigation was conducted in five prefectures in December 2021 (pre-Omicron) and February-March 2022 (Omicron [BA.1/BA.2]-peak). Anti-nucleocapsid and anti-spike antibodies were measured to detect infection-induced and vaccine/infection-induced antibodies, respectively. Logistic regression was used to identify associations between various factors and past infection. RESULTS: Among 16 296 participants (median age: 53 [43-64] years), overall prevalence of infection-induced antibodies was 2.2% (95% CI: 1.9-2.5%) in December 2021 and 3.5% (95% CI: 3.1-3.9%) in February-March 2022. Factors associated with past infection included those residing in urban prefectures (Tokyo: aOR 3.37 [95% CI: 2.31-4.91], Osaka: aOR 3.23 [95% CI: 2.17-4.80]), older age groups (60s: aOR 0.47 [95% CI 0.29-0.74], 70s: aOR 0.41 [95% CI 0.24-0.70]), being vaccinated (twice: aOR 0.41 [95% CI: 0.28-0.61], three times: aOR 0.21 [95% CI: 0.12-0.36]), individuals engaged in occupations such as long-term care workers (aOR: 3.13 [95% CI: 1.47-6.66]), childcare workers (aOR: 3.63 [95% CI: 1.60-8.24]), food service workers (aOR: 3.09 [95% CI: 1.50-6.35]), and history of household contact (aOR: 26.4 [95% CI: 20.0-34.8]) or non-household contact (aOR: 5.21 [95% CI:3.80-7.14]) in February-March 2022. Almost all vaccinated individuals (15 670/15 681) acquired binding antibodies with higher titers among booster dose recipients. CONCLUSIONS: Before Omicron, the cumulative burden was >10 times lower in Japan (2.2%) compared with the US (33%), the UK (25%), or global estimates (45%), but most developed antibodies owing to vaccination