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

DPP-4 inhibition improves early mortality, β cell function, and adipose tissue inflammation in db/db mice fed a diet containing sucrose and linoleic acid

Additional file 3: Figure S2. Liver and epididymal fat weights in db/+ mice and db/db mice. The experiments were performed in db/+ or db/db mice fed an SL diet, SO diet, SL containing DPP-4 inhibitor (0.4% des-fluoro-sitagliptin) diet, or SO containing DPP-4 inhibitor diet for 8 weeks. (left) Liver weights as a proportion of body weight (n = 5). (right) Epididymal fat weights as a proportion of body weight (n = 5)

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

Latitudinal cline in the foraging dichotomy of loggerhead sea turtles reveals the importance of East China Sea for priority conservation

Special Issue: Biological traits, geographic distributions and species conservation in aquatic ecosystems[Aim]Quantifying the importance of habitat areas for conservation of highly migratory marine species with complex life histories can be challenging. For example loggerhead turtles (Caretta caretta) nesting in Japan forage both oceanically and neritically after their reproductive period. Here, we aimed to quantify the proportions of turtles using these two contrasting habitats (foraging dichotomy) to suggest priority conservation areas. [Location]North Pacific Ocean. [Methods]We examined the occurrence of foraging dichotomy at three nesting sites (Ishigaki, Okinoerabu Islands and Ichinomiya) based on stable isotope analysis of the egg yolks for 82 turtles and satellite tracking of post-nesting migration for 12 turtles. Moreover, we used the data of three other sites from previous studies (Yakushima Island, Minabe and Omaezaki). [Results]Two neritic foraging grounds (East China Sea and the coastal area of the Japanese archipelago), and an oceanic ground (North Pacific Ocean) were identified. We found a latitudinal cline with respect to the occurrence of foraging dichotomy; >84% of the females nesting at southern sites (Ishigaki and Okinoerabu Islands), 73% at middle sites (Yakushima Island and Minabe) and <46% at northern sites (Omaezaki and Ichinomiya) were neritic foragers; the proportion of oceanic foragers increased at northern sites. Based on the annual number of nests in the entire nesting region of Japan, satellite tracking and the latitudinal cline of foraging dichotomy, we estimated that 70% and 9% of annual nesting females in Japan utilize the neritic foraging habitat in the East China Sea and the coastal area of the Japanese archipelago, respectively, and that and 22% utilize the oceanic habitat of the North Pacific Ocean. [Main conclusions]The East China Sea represents a critical foraging habitat for the North Pacific populations of endangered loggerhead sea turtles. Our findings emphasize the need for international management to ensure their protection

Risk factors for CAR-T cell manufacturing failure among DLBCL patients: A nationwide survey in Japan

CAR-T細胞製造を成功させるためのレシピ --アフェレーシス前の下ごしらえでの工夫--. 京都大学プレスリリース. 2023-04-27.For successful chimeric antigen receptor T (CAR-T) cell therapy, CAR-T cells must be manufactured without failure caused by suboptimal expansion. In order to determine risk factors for CAR-T cell manufacturing failure, we performed a nationwide cohort study in Japan and analysed patients with diffuse large B-cell lymphoma (DLBCL) who underwent tisagenlecleucel production. We compared clinical factors between 30 cases that failed (7.4%) with those that succeeded (n = 378). Among the failures, the proportion of patients previously treated with bendamustine (43.3% vs. 14.8%; p < 0.001) was significantly higher, and their platelet counts (12.0 vs. 17.0 × 10⁴/μL; p = 0.01) and CD4/CD8 T-cell ratio (0.30 vs. 0.56; p < 0.01) in peripheral blood at apheresis were significantly lower than in the successful group. Multivariate analysis revealed that repeated bendamustine use with short washout periods prior to apheresis (odds ratio [OR], 5.52; p = 0.013 for ≥6 cycles with washout period of 3–24 months; OR, 57.09; p = 0.005 for ≥3 cycles with washout period of <3 months), low platelet counts (OR, 0.495 per 105/μL; p = 0.022) or low CD4/CD8 ratios (<one third) (OR, 3.249; p = 0.011) in peripheral blood at apheresis increased the risk of manufacturing failure. Manufacturing failure remains an obstacle to CAR-T cell therapy for DLBCL patients. Avoiding risk factors, such as repeated bendamustine administration without sufficient washout, and risk-adapted strategies may help to optimize CAR-T cell therapy for DLBCL patients

認知症高齢者の在宅療養継続を目指した訪問看護師の支援－対象理解に焦点をあてて－

本研究は、対象理解に焦点をあてた認知症高齢者の在宅療養継続を目指した訪問看護師の支援について明らかにすることを目的とした。対象は訪問看護師３名で、半構成的面接法を用いてインタビューした内容を質的記述的に分析した。その結果、訪問看護師は、【培ってきた人生に敬意を払い療養者の尊厳を守る】という信念に立ち、【言葉に頼らず全身を使って気遣いを表現し焦らず徐々に心を通わせ】、【観察とケアチームとの連携により療養者が自ら表現できない状態をアセスメント】して療養者の世界に身を置いていた。その上で、【療養者の状態を経時的に捉え起こりうるリスクをアセスメントし予防】し、【療養者が言葉にできない症状を感知し適切な治療につなげ】、【療養者のできる力を最大限に引き出し生活に取り入れ】回復を助ける支援を行っており、カテゴリーの１つ１つが連動して実施されることが、認知症高齢者への支援に重要であることが示唆された

抗原誘発性Th1・Th2サイトカイン産生に対する性ホルモンの影響の性差

The incidence, severity and prognosis of asthma can be affected by a number of factors, including the patient\u27s age and sex. Clinical observations and epidemiologic studies indicate that the prevalence and severity of asthma is higher among boys than girls, but that the ratio inverts after puberty. The reversal of the male/female prevalence of asthma at puberty strongly suggests a role of sex hormones. However, the mechanisms underlying the gender differences in the prevalence of asthma are not clear. Recently, we suggested that the sex differences were due to those in not only sex hormones but also lymphocyte functions based on findings in a murine model of allergic asthma. Therefore, we investigated the effect of sex hormones on antigen-induced cytokine production by lymphocytes to further investigate these gender differences. Splenocytes from ovalbumin (OVA)-sensitized female mice produced more IL-5, Th2 cytokine, than those from OVA-sensitized male mice, upon simulation with OVA. Progesterone decreased the production of IFN-g, Th1 cytokine, by splenocytes from both sensitized male and female mice. 17β-estradiol had no effect on Th1 and Th2 cytokine production by splenocytes from both mice. However, 5a-dihydrotestosterone decreased the production of Th2 cytokines by splenoytes from sensitized female mice but not these from male mice. Our findings suggest that lymphocytes from males and females have different sensitivities to sex hormones in antigen-induced cytokine production

The Roles of the IGF Axis in the Regulation of the Metabolism: Interaction and Difference between Insulin Receptor Signaling and IGF-I Receptor Signaling

It has been well established that insulin-like growth factors (IGFs) mainly mediate long-term actions in cell fates, whereas insulin predominantly exerts its role on metabolic activity. Indeed, insulin mediates multiple anabolic biological activities in glucose and amino acid transport, lipid and protein synthesis, the induction of glycogen, the inhibition of gluconeogenesis, lipolysis, and protein degradation. The interactions and differences between insulin receptor signaling and IGF-I receptor signaling in the metabolism and the cell fates are quite complicated. Because of the overlapping actions of IGF-I singling with insulin signaling, it has been difficult to distinguish the role of both signaling mechanisms on the metabolism. Furthermore, comprehensive information on the IGF-I function in respective tissues remains insufficient. Therefore, we need to clarify the precise roles of IGF-I signaling on the metabolism separate from those of insulin signaling. This review focuses on the metabolic roles of IGFs in the respective tissues, especially in terms of comparison with those of insulin, by overviewing the metabolic phenotypes of tissue-specific IGF-I and insulin receptor knockout mice, as well as those in mice treated with the dual insulin receptor/IGF-I receptor inhibitor OSI-906