Dysbindin Regulates the Transcriptional Level of Myristoylated Alanine-Rich Protein Kinase C Substrate via the Interaction with NF-YB in Mice Brain

BACKGROUND: An accumulating body of evidence suggests that Dtnbp1 (Dysbindin) is a key susceptibility gene for schizophrenia. Using the yeast-two-hybrid screening system, we examined the candidate proteins interacting with Dysbindin and revealed one of these candidates to be the transcription factor NF-YB. METHODS: We employed an immunoprecipitation (IP) assay to demonstrate the Dysbindin-NF-YB interaction. DNA chips were used to screen for altered expression of genes in cells in which Dysbindin or NF-YB was down regulated, while Chromatin IP and Reporter assays were used to confirm the involvement of these genes in transcription of Myristoylated alanine-rich protein kinase C substrate (MARCKS). The sdy mutant mice with a deletion in Dysbindin, which exhibit behavioral abnormalities, and wild-type DBA2J mice were used to investigate MARCKS expression. RESULTS: We revealed an interaction between Dysbindin and NF-YB. DNA chips showed that MARCKS expression was increased in both Dysbindin knockdown cells and NF-YB knockdown cells, and Chromatin IP revealed interaction of these proteins at the MARCKS promoter region. Reporter assay results suggested functional involvement of the interaction between Dysbindin and NF-YB in MARCKS transcription levels, via the CCAAT motif which is a NF-YB binding sequence. MARCKS expression was increased in sdy mutant mice when compared to wild-type mice. CONCLUSIONS: These findings suggest that abnormal expression of MARCKS via dysfunction of Dysbindin might cause impairment of neural transmission and abnormal synaptogenesis. Our results should provide new insights into the mechanisms of neuronal development and the pathogenesis of schizophrenia

Successful Treatment of MMP-9-Expressing Angiosarcoma with Low-Dose Docetaxel and Bisphosphonate

We describe a 78-year-old Japanese patient with angiosarcoma on the scalp. Interestingly, immunohistochemical staining revealed this tumor as positive for matrix metalloproteinase 9 (MMP-9). After conventional therapy for angiosarcoma with surgical treatment and radiation therapy, we intravenously administered docetaxel at 40 mg/m2 body surface area together with oral administration of 17.5 mg sodium risedronate hydrate. One and a half years after the standard treatment, there was no evidence of local recurrence or metastasis

Catheterization and embolization of a replaced left hepatic artery via the right gastric artery through the anastomosis: a case report

<p>Abstract</p> <p>Introduction</p> <p>Conversion of multiple hepatic arteries into a single vascular supply is a very important technique for repeat hepatic arterial infusion chemotherapy using an implanted port catheter system. Catheterization of a replaced left hepatic artery arising from a left gastric artery using a percutaneous catheter technique is sometimes difficult, despite the recent development of advanced interventional techniques.</p> <p>Case presentation</p> <p>We present a case of a 70-year-old Japanese man with multiple hepatocellular carcinomas in whom the replaced left hepatic artery arising from the left gastric artery needed to be embolized. After several failed procedures, the replaced left hepatic artery was successfully catheterized and embolized with a microcatheter and microcoils via the right gastric artery through the anastomosis.</p> <p>Conclusion</p> <p>A replaced left hepatic artery arising from a left gastric artery can be catheterized via a right gastric artery by using the appropriate microcatheter and microguidewires, and multiple hepatic arteries can be converted into a single supply.</p

Role of Sphingomyelinase in Infectious Diseases Caused by Bacillus cereus

Bacillus cereus (B. cereus) is a pathogen in opportunistic infections. Here we show that Bacillus cereus sphingomyelinase (Bc-SMase) is a virulence factor for septicemia. Clinical isolates produced large amounts of Bc-SMase, grew in vivo, and caused death among mice, but ATCC strains isolated from soil did not. A transformant of the ATCC strain carrying a recombinant plasmid containing the Bc-SMase gene grew in vivo, but that with the gene for E53A, which has little enzymatic activity, did not. Administration of an anti-Bc-SMase antibody and immunization against Bc-SMase prevented death caused by the clinical isolates, showing that Bc-SMase plays an important role in the diseases caused by B. cereus. Treatment of mouse macrophages with Bc-SMase resulted in a reduction in the generation of H2O2 and phagocytosis of macrophages induced by peptidoglycan (PGN), but no effect on the release of TNF-α and little release of LDH under our experimental conditions. Confocal laser microscopy showed that the treatment of mouse macrophages with Bc-SMase resulted in the formation of ceramide-rich domains. A photobleaching analysis suggested that the cells treated with Bc-SMase exhibited a reduction in membrane fluidity. The results suggest that Bc-SMase is essential for the hydrolysis of SM in membranes, leading to a reduction in phagocytosis

The validity of multi-center common normal database for identifying myocardial ischemia: Japanese Society of Nuclear Medicine Working Group Database

金沢大学医薬保健研究域医学系Purpose The Japanese Society of Nuclear Medicine (JSNM) working group has created a myocardial perfusion imaging database applicable to standard acquisition protocol. The aim of this study is to validate the diagnostic accuracy of the common normal database compared with the expert interpretation of each institute. Methods Five institutions participated in this study and used different acquisition settings which included 360°/ 180° rotation, camera configuration and camera orbits. The software and its version used in each institution also varied. The working group database was applied to detect the culprit coronary territory from a total of 166 patients with coronary artery disease (CAD) and 145 patients with lowlikelihood of CAD. Results When summed stress score C4 was defined as significant abnormality, overall sensitivity, specificity and accuracy of patient-based analysis were 77, 72 and 75%, respectively, based on quantitative analysis using the common database, whereas those by institutional visual expert reading were 72, 79 and 75%, respectively. Conclusion The common database, which was created by a multi-center working group and separated between male/ female with 180/360° acquisitions, demonstrated comparable diagnostic accuracy to expert interpretation by each institute, and it may be applicable to multi-center studies

Human iPS cell–derived respiratory organoids as a model for respiratory syncytial virus infection

Respiratory syncytial virus (RSV) is a seasonal respiratory pathogen that primarily affects young children, potentially causing severe lower respiratory tract disease. Despite the high disease burden, understanding of RSV pathophysiology remains limited. To address this, advanced RSV infection models are needed. Whereas HEp-2 cells are widely used because of their high susceptibility to RSV, they do not accurately reflect the host response of the human respiratory tract. In this study, we evaluated human-induced pluripotent stem cell-derived respiratory organoids, which contain respiratory epithelial cells, immune cells, fibroblasts, and vascular endothelial cells, for their potential to model RSV infection and support pharmaceutical research. RSV-infected organoids exhibited high viral genome and protein expression, epithelial layer destruction, and increased collagen accumulation. Pro-inflammatory cytokine levels in culture supernatants also increased post-infection. Furthermore, RSV infection was significantly inhibited by monoclonal antibodies (nirsevimab, palivizumab, suptavumab, or clesrovimab), although ribavirin showed limited efficacy. These findings highlight the utility of respiratory organoids for RSV research

Increased Stathmin1 Expression in the Dentate Gyrus of Mice Causes Abnormal Axonal Arborizations

Pituitary adenylate cyclase-activating polypeptide (PACAP) is involved in multiple brain functions. To clarify the cause of abnormal behavior in PACAP deficient-mice, we attempted the identification of genes whose expression was altered in the dentate gyrus of PACAP-deficient mice using the differential display method. Expression of stathmin1 was up-regulated in the dentate gyrus at both the mRNA and protein levels. PACAP stimulation inhibited stathmin1 expression in PC12 cells, while increased stathmin1expression in neurons of the subgranular zone and in primary cultured hippocampal neurons induced abnormal arborization of axons. We also investigated the pathways involved in PACAP deficiency. Ascl1 binds to E10 box of the stathmin1 promoter and increases stathmin1 expression. Inhibitory bHLH proteins (Hes1 and Id3) were rapidly up-regulated by PACAP stimulation, and Hes1 could suppress Ascl1 expression and Id3 could inhibit Ascl1 signaling. We also detected an increase of stathmin1 expression in the brains of schizophrenic patients. These results suggest that up-regulation of stathmin1 in the dentate gyrus, secondary to PACAP deficiency, may create abnormal neuronal circuits that cause abnormal behavior

Long-term Outcomes of Hypofractionated Stereotactic Radiotherapy for the Treatment of Perioptic Nonfunctioning Pituitary Adenomas

The efficacy of stereotactic radiotherapy (SRT) has been well established for postoperative residual and recurrent nonfunctioning pituitary adenomas (NFPAs). However, the risk of visual impairment due to SRT for lesions adjacent to the optic pathways remains a topic of debate. Herein, we evaluated the long-term clinical outcomes of hypofractionated stereotactic radiotherapy (HFSRT) for perioptic NFPAs. From December 2002 to November 2015, 32 patients (18 males and 14 females; median age 63 years; range, 36–83 years) with residual or recurrent NFPAs abutting or displacing the optic nerve and/or chiasm (ONC) were treated with HFSRT. The median marginal dose was 31.3 Gy (range, 17.2–39.6) in 8 fractions (range, 6–15). Magnetic resonance imaging (MRI) and visual and hormonal examinations were performed before and after HFSRT. The median follow-up period was 99.5 months (range, 9–191). According to MRI findings at the last follow-up, the tumor size had decreased in 28 (88%) of 32 patients, was unchanged in 3 (9%), and had increased in 1 (3%). The successful tumor size control rate was 97%. Visual functions remained unchanged in 19 (60%) out of 32 patients, improved in 11 (34%), and deteriorated in 2 (6%). Two patients had deteriorated visual functions; no complications occurred because of the HFSRT. One patient developed hypopituitarism that required hormone replacement therapy. The result of this long-term follow-up study suggests that HFSRT is safe and effective for the treatment of NFPAs occurring adjacent to the ONC

Potential application of measuring serum infliximab levels in rheumatoid arthritis management: A retrospective study based on KURAMA cohort data

Infliximab (IFX) therapy has considerably improved the treatment of rheumatoid arthritis (RA). However, some patients still do not respond adequately to IFX therapy, or the efficacy of the treatment diminishes over time. Although previous studies have reported a relationship between serum IFX levels and therapeutic efficacy, the potential applications of IFX therapeutic drug monitoring (TDM) in clinical practice remain unclear. The purpose of this study was to investigate the potential applications of IFX TDM by analyzing a Japanese cohort database. Data were collected retrospectively from the Kyoto University Rheumatoid Arthritis Management Alliance cohort between January 1, 2011, and December 31, 2018. Serum IFX levels were measured using a liquid chromatography-tandem mass spectrometer. Out of the 311 RA patients that used IFX, 41 were eligible for the analysis. Serum IFX levels were significantly higher in responders than in non-responders. An optimal cut-off value was determined to be 0.32 μg/mL based on a receiver operating characteristic curve. At the IFX measurement point, a better therapeutic response was observed in the high IFX group (n = 32) than in the low IFX group (n = 9). Conversely, at the maximum effect point, when DAS28-ESR was the lowest between IFX introduction and measurement points, there were no differences in responder proportions between the low and high IFX groups. IFX primary ineffectiveness could be avoided with appropriate dose escalation without blood concentration measurement in clinical practice. In conclusion, IFX TDM could facilitate the identification of secondary non-responders and in turn, proper IFX use