Difference in the ligand affinity among redundant plant hormone receptors of rice OsCOI1a/1b/2-OsJAZs.

(3R, 7S)-jasmonoyl-L-isoleucine (JA-Ile) is a lipid-derived plant hormone that regulates plant responses, including biotic/abiotic stress adaptation. In the plant cells, JA-Ile is perceived by COI1-JAZ co-receptor by causing protein-protein interaction between COI1 and JAZ proteins to trigger gene expressions. In this study, we focused on Oryza sativa, a model monocot and an important crop, with 45 possible OsCOI-OsJAZ co-receptor pairs composed of three OsCOI homologs (OsCOI1a, OsCOI1b, and OsCOI2) and 15 OsJAZ homologs. We performed fluorescein anisotropy and pull-down assays to examine the affinity between JA-Ile and OsCOI1a/1b/2-OsJAZ1-15 co-receptor pairs. The results revealed a remarkable difference in the modes of ligand perception by OsCOI1a/1b and OsCOI2. Recently, the unique function of OsCOI2 in some of the JA-responses were revealed. Our current results will lead to the possible development of OsCOI2-selective synthetic ligand.

Transcription factor old astrocyte specifically induced substance is a novel regulator of kidney fibrosis.

Prevention of kidney fibrosis is an essential requisite for effective therapy in preventing chronic kidney disease (CKD). Here, we identify Old astrocyte specifically induced substance (OASIS)/cAMP responsive element-binding protein 3-like 1 (CREB3l1), a CREB/ATF family transcription factor, as a candidate profibrotic gene that drives the final common pathological step along the fibrotic pathway in CKD. Although microarray data from diseased patient kidneys and fibrotic mouse model kidneys both exhibit OASIS/Creb3l1 upregulation, the pathophysiological roles of OASIS in CKD remains unknown. Immunohistochemistry revealed that OASIS protein was overexpressed in human fibrotic kidney compared with normal kidney. Moreover, OASIS was upregulated in murine fibrotic kidneys, following unilateral ureteral obstruction (UUO), resulting in an increase in the number of OASIS-expressing pathological myofibroblasts. In vitro assays revealed exogenous TGF-ß1 increased OASIS expression coincident with fibroblast-to-myofibroblast transition and OASIS contributed to TGF-ß1-mediated myofibroblast migration and increased proliferation. Significantly, in vivo kidney fibrosis induced via UUO or ischemia/reperfusion injury was ameliorated by systemic genetic knockout of OASIS, accompanied by reduced myofibroblast proliferation. Microarrays revealed that the transmembrane glycoprotein Bone marrow stromal antigen 2 (Bst2) expression was reduced in OASIS knockout myofibroblasts. Interestingly, a systemic anti-Bst2 blocking antibody approach attenuated kidney fibrosis in normal mice but not in OASIS knockout mice after UUO, signifying Bst2 functions downstream of OASIS. Finally, myofibroblast-restricted OASIS conditional knockouts resulted in resistance to kidney fibrosis. Taken together, OASIS in myofibroblasts promotes kidney fibrosis, at least in part, via increased Bst2 expression. Thus, we have identified and demonstrated that OASIS signaling is a novel regulator of kidney fibrosis.

Maresin-1 induces cardiomyocyte hypertrophy through IGF-1 paracrine pathway.

The resolution of inflammation is closely linked with tissue repair. Recent studies have revealed that macrophages suppress inflammatory reactions by producing lipid mediators, called specialized proresolving mediators (SPMs); however, the biological significance of SPMs in tissue repair remains to be fully elucidated in the heart. In this study, we focused on maresin-1 (MaR1) and examined the reparative effects of MaR1 in cardiomyocytes. The treatment with MaR1 increased cell size in cultured neonatal rat cardiomyocytes. Since the expression of fetal cardiac genes was unchanged by MaR1, physiological hypertrophy was induced by MaR1. SR3335, an inhibitor of retinoic acid-related orphan receptor α (RORα), mitigated MaR1-induced cardiomyocyte hypertrophy, consistent with the recent report that RORα is one of MaR1 receptors. Importantly, in response to MaR1, cardiomyocytes produced IGF-1 via RORα. Moreover, MaR1 activated phosphoinositide 3-kinase (PI3K)/Akt signaling pathway and wortmannin, a PI3K inhibitor, or triciribine, an Akt inhibitor, abrogated MaR1-induced cardiomyocyte hypertrophy. Finally, the blockade of IGF-1 receptor by NVP-AEW541 inhibited MaR-1-induced cardiomyocyte hypertrophy as well as the activation of PI3K/Akt pathway. These data indicate that MaR1 induces cardiomyocyte hypertrophy through RORα/IGF-1/PI3K/Akt pathway. Considering that MaR1 is a potent resolving factor, MaR1 could be a key mediator that orchestrates the resolution of inflammation with myocardial repair.

Distinct features between HLA-DR+ and HLA-DR- PD-1hi CXCR5- T peripheral helper cells in seropositive rheumatoid arthritis.

OBJECTIVES: PD-1hi CXCR5- T peripheral helper (Tph) cells are newly identified pathogenic CD4 helper T cells in RA. We evaluated the usefulness of Tph cell subsets as biomarkers of RA. METHODS: RA patients who visited our rheumatology department between May 2015 and September 2017 and met the 2010 ACR/EULAR classification criteria were included. We compared the correlation of DAS28-ESR between Tph cell subsets and 40 immune cell subsets. We also explored which subsets reflected the chronological changes in the disease activity after treatment. RESULTS: Thirty-four seropositive RA patients, 11 seronegative RA patients and 34 healthy controls were included. Tph cell subsets that correlated with the DAS28-ESR were HLA-DR+ Tph cells (rs = 0.50, P = 0.002), HLA-DR- Tph cells (rs = 0.39, P = 0.03) and Tph1 cells (rs = 0.41, P = 0.02). Among the other 40 immune cell subsets, HLA-DR+ Th1-17 cells (rs = 0.38, P = 0.03), activated B cells (rs = -0.35, P = 0.04), plasma cells (rs = 0.43, P = 0.01) and CD14++ CD16+ monocytes (rs = 0.36, P = 0.04) correlated, but not strongly as HLA-DR+ Tph cells. However, MTX treatment reduced the proportion of HLA-DR+ Tph cells independently of the disease activity. In contrast, HLA-DR- Tph cells accurately reflected the change in the DAS28-ESR during MTX treatment. CONCLUSION: HLA-DR+ Tph cells were decreased with MTX treatment, independent of the disease activity, while HLA-DR- Tph cells reflected the disease activity accurately during the treatment.

Construction of Boronophenylalanine-Loaded Biodegradable Periodic Mesoporous Organosilica Nanoparticles for BNCT Cancer Therapy.

Biodegradable periodic mesoporous organosilica (BPMO) has recently emerged as a promising type of mesoporous silica-based nanoparticle for biomedical applications. Like mesoporous silica nanoparticles (MSN), BPMO possesses a large surface area where various compounds can be attached. In this work, we attached boronophenylalanine (10BPA) to the surface and explored the potential of this nanomaterial for delivering boron-10 for use in boron neutron capture therapy (BNCT). This cancer therapy is based on the principle that the exposure of boron-10 to thermal neutron results in the release of a-particles that kill cancer cells. To attach 10BPA, the surface of BPMO was modified with diol groups which facilitated the efficient binding of 10BPA, yielding 10BPA-loaded BPMO (10BPA-BPMO). Surface modification with phosphonate was also carried out to increase the dispersibility of the nanoparticles. To investigate this nanomaterial's potential for BNCT, we first used human cancer cells and found that 10BPA-BPMO nanoparticles were efficiently taken up into the cancer cells and were localized in perinuclear regions. We then used a chicken egg tumor model, a versatile and convenient tumor model used to characterize nanomaterials. After observing significant tumor accumulation, 10BPA-BPMO injected chicken eggs were evaluated by irradiating with neutron beams. Dramatic inhibition of the tumor growth was observed. These results suggest the potential of 10BPA-BPMO as a novel boron agent for BNCT.

Significant association between clinical characteristics and immuno-phenotypes in patients with ANCA-associated vasculitis.

OBJECTIVES: To elucidate the association between clinical characteristics and immuno-phenotypes in patients with ANCA-associated vasculitis (AAV). METHODS: Peripheral blood from 36 patients with active AAV and 18 healthy controls was examined for numbers of circulating T cells, B cells, NK cells, dendritic cells, monocytes and granulocytes using flow cytometry. These immuno-phenotyping data were subjected to cluster analysis and principal components analysis to divide AAV patients into subgroups. Associated organ involvement or therapeutic prognosis were assessed for each subgroup. RESULTS: AAV patients had higher proportions of plasma cells, plasmablasts, activated T cells, CD14++ CD16+ monocytes, eosinophils and neutrophils than healthy controls. Immuno-phenotyping findings were similar between patients with microscopic polyangiitis, granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis. Cluster analysis indicated that AAV patients could be divided into three subgroups according to peripheral immune cell numbers: antibody production-related (n = 9), cytotoxic activity-related (n = 4) and neutrocytosis/lymphocytopenia-related (n = 23). The antibody production-related or cytotoxic activity-related group was associated with CNS involvement, and the neutrocytosis/lymphocytopenia-related group was associated with high incidence of kidney involvement. Incidence of severe infection was markedly higher in the neutrocytosis/lymphocytopenia-related group than the other two groups. Incidence of disease relapse was comparable among the three groups. CONCLUSION: Patients with active AAV can be divided into three subgroups based on immuno-phenotyping. These results may provide a hint to understanding disease pathophysiology and prognosis, and determining appropriate treatment.

Fructo-oligosaccharides ameliorate steatohepatitis, visceral adiposity, and associated chronic inflammation via increased production of short-chain fatty acids in a mouse model of non-alcoholic steatohepatitis.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome. Within the spectrum of NAFLD, non-alcoholic steatohepatitis (NASH) in combination with hepatic inflammation and fibrosis can lead to liver cirrhosis and hepatocellular carcinoma. Dysbiosis was reported to contribute to NASH pathogenesis. This study aimed to determine the effects of fructo-oligosaccharides (FOS) on steatohepatitis and visceral adiposity in an obese mouse model of NASH. METHODS: Twelve newborn C57BL/6 J male mice were subcutaneously injected with monosodium glutamate (MSG) to induce obesity on a conventional diet. Six mice were also administered 5% FOS via drinking water from 10 weeks of age. At 18 weeks, histological characteristics of the liver and epididymal fat were compared between the groups. Hepatic mRNA expression of lipid metabolism enzymes and SCFA in feces and sera were measured. RESULTS: Hepatic steatosis, inflammatory cell infiltration, and hepatocyte ballooning in the liver and increased hepatic mRNA expression of fatty acid synthase and glycerol-3-phosphate acyltransferase were observed in the MSG-treated mice. FOS treatment improved the liver pathology and blunted the increases in the mRNA expression levels of lipid metabolism enzymes. In addition, FOS inhibited adipocyte enlargement and formation of crown-like structures and reduced the M1 macrophage frequency in the epididymal fat of the MSG mice (39.4% ± 3.0% vs. 22.8% ± 0.7%; P = 0.001). FOS increased not only the fecal concentrations of n-butyric acid (0.04 ± 0.01 vs. 0.38 ± 0.14 mg/g, P = 0.02), propionic acid (0.09 ± 0.03 vs. 0.42 ± 0.16 mg/g, P = 0.02), and acetic acid (0.65 ± 0.16 vs. 1.48 ± 0.29 mg/g, P = 0.03) but also the serum concentration of propionic acid (3.9 ± 0.5 vs. 8.2 ± 0.5 µmol/L, P = 0.001). CONCLUSIONS: FOS ameliorates steatohepatitis, visceral adiposity, and chronic inflammation by increasing SCFA production.

Distinguishing coagulase-negative Staphylococcus bacteremia from contamination using blood-culture positive bottle detection pattern and time to positivity.

AIM: Detection of coagulase-negative Staphylococcus in blood culture may be a result of either bacteremia or contamination. This often leads to diagnostic uncertainly. Our objective was to develop a method for differentiating whether a coagulase-negative Staphylococcus sp. positive blood culture represents bacteremia or contamination based on positive bottle detection pattern and time to positivity (TTP). METHODS: This study included 155 and 51 adults with positive blood cultures for Staphylococcus epidermidis and Staphylococcus hominis, respectively, over a three-year period from 2016 to 2018. Positive blood culture cases were categorized as either bacteremia or contamination based on the clinically available information, and the detection pattern and TTP in each category were investigated. RESULTS: A total of 57, 92, and 6 S. epidermidis positive blood cultures were categorized as bacteremia, contamination, and undetermined, respectively, whereas 15 and 36 S. hominis positive blood cultures were categorized as bacteremia and contamination, respectively. For positive blood cultures categorized as bacteremia, all four bottles in two sets of blood cultures were positive in 47/47 S. epidermidis and 14/14 S. hominis, respectively, whereas either one bottle in each of two sets or three bottles in two sets were positive in 10/19 S. epidermidis and 1/4 S. hominis, respectively; most of those TTPs were <48 h. Among them, the TTP in catheter-related blood stream infection was <24 h. CONCLUSION: Although clinical assessment is crucial to differentiate between bacteremia and contamination, a combination of positive bottle detection pattern and TTP is a valuable diagnostic auxiliary tool.

[Mixed connective tissue disease with pulmonary hypertension developing in a chronic myeloid leukemia patient on dasatinib treatment].

A 37-year-old woman was diagnosed with chronic phase chronic myeloid leukemia. Nilotinib treatment was initiated; however, it had to be discontinued due to an allergic reaction one month later, and dasatinib treatment was provided. Although favorable response was obtained, she started complaining of shortness of breath 7 months after initiating dasatinib treatment. Chest X-ray and echocardiography indicated pulmonary congestion and hypertension. Further, she was diagnosed with mixed connective tissue disease (MCTD) based on Raynaud phenomenon, swollen fingers, sclerodactyly, pancytopenia, hypocomplementemia, and positive anti-U1-RNP antibody. Consequently, dasatinib treatment was discontinued, and she was administered prednisolone (1 mg/kg/day), which was effective and successfully tapered with concomitant administration of cyclophosphamide. This is the first case of MCTD that developed during dasatinib treatment. However, because the present case was a young woman, the development of MCTD could probably be attributed to autoimmune diatheses or it may be a coincidence. However, the possibility of patients receiving dasatinib treatment developing autoimmune diseases needs to be assessed.

Splenic lymph follicles generate immunoglobulin M-producing B cells in primary biliary cirrhosis.

AIM: To reveal the site of immunoglobulin (Ig)M production in primary biliary cirrhosis (PBC) we performed immunohistochemical analysis on spleens collected from patients with PBC. METHODS: Splenic tissue samples were collected at the time of the autopsy from patients with hepatic failure. Immunostaining for IgM, CD21 and CXCL13 were performed using the splenic tissue samples. RESULTS: The samples from five out of eight cases with PBC but not in eight cases of chronic hepatitis C virus infection showed accumulation of IgM positive cells in CD21 positive lymph follicles. The CXCL13 positive cells also accumulated in the center of the lymph follicles where the IgM positive cells accumulated. CONCLUSION: The present results suggest that excess IgM is produced from the spleen of PBC. Furthermore, it was suggested that CXCL13 positive follicular dendritic cells possibly contribute to this process.

Two distinct modes of action of molecular glues in the plant hormone co-receptor COI1-JAZ system.

The plant hormone (3R, 7S)-jasmonoyl-L-isoleucine ((3R, 7S)-JA-Ile) is perceived by the COI1-JAZ co-receptor in Arabidopsis thaliana, leading to the activation of gene expression for plant defense responses, growth, development, and other processes. Therefore, understanding the interaction between the COI1-JAZ co-receptor and its ligands is essential for the development of COI1-JAZ agonists and antagonists as potent chemical tools for regulating (3R, 7S)-JA-Ile signaling. This study demonstrated that COI1-JAZ has two independent modes of ligand perception using a differential scanning fluorimetry (DSF) assay. (3R, 7S)-JA-Ile is perceived through a one-step model in which (3R, 7S)-JA-Ile causes protein-protein interaction between COI1 and JAZ. In contrast, coronatine (COR), a mimic of (3R, 7S)-JA-Ile, is perceived through a two-step model in which COR is first perceived by COI1 and then recruits JAZ to form the COI1-COR-JAZ complex. Our results demonstrate two distinct modes of action of molecular glues causing protein-protein interactions.

Tissue responses to everolimus-eluting stents implanted in severely calcified lesions following atherectomy.

Histopathological examination has revealed that stents on severely calcified plaques were associated with delayed vascular healing. Although atherectomy devices can increase the number of malapposed struts, tissue responses to implanted drug eluting stents in atherectomy patients remain largely unknown. This retrospective observational study included 30 patients who underwent atherectomy and everolimus-eluting stent (EES) deployment for severely calcified coronary lesions (biodegradable polymer EES (BP-EES), n = 15; durable polymer EES (DP-EES), n = 15). Optical coherence tomography was carried out at baseline and follow-up, and struts with acute stent malapposition (ASM) were categorized as struts on modified calcium (mod-Ca), non-modified calcium (non-mod-Ca), or non-calcium (non-Ca). Adequate vascular healing, defined as ASM resolution with neointimal coverage, was compared between the BP-EES and DP-EES groups. Multivariate linear regression analysis using a generalized estimated equation revealed that BP-EES use was associated with significantly better adequate vascular healing compared with DP-EES (odds ratio [OR]: 3.691, 95% confidence interval [CI] 1.175-11.592, P = 0.025). adequate vascular healing was associated with the underlying plaque morphology (mod-Ca vs non-mod-Ca: OR 2.833, 95% CI 1.491-5.384, P = 0.001; non-Ca vs non-mod-Ca: OR 1.248, 95% CI 0.440-3.543, P = 0.677). This study demonstrates that drug-eluting stent selection and calcium modification are possible factors affecting vascular healing of malapposed struts in severely calcified lesions.

Changes in the molecular profiles of large-vessel vasculitis treated with biological disease-modifying anti-rheumatic drugs and Janus kinase inhibitors.

Giant cell arteritis and Takayasu arteritis are two types of primary large-vessel vasculitis (LVV). Although glucocorticoids (GC) are the standard treatment for LVV, the disease relapse rates are high. Recent clinical trials on biological disease-modifying anti-rheumatic drugs (bDMARDs) and Janus kinase (JAK) inhibitors have demonstrated their efficacy in reducing LVV relapse rates and GC dosages. However, the control of residual inflammation and degenerative alterations in the vessel wall remains an outstanding requirement in the clinical management of LVV. The analysis of immune cell phenotypes in patients with LVV may predict their response to treatment with bDMARDs and JAK inhibitors and guide their optimal use. In this mini-review, we focused on molecular markers, including the immune cell proportions and gene expression, in patients with LVV and in mouse models of LVV treated with bDMARDs and JAK inhibitors.

Histological improvement in chronic hepatitis C-autoimmune hepatitis overlap syndrome by glecaprevir and pibrentasvir.

A 60-year-old man with type-2 diabetes and chronic hepatitis C (HCV) was diagnosed with single hepatocellular carcinoma (HCC) of 67 mm in the hepatic posterior right lobe. Lenvatinib 8 mg was initiated but discontinued because of grade 3 liver injury. The patient continued to have prolonged liver injury and persistently high immunoglobulin G levels. Antinuclear antibody titer increased from 1:40 to 1:320. Histopathological examination of a liver biopsy specimen revealed interface hepatitis with lymphocyte and plasma cell infiltration, rosette formation, and emperipolesis, suggesting the possibility of autoimmune hepatitis (AIH). First, treatment with prednisolone was initiated; however, the response was poor. After starting glecaprevir/pibrentasvir (GLE/PIB) as direct-acting antivirals (DAA), HCV RNA rapidly disappeared, and serological liver function improved. After confirmation of sustained virological response 24, HCC recurrence was observed, and partial hepatectomy was performed. Background liver findings showed that liver parenchymal inflammation improved compared with that before DAA treatment. This is the first case of HCV-AIH overlap syndrome treated with DAA using GLE/PIB. Liver function improved within a short treatment period of 8 weeks, as confirmed using serology and histology.

Quantitative analysis of tissue area of endoscopic ultrasound-guided liver biopsy specimens using 19-gauge fine-needle biopsy needle in patients with diffuse liver disease: A single-center retrospective study.

BACKGROUND/PURPOSE: Endoscopic ultrasound-guided liver biopsy (EUS-LB) is a novel liver biopsy technique. We aimed to evaluate the efficacy and safety of EUS-LB in comparison with percutaneous liver biopsy (PLB). METHODS: This retrospective study evaluated the safety and efficacy of EUS-LB using a 19-gauge fine needle biopsy (FNB) needle compared with PLB using a spring-loaded 16-gauge needle in patients with diffuse liver disease at our hospital from April 2017 to December 2020. The primary outcomes included the total hepatic tissue surface area and the total number of portal tracts. Secondary outcomes included the success and adverse event rates. RESULTS: Twenty patients each underwent EUS-LB and PLB. There was no statistical difference in the sum of liver tissue surface area (22 mm2 vs 22.6 mm2 , P = .910) and the total number of portal tracts (29 vs 25, P = .916). The success rate was 95% (19/20) for EUS-LB and 100% (20/20) for PLB (P = 1). There were two adverse events in the PLB group but none in the EUS-LB group (P = .487). CONCLUSIONS: Endoscopic ultrasound-guided liver biopsy using FNB has an optimal tissue yield and success rate and is safe compared to PLB. Thus, EUS-LB may be a new alternative to PLB.

Secondary right atrial thrombosis in three dogs: Antithrombotics therapy and echocardiographic follow-up.

Three dogs were diagnosed with right atrial thrombosis, thought to be secondary to systemic diseases. Specifically, two cases had hyperadrenocorticism and one case was diagnosed with pancreatitis with acute renal injury. In all cases, the thrombi were found within the right atrium, necessitating a differentiation from cardiac neoplasia. In all three cases, the structures assumed to be thrombi had irregular margins with interspersed hypoechoic regions, which were later confirmed as thrombi based on the responsiveness to therapy. All three cases were prescribed with the combination of clopidogrel and rivaroxaban.The thrombi gradually disappeared after initiation of the combination therapy. Complete resolution of right atrial thrombosis was noted in each dog treated with clopidogrel and rivaroxaban. This combination therapy appears to be safe and well tolerated. Diligent observation of the echocardiographic findings and clinical course allows the diagnosis of thrombosis.

Seasonal changes of the prostate gland in the raccoon (Procyon lotor) inhabiting Hokkaido, Japan.

In the prostate gland of the raccoon (Procyon lotor), the morphological appearance of the epithelial cells, such as basal and luminal cells, and the expressions of p63, androgen receptor (AR), and proliferating cell nuclear antigen (PCNA) were examined histologically and immunohistochemically to clarify their seasonal dynamics throughout the year. In this study, the regression with luminal cell defluxion and the regeneration process of the prostatic glandular epithelium was revealed in the seasons with declined spermatogenesis (June to August). The expression of p63 was observed only in the basal cells. AR immunoreactivity in the luminal cells was shown in the developed and regenerating (close to developed) prostates, whereas the basal cells exhibited AR immunoreactivity all year round. PCNA expression was rare in epithelial cells of the developed prostate gland. In the regressed gland, the basal cells demonstrated proliferative ability, whereas PCNA of the luminal cells appeared for the first time in the regenerating phase. This study is the first to clarify the regression with luminal cell defluxion and restoration and the seasonal dynamics of AR expression and proliferative activity in the prostate gland of seasonal breeders.

Organosilica nanoparticles containing sodium borocaptate (BSH) provide new prospects for boron neutron capture therapy (BNCT): efficient cellular uptake and enhanced BNCT efficacy.

Boron neutron capture therapy (BNCT), a method based on the fission of boron-10 upon neutron irradiation, has emerged as an attractive option for radiation therapy. To date, the main drugs used in BNCT are 4-boronophenylalanine (BPA) and sodium borocaptate (BSH). While BPA has been extensively tested in clinical trials, the use of BSH has been limited, mainly due to its poor cellular uptake. Here, we describe a novel type of mesoporous silica-based nanoparticle containing BSH covalently attached to a nanocarrier. Synthesis and characterization of these nanoparticles (BSH-BPMO) are presented. The synthetic strategy involves a click thiol-ene reaction with the boron cluster, providing hydrolytically stable linkage with the BSH in four steps. The BSH-BPMO nanoparticles were efficiently taken up into cancer cells and accumulated in the perinuclear region. Inductively coupled plasma (ICP) measurements of boron uptake in cells highlight the important role of the nanocarrier in the enhancement of boron internalization. BSH-BPMO nanoparticles were also taken up and distributed throughout tumour spheroids. BNCT efficacy was examined by the neutron exposure of the tumour spheroids. BSH-BPMO loaded spheroids were completely destroyed upon neutron irradiation. In contrast, neutron irradiation of tumour spheroids loaded with BSH or BPA resulted in significantly less spheroid shrinkage. The significant difference in BNCT efficacy of the BSH-BPMO was correlated with the improved boron uptake via the nanocarrier. Overall, these results demonstrate the critical role of the nanocarrier in BSH internalization and the enhanced BNCT efficacy of the BSH-BPMO compared with BSH and BPA, two drugs used in BNCT clinical trials.

Longitudinal monitoring of circulating immune cell phenotypes in anti-neutrophil cytoplasmic antibody-associated vasculitis.

Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is a necrotizing multiorgan autoimmune disease that affects small- to medium-sized blood vessels. Despite the improvements in treatments, half of the patients with AAV still experience disease relapses. In this review, we focus on peripheral leukocyte properties and phenotypes in patients with AAV. In particular, we explore longitudinal changes in circulating immune cell phenotypes during the active phase of the disease and treatment. The numbers and phenotypes of leukocytes in peripheral blood were differs between AAV and healthy controls, AAV in active versus inactive phase, AAV in treatment responders versus non-responders, and AAV with and without severe infection. Therefore, biomarkers detected in peripheral blood immune cells may be useful for longitudinal monitoring of disease activity in AAV.

Distinct gene signatures of monocytes and B cells in patients with giant cell arteritis: a longitudinal transcriptome analysis.

BACKGROUND: Giant cell arteritis (GCA) is a primary large-vessel vasculitis (LVV) of unknown origin. Its management is a challenge due to the late onset of disease symptoms and frequent relapse; therefore, clarifying the pathophysiology of GCA is essential to improving treatment. This study aimed to identify the transition of molecular signatures in immune cells relevant to GCA pathogenesis by analyzing longitudinal transcriptome data in patients. METHODS: We analyzed the whole blood transcriptome of treatment-naive patients with GCA, patients with Takayasu arteritis (TAK), age-matched, old healthy controls (HCs), and young HCs. Characteristic genes for GCA were identified, and the longitudinal transition of those genes was analyzed using cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT). RESULTS: Repeated measures analysis of variance revealed 739 differentially expressed genes among all patients and HCs. Of the 739 genes, 15 were characteristically upregulated and 36 were downregulated in patients with GCA compared to those with TAK and HCs. Pathway enrichment analysis showed that downregulated genes in GCA were associated with B cell activation. CIBERSORT analysis revealed that upregulation of "M0-macrophages" and downregulation of B cells were characteristic of GCA. Upregulation of "M0-macrophages" reflects the activation of monocytes in GCA toward M0-like phenotypes, which persisted under 6 weeks of treatment. Combined treatment with prednisolone and an interleukin-6 receptor antagonist normalized molecular profiles more efficiently than prednisolone monotherapy. CONCLUSIONS: Gene signatures of monocyte activation and B cell inactivation were characteristic of GCA and associated with treatment response.