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Background/Aim: Concomitant proton pump inhibitor (PPI) and immune checkpoint inhibitor (ICPI) were determined as risk factors of acute kidney injury. To identify the type of PPI associated with ICPI-induced nephritis, we used the Japanese Adverse Drug Event Report database. Patients and Methods: ICPIs (nivolumab, pembrolizumab, ipilimumab, atezolizumab, durvalumab, and avelumab) and PPIs (esomeprazole, omeprazole, vonoprazan, rabeprazole, and lansoprazole) were selected as suspected nephritis-inducing drugs. Results: The cases of concomitant use of atezolizumab and rabeprazole, ipilimumab and omeprazole, ipilimumab and lansoprazole, nivolumab and esomeprazole, nivolumab and omeprazole, nivolumab and rabeprazole, nivolumab and lansoprazole, pembrolizumab and esomeprazole, as well as pembrolizumab and lansoprazole had a significantly higher reported odds ratio than monotherapy cases. Conclusion: Male patients or patients using ICPIs and PPIs (excluded vonoprazan) concomitantly should be monitored for renal function after chemotherapy.

Background Although the 2018 revised International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification was proposed recently, until now, no reports have been made comparing the association of renal prognosis between the 2018 revised ISN/RPS classification and the 2003 ISN/RPS classification. The present study aimed to assess the usefulness, especially of activity and chronicity assessment, of the 2018 revised ISN/RPS classification for lupus nephritis (LN) in terms of renal prognosis compared to the classification in 2003. Methods We retrospectively collected medical records of 170 LN patients from the database of renal biopsy at Fujita Health University from January 2003 to April 2019. Each renal biopsy specimen was reevaluated according to both the 2003 ISN/RPS classification and the 2018 revised ISN/RPS classification. Renal endpoint was defined as a 30% decline of estimated glomerular filtration rate (eGFR). Results A total of 129 patients were class III/IV±V (class III, 44 patients; class IV, 35 patients; class III/IV+V, 50 patients). The mean age was 42 years, 88% were female, and the median observation period was 50.5 months. Renal prognosis was significantly different among the classes and significantly poor in the patients with higher modified National Institute of Health (mNIH) chronicity index (C index, ≥ 4) by a log-rank test (p = 0.05 and p = 0.02, respectively). By Cox proportional hazard models, only the C index was significantly associated with renal outcome (hazard ratio 1.32, 95% CI 1.11–1.56, p ≤ 0.01), while the classes, the 2003 activity and chronicity subdivision, and the mNIH activity index had no significant association with renal outcome. Each component of the C index was significantly associated with renal outcome in different models. Conclusion This study demonstrates that the 2018 revised ISN/RPS classification was more useful in terms of association with renal prognosis compared to the 2003 ISN/RPS classification.

Background The present study aimed to investigate associations between long-term renal function, whether IgG4-related tubulointerstitial nephritis (TIN) was diagnosed by renal biopsy at initial examination, chronic kidney disease (CKD) stage, and histological stage in patients with IgG4-related TIN. Methods This study used a retrospective cohort design including almost all patients who underwent renal biopsy at Fujita Health University Hospital and Nagoya University or its affiliated hospitals in Aichi between April 2003 and March 2015 (n = 6977 renal biopsies). The primary outcome was longitudinal changes in eGFR. Main exposures were whether IgG4-related TIN was diagnosed by renal biopsy at the initial examination, CKD stage, and its histological stage. Linear mixed models were performed to examine associations. Results Of the 6977 samples, there were 24 patients (with 201 records due to repeated measures) with IgG4-related TIN (20 men, mean age, 68.7 ± 9.7 years). They were followed up 6.6 ± 2.8 years after the renal biopsy and underwent glucocorticoid treatment. We found significant increase in eGFR from the baseline to 2 and 6 months after treatment initiation, which was maintained until 60 months. Patients initially diagnosed with IgG4-related TIN had higher eGFR from the baseline (at the start of treatment) to 60 months than those who were not. Compared with patients with CKD stage 3, patients with CKD stages 4 and 5 had lower eGFR at the baseline and other time points. Patients with histological stage B had comparatively lower eGFR at each point than stage A patients. Those mean differences of eGFR were stable from the baseline to 60 months. Conclusions After the treatment initiation, renal function rapidly improved and maintained for a long period, even with advanced CKD stage. We showed importance of early diagnosis of IgG4-related TIN in maintaining eGFR.

The damping rate for the surface wave propagating on the sharp boundary of half-space turbulent plasma is investigated. To derive the bona fide dispersion relation and the damping rate, the transve...

The effect of quantum recoil on the low-frequency electrostatic surface waves on a semi-bounded quantum turbulent plasma is investigated based on the kinetic dielectric permittivity of a plasma whe...

INTRODUCTION: Protein glycosylation influences characteristics such as folding, stability, protein interactions, and solubility. Therefore, glycan moieties of therapeutic proteins and proteins that are likely associated with disease pathogenesis should be analyzed in-depth, including glycan heterogeneity and modification sites. Recent advances in analytical methods and instrumentation have enabled comprehensive characterization of highly complex glycosylated proteins. AREA COVERED: The following aspects should be considered when analyzing glycosylated proteins: sample preparation, chromatographic separation, mass spectrometry (MS) and fragmentation methods, and bioinformatics, such as software solutions for data analyses. Notably, analysis of glycoproteins with heavily sialylated glycans or multiple glycosylation sites requires special considerations. Here, we discuss recent methodological advances in MS that provide detailed characterization of heterogeneous glycoproteins. EXPERT OPINION: As characterization of complex glycosylated proteins is still analytically challenging, the function or pathophysiological significance of these proteins is not fully understood. To reproducibly produce desired forms of therapeutic glycoproteins or to fully elucidate disease-specific patterns of protein glycosylation, a highly reproducible and robust analytical platform(s) should be established. In addition to advances in MS instrumentation, optimization of analytical and bioinformatics methods and utilization of glycoprotein/glycopeptide standards is desirable. Ultimately, we envision that an automated high-throughput MS analysis will provide additional power to clinical studies and precision medicine.

Renal anemia in chronic kidney disease is treated with recombinant human erythropoietin (rhEPO). However, some patients with anemia do not respond well to rhEPO, emphasizing the need for a more biocompatible EPO. Differentiation protocols for hepatic lineages have been modified to enable production from human induced pluripotent stem cell (hiPSC)‐derived EPO‐producing cells (EPO cells). However, markers for hiPSC‐EPO cells are lacking, making it difficult to purify hiPSC‐EPO cells and therefore to optimize EPO production and cell counts for transplantation. To address these issues, we investigated whether CD140b and CD73 could be used as markers for hiPSC‐EPO cells. We measured the expression of EPO, CD140b, and CD73 in hiPSC‐EPO cells and the EPO concentration in the cell supernatant by immunohistochemistry and enzyme‐linked immunosorbent assays on culture day 13, revealing that expression levels of CD140b and CD73 are correlated with the level of EPO. In addition, rates of CD140b+ CD73+ cells were observed to be correlated with the concentration of EPO. Thus, our results suggest that CD140b and CD73 may be markers for hiPSC‐EPO cells., We established differentiation protocols for human induced pluripotent stem cell (hiPSC)‐derived erythropoietin‐producing cells (EPO cells). However, markers for hiPSC‐EPO cells are lacking, making it difficult to purify hiPSC‐EPO cells and therefore to optimize EPO production and cell counts for transplantation. Here, we elucidated that CD140b and CD73 may be markers for hiPSC‐EPO cells.

Introduction There are few studies on the association between serum uric acid (UA) level and mortality in incident dialysis patients. We aimed to clarify whether the serum UA level at dialysis initiation is associated with mortality during maintenance dialysis. Methods We enrolled 1486 incident dialysis patients who participated in a previous multicenter prospective cohort study in Japan. We classified the patients into the following five groups according to their serum UA levels at dialysis initiation: G1 with a serum UA level

A common renal disease, immunoglobulin A (IgA) nephropathy (IgAN), is associated with glomerular deposition of IgA1-containing immune complexes. IgA1 hinge region (HR) has up to six clustered O-glycans consisting of Ser/Thr-linked N-acetylgalactosamine with β1,3-linked galactose and variable sialylation. IgA1 glycoforms with some galactose-deficient (Gd) HR O-glycans play a key role in IgAN pathogenesis. The clustered and variable O-glycans make the IgA1 glycomic analysis challenging and better approaches are needed. Here, we report a comprehensive analytical workflow for IgA1 HR O-glycoform analysis. We combined an automated quantitative analysis of the HR O-glycopeptide profiles with sequential deglycosylation to remove all but Gd O-glycans from the HR. The workflow was tested using serum IgA1 from healthy subjects. Twelve variants of glycopeptides corresponding to the HR with three to six O-glycans were detected; nine glycopeptides carried up to three Gd O-glycans. Sites with Gd O-glycans were unambiguously identified by electron-transfer/higher-energy collision dissociation tandem mass spectrometry. Extracted ion chromatograms of isomeric glycoforms enabled quantitative assignment of Gd sites. The most frequent Gd site was T236, followed by S230, T233, T228, and S232. The new workflow for quantitative profiling of IgA1 HR O-glycoforms with site-specific resolution will enable identification of pathogenic IgA1 HR O-glycoforms in IgAN.

Objectives: Favipiravir is an antiviral that is being evaluated for the treatment of COVID-19. Use of favipiravir is associated with elevation of serum uric acid levels. Risk factors for the occurrence of hyperuricemia are unclear. Methods: Specimens from COVID-19 patients who received 10 days of favipiravir in a previous clinical trial (jRCTs041190120) were used. Serum favipiravir concentrations were measured by LC-MS. Factors associated with the development of hyperuricemia were investigated using logistic regression analysis. Optimal cut-off values for the baseline serum uric acid levels and steady-state serum favipiravir concentrations in predicting the occurrence of hyperuricemia were determined by ROC curve analysis. Results: Among the 66 COVID-19 patients who were treated with favipiravir for 10 days, the steady-state serum favipiravir concentrations were significantly correlated with serum uric acid levels. High baseline serum uric acid levels and steady-state serum favipiravir concentrations during therapy were factors associated with the development of hyperuricemia. The cut‑off baseline serum uric acid level and steady-state serum favipiravir concentration during favipiravir administration determined to predict hyperuricemia were 3.7 mg/dL and 46.14 μg/mL, respectively. Conclusions: Patients with high baseline serum uric acid levels or who achieved high steady-state serum favipiravir concentrations during therapy were susceptible to hyperuricemia.

Monocarboxylates, such as lactate and pyruvate, are precursors for biosynthetic pathways, including those for glucose, lipids, and amino acids via the tricarboxylic acid (TCA) cycle and adjacent metabolic networks. The transportation of monocarboxylates across the cellular membrane is performed primarily by monocarboxylate transporters (MCTs), the membrane localization and stabilization of which are facilitated by the transmembrane protein basigin (BSG). Here, we demonstrate that the MCT/BSG axis sits at a crucial intersection of cellular metabolism. Abolishment of MCT1 in the plasma membrane was achieved by Bsg depletion, which led to gluconeogenesis impairment via preventing the influx of lactate and pyruvate into the cell, consequently suppressing the TCA cycle. This net anaplerosis suppression was compensated in part by the increased utilization of glycogenic amino acids (e.g., alanine and glutamine) into the TCA cycle and by activated ketogenesis through fatty acid β-oxidation. Complementary to these observations, hyperglycemia and hepatic steatosis induced by a high-fat diet were ameliorated in Bsg-deficient mice. Furthermore, Bsg deficiency significantly improved insulin resistance induced by a high-fat diet. Taken together, the plasma membrane-selective modulation of lactate and pyruvate transport through BSG inhibition could potentiate metabolic flexibility to treat metabolic diseases.

A common renal disease, immunoglobulin A (IgA) nephropathy (IgAN), is associated with glomerular deposition of IgA1-containing immune complexes. IgA1 hinge region (HR) has up to six clustered O-glycans consisting of Ser/Thr-linked N-acetylgalactosamine with β1,3-linked galactose and variable sialylation. IgA1 glycoforms with some galactose-deficient (Gd) HR O-glycans play a key role in IgAN pathogenesis. The clustered and variable O-glycans make the IgA1 glycomic analysis challenging and better approaches are needed. Here, we report a comprehensive analytical workflow for IgA1 HR O-glycoform analysis. We combined an automated quantitative analysis of the HR O-glycopeptide profiles with sequential deglycosylation to remove all but Gd O-glycans from the HR. The workflow was tested using serum IgA1 from healthy subjects. Twelve variants of glycopeptides corresponding to the HR with three to six O-glycans were detected; nine glycopeptides carried up to three Gd O-glycans. Sites with Gd O-glycans were unambiguously identified by electron-transfer/higher-energy collision dissociation tandem mass spectrometry. Extracted ion chromatograms of isomeric glycoforms enabled quantitative assignment of Gd sites. The most frequent Gd site was T

Dysfunction of immunoinhibitory signals and persistent T cell activation reportedly play important roles in the development of vasculitis. The skin is one of the most accessible organs, and it is suitable for the characterization of immune cell signatures. However, the inhibitory checkpoint molecules in the skin and their relevance to vasculitis have not been studied. Here, we investigated the profile of immune checkpoint molecules in the skin and peripheral blood of patients with vasculitis and healthy donors. We found that some of the inhibitory checkpoint molecules, including programmed cell death 1 receptor (PD-1), were elevated in T-cells in the blood of patients with systemic and cutaneous vasculitis. In addition, programmed death-ligand 1 (PD-L1) expression was elevated in the skin of patients with cutaneous vasculitis. Histologically, PD-L1 was highly expressed in the vessels in the skin along with CD4+ and CD8+ T-cell infiltration in patients with cutaneous vasculitis. Notably, plasma soluble PD-L1 levels were increased, and these correlated with C-reactive protein in patients with systemic vasculitis. Our findings suggest that inhibitory checkpoint molecules might be differentially modulated in the skin and peripheral blood of patients with vasculitis, and that the alteration of the PD-L1/PD-1 axis may be associated with the regulation of T-cell activation in vasculitis.

The number of cancer survivors with cardiovascular disease is increasing. However, the effect of cancer on body fluid regulation remains to be clarified. In this study, we evaluated body osmolyte and water imbalance in rats with hepatocellular carcinoma.Wistar rats were administered diethylnitrosamine, a carcinogenic drug, to establish liver cancer. We analyzed tissue osmolyte and water content, and their associations with aldosterone secretion.Hepatocellular carcinoma rats had significantly reduced body mass and the amount of total body sodium, potassium, and water. However, these rats had significantly increased relative tissue sodium, potassium, and water content per tissue dry weight. Furthermore, these changes in sodium and water balance in hepatocellular carcinoma rats were significantly associated with increased 24-h urinary aldosterone excretion. Supplementation with 0.25% salt in drinking water improved body weight reduction associated with sodium and water retention in hepatocellular carcinoma rats, which was suppressed by treatment with spironolactone, a mineralocorticoid receptor antagonist. Additionally, the urea-driven water conservation system was activated in hepatocellular carcinoma rats.These findings suggest that hepatocellular carcinoma induces body mass loss in parallel with activation of the water conservation system including aldosterone secretion and urea accumulation to retain osmolyte and water. The osmolyte and water retention at the tissue level may be a causative factor for ascites and edema formation in liver failure rats.

Structures of Coulomb crystals were analyzed in cylindrical discharge plasmas under gravity and microgravity by using an apparatus similar to the PK-4 on the International Space Station (ISS). Under gravity, layers of cylindrical dust clouds were found to locally form the lattices of the face-centered orthorhombic (FCO) structure, which is a deformation from the face-centered-cubic structure. We also observed that the average density increases with the size of dust clouds. Under microgravity, the structure could be regarded as an assembly of linear chains along the cylinder axes. At the same time, the interparticle distance and the plasma parameters measured by a double-probe method indicated that the structure was formed not only from the wake potential but also from mutual interactions between dust particles in neighboring chains.

Cell-free and concentrated ascites reinfusion therapy (CART) by internal filtration pressure method (internal method) and external filtration pressure method (external method) using the same cancerous ascites was performed. The rate of rise in circuit pressure and recovered components were compared between the two methods. The factors related to circuit pressure rise were also researched. In both methods, circuit pressure rose in 50% of cases. The recovery rates of IgG, IgA, IgM, and haptoglobin were significantly higher for the internal method than for the external method, whereas the recovery rate of α1 -antitrypsin was significantly lower in the internal method than in the external method. The levels of IL-6, haptoglobin, α1 -antitrypsin, and fibrinogen/fibrindegradation products (FDP) in the original ascites were significantly higher in the group wherein circuit pressure rose than in that without circuit pressure rise. These proteins might be related to the rise in circuit pressure.

GalNAc-type O-glycans are often added to proteins post-translationally in a clustered manner in repeat regions of proteins, such as mucins and IgA1. Observed IgA1 glycosylation patterns show that glycans occur at similar sites with similar structures. It is not clear how the sites and number of glycans added to IgA1, or other proteins, can follow a conservative process. GalNAc-transferases initiate GalNAc-type glycosylation. In IgA nephropathy, an autoimmune disease, the sites and O-glycan structures of IgA1 hinge-region are altered, giving rise to a glycan autoantigen. To better understand how GalNAc-transferases determine sites and densities of clustered O-glycans, we used IgA1 hinge-region (HR) segment as a probe. Using LC-MS, we demonstrated a semi-ordered process of glycosylation by GalNAc-T2 towards the IgA1 HR. The catalytic domain was responsible for selection of four initial sites based on amino-acid sequence recognition. Both catalytic and lectin domains were involved in multiple second site-selections, each dependent on initial site-selection. Our data demonstrated that multiple start-sites and follow-up pathways were key to increasing the number of glycans added. The lectin domain predominately enhanced IgA1 HR glycan density by increasing synthesis pathway exploration by GalNAc-T2. Our data indicated a link between site-specific glycan addition and clustered glycan density that defines a mechanism of how conserved clustered O-glycosylation patterns and glycoform populations of IgA1 can be controlled by GalNAc-T2. Together, these findings characterized a correlation between glycosylation pathway diversity and glycosylation density, revealing mechanisms by which a single GalNAc-T isozyme can limit and define glycan heterogeneity in a disease-relevant context.

The glomerulus primarily comprises mesangial cells, glomerular microvascular endothelial cells, and podocytes. IgA nephropathy is the most common primary glomerulonephritis worldwide and has a risk of progression to end-stage renal disease. IgA nephropathy is characterized by predominant IgA deposition in the glomerular mesangial area, where TG2 is significantly enhanced. Therefore, identification of glomerular TG2 substrates is the first step in elucidating the role of TG2 as a crosslinking enzyme during disease progression. To clarify potential glomerular TG2 substrates, and to establish a procedure for substrate identification, we attempted to identify those molecules using normal mouse glomeruli. Extracts from mouse glomerular and non-glomerular fractions were treated with our established biotin-labeled substrate peptide, which specifically crosslinks to the lysine-donor substrates depending on TG2 activity. Peptide-incorporated proteins were then purified using avidin resin and identified via mass spectrometry. In parallel, we performed the identification using corresponding samples from TG2 knockout mice. Consequently, potential TG2 substrates were separately identified in glomerular and non-glomerular fractions. They were mainly identified as novel TG2 substrates and partly include the well-known substrates. These results potentially provide novel insights into the mechanism underlying IgA nephropathy and may help elucidate the physiological functions of TG2.

It has been reported that C7 and C8 nerve root impairment can cause drop finger; however, the clinical characteristics of each injured nerve root and post-operative outcomes remain unclear. This study aimed to investigate the detailed features and surgery-related prognostic factors of drop finger caused by cervical radiculopathy. We retrospectively investigated the clinical characteristics, paralysis patterns and surgery-related prognostic factors of 23 patients with drop finger caused by cervical radiculopathy who underwent posterior cervical foraminotomy. We classified paralysis into three patterns based on the fingers predominantly exhibiting extensor digitorum communis (EDC) muscle weakness: index finger side-dominant, middle and ring fingers-dominant and little finger side-dominant. The aetiologies were cervical disc hernia (CDH) in ten patients, cervical spondylotic radiculopathy (CSR) in eight and both CDH and CSR in five. The levels of the decompressed root were C7 in one patient, C8 in 11 and both C7 and C8 in 11. Scapular pain was frequently observed as the initial symptom (78%), especially in patients with only C8 nerve root disorder (91%). Drop finger recovered to a score of ≥ 3 on manual muscle testing in 17 patients; patients with the little finger side-dominant pattern tended to have poor recoveries. Patients with CDH improved significantly than those with CSR or both CDH and CSR (p

IntroductionDegenerative aortic valve stenosis (AS) is a chronic progressive disease that resembles atherosclerosis development. Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is reportedly associated with accelerated atherosclerosis. This study aimed to examine the development of AS in patients with myeloperoxidase-AAV (MPO-AAV) with renal involvement at more than 1 year after the onset of vasculitis.MethodsWe performed a retrospective review of clinical records of MPO-AAV patients with renal involvement without AS at the onset of vasculitis who were treated in three hospitals and three dialysis clinics.ResultsThe study included 97 MPO-AAV patients with renal involvement and 230 control patients with chronic kidney disease (CKD). Among them, 64 patients had AS. The prevalence rates of AS were 28.9% and 15.7% in MPO-AAV and control patients, respectively (p = 0.006). The multivariable logistic regression analysis showed that MPO-AAV, dialysis dependence, and hypertension were independently associated factors for AS. In MPO-AAV patients, systolic blood pressure was positively significantly associated with AS, whereas glucocorticoid dose of induction therapy was negatively significantly associated. The use of cyclophosphamide tended to be negatively associated with AS. The survival rate was significantly lower for patients with AS than for those without AS.ConclusionsThe AS prevalence rate was significantly higher in MPO-AAV patients at more than 1 year after the onset of vasculitis than in control CKD patients. Therefore, regular monitoring of echocardiography during MPO-AAV treatment is suggested.

Background The benefits of vitamin D receptor activators (VDRAs) for patients with chronic kidney disease are well recognized. However, the optimal criteria for patient selection, dosage forms, and duration providing the highest benefit and the least potential risk remain to be confirmed. Materials and methods The study population was derived from the Aichi Cohort Study of Prognosis in Patients Newly Initiated into Dialysis, a multicenter prospective cohort study of 1520 incident dialysis patients. According to the VDRA usage status in March 2015 (interim report), the 967 patients surviving after March 2015 were classified into three groups: without VDRA (NV, n = 177), oral VDRA (OV, n = 447), and intravenous VDRA (IV, n = 343). Mortality rates were compared using the log-rank test, and factors contributing to all-cause mortality were examined using both univariate and multivariate Cox proportional hazard regression analyses. Results There were 104 deaths (NV, n = 27; OV, n = 53; IV, n = 24) during the follow-up period (1360 days, median), and significant differences in cumulative survival rates were observed between the three groups (p = 0.010). Moreover, lower all-cause mortality was associated with IV versus NV (hazard ratio, 0.46 [95% confidence interval 0.24–0.89]; p = 0.020). Conclusion This study demonstrated the impact of the VDRA dosage form on the short-term survival of incident hemodialysis patients during the introduction period. Our results suggest that relatively early initiation of intravenous VDRA in patients beginning hemodialysis may have some clinical potential.

Mucin-type O-glycosylation occurs on many proteins that transit the Golgi apparatus. These glycans impact structure and function of many proteins and have important roles in cellular biosynthetic processes, signaling and differentiation. Although recent technological advances have enhanced our ability to profile glycosylation of glycoproteins, limitations in the understanding of the biosynthesis of these glycan structures remain. Some of these limitations stem from the difficulty to track the biosynthetic process of mucin-type O-glycosylation, especially when glycans occur in dense clusters in repeat regions of proteins, such as the mucins or immunoglobulin A1 (IgA1). Here, we describe a series of nano-liquid chromatography (LC)–mass spectrometry (MS) analyses that demonstrate the range of glycosyltransferase enzymatic activities involved in the biosynthesis of clustered O-glycans on IgA1. By utilizing nano-LC–MS relative quantitation of in vitro reaction products, our results provide unique insights into the biosynthesis of clustered IgA1 O-glycans. We have developed a workflow to determine glycoform-specific apparent rates of a human UDP-N-acetylgalactosamine:polypeptide N-acetylgalactosaminyltrasnfersase (GalNAc-T EC 2.4.1.41) and demonstrated how pre-existing glycans affect subsequent activity of glycosyltransferases, such as core 1 galactosyltransferase and α2,3- and α2,6-specific sialyltransferases, in successive additions in the biosynthesis of clustered O-glycans. In the context of IgA1, these results have potential to provide insight into the molecular mechanisms implicated in the pathogenesis of IgA nephropathy, an autoimmune renal disease involving aberrant IgA1 O-glycosylation. In a broader sense, these methods and workflows are applicable to the studies of the concerted and competing functions of other glycosyltransferases that initiate and extend mucin-type core 1 clustered O-glycosylation.

application/pdf, (Pro)renin receptor [(P)RR] has a role in various diseases, such as cardiovascular and renal disorders and cancer. Aberrant (P)RR expression is prevalent in pancreatic ductal adenocarcinoma (PDAC) which is the most common pancreatic cancer. Here we show whether aberrant expression of (P)RR directly leads to genomic instability in human pancreatic ductal epithelial (HPDE) cells. (P)RR-expressing HPDE cells show obvious cellular atypia. Whole genome sequencing reveals that aberrant (P)RR expression induces large numbers of point mutations and structural variations at the genome level. A (P)RR-expressing cell population exhibits tumour-forming ability, showing both atypical nuclei characterised by distinctive nuclear bodies and chromosomal abnormalities. (P)RR overexpression upregulates SWItch/Sucrose Non-Fermentable (SWI/SNF)-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 5 (SMARCA5) through a direct molecular interaction, which results in the failure of several genomic stability pathways. These data reveal that aberrant (P)RR expression contributes to the early carcinogenesis of PDAC.

Treatment of eosinophilic granulomatosis with polyangiitis (EGPA) remains a challenge because currently available therapies, corticosteroids and immunomodulators, do not always control symptoms and are often associated with significant morbidity and relapse. Mepolizumab has been demonstrated to be an effective add-on therapy with steroid-sparing effect in cases of relapsing or refractory EGPA. Intravenous immunoglobulin (IVIG) therapy is effective against mononeuritis multiplex or heart failure in patients with EGPA who do not respond to corticosteroid-cyclophosphamide treatment. We present two cases of EGPA in which earlier add-on administration of adjunct mepolizumab and IVIG led to significant improvement in EGPA symptoms and prevention of flare-up of the disease. We suggested that earlier add-on combination administration of IVIG and mepolizumab might be a useful adjunct treatment to induce clinical remission of EGPA and improve the rate of remission, decrease relapse rate, and allow for reduced glucocorticoid use without any serious adverse drug effects.

Background: Although 2018 revised ISN/RPS classification was proposed recently, until now, no reports have been made comparing the association of renal prognosis between 2018 revised ISN/RPS classification and 2003 ISN/RPS classification. The present study aimed to assess the usefulness, especially of activity and chronicity assessment, of the 2018 revised International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification for lupus nephritis (LN) in terms of renal prognosis compared to the classification in 2003.Methods: We retrospectively collected medical records of 170 LN patients from the database of renal biopsy in Fujita Health University from January 2003 to April 2019. Each renal biopsy specimen was reevaluated according to both the 2003 ISN/RPS classification and the 2018 revised ISN/RPS classification. Renal endpoint was defined as 30% decline of estimated glomerular filtration rate (eGFR). Results: A total 129 patients were class III/IV±V (class III, 44 patients; class IV, 35 patients; class III/IV+V, 50 patients). Mean age was 42 years, 88% were female, and median observation period was 50.5 months. Renal prognosis was significantly different among the classes, and significantly poor in the patients with higher modified National Institute of Health (mNIH) Chronicity index (C index, ≥4) by a log-rank test (p=0.05, p=0.02 respectively). By Cox proportional hazard models, only C index was significantly associated with renal outcome (Hazard Ratio; 1.32, 95% CI; 1.11-1.56, p≤0.01), while the classes, the 2003 activity and chronicity subdivision, and mNIH activity index had no significant association with renal outcome. Each component of C index was significantly associated with renal outcome in different models. Conclusion: This study demonstrates that the 2018 revised ISN/RPS classification was more useful in terms of association with renal prognosis compared to the 2003 ISN/RPS classification

WHAT IS KNOWN AND OBJECTIVE Hypertension (HTN) and chronic kidney disease (CKD) are recognized as silent killers because they are asymptomatic conditions that contribute to the burden of multiple comorbidities. The achievement of a blood pressure (BP) goal can dramatically reduce the risks of CKD. In this study, we aimed to assess the effectiveness of pharmacist intervention on BP control in patients with CKD and evaluate the usefulness of home-based BP telemonitoring. METHODS The terms "chronic kidney disease," "pharmacist," "BP" and "randomized controlled trial (RCT)" were used five databases to search for information regarding pharmacist intervention on BP control in patients with CKD. The inclusion criteria were as follows: (a) studies for adult patients with uncontrolled HTN and (b) studies with adequate data for meta-analysis. The primary outcome was an evaluation of achievement of BP goal in patients with CKD. The secondary outcome was usefulness of home-based BP telemonitoring by pharmacists in patients with CKD. RESULTS AND DISCUSSION Six RCTs were identified and included in the meta-analysis with a total of 2573 patients (mean age 66.0 years and 63.9% male). Pharmacist interventions resulted in significantly better BP control vs usual care (OR = 1.53, 95% CI = 1.15-2.04, P

Extracellular histones induce lethal thrombosis by promoting platelet aggregation, neutrophil migration, and cell injuries. Heparin, which has negative charges, can bind to extracellular histones; however, heparin strongly inhibits the activation of coagulation. Since chondroitin sulfate (CS) shows less effect on the coagulation system than heparin does, CS has the potential to become an effective drug for lethal thrombosis with high risk of bleeding. To elucidate the therapeutic mechanisms of CS in lethal thrombosis, we investigated the interaction between CS and extracellular histones. Mouse vascular endothelial cells were incubated with histones in the presence of heparin or CS, and the expression of caspase-3/7 was measured. The interactions between histones and heparin or CS were measured by surface plasmon resonance analysis. Vascular permeability, platelet counts, liver and renal functions, and coagulation times were evaluated in an in vivo assay. The apoptosis induced by histones was inhibited by treatment with heparin or CS. Heparin and CS showed strong binding to histones and inhibited vascular hyperpermeability. The platelet counts as well as liver and renal functions were not decreased by the treatment with heparin or CS. Moreover, CS showed less effect on the coagulation system than heparin did. These results suggested that CS can be a novel agent for lethal thrombosis with the risk for hemorrhage. Since vascular endothelial cell injuries occur at an early stage of lethal thrombosis, administration of CS might be a useful approach.

Aim Some observational studies of the general population showed that resting heart rate was associated with mortality. However, the relationship was unclear in dialysis patients. Methods The study was a multicenter prospective cohort analysis including 1,102 patients. Patients were classified into four groups based on resting heart rate just before starting the first dialysis session

In dusty plasmas, dust particles are levitated by balance of forces inward to the plasmas (typically corresponding to electrostatic force) and outward from the plasmas (ion drag force) as well as gravity. The balance of the forces tends to make a region free from dust particles, so-called void at the center of the plasmas. This paper made it clear in measurements of ion density and electron temperature with a double-probe method that the void was a region involving ionization. The dust particles were distributed in the other region diffusion dominant for electrons and ions. The void is shown to be reduced by restricting the region involving ionization.

Cold atmospheric pressure plasma (CAP) does not cause thermal damage or generate toxic residues; hence, it is projected as an alternative agent for sterilization in food and pharmaceutical industries. The fungicidal effects of CAP have not yet been investigated as extensively as its bactericidal effects. We herein examined the effects of CAP on yeast proteins using a new CAP system with an improved processing capacity. We demonstrated that protein ubiquitination and the formation of protein aggregates were induced in the cytoplasm of yeast cells by the CAP treatment. GFP-tagged Tsa1 and Ssa1, an H2O2-responsive molecular chaperone and constitutively expressed Hsp70, respectively, formed cytoplasmic foci in CAP-treated cells. Furthermore, Tsa1 was essential for the formation of Ssa1-GFP foci. These results indicate that the denaturation of yeast proteins was caused by CAP, at least partially, in a H2O2-dependent manner. Furthermore, misfolded protein levels in the endoplasmic reticulum (ER) and the oligomerization of Ire1, a key sensor of ER stress, were enhanced by the treatment with CAP, indicating that CAP causes ER stress in yeast cells as a specific phenomenon to eukaryotic cells. The pretreatment of yeast cells at 37 °C significantly alleviated cell death caused by CAP. Our results strongly suggest that the induction of protein denaturation is a primary mechanism of the fungicidal effects of CAP.

Mannosylation in the endoplasmic reticulum is a key process for synthesizing various glycans. Guanosine diphosphate mannose (GDP-Man) and dolichol phosphate-mannose serve as donor substrates for mannosylation in mammals and are used in N-glycosylation, O-mannosylation, C-mannosylation, and the synthesis of glycosylphosphatidylinositol-anchor (GPI-anchor). Here, we report for the first time that low-abundant uridine diphosphate-mannose (UDP-Man), which can serve as potential donor substrate, exists in mammals. Liquid chromatography-mass spectrometry (LC-MS) analyses showed that mouse brain, especially hypothalamus and neocortex, contains higher concentrations of UDP-Man compared to other organs. In cultured human cell lines, addition of mannose in media increased UDP-Man concentrations in a dose-dependent manner. These findings indicate that in mammals the minor nucleotide sugar UDP-Man regulates glycosylation, especially mannosylation in specific organs or conditions.

We demonstrated direct fabrication of a diffraction grating onto organic oligomer crystals by focused ion beam (FIB) lithography followed by argon/oxygen plasma etching. Surface analysis suggested that FIB irradiation broke the oligomer molecules near the crystal surface to form a carbonized layer resulting in emission quenching. The plasma etching removed the damaged layer near the crystal surface and successfully recovered the emission. This technique was applied to fabricate the diffraction grating onto organic oligomer crystals and provided diffracted peaks in their fluorescence spectra without significant emission quenching.

Background: Several human studies reported that the combined use of renin-angiotensin system blockers (RASBs) and vitamin D receptor activators (VDRAs) resulted in decreased urinary protein excretion. However, it is unknown whether this combination therapy influences the incidence of cardiovascular (CV) events in dialysis patients. Methods: The study was a multicenter nonrandomized prospective cohort analysis including 1,518 patients. Patients were classified into 4 groups based on medications prescribed before dialysis initiation: those who did not receive RASBs or oral VDRAs (N group), those receiving only RASBs, those receiving only VDRAs, and those receiving a combination of RASBs and VDRAs (RD group). CV events after dialysis initiation were compared using the log-rank test. Factors contributing to the incidence of CV events were examined using multivariate Cox proportional hazard regression analysis. Results: Significant differences were observed in the incidence of CV events and all-cause mortality between the 4 groups (p = 0.021 and p = 0.001, respectively). Cox proportional hazard analysis revealed that the incidence of CV events was significantly lower in the RD group than in the N group (hazard ratio [HR] = 0.65, 95% confidence interval [CI]: 0.50-0.86, p = 0.002). Multivariate analysis revealed that the incidence of CV events was significantly lower in the RD group than in the N group (HR = 0.66, 95% CI: 0.47-0.93, p = 0.016). Conclusion: Combination therapy with RASBs and VDRAs in patients before dialysis initiation was associated with a reduction in CV events during maintenance dialysis.

The reactions of O(3P) atoms with furan, 2-methylfuran (2-MF), and 2,5-dimethylfuran (2,5-DMF) were studied at elevated temperatures by using a shock tube technique coupled with atomic resonance absorption spectroscopy (ARAS). The rate coefficients (k) determined from the time profiles of O(3P) atoms were expressed by the relation of kO+2,5-DMF > kO+2-MF > kO+FURAN. The molecular orbital calculations with CBS-QB3 level were also performed and the possible product channels of these reactions were discussed.

Some studies have shown that the estimated glomerular filtration rate (eGFR) at the time of initiating dialysis was associated with mortality. However, the relationship between ratio of blood urea nitrogen to serum creatinine (BUN/Cr) and mortality is unknown. The study was a multicenter, prospective cohort analysis including 1520 patients. Patients were classified into four quartiles based on the BUN/Cr ratio at the dialysis initiation, with Q1 having the lowest ratio and Q4 the highest. All-cause mortality after initiating dialysis was compared using the log-rank test. All-cause mortality of Q1, Q2, and Q3 was compared with that of Q4 using multivariate Cox proportional hazard regression analysis. Moreover, we compared the renal parameters including BUN/Cr ratio, eGFR, and creatinine clearance for sensitivity and specificity using receiver operative characteristic (ROC) curve. Significant differences were observed in all-cause mortality among the four groups (p

The thermal decomposition reactions of 2,3,3,3- and trans-1,3,3,3-tetrafluoropropenes (TFPs) have been studied both experimentally and computationally to elucidate their kinetics and mechanism. The experiments were performed by observing the temporal profiles of HF produced in the decomposition of the tetrafluoropropenes behind shock waves at temperatures of 1540–1952 K (for 2,3,3,3-TFP) or 1525–1823 K (for trans-1,3,3,3-TFP) and pressure of 100–200 kPa in Ar bath. The reaction pathways responsible for the profiles were explored based on quantum chemical calculations. The decomposition of 2,3,3,3-TFP was predicted to proceed predominantly via direct 1,2-HF elimination to yield CHCCF3, while trans-1,3,3,3-TFP was found to decompose to HF and a variety of isomeric C3HF3 products including CHCCF3, CF2CCHF, CCHCF3, and CF2CHCF. The C3HF3 isomers can subsequently decompose to either CF2 + CHCF or CF2CC + HF products. Multichannel RRKM/master-equation calculations were performed for the identified decomposition...

Hiroyuki Onodera,1 Takeru Urayama,2 Kazue Hirota,3 Kazuhiro Maeda,3 Ritsuko Kubota-Koketsu,3,4 Kazuo Takahashi,5 Katsuro Hagiwara,6 Yoshinobu Okuno,3 Kazuyoshi Ikuta,3,4 Mikihiro Yunoki,2,4,6 1Medical Information Department, 2Research and Development Division, Japan Blood Products Organization, Tokyo, 3Research and Development Division, The Research Foundation for Microbial Diseases of Osaka University, Kagawa, 4Former Department of Virology, Research Institute for Microbial Diseases, Osaka University, 5Virology Division, Department of Infectious Diseases, Osaka Prefectural Institute of Public Health, Osaka, 6Pathogenic Risk Evaluation, Graduate School of Veterinary Medicine, Rakuno Gakuen University, Hokkaido, Japan Abstract: Influenza viruses A/H1N1, A/H3N2, and B are known seasonal viruses that undergo annual mutation. Intravenous immunoglobulin (IVIG) contains anti-seasonal influenza virus globulins. Although the virus-neutralizing (VN) titer is an indicator of protective antibodies, changes in this titer over extended time periods have yet to be examined. In this study, variations in hemagglutination inhibition (HI) and VN titers against seasonal influenza viruses in IVIG lots over extended time periods were examined. In addition, the importance of monitoring the reactivity of IVIG against seasonal influenza viruses with varying antigenicity was evaluated. A/H1N1, A/H3N2, and B influenza virus strains and IVIG lots manufactured from 1999 to 2014 were examined. The HI titer was measured by standard methods. The VN titer was measured using a micro-focus method. IVIG exhibited significant HI and VN titers against all investigated strains. Our results suggest that the donor population maintains both specific and cross-reactive antibodies against seasonal influenza viruses, except in cases of pandemic viruses, despite major antigen changes. The titers against seasonal influenza vaccine strains, including past strains, were stable over short time periods but increased slowly over time. Keywords: IVIG, influenza, seasonal, neutralization, vaccine

Background Usage of vitamin D receptor activator (VDRA) for chronic kidney disease (CKD) including patients on dialysis patients has been controversial yet. It is unknown when to begin or discontinue VDRA therapy, the type of VDRA to administer, and the method of delivery, intravenous or oral for survival in CKD patients. Therefore, we examined whether intravenous or oral VDRA early after dialysis initiation affected mortality in incident dialysis patients. Methods The study database was derived from the Aichi Cohort Study of Prognosis in Patients Newly Initiated into Dialysis (AICOPP), a multicenter, prospective, cohort analysis of 1,520 consecutive patients who began dialysis at the 17 AICOPP group centers between October 2011 and September 2013. We excluded the 262 patients who died by March 2015, 15 patients were lost to follow-up, 241 patients with unconfirmed information about use of VDRA in March 2015, and 35 patients who discontinued VDRA between dialysis initiation and March 2015. Finally, 967 patients participated in the present study. We classified the participating patients into three groups according to the usage of VDRA in March 2015: no use of VDRA (NV group), oral VDRA (OV group), and intravenous VDRA (IV group) and compared their all-cause mortality. Results There were 104 deaths during the follow-up period (NV group, 27 cases; OV group, 53 cases; IV group, 24 cases). Significant differences between the cumulative survival rates were observed for the three groups (p = 0.010). The IV group was associated with low all-cause mortality compared to the NV group (Hazard ratio = 0.46, 95% CI = 0.24−0.89, p = 0.020) by multivariate Cox proportional hazard analysis using the stepwise method. Conclusions Our study shows that early introduction of intravenous VDRA to patients on hemodialysis seems to be associated with better prognosis.Trial Registration The trial registration no. is UMIN 000007096, registered on January 18, 2012. 298words, Text: 2967 words

Aim Some reports claim that intravenous iron supplements reduce serum phosphate levels in patients with chronic kidney disease (CKD), including those on dialysis. However, whether divalent oral iron supplements influence serum phosphate levels in patients with CKD remains unclear; thus, this study aimed to address this topic. Materials and methods The study database was derived from the Aichi Cohort Study of Prognosis in Patients Newly Initiated into Dialysis (AICOPP), which is a multicenter, prospective, cohort study. Patients were classified into two groups: those who received iron orally (iron group, n = 255) from pre-dialysis to dialysis initiation and those who did not receive iron supplements (no-iron group, n = 1,261). Moreover, patients were classified into two groups (255 patients in each) by propensity score (PS) matching. We compared serum phosphate level at dialysis initiation and all-cause mortality. Multivariate regression analysis was used to extract factors contributing to serum phosphate level at dialysis initiation through a stepwise method. Results Serum phosphate levels at dialysis initiation were significantly lower in the iron group (all cohort, 6.0 ± 1.6 vs. 6.4 ± 1.9 mg/dL, p = 0.001; PS-matched cohort, 6.0 ± 1.6 vs. 6.5 ± 1.7 mg/dL, p = 0.001). Multivariate regression analysis revealed that oral iron supplementation was significantly correlated to serum phosphate level (p = 0.023). There were no significant differences in all-cause mortality after dialysis initiation. Conclusion This study showed that oral ferrous citrate or ferrous sulfate use during predialysis was associated with differences in serum phosphate level at dialysis initiation.