Efficacy and safety of dupilumab in Japanese adults with moderate-to-severe atopic dermatitis: a subanalysis of three clinical trials.

BACKGROUND: Dupilumab, a human monoclonal antibody, blocks the shared receptor unit for interleukin-4 and interleukin-13. International phase II and III studies have evaluated the efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis (AD), but the effects of dupilumab in Japanese patients have not been reported. OBJECTIVES: To evaluate the efficacy and safety of dupilumab in Japanese patients with moderate-to-severe AD. METHODS: We analysed the efficacy and safety of dupilumab in the Japanese cohorts of a 16-week, phase IIb dose-finding trial (AD-1021; NCT01859988); a 16-week, phase III, placebo-controlled monotherapy trial (LIBERTY AD SOLO 1; NCT02277743) and a 52-week, phase III, placebo-controlled study of dupilumab with topical corticosteroids (LIBERTY AD CHRONOS; NCT02260986). RESULTS: Twenty-seven, 106 and 117 Japanese patients were enrolled in AD-1021, SOLO 1 and CHRONOS, respectively. Baseline disease severity was numerically higher in the Japanese cohort than in the overall study population. Generally, dupilumab significantly improved signs and symptoms of AD, including pruritus and patient quality of life, compared with placebo in the Japanese cohort, consistent with the overall study population. The combined safety profile of dupilumab in the Japanese cohort was similar to that in the total study populations; dupilumab was associated with an increased incidence of injection-site reactions and conjunctivitis compared with placebo. Dupilumab was associated with rapid reduction in thymus and activation-regulated chemokine and gradual IgE reductions. CONCLUSIONS: Dupilumab alone or with topical corticosteroids improved signs and symptoms of AD, had an acceptable safety profile, and suppressed biomarkers of type 2 inflammation compared with placebo in Japanese adult patients with moderate-to-severe AD. What's already known about this topic? Differences in atopic dermatitis (AD) pathology have been reported between Asian and Western populations, in which distinct helper T-cell activation profiles have been observed. International clinical studies in adults with moderate-to-severe AD have evaluated the efficacy and safety of dupilumab, which blocks interleukin-4 and interleukin-13, key molecules in type 2 inflammation. The effects of dupilumab in Japanese patients specifically have not yet been reported. What does this study add? Dupilumab alone or with topical corticosteroids improved signs and symptoms of AD and had an acceptable safety profile compared with placebo in Japanese patients with moderate-to-severe AD. The effects were comparable with those observed in the overall study population. Reported immunological differences in AD pathology in Asian patients may be secondary to type 2 immune activation.

Effect of Donor Age on Graft Function and Pathologic Findings in Living Donor Transplantation.

BACKGROUND: The frequency of renal transplants from elderly living donors has increased because of a shortage of donors. However, the results of renal transplantation using aged kidney grafts have yet to be determined conclusively. METHODS: We evaluated 45 patients who underwent living donor kidney transplantation at our institution. The patients were categorized according to donor age at the time of the transplant: ≥ 60 years (elderly donor group, n = 21) and <60 years (young donor group, n = 24). We reviewed the renal function of the recipients and pathologic findings of the graft including interstitial fibrosis score, tubular atrophy score, tubular atrophy and interstitial fibrosis grades, and arteriosclerosis up to 2 years posttransplantation. RESULTS: Significant differences were observed in the preoperative creatinine clearance of the donor, prevalence of hypertension in the donor, and age of the recipient. Serum creatinine levels in the elderly donor group were significantly higher from 2 months to 1 year posttransplantation, and the estimated glomerular filtration rate was significantly lower from 7 days to 1 year posttransplantation. However, the decline in estimated glomerular filtration rate from 14 days to up to 2 years posttransplantation was similar in the 2 groups. There was no significant difference in the renal biopsy findings between the 2 groups except for arteriosclerosis 1 year posttransplantation. CONCLUSION: Kidney grafts from elderly living donors were not associated with a deterioration in renal function, and their pathologic findings were comparable with those of young donors for up to 2 years posttransplantation.

miR-9-3p plays a tumour-suppressor role by targeting TAZ (WWTR1) in hepatocellular carcinoma cells.

BACKGROUND: The inactivation of the Hippo pathway lead to TAZ (PDZ-binding motif)/YAP (yes-associated protein) overexpression, and is associated with worse prognostic outcomes in various cancers including hepatocellular carcinoma (HCC). Although there are several reports of microRNA (miR) targeting for YAP, miR targeting for TAZ remains unclear. The aim of this study is to identify the miR targeting TAZ expression in HCC. METHODS: MicroRNA expression was analysed using the Human miFinder 384HC miScript miR PCR array, and was compared between low and high TAZ expression cell lines. Then, we extracted miR-9-3p as a tumour-suppressor miR targeting TAZ. We examined the functional role of miR-9-3p using miR-9-3p mimic and inhibitor in HCC cell lines). RESULTS: In HCC cell lines and HCC clinical samples, there was the inverse correlation between miR-9-3p and TAZ expressions. TAZ expression was induced by treatment of miR-9-3p inhibitor and was downregulated by treatment of miR-9-3p mimic. Treatment of miR-9-3p mimic inhibited cell proliferative ability with downregulated phosphorylations of Erk1/2, AKT, and ß-catenin in HLF. Inversely, treatment of miR-9-3p inhibitor accelerated cell growth compared with control in HuH1. CONCLUSIONS: MicroRNA-9-3p was identified as the tumour-suppressor miR targetting TAZ expression in HCC cells.

Accuracy of spinal curvature assessed by a computer-assisted device and anthropometric indicators in discriminating vertebral fractures among individuals with back pain.

UNLABELLED: This study examined the accuracy of thoracic and lumbar kyphotic angles as well as anthropometric indicators for discriminating patients with vertebral fracture among Japanese women >50 years old with back pain. Along with region-specific kyphotic angles and anthropometric indicators, the combination of thoracic and lumbar kyphotic angles offered the highest accuracy. INTRODUCTION: Vertebral fractures have been associated with thoracic kyphosis. However, reports on lumbar kyphotic changes in association with vertebral fracture are scarce. This study investigated the accuracy of thoracic kyphotic angle (TKA) and lumbar kyphotic angle (LKA) measurements as well as anthropometric indicators (wall-occiput distance (WOD) and rib-pelvis distance (RPD)) in discriminating patients with vertebral fracture. METHODS: Lateral radiographs of the spine were obtained in 70 postmenopausal Japanese women who visited an orthopedic clinic with low back pain (mean age, 76.2 ± 9.0 years). Radiographic vertebral fracture was diagnosed using quantitative measurement according to Japanese criteria. Osteoarthritis (OA) was defined as Kellgren-Lawrence (KL) grade 3 or higher. TKA and LKA were measured using SpinalMouse®. WOD and RPD were also measured. RESULTS: At least one vertebral fracture was present in 49 subjects (70 %). Women with vertebral fractures showed significant increases in LKA, TKA + LKA, and WOD and decreases in RPD. Logistic regression analysis showed significant association between TKA + LKA and vertebral fracture independent of the presence of OA. Receiver operating characteristic analysis revealed that TKA was useful for discriminating thoracic fractures (area under the curve (AUC), 0.730) and LKA was useful for lumbar fractures (AUC, 0.691). The combination of TKA + LKA offered the highest accuracy for detecting thoracic, lumbar, and any vertebral fractures, with AUCs of 0.779, 0.728, and 0.783, respectively. WOD and RPD showed low-to-moderate accuracies for thoracic, lumbar, and any vertebral fractures. CONCLUSIONS: Assessment of spinal kyphosis by SpinalMouse® as well as anthropometric indicators proved useful in discriminating subjects with vertebral fractures. These convenient and radiation-free methods could contribute to early diagnosis of vertebral fractures and subsequent appropriate treatment, thus preventing additional osteoporotic fractures.

Usefulness of monitoring cell-mediated immunity for predicting post-kidney transplantation viral infection.

BACKGROUND: Monitoring cell-mediated immunity (CMI) can be used to estimate the risk of viral infections in kidney transplant recipients. The Immuknow (IMK) assay measures CD4(+) T-cell adenosine triphosphate activity, assesses patient CMI status, and assists clinicians in determining the risk of viral infection. METHODS: We retrospectively analyzed 224 IMK values in 39 kidney transplant recipients at our institution from April 2012 to January 2013. We analyzed the relationship between IMK value and viral infection during the early and late post-transplantation periods. Multiple regression analyses were performed, to determine which factors impacted the results of the IMK assay. RESULTS: Eight patients developed viral infections, including BK virus, cytomegalovirus, herpes simplex, and shingles. Five infections occurred in the early post-transplantation period (<50 d) and 3 in the late period (>120 d). The IMK levels in patients who developed an infection in the early period were within normal limits; however, those in the late period were significantly lower than 200 ng/mL (421.0 ± 062.6 for early vs 153.7 ± 72.7 for late; P = .02). Our multiple regression analyses indicated that peripheral white blood cell and neutrophil counts affected IMK values (P = .03 and P = .02, respectively). CONCLUSIONS: The IMK assay is a useful test for identifying patients at risk for post-transplantation viral infections in the late transplant period.

Ubiquilin-1 immunoreactivity is concentrated on Hirano bodies and dystrophic neurites in Alzheimer's disease brains.

AIMS: Ubiquilin-1 acts as an adaptor protein that mediates the translocation of polyubiquitinated proteins to the proteasome for degradation. Although previous studies suggested a key role of ubiquilin-1 in the pathogenesis of Alzheimer's disease (AD), a direct relationship between ubiquilin-1 and Hirano bodies in AD brains remains unknown. METHODS: By immunohistochemistry, we studied ubiquilin-1 and ubiquilin-2 expression in the frontal cortex and the hippocampus of six AD and 13 control cases. RESULTS: Numerous Hirano bodies, accumulated in the hippocampal CA1 region of AD brains, expressed intense immunoreactivity for ubiquilin-1. They were much less frequently found in control brains. However, Hirano bodies did not express a panel of markers for proteasome, autophagosome or pathogenic proteins, such as ubiquilin-2, ubiquitin, p62, LC3, beclin-1, HDAC6, paired helical filament (PHF)-tau, protein-disulphide isomerase (PDI) and phosphorylated TDP-43, but some of them expressed C9orf72. Ubiquilin-1-immunoreactive deposits were classified into four distinct morphologies, such as rod-shaped structures characteristic of Hirano bodies, dystrophic neurites contacting senile plaques, fragmented structures accumulated in the lesions affected with severe neuronal loss, and thread-shaped structures located mainly in the molecular layer of the hippocampus. CONCLUSIONS: Ubiquilin-1 immunoreactivity is concentrated on Hirano bodies and dystrophic neurites in AD brains, suggesting that aberrant expression of ubiquilin-1 serves as one of pathological hallmarks of AD.

Accumulation of a repulsive axonal guidance molecule RGMa in amyloid plaques: a possible hallmark of regenerative failure in Alzheimer's disease brains.

AIMS: RGMa is a repulsive guidance molecule that induces the collapse of axonal growth cones by interacting with the receptor neogenin in the central nervous system during development. It remains unknown whether RGMa plays a role in the neurodegenerative process of Alzheimer's disease (AD). We hypothesize that RGMa, if it is concentrated on amyloid plaques, might contribute to a regenerative failure of degenerating axons in AD brains. METHODS: By immunohistochemistry, we studied RGMa and neogenin (NEO1) expression in the frontal cortex and the hippocampus of 6 AD and 12 control cases. The levels of RGMa expression were determined by qRT-PCR and Western blot in cultured human astrocytes following exposure to cytokines and amyloid beta (Aß) peptides. RESULTS: In AD brains, an intense RGMa immunoreactivity was identified on amyloid plaques and in the glial scar. In the control brains, the glial scar and vascular foot processes of astrocytes expressed RGMa immunoreactivity, while oligodendrocytes and microglia were negative for RGMa. In AD brains, a small subset of amyloid plaques expressed a weak NEO1 immunoreactivity, while some reactive astrocytes in both AD and control brains showed an intense NEO1 immunoreactivity. In human astrocytes, transforming growth factor beta-1 (TGFß1 ), Aß 1-40 or Aß 1-42 markedly elevated the levels of RGMa, and TGFß1 also increased its own levels. Coimmunoprecipitation analysis validated the molecular interaction between RGMa and the C-terminal fragment ß of amyloid beta precursor protein (APP). Furthermore, recombinant RGMa protein interacted with amyloid plaques in situ. CONCLUSIONS: RGMa, produced by TGFß-activated astrocytes and accumulated in amyloid plaques and the glial scar, could contribute to the regenerative failure of degenerating axons in AD brains.

Prophylactic and therapeutic efficacies of a selective inhibitor of the immunoproteasome for Hashimoto's thyroiditis, but not for Graves' hyperthyroidism, in mice.

Major histocompatibility complex (MHC) class I-restricted T cell epitopes are generated mainly by the immunoproteasome in antigen-presenting cells. Therefore, inhibition of activity of this proteolytic complex molecule is thought to be a potential treatment for cell-mediated autoimmune diseases. We therefore studied the efficacy of an immunoproteasome inhibitor, ONX 0914 (formerly PR-957), for the treatment of autoimmune thyroid diseases, including cell-mediated Hashimoto's thyroiditis and autoantibody-mediated Graves' hyperthyroidism using mouse models. Our data show that ONX 0914 was effective prophylactically and therapeutically at suppressing the degree of intrathyroidal lymphocyte infiltration and, to a lesser degree, the titres of anti-thyroglobulin autoantibodies in non-obese diabetic (NOD)-H2(h4) mice, an iodine-induced autoimmune thyroiditis model. It also inhibited differentiation of T cells to T helper type 1 (Th1) and Th17 cells, effector T cell subsets critical for development of thyroiditis in this mouse strain. In contrast, its effect on the Graves' model was negligible. Although ONX 0914 exerts its immune-suppressive effect through not only suppression of immune proteasome but also other mechanism(s), such as inhibition of T cell differentiation, the present results suggest that the immunoproteasome is a novel drug target in treatment of Hashimoto's thyroiditis in particular and cell-mediated autoimmune diseases in general.

Immunohistochemical characterization of γ-secretase activating protein expression in Alzheimer's disease brains.

AIMS: A recent study showed that γ-secretase activating protein (GSAP), derived from a C-terminal fragment of pigeon homolog (PION), increases amyloid-ß (Aß) production by interacting with presenilin-1 (PS1) and the ß-secretase-cleaved C-terminal fragment of amyloid precursor protein (APP-CTF). In the study, knockdown of GSAP reduces production of Aß and plaque formation in the brain of APPswe and PS1ΔE9 double transgenic mice without affecting the Notch-dependent pathway. Therefore, GSAP is an ideal target for designing γ-secretase modulators with least side effects in Alzheimer's disease (AD). However, at present, the precise distribution of GSAP in AD brains remains to be characterized. METHODS: By immunohistochemistry, we studied GSAP expression in the frontal cortex and the hippocampus of 11 aged AD and 17 age-matched control cases. RESULTS: GSAP immunoreactivity exhibited distinct morphological features, such as fine granular cytoplasmic deposits, dense nodular and patchy deposits, beads and string-like deposits, and diffuse dot-like deposits. In both AD and control brains, a fairly small subset of cerebral cortical and hippocampal neurones expressed fine granular cytoplasmic deposits, while diffuse dot-like deposits were more frequently found in the neuropil and neuronal processes, particularly enriched in the hippocampal CA2 and CA3 regions. Among GSAP-immunoreactive deposits, dense nodular and patchy deposits, located in the neuropil and closely associated with PS1 expression and Aß deposition, indicated the most distinguishing features of AD pathology. CONCLUSIONS: Aberrant regulation of GSAP expression plays a key role in acceleration of γ-cleavage of APP-CTF and accumulation of Aß in AD brains.

Contribution of anti-CCP antibodies, proximal interphalangeal joint involvement, HLA-DRB1 shared epitope, and PADI4 as risk factors for the development of rheumatoid arthritis in palindromic rheumatism.

OBJECTIVES: To determine which variables at baseline are predictive for the development of rheumatoid arthritis (RA) from palindromic rheumatism (PR) in a Japanese population. METHODS: Anti-cyclic citrullinated peptide (anti-CCP) antibodies, joint involvement pattern, genotypes of HLA-DRB1, peptidylarginine deiminase (PADI4), and protein tyrosine phosphatase (PTPN22) were examined in 28 patients with PR at baseline, and their clinical outcome was prospectively evaluated. The same variables were also investigated in 38 healthy controls. RESULTS: Eleven out of 28 patients with PR developed RA. The prevalence of anti-CCP antibodies in the PR patients who developed RA was significantly higher compared to the patients who did not. Proximal interphalangeal (PIP) joint involvement at baseline was also predictive towards the development of RA. Compared with the controls, differences in the frequency of single-nucleotide polymorphism (SNP) on padi4_104 [T(RA susceptible)-->C(RA non-susceptible)] and the presence of an RA susceptible homozygote of the PADI4 haplotype were detected in patients with PR whereas we could not find any further difference in PR patients who developed RA compared to PR patients who do not develop RA in PADI4. None of the subjects possessed the PTPN22 SNP (1858C-->T). Cox regression analysis revealed that anti-CCP antibodies as well as PIP involvement are the most relevant variables for the development of RA from PR. None of the PR patients with either HLA-DRB1*SE alleles (or the HLA-DRB1*0405 allele) or anti-CCP antibodies developed RA. CONCLUSIONS: Anti-CCP antibodies, in relation to HLA-DRB1*SE carriership, and PIP involvement are predictive for the development of RA from PR in the Japanese population.

Aberrant microRNA expression in the brains of neurodegenerative diseases: miR-29a decreased in Alzheimer disease brains targets neurone navigator 3.

AIMS: MicroRNAs (miRNAs) are small non-coding RNAs that regulate translational repression of target mRNAs. Accumulating evidence indicates that various miRNAs, expressed in a spatially and temporally controlled that manner in the brain plays a key role in neuronal development. However, at present, the pathological implication of aberrant miRNA expression in neurodegenerative events remains largely unknown. To identify miRNAs closely associated with neurodegeneration, we performed miRNA expression profiling of brain tissues of various neurodegenerative diseases. METHODS: We initially studied the frontal cortex derived from three amyotrophic lateral sclerosis patients by using a microarray of 723 human miRNAs. This was followed by enlargement of study population with quantitative RT-PCR analysis (n = 21). RESULTS: By microarray analysis, we identified up-regulation of miR-29a, miR-29b and miR-338-3p in amyotrophic lateral sclerosis brains, but due to a great interindividual variation, we could not validate these results by quantitative RT-PCR. However, we found significant down-regulation of miR-29a in Alzheimer disease (AD) brains. The database search on TargetScan, PicTar and miRBase Target identified neurone navigator 3 (NAV3), a regulator of axon guidance, as a principal target of miR-29a, and actually NAV3 mRNA levels were elevated in AD brains. MiR-29a-mediated down-regulation of NAV3 was verified by the luciferase reporter assay. By immunohistochemistry, NAV3 expression was most evidently enhanced in degenerating pyramidal neurones in the cerebral cortex of AD. CONCLUSIONS: These observations suggest the hypothesis that underexpression of miR-29a affects neurodegenerative processes by enhancing neuronal NAV3 expression in AD brains.

Effect of the brain-derived neurotrophic factor and the apolipoprotein E polymorphisms on disease progression in preclinical Alzheimer's disease.

Genetic factors, such as apolipoprotein E (ApoE) polymorphisms, are thought to play an important role in the etiology of Alzheimer's disease (AD). Recent association studies have suggested that the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene could play a role in the development of AD. To identify genotypic effects of the BDNF and the ApoE genes on disease progression in preclinical AD, we assessed morphological changes using serial magnetic resonance imaging during the preclinical period of AD in 35 individuals. When all subjects were analyzed as one group, progressive atrophy was noted in the limbic, paralimbic and neocortical areas. Individuals of the BDNF Val/Val genotype showed progressive atrophy in the left medial temporal areas, whereas the BDNF Met allele carriers showed additional changes in the anterior cingulate cortex (ACC), posterior cingulate cortex (PCC) and the precuneus. An interaction between the BDNF genotype and progressive morphological changes was found in the PCC. The noncarriers for the ApoE epsilon4 allele showed progressive atrophy in the bilateral medial temporal areas. In addition to changes in the medial temporal areas, epsilon4 carriers showed progressive atrophy in the PCC, ACC and precuneus. An interaction between the ApoE genotype and progressive morphological change was noted in the right medial temporal area. The present preliminary study indicates that polymorphisms of the ApoE and the BDNF genes could affect disease progression in preclinical AD and implies that the Met-BDNF polymorphism could be an additional risk factor for rapid disease progression in preclinical AD.

Recent progress in understanding the diversity of the human ov-serpin/clade B serpin family.

The inhibitory mechanism against proteases is important in the maintenance of homeostasis or health in the body. The human ovalbumin serpin (ov-serpin)/clade B serpin family is one group of the human serpins, a family of serine protease inhibitors. They have acquired diversity in the profiles of target proteases, inhibitory mechanisms, and localization patterns during their evolution. Most serpins target serine proteases, however, some ov-serpins target only cysteine proteases or both serine and cysteine proteases and furthermore, several ov-serpins do not possess inhibitory activities. Although the ov-serpins act primarily as intracellular serpins, some show extracellular and nuclear localizations. Such diversity enables the ov-serpins to play multiple physiological roles in the body. Recent analyses have revealed that the functions of human ov-serpins are more diversified than we previously knew. In this article, we describe recent progress in our understanding of how the human ov-serpin/clade B serpin family demonstrates diversity.