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Introduction: While genetic aberrations are becoming increasingly critical in disease classification, morphological abnormalities defined by a 10% threshold in each lineage continue to play a significant role as a diagnostic tool for myelodysplastic neoplasms (MDS). However, erythroid lineage dysplasia has been reported in some cases of aplastic anemia (AA), a phenomenon noted as common in the UK guidelines. Methods: We assessed the impact of erythroid dysplasia on the survival in AA patients enrolled in an ongoing prospective registry, central morphological review (blinded), and follow-up study of AA and MDS conducted by the Japanese National Research Group on Idiopathic Bone Marrow Failure Syndromes. Furthermore, we compared the prognosis of AA patients with erythroid dysplasia with that of patients diagnosed in the same study with MDS presenting with single-lineage erythroid dysplasia (“MDS-SLED”). According to this study's definition, the criteria for excluding MDS are stringent, considering both bone marrow cellularity and megakaryocyte counts. Therefore, AA is not diagnosed when a decrease is not observed in the megakaryocyte count. Results: The study included a total of 32 cases of AA with erythroid dysplasia, 56 cases of AA without dysplasia, and 47 cases of MDS-SLED. The overall survival or leukemia-free survival showed no significant difference between AA patients with and without erythroid dysplasia (both p=0.14). Nevertheless, distinct differences were seen between AA with erythroid dysplasia and those diagnosed with MDS-SLED (both p

Purpose: Patients with rheumatoid arthritis (RA) who have undergone primary total knee arthroplasty (TKA) have a different recovery process of walking ability compared with patients with osteoarthritis (OA). However, how this relates to pain and other physical functions is unknown. This study aimed to evaluate and compare physical function after TKA in patients with RA and knee OA. Methods: This study enrolled 146 patients (24 with RA and 122 with OA) who underwent primary TKA. Data on the following were collected pre- and post-TKA (3 weeks and 1 year): 10 Meter Walk Test (10MWT), Timed Up and Go (TUG) test, knee pain, physical activity, isometric knee extensor and flexor strength, passive knee extension and flexion angle, and one-leg standing time. Two-way repeated measures analysis of variance (ANOVA) with Bonferroni post hoc comparisons was performed to examine the influence of the different diseases on post-operative changes in physical function over time. Results: The RA group had a significantly more severe pre-operative pain score than the OA group (p ​

Purpose: Bone and vascular diseases are considered to share pathogenic mechanisms. Excess glucocorticoids, key regulators of cardiovascular and metabolic homeostasis, may promote both diseases simultaneously. We used endogenous Cushing's syndrome (CS) to investigate whether glucocorticoid excess underlies coexisting bone and vascular diseases. Methods: We included 194 patients with adrenal tumors (ATs): autonomous cortisol secretion (ACS, n = 97) and non-functional AT (n = 97). ACS was further classified into overt CS (n = 17) and subclinical CS (SCS, n = 80). Arterial stiffness was defined as a brachial-ankle pulse wave velocity (baPWV) ≥ 1800 cm/s. Results: Patients with ACS had higher coexistence rates of vertebral fracture and arterial stiffness (23 % vs. 2 %; p

In glioblastoma, differentiation between cerebral edema and tumor infiltration is an important clinical question. Amide proton transfer (APT) and cerebral blood flow (CBF) are useful for evaluating the tumor invasion. In this case series, arterial spin-labeling (ASL)-CBF and APT were compared to determine which method was superior for predicting tumor infiltration in glioblastomas. Twelve specimens from 4 glioblastoma patients with confirmed selective sampling were obtained. APT signal intensity (SI) showed a strong correlation with cell density (R = 0.905; P

Background: Surgical site infection (SSI) is common following cranioplasty after decompressive craniectomy (DC). The aim of this study was to assess the risk of SSI following cranioplasty in terms of the preservation method of autogenous bone graft (ABG), comparing preservation in 80% ethanol versus the standard method of subcutaneous ABG preservation. Material and methods: The patients who underwent cranioplasty using ABGs after DC between 2008 and 2019 were retrospectively reviewed. SSIs were compared between patients whose ABG was preserved in 80% ethanol (group A) and those whose ABG was preserved subcutaneously (group B) using inverse probability of treatment weighting (IPTW) based on propensity scores to balance measurable confounders including elderly age, sex, expanded polytetrafluoroethylene, stroke, interval to cranioplasty, and diabetes mellitus. Results: Total number of 127 patients consisted of 56 in group A and 71 in group B. SSI after cranioplasty occurred in five patients each in groups A and B (8.9% vs. 7%, p = 0.748). IPTW analysis demonstrated that preservation in 80% ethanol was associated with a lower risk of SSI (odds ratio: 0.239, 95％ confidence interval: 0.0615–0.927, p = 0.039). Conclusion: The simple and less-invasive method of preserving ABGs in 80% ethanol for cranioplasty after DC might be potentially safe from an SSI perspective.

Dissimilar material joining via friction stir spot welding (FSSW) has been implemented in some automobiles. However, the effectiveness of this method is easily affected by the surface condition of the lower plate. To solve this problem, a method that combines tool contact to the lower plate and material refilling via refill FSSW (RFSSW) was developed. This method was named scrubbing RFSSW (Sc-RFSSW). In Sc-RFSSW, the plunging depth of the shoulder is larger than that in conventional RFSSW. In this study, the relationship between the process parameters and maximum joint load of an Sc-RFSSW joint composed of an aluminum alloy and non-coated mild steel was determined using design of experiments (DoE). The results of DoE showed that the maximum joint load was improved by reduction of the tool plunging depth into the lower plate, such that it was only scrubbing the lower plate interface. In the optimized Sc-RFSSW joining condition, a nugget pull out was stably obtained in both TSS and CTS. In addition, it was demonstrated that, in joining an aluminum alloy and non-coated mild steel, Sc-RFSSW provides a higher maximum joint load than that of conventional FSSW. The unloading test results confirmed that the maximum joint load of Sc-RFSSW was within the welded area, which was equivalent to the tool outer diameter. Moreover, an extremely thin amorphous layer with a thickness of 4–6 nm was observed at the interface of the Sc-RFSSW joint.

Calcinosis is frequently observed in patients with systemic sclerosis (SSc). The fundamental treatment of calcinosis has not yet been established. During follow-up, calcinosis in the subcutaneous surface is often spontaneously extracted or remains confined by fibrous tissues. We previously identified a new symptom in SSc patients, multiple external root resorption (MERR), and these patients had calcifications in the nasal spine. Here, we report for the first time that calcinosis at the nasal spine in patients with MERR can be replaced by cancellous bone-like tissue. Patients 1 and 2 were a 62-year-old Japanese female and a 45-year-old Japanese female (respectively) with MERR who had been previously treated for SSc (Patient 1: limited type, positive for anti-centromere antibody; Patient 2: diffuse type, positive for anti-Scl70 and anti-SS-A antibodies). Patient 3 was a 57-year-old female with MERR who had been previously treated for SSc (diffuse type, positive anti-Scl-70 antibody) and underwent denosumab injection for osteoporosis. Cone-beam computed tomography (CBCT) and CT images in the calcifications at the nasal spine in Patient 1 and 2 were replaced with cancellous bone-like tissue, but not in Patient 3. Serum laboratory examination was performed to assess the systemic bone disease. All three patients had normal clinical data within the references, apart from slightly higher 1,25-dihydroxyvitamin D levels in Patient 1. SSc patients with calcinosis in the maxillofacial area need to be examined carefully for bone replacement using CBCT or CT.

Vapor-liquid equilibria (VLE) were measured for ethanol – heptane by a modified Rose-Williams equilibrium still combined with ebulliometer at three isotherms (363.15, 393.15 and 423.15 K) and an isobar (101.33 kPa). The azeotropes were observed in VLE, and the experimental data were correlated with the Peng-Robinson-Stryjek-Vera (PRSV) equation of state. The conventional mixing rule, with kij equal to zero calculates the azeotropic pressure close to the vapor pressure of ethanol. The Adachi-Sugie (AS) mixing rule provides 0.282% average absolute relative deviation (AARD) in temperature for isobaric VLE and 1.711% AARD for isothermal VLE. Eyring theory combined with the PRSV equation enabled an average of 2.810% AARD in correlation of literature liquid viscosity data, which is sufficient for considering biofuel injector. The method will be applied to flow analysis in general process design using mixtures because viscosity can be evaluated from equation of states.

Summary: The XPC protein complex plays a central role in DNA lesion recognition for global genome nucleotide excision repair (GG-NER). Lesion recognition can be accomplished in either a UV-DDB-dependent or -independent manner; however, it is unclear how these sub-pathways are regulated in chromatin. Here, we show that histone deacetylases 1 and 2 facilitate UV-DDB-independent recruitment of XPC to DNA damage by inducing histone deacetylation. XPC localizes to hypoacetylated chromatin domains in a DNA damage-independent manner, mediated by its structurally disordered middle (M) region. The M region interacts directly with the N-terminal tail of histone H3, an interaction compromised by H3 acetylation. Although the M region is dispensable for in vitro NER, it promotes DNA damage removal by GG-NER in vivo, particularly in the absence of UV-DDB. We propose that histone deacetylation around DNA damage facilitates the recruitment of XPC through the M region, contributing to efficient lesion recognition and initiation of GG-NER.

Summary: Polygenic risk scores (PRS) measure genetic disease susceptibility by combining risk effects across the genome. For coronary artery disease (CAD), type 2 diabetes (T2D), and breast and prostate cancer, we performed cross-ancestry evaluation of genome-wide PRSs in six biobanks in Europe, the United States, and Asia. We studied transferability of these highly polygenic, genome-wide PRSs across global ancestries, within European populations with different health-care systems, and local population substructures in a population isolate. All four PRSs had similar accuracy across European and Asian populations, with poorer transferability in the smaller group of individuals of African ancestry. The PRSs had highly similar effect sizes in different populations of European ancestry, and in early- and late-settlement regions with different recent population bottlenecks in Finland. Comparing genome-wide PRSs to PRSs containing a smaller number of variants, the highly polygenic, genome-wide PRSs generally displayed higher effect sizes and better transferability across global ancestries. Our findings indicate that in the populations investigated, the current genome-wide polygenic scores for common diseases have potential for clinical utility within different health-care settings for individuals of European ancestry, but that the utility in individuals of African ancestry is currently much lower.

Summary: The killer cell immunoglobulin-like receptor (KIR) recognizes human leukocyte antigen (HLA) class I molecules and modulates the function of natural killer cells. Despite its role in immunity, the complex genomic structure has limited a deep understanding of the KIR genomic landscape. Here we conduct deep sequencing of 16 KIR genes in 1,173 individuals. We devise a bioinformatics pipeline incorporating copy number estimation and insertion or deletion (indel) calling for high-resolution KIR genotyping. We define 118 alleles in 13 genes and demonstrate a linkage disequilibrium structure within and across KIR centromeric and telomeric regions. We construct a KIR imputation reference panel (nreference = 689, imputation accuracy = 99.7%), apply it to biobank genotype (ntotal = 169,907), and perform phenome-wide association studies of 85 traits. We observe a dearth of genome-wide significant associations, even in immune traits implicated previously to be associated with KIR (the smallest p = 1.5 × 10−4). Our pipeline presents a broadly applicable framework to evaluate innate immunity in large-scale datasets.

Dental caries, the world’s most prevalent infectious disease, is caused by the diffusion of hydroxyl ions into tooth structures. To prevent dental caries, the application of fluoride (F) and zinc (Zn) ions to teeth surfaces are potential effective measures. In this study, The ionic influence, especially the chemical bond of F and Zn, on the acid resistance of dentin were investigated by particle induced X-ray / gamma-ray emission, X-ray diffraction, X-ray photoelectron spectroscopy and X-ray absorption spectroscopy. The results showed Zn was distributed in the limited surface layer of dentin without altering its crystal structure. From the Zn K edge extended X-ray absorption fine structure, Zn incorporated into dentin was surrounded by oxygen and demonstrated four-fold coordination. The bond length and chemical state of Zn–O in Zn doped dentin suggested newly generated Zn–O covalent bond, which may improve acid resistance of dentin. This study showed that the atomic and molecular structures, such as the molecular distances and chemical state, influenced acid resistance of teeth, emphasizing the validity of chemical state analysis for understanding properties in biomaterials.

We report on the first measurement of exclusive single-photon muoproduction on the proton by COMPASS using 160GeV/c polarised μ+ and μ− beams of the CERN SPS impinging on a liquid hydrogen target. We determine the dependence of the average of the measured μ+ and μ− cross sections for deeply virtual Compton scattering on the squared four-momentum transfer t from the initial to the final proton. The slope B of the t-dependence is fitted with a single exponential function, which yields B=(4.3±0.6stat|sys−0.3+0.1)(GeV/c)−2. This result can be converted into a transverse extension of partons in the proton, 〈r⊥2〉=(0.58±0.04stat|sys−0.02+0.01±0.04model)fm. For this measurement, the average virtuality of the photon mediating the interaction is 〈Q2〉=1.8(GeV/c)2 and the average value of the Bjorken variable is 〈xBj〉=0.056. Keywords: Quantum chromodynamics, Deep inelastic scattering, Exclusive reactions, Deeply virtual Compton scattering, Generalized Parton Distributions, Proton size, COMPASS

The anti-CD19 chimeric antigen receptor (CAR) T cells showed excellent effect against acute lymphoblastic leukemia (ALL) in bone marrow (BM) in clinical trials. However, it remains to be elucidated whether the CD19 CAR T cell therapy is effective for ALL cells in central nervous system (CNS) because the patients with isolated or advanced CNS disease were excluded from clinical trials of systemic intravenous (i.v.) delivery of CAR T cells. Therefore, the preclinical evaluation for the efficacy of CAR T cell therapy against ALL cells in CNS is essential for clinical application. We evaluated the effect and adverse reaction of CD19 CAR T cells against ALL in CNS using a xenograft mouse model by i.v. or intra-cerebroventricular (i.c.v.) delivery of CAR T cells. Injection of piggyBac CD19 CAR T cells by i.v. had partial effects, whereas all CAR T i.c.v.-delivered mice had eliminated ALL in CNS. Although some CAR T i.c.v.-delivered mice showed transient changes of clinical symptoms during the first few days after treatment, none of CAR T i.c.v.-delivered mice displayed fatal adverse events. In this study, we demonstrated that direct delivery into CNS of CAR T cells is a possible therapeutic approach with the xenograft mouse model.

Rationale & Objective: Chronic kidney disease (CKD) in children is associated with cognitive dysfunction that affects school performance and quality of life. The relationship between CKD–mineral and bone disorder and cognitive function in children is unknown. Study Design: Observational study. Participants: 702 children enrolled in the Chronic Kidney Disease in Children (CKiD) Study. Predictors: Plasma fibroblast growth factor 23 (FGF-23), parathyroid hormone (PTH), calcium, phosphorus, 25 hydroxyvitamin D (25[OH]D), and 1,25 dihydroxyvitamin D (1,25[OH]2D). Outcomes: Neurocognitive tests of intelligence, academic achievement, and executive functions. Analytical Approach: Linear regression models to analyze the cross-sectional associations between log2FGF-23, 25(OH)D, 1,25(OH)2D, PTH, calcium, and phosphorus z scores and the cognitive test scores of interest after adjustment for demographics, blood pressure, proteinuria, and kidney function. Results: At baseline, median age was 12 (95% CI, 8.3, 15.2) years and estimated glomerular filtration rate was 54 (40.5, 67.8) mL/min/1.73 m2. In fully adjusted analyses, 25(OH)D, 1,25(OH)2D, PTH, calcium, and phosphorus z scores did not associate with cognitive test scores. In fully adjusted analyses, log2FGF-23 was associated with abnormal test scores for attention regulation (P

Thrombomodulin (TM) is an integral membrane protein expressed on the surface of vascular endothelial cells that suppresses blood coagulation. Recent studies have shown that TM exhibits anti-inflammatory effects by inhibiting leukocyte recruitment. However, the actual modes of action of TM in vivo remain unclear. Here, we describe the pharmacological effects of recombinant human soluble TM (TM alfa) on leukocyte dynamics in living mice using intravital imaging techniques. Under control conditions, neutrophils exhibited three distinct types of adhesion behavior in vessels: 1) “non-adhesion”, in which cells flowed without vessel adhesion; 2) “rolling adhesion”, in which cells transiently interacted with the endothelium; and 3) “tight binding”, in which cells bound strongly to the endothelial cells. Compared to control conditions, local lipopolysaccharide stimulation resulted in an increased frequency of rolling adhesion that was not homogeneously distributed on vessel walls but occurred at specific endothelial sites. Under inflammatory conditions, TM alfa, particularly the D1 domain which is a lectin-like region of TM, significantly decreased the frequency of rolling adhesion, but did not influence the number of tight bindings. This was the first study to demonstrate that TM alfa exerts anti-inflammatory effects by inhibiting rolling adhesion of neutrophils to vascular endothelial cells in living mice. Keywords: Thrombomodulin, Rolling adhesion, Leukocyte, Endothelial cell, Intravital imaging

Background: Obesity affects the pathogenesis of various chronic diseases, including asthma. Research on correlations between obesity/BMI and eosinophilic inflammation in asthma has yielded contradictory results, which could be partly ascribed to the absence of epidemiological data on the correlations. We aimed to elucidate the correlations between blood eosinophil count, its genetic backgrounds, and BMI in the general population. Methods: This community-based Nagahama study in Japan enrolled 9789 inhabitants. We conducted self-reporting questionnaires, lung function tests, and blood tests in the baseline and 5-year follow-up studies. A genome-wide association study (GWAS) was performed in 4650 subjects at the baseline and in 4206 of these at the follow-up to determine single-nucleotide polymorphisms for elevated blood eosinophil counts. We assessed the correlations between BMI and eosinophil counts using a multifaceted approach, including the cluster analysis. Results: Eosinophil counts positively correlated with BMI, observed upon the interchange of an explanatory variable, except for subjects with the highest quartile of eosinophils (≥200/μL), in whom BMI negatively correlated with eosinophil counts. GWAS and human leukocyte antigen (HLA) imputation identified rs4713354 variant (MDC1 on chromosome 6p21) for elevated eosinophil counts, independent of BMI and IgE. Rs4713354 was accumulated in a cluster characterized by elevated eosinophil counts (mean, 498 ± 178/μL) but normal BMI. Conclusions: Epidemiologically, there may be a positive association between blood eosinophil counts and BMI in general, but there was a negative correlation in the population with high eosinophil counts. Factors other than BMI, particularly genetic backgrounds, may contribute to elevated eosinophil counts in such populations. Keywords: BMI, Cluster analysis, Eosinophil, Epidemiological study, Genome-wide association study

Background & Aims: Organ-level research using an animal model lacking Il2rg, the gene responsible for X-linked severe combined immunodeficiency (X-SCID), is clinically unavailable and would be a powerful tool to gain deeper insights into the symptoms of patients with X-SCID. Methods: We used an X-SCID animal model, which was first established in our group by the deletion of Il2rg gene in pigs, to understand the clinical signs from multiple perspectives based on pathology, immunology, microbiology, and nutrition. We also treated the X-SCID pigs with bone marrow transplantation (BMT) for mimicking a current therapeutic treatment for patients with X-SCID and investigated the effect at the organ-level. Moreover, the results were confirmed using serum and fecal samples collected from patients with X-SCID. Results: We demonstrated that X-SCID pigs completely lacked Peyer’s patches (PPs) and IgA production in the small intestine, but possessed some dysfunctional intestinal T and B cells. Another novel discovery was that X-SCID pigs developed a heterogeneous intestinal microflora and possessed abnormal plasma metabolites, indicating that X-SCID could be an immune disorder that affects various in vivo functions. Importantly, the organogenesis of PPs in X-SCID pigs was not promoted by BMT. Although a few isolated lymphoid follicles developed in the small intestine of BMT-treated X-SCID pigs, there was no evidence that they contributed to IgA production and microflora formation. Consistently, most patients with X-SCID who received BMT possessed abnormal intestinal immune and microbial environments regardless of the presence of sufficient serum IgG. Conclusions: These results indicate that the current BMT therapies for patients with X-SCID may be insufficient to induce the organogenesis of intestinal lymphoid tissues that are associated with numerous functions in vivo.

Patients with granulomatosis with polyangiitis (GPA), formerly known as Wegener's granulomatosis, sometimes exhibit no clinical features. Here, we describe a case of antineutrophil cytoplasmic antibody (ANCA)-negative GPA presenting with only lung granuloma. A 55-year-old woman with a right upper lung mass underwent lobectomy for suspected lung cancer; however, only granuloma was detected, and the etiology was not identified. Serum ANCA results were negative. Four years postoperatively, another pulmonary nodule appeared in the left lung's apex. The kidneys and sinuses were not impaired, but re-examination of the resected specimen revealed necrotizing vasculitis and granulomas around the vessels. Thus, the patient was diagnosed with GPA localized to the lungs. Although this was a non-life-threatening disease, the patient was administered oral prednisolone (PSL) and intravenous cyclophosphamide (IVCY) to prevent fatal complications of GPA as she was non-elderly and had no comorbidities, leading to a decrease in the mass size. Detailed re-examination by expert pulmonary pathologists could aid in GPA diagnosis when clinical features are absent, as in our case. In patients with granulomas of unknown etiology, a careful multidisciplinary approach is pivotal in the diagnosis. If patients tolerate adverse effects, a PSL and IVCY combination may prevent fatal outcomes, even in patients with non-life-threatening disease.

Opportunistic infections are life-threatening conditions in immunocompromised patients including those with primary immunodeficiency. We describe a case of X-linked chronic granulomatous disease presenting with mesenteric abscess caused by a coinfection with Bacillus Calmette-Guérin (BCG) and Phialemonium sp. The patient received BCG vaccination at 5 months old. He developed left axillary BCG lymphadenitis at 17 months of age, and 3 months later mesenteric abscess occurred. Concomitant use of rifampicin and itraconazole at 17 months of age might have reduced serum itraconazole concentrations and led to superinfection with Phialemonium sp. in our patient, which was susceptible to itraconazole and voriconazole in vitro. The patient was successfully treated with a combination of isoniazid, rifampicin, streptomycin, ciprofloxacin, prednisolone, interferon-γ, and an increased dose of itraconazole, followed by hematopoietic stem cell transplantation. Our results suggest that clinician need to be aware of rifampicin drug interactions, and that precise detection and identification of pathogens are essential to appropriate treatment.

Case 1 describe a 73-year-old man with an abnormal opacity in the upper lobe of the right lung on chest computed tomography (CT), which was done during the postoperative follow-up for bile duct cancer. The chest CT scan showed a ground glass nodule (GGN) measuring 1.0 cm and another one measuring 0.6 cm of the right lung. Case 2 involved a 79-year-old woman with an abnormal opacity in the upper lobe of the right lung on a chest CT that was obtained after she fell down the stairs. The CT scan showed a solid mass measuring 3.0 cm in the right upper lung. Both the patients underwent bronchoscopy before surgery and showed bronchial branching abnormalities. The surgical procedures could be performed accurately since sufficient information had been acquired pre-operatively and they diagnosed lung cancer. Both the patients were able to undergo radical surgery for lung cancer and are currently doing well with no postoperative complications or recurrence of lung cancer.

Introduction: Triamcinolone acetonide (TA), a steroid, is often used clinically to prevent dysfunctions associated with fibrosis. The objective of this study was to examine whether TA can be suspended in a gelatin sheet for tissue engineering using a mouse skin wound model. Methods: TA was suspended in biodegradable gelatin and freeze-dried in a sheet form. The sheet was analyzed for homogeneity and controlled release of TA by high-performance liquid chromatography. We made two skin wounds on the dorsal side of mice. Gelatin sheets with TA (TA sheet) and without TA (control sheet) were attached to each skin wound. To determine the efficacy of the prepared TA sheet on the skin wounds, TA-sheet versus TA-injection experiments were conducted. Hematoxylin and eosin staining was performed to assess the grade of epithelialization and alpha smooth muscle actin (α-SMA) immunohistochemical staining was conducted to evaluate myofibroblast infiltration. Results: In the TA-release test in vitro, 7.7 ± 2.3% of TA was released from the sheet by 24 h. After replacing the initial phosphate-buffered saline (PBS) with collagenase PBS, the amount of released TA increased over time. The wound area/original skin wound area after 15 days with the TA sheet was significantly larger than that with the control sheet (26.9 ± 5.5% vs 10.7 ± 2.6%, p = 0.023). The α-SMA positive area/whole area with the TA sheet was significantly lower than that with the control sheet (4.65 ± 0.66% vs 7.24 ± 0.7%, p = 0.023). Furthermore, the α-SMA positive area/whole area with the TA sheet was significantly lower than that with TA injection (5.32 ± 0.45% vs 7.93 ± 0.75%, p = 0.013). Conclusions: We developed a TA sheet and confirmed both the homogeneity of the suspended TA and controlled-release of the TA in the presence of collagenase in vitro. The TA sheet caused less myofibroblast infiltration into the tissue than the control sheet or TA injection did. Keywords: Fibrosis, Triamcinolone acetonide, Drug delivery systems, Gelatin, Biodegradable

Type 1 regulatory T (Tr1) cells are CD4+ T cells that produce a large amount of IL-10, an anti-inflammatory cytokine. However, it has not been fully elucidated whether Tr1 cells suppress allergic asthma. In this study, the effects of adoptive transfer of in vitro-induced Tr1 cells on allergic asthma were evaluated. Splenocytes from ovalbumin (OVA)-sensitized BALB/c mice were cultured with OVA, IL-21, IL-27, and TGF-β. After culture, IL-10-producing CD4+ T cells were isolated by Dynabeads mouse CD4 and IL-10 secretion assay, and analyzed by flow cytometry. Purified Tr1 cells (IL-10+ CD4+ T cells) were intravenously injected into OVA-sensitized BALB/c mice. The recipient mice were intratracheally challenged with OVA. Airway hyperresponsiveness to methacholine was assessed by the forced oscillation technique, followed by bronchoalveolar lavage (BAL). Almost all of the induced IL-10-producing CD4+ T cells were negative for interferon-γ, IL-4, IL-17A, and forkhead box P3, suggesting that the cells were Tr1 cells. The adoptive transfer of Tr1 cells significantly suppressed the development of airway hyperresponsiveness, and increases in IL-5, eosinophils, and neutrophils in BAL fluid. In conclusion, we demonstrated that Tr1 cells suppressed allergic asthma in mice. Keywords: Asthma, Airway hyperresponsiveness, IL-10, Immunotherapy, T cell

We present a precise measurement of the proton longitudinal double-spin asymmetry A1p and the proton spin-dependent structure function g1p at photon virtualities 0.006(GeV/c)2

Currently approved therapies for age-related macular degeneration (AMD) are inhibitors against vascular endothelial growth factor (VEGF), which is a major contributor to the pathogenesis of neovascular AMD (nAMD). Intravitreal injections of anti-VEGF drugs have shown dramatic visual benefits for AMD patients. However, a significant portion of AMD patients exhibit an incomplete response to therapy and, over the extended management course, can lose vision, with the formation of submacular fibrosis as one risk factor. We investigated a novel target for AMD treatments, fibroblast growth factor 2 (FGF2), which has been implicated in the pathophysiology of both angiogenesis and fibrosis in a variety of tissue and organ systems. The anti-FGF2 aptamer, RBM-007, was examined for treatment of nAMD in animal models. In in vivo studies conducted in mice and rats, RBM-007 was able to inhibit FGF2-induced angiogenesis, laser-induced choroidal neovascularization (CNV), and CNV with fibrosis. Pharmacokinetic studies of RBM-007 in the rabbit vitreous revealed high and relatively long-lasting profiles that are superior to other approved anti-VEGF drugs. The anti-angiogenic and anti-scarring dual action of RBM-007 holds promise as an additive or alternative therapy to anti-VEGF treatments for nAMD. Keywords: FGF2, aptamer, AMD, VEGF inhibitors, angiogenesis, fibrosis

We report a case of a patient with type IIIB endoleak after thoracic endovascular aortic repair that remained undetected by computed tomography and was first diagnosed during open conversion surgery. The aneurysm enlarged gradually from 60 to 78 mm without type I and type II endoleaks during 3 to 6 years after thoracic endovascular aortic repair. Type IIIB endoleaks from nitinol stent suture lines were detected, and the endograft was then explanted and replaced by a vascular graft. Keywords: Type IIIB endoleak, Thoracic endovascular aneurysm repair, Endograft

Summary: For long QT syndrome (LQTS), recent progress in genome-sequencing technologies enabled the identification of rare genomic variants with diagnostic, prognostic, and therapeutic implications. However, pathogenic stratification of the identified variants remains challenging, especially in variants of uncertain significance. This study aimed to propose a phenotypic cell-based diagnostic assay for identifying LQTS to recognize pathogenic variants in a high-throughput manner suitable for screening. We investigated the response of LQT2-induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC-CMs) following IKr blockade using a multi-electrode array, finding that the response to IKr blockade was significantly smaller than in Control-iPSC-CMs. Furthermore, we found that LQT1-iPSC-CMs and LQT3-iPSC-CMs could be distinguished from Control-iPSC-CMs by IKs blockade and INa blockade, respectively. This strategy might be helpful in compensating for the shortcomings of genetic testing of LQTS patients. : The methods presented by the authors allowed recognition of long QT syndrome (LQTS) subtypes 1, 2, and 3 using specific ion-channel current blockade with a combination of patient-derived iPSCs and a multi-electrode array system. This strategy might potentially compensate for the shortcomings of genetic testing for LQTS, especially in patients who have variants of unknown significance or no identified mutations. Keywords: long QT syndrome, induced pluripotent stem cell, phenotype-based diagnosis, multi-electrode array, genome editing

Introduction: The purpose of this study was to evaluate whether cryopreserved (frozen) adipose-derived regenerative cells (ADRCs) have a therapeutic effect on burn wound healing as well as freshly isolated (fresh) ADRCs. Methods: Full thickness burns were created on dorsum of nude mice and burn wound was excised. The wound was covered by artificial dermis with; (i) fresh ADRCs, (ii) frozen ADRCs, and (iii) PBS (control). The assessment for wound healing was performed by morphological, histopathological and immunohistochemical analyses. Results: In vivo analyses exhibited the significant therapeutic effect of frozen ADRCs on burn wound healing up to the similar or higher level of fresh ADRCs. There were significant differences of wound closure, epithelized tissue thickness, and neovascularization between the treatment groups and control group. Although there was no significant difference of therapeutic efficacy between fresh ADRC group and frozen ADRC group, frozen ADRCs improved burn wound healing process in dermal regeneration with increased great type I collagen synthesis compared with fresh ADRCs. Conclusions: These findings indicate that frozen ADRCs allow us to apply not only quickly but also for multiple times, and the cryopreserved ADRCs could therefore be useful for the treatment of burn wounds in clinical settings. Keywords: Burn, Stem cells, Wound healing

We tested whether NNC 55-0396 (NNC), a T-type calcium channel (T-channel) blocker, reduces the brain injury caused by middle cerebral artery occlusion and reperfusion (MCAO/R) in mice. NNC, administered i.c.v. before the occlusion, greatly reduced the MCAO/R-induced brain infarct and neurological dysfunctions, although it, given toward the end of occlusion, was less effective. Systemic administration of NNC before the occlusion also attenuated the infarct and neurological dysfunctions. Our data imply that blood-brain-barrier-permeable T-channel blockers such as NNC are capable of reducing MCAO/R-induced brain damage, and that T-channels are involved in neuronal damage induced by ischemia rather than reperfusion. Keywords: T-type calcium channel, Middle cerebral artery occlusion, Ischemia-reperfusion

Background: To investigate the potential roles of periostin (POSTN), an extracellular matrix preferentially expressed in Th2-skewed conditions in the pathophysiology of allergic conjunctivitis. Methods: The roles of POSTN in ragweed-induced experimental allergic conjunctivitis (RW-EAC) were evaluated using both POSTN-knockout (KO) and congenic BALB/c wild-type mice. Histological analysis was carried out to enumerate eosinophils/basophils in the conjunctival tissue. Th2 cytokine expression was evaluated by quantitative polymerase chain reaction (Q-PCR), and microarray analysis was performed to elucidate genes differentially expressed in POSTN-KO and wild-type mice in the RW-EAC model. Results: Upregulation of POSTN expression and eosinophil infiltration was observed in subconjunctival tissue of RW-EAC in the wild-type mice. The number of infiltrating eosinophils in the conjunctivae of RW-EAC was diminished in POSTN-KO mice compared to wild-type mice. Q-PCR analysis of conjunctival tissue showed induction of Th2 cytokine (Ccl5, Il4, Il5, Il13) expression in the RW-EAC and attenuated Ccl5, Il4, Il13 mRNA expression in the conjunctivae of the RW-EAC using POSTN-KO mice. Microarray analysis and immunohistochemical analysis showed diminished basophil marker (Mcpt8) expression and reduced numbers of infiltrating basophils in the conjunctivae of RW-EAC in POSTN-KO mice. Conclusions: POSTN expression in conjunctival tissue plays an indispensable role in the late-phase reaction of the RW-EAC model by facilitating eosinophil/basophil infiltration and augmenting Th2 cytokine expression. Keywords: Allergic conjunctivitis, Basophils, Eosinophils, Extracellular matrix, Mouse

Background: Graft-versus host disease (GVHD) is a complication of stem cell transplantation associated with significant morbidity and mortality. Non-specific immune-suppression, the mainstay of treatment, may result in immune-surveillance dysfunction and disease recurrence. Methods: We created humanised mice model for chronic GVHD (cGVHD) by injecting cord blood (CB)-derived human CD34+CD38−CD45RA− haematopoietic stem/progenitor cells (HSPCs) into hIL-6 transgenic NOD/SCID/Il2rgKO (NSG) newborns, and compared GVHD progression with NSG newborns receiving CB CD34− cells mimicking acute GVHD. We characterised human immune cell subsets, target organ infiltration, T-cell repertoire (TCR) and transcriptome in the humanised mice. Findings: In cGVHD humanised mice, we found activation of T cells in the spleen, lung, liver, and skin, activation of macrophages in lung and liver, and loss of appendages in skin, obstruction of bronchioles in lung and portal fibrosis in liver recapitulating cGVHD. Acute GVHD humanised mice showed activation of T cells with skewed TCR repertoire without significant macrophage activation. Interpretation: Using humanised mouse models, we demonstrated distinct immune mechanisms contributing acute and chronic GVHD. In cGVHD model, co-activation of human HSPC-derived macrophages and T cells educated in the recipient thymus contributed to delayed onset, multi-organ disease. In acute GVHD model, mature human T cells contained in the graft resulted in rapid disease progression. These humanised mouse models may facilitate future development of new molecular medicine targeting GVHD. Keywords: Acute GVHD, Chronic GVHD, IL-6, Humanised mouse

The transverse spin asymmetries measured in semi-inclusive leptoproduction of hadrons, when weighted with the hadron transverse momentum PT, allow for the extraction of important transverse-momentum-dependent distribution functions. In particular, the weighted Sivers asymmetries provide direct information on the Sivers function, which is a leading-twist distribution that arises from a correlation between the transverse momentum of an unpolarised quark in a transversely polarised nucleon and the spin of the nucleon. Using the high-statistics data collected by the COMPASS Collaboration in 2010 with a transversely polarised proton target, we have evaluated two types of PT-weighted Sivers asymmetries, which are both proportional to the product of the first transverse moment of the Sivers function and of the fragmentation function. The results are compared to the standard unweighted Sivers asymmetries and used to extract the first transverse moments of the Sivers distributions for u and d quarks.

We present a 76-year-old Japanese male who had a history of removal of a gastric gastrointestinal stromal tumor (GIST) 6 years ago. Although asymptomatic and having no evidence of recurrence, follow-up endoscopy revealed a small, white depressed lesion of approximately 1 cm with converging mucosal folds in the greater curvature of the fundus, which was suspicious of depressed-type early gastric cancer (GC) by conventional endoscopy. However, no evidence of GC except a “white globe appearance”-like area was identified by magnifying endoscopy with blue laser imaging. The biopsy specimens showed a proliferation of anaplastic lymphoma kinase (ALK)-positive spindle cells in the gastric mucosa, and ALK-rearrangement was detected by fluorescent in situ hybridization. Furthermore, clathrin heavy chain (CLTC)-ALK fusion was seen by genetic analysis, thus the lesion was preoperatively diagnosed as gastric inflammatory myofibroblastic tumor (IMT). For the curative intent, a laparoscopic endoscopic cooperative surgery (LECS) was performed. On the specimens resected by LECS, ALK-positive cells were sporadically distributed in the gastric mucosa and submucosa in the depressed area. In addition, two sporadic GISTs originating from the muscularis propria were found under the gastric IMT. Although there have been many reported cases of gastric IMTs, almost all those cases showed huge elevated tumors. Thus, this lesion is an extremely rare IMT case presenting a superficial depressed-type appearance, like 0-IIc type early GC. Keywords: Stomach, Superficial depressed-type, IMT, CLTC-ALK fusion