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This study introduces a compact, portable femtosecond fibre laser system designed for synchronization with SPring-8 synchrotron X-ray pulses in a uniform filling mode. Unlike traditional titanium–sapphire mode-locked lasers, which are fixed installations, our system utilizes fibre laser technology to provide a practical alternative for time-resolved spectroscopy, striking a balance between usability, portability and cost-efficiency. Comprehensive evaluations, including pulse characterization, timing jitter and frequency stability tests revealed a centre wavelength of 1600 nm, a pulse energy of 4.5 nJ, a pulse duration of 35 fs with a timing jitter of less than 9 ps, confirming the suitability of the system for time-resolved spectroscopic studies. This development enhances the feasibility of experiments that combine synchrotron X-rays and laser pulses, offering significant scientific contributions by enabling more flexible and diverse research applications.

Abstract Here we report the largest Asian genome-wide association study (GWAS) for systemic sclerosis performed to date, based on data from Japanese subjects and comprising of 1428 cases and 112,599 controls. The lead SNP is in the FCGR/FCRL region, which shows a penetrating association in the Asian population, while a complete linkage disequilibrium SNP, rs10917688, is found in a cis-regulatory element for IRF8. IRF8 is also a significant locus in European GWAS for systemic sclerosis, but rs10917688 only shows an association in the presence of the risk allele of IRF8 in the Japanese population. Further analysis shows that rs10917688 is marked with H3K4me1 in primary B cells. A meta-analysis with a European GWAS detects 30 additional significant loci. Polygenic risk scores constructed with the effect sizes of the meta-analysis suggest the potential portability of genetic associations beyond populations. Prioritizing the top 5% of SNPs of IRF8 binding sites in B cells improves the fitting of the polygenic risk scores, underscoring the roles of B cells and IRF8 in the development of systemic sclerosis. The results also suggest that systemic sclerosis shares a common genetic architecture across populations.

We investigated the effect of post-labeling delay (PLD) on the evaluation of brain tumor blood flow using arterial spin labeling (ASL) magnetic resonance (MR) imaging to assess the need for imaging with two PLDs. Retrospective analysis was conducted on 63 adult patients with brain tumors who underwent contrast-enhanced MR imaging including ASL imaging with PLDs of both 1525 and 2525 ms on a 1.5 T or 3 T MR unit. Blood flow was estimated in the tumors and normal-appearing brain parenchyma, and tumor blood flow was normalized by parenchymal flow. Estimates of tumor blood flow, parenchymal flow, and normalized tumor flow showed no statistically significant differences between PLDs of 1525 and 2525 ms. Close correlations between different PLDs were found, with the closest correlation for normalized tumor flow. These results were similarly observed for the 1.5 T and 3 T units. The blood flow estimates obtained using ASL MR imaging in patients with brain tumors were highly concordant between PLDs of 1525 and 2525 ms, irrespective of the magnetic field strength. It is indicated that imaging with a single, standard PLD is acceptable for ASL assessment of brain tumor perfusion and that additional imaging with a long PLD is not required.

Abstract Loss-of-function homozygous or compound heterozygous mutations in IL36RN, which encodes interleukin-36 receptor antagonist (IL-36Ra), have been implicated in the pathogenesis of skin disorders. We previously reported that Il36rn −/− mice exhibit an enhanced contact hypersensitivity (CHS) response through increased neutrophil recruitment. In addition, Il36rn −/− mice show severe imiquimod-induced psoriatic skin lesions and enhanced neutrophil extracellular trap (NET) formation. We hypothesized that NETs may play an important role in the CHS response. To confirm this, we examined the CHS response and NET formation in Il36rn −/− mice. Il36rn −/− mice showed enhanced CHS responses, increased infiltration of inflammatory cells, including neutrophils, CD4+ T cells, and CD8+ T cells, NET formation, and enhanced mRNA expression of cytokines and chemokines, including IL-1β, C-X-C motif chemokine ligand (CXCL)1, CXCL2, and IL-36γ. Furthermore, NET formation blockade improved the CHS response, which consequently decreased inflammatory cell infiltration and NET formation. Consistently, we observed decreased expression of these cytokines and chemokines. These findings indicate that IL-36Ra deficiency aggravates the CHS response caused by excessive inflammatory cell recruitment, NET formation, and cytokine and chemokine production, and that NET formation blockade alleviates the CHS response. Thus, NET formation may play a prominent role in the CHS response.

Abstract Background The indication for endoscopic resection for submucosally invasive colorectal cancer (T1-CRC) depends on the preoperative diagnosis of invasion depth. The aim of this investigation was to evaluate the association between barium enema examination (BE) profile views and depth of submucosal (SM) invasion in CRCs. Methods We reviewed the radiographic and endoscopic findings of 145 T1-CRCs diagnosed from 2008 to 2019. We measured the widths of horizontal and vertical rigidity under a BE profile view corresponding to CRC and compared the values with SM invasion depth. Horizontal rigidity was defined as the horizontal length and vertical rigidity as the vertical width of the barium defect corresponding to each target lesion. The most appropriate cut-off values for predicting SM invasion ≥1.8 mm were calculated by receiver operating characteristic curve analysis. Results Values of horizontal rigidity (r = 0.626, P

Introduction: Real-world evidence for the effectiveness and safety of golimumab (GLM) in patients with ulcerative colitis (UC) is limited. The aim of this study was to investigate the 52-week effectiveness and safety of GLM treatment for UC. Methods: This prospective, multicentre, post-marketing surveillance study is conducted in 393 patients with UC in Japan (UMIN000027542). Clinical remission (partial Mayo score ≤2), adverse drug reactions (ADRs) and their predictors, and treatment persistence were analysed. Results: The safety analysis sets comprised 391 patients. Patients in clinical remission at baseline were excluded, and 336 were used for effectiveness analysis. Clinical remission was 47.9%, 48.5%, 44.6%, and 39.6% at weeks 6, 22, 36, and 52, respectively, in the intent-to-treat analysis. In biologic-naïve patients, clinical remission was slightly higher than that in biologic-experienced patients. At week 52, patients who concomitantly used corticosteroids at baseline showed numerically lower clinical remission rates than non-users of corticosteroids (34.9% vs 44.5%). Multivariate analysis showed that smoking history (P=0.040, odds ratio [OR]=1.911, 95% confidence interval [CI] 1.030–3.546) was an independent factor associated with clinical remission at week 52. ADRs occurred in 71 patients (18.2%) and included 9 cases of rash. Serious ADRs occurred in 40 patients (10.2%), including 8 cases of UC exacerbation. Additionally, the presence of comorbidities was associated with ADR incidence (P=0.010, OR=2.000, 95% CI 1.183–3.380). Conclusion: The real-world effectiveness of GLM treatment was confirmed in biologic-naïve and -experienced populations. The safety profile of GLM treatment was consistent with previous findings.

BackgroundAlthough MicroRNAs (miRNAs) play important roles in various biological processes, the biological functions of miRNAs are achieved through mRNAs. The aim of this study is to identify dysregulated miRNA/mRNA expression patterns in colorectal tumors.MethodsWe examined 42 colorectal tumors [15 adenomas, 8 intramucosal cancers (IMCs), and 19 invasive colorectal cancers (CRCs)] with the microsatellite stable (MSS) phenotype (first cohort). The first cohort was used for genome-wide miRNA and mRNA expression arrays, whereas the second cohort (37 colorectal neoplasias) was used for validation analyses. Finally, we used 15 cases of “adenoma in/with carcinoma” to identify network patterns of miRNAs/mRNAs that were directly associated with neoplastic progression. In addition, simple regression analysis for array-based and RT-PCR analyses was performed to select candidate miRNA–mRNA pairs. Transfection of miRNA mimics was also performed to confirm whether target mRNA expression is affected by specific miRNAs.ResultsSpecific paired miRNA/mRNA networks, including hsa-miR-34a-5p/SLC12A2, hsa-miR-15b-5p/SLC12A2, hsa-miR-195-5p/SLC12A2, hsa-miRNA-502-3p/OLFM4, hsa-miRNA-6807-5p/ZG16, and hsa-miRNA 3064-5p/SH3BGRL3, were identified in samples of adenoma, IMC, and CRC with the MSS phenotype. In adenomatous lesions obtained from the same tumor with a carcinomatous lesion, we identified pairs of miRNA-130a-3p/HSPA8 and miRNA-22-3p/RP53 that were linked to multiple pathways. On the other hand, 2 pairs of miRNA/mRNA (miRNA-660-5p and miRNA-664a-5p/APP) were found in isolated carcinomatous glands. Ectopic expression of miRNA 3064-5p suppressed SH3BGRL3 expression.ConclusionsWe found that networks based on specific pairs of miRNAs/mRNAs contribute to progression from adenomatous and carcinomatous lesions. Our results provide insights into the molecular tumorigenesis of colorectal tumors.

Abstract Background Malignant phyllodes tumors (PTs) of the breast occur infrequently and are difficult to treat with adjuvant therapy. Here, we present a case of a female patient with a huge malignant PT with rapid progression in a short period. Case presentation A 44-year-old woman presented to our hospital with a rapid growth mass in her right breast, measuring 20 cm. She was initially diagnosed as having a borderline phyllodes tumor by core needle biopsy and underwent total mastectomy and artificial dermis was grafted, 20 days later, latissimus dorsi muscle flap and free skin grafting were performed. Two courses of doxorubicin–ifosfamide therapy were administered because of recurrence, but the patient died 4 months after the mastectomy. Conclusions A standard therapeutic strategy for malignant PTs is needed in urgently to reduce the risk of tumor recurrence.

Background: The INPULSIS trials revealed that nintedanib reduced the decline in lung function in patients with idiopathic pulmonary fibrosis. We aimed to evaluate the efficacy and safety of nintedanib in Japanese idiopathic pulmonary fibrosis patients in real-world settings. Method: Medical records of idiopathic pulmonary fibrosis patients, who received treatment with nintedanib in five institutions between July 2015 and June 2017, were reviewed. Patients with % forced vital capacity ⩾50% and % predicted diffusing capacity of the lung carbon monoxide ⩾30% were classified as the moderate group and those with more impaired lung functions as the severe group. Result: Among 158 patients analyzed, 132 (84.6%) were classified as the moderate group and 26 (15.4%) as the severe group. In the moderate group, changes in forced vital capacity in 12 months were significantly different between before and after nintedanib administration (−253 ± 163 vs −125 ± 235 mL; p = 0.0027). In contrast, changes in forced vital capacity in 12 months were not significantly changed by nintedanib treatment in the severe group (−353 ± 250 vs −112 ± 341 mL; p = 0.2374). Incidence of acute exacerbation was higher in the severe group than in the moderate group (30.8% vs 18.9%). The overall survival of the moderate and the severe groups was 17.2 and 10.1 months. Conclusion: In real-world practice, nintedanib showed comparable efficacy to those observed in previous trials. In the severe group, the efficacy of nintedanib might be limited.

Purpose: We report a case of severe choroidal detachments (CDs) in both eyes caused by systemic lupus erythematosus (SLE). Observations: The patient was a 50-year-old woman who presented with conjunctival edema in both eyes, visual dysfunction, and generalized fatigue. At the first visit, the best corrected visual acuity (BCVA) was 20/70 OD and 20/70 OS, and the intraocular pressure (IOP) was 22 mmHg OD and 27 mmHg OS. She had serous retinal detachments (SRDs), CDs, ciliary dissections, and a shallow anterior chamber with partial angle closure in both eyes. Systemic findings included hypoalbuminemia, pleural fluid, generalized fatigue, and brown papules on the back and both legs. First, we suspected Vogt-Koyanagi-Harada disease and administered two courses of methylprednisolone pulse therapy, but the CDs in both eyes gradually deteriorated and worsened to the extent that the optic nerve in both eyes could not be observed, and the BCVA deteriorated to 20/200 OD and 6/200 OS. Further multidisciplinary evaluations for diagnosing collagen diseases revealed vasculitis in the skin histopathology examination, positive results for anti-double stranded DNA antibody and anti-SS-A antibody, and hypocomplementemia in the blood examination, and she was diagnosed with severe SLE in the dermatology department. After administration of high dose intravenous γ-globulin therapy, albumin infusion, and intravenous cyclophosphamide pulse therapy, the SRDs and severe CDs improved along with improvement in hypoalbuminemia, pleural fluid, and generalized fatigue. Moreover, the shallow anterior chamber and high IOP improved to normal in both eyes. The CDs and SRDs completely disappeared, and the BCVA improved to 20/13 OU 6 months after the SLE therapy. Conclusion and importance: In patients with observed SRDs and CDs accompanying hypoalbuminemia, it is necessary to consider collagen diseases such as SLE.

Abstract Background We aimed to evaluate the efficacy and safety of nab-paclitaxel in patients with refractory advanced non-small cell lung cancer who failed previous chemotherapy. Methods Patients were required to have an Eastern Cooperative Oncology Group performance status of 0–2 and adequate organ function. Patients received nab-paclitaxel, 100 mg/m2 i.v. on days 1, 8, and 15 every 4 weeks. The primary endpoint was the overall response rate. Secondary endpoints were the progression-free survival time, overall survival, and the toxicity profile. Results From July 2013 to July 2015, a total of 31 patients were enrolled. Fourteen patients received nab-paclitaxel as a second-line and 17 received it as an over third-line therapy. Each patient received a median of 5 treatment cycles (range, 1–11). The overall response rate was 19.3% (95% confidence interval, 9.1–36.2%) (complete response (n = 0), partial response (n = 6), stable disease (n = 17), and progressive disease (n = 8)). The median progression-free survival time was 4.5 months (95% confidence interval 3.5–6.3 months), median overall survival time was 15.7 months, and 1-year survival rate was 54.8%. Most common grade 3 or 4 non-hematological toxicities were elevated aspartate transaminase level (3.2%) and sensory neuropathy (9.6%). Neutropenia was the most common grade 3 or 4 adverse events (38.6%), and febrile neutropenia developed in 12.9% patients. No treatment-related deaths were observed in this study. Conclusion Primary endpoint was met. Single agent nab-paclitaxel showed significant clinical efficacy and manageable toxicities for patients with chemorefractory advanced non-small cell lung cancer even if late line setting. Trial registration UMIN000011696 . The date of registration was July 11th, 2013.

Abstract Background Thyrotoxic crisis and pheochromocytoma multisystem crisis are rare, life-threatening, emergency endocrine diseases with various clinical manifestations. Here we report a case of a patient who simultaneously developed thyrotoxic crisis and pheochromocytoma multisystem crisis and required intensive cardiovascular management. Case presentation A 60-year-old Asian man experienced nausea and vomiting, and subsequently developed dyspnea and cold sweats while farming. His serum free thyroxine, free triiodothyronine, and thyrotropin receptor antibody levels were elevated at 2.9 ng/dL, 7.2 pg/dL, and 4.7 IU/L, respectively. Serum thyrotropin levels were suppressed at less than 0.01 μIU/mL. Thyroid echography demonstrated no thyroid swelling (23 × 43 mm). A whole body computed tomography was performed for systemic evaluation. This revealed exophthalmos and a mass of size 57 × 64 mm in the anterior pararenal space. Based on these findings, we made an initial diagnosis of thyrotoxic crisis secondary to exacerbation of Grave’s hyperthyroidism. Treatment was begun with an iodine agent at a dose of 36 mg/day, thiamazole at a dose of 30 mg/day, and hydrocortisone at a dose of 300 mg daily for 3 consecutive days. To control tachycardia, continuous intravenously administered propranolol and diltiazem infusions were given. At the same time, small doses of doxazosin and carvedilol were used for both alpha and beta adrenergic blockade. On hospital day 5, his blood pressure and serum catecholamine concentrations (adrenalin 42,365 pg/mL, dopamine 6409 pg/mL, noradrenalin 72,212 pg/mL) were still high despite higher beta blocker and calcium channel blocker doses. These findings contributed to the diagnosis of pheochromocytoma multisystem crisis with simultaneous thyrotoxic crisis. We increased the doses of doxazosin and carvedilol, which stabilized his hemodynamic status. On hospital day 16, metaiodobenzylguanidine scintigraphy showed high accumulation in the right adrenal gland tumor. After retroperitoneal laparoscopic adrenalectomy on hospital day 33, his condition stabilized. He was discharged on hospital day 58. Conclusions Since he required more intensive cardiovascular management for thyrotoxic crisis, beta blockade was increased under intensive care unit monitoring even though initial alpha blockade is recommended in pheochromocytoma. When these crises occur simultaneously, cardiovascular management can be very challenging.

Background: Allergic rhinitis (AR) is well known to be an IgE-mediated chronic inflammatory disease in the nasal wall, which is primarily mediated by Th2-type cytokines such as IL-4, IL-5, and IL-13. Although quercetin is also accepted to attenuate the development of allergic diseases such as AR, the influence of quercetin on Th2-type cytokine production is not well understood. The present study was designed to examine whether quercetin could attenuate the development of AR via the modulation of Th2-type cytokine production using an in vitro cell culture technique. Methods: Human peripheral-blood CD4+ T cells (1 × 106 cells/mL) were cultured with 10.0 ng/mL IL-4 in the presence or absence of quercetin. The levels of IL-5, IL-13, and INF-γ in 24 h culture supernatants were examined by ELISA. The influence of quercetin on the phosphorylation of transcription factors NF-κB and STAT6, and mRNA expression for cytokines were also examined by ELISA and RT-PCR, respectively. Results: Treatment of cells with quercetin at more than 5.0 μM inhibited the production of IL-5 and IL-13 from CD4+ T cells induced by IL-4 stimulation through the suppression of transcription factor activation and cytokine mRNA expression. On the other hand, quercetin at more than 5.0 μM abrogated the inhibitory action of IL-4 on INF-γ production from CD4+ T cells in vitro. Conclusions: The immunomodulatory effects of quercetin, especially on cytokine production, may be responsible, in part, for the mode of therapeutic action of quercetin on allergic diseases, including AR.

An experimental and computational investigation of the space-charge effects occurring in ultrafast photoelectron spectroscopy from the gas phase is presented. The target sample CF _3 I is excited by ultrashort (100 fs) far-ultraviolet radiation pulses produced by a free-electron laser. The modification of the energy distribution of the photoelectrons, i.e. the shift and broadening of the spectral structures, is monitored as a function of the pulse intensity. The experimental results are compared with computational simulations which employ a Barnes–Hut algorithm to calculate the effect of individual Coulomb forces acting among the particles. In the presented model, a survey spectrum acquired at low radiation fluence is used to determine the initial energy distribution of the electrons after the photoemission event. The spectrum modified by the space-charge effects is then reproduced by N -body calculations that simulate the dynamics of the photoelectrons subject to the individual mutual Coulomb repulsion and to the attractive force of the positive ions. The employed numerical method accounts for the space-charge effects on the energy distribution and allows to reproduce the complete photoelectron spectrum and not just a specific photoemission structure. The simulations also provide information on the time evolution of the space-charge effects on the picosecond scale. Differences with the case of photoemission from solid samples are highlighted and discussed. The presented simulation procedure, although it omits the analysis of angular distribution, constitutes an effective simplified model that allows to predict and account for space-charge effects on the photoelectron energy spectrum in time-resolved photoemission experiments with high-intensity pulsed sources.

Unraveling the origin of ultrafast demagnetization in multisublattice ferromagnetic materials requires femtosecond x-ray techniques to trace the magnetic moment dynamics on individual elements, but this could not yet be achieved in the hard x-ray regime. We demonstrate here the first ultrafast demagnetization dynamics in the ferromagnetic heavy 5d-transition metal Pt using circularly-polarized hard x-rays at an x-ray free electron laser (XFEL). The decay time of laser-induced demagnetization of L1 _0 -FePt is determined to be ${\tau }_{{\rm{Pt}}}=0.61\pm 0.04\,{\rm{ps}}$ using time-resolved x-ray magnetic circular dichroism at the Pt L _3 edge, whereas magneto-optical Kerr measurements indicate the decay time for the total magnetization as ${\tau }_{{\rm{total}}}\lt 0.1\,\mathrm{ps}$ . A transient magnetic state with a photo-modulated ratio of the 3d and 5d magnetic moments is demonstrated for pump–probe delays larger than 1 ps. We explain this distinct photo-modulated transient magnetic state by the induced-moment behavior of the Pt atom and the x-ray probing depth. Our findings pave the way for the future use of XFELs to disentangle atomic spin dynamics contributions.

We achieved stable operation of a free-electron laser (FEL) based on the self-amplified spontaneous-emission (SASE) scheme at the SPring-8 Compact SASE Source (SCSS) test accelerator in the extremely ultraviolet region. Saturation of the SASE FEL power has been achieved at wavelengths ranging from 50 to 60 nm. The pulse energy has reached ∼30 μJ at 60 nm. The observed fluctuation of the pulse energy is about 10% (standard deviation) for several hours, which agrees with the expectation from the SASE theory showing the stable operation of the accelerator. The SASE FEL has been routinely operated to provide photon beams for user experiments over a period of a few weeks. Analysis on the experimental data gave the normalized-slice emittance at the lasing part is around 0.7π mm mrad. This result indicates that the normalized-slice emittance of the initial electron beam, 0.6π mm mrad in a 90% core part, is kept almost unchanged after the bunch compression process with a compression factor of approximately 300. The success of the SCSS test accelerator strongly encourages the realization of a compact XFEL source.

From the direction finding (DF) observations based on the measurement of wave arrival time differences among three spaced points around Syowa Station (geomagnetic lat. -70.0°), the arrival direction of narrow-band auroral hiss was examined. It is found that the ionospheric exit from which the narrow-band auroral hiss comes out is usually located in the lower latitude side than the position of quiet auroral arcs. These results demonstrate that the propagation path of auroral hiss is deviated from the geomagnetic field lines along which auroral particles precipitate. Therefore, it is concluded that the waves propagate downwards to the ionosphere in a non-ducted mode. Comparing the location of the ionospheric exit of auroral hiss with the ratio of 8kHz hiss intensity at Syowa to that at Mizuho, it is estimated that the loss rate of auroral hiss is, on the average, 2-3 dB/100km with respect to the horizontal direction.