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ObjectivesRiociguat is approved for pulmonary arterial hypertension and has antiproliferative, anti-inflammatory and antifibrotic effects in animal models of tissue fibrosis. We evaluated the efficacy and safety of riociguat in patients with early diffuse cutaneous systemic sclerosis (dcSSc) at high risk of skin fibrosis progression.MethodsIn this randomised, double-blind, placebo-controlled, phase IIb trial, adults with dcSSc of ResultsAt week 52, change from baseline in mRSS units was –2.09±5.66 (n=57) with riociguat and –0.77±8.24 (n=52) with placebo (difference of least squares means –2.34 (95% CI –4.99 to 0.30; p=0.08)). In patients with interstitial lung disease, forced vital capacity declined by 2.7% with riociguat and 7.6% with placebo. At week 14, average Raynaud’s condition score had improved ≥50% in 19 (41.3%)/46 patients with riociguat and 13 (26.0%)/50 patients with placebo. Safety assessments showed no new signals with riociguat and no treatment-related deaths.ConclusionsRiociguat did not significantly benefit mRSS versus placebo at the predefined p

To investigate the formation of quantum turbulence in superfluid $$^4\hbox {He}$$ , we have studied the vortex emission from a turbulence region generated by a vibrating wire. The time of flight of vortex rings emitted from a generator to a detector exhibits a single exponential distribution, suggesting that vortex detection is a Poisson process. This means that the detector observes vortex rings at irregular intervals with a mean interval time. Therefore, the single exponential distribution suggests a constant emission rate of vortex rings during turbulence generation, which is proportional to the mean detection rate. By setting a limit on the diameter of detected vortex rings, we find that the emission rate exhibits a power law relationship with the ring diameter. Since the diameter of a vortex ring is related to the vortex line spacing within turbulence when reconnection occurs, the distribution of vortex line spacings is considered to be reflected in the size distribution of the emission rate. Therefore, the power law dependence of the emission rate suggests that the vortex lines within turbulence have a self-similar fractal structure.

18 F-Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) is usually used to screen malignancy in patients with dermatomyositis (DM). Additionally, it is well known that FDG-PET/CT provides valuable information for evaluating the activity of several inflammatory diseases, such as sarcoidosis, atherosclerosis, inflammatory bowel disease and rheumatoid arthritis. Therefore, the objective of this study was to evaluate the clinical usefulness of FDG-PET/CT for the detection of inflammatory lesions and disease activity of both myopathy and interstitial lung disease (ILD) in DM patients. We measured the maximum standardized uptake value (SUVmax) in the muscles and lungs in 22 DM patients, and compared with magnetic resonance imaging (MRI) and high-resolution computed tomography (HRCT) findings in the same muscle and lung regions as well as with clinical findings. We found that the location of increased FDG uptake was nearly consistent with the region of ILD and myositis detected by HRCT or MRI, respectively. There was a significant positive correlation between lung HRCT score and SUVmax in each lung. Serum Krebs von den Lungen-6 levels also revealed significant positive correlation with total SUVmax of right and left lungs. Regarding FDG-PET/CT and myopathy, total SUVmax in the muscles was significantly correlated with serum cytokeratin levels. Our results suggest that FDG uptake (SUVmax) might be useful for not only the detection of malignant tumors, but also the evaluation of the location and activity of ILD and myositis in DM patients.

Objective Several studies have demonstrated that the secreted glycoprotein and integrin ligand milk fat globule-associated protein with epidermal growth factor- and factor VIII-like domains (MFG-E8) negatively regulates fibrosis in the liver, lungs, and respiratory tract. However, the mechanisms and roles of MFG-E8 in skin fibrosis in systemic sclerosis (SSc) have not been characterized. We undertook this study to elucidate the role of MFG-E8 in skin fibrosis in SSc. Methods We assessed expression of MFG-E8 in the skin and serum in SSc patients. We examined the effect of recombinant MFG-E8 (rMFG-E8) on latent transforming growth factor β (TGFβ)-induced gene/protein expression in SSc fibroblasts. We examined the effects of deficiency or administration of MFG-E8 on fibrosis mouse models. Results We demonstrated that MFG-E8 expression around dermal blood vessels and the serum MFG-E8 level in SSc patients (n = 7 and n = 44, respectively) were lower than those in healthy individuals (n = 6 and n = 28, respectively). Treatment with rMFG-E8 significantly inhibited latent TGFβ-induced expression of type I collagen, α-smooth muscle actin, and CCN2 in SSc fibroblasts (n = 3-8), which suggested that MFG-E8 inhibited activation of latent TGFβ as well as TGFβ signaling via binding to αv integrin. In a mouse model of bleomycin-induced fibrosis (n = 5-8) and in a TSK mouse model (a genetic model of SSc) (n = 5-10), deficient expression of MFG-E8 significantly enhanced both pulmonary and skin fibrosis, and administration of rMFG-E8 significantly inhibited bleomycin-induced dermal fibrosis. Conclusion These results suggest that vasculopathy-induced dysfunction of pericytes and endothelial cells, the main cells secreting MFG-E8, may be associated with the decreased expression of MFG-E8 in SSc and that the deficient inhibitory regulation of latent TGFβ-induced skin fibrosis by MFG-E8 may be involved in the pathogenesis of SSc and may be a therapeutic target for fibrosis in SSc patients.

Dermatomyositis (DM) patients are known to have various infectious complications, such as cytomegalovirus (CMV) reactivation, due to immune dysfunction caused by DM itself and immunosuppressants used for treatment. Although CMV reactivation has been known to be a major cause of mortality in immunocompromised hosts, there has not been sufficient study of CMV reactivation in DM patients. The objective of this study was to examine the frequency of CMV reactivation in DM patients and to investigate risk factors potentially associated with development of CMV reactivation. We analyzed 52 Japanese DM patients, and CMV reactivation was observed in 21 (40.4%). The mean duration from the initiation of prednisolone (PSL) to the diagnosis of CMV reactivation was 6.1 ± 0.5 weeks. The total amount of oral PSL before the diagnosis of CMV reactivation was 2000.3 ± 169.3 mg. Using a univariate analysis, we found that the prevalence of interstitial lung disease and the frequency of diabetes mellitus complications in DM patients with CMV reactivation was significantly higher than that in DM patients without CMV. We identified that low lymphocytes (

OBJECTIVEThe purpose of the present study was to compare the treatment success rates of primary neurosurgical and endovascular treatments in patients with spinal dural arteriovenous fistulas (dAVFs).METHODSData from 199 consecutive patients with thoracic and lumbosacral spinal dAVFs were collected from 18 centers. Angiographic and clinical findings, the rate of initial treatment failure or recurrence by procedures, risk factors for treatment failure, complications, and neurological outcomes were statistically analyzed.RESULTSSpinal dAVFs were frequently detected in the thoracic region (81%), fed by a single feeder (86%), and shunted into an intradural vein via the dura mater. The fistulous connection between the feeder(s) and intradural vein was located at a single spinal level in 195 patients (98%) and at 2 independent levels in 4 patients (2%). Among the neurosurgical (n = 145), and endovascular (n = 50) treatment groups of single dAVFs (n = 195), the rate of initial treatment failure or recurrence was significantly higher in the index endovascular treatment group (0.68% and 36%). A multivariate analysis identified endovascular treatment as an independent risk factor with significantly higher odds of initial treatment failure or recurrence (OR 69; 95% CI 8.7–546). The rate of complications did not significantly differ between the two treatment groups (4.1% for neurosurgical vs 4.0% for endovascular treatment). With a median follow-up of 26 months, improvements of ≥ 1 point in the modified Rankin Scale (mRS) score and Aminoff-Logue gait and Aminoff-Logue micturition grades were observed in 111 (56%), 121 (61%), and 79 (40%) patients, respectively. Independent risk factors for lack of improvement in the Aminoff-Logue gait grades were multiple treatments due to initial treatment failure or recurrence (OR 3.1) and symptom duration (OR 1.02).CONCLUSIONSBased on data obtained from the largest and most recently assessed multicenter cohort, the present study shows that primary neurosurgery is superior to endovascular treatment for the complete obliteration of spinal dAVFs by a single procedure.

Ischemia-reperfusion (I/R) is associated with various pathogenic conditions, and there has been increasing evidence that cutaneous I/R injury is associated with the pathogenesis of pressure ulcers (PUs), especially at the early stage presenting as non-blanchable erythema. Several studies demonstrated that oxidative stress is a key player in I/R injury, and the inhibition of oxidative stress may be capable of protecting tissue damage after I/R injury in various organs including skin. Dimethyl fumarate (DMF) approved by the Food and Drug Administration is Nrf2 activator, and recent studies revealed the antioxidative and anti-inflammatory effects of DMF on I/R injury in animal models. Our objective was to assess the effects of oral administration of DMF on the development of PUs after cutaneous I/R injury in mice. We found that DMF administration significantly decreased the size of PUs after cutaneous I/R. Cutaneous I/R-induced oxidative stress was also significantly inhibited by DMF in OKD48 mice, in which oxidative stress can be visually assessed. In addition, DMF treatment decreased hypoxic area, the numbers of apoptotic cells, and vascular loss in I/R area. DMF treatment suppressed the infiltration of MPO+ neutrophils and the production of proinflammatory cytokines in I/R site after cutaneous I/R injury. in vitro experiments, DMF treatment suppressed the production of reactive oxygen species in pericyte-like cells. These results suggest that DMF treatment might prevent the formation of PUs induced by cutaneous I/R injury via suppressing oxidative stress and subsequent inflammation. DMF treatment during the early phase of decubitus ulcers might protect against further progression.

Patients with systemic sclerosis (SSc) develop various vasculopathy-induced vascular disorders such as Raynaud's phenomenon, abnormal nail-fold capillaries, persistent digital ischemia, digital ulcers (DU), and sometimes develop renal crisis and pulmonary artery hypertension (PAH), affecting prognosis. Earlobe crease (ELC), also known as Frank's sign, is a wrinkle extending from the tragus to the outer border of the earlobe and is generally recognized as the sign of cardiovascular events. However, no previous study analyzed the association between ELC and SSc. In this study, we examined the prevalence and clinical characteristics of ELC in SSc patients. We analyzed 145 Japanese SSc patients and found that the prevalence of ELC in SSc patients was 23.4% (43/145), similar to that previously reported in the general population without SSc. Using univariate analysis, we found that SSc patients with ELC were characterized by old age, high incidence of DU, ILD and PAH, and high complication of coronary artery diseases (CAD) compared with SSc patients without ELC. In multivariate analysis, ELC was significantly associated with old age and incidence of DU. PAH tended to correlate with ELC without statistical significance. These results suggest that ELC may be associated with vascular disorders in SSc patients. This is the first report concerning the prevalence and clinical characteristics of ELC in patients with SSc. ELC is very easy to detect in clinical practice and helps physicians to identify SSc patients at risk of developing vascular disorders such as DU and PAH.

Preoperative chemoradiation therapy is a promising strategy for pancreatic cancer. Peritoneal recurrence is a major recurrence pattern after surgery for pancreatic cancer following preoperative chemoradiation therapy, even in patients with negative peritoneal lavage fluid cytology. Previous reports have indicated that the detection of carcinoembryonic antigen mRNA by reverse transcription polymerase chain reaction is useful for evaluating subclinical tumor cell dissemination in peritoneal lavage fluid.Patients with resectable and borderline resectable pancreatic cancer treated with preoperative gemcitabine-based chemoradiation therapy and subsequent surgery were enrolled in this study. In all patients, a conventional cytologic examination of peritoneal lavage fluid from laparotomy confirmed the negative peritoneal cytology status. Carcinoembryonic antigen mRNA was detected in the peritoneal lavage fluid at laparotomy using reverse transcription polymerase chain reaction. Recurrence patterns and survival were evaluated in association with the carcinoembryonic antigen mRNA status in the peritoneal lavage fluid.The peritoneal lavage fluid from 57 of the 237 patients (24%) was carcinoembryonic antigen mRNA(+). The carcinoembryonic antigen mRNA(+) patients had a significantly higher incidence of peritoneal recurrence than the carcinoembryonic antigen mRNA(-) patients (36% vs. 15%, P.001). The 5-year survival rates of the carcinoembryonic antigen mRNA(+) and carcinoembryonic antigen mRNA(-) patients were 31% and 51%, respectively (P = .037). A multivariable analysis for survival revealed that borderline resectability, positive nodal status, and positive carcinoembryonic antigen mRNA status were independent variables for impaired survival.Carcinoembryonic antigen mRNA(+) status was associated with a significantly increased incidence of peritoneal recurrence in patients with pancreatic cancer treated with preoperative chemoradiation therapy, resulting in impaired survival.

Chronic oral ulcers are induced by various causative factors. Biopsy from an active site around ulceration is critical for both the definitive diagnosis and proper treatment. We report two cases of chronic oral ulcers, circumorificial plasmacytosis (CP) and traumatic ulcerative granuloma with stromal eosinophilia (TUGSE). A 65-year-old man presented with a mucosal ulcer on the right half of the lower lip. The dense plasmacytic inflammatory infiltration was histologically consistent with CP. A 32-year-old woman presented with a mucosal ulcer on the right mouth commissure. The dense mixed inflammatory cell infiltrates composed of eosinophils, lymphocytes and histiocytes extending from the submucosal tissue to underlying striated muscle fibers were histologically consistent with TUGSE. p.o. administration of corticosteroid was effective in both cases. A broad differential diagnosis is required for chronic oral ulcers. If the oral ulcer did not respond to the first therapy, clinical re-evaluation and biopsy is essential.

Objective Apelin/APJ signaling has been determined to regulate cardiac and arterial fibrosis and to be involved in the pathogenesis of pulmonary arterial hypertension. Our objective was to elucidate the role of apelin in skin fibrosis in systemic sclerosis (SSc). Methods Expression of apelin/APJ in normal and SSc fibroblasts was compared. Effects of small interfering RNA depletion and the addition of apelin in fibroblasts were analyzed. The effect of apelin injections on bleomycin-induced dermal fibrosis in mice was investigated. We analyzed the effects of the biased agonist of APJ, MM07, on skin fibrosis in vitro and in vivo. Results The expression of apelin in SSc fibroblasts was significantly lower than that in normal fibroblasts. Serum apelin levels were negatively correlated with the modified Rodnan skin thickness score in SSc patients. Stimulation with transforming growth factor β1 (TGFβ1) inhibited apelin expression in fibroblasts, suggesting that activation of TGFβ1 signaling in SSc might be responsible for reduced apelin expression in SSc fibroblasts. Small interfering RNA depletion of apelin from fibroblasts significantly enhanced fibrosis-related gene expression, and treatment with apelin protein significantly inhibited TGFβ1 signaling in fibroblasts. Administration of apelin significantly inhibited bleomycin-induced dermal fibrosis in mice. We demonstrated that MM07 had greater potential than apelin to inhibit fibrosis in vivo and in vitro. Conclusion Collectively, TGFβ1 signaling and apelin signaling may counteract each other in the fibrotic process of SSc. Inhibitory regulation of TGFβ1-induced skin fibrosis by apelin/APJ signaling may be involved in the pathogenesis of SSc and could be a therapeutic target for fibrosis in SSc patients.

Background We previously identified that botulinum toxin A (BTX-A) suppressed pressure ulcer (PU) formation after cutaneous ischemia-reperfusion (I/R) injury; however, regulation of cutaneous I/R-induced oxidative and endoplasmic reticulum (ER) stress by BTX-B was not investigated. Additionally, the efficacy of BTX-B injection has never been examined. Objective Objective was to assess the effects of BTX-B on the formation of PU by cutaneous I/R injury, and the regulation of oxidative and ER stress in I/R injury by BTX-B. Methods BTX-B was subcutaneously injected into I/R area, and wound size, vascular damage, hypoxic area, and apoptotic cells in I/R area were analyzed. We evaluated the extent of oxidative and ER stress in I/R area by using OKD48 mice and ERAI mice, respectively, which enabled evaluating oxidative and ER stress through bioluminescence detection. Results BTX-B injection significantly suppressed the formation of PU by cutaneous I/R injury. Cutaneous I/R-induced vascular damage, hypoxic area, and number of oxidative-damaged cells and apoptotic cells were suppressed by BTX-B injection. BTX-B administration significantly inhibited I/R-induced oxidative stress signal in OKD48 mice. BTX-B reduced the I/R-induced oxidative stress-associated factors. BTX-B significantly inhibited the oxidant-induced reactive oxygen species and apoptosis of endothelial cells and fibroblasts. BTX-B significantly inhibited I/R-induced ER stress signal in ERAI mice. Cutaneous I/R injury-induced ER stress-response factors and GRP78/BiP and CHOP-positive cells in I/R area were significantly decreased by BTX-B injection. Conclusion BTX-B injection might have protective effects against PU formation after cutaneous I/R injury by reducing vascular damage, hypoxia-induced oxidative and ER stress, and apoptosis.

The aim of this study was to propose a new animal model evaluating the serial time course of in-stent stenosis by repeated carotid artery catheterization in the same animal. 16 bare-metal stents were implanted in the normal external and internal iliac artery of 8 miniature pigs. Repeated measurements were performed in the same animal every 2 weeks for 12 weeks through carotid artery catheterization. The time course and peak neointimal proliferation were evaluated by intravascular ultrasound. Health of all animals was assessed by clinical and hematological examinations. As a result, 7 times of carotid artery catheterization was performed per pig, but all animals remained healthy without both any complications and hematological inflammatory abnormalities. The time course of neointimal proliferation of each stent was observed from the stage of hyperplasia to partial regression. The peak neointimal proliferation varied from 6 to 12 weeks despite implantation of identical stents using the same deployment method. In conclusion, repeated carotid artery catheterization to the same animal is feasible without animal health deterioration. This model should be useful to evaluate the time course of neointimal proliferation after stent deployment in preclinical study.

It is debated whether the efficacy and long-term safety of gamma knife radiosurgery (GKRS) for arteriovenous malformations (AVMs) differs between adult and pediatric patients. We aimed to clarify the long-term outcomes of GKRS in pediatric patients and how they compare to those in adult patients. We collected data for 736 consecutive patients with AVMs treated with GKRS between 1990 and 2014 and divided the patients into pediatric (age < 20 years, n = 144) and adult (age ≥ 20 years, n = 592) cohorts. The mean follow-up period in the pediatric cohort was 130 months. Compared to the adult patients, the pediatric patients were significantly more likely to have a history of hemorrhage (P < 0.001). The actuarial rates of post-GKRS nidus obliteration in the pediatric cohort were 36%, 60%, and 87% at 2, 3, and 6 years, respectively. Nidus obliteration occurred earlier in the pediatric cohort than in the adult cohort (P = 0.015). The actuarial rates of post-GKRS hemorrhage in the pediatric cohort were 0.7%, 2.5%, and 2.5% at 1, 5, and 10 years, respectively. Post-GKRS hemorrhage was marginally less common in the pediatric cohort than in the adult cohort (P = 0.056). Cyst formation/encapsulated hematoma were detected in seven pediatric patients (4.9%) at a median post-GKRS timepoint of 111 months, which was not significantly different from the rate in the adult cohort. Compared to adult patients, pediatric patients experience earlier therapeutic effects from GKRS for AVMs, and this improves long-term outcomes.

Background Diabetic wounds are intractable due to complex factors, such as the inhibition of angiogenesis, dysfunction of phagocytosis by macrophages and abnormal inflammatory responses. It is recognized that mesenchymal stem cells (MSCs) promote wound healing in diabetic mice. We previously demonstrated that MSCs produce large amounts of MFG-E8. Object The objective was to ascertain the role of MSCs-derived MFG-E8 in murine diabetic wounds. Methods MFG-E8 WT/KO MSCs or rMFG-E8 were subcutaneously injected around the wound in diabetic db/db mice, and wound areas were analyzed. Quantification of angiogenesis, infiltrating inflammatory cells, apoptotic cells at the wound area was performed by immunofluorescence staining and real-time PCR. Phagocytosis assay was performed using peritoneal macrophages from WT or db/db mice. Results MFG-E8 expression in granulation tissue in diabetic mice was significantly reduced compared with that in non-diabetic mice. We next examined the effect of subcutaneous injection of MFG-E8 WT/KO MSCs around the wound. Diabetic wound healing was significantly accelerated by the injection of MSCs. Diabetic wound healing in MFG-E8 KO MSCs-injected wounds was significantly delayed compared to that in WT MSCs-injected wounds. The numbers of CD31 + EC and NG2 + pericytes, as well as M2 macrophages in wounds in KO MSCs-injected mice were significantly decreased. MFG-E8 WT MSCs treatment suppressed the number of apoptotic cells and TNF-α + cells in wounds. In an in vitro assay, MFG-E8 WT MSCs-conditioned medium enhanced phagocytosis of apoptotic cells by peritoneal macrophages from diabetic mice. Conclusion MSCs-derived MFG-E8 might accelerate diabetic wound healing by promoting angiogenesis, the clearance of apoptotic cells, and the infiltration of M2 macrophages, and by suppressing inflammatory cytokines in wound area.

This paper reports the technical details of the development of a low-temperature amplifier for nuclear magnetic resonance measurements of superfluid $${}^3$$ He in very confined geometries. The amplifier consists of commercially available enhancement-mode pseudomorphic high-electron-mobility transistor devices and temperature-insensitive passive components with an operating frequency range of 0.2–6 MHz.

Pancreatic fistula (PF) is a challenging complication of pancreaticoduodenectomy (PD). ‘Soft pancreas’ is reported as a risk factor for PF; however, palpation by the surgeon is not an objective method of evaluating pancreatic texture. We conducted this study to investigate whether a texture analyzer called a “Tensipresser” can be used to quantify pancreatic tissue hardness and predict the development of postoperative PF. We assessed pancreatic texture in 85 patients who underwent PD. After surgeons assessed the texture of the pancreas subjectively, the physical properties were measured on the pancreatic margin intraoperatively, by the two-bite method using the “Tensipresser”. The incidence and severity of PF were based on the definitions of the International Study Group on Pancreatic Fistula. Symptomatic PF (grade B and C) developed in 16% of the patients. Patients were divided into two groups based on the Tensipresser measurement: those with a soft and fragile pancreas with hardness

OBJECTIVE Chronic subdural hematoma (CSDH) is a common form of intracranial hemorrhage with a recurrence rate of 9.2%–26.5% after bur hole surgery. Occasionally patients with bilateral CSDH undergo unilateral surgery because the contralateral hematoma is deemed to be asymptomatic, and in some of these patients the contralateral hematoma may subsequently enlarge, requiring additional surgery. The authors investigated the factors related to the growth of these hematomas. METHODS Ninety-three patients with bilateral CSDH who underwent unilateral bur hole surgery at Aizu Chuo Hospital were included in a retrospective analysis. Findings on preoperative MRI, preoperative thickness of the drained hematoma, and the influence of antiplatelet or anticoagulant drugs were considered and evaluated in univariate and multivariate analyses. RESULTS The overall growth rate was 19% (18 of 93 hematomas), and a significantly greater percentage of the hematomas that were iso- or hypointense on preoperative T1-weighted imaging showed growth compared with other hematomas (35.4% vs 2.3%, p < 0.001). Multivariate logistic regression analysis showed that findings on preoperative T1-weighted MRI were the sole significant predictor of hematoma growth, and other factors such as antiplatelet or anticoagulant drug use, patient age, patient sex, thickness of the treated hematoma, and T2-weighted MRI findings were not significantly related to hematoma growth. The adjusted odds ratio for hematoma growth in the T1 isointense/hypointense group relative to the T1 hyperintense group was 25.12 (95% CI 3.89–51.58, p < 0.01). CONCLUSIONS The findings of preoperative MRI, namely T1-weighted sequences, may be useful in predicting the growth of hematomas that did not undergo bur hole surgery in patients with bilateral CSDH.

Background:RISE-SSc (NCT02283762) was a multicenter, double-blind, Phase IIb study of riociguat in early dcSSc. Primary endpoint was change in mRSS from baseline to Wk 52.Objectives:Exploratory, descriptive analyses of riociguat target engagement and effects on disease biomarkers in RISE-SSc and their relationship with effects on the primary endpoint. All biomarker p-values are for information only.Methods:Pts with dcSSc (duration ≤18 mo; modified Rodnan skin score [mRSS] 10–22 units) were randomized to riociguat 0.5−2.5 mg tid (n=60) or placebo (n=61). Biomarkers of target engagement (cGMP), inflammation and/or vascular/endothelial function (e.g. high-sensitivity C-reactive protein [hsCRP], soluble platelet endothelial cell adhesion molecule 1 [sPECAM-1], soluble E-selectin, chemokine ligand 4 [CXCL-4]), and fibrosis (e.g. alpha-smooth muscle cell actin [alphaSMA], pro-collagen mRNA expression) were measured in plasma, serum, and skin biopsies at baseline and Wk 14.Results:Mean±SD change from baseline in mRSS was –2.09±5.66 (n=57) with riociguat and –0.77±8.24 (n=52) with placebo (p=0.08). From baseline to Wk 14, plasma cGMP rose by mean (SD) 94% (78%) (n=52) with riociguat and 10% (39%) (n=52) with placebo (nominal pConclusion:Primary study endpoint (change in mRSS) was not met. Plasma cGMP rose with riociguat, confirming engagement with the NO-sGC-cGMP pathway. Serum sPECAM-1 (marker of endothelial activation) and CXCL-4 (marker of progressive SSc) fell with riociguat; hsCRP and E-selectin did not. Some serum and skin biomarkers of higher disease activity at baseline were associated with a greater effect of riociguat on skin fibrosis.Acknowledgments:RISE-SSc was jointly funded by Bayer AG and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Disclosure of Interests:Oliver Distler Grant/research support from: Grants/Research support from Actelion, Bayer, Boehringer Ingelheim, Competitive Drug Development International Ltd. and Mitsubishi Tanabe; he also holds the issued Patent on mir-29 for the treatment of systemic sclerosis (US8247389, EP2331143)., Consultant of: Consultancy fees from Actelion, Acceleron Pharma, AnaMar, Bayer, Baecon Discovery, Blade Therapeutics, Boehringer, CSL Behring, Catenion, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos NV, GSK, Glenmark Pharmaceuticals, Inventiva, Italfarmaco, iQvia, medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Roche, Sanofi and UCB, Speakers bureau: Speaker fees from Actelion, Bayer, Boehringer Ingelheim, Medscape, Pfizer and Roche, Frank Kramer Employee of: Bayer AG, Josef Höfler Employee of: Josef Höfler is an employee of Staburo GmbH, Munich, Germany, contracted by Bayer AG to perform the biomarker analyses, Mercedeh Ghadessi Employee of: Bayer AG, Peter Sandner Employee of: Bayer AG, Yannick Allanore Grant/research support from: BMS, Inventiva, Roche, Sanofi, Consultant of: Actelion, Bayer AG, BMS, BI, Christopher Denton Grant/research support from: GlaxoSmithKline, CSL Behring, and Inventiva, Consultant of: Medscape, Roche-Genentech, Actelion, GlaxoSmithKline, Sanofi Aventis, Inventiva, CSL Behring, Boehringer Ingelheim, Corbus Pharmaceuticals, Acceleron, Curzion and Bayer, Masataka Kuwana Grant/research support from: Acetelion, Consultant of: Acetelion, Bayer, Chugai, Corbus Pharmaceuticals, CSL Behring and Reata Pharmaceuticals. He was a member of the SENSCIS trial Steering Committee (Boehringer Ingelheim), Marco Matucci-Cerinic Grant/research support from: Actelion, MSD, Bristol-Myers Squibb, Speakers bureau: Acetelion, Lilly, Boehringer Ingelheim, Janet Pope Grant/research support from: AbbVie, Bristol-Myers Squibb, Eli Lilly & Company, Merck, Roche, Seattle Genetics, UCB, Consultant of: AbbVie, Actelion, Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eicos Sciences, Eli Lilly & Company, Emerald, Gilead Sciences, Inc., Janssen, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, UCB, Speakers bureau: UCB, Tatsuya Atsumi Grant/research support from: Eli Lily Japan K.K., Alexion Pharmaceuticals, Inc., Bristol-Myers Squibb Co., AbbVie Inc., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Astellas Pharma Inc., Consultant of: Gilead Sciences, Inc., Eli Lilly Japan K.K., UCB Japan Co. Ltd., AbbVie Inc., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Speakers bureau: Eli Lilly Japan K.K., UCB Japan Co. Ltd., Bristol-Myers Squibb Co., AbbVie Inc., Eisai Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Takeda Pharmaceutical Co., Ltd., Astellas Pharma Inc., Radim Bečvář Consultant of: Actelion, Roche, László Czirják Consultant of: Actelion, BI, Roche-Genentech, Lilly, Medac, Novartis, Pfizer, Bayer AG, Ellen De Langhe Consultant of: member of advisory board for Boehringer, Eric Hachlla: None declared, Tomonori Ishii: None declared, Osamu Ishikawa: None declared, Sindhu Johnson Grant/research support from: Boehringer Ingelheim, Corbus Pharmaceuticals, GlaxoSmithKline, Roche, Merck, Bayer, Consultant of: Boehringer Ingelheim, Ikaria, Kaisa Laapas Employee of: Partly in-sourced to Bayer, Valeria Riccieri: None declared, Elena Schiopu: None declared, Richard Silver: None declared, Vanessa Smith Grant/research support from: The affiliated company received grants from Research Foundation - Flanders (FWO), Belgian Fund for Scientific Research in Rheumatic diseases (FWRO), Boehringer Ingelheim Pharma GmbH & Co and Janssen-Cilag NV, Consultant of: Boehringer-Ingelheim Pharma GmbH & Co, Speakers bureau: Actelion Pharmaceuticals Ltd, Boehringer-Ingelheim Pharma GmbH & Co and UCB Biopharma Sprl, Chiara Stagnaro: None declared, Viginia Steen Grant/research support from: The associated affiliation has received grants/research from Boehringer Ingelheim, Corbus Pharmaceuticals, CSL Behring, Eicos, Galapagos, Immune Tolerance Network, Reata, Consultant of: Virginia Steen has acted as a consultant for Boehringer Ingelheim, Corbus, CSL Behring, Eicos, Forbius, Wendy Stevens: None declared, Gabriella Szücs: None declared, Marie-Elise Truchetet: None declared, Melanie Wosnitza Employee of: Bayer AG, Dinesh Khanna Shareholder of: Eicos Sciences, Inc./Civi Biopharma, Inc., Grant/research support from: Dr Khanna was supported by NIH/NIAMS K24AR063120, Consultant of: Acceleron, Actelion, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Corbus Pharmaceuticals, Horizon Therapeutic, Galapagos, Roche/Genentech, GlaxoSmithKline, Mitsubishi Tanabe, Sanofi-Aventis/Genzyme, UCB

Several studies have demonstrated potential roles for apelin/APJ signaling in the regulation of oxidative stress associated with ischemia-reperfusion (I/R) injury in several organs. Objective was to assess the role of apelin/APJ signaling in the development of pressure ulcers (PUs) formation after cutaneous I/R injury in mice. We identified that cutaneous I/R injury increased the expression of apelin in the skin at I/R site. Administration of apelin significantly inhibited the formation of PUs. The reductions of blood vessels, hypoxic area and apoptosis in I/R site were inhibited by apelin injection. Oxidative stress signals in OKD48 mice and the expressions of oxidative stress related genes in the skin were suppressed by apelin injection. H2O2-induced intracellular ROS and apoptosis in endothelial cells and fibroblasts were suppressed by apelin in vitro. Furthermore, MM07, biased agonist of APJ, also significantly suppressed the development of PUs after cutaneous I/R, and the inhibitory effect of MM07 on PUs formation was higher than that in apelin. We conclude that apelin/APJ signaling may inhibit cutaneous I/R injury-induced PUs formation by protecting the reduction of vascularity and tissue damage via suppression of oxidative stress. Exogenous application of apelin or MM07 might have therapeutic potentials against the development of PUs.

To identify initial parameters that predict worsening of skin thickening in patients with diffuse cutaneous systemic sclerosis (dcSSc) using a multicentre, prospective, observational cohort in Japan. A total of 171 patients with dcSSc were selected from a prospective cohort database based on the following criteria: dcSSc, modified Rodnan total skin thickness score (mRSS) ≥7, disease duration

Nuclear factor (NF)-κB essential modifier (NEMO), also known as IκB kinase subunit-γ (IKKγ), is a pivotal molecule in the NF-κB signaling pathway. Mutations of NEMO cause incontinentia pigmenti and X-linked ectodermal dysplasia with immunodeficiency. Mendelian susceptibility to mycobacterial diseases (MSMD), which confers an almost selective predisposition to mycobacterial infection, is also caused by NEMO mutations. We herein report the first case of a patient with X-linked recessive (XR) MSMD who developed cutaneous squamous cell carcinoma, thyroid cancer and Langerhans cell histiocytosis. The relationship between NEMO mutation and oncogenesis is discussed.

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody has been recognized to be significantly associated with a subset of dermatomyositis patients with rapidly progressive interstitial lung disease (RP-ILD). To elucidate the clinical characteristics and poor prognostic factors in Japanese dermatomyositis patients with anti-MDA5 antibody. Clinical features of anti-MDA5 antibody-positive dermatomyositis patients and risk factors, potentially associated with a poor prognosis, were retrospectively analysed. A total of 37.3% (28/75) dermatomyositis patients were positive for anti-MDA5 antibody. The frequency of Gottron’s papules, palmar violaceous macules, antihelix/helix violaceous macules, and clinically amyopathic dermatomyositis (CADM) was significantly higher in patients with anti-MDA5 antibody. Of anti-MDA5 antibody-positive dermatomyositis patients, 57.1% developed RP-ILD, and in those with RP-ILD, serum ferritin level was markedly high and partial pressure of arterial oxygen (PaO2) was significantly low at first visit. Among patients with anti-MDA5 antibody with RP-ILD, non-survivors were older and revealed lower PaO2 at first visit relative to survivors. Furthermore, patients who did not take triple therapy (prednisolone, calcineurin inhibitor and cyclophosphamide) as initial treatment resulted in poor outcome. Anti-MDA5 antibody may be associated with CADM, the progression to RP-ILD, high serum ferritin level, and characteristic skin manifestations. High serum ferritin level in patients with anti-MDA5 antibody may be associated with the development of RP-ILD and poor prognosis. Early treatment with triple therapy, including intravenous cyclophosphamide, may improve the prognosis of RP-ILD.

Perforating pilomatricoma (PP) is a rare clinical variant of pilomatricoma presenting as a crusted or ulcerated nodule. Previous reports have suggested that the tumor cells perforate the epidermis through a process of transepithelial elimination. Here, we report six cases of PP and examine the mechanism of transepithelial elimination in PP. Histologically, the dermis above or around the tumor nest exhibited edema, dilated vascular spaces, sparse collagen bundles and absence of elastic fibers, suggesting anetodermic changes in all cases. Immunohistochemistry demonstrated many CD68-positive macrophages around the tumor nests. Matrix metallopeptidase (MMP)-9 and MMP-12 were expressed in the inflammatory cells and tumor cells, and were also present in the epidermis and fibroblasts in all cases. We speculate that in PP anetodermic change caused by MMP and elastases including MMP-9 and MMP-12 may precede elimination of the tumor.

Objectives: Overactive bladder (OAB) is a clinical diagnosis defined with the presence of urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary inc...

Although a suction vortex is one of the most common vortices appearing in everyday life, its internal structure has not been fully understood yet. We experimentally generate directly a superfluid suction vortex with a superfluid stirring system. A quantum vortex line carries all the microscopic circulation, and the distribution of vortex lines can be measured by combining two acoustic techniques. The results show that the vortex lines accumulate in the narrow region around the axis of symmetry. However, the vortex lines are not a simple bundle of straight vertical lines, but most of them incline in the horizontal direction.

L-type amino acid transporter 1 (LAT1) and CD98 are frequently expressed in various human cancers, and closely correlated with tumor aggressiveness and survival. However, little is known about the expression of LAT1 and CD98 in cutaneous angiosarcoma. The aim of this study is to investigate the clinicopathological significance of these markers in the dismal disease. A total of 52 patients with cutaneous angiosarcoma were retrospectively reviewed. Immunohistochemical staining of tumor specimens were evaluated using anti-LAT1, CD98 and Ki-67 antibodies. The rates of high expression for LAT1 and CD98 were 56% (29/52) and 79% (41/52), respectively. The frequency of high expression for CD98 was significantly higher than that for LAT1 (p=0.021). The low expression of CD98 was significantly associated with distant metastasis (p=0.044) and was identified as a significant prognostic predictor by multivariate analysis. The expression level of LAT1 was not significantly correlated with prognosis. The low expression of CD98 is a novel biomarker for predicting poor prognosis in patients with cutaneous angiosarcoma.

Cutaneous angiosarcoma (CA) is extremely rare, and little is known about the biological significance of possible biomarkers for chemotherapeutic agents. Thymidylate synthase (TS) is an attractive target for cancer treatment in various human neoplasms. It remains unclear whether the expression of TS is associated with the clinicopathological features of CA patients. The aim of this study was to elucidate the relationship between TS expression and the clinicopathological significance in CA patients. Fifty-one patients with CA were included in this study. TS expression and Ki-67 labeling index were examined using immunohistochemical analysis. TS was positively expressed in 39% (20/51) of CA patients. No statistically significant prognostic factor was identified as a predictor of overall survival (OS) for all patients by univariate analysis, whereas a significant prognostic variable for progression free survival (PFS) was found to be the clinical stage. In addition, both univariate and multivariate analyses confirmed that positive expression of TS was a significant predictor of worse PFS in CA patients of clinical stage 1. CONCLUSION Positive TS expression in CA was identified as a significant predictor of worse outcome in patients of clinical stage 1.

To investigate the formation of quantum turbulence in superfluid $${}^{4}\hbox {He}$$ , we have studied the emission of vortex rings with a ring size of larger than 38 $$\upmu \hbox {m}$$ in diameter from turbulence generated by a vibrating wire. The emission rate of vortex rings from a turbulent region remains low until the beginning of high-rate emissions, suggesting that some of the vortex lines produced by the wire combine to form a vortex tangle, until an equilibrium is established between the rate of vortex line combination with the tangle and dissociation. The formation times of equilibrium turbulence are proportional to $$\varepsilon ^{-1.2}$$ and $$\varepsilon ^{-0.6}$$ in the directions perpendicular and parallel to the vibrating direction of the generator, respectively, indicating the anisotropic formation of turbulence. Here, $$\varepsilon $$ is the generation power of the turbulence. This power dependence may be associated with the characteristics of quantum turbulence with a constant energy flux.

Purpose Programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1) targeted therapies have shown promising survival outcomes in several human neoplasms. However, it is unclear whether the expression of PD-L1 can be correlated to any clinical and pathologic variables in patients with cutaneous angiosarcoma (CA). The aim of this study was to evaluate the clinicopathological significance of PD-L1 expression in CA patients. Materials and Methods Data from 52 patients with CA were retrospectively reviewed. PD-L1 expression, tumor proliferation determined by Ki-67 index, and immunohistochemical evaluation of tumor-infiltrating lymphocytes, CD4+ and CD8+, were used to determine correlation with clinicopathological variables. Results PD-L1 was positively expressed in 40% of all patients. PD-L1 expression was significantly associated with tumor cell proliferation. Multivariate analysis confirmed that high levels of CD8+ tumor-infiltrating lymphocytes were a significant predictor in patients with clinical stage I CA and the positive expression of PD-L1 was an independent prognostic factor in predicting worse outcome. Conclusion PD-L1 expression is a novel pathologic marker for predicting worse outcome in patients with CA.

Secretion of the powerful angiogenic factor MFG-E8 by pericytes can bypass the therapeutic effects of anti-VEGF therapy, but the mechanisms by which MFG-E8 acts are not fully understood. In this study, we investigated how this factor acts to promote the growth of melanomas that express it. We found that mouse bone marrow–derived mesenchymal stromal cells (MSC) expressed a substantial amount of MFG-E8. To assess its expression from this cell type, we implanted melanoma cells and MSC derived from wild type (WT) or MFG-E8 deficient [knockout (KO)] into mice and monitored tumor growth. Tumor growth and M2 macrophages were each attenuated in subjects coimplanted with KO-MSC compared with WT-MSC. In both xenograft tumors and clinical specimens of melanoma, we found that MFG-E8 expression was heightened near blood vessels where MSC could be found. Through in vitro assays, we confirmed that WT-MSC–conditioned medium was more potent at inducing M2 macrophage polarization, compared with KO-MSC–conditioned medium. VEGF and ET-1 expression in KO-MSC was significantly lower than in WT-MSC, correlating in vivo with reduced tumor growth and numbers of pericytes and M2 macrophages within tumors. Overall, our results suggested that MFG-E8 acts at two levels, by increasing VEGF and ET-1 expression in MSC and by enhancing M2 polarization of macrophages, to increase tumor angiogenesis. Cancer Res; 76(14); 4283–92. ©2016 AACR.

Ischaemia-reperfusion (I/R) is involved in the development of various organ diseases. There has been increasing evidence that cutaneous I/R injury is associated with the pathogenesis of pressure ulcers (PUs), especially at the early stage presenting as non-blanchable erythema. However, there is no evidence-based treatment for early-stage PUs. Our objective was to assess the effects of topical steroid on the development of PUs after cutaneous I/R injury in mice. Cutaneous I/R was performed by trapping the dorsal skin between two magnetic plates for 12 h, followed by plate removal. Topical application of betamethasone butyrate propionate (BBP) in I/R areas significantly increased the size of PUs after I/R. The number of thromboses was increased, and CD31(+) vessels were decreased in the I/R area treated with topical BBP. The number of oxidative stress-associated DNA-damaged cells and apoptotic cells in the I/R area was increased by topical BBP treatment. In addition, the mRNA level of NADPH oxidase 4 (Nox4), the essential enzyme that produces reactive oxygen species, was significantly increased and that of NF-E2-related factor 2 (Nrf2), a transcription factor that regulates the expression of antioxidant proteins, was inhibited in the I/R area treated by BBP. The number of CD68(+) macrophages and the level of transforming growth factor-beta in lesional skin were also decreased by BBP. These results suggest that a topical steroid might accelerate the formation of PUs induced by cutaneous I/R injury by aggravating oxidative stress-induced tissue damage. Topical steroids might not be recommended for the treatment of acute-phase decubitus ulcers.

Liver cancer, which is most often associated with virus infection, is prevalent worldwide, and its underlying etiology and genomic structure are heterogeneous. Here we provide a whole-genome landscape of somatic alterations in 300 liver cancers from Japanese individuals. Our comprehensive analysis identified point mutations, structural variations (STVs), and virus integrations, in noncoding and coding regions. We discovered mutational signatures related to liver carcinogenesis and recurrently mutated coding and noncoding regions, such as long intergenic noncoding RNA genes (NEAT1 and MALAT1), promoters, CTCF-binding sites, and regulatory regions. STV analysis found a significant association with replication timing and identified known (CDKN2A, CCND1, APC, and TERT) and new (ASH1L, NCOR1, and MACROD2) cancer-related genes that were recurrently affected by STVs, leading to altered expression. These results emphasize the value of whole-genome sequencing analysis in discovering cancer driver mutations and understanding comprehensive molecular profiles of liver cancer, especially with regard to STVs and noncoding mutations.

Preoperative chemoradiotherapy (CRT) with gemcitabine (GEM) for pancreatic cancer is often accompanied by vertebral compression fractures (VCFs). This study aimed to establish the incidence of VCFs and identify the related risk factors (RFs) to elucidate how to decrease the overall incidence of VCF.We investigated 220 patients with resectable or borderline-resectable pancreatic cancers who had completed preoperative CRT between 2006 and 2011. The RFs associated with VCF were analyzed in a total of 1308 thoracolumbar vertebral bodies.Thirty-seven VCFs occurred in 25 patients (11%); the cumulative incidence at two years was 18.9%. Univariate analysis revealed female sex, age and high daily GEM concentration during radiotherapy as RFs for VCF. The multivariate mixed effects logistic regression model demonstrated that the most responsible factor was radiation dose (p0.001). We estimated the radiation condition resulting in a fracture incidence of ⩽5% by counting the patient's number of the three RFs. For patients with three factors, the mean vertebral dose was 22.0 Gy.The RFs for VCF after CRT were identified. The side effect of VCF might be avoided by regulating the radiation dose to neighboring vertebral bodies after considering the RFs.

Background: Neuroendovascular therapy is now the choice for the management of many neurovascular pathologies, and physicians with endovascular skills are in high demand. In addition to the traditional method of practicing hand movements to learn skills, a new strategy of practicing eye movements to learn skills is also attracting attention. This preliminary study explored the differences in gaze behavior depending on experience with endovascular procedures to be facilitated in future skill training in neuroendovascular therapy. Methods: Four physicians with experience of 3-412 neuroendovascular procedures wore eye-tracking devices during coil embolization of swine cervical arteries. Gaze metrics with direct correlations to the expertise of endovascular procedures were explored. Results: Gaze metrics with a positive direct correlation to experience included the proportion of fixation durations (PFD) in the screen area and the native images. Those with a negative direct correlation included the PFD in the off-screen area and the roadmap images and the average fixation durations in the off-screen and coil areas. During the parent artery occlusion procedure with detachable coils, more experienced operators preferred to look at native images rather than roadmap images and that less experienced operators tended to look down at their hands more frequently. Conclusion: This preliminary study demonstrated the feasibility of eye tracking to identify the differences in gaze behavior depending on the experience of endovascular procedures and may guide future eye-tracking studies in neuroendovascular therapy.