ライフサイエンスコーパス: SSc

1 SSc dermal fibroblasts retained most of the molecular di

2 SSc lung fibroblasts remained growth factor dependent, d

3 SSc pathophysiology involves systemic inflammation and o

4 SSc results in dysfunctional connective tissues with exc

5 SSc was induced in BALB/c mice by daily s.c. injections

6 SSc-ILD does not share the genetic risk architecture obs

7 SSc-ILD shares similarities with IPF, although clear dif

8 SSc-PAH patients showed significant thickening of Intima

9 l normalized ratios were 1.9 (IPAH) and 2.0 (SSc-PAH).

10 n fibroblasts from 10 normal subjects and 10 SSc patients, showing increased expression in SSc fibrob

11 A total of 138 SSc patients with technically adequate echocardiograms w

12 een SSc and periodontitis was examined in 58 SSc patients and 52 control patients, matched for age an

13 meta-analysis including GWAS data from 5,734 SSc patients, 4,588 CD patients and 14,568 controls of E

14 ere prospectively measured in IPAH (n=9) and SSc-PAH (n=15) patients at rest and during incremental a

15 ch induces collagen production by normal and SSc dermal fibroblasts.

16 o fibrotic responses in explanted normal and SSc fibroblasts and in 3D human skin equivalents, in par

17 ical oxygen species generation in normal and SSc fibroblasts.

18 ed in SSc skin biopsy samples, and serum and SSc fibroblasts, and in fibrotic skin tissues from mice.

19 genesis of immune-mediated diseases, such as SSc.

20 on to avoid missing secondary causes such as SSc.

21 LD in a unique, nationwide, population-based SSc cohort.Methods: ILD was assessed prospectively in th

22 The association between SSc and periodontitis was examined in 58 SSc patients an

23 A direct correlation between SSc prevalence and HLA-DPB1*13:01 allele frequency in mu

24 dy indicates a possible relationship between SSc and periodontitis.

25 We identified 4 new loci shared between SSc and CD, IL12RB2, IRF1/SLC22A5, STAT3 and an intergen

26 ferences observed in regional strain between SSc and control were unchanged after adjusting for RV sy

27 n contrast, Treg cells from skin affected by SSc produced significant amounts of IL-4 and IL-13.

28 the impaired angiogenesis that characterizes SSc.

29 Skin-resident and circulating SSc CD8(+)CD28(-) T cells produce high levels of the pro

30 Consequently, SSc patients may be complicated by erosive esophagitis a

31 es of freshly isolated and in vitro cultured SSc dermal fibroblasts were characterized using whole tr

32 26 in patients affected by diffuse cutaneous SSc (dcSSc); (ii) the ability of Transforming Growth Fac

33 ial in which patients with diffuse cutaneous SSc were treated with C-82 or placebo on opposite forear

34 xposed to HOCl developed a diffuse cutaneous SSc with pulmonary fibrosis and anti-DNA topoisomerase 1

35 -1 expression and pantothenic acid determine SSc severity and can be used as markers of disease sever

36 Remarkably, patients with diffuse SSc also had increased expression of vanin-1 in skin and

37 in skin biopsies from patients with diffuse SSc.

38 EGFL7 decreases COL1A1 expression in EOS SSc-FBs while EGFL7 silencing up-regulates COL1A1 expres

39 EGFL7 promotes migration/invasion of EOS SSc-FBs but not proliferation.

40 In contrast to healthy control fibroblasts, SSc fibroblasts proliferated in response to PDGFAA, wher

41 Finally, SSc-FBs, partially inhibit angiogenesis in organotypic c

42 sents an attractive therapeutic approach for SSc.

43 ide an overview of management approaches for SSc-associated Raynaud phenomenon and digital ulcers.

44 ts potential as a disease-modifying drug for SSc.

45 with the apex was significantly greater for SSc than for controls (P<0.0001 for interaction).

46 ti-factorial with many genetic risk loci for SSc generally and for specific clinical manifestations.

47 ped SSc dermal fibroblasts as a platform for SSc target and drug discovery.

48 the number of genome-wide hits reported for SSc thus far.

49 sing of the existing therapeutic targets for SSc and places them in the context of our evolving under

50 Current disease-modifying therapies for SSc predominantly target inflammatory and vascular pathw

51 capabilities of RSOM as an imaging tool for SSc and establishes it as a modality that facilitates mo

52 ages from state-of-the-art imaging tools for SSc, dermoscopy and high magnification capillaroscopy.

53 whether DMF is effective as a treatment for SSc dermal fibrosis.

54 y supports the use of DMF as a treatment for SSc dermal fibrosis.

55 migration of skin and lung fibroblasts from SSc patients and healthy controls.

56 Pathologic lung fibroblasts from SSc patients modify ECM during migration but remain grow

57 vitro upon challenge with serum signals from SSc patients or released by activated macrophages.

58 clinically affected and unaffected skin from SSc patients.

59 Genetically, SSc is multi-factorial with many genetic risk loci for S

60 However, SSc-PAH patients receiving warfarin within the previous

61 -associated pulmonary arterial hypertension (SSc-PAH) is a rare disease characterized by a very disma

62 hogenesis of fibrosis in SSc-associated ILD (SSc-ILD) involves cellular injury, activation/differenti

63 In SSc fibroblasts, DZNep dose-dependently reduced the expr

64 In SSc patients, serum CCN1 levels were significantly incre

65 In SSc-PAH patients, long-term warfarin was associated with

66 f IL-6Ralpha expression on ILC is altered in SSc.

67 m for CXCL4-mediated immune amplification in SSc, in which CXCL4 organizes "self" and microbial DNA i

68 VEGF did not induce angiogenesis in SSc ECs, but vitamin E or TXAR inhibition restored its e

69 tion of EZH2 restored normal angiogenesis in SSc via activating the Notch pathway, specifically by up

70 nin-1 can open new therapeutic approaches in SSc.

71 We examined HLA associations in SSc and its autoantibody subsets in a large, newly recru

72 IPAH patients, but were markedly blunted in SSc-PAH.

73 ed fibroblasts are the key effector cells in SSc responsible for the excessive production of collagen

74 ties in regional and global contractility in SSc patients.

75 ing pathways, but the exact role of CXCL4 in SSc pathogenesis is unclear.

76 s, ventricular-vascular coupling declined in SSc-PAH.

77 lar calcium recycling, was also depressed in SSc-PAH (0.32+/-0.05 versus 0.50+/-0.05; P=0.039).

78 s that RV functional reserve is depressed in SSc-PAH patients.

79 RV contractile reserve is depressed in SSc-PAH versus IPAH subjects, associated with reduced ca

80 In conclusion, EdCs in SSc might be defective because of commitment to a mesenc

81 tropic SNPs have opposite allelic effects in SSc and CD reveals the complexity of the molecular mecha

82 Both EZH2 and H3K27me3 were elevated in SSc dermal fibroblasts and endothelial cells compared wi

83 n of TXAR, RhoA, and ROCK1/2 was elevated in SSc ECs.

84 Levels of tenascin-C are elevated in SSc skin biopsy samples, and serum and SSc fibroblasts,

85 Sc patients, showing increased expression in SSc fibroblasts.

86 s demonstrate that overexpression of EZH2 in SSc fibroblasts and endothelial cells is profibrotic and

87 tibility and clinically apparent fibrosis in SSc skin, and can be an important driver of SSc pathogen

88 The pathogenesis of fibrosis in SSc-associated ILD (SSc-ILD) involves cellular injury, a

89 TGF-beta in the pathogenesis of fibrosis in SSc.

90 have provided the MCID estimates for FVC% in SSc-ILD based changes at 12 months from baseline in two

91 ulopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types f

92 ROCK activation were significantly higher in SSc ECs, whereas VEGF had no effect.

93 STAT3 signaling is hyperactivated in SSc in a TGFbeta-dependent manner.

94 correlate with type I interferon (IFN-I) in SSc blood, and that CXCL4-positive skin pDCs coexpress I

95 lysine-modifying enzymes were identified in SSc but not control fibroblast extracellular matrix prep

96 umab and elucidate the role of type I IFN in SSc.

97 ic and end-diastolic RV volumes increased in SSc-PAH patients to offset contractile deficits, whereas

98 gest alteration of cell-cell interactions in SSc lesions.

99 r the TXAR was activated by 8-isoprostane in SSc endothelial cells (ECs) and whether this pathway inh

100 eins; however, the roles of these ligases in SSc-TGF-beta signaling remain unclear.

101 Although fractional area change was lower in SSc patients than in controls (mean, 48.9 versus 55; P=0

102 to model pathogenic fibroblast migration in SSc in order to identify enhancing factors, measure the

103 plains EZH2-mediated fibroblast migration in SSc.

104 beta on Healthy Controls (HC) FBs but not in SSc-FBs.

105 eduction in BMPRII expression is observed in SSc lung tissue and fibroblasts.

106 al pneumonia pattern is commonly observed in SSc-ILD, whereas IPF is defined by usual interstitial pn

107 I, these mutations have not been observed in SSc-PAH.

108 stinal tract evaluation is justified only in SSc and not in morphea.

109 (adjusted hazard ratio, 1.37; P=0.21) or in SSc-PAH patients (adjusted hazard ratio, 1.60; P=0.15) i

110 ILD at baseline appears to affect outcome in SSc, suggesting that all patients with SSc should underg

111 d genes might be of therapeutic potential in SSc.

112 c signaling, indicating a role of PPP2R5e in SSc.

113 verview of important unanswered questions in SSc research that might inform the design of future stud

114 ough which tissue fibrosis may be reduced in SSc patients.

115 ger treatment to promote fat regeneration in SSc skin.

116 P2R5e axis controls profibrotic signaling in SSc lung fibroblasts.

117 Restoring adiponectin signaling in SSc patients therefore might represent an innovative pha

118 we sought to assess adiponectin signaling in SSc skin biopsies, and evaluate fibrosis in mice with ad

119 HL42 may ameliorate profibrotic signaling in SSc.

120 erexpression and the IFN-I-gene signature in SSc and outline a paradigm in which chemokines can drast

121 rogenous pattern of regional heart strain in SSc that is not detected by conventional measures of fun

122 pathy, autoimmunity, and oxidative stress in SSc.

123 ells represent a pathogenic T-cell subset in SSc and likely play a critical role in the early stage o

124 gradation, may promote PAH susceptibility in SSc and provide a unifying mechanism across different fo

125 migration individually but showed synergy in SSc cells.

126 transforming growth factor-beta (TGFbeta) in SSc skin fibroblasts.

127 ogenous danger signal that is upregulated in SSc and drives TLR4-dependent fibroblast activation, and

128 In a stepwise logistic regression, including SSc status, age, sex, education, smoking, alcohol consum

129 ion in mice with HOCl- and bleomycin-induced SSc.

130 c mice with hypochlorous acid (HOCl)-induced SSc by ELISA and Western blotting.

131 closamide in the mouse model of HOCl-induced SSc as well as the well-documented safety profile of thi

132 nn1 gene in vnn1(-/-) mice with HOCl-induced SSc prevented the development of characteristic features

133 In wild-type mice with HOCl-induced SSc, the vanin-1/pantetheinase pathway was dysregulated,

134 investigate, in a mouse model of ROS-induced SSc, the effects of niclosamide, an antihelmintic drug t

135 No approved medicines to manage lung SSc currently exist.

136 echanism by which cyclophosphamide mitigates SSc vasculopathy, we employed endothelial cell-specific

137 red with 40 age- and sex-matched healthy non-SSc controls.

138 at study end (2018) in the 630 incident Nor-SSc cases and 15 individually matched control subjects.

139 ssed prospectively in the Norwegian SSc (Nor-SSc) cohort, including all 815 patients with SSc residen

140 was assessed prospectively in the Norwegian SSc (Nor-SSc) cohort, including all 815 patients with SS

141 normalities were seen in 32 cases (68.1%) of SSc and none in morphea.

142 rtery thrombus formation was found in 19% of SSc-PAH patients.

143 ented abnormal reflux in 33 cases (80.5%) of SSc and no such abnormality in morphea.

144 symptoms were present in 39 cases (69.6%) of SSc which were mild in 22 (39.3%), moderate in 14 (25%),

145 esophagitis was seen in 17 cases (32.7%) of SSc and only two cases (7.14%) of morphea.

146 in, has been implicated in the activation of SSc fibroblasts.

147 ic genes and inhibited migratory activity of SSc fibroblasts.

148 ugh the first cross-disease meta-analysis of SSc and CD, we identified genetic variants with pleiotro

149 thogenesis, classification and assessment of SSc-associated digital ulcers are also covered, alongsid

150 The strength of the association of SSc with AL remained statistically significant after add

151 better understanding of the genetic basis of SSc and provides directions for future functional experi

152 and 31 newly and already diagnosed cases of SSc and morphea respectively were taken up for the study

153 y fibrosis within 5 years, the main cause of SSc mortality.

154 ral vascular abnormalities characteristic of SSc.

155 the fibrotic and inflammatory components of SSc and endothelial cell-specific Fli1-knockout mice rec

156 The course of SSc-ILD is variable, ranging from minor, stable disease

157 SSc skin, and can be an important driver of SSc pathogenesis.

158 ells (DCs) exhibit the highest enrichment of SSc-associated single-nucleotide polymorphisms (SNPs) an

159 s, genetic risk, and distinctive features of SSc-ILD and identification of robust prognostic biomarke

160 ity variants shows the potential function of SSc signals, with the identification of 43 robust target

161 in on the key pathological manifestations of SSc, including inflammation, vasculopathy, and tissue fi

162 ely inhibited proliferation and migration of SSc and healthy control fibroblasts and attenuated basal

163 ogy and may be a novel potential modifier of SSc fibroblast biology.

164 plicating epigenetics in the pathogenesis of SSc is discussed with an emphasis on the therapeutic pot

165 R-126 may be involved in the pathogenesis of SSc vasculopathy and fibrosis.

166 c pathways implicated in the pathogenesis of SSc, this Review discusses emerging treatment targets an

167 like receptors (TLRs) in the pathogenesis of SSc.

168 nvironmental triggers in the pathogenesis of SSc.

169 ested this pathway in the pathophysiology of SSc.

170 nes affecting the myofibroblast phenotype of SSc skin fibroblasts.

171 isease state such as the risk or presence of SSc-ILD, the activity of lung involvement and the likeli

172 Despite FPR overexpression, the response of SSc fibroblasts to the same agonists was greatly reduced

173 Sera of SSc patients with anti-Scl70 Abs, at higher risk of visc

174 aling pathways was observed among the set of SSc-CD common genetic risk loci.

175 lain the increased frequency and severity of SSc among the AA population.

176 at correlate negatively with the severity of SSc skin disease.

177 increased in the blood and affected skin of SSc patients, independent of patient age, and correlates

178 N2 and other fibrotic markers in the skin of SSc patients.

179 y play a critical role in the early stage of SSc skin disease.

180 l information in assessing the ILD status of SSc patients.

181 ve received little attention in the study of SSc or fibrosis.

182 ere antifibrillarin (AFA) antibody subset of SSc (odds ratio = 7.4).

183 -DPB1*13:01 allele with the ATA(+) subset of SSc in both AA and EA patients demonstrated a transances

184 ity was significantly reduced in a subset of SSc skin biopsies.

185 onal analysis in the autoantibody subsets of SSc revealed several associated amino acid residues, mos

186 anticentromere antibody-positive subsets of SSc, respectively, than with overall SSc risk, emphasizi

187 including 'red flags' that are suggestive of SSc.

188 andidate for molecular targeted therapies of SSc.

189 ht be a viable strategy for the treatment of SSc.

190 was to provide insights into the utility of SSc dermal fibroblast primary cells for therapeutic targ

191 the beneficial effect of cyclophosphamide on SSc vasculopathy.

192 sease, elicits a disease-modifying effect on SSc vasculopathy, such as fostering microvascular de-rem

193 cohol consumption, and body mass index, only SSc status, age, and sex remained significantly associat

194 1*11:02 alleles were associated with overall SSc risk, and the HLA-DRB1*08:04 allele was strongly ass

195 sets of SSc, respectively, than with overall SSc risk, emphasizing the importance of HLA in defining

196 monstrated the value of carefully-phenotyped SSc dermal fibroblasts as a platform for SSc target and

197 associated with SSc-ILD severity and predict SSc-ILD progression.

198 h (CRF-GSEA) proved successful in predicting SSc patient ILD status with a high degree of success (>8

199 Here we utilized primary SSc patient lung cells for high-throughput screening of

200 Risk factors for progressive SSc-ILD include older age, male sex, degree of lung invo

201 l-specific Fli1-knockout mice recapitulating SSc vasculopathy.

202 Scleroderma (SSc) is a complex disease that involves activation of th

203 ation of fibrotic diseases like scleroderma (SSc).

204 The pathogenesis of scleroderma (SSc) includes components of autoimmunity, vascular dysfu

205 Systemic scleroderma (SSc) is an autoimmune disease that affects over 2.5 mill

206 olvement in systemic sclerosis (scleroderma [SSc]) adversely affects long-term prognosis, often remai

207 Systemic sclerosis (scleroderma, SSc) is a devastating fibrotic disease with few treatmen

208 Systemic sclerosis (SSc or scleroderma) is an auto-immune disease characteri

209 isk loci associated with systemic sclerosis (SSc) and Crohn's disease (CD), some of which confer susc

210 tually all patients with systemic sclerosis (SSc) and is often the earliest clinical manifestation to

211 the association between systemic sclerosis (SSc) and periodontitis.

212 istent organ fibrosis in systemic sclerosis (SSc) are not known but emerging evidence implicates toll

213 bute to skin fibrosis in systemic sclerosis (SSc) by affecting the differentiation of pluripotent der

214 The autoimmune disease systemic sclerosis (SSc) causes microvascular changes that can be easily obs

215 equate vasculogenesis in systemic sclerosis (SSc) has been associated with an endothelial defect.

216 Systemic sclerosis (SSc) has the highest cause-specific mortality of all the

217 Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fi

218 Systemic sclerosis (SSc) is a clinically heterogeneous autoimmune disease ch

219 Systemic sclerosis (SSc) is a complex, multiorgan, autoimmune disease.

220 Systemic sclerosis (SSc) is a connective tissue disorder characterized by fi

221 Systemic sclerosis (SSc) is a disease at the intersection of autoimmunity an

222 Systemic sclerosis (SSc) is a multi-organ fibrotic disease with few treatmen

223 Systemic sclerosis (SSc) is a multisystem inflammatory and vascular disease

224 Systemic sclerosis (SSc) is a rare autoimmune disorder characterised by skin

225 Systemic sclerosis (SSc) is a rare systemic autoimmune disease characterized

226 Systemic sclerosis (SSc) is a spreading fibrotic disease affecting the skin

227 Skin fibrosis in systemic sclerosis (SSc) is accompanied by attrition of dermal white adipose

228 Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis

229 Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis

230 Systemic sclerosis (SSc) is an autoimmune disease that shows one of the high

231 Systemic sclerosis (SSc) is an autoimmune disorder characterized by fibrosis

232 Systemic sclerosis (SSc) is characterized by microangiopathy with impaired r

233 of <2 mm in diameter in Systemic Sclerosis (SSc) patients with (n = 17) and without (n = 5) associat

234 s in the pathogenesis of systemic sclerosis (SSc), a connective tissue disorder characterized by auto

235 lood of individuals with systemic sclerosis (SSc), a disease characterized by fibrotic and vascular p

236 long been implicated in systemic sclerosis (SSc), as expression of TGF-beta-regulated genes is incre

237 nts a major challenge in systemic sclerosis (SSc), but there are no precise, population-based data on

238 a standard treatment for systemic sclerosis (SSc)-related interstitial lung disease, elicits a diseas

239 rotic diseases including systemic sclerosis (SSc).

240 n the pathophysiology of systemic sclerosis (SSc).

241 T scans in patients with systemic sclerosis (SSc).

242 ic process is limited in systemic sclerosis (SSc).

243 study participants with systemic sclerosis (SSc).

244 PAH associated with systemic sclerosis (SSc-PAH) has a substantially worse prognosis than idiopa

245 on (PAH) associated with systemic sclerosis (SSc-PAH).

246 haracteristic feature of systemic sclerosis (SSc; scleroderma).

247 epresents an early serum biomarker of severe SSc and likely contributes to inflammation via chemokine

248 Additionally, we identify specific SSc subtype-associated signals.

249 sease and is time dependent, suggesting that SSc is a susceptibility factor.

250 The SSc disease module includes the emerging molecular targe

251 The SSc intrinsic gene expression subsets (inflammatory, fib

252 ase (-32.2% versus -23.3%; P=0.0001) for the SSc group.

253 tive into a drug's therapeutic effect in the SSc disease module.

254 emarkable in the inflammatory subsets of the SSc patients receiving TyKI therapy.

255 Suppression of the SSc-relevant pathways and alleviation of the skin fibros

256 iated genes and distinctive proximity to the SSc-relevant pathways, depending on their class and targ

257 t the gene expression changes underlying the SSc subsets may be long-lived, but mechanistically inter

258 te picture of the complex pathway leading to SSc disease pathogenesis.

259 rugs showed a wide variation in proximity to SSc-associated genes and distinctive proximity to the SS

260 h factor beta (TGF-beta) is directly tied to SSc.

261 d the contributions of diverse cell types to SSc remain unclear.

262 At matched exercise (25 W), SSc-PAH patients did not augment contractility (end-syst

263 C-reactive protein are both associated with SSc-ILD severity and predict SSc-ILD progression.

264 Over three-quarters of individuals with SSc develop pulmonary fibrosis within 5 years, the main

265 Results Sixteen participants with SSc (seven with pulmonary fibrosis at high-resolution CT

266 ted healthy volunteers and participants with SSc and high-resolution CT (within the previous 3 months

267 healthy volunteers and in participants with SSc without fibrosis, but not in participants with fibro

268 althy volunteers and study participants with SSc.

269 trospective study included 208 patients with SSc (median age, 57 years; 167 women) evaluated between

270 cells in the blood and skin of patients with SSc acquired abnormal production of effector cytokines.

271 The nailfolds of 23 patients with SSc and 19 controls were imaged using RSOM.

272 expression of this cytokine in patients with SSc and expression of the ST2 chain of the IL-33 recepto

273 study, nailfold capillaries of patients with SSc and healthy controls are imaged and compared with ea

274 heinase pathway in a cohort of patients with SSc and in controls.

275 from an independent cohort of patients with SSc confirm a significant increase of DCs in lesioned sk

276 Materials and Methods Patients with SSc evaluated between January 2009 and October 2017 who

277 Adjusted for age and sex, patients with SSc had a 0.52 mm higher AL compared with controls (95%

278 Treg cells in the blood of patients with SSc had a normal phenotype and did not produce T-effecto

279 In unadjusted analyses, patients with SSc had a significant 0.61 mm higher AL (95% confidence

280 cytosol of CD8(+) T cells from patients with SSc reduces T-bet translocation into the nucleus and its

281 SSc) cohort, including all 815 patients with SSc resident in the country from 2000 to 2012.

282 me in SSc, suggesting that all patients with SSc should undergo a baseline pulmonary function test an

283 the blood and lesional skin of patients with SSc with severe skin thickening.

284 duction by CD8(+) T cells from patients with SSc, focusing on T-bet modulation of GATA-3 activity, wh

285 us TLR activators in skin from patients with SSc, skin fibroblasts, and in mouse models of organ fibr

286 tudy demonstrates higher AL in patients with SSc, which remained significant after adjustment.

287 Although appropriately treated patients with SSc-ILD have better chances of stabilization and surviva

288 ound reduced BMPRII protein in patients with SSc-PAH and a relevant mouse model associated with incre

289 onal status in treatment-naive patients with SSc-PAH and may represent a very effective therapy for t

290 abel trial, 24 treatment-naive patients with SSc-PAH received ambrisentan 10 mg and tadalafil 40 mg d

291 ont combination PAH therapy in patients with SSc-PAH.

292 ction to assess CT images from patients with SSc-related ILD.Supplemental material is available for t

293 of digital vascular injury in patients with SSc.

294 n in CD8(+)IL-13(+) cells from patients with SSc.

295 expressed in fibroblasts from patients with SSc.

296 n multiple clinical cohorts of patients with SSc.

297 ight contribute to fibrosis in patients with SSc.

298 eased in the skin and lungs of patients with SSc.

299 ung fibrosis occurs in ~80% of patients with SSc; 25% to 30% develop progressive interstitial lung di

300 sults: At baseline, 50% of the subjects with SSc (n = 324) had ILD by HRCT and 46% displayed pulmonar