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Insulin-like growth factor-1 receptor (IGF-1R) has been made an attractive anticancer target due to its overexpression in cancers. However, targeting it has often produced the disappointing results as the role played by cross talk with numerous downstream signalings. Here, we report a disobliging IGF-1R signaling which promotes growth of cancer through triggering the E3 ubiquitin ligase MEX3A-mediated degradation of RIG-I. The active β-arrestin-2 scaffolds this disobliging signaling to talk with MEX3A. In response to ligands, IGF-1Rβ activated the basal βarr2 into its active state by phosphorylating the interdomain domain on Tyr64 and Tyr250, opening the middle loop (Leu130‒Cys141) to the RING domain of MEX3A through the conformational changes of βarr2. The models of βarr2/IGF-1Rβ and βarr2/MEX3A could interpret the mechanism of the activated-IGF-1R in triggering degradation of RIG-I. The assay of the mutants βarr2Y64A and βarr2Y250A further confirmed the role of these two Tyr residues of the interlobe in mediating the talk between IGF-1Rβ and the RING domain of MEX3A. The truncated-βarr2 and the peptide ATQAIRIF, which mimicked the RING domain of MEX3A could prevent the formation of βarr2/IGF-1Rβ and βarr2/MEX3A complexes, thus blocking the IGF-1R-triggered RIG-I degradation. Degradation of RIG-I resulted in the suppression of the IFN-I-associated immune cells in the TME due to the blockade of the RIG-I-MAVS-IFN-I pathway. Poly(I:C) could reverse anti-PD-L1 insensitivity by recovery of RIG-I. In summary, we revealed a disobliging IGF-1R signaling by which IGF-1Rβ promoted cancer growth through triggering the MEX3A-mediated degradation of RIG-I.
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The well-known insulin-like growth factor 1 (IGF1)/IGF-1 receptor (IGF-1R) signaling pathway is overexpressed in many tumors, and is thus an attractive target for cancer treatment. However, results have often been disappointing due to crosstalk with other signals. Here, we report that IGF-1R signaling stimulates the growth of hepatocellular carcinoma (HCC) cells through the translocation of IGF-1R into the ER to enhance sarco-endoplasmic reticulum calcium ATPase 2 (SERCA2) activity. In response to ligand binding, IGF-1Rβ is translocated into the ER by β-arrestin2 (β-arr2). Mass spectrometry analysis identified SERCA2 as a target of ER IGF-1Rβ. SERCA2 activity is heavily dependent on the increase in ER IGF-1Rβ levels. ER IGF-1Rβ phosphorylates SERCA2 on Tyr990 to enhance its activity. Mutation of SERCA2-Tyr990 disrupted the interaction of ER IGF-1Rβ with SERCA2, and therefore ER IGF-1Rβ failed to promote SERCA2 activity. The enhancement of SERCA2 activity triggered Ca2+ER perturbation, leading to an increase in autophagy. Thapsigargin blocked the interaction between SERCA2 and ER IGF-1Rβ and therefore SERCA2 activity, resulting in inhibition of HCC growth. In conclusion, the translocation of IGF-1R into the ER triggers Ca2+ER perturbation by enhancing SERCA2 activity through phosphorylating Tyr990 in HCC.
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Objective:To investigate the expression and clinical significance of peptide/histidine transporter solute carrier family 15 member 4 (SLC15A4) in peripheral blood mononuclear cells (PBMCs) of patients with systemic lupus erythematosus (SLE).Methods:Fifty-five patients with SLE were divided into active SLE group and stable SLE group according to SLE disease activity index (SLEDAI) score, and 13 healthy volunteers were used as controls. The expression of SLC15A4 in PBMCs were detected by Western blot method. Moreover, the correlation between the expression of SLC15A4 and clinical and laboratory parameters of SLE patients were analyzed. The expression of SLC15a4 in the three groups was compared based on one-way analysis of variance (ANOVA), and the correlation between SLC15A4 expression level and clinical indicators was analyzed by Pearson correlation.Results:The expression levels of SLC15A4 in active SLE group, stable SLE group and healthy control group were (0.96±0.19), (0.88±0.14), (0.78±0.24), respectively. The expression level of SLC15A4 in SLE with active disease was higher than that in healthy controls ( F=4.47, P=0.015). In addition, the expression of SLC15A4 in PBMCs of SLE patients was positively correlated with the quantity of anti-double stranded DNA (anti-dsDNA) antibody, erythrocyte sedimentation rate (ESR) and systemic lupus erythematosus disease activity index (SLEDAI) ( r=0.29, P=0.031; r=0.36, P=0.007; r=0.32, P=0.017, respectively). However, the expression of SLC15A4 in PBMCs had no significant correlation with 24-h urinary protein ( r=0.45, P=0.127) and C3 ( r=0.20, P=0.133). Conclusion:SLC15A4 is involved in the pathogenesis of SLE and its expression in PBMCs of SLE patients can be used as an index to evaluate disease activity.
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In order to develop a method to more accurately determine the surgical boundary of extramammary Paget′s disease, reflectance confocal microscopy was used to determine the tumor boundary followed by modified extended excision in 2 cases of pathologically diagnosed extramammary Paget′s disease of the vulva. No residual tumor was observed in the resection margins by postoperative pathological examination at 4 positions (12, 3, 6 and 9 o′clock) , and follow-up showed no recurrence 1 year later.
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Objective The aims of this study were to evaluate the morbidity of osteoporosis and the relationship between bone mineral density ( BMD ) and bone metabolic markers in the patients with spine degeneration disease needing surgery, at the same time to observe the influence of type 2 diabetes mellitus on bone metabolism and BMD.Methods This retrospective analysis included 139 patients suffered by spine degeneration disease needing surgery from the October 2013 to October 2014 in Beijing Jishuitan Hospital. Lumbar BMD was measured by quantitative computed tomography ( QCT) before surgery.Serum N-terminal propeptide of type I procollagen ( PINP) , βC-terminal cross-linked telopeptide of type I collagen (β-CTX), osteocalcin (OC) , 25-hydroxyvitamin D[25(OH)D], parathyroid hormone (PTH), calcium and phosphorus were quantified simultaneously.The relationship between the results of lumbar BMD measured by QCT and bone metabolic markers was analyzed by partial correlation.The differences of bone metabolic markers among three groups classified according to BMD were performed by one-way ANOVA and analysis of covariance.The influence factors of lumbar BMD measured by QCT were analyzed by multifactor linear regression.T-test was used to analyze the differences of BMD and bone metabolic markers between two groups with and without type 2 diabetes mellitus.Results The average age of 139 patients was(62.74 ± 6.83) years old.Lumbar BMD revealed that the percentage of osteoporosis, osteopenia and normal BMD were 40.2%(56/139) , 43.8% (61/139) and 16% (22/139) separately.The percentage was 47%(66/139) in subjects with 25(OH)D below 30 nmol/L.The percentage of subjects with the concentrations of 25 ( OH ) D between 30-50 nmol/L was 40% ( 55/139 ) , while the percentage of subjects with the concentrations of 25(OH)D between 50-125 nmol/L was only 13% (18/139).Partial correlation analysis revealed that lumbar BMD measured by QCT was negatively correlated with PINP ( r=-0.352, P<0.01) ,β-CTX ( r=-0.356, P<0.01 ) and OC ( r=-0.276, P=0.001 ) with gender and type 2 diabetes mellitus as covariates.Along with the age of patients increasing and BMD reducing, the levels of PINP,β-CTX and OC increased gradually and the differences were statistically significant ( F=11.575, P<0.01;F=11.550, P<0.01; F=9.738, P<0.01).Multiple linear regression analysis revealed that age and PINP were the main factors that influenced the change of BMD in the patients with spine degeneration disease needing surgery (β=-1.863, t=-5.425, P<0.01;β=-0.393, t=-2.061, P=0.041) .Subjects were divided into diabetes group and non-diabetes group according to the clinical diagnosis and whether having abnormal serum glucose.The levels of PINP (36.56 ±14.56 versus 49.51 ±16.68μg/L) ,β-CTX (0.39 ±0.20 versus 0.52 ±0.21 μg/L) and OC (14.21 ±5.13 versus 20.74 ±6.84 μg/L) in serum between two groups had significant differences (t=3.648, P<0.01;t=2.754, P<0.01;t=4.573, P<0.01) .Conclusions There was prevalence of osteoporosis, osteopenia and vitamin D deficiency in the patients with spine degeneration disease needing surgery.The patients with high level of PINP and age were more prone to appear lower BMD which increasing the risk of osteoporosis.The patients combined with type 2 diabetes mellitus had suppressed bone markers which maybe the risk factor, independent of BMD, increasing fracture risk.
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Objective The aim of this study was to describe the clinical outcomes and improvement of clivo-axial angle (CAA) during the posterior approach surgery of upper cervical anomaly instability patients.Methods All of 32 patients with symptomatic upper cervical anomaly instability were followed up from 2004 Apr.to 2014 Aug.in which 1 patient was excluded because of reoperation.There were 10 patients with OS odontiodeum,5 with odontoid deformity,4 with Klipple-Feil syndrome,4 with atlantoaxial dislocation,4 with atlantoaxial instability,1 with rheumatoid arthritis,1 with old odontoid fracture,1 with OS odontoideum and foramen magnum stenosis,1 with basilarinvagination and Klipple-Feil syndrome.They were all performed posterior reduction internal fixation and fusion,and then released spinal cord compression with the promotion of CAA.The patients were divided into two groups on the basis of decompression or not:non-decompression group 17 cases (male 8 cases,female 9 cases;age 13-65 years old,average 50.1 years old) and decompression group 14 cases (male 7 cases,female 7 cases;age 19-68 years old,average 49.6 years old).The CAA numbers were measured and compared.The clinic date was compared between preoperatively and postoperatively,which included Neck Disability Index and Nurick Classification System for Myelopathy.Results All patients were followed up,the follow-up time of non-decompression group was 0.7-10.7 years,average 2.9 years;the follow-up time of compression group was 0.3-5.5 years,average 2.9 years.Analysis of CAA,NDI and Nurick score were performed with t-test.The postoperative CAA,NDI and Nurick score improved significantly compared to preoperative ones.There was no difference between non-decompression group and decompression group.One patient felt nausea and vomited,one got soleal vein thrombosis,one had a swelling face and blurring vision and one had decompression syndrome after operation,all of these were improved using respectively therapy.No such serious complications as injury to vertebral artery,infection or internal fixation loosening occurred.Conclusion Neck ability and spinal cord function was significantly improved through increasing CAA for the upper cervical anomaly instability patients underwent posterior reduction internal fixation and fusion.
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Objective To measure the clivus-axial angle (CAA) of Chinese,provide a normal value,and explore the correlation between CAA with cervico-medullary angle (CMA).Methods The CAA was measured on the CT of cervical spine in 225 Chinese with normal cranio-vertebral junction (CVJ).Both the CAA and the CMA were measured on the MRI of cervical spine in 117 subjects.All measurements were performed under a bone window (window level,300 Hu; window width,1 000 Hu) with an accuracy of 0.01°.A regression analysis was used for analyzing the correlation between CAA and CMA.The angle between the clivus plane and the straight line parallel to that of the posterior margin of the C2 vertebral body was defined as CAA; moreover,the angle between the strajght line parallel to the ventral side of the cervical spinal cord and the straight line parallel to that of the ventral side of the medulla oblongata was defined as CMA.Two experienced spinal surgeons performed the measurements.The CAA and CMA were measured three times,and the mean value was considered as the result.Results The CAA of 225 subjects was 133.52°-172.16° (156.93°±6.53°).The 95％ confidence interval was 145.10°-170.19° in male and 142.67°-168.47° in female.If the patients were divided into five groups according to their age,a comparison of these groups showed that there were no significant differences among the groups with respect to CAA.It showed that there was consistency between the CAAs measured with MRI and CT.The CMA for 117 patients ranged from 130.38° to 168.75° with a mean value of 154.17°±6.54°,and its 95％ confidence interval ranged from 141.35° to 166.99°.If the patients were distributed according to their gender or to their age,there were no significant differences among the groups.The relationship between CAA and CMA was linearity,and the regression coefficient was as high as 0.95 (P=0.007).Conclusion The normal CAA of Chinese is from 133.52° to 172.16°.The 95％ confidence interval goes from 145.10° to 170.19° in male,and 142.67° to 168.47° in female,close to CMA.It is valuable for measuring the compression of spinal cord,which can be accessed easily during the procedure.
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Objective To evaluate the efficacy and safety of triethanolamine cream in the treatment of skin ulcer. MethodsA multicenter,single-blind,randomized,positive-control study was conducted.One-hundred and twenty patients aging 18-65 years with skin ulcer were randomly classified into the test and control group at a ratio of 2 ∶ 1 to be treated with triethanolamine cream and recombinant bovine basic fibroblast growth factor gel respectively for 4 weeks.The healing rate of ulcer,granulation tissue production rate and epithelialization rate were calculated.Results After the beginning of treatment,the condition of all patients was improved with time.In total,76 out of 80 triethanolamine-treated patients and 38 out of 40 basic fibroblast growth factor gel-treated patients completed the 4-week trial.Significant differences were observed in the healing rate of ulcer,epithelialization rate and granulation tissue production rate between the test and control group (71.05％ vs.34.21％,P =0.0002; 85％ vs.50％,P =0.0001; 66.25％ vs.37.5％,P =0.0035).No adverse events occurred in any of the patients.Conclusions Triethanolamine cream seems superior to recombinant bovine basic fibroblast growth factor gel with regard to the healing rate of ulcer,epithelialization rate and granulation tissue production rate,and may be a promising drug for the treatment of skin ulcer.
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ObjectiveTo investigate the correlation between the methylation status of HLA class Ⅰ genes(HLA-A, -B and -C) in psoriatic epidermis and disease severity in patients with psoriasis vulgaris. MethodsDNA specimens were obtained from the lesional and nonlesional epidermis of 46 patients with psoriasis vulgaris and from the normal skin of 28 human controls. Methylation specific PCR (MSP) was conducted to detect the methylation status of CpG islands in the promoter region of HLA-A, -B and -C genes. The severity of psoriasis was evaluated by psoriasis area and severity index(PASI) scores. ResultsThe percentage of promoter methylation of HLA-B and HLA-C genes was 4.35％(2/46) and 21.74％(10/46), respectively in nonlesional epidermis, 4.35％ (2/46) and 4.35％ (2/46), respectively in lesional epidermis from these patients. No methylation was observed for the promoter of HLA-A, -B or -C gene in the normal control epidermis or for that of HLA-A gene in the nonlesional or lesional epidermis from the patients. The frequency of HLA-C gene promoter methylation in the nonlesional epidermis was significantly higher than that in the lesional epidermis and control epidermis, but was uncorrelated to the disease severity. No significant difference was observed for the methylation frequency of HLA-A or -B gene promoter among the three groups of specimens. Conclusion Abnormal methylation of HLA-C gene promoter is observed in patients with psoriasis vulgaris.
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Objective To investigate and evaluate the biomechanical property of the skin in pig's back in order to provide the essential theoretical basis for clinical and skin products.Method Taking the skin in pig's back as experimental material,the monotonic tensile and cyclic tension-tension tests with difierent loading rates was researohed respectivaly.Meanwhile,with different loading directions and stress levels the creep and cy-clic tension-tension tests were also been studied experimentally.Result The capacity of resisting tensile,creep and cyclic deformation of pig's skin in the direction along the Langer's line is stronger than that perpen-dicuiar to the Langer's line.The creep curve of pig's skin is load-dependent and consisted of three phases a-bout deceleration phase,stabilization phase and destruction stage.Pig's skin exhibits apparent ratcheting un-der asymmetry stress cycle.Ratcheting deformation displays significant mean stress,stress amplitude and loading speed dependence.Condusion Based on the experiment,the biomechanics property of skin's vis-coelasticity and anisotropic feature have been sysmarie stadied,it's provide necessaw theoretical fundation for clinical and leather products.
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Objective To observe the treatment outcome of different surgical strategies in nevus-like benign melanocytic tumors with various size and shape in the head and face. Methods A total of 180 cases with nevus-like benign melanocytic tumors received surgical treatment from February 2005 to February 2008.The following surgical strategies were selected, including direct excision, partial excision, skin grafting, skin soft tissue expanding and application of local flaps (inter-flap, diamond-shaped flap, A-T flap, kite flap, etc),to treat skin lesions in the head, nose, cheek and eyelid. All patients were followed up for 3 to 6 months. Results The incisions for direct and partial excision were well healed without infection or recurrence. Of those cases treated with local flaps or expander, 3 (1 on the face and 2 on the head) experienced recurrence, 2 on the head suffered from post-operational infection. Conclusion To select different surgical strategies according to lesion size, sites and shape may lead to a favorable cosmetic result in the treatment of nevus-like benign melanocytic tumors in the head and face.
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Objective To investigate the role of connective tissue growth factor(CTGF)in the pathogenesis of keloid.Methods The expression of CTGF mRNA was detected with semiquantitative RT-PCR technique in keloid tissue and adjacent uninvolved skin from30patients.The expression of CTGF pro-tein was determined by SP immunohistochemistry in5keloid tissues and5normal skin samples.Results Compared with normal controls,the mean levels of CTGF mRNA expression were significantly increased in both keloid lesions and adjacent uninvolved skin(P0.05).In immunohistochemistry study,CTGF protein was strongly expressed in keloid tissue,whereas it was not expressed in normal skin.Transitional phenomenon was observed from strong to weak expression of CTGF protein at the edge of keloid tissue.Conclusion These findings suggest that CTGF may be related to the development of persistent fibrotic tissue formation in keloids.CTGF may be a new potential target for the therapeutic intervention of keloids.
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Objective To report the surgical approach for the treatment of giant or extensive skin lesions due to the infection of human papilloma virus (HPV). Method Surgical treatment was performed for 10 patients with verruca vulgris, 20 with condyloma acuminatum, and 8 with epidermodyplasia verruciformis, whose giant or extensive lesions were poorly responsive to routine non-surgical therapy. Results Recurrence of lesions was found in 2 of 10 patients with verruca vulgris and 5 of 20 condyloma acuminatum in 6 months after operation, with a total recurrent rate of 25%. The extensive skin lesions were removed and the functions of affected limbs were recovered in patients with epidermodyplasia verruciformis after operation, however, the long-term topical retinoids was needed to control the recurrence of the lesions. Conclusion Surgical approach is effective for the treatment of the giant or extensive skin lesions due to HPV infection.
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Objective To validate the therapeutic effect of Centella Triterpenes after surgical excision and X-ray irradiation.Methods Surgical excision was performed on one hundred and six patients with keloid,after operation superficial X-ray irradiation was given to the patients.Then,they were divided into three groups:36cases in group A treated with higher dose of Centella Triterpenes;39cases in group B treated with lower dose of Centella Triterpenes;31cases took placebo as controls.All patients were followed up for12months after treatment.Results All patients were healed completely after operation.The effective rate was significantly higher in Centella Triterpenes groups than that in the control group(P