Publications by authors named "Xiaohu Deng"

41 Publications

From Lab Formulation Development to CTM Manufacturing of KO-947 Injectable Drug Products: a Case Study and Lessons Learned.

AAPS PharmSciTech 2021 Jun 2;22(5):168. Epub 2021 Jun 2.

WuXi AppTec Co., Ltd., 288 Fute Zhong Road, Waigaoqiao Pilot Free Trade Zone, Shanghai, 200131, China.

Formulation development of KO-947-K mesylate injectable drug products was described. Solution formulations were initially attempted, and key parameters such as drug concentration, buffer, pH, complexing agent, and tonicity modifying agent were carefully evaluated in the lab setting, mainly focusing on solubility and chemical stability. A lead solution formulation was advanced to a scaleup campaign. An unexpected stability issue was encountered, and the root cause was attributed to the heterogeneous liquid freezing process of the formulated solution at -20°C, which had not been captured in the lab setting. A lyophilized product was then designed to overcome the issue and supplied to the phase I clinical trial.
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http://dx.doi.org/10.1208/s12249-021-02059-xDOI Listing
June 2021

Eosinophilic fasciitis associated with generalized morphea and IgA nephropathy.

Dermatol Ther 2020 07 20;33(4):e13641. Epub 2020 Jun 20.

Department of Rheumatology, PLA General Hospital, Beijing, China.

Eosinophilic fasciitis (EF) is a rare connective tissue disease characterized by increased peripheral blood eosinophils and diffuse fasciitis, generalized morphea (GM) is a subtype of localized scleroderma, and IgA nephropathy is a chronic glomerulonephritis caused by abnormal deposition of IgA in the mesangial area of the glomeruli. We describe a 49-year-old male patient with hard skin, cutaneous hyperpigmentation, and proteinuria. The patient had suffered from a long disease course of hard skin, while urine protein was newly detected. Finally, the clinical presentation and physical examination, limb MRI, skin biopsy, and renal biopsy confirmed the diagnosis of eosinophilic fasciitis associated with generalized morphea and IgA nephropathy. This case is the first report of EF associated with GM and IgA nephropathy.
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http://dx.doi.org/10.1111/dth.13641DOI Listing
July 2020

Improvement on Selective Laser Sintering and Post-Processing of Polystyrene.

Polymers (Basel) 2019 Jun 1;11(6). Epub 2019 Jun 1.

School of Mechatronics Engineering, University of Electronic Science and Technology of China, Chengdu 611731, China.

Amorphous polymers are heavily utilized materials in selective laser sintering (SLS) due to their good dimensional accuracy. However, sintered parts of amorphous polymers cannot be used as functional parts owing to their poor forming performance, including their low relative densities and tensile strength. Therefore, post-processing methods are employed to enhance the mechanical properties of amorphous polymers SLS parts without damaging their relatively high dimensional accuracy. In this study, the forming process of selective laser sintering (SLS) and post-processing on polystyrene (PS) was investigated. The orthogonal experiment was designed to obtain the optimal combination of process parameters. The effect of a single process parameter and the laser volumetric energy density (LVED) on dimension accuracy and warpage of the sintered parts were also discussed. In addition, a three-dimensional (3D) thermal model was developed to analyze the temperature fields of single-layer SLS parts and PS powder sintering mechanism. Then, infiltrating with epoxy resin was employed to enhance the mechanical properties of the PS parts. Good resin-infiltrated formulation was obtained based on the mechanical property tests and fractured surface analysis. This research provides guidance for SLS process and post-processing technology in polymers.
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http://dx.doi.org/10.3390/polym11060956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6631003PMC
June 2019

When brucellosis met the Assessment of SpondyloArthritis international Society classification criteria for spondyloarthritis: a comparative study.

Clin Rheumatol 2019 Jul 26;38(7):1873-1880. Epub 2019 Feb 26.

Department of Rheumatology, Chinese PLA General Hospital, 28 Fuxing Rd, Beijing, 100853, China.

Objectives: To distinguish brucellosis patients fulfilling the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for spondyloarthritis (SpA) from SpA patients.

Methods: Brucellosis patients diagnosed from September 2012 to December 2017 who met the ASAS classification criteria for SpA were analyzed with clinical characteristics and laboratory and imaging examinations. Axial or peripheral SpA patients were respectively included into the comparative analysis with a 4:1 ratio.

Results: Twenty-two brucellosis (10 axial and 12 peripheral) patients (male, 16 cases; 72.72%; mean (S.D.) age, 40.23 (16.49) years) and 88 SpA patients were included. All brucellosis patients had been misdiagnosed or considered as SpA before admission to our center. The brucellosis patients had shorter disease duration (axial, P = 0.001; peripheral, P = 0.108). More than half (59.09%) of the patients had contact history with livestock. The low back pain (LBP) of brucellosis patients was generally less improved with exercise (axial, P = 0.001; peripheral, P = 0.008). More brucellosis patients had myalgia (axial, P < 0.001; peripheral, P = 0.071) or fever (axial, P < 0.001; peripheral, P = 0.107). None of them had positive HLA-B27. Blood culture tests were performed in all brucellosis patients and only 4 (18.18%) were positive. Twenty (90.91%) brucellosis patients were gold-immunochromatographic assay (GICA) positive. Bone marrow edema and bone erosion in sacroiliac joints were respectively detected in 100% (10/10) and 90% (9/10) axial brucellosis patients by MRI. Adjacent muscle involvement was found in 80% (8/10) of the patients.

Conclusions: Indicators including disease duration, contact history of livestock, features of LBP, myalgia, fever, and HLA-B27 can help the differential diagnosis of brucellosis and SpA. GICA test and sacroiliac joints MRI can furtherly confirm the diagnosis of brucellosis.
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http://dx.doi.org/10.1007/s10067-019-04481-wDOI Listing
July 2019

Detection of Erosions in Sacroiliac Joints of Patients with Axial Spondyloarthritis Using the Magnetic Resonance Imaging Volumetric Interpolated Breath-hold Examination.

J Rheumatol 2019 11 15;46(11):1445-1449. Epub 2019 Feb 15.

From the Rheumazentrum Ruhrgebiet, Herne, Ruhr-University Bochum, Herne, Germany; and the Department of Rheumatology, Chinese PLA General Hospital, Beijing, China.

Objective: The volumetric interpolated breath-hold examination (VIBE) magnetic resonance imaging (MRI) technique can visualize erosive cartilage defects in peripheral joints. We evaluated the ability of VIBE to detect erosions in sacroiliac joints (SIJ) of patients with axial spondyloarthritis (axSpA) compared to the established T1-weighted MRI sequence and computed tomography (CT).

Methods: MRI (T1-weighted and VIBE) and CT scans of SIJ of 109 patients with axSpA were evaluated by 2 blinded readers based on SIJ quadrants (SQ). Erosions were defined according to Assessment of Spondyloarthritis international Society (ASAS) definitions. Scores were recorded if readers were in agreement.

Results: Erosions were less frequently detected by CT (153 SQ) than by T1-weighted MRI (182 SQ; p = 0.008) and VIBE-MRI (199 SQ; p < 0.001 vs CT and p = 0.031 vs T1-weighted MRI). Taking CT as the gold standard, the sensitivity of VIBE-MRI (71.2%) was higher than that for T1-weighted MRI (63.4%), with similar specificity (87.3% vs 88%, respectively). In linear regression analysis, younger age was significantly associated with occurrence of erosions independently in VIBE-MRI (β = 0.384, p < 0.001) and T1-weighted MRI (β = 0.369, p < 0.001) compared to CT.

Conclusion: The VIBE-MRI sequence was more sensitive than T1-weighted MRI in identifying erosive damage in the SIJ, especially in younger patients. This might be due to the ability of VIBE-MRI to identify structural changes in the cartilage that have not yet extended to the underlying bone, where CT seems to be superior.
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http://dx.doi.org/10.3899/jrheum.181304DOI Listing
November 2019

Progressive pseudorheumatoid dysplasia with new-found gene mutation of Wntl inducible signaling pathway protein 3.

Pediatr Rheumatol Online J 2018 Sep 10;16(1):55. Epub 2018 Sep 10.

Department of Rheumatology, Hainan Branch of Chinese People's Liberation Army General Hospital, Haitang Bay, Sanya, China.

Background: As one kind of osteochondrodysplasia, progressive pseudorheumatoid dysplasia (PPD) is also known as spondyloepiphyseal dysplasia tarda with progressive arthropathy or arthropathy progressive pseudorheumatoid of childhood. PPD is a very rare disease, especially in China, and has an estimated prevalence of 1/1000000 due to lacking definite prevalence survey. It is an autosomal recessive disorder caused by gene mutation of Wntl inducible signaling pathway protein 3 (WISP3). Its basic pathological change is persistent degeneration and loss of articular cartilage in multiple joints. Its clinical appearances include bone enlargement, platyspondyly, irregular endplate, secondary osteoarthritis, extensive osteoporosis, joint rigidity and function loss. Clinical diagnosis of PPD is made based on clinical appearance and imaging examinations, whereas its definite diagnosis depends on gene sequencing. PPD has no severe effect on life span, but causes high disability rate and very poor prognosis. There are only case reports with limited information in China.

Case Presentation: One female patient was diagnosed as PPD and secondary osteoarthritis. She had typical clinical appearance and imaging examinations, and received individualized therapeutic regimens. She had a gene mutation (c.72delT, p.T24TfsX4) of WISP3. This gene mutation has not been reported by previous literatures and included in Single Nucleotide Polymorphism Database.

Conclusions: As the first time, this paper reported a patient with PPD caused by new-found gene mutation (c.72delT, p.T24TfsX4) of WISP3.
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http://dx.doi.org/10.1186/s12969-018-0272-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131911PMC
September 2018

Mechanical Properties Optimization of Poly-Ether-Ether-Ketone via Fused Deposition Modeling.

Materials (Basel) 2018 Jan 30;11(2). Epub 2018 Jan 30.

School of Mechatronics Engineering, University of Electronic Science and Technology of China, Chengdu 611731, China.

Compared to the common selective laser sintering (SLS) manufacturing method, fused deposition modeling (FDM) seems to be an economical and efficient three-dimensional (3D) printing method for high temperature polymer materials in medical applications. In this work, a customized FDM system was developed for polyether-ether-ketone (PEEK) materials printing. The effects of printing speed, layer thickness, printing temperature and filling ratio on tensile properties were analyzed by the orthogonal test of four factors and three levels. Optimal tensile properties of the PEEK specimens were observed at a printing speed of 60 mm/s, layer thickness of 0.2 mm, temperature of 370 °C and filling ratio of 40%. Furthermore, the impact and bending tests were conducted under optimized conditions and the results demonstrated that the printed PEEK specimens have appropriate mechanical properties.
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http://dx.doi.org/10.3390/ma11020216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5848913PMC
January 2018

Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor.

Cell 2018 01;172(3):578-589.e17

Janssen Research & Development, Spring House, PA, USA.

KRAS was recently identified to be potentially druggable by allele-specific covalent targeting of Cys-12 in vicinity to an inducible allosteric switch II pocket (S-IIP). Success of this approach requires active cycling of KRAS between its active-GTP and inactive-GDP conformations as accessibility of the S-IIP is restricted only to the GDP-bound state. This strategy proved feasible for inhibiting mutant KRAS in vitro; however, it is uncertain whether this approach would translate to in vivo. Here, we describe structure-based design and identification of ARS-1620, a covalent compound with high potency and selectivity for KRAS. ARS-1620 achieves rapid and sustained in vivo target occupancy to induce tumor regression. We use ARS-1620 to dissect oncogenic KRAS dependency and demonstrate that monolayer culture formats significantly underestimate KRAS dependency in vivo. This study provides in vivo evidence that mutant KRAS can be selectively targeted and reveals ARS-1620 as representing a new generation of KRAS-specific inhibitors with promising therapeutic potential.
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http://dx.doi.org/10.1016/j.cell.2018.01.006DOI Listing
January 2018

A Dipolar Cycloaddition Reaction To Access 6-Methyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridines Enables the Discovery Synthesis and Preclinical Profiling of a P2X7 Antagonist Clinical Candidate.

J Med Chem 2018 01 20;61(1):207-223. Epub 2017 Dec 20.

Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States.

A single pot dipolar cycloaddition reaction/Cope elimination sequence was developed to access novel 1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine P2X7 antagonists that contain a synthetically challenging chiral center. The structure-activity relationships of the new compounds are described. Two of these compounds, (S)-(2-fluoro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone (compound 29) and (S)-(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone (compound 35), were found to have robust P2X7 receptor occupancy at low doses in rat with ED values of 0.06 and 0.07 mg/kg, respectively. Compound 35 had notable solubility compared to 29 and showed good tolerability in preclinical species. Compound 35 was chosen as a clinical candidate for advancement into phase I clinical trials to assess safety and tolerability in healthy human subjects prior to the initiation of proof of concept studies for the treatment of mood disorders.
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http://dx.doi.org/10.1021/acs.jmedchem.7b01279DOI Listing
January 2018

Identification of Novel Proteins Interacting with Vascular Endothelial Growth Inhibitor 174 in Renal Cell Carcinoma.

Anticancer Res 2017 08;37(8):4379-4388

Beijing Institute for Cancer Research, Department of Urology, Beijing Cancer Hospital, Beijing, P.R. China

Background/aim: Vascular endothelial growth inhibitor (VEGI) is a multipotential cytokine that plays a role in regulating immunity, anti-angiogenesis, and inhibiting tumor growth. However, the proteins that interact with it are still unknown. In the present study, we examined the proteins that interact with VEGI174 and their expression in renal cell carcinoma (RCC).

Materials And Methods: The proteins that interact with VEGI174 were identified using western blot, pull-down assay, and mass spectrometry. The expressions of VEGI174 and the interacting proteins were examined in RCC and were compared to normal renal tissues using immunohistochemical staining and RNA-seq respectively.

Results: The results of the mass spectrometric analysis showed that ACLY, ENO1, ZIK1, AKR1C3, and MYC may interact with VEGI174. When compared to the TCGA database, the expression level of VEGI174 in RCC was lower than that in normal kidney using RNAseq (p<0.001). The expression levels of ACLY, ENO1, ZIK1, AKR1C3 and MYC in RCC were higher than those in normal kidney (p<0.05, all of above factors). Moreover, immunochemical staining results also showed that the expression levels of AKR1C3 in RCC were significantly higher those that in normal kidney (p<0.001) and was also positively correlated with higher RCC stage and grade.

Conclusion: Taken together, our findings showed that VEGI174 may interact with ACLY, ENO1, ZIK1, AKR1C3, and MYC. The expression of ACLY, ENO1, AKR1C3 and MYC is increased in RCC. AKR1C3 was a new factor that may correlate with the progression of RCC. The results indicated that VEGI174 has more functions than we currently know in the development and progression of RCC.
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http://dx.doi.org/10.21873/anticanres.11832DOI Listing
August 2017

Protein of Vascular Endothelial Growth Inhibitor 174 Inhibits Epithelial-Mesenchymal Transition in Renal Cell Carcinoma .

Anticancer Res 2017 08;37(8):4269-4275

Beijing Institute for Cancer Research, Department of Urology, Beijing Cancer Hospital, Beijing, P.R. China

Background: Vascular endothelial growth inhibitor (VEGI) is a member of the tumor necrosis factor superfamily, identified as an anti-angiogenic cytokine. However, the effect of VEGI on epithelial-mesenchymal transition (EMT) in renal cell carcinoma (RCC) is still unknown.

Materials And Methods: In this study, protein VEGI174 was designed and synthesized. Renal cell carcinoma A498 cells were implanted into immune-deficient mice to establish tumor models. Two groups were included: control group treated with saline, and VEGI174-treated group. Data of tumor growth were collected every 3 to 4 days. Two weeks later, the tumor specimens were harvested for immunohistochemical staining of EMT markers (E-cadherin, N-cadherin, vimentin).

Results: Compared to the saline-treated group, the VEGI174-treated group showed significant inhibition of tumor growth (p<0.05). The expression of E-cadherin was significantly higher in the VEGI174-treated group compared to the saline-treated group (p<0.01). However, the expression of N-cadherin and vimentin were reduced in the VEGI174-treated group.

Conclusion: Our findings indicate that VEGI174 prevents progression and tumor metastasis through inhibiting EMT in RCC in vivo. This may provide a new approach for the treatment of RCC.
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http://dx.doi.org/10.21873/anticanres.11819DOI Listing
August 2017

LC/MS/MS Profiling of Tissue Oxysterols and its Application in Dextran Sodium Sulphate Induced Mouse Colitis Models.

Curr Top Med Chem 2017 ;17(24):2781-2790

Janssen R&D, LLC., 3210 Merryfield Row, San Diego, CA 92121. United States.

We have developed a workflow to extract, separate, and semi-quantify bioactive oxysterols from mouse colon tissues and fecal matters using solid- and liquid-phase extractions, enzymatic and chemical modifications, and stable-isotope dilution LC/MS/MS. The method was applied to a dextran sodium sulphate (DSS)-induced mouse colitis model, which revealed that one particular dihydroxycholesterol (diOHC), 7α,25-diOHC, was significantly elevated in both colon tissue and fecal matters of mice with colitis compared to that in naïve mice. The extent of 7α,25-diOHC elevation was positively correlated with colitis severity.
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http://dx.doi.org/10.2174/1568026617666170713165519DOI Listing
September 2017

Vascular endothelial growth inhibitor 174 and its functional domains inhibit epithelial-mesenchymal transition in renal cell carcinoma cells in vitro.

Int J Mol Med 2017 Aug 19;40(2):569-575. Epub 2017 Jun 19.

Department of Urology, Peking University First Hospital, Beijing 100034, P.R. China.

The present study was carried out to investigate the effects of vascular endothelial growth inhibitor 174 (VEGI174) and its functional domains (V7 and V8) on epithelial‑mesenchymal transition (EMT) in renal cell carcinoma (RCC) cells in vitro. The RCC cell lines A498 and 786‑O were used in this study. Based on our preliminary study, we selected full‑length VEGI174 and its functional domains (V7 and V8) as the target genes in this study. Plasmids containing VEGI174, V7 or V8 transgenes were constructed and transfected into A498 and 786‑O cell lines. Cytological activity was tested during cell culture. Quantitative PCR and western blot analysis were performed to determine the expression levels of EMT markers (E‑cadherin, vimentin, β‑catenin and Slug). Overexpression of VEGI174, V7 or V8 did not have a significant influence on cell viability (P>0.05). The mRNA level of E‑cadherin was significantly upregulated, while that of vimentin was downregulated in A498VEGIexp, A498V7exp, A498V8exp, 786‑OVEGIexp, 786‑OV7exp and 786‑OV8exp cells compared with the cells containing the empty plasmid controls (P<0.05). The western blot results showed that changes in protein expression levels were consistent with the changes in mRNA expression. Both the mRNA and protein expression levels of β‑catenin and Slug were downregulated in the A498VEGIexp, A498V7exp, A498V8exp, 786‑OVEGIexp, 786‑OV7exp and 786‑OV8exp cells. In conclusion, overexpression of VEGI174, V7 or V8 inhibited EMT in A498 and 786‑O cells. Notably, V7 and V8 are two effective functional domains of VEGI174 that have the potential to be studied for peptide synthesis and the treatment of RCC.
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http://dx.doi.org/10.3892/ijmm.2017.3033DOI Listing
August 2017

Intra-tumour molecular heterogeneity of clear cell renal cell carcinoma reveals the diversity of the response to targeted therapies using patient-derived xenograft models.

Oncotarget 2017 Jul;8(30):49839-49850

Department of Urology, Beijing Cancer Hospital, Beijing Institute for Cancer Research, Beijing, P.R. China.

Inter- and intra-tumour molecular heterogeneity is increasingly recognized in clear cell renal cell carcinoma (ccRCC). It may partially explain the diversity of responses to targeted therapies and the various clinical outcomes. In this study, a 56-year-old male ccRCC patient with multiple metastases received radical nephrectomy and resection of the metastatic tumour in chest wall. The surgical specimens were implanted into nude mice to establish patient-derived xenograft (PDX) models with KI2367 model derived from the primary tumour and KI2368 model from the metastastic tumour. The two modles were treated with Sorafenib, Sunitinib, Axitinib, combined Sorafenib/Sunitinib, or alternating therapy of Sorafenib and Sunitinib. Significant anti-tumour activity was found in KI2367 treated with Sorafenib/Sunitinib monotherapy, combined Sorafenib/Sunitinib, and alternating therapy of Sorafenib/Sunitinib (P<0.05) but not in that treated with Axitinib monotherapy. In contrast, KI2368 was significantly responsive to Sunitinib monotherapy, combined Sorafenib/Sunitinib therapy and alternating therapy of Sorafenib/Sunitinib but not responsive to Sorafenib and Axitinib monotherapy (P<0.05). RNAseq of the two models demonstrated that the expression levels of 1,725 genes including the drug targeted genes of PDGFA, PDGFB and PDGFRA were >5-fold higher in KI2367 than in KI2368 and the expression levels of 994 genes were > 5-fold higher in KI2368 than in KI2367. These results suggest the presence of intra-tumour molecular heterogeneity in this patient. This heterogeneity may influence the response to targeted therapies. Multiple biopsy, liquid biopsy and genomic analysis of intra- tumour molecular heterogeneity may help guide a more precise and effective plan in selecting targeted therapies for ccRCC patients.
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http://dx.doi.org/10.18632/oncotarget.17765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5564811PMC
July 2017

Vascular Endothelial Growth Inhibitor, a Cytokine of the Tumor Necrosis Factor Family, is Associated With Epithelial-Mesenchymal Transition in Renal Cell Carcinoma.

Appl Immunohistochem Mol Morphol 2018 Nov/Dec;26(10):727-733

Department of Urology, Peking University Cancer Hospital, Beijing Institute for Cancer Research.

Previous studies have revealed that the activation of the epithelial-mesenchymal transition (EMT) endows metastatic properties upon cancer cells to promote invasion and migration. In this study, immunohistochemical analysis was performed in 50 cases of clear cell renal cell carcinoma (RCC) and paired normal kidney tissues. We detected the expression of vascular endothelial growth inhibitor (VEGI) and EMT markers (E-cadherin, fibronectin, and Slug) and recorded the clinical, pathologic, and follow-up (median follow-up: 79.0 mo) information. The expression of VEGI and E-cadherin was significantly lower in RCC tissues compared with normal kidney tissues (P<0.001). However, the expression of fibronectin and Slug was higher in RCC tissues (P<0.05). VEGI and EMT marker expression marginally differed in tumor size and stage. Significant differences were found in the pathologic grade (P<0.05). The Spearman correlation analysis suggested a positive correlation between VEGI and E-cadherin (r=0.451, P<0.01). A negative correlation was shown between VEGI and fibronectin (r=-0.465, P<0.01). There was also a negative correlation between VEGI and Slug (r=-0.758, P<0.01). During the 79.0 months (range, 7 to 119 mo) of follow-up, 6 patients died due to RCC, and the tumor-free survival rate was 88% (44/50). We did not find a significant correlation between VEGI/EMT markers (E-cadherin, fibronectin, and Slug) and overall survival (P>0.05). Our findings indicate that VEGI plays an important role in EMT in RCC. It suggests that VEGI may be investigated as a disease biomarker and therapeutic target in RCC.
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http://dx.doi.org/10.1097/PAI.0000000000000517DOI Listing
September 2019

Treatment application of rivaroxaban in Chinese patients with livedoid vasculopathy.

J Pain Res 2017 17;10:621-624. Epub 2017 Mar 17.

Department of Rheumatology, Chinese People's Liberation Army General Hospital, Beijing, People's Republic of China.

Livedoid vasculopathy (LV) is a chronic prothrombotic disease of cutaneous micro-circulation resulting in cutaneous ischemia and infarction. As a rare disease, LV has an estimated incidence of ten cases per million. Not only correct diagnosis but also effective treatments are very difficult for patients with LV. Due to the lack of large-scale studies in this rare disease, LV poses a great challenge to the doctors, and existing treatment has always been an individual attempt with off-label application. The main goals in the treatment of patients with LV are to avoid the repeated occurrence of active cutaneous lesions and prevent painful ulceration and irreversible scarring. The current report describes the cases of three Chinese patients with LV receiving rivaroxaban treatment, an oral direct inhibitor of factor Xa inhibitor, and observes the treatment effect of rivaroxaban during the follow-up. As an injection-free alternative to low-molecular-weight heparin (LMWP) and monitoring-free alternative to warfarin, rivaroxaban improves the quality of life and enhances the compliance of patients. All patients consider rivaroxaban as more tolerable than previous drugs and, therefore, continue the application of rivaroxaban, effectively improving the treatment effect of drugs and successfully avoiding the repeated occurrence of active cutaneous lesions. Treatment application of rivaroxaban in Chinese patients with LV successfully avoids the recurrence of active cutaneous lesions and prevents the progressive ulceration and scarring.
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http://dx.doi.org/10.2147/JPR.S133462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5364015PMC
March 2017

Cobalt Chloride-induced Hypoxia Induces Epithelial-mesenchymal Transition in Renal Carcinoma Cell Lines.

Ann Clin Lab Sci 2017 Jan;47(1):40-46

Department of Urology, Peking University First Hospital, Beijing, People's Republic of China

Objective: To establish epithelial-mesenchymal transition (EMT) models in renal cell carcinoma (RCC) cell lines.

Materials And Methods: The RCC cell lines A498 and 786-O were used in the experiment and CoCl was used to simulate hypoxia. Cells were cultured with different concentrations of CoCl. Morphology and changes in cytoactivity were observed. After CoCl2 treatment, the expression of HIF-1α and the changes of EMT-related molecules (E-cadherin, fibronectin) were detected.

Results: Cell conjunctions of CoCl-treated groups were loose and scattered compared to the control. CoCl did not promote or attenuate the viability of A498 cells at low dosage, but when the concentration of CoCl reached 250 μM, cell activity gradually declined. In contrast, CoCl induced 786-O cell proliferation in the range of 50 μ M-200 μ M, but inhibited cell growth at dosages higher than 200 μM. The expression of E-cadherin was significantly down-regulated, and fibronectin was up-regulated in both A498 and 786-O cell lines under CoCl-simulated hypoxia in comparison with normoxic conditions (<0.01).

Conclusions: CoCl-induced hypoxia could induce EMT in RCC cell lines. The models will help us further study the mechanisms of EMT and investigate novel therapeutic targets to inhibit tumor invasion and metastasis.
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January 2017

Fluoro analogs of bioactive oxy-sterols: Synthesis of an EBI2 agonist with enhanced metabolic stability.

Bioorg Med Chem Lett 2016 10 12;26(20):4888-4891. Epub 2016 Sep 12.

Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, United States. Electronic address:

Synthesis of several 7-hydroxy oxysterols and their potential roles as signaling molecules in the innate and adaptive immune responses is discussed. Discovery of a new, fluorinated, synthetic analog of the 7α,25-dihydroxycholesterol-the endogenous ligand of GPR 183 (EBI2), a G-protein coupled receptor highly expressed upon Epstein-Barr virus infection is described. Fluoro oxysterol 12 showed good metabolic stability while maintaining excellent EBI2 agonist activity.
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http://dx.doi.org/10.1016/j.bmcl.2016.09.029DOI Listing
October 2016

Allyl-Assisted, Cu(I)-Catalyzed Azide-Alkyne Cycloaddition/Allylation Reaction: Assembly of the [1,2,3]Triazolo-4,5,6,7-tetrahydropyridine Core Structure.

J Org Chem 2015 Nov 20;80(21):11003-12. Epub 2015 Oct 20.

Janssen Research & Development LLC , 3210 Merryfield Row, San Diego, California 92121, United States.

We report a Cu(I)-catalyzed azide-alkyne-allyl halide three-component reaction for a one-pot synthesis of 1,4-disubstituted 5-allyl-1,2,3-triazoles. The allyl moiety provides not only the electrophile but also a coordinating ligand to Cu, which is essential for the reaction to occur under mild conditions. A concise synthesis of a potential drug candidate 1 is realized based on this key reaction.
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http://dx.doi.org/10.1021/acs.joc.5b02174DOI Listing
November 2015

[An analysis of abnormal magnetic resonance imaging of sacroiliac joints in patients misdiagnosed as spondyloarthritis].

Zhonghua Nei Ke Za Zhi 2014 Sep;53(9):724-9

Department of Rheumatology, Chinese PLA General Hospital, Beijing 100853, China. Email:

Objective: To study the imaging features of sacroiliac joints (SIJ) in patients who were misdiagnosed as spondyloarthritis (SpA).

Methods: A total of 34 patients with chief complaint of back pain and misdiagnosed as SpA from January 2007 to April 2013 in Department of Rheumatology Chinese PLA General Hospital were enrolled. The imaging, clinical manifestations, laboratory examinations data were analyzed.

Result: The main reason for misdiagnosis as SpA was because of sacroiliitis presenting on imaging. The final diagnoses included 24 patients as SIJ infection, 4 patients as neoplastic diseases, 2 patients as metabolic bone diseases, 2 patients as sacroiliac joint degeneration, 1 patient as gout of sacroiliac joint, 1 patient as diffuse idiopathic bone hypertrophy. For patients with infection, there were 10 patients receiving X-ray and 22 patients receiving CT of SIJ. However, 5 and 7 patients had negative results respectively. These patients with infection had abnormalities in MRI including all with bone marrow edema, 21 patients with erosion of bone and joint, 22 patients with muscle involved. As to the patients with malignancies, SIJ CT scan appeared normal. Bone marrow edema and erosion in MRI were found in all neoplasm patients expect one as ependymoma. Adjacent muscles were involved in the patient with Ewing's sarcoma. Either X-ray or CT in other patients demonstrated obvious abnormalities, but only mild erosion of bone was found in MRI.

Conclusion: Bone marrow edema of SIJ in MRI represented not only in patients with SpA. Rheumatologists should analyze the clinical manifestations and laboratory examinations comprehensively in order to avoid the misdiagnoses.
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September 2014

Oxysterols are agonist ligands of RORγt and drive Th17 cell differentiation.

Proc Natl Acad Sci U S A 2014 Aug 4;111(33):12163-8. Epub 2014 Aug 4.

Janssen Research and Development, Spring House, PA 19002.

The RAR-related orphan receptor gamma t (RORγt) is a nuclear receptor required for generating IL-17-producing CD4(+) Th17 T cells, which are essential in host defense and may play key pathogenic roles in autoimmune diseases. Oxysterols elicit profound effects on immune and inflammatory responses as well as on cholesterol and lipid metabolism. Here, we describe the identification of several naturally occurring oxysterols as RORγt agonists. The most potent and selective activator for RORγt is 7β, 27-dihydroxycholesterol (7β, 27-OHC). We show that these oxysterols reverse the inhibitory effect of an RORγt antagonist, ursolic acid, in RORγ- or RORγt-dependent cell-based reporter assays. These ligands bind directly to recombinant RORγ ligand binding domain (LBD), promote recruitment of a coactivator peptide, and reduce binding of a corepressor peptide to RORγ LBD. In primary cells, 7β, 27-OHC and 7α, 27-OHC enhance the differentiation of murine and human IL-17-producing Th17 cells in an RORγt-dependent manner. Importantly, we showed that Th17, but not Th1 cells, preferentially produce these two oxysterols. In vivo, administration of 7β, 27-OHC in mice enhanced IL-17 production. Mice deficient in CYP27A1, a key enzyme in generating these oxysterols, showed significant reduction of IL-17-producing cells, including CD4(+) and γδ(+) T cells, similar to the deficiency observed in RORγt knockout mice. Our results reveal a previously unknown mechanism for selected oxysterols as immune modulators and a direct role for CYP27A1 in generating these RORγt agonist ligands, which we propose as RORγt endogenous ligands, driving both innate and adaptive IL-17-dependent immune responses.
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http://dx.doi.org/10.1073/pnas.1322807111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143045PMC
August 2014

[Clinical significance of high sensitivity C-reactive protein for evaluating the efficacy of etanercept in active ankylosing spondylitis].

Zhonghua Yi Xue Za Zhi 2014 Jan;94(3):204-7

Department of Rheumatology, Chinese PLA General Hospital, Beijing 100853, China.

Objective: To evaluate the therapeutic efficacy of etanercept for active ankylosing spondylitis (AS) at different levels of high sensitivity C-reactive protein (hs-CRP).

Methods: Patients with active AS received a subcutaneous injection of etanercept (50 mg, once per week) for 12 weeks. According to the baseline hs-CRP, they were divided into group A (hs-CRP ≤ 3 mg/L), group B (3 < hs-CRP ≤ 11 mg/L), group C (11< hs-CRP ≤ 26 mg/L) and group D (hs-CRP > 26 mg/L). The following clinical data were recorded: VAS (visual analogue score) of spinal pain, time of morning stiffness, patient global assessment (PGA), BASDAI, BASFI, ASDAS, indices of joint tenderness on baseline and week 12. And the percents of ASAS20, ASAS40, ASAS partial remission, BASDAI20, BASDAI50, ASDAS clinically important improvement and major improvement responders were assessed in all groups.

Results: A total of 161 patients finished the study, including group A (n = 18), group B (n = 47), group C (n = 49) and group D (n = 47). Group B was similar with group A. Groups C and D were higher than group A in terms of ASDAS improvement score, percents of ASDAS clinically important improvement and major improvement responders.

Conclusion: Patients with moderately and significantly elevated hs-CRP may achieve ASDAS improvement more easily than those with normal and mildly elevated levels.
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January 2014

Vascular endothelial growth inhibitor 174 is a negative regulator of aggressiveness and microvascular density in human clear cell renal cell carcinoma.

Anticancer Res 2014 Feb;34(2):715-22

Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, No. 8, Gongti South Road, Chaoyang District, Beijing 100020, P.R. China. or Kan Gong, Department of Urology, Peking University First Hospital, Xicheng District, Beijing, P.R. China. E-mail:

Aims: To evaluate the role and expression of vascular endothelial growth inhibitor isoform 174 (VEGI 174) in the microvessels and its correlation with microvessel density (MVD) and prognosis of clear cell renal cell carcinoma (CCRCC).

Materials And Methods: Immunohistochemical analysis was performed in 98 cases of renal cell carcinoma and paired normal kidney tissues for VEGI 174 and CD34. The clinical, pathological and follow-up (median follow-up: 54.5 months) information were recorded and analyzed against the VEGI174 and MVD expression.

Results: There was an inverse correlation between VEGI 174 and MVD (r=-0.420, p<0.05) in normal human renal tissues and CCRCC specimens. Compared to normal kidney tissues, the expression of VEGI 174 was significantly lower in CCRCC (0.420±0.151 vs 0.107±0.063, p<0.01, respectively). On the contrary, MVD was higher in CCRCC specimens than in normal renal tissues (72.020±31.709 vs. 53.480±11.071, p<0.01, respectively). The expression of VEGI 174 in G1+G2 tumors was significantly higher than in G3 tumors (0.132±0.055 vs. 0.044±0.025, p<0.05, respectively). There was also a statistical significance in the expression of VEGI 174 in patients of different ages (<60y, 0.102±0.054 vs. ≥60 years, 0.117±0.083, p<0.01, respectively). However, between the staining of VEGI 174 and other pathological parameters (gender, tumour size and stage), there were no significant statistical differences (p>0.05). In addition, MVDs did not differ statistically by pathological grade, stage, gender, age or tumor size (p>0.05). Four patients died of CCRCC-related conditions during follow-up. However, no relationship between the expression of VEGI 174/MVD and overall survival was found in the study (p>0.05).

Conclusion: VEGI 174 has a significant role in angiogenesis in CCRCC, and appears to be a negative regulator of aggressiveness during the development and progression of CCRCC.
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February 2014

Expression of bone morphogenetic protein-10 (BMP10) in human urothelial cancer of the bladder and its effects on the aggressiveness of bladder cancer cells in vitro.

Anticancer Res 2013 May;33(5):1917-25

Department of Urology, Beijing Chaoyang Hospital, Capital Medical University No. 8, Gongti South Road, Chaoyang District, Beijing 100020, P.R. China.

Background: Bone morphogenetic protein-10 (BMP10), a novel member of the bone morphogenetic protein (BMP) family, has been indicated as a possible tumour suppressor in prostate and breast cancer. However, its role in urothelial tumours remains unknown. In the present study, we examined the role of BMP10 in urothelial cancer cells and the expression of BMP10 in human urethelial cancer of the bladder.

Materials And Methods: The expression of BMP10 was examined in human bladder tissues and in the T24 human bladder cancer cell line using immunochemical staining and reverse transcription polymerase chain reaction (RT-PCR), respectively. The biological impact of modifying BMP10 expression, through genetic manipulation, in urothelial cancer cells was evaluated using in vitro models.

Results: mRNA for BMP10 and receptors of BMPs was expressed in T24 cell lines. BMP10 protein expression was observed in normal urothelial and stromal cells, but was found to be decreased in or absent from urothelial cancer cells. The frequency of positive staining in normal tissues (9/9) was significantly higher than that in urothelial cancer tissues (6/15) (p=0.007). T24 cells were transfected with BMP10 expression plasmid. It was further demonstrated that overexpression of BMP10 reduced the growth rate of T24 cells, and markedly reduced the motility, and adhesion of T24 cells in vitro. No significant effects were seen on in vitro invasiveness of T24 cells following BMP10 transfection.

Conclusion: Expression of BMP10 protein is reduced in cancer cells of bladder tumours. Overexpression of BMP10 has an inhibitory effect on the growth, adhesion, and migration of bladder cancer cells in vitro. This would suggest a potential tumour suppressor role of BMP10 in bladder cancer.
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May 2013

Identification of benzofuran central cores for the inhibition of leukotriene A(4) hydrolase.

Bioorg Med Chem Lett 2013 Feb 5;23(3):811-5. Epub 2012 Dec 5.

Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA.

Leukotrienes (LT's) are known to play a physiological role in inflammatory immune response. Leukotriene A(4) hydrolase (LTA(4)H) is a cystolic enzyme that stereospecifically catalyzes the transformation of LTA(4) to LTB(4). LTB(4) is a known pro-inflammatory mediator. This paper describes the identification and synthesis of substituted benzofurans as LTH(4)H inhibitors. The benzofuran series demonstrated reduced mouse and human whole blood LTB(4) levels in vitro and led to the identification one analog for advanced profiling. Benzofuran 28 showed dose responsive target engagement and provides a useful tool to explore a LTA(4)H inhibitor for the treatment of inflammatory diseases, such as asthma and inflammatory bowel disease (IBD).
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http://dx.doi.org/10.1016/j.bmcl.2012.11.074DOI Listing
February 2013

Thalidomide reduces recurrence of ankylosing spondylitis in patients following discontinuation of etanercept.

Rheumatol Int 2013 Jun 11;33(6):1409-13. Epub 2012 Nov 11.

Department of Rheumatology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853, China.

A previous study showed that most ankylosing spondylitis (AS) patients presented recurrence within 6 months post-discontinuation of etanercept. How to reduce recurrence following discontinuation of etanercept should be further researched. In this study, 111 ankylosing spondylitis patients meeting the Assessment in AS 20 % response (ASAS20) criteria after 12-week administration of etanercept were randomized into three groups: Group I, 150 mg thalidomide once/day; Group II, 1 g sulfasalazine, twice/day; Group III, NSAIDs for the maintenance treatment. The patients were regularly followed up once a month, and AS recurrence was evaluated with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Bath Ankylosing Spondylitis Functional Index (BASFI), the patient global assessment (PGA), and rachialgia. The follow-up lasted for 1 year, and AS recurrence was considered as the end of a visit. Finally, 100 patients completed the follow-up study, of whom 30 were in Group I, 33 in Group II, and 37 in Group III. The average follow-up period was 5.1 ± 3.9 months and the longest lasted for 12 months. At the end of the follow-up study, the recurrence rates in Groups I, II, and III were, respectively, 60.0 % (18/30), 84.8 % (28/33), and 89.2 % (33/37). The recurrence rates of Group I were statistically significantly lower than that of Group II and III (P = 0.0265; P = 0.0053), while there was no significant difference between Group II and Group III. In addition, we found that PGA, C-reactive protein (CRP), and spinal inflammation could be regarded as predictive factors for AS recurrence by analysis with the Cox proportional hazard model. This study points to a new way for maintenance therapy of AS following discontinuation of etanercept and reveals several useful indicators for prediction of AS recurrence.
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http://dx.doi.org/10.1007/s00296-012-2571-5DOI Listing
June 2013

Identification of structural motifs critical for epstein-barr virus-induced molecule 2 function and homology modeling of the ligand docking site.

Mol Pharmacol 2012 Dec 28;82(6):1094-103. Epub 2012 Aug 28.

Janssen Pharmaceutical Research and Development, San Diego, California, USA.

Epstein-Barr virus-induced molecule 2 (EBI2) (also known as G-protein-coupled receptor 183) is a G-protein-coupled receptor (GPCR) that is best known for its role in B cell migration and localization. Our recent deorphanization effort led to the discovery of 7α,25-dihydroxycholesterol (7α,25-OHC) as the endogenous ligand for EBI2, which provides a tool for mechanistic studies of EBI2 function. Because EBI2 is the first GPCR known to bind and to be activated by an oxysterol, the goal of this study was to understand the molecular and structural bases for its ligand-dependent activation; this was achieved by identifying structural moieties in EBI2 or in 7α,25-OHC that might affect receptor-ligand interactions. By using a series of chemically related OHC analogs, we demonstrated that all three hydroxyl groups in 7α,25-OHC contributed to ligand-induced activation of the receptor. To determine the location and composition of the ligand binding domain in EBI2, we used a site-directed mutagenesis approach and generated mutant receptors with single amino acid substitutions at selected positions of interest. Biochemical and pharmacological profiling of these mutant receptors allowed for structure-function analyses and revealed critical motifs that likely interact with 7α,25-OHC. By using a hybrid β(2)-adrenergic receptor-C-X-C chemokine receptor type 4 structure as a template, we created a homology model for EBI2 and optimized the docking of 7α,25-OHC into the putative ligand binding site, so that the hydroxyl groups interact with residues Arg87, Asn114, and Glu183. This model of ligand docking yields important structural insight into the molecular mechanisms mediating EBI2 function and may facilitate future efforts to design novel therapeutic agents that target EBI2.
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http://dx.doi.org/10.1124/mol.112.080275DOI Listing
December 2012

Direct, metal-free amination of heterocyclic amides/ureas with NH-heterocycles and N-substituted anilines in POCl3.

J Org Chem 2011 Oct 7;76(20):8262-9. Epub 2011 Sep 7.

Johnson & Johnson Pharmaceutical Research & Development, LLC, 3210 Merryfield Row, San Diego, California 92121, United States.

A POCl(3)-mediated, direct amination reaction of heterocyclic amides/ureas with NH-heterocycles or N-substituted anilines is described. Compared to the existing methods, this operationally simple protocol provides unique reactivity and functional group compatibility because of the metal-free, acidic reaction conditions. The yields are generally excellent.
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http://dx.doi.org/10.1021/jo201425qDOI Listing
October 2011

Similarities and differences between spondyloarthritis in Asia and other parts of the world.

Curr Opin Rheumatol 2011 Jul;23(4):334-8

Department of Rheumatology, Chinese PLA General Hospital, Beijing, China.

Purpose Of Review: Spondyloarthritis (SpA) is a group of diverse interrelated inflammatory arthritides, which share multiple clinical features as well as common genetic predisposing factors. Ankylosing spondylitis (AS) is regarded as the most typical subtype. The purpose of this article is to review relevant studies conducted in Asia and other parts of the world, which may open a window to a better understanding of the epidemiology, clinical feature, diagnosis, and management of this condition.

Recent Findings: The prevalence, clinical feature, diagnosis, and therapy of SpA and its correlation with HLA-B27 in Asia are generally similar to other parts of the world. NSAIDs form the cornerstone of the treatment for AS. The new treatment options with tumor necrosis factor (TNF)-α blocking agents seem a breakthrough for patients with SpA refractory to conventional treatment. Recent results showed that thalidomide was an effective, well tolerated, and economic option for refractory AS patients, especially in maintaining disease remission after etanercept or infliximab treatment was discontinued.

Summary: The similarities between spondyloarthritides in Asia and other parts of the world are major and the differences are minor. Because of the major socioeconomic burden and poor access to expensive means of treatment of SpA in Asia, the rheumatologists and physicians in Asia are working hard to look for effective but cheaper alternatively regimens for refractory SpA patients. Thalidomide may be a potentially effective option for patients who cannot afford biologicals in undeveloped areas.
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http://dx.doi.org/10.1097/BOR.0b013e32834640a9DOI Listing
July 2011

Protecting-group-free synthesis of a dual CCK1/CCK2 receptor antagonist.

Org Biomol Chem 2011 Apr 2;9(8):2654-60. Epub 2011 Mar 2.

Johnson & Johnson Pharmaceutical Research and Development, L.L.C. 3210 Merryfield Row, San Diego, CA 92121, USA.

In our pursuit of an efficient, protecting-group-free synthesis of the dual CCK1/CCK2 receptor antagonist 1, we have developed chemoselective conditions for sulfonamide formation reaction in pure water and a PhNMe(2) mediated carboxamide formation, both in the presence of a carboxylic acid. Practical synthesis of an unnatural, chiral β-aryl-α-amino acid is also described.
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http://dx.doi.org/10.1039/c0ob01004aDOI Listing
April 2011