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BACKGROUND: Systemic lupus erythematosus (SLE), characterized by the production of autoantibodies and widespread deposition of immune complexes, predominantly affects women of childbearing age. More than one-third of SLE patients present ocular manifestations. Choroidal disease is currently not completely understood, and its precise differentiation from central serous chorioretinopathy is rarely achieved. To date, no more than 60 patients with choroidal involvement have been reported. CASE SUMMARY: A 37-year-old Chinese woman experienced decreased visual acuity bilaterally, accompanied by increasing periorbital swelling and severe conjunctival chemosis. Decreased breath sounds in both bases were detected via auscultation, as well as pitting edema in both ankles. SLE and lupus nephritis were diagnosed based on serositis, renal disorder, leukopenia and positive anti-Smith and anti-nuclear antibodies. Lupus choroidopathy was diagnosed based on ocular presentation and imaging. The patient was treated with systemic corticosteroids, spironolactone, hydroxychloroquine (HCQ), mycophenolate mofetil (MMF), and intravenous immunoglobulin. After 4 wk of hospitalization, the patient was discharged. Indocyanine green angiography showed no leakage from choroidal vessels, and ocular coherence tomography detected low amounts of subretinal fluid right before discharge. The patient was prescribed oral methylprednisolone, HCQ, and MMF. Two months after the first visit, ophthalmological examination revealed a visual acuity of 20/20 bilaterally, and SLE disease activity was well controlled; her symptoms disappeared completely. CONCLUSION: Here we presented a case of lupus choroidopathy, successfully treated with systemic corticosteroids, and discussed previously reported cases, focusing on differential diagnosis with a central serous chorioretinopathy.
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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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Química Farmacéutica/métodos , Composición de Medicamentos/métodos , Desarrollo de Medicamentos/métodos , Inhibidores Enzimáticos/síntesis química , Estabilidad de Medicamentos , Inhibidores Enzimáticos/administración & dosificación , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Liofilización , Congelación , Inyecciones , Preparaciones Farmacéuticas/administración & dosificación , Preparaciones Farmacéuticas/síntesis química , SolubilidadRESUMEN
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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Eosinofilia , Fascitis , Glomerulonefritis por IGA , Esclerodermia Localizada , Eosinofilia/complicaciones , Eosinofilia/diagnóstico , Fascitis/complicaciones , Fascitis/diagnóstico , Glomerulonefritis por IGA/complicaciones , Glomerulonefritis por IGA/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Esclerodermia Localizada/complicaciones , Esclerodermia Localizada/diagnósticoRESUMEN
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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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 (ß = 0.384, p < 0.001) and T1-weighted MRI (ß = 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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Imagen por Resonancia Magnética/métodos , Articulación Sacroiliaca/diagnóstico por imagen , Articulación Sacroiliaca/patología , Espondilitis Anquilosante/diagnóstico por imagen , Adulto , Factores de Edad , Contencion de la Respiración , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Sensibilidad y Especificidad , Tomografía Computarizada por Rayos XRESUMEN
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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Brucelosis/diagnóstico , Errores Diagnósticos/estadística & datos numéricos , Espondiloartritis/clasificación , Espondiloartritis/diagnóstico , Adulto , Animales , Brucelosis/fisiopatología , China , Diagnóstico Diferencial , Errores Diagnósticos/prevención & control , Femenino , Antígeno HLA-B27/sangre , Humanos , Dolor de la Región Lumbar/fisiopatología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Sacroileítis/fisiopatología , Sociedades Médicas , Espondiloartritis/fisiopatología , Adulto JovenRESUMEN
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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Proteínas CCN de Señalización Intercelular/genética , Artropatías/congénito , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Artropatías/diagnóstico , Artropatías/genética , Mutación , Transducción de Señal/genética , Adulto JovenRESUMEN
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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KRASG12C 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 KRASG12C 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 KRASG12C. 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 KRASG12C-specific inhibitors with promising therapeutic potential.
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Antineoplásicos/farmacología , Neoplasias Experimentales/tratamiento farmacológico , Piperazinas/farmacología , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Quinazolinas/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Femenino , Células HCT116 , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Simulación del Acoplamiento Molecular , Mutación , Piperazinas/química , Piperazinas/uso terapéutico , Unión Proteica , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Quinazolinas/química , Quinazolinas/uso terapéuticoRESUMEN
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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Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales , Transición Epitelial-Mesenquimal , Neoplasias Renales , Proteínas de Neoplasias/metabolismo , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/metabolismo , Adulto , Anciano , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Neoplasias Renales/metabolismo , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Tasa de SupervivenciaRESUMEN
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 ED50 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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Diseño de Fármacos , Antagonistas del Receptor Purinérgico P2X/síntesis química , Antagonistas del Receptor Purinérgico P2X/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Receptores Purinérgicos P2X7/metabolismo , Animales , Reacción de Cicloadición , Perros , Humanos , Masculino , Ratones , Modelos Moleculares , Conformación Molecular , Antagonistas del Receptor Purinérgico P2X/química , Antagonistas del Receptor Purinérgico P2X/farmacocinética , Piridinas/química , Piridinas/farmacocinética , Ratas , Estereoisomerismo , Distribución TisularRESUMEN
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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Carcinoma de Células Renales/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genética , Animales , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Movimiento Celular/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Inhibidores de Crecimiento/administración & dosificación , Humanos , Ratones , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/antagonistas & inhibidores , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/biosíntesis , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
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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Carcinoma de Células Renales/metabolismo , Redes Reguladoras de Genes , Neoplasias Renales/metabolismo , Mapeo de Interacción de Proteínas/métodos , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genética , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/metabolismo , Animales , Células CHO , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Cricetulus , Regulación hacia Abajo , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Humanos , Neoplasias Renales/patología , Unión Proteica , Mapas de Interacción de Proteínas , Isoformas de Proteínas/metabolismo , Análisis de Secuencia de ARNRESUMEN
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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Colitis/inducido químicamente , Colon/química , Modelos Animales de Enfermedad , Oxiesteroles/aislamiento & purificación , Animales , Cromatografía Liquida , Colon/patología , Sulfato de Dextran , Femenino , Ratones , Ratones Endogámicos C57BL , Oxiesteroles/química , Espectrometría de Masas en TándemRESUMEN
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 epithelialmesenchymal transition (EMT) in renal cell carcinoma (RCC) cells in vitro. The RCC cell lines A498 and 786O were used in this study. Based on our preliminary study, we selected fulllength 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 786O 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 (Ecadherin, vimentin, ßcatenin and Slug). Overexpression of VEGI174, V7 or V8 did not have a significant influence on cell viability (P>0.05). The mRNA level of Ecadherin was significantly upregulated, while that of vimentin was downregulated in A498VEGIexp, A498V7exp, A498V8exp, 786OVEGIexp, 786OV7exp and 786OV8exp 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 ßcatenin and Slug were downregulated in the A498VEGIexp, A498V7exp, A498V8exp, 786OVEGIexp, 786OV7exp and 786OV8exp cells. In conclusion, overexpression of VEGI174, V7 or V8 inhibited EMT in A498 and 786O 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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Carcinoma de Células Renales/patología , Transición Epitelial-Mesenquimal , Neoplasias Renales/patología , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/metabolismo , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Línea Celular Tumoral , Supervivencia Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Dominios Proteicos , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/química , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genética , Regulación hacia ArribaRESUMEN
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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Biomarcadores de Tumor , Carcinoma de Células Renales/genética , Heterogeneidad Genética , Neoplasias Renales/genética , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Expresión Génica , Xenoinjertos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Ratones , Terapia Molecular Dirigida , Proteínas de Fusión Oncogénica/genética , Análisis de Secuencia de ARN , Carga Tumoral/efectos de los fármacos , Carga Tumoral/genéticaRESUMEN
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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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 CoCl2 was used to simulate hypoxia. Cells were cultured with different concentrations of CoCl2. 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 CoCl2-treated groups were loose and scattered compared to the control. CoCl2 did not promote or attenuate the viability of A498 cells at low dosage, but when the concentration of CoCl2 reached 250 µM, cell activity gradually declined. In contrast, CoCl2 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 CoCl2-simulated hypoxia in comparison with normoxic conditions (P<0.01). CONCLUSIONS: CoCl2-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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Carcinoma de Células Renales/patología , Cobalto/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Neoplasias Renales/patología , Carcinoma de Células Renales/metabolismo , Hipoxia de la Célula/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Forma de la Célula/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Neoplasias Renales/metabolismoRESUMEN
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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Oxiesteroles/química , Animales , Línea Celular , Herpesvirus Humano 4/efectos de los fármacos , Herpesvirus Humano 4/metabolismo , Humanos , Oxiesteroles/síntesis química , Oxiesteroles/farmacología , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
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.