This study is part of an ongoing project to enable the full specification of the Design Space for roller compactor systems and shows how the processing parameters influence the behaviour of the product granulate from ...This study is part of an ongoing project to enable the full specification of the Design Space for roller compactor systems and shows how the processing parameters influence the behaviour of the product granulate from a placebo formulation. Granulate was produced using a proprietary roller compactor by varying the compaction pressure and gap width,and the dynamic, bulk and shear properties of the resultant granulates were measured.The results demonstrate several rheological properties of the granulate, which have been shown to be closely correlated with variance in die filling and tablet strength, and are predictably influenced by the processing parameters.展开更多
在2011巴隆工艺收藏展上，7000多块巴隆公司生产的不同形状的毛毡铺满了展位的墙壁，带来极富冲击力的视觉享受。墙上的一副“跳芭蕾的女孩”图像，则是来自瑞典设计团队“爱与我们在一起（Form Us With Love）”的富有激情的创意，围...在2011巴隆工艺收藏展上，7000多块巴隆公司生产的不同形状的毛毡铺满了展位的墙壁，带来极富冲击力的视觉享受。墙上的一副“跳芭蕾的女孩”图像，则是来自瑞典设计团队“爱与我们在一起（Form Us With Love）”的富有激情的创意，围绕着解构、转化和重塑的概念。展开更多
PURPOSE: To evaluate the rate of infectious and noninfectious endophthalmitis after intravitreal injection of a high-dosage of triamcinolone acetonide. DESIGN: Clinical interventional case-series study. METHODS: The s...PURPOSE: To evaluate the rate of infectious and noninfectious endophthalmitis after intravitreal injection of a high-dosage of triamcinolone acetonide. DESIGN: Clinical interventional case-series study. METHODS: The study included 1135 intravitreal injections of approximately 20 mg triamcinolone performed for 915 eyes with diabetic macular edema (n=257),exudative age-related macular degeneration (n=561),retinal vein occlusions (n=82),and other reasons. Among the injections were 220 reinjections. Triamcinolone was filtered to remove the solvent agent. Mean follow-up was 8.1± 7.4 months. RESULTS: In none of the eyes,signs of an infectious or noninfectious endophthalmitis were observed such as noncrystalline hypopyon,cellular infiltration,or amorphous opacification of the vitreous,retinal infiltration,or pain. One patient developed infectious endophthalmitis 2 days after a traumatic rupture of a previous corneoscleral cataract incision. CONCLUSIONS: The rate of infectious or noninfectious endophthalmitis after an intravitreal high-dosage triamcinolone injection may be approximately 1:1000,if the solvent agent was removed.展开更多
In the paper, we aim to show N-(2,4,6-trinitrophenyl)-1H-1,2,4-triazol-3-amine (HM-I) as explosive material that satisfies requirements of sensitivity and hydrolytically stability. The influence of nitro group substit...In the paper, we aim to show N-(2,4,6-trinitrophenyl)-1H-1,2,4-triazol-3-amine (HM-I) as explosive material that satisfies requirements of sensitivity and hydrolytically stability. The influence of nitro group substitutions on the thermal and chemical stability as well as the explosive performance of HM-I is also investigated. We found that nitro group substitution to the triazole ring of HM-I can significantly improve the properties of this new material. Only -NH2 substitution position (but not their number) in the core molecule is appropriate to increase the stability and improve explosive performances of HM-I.展开更多
The phosphatidylinositol 3-kinase(PI3K)-Akt-mechanistic target of rapamycin(mTOR)pathway is constitutively activated in human acute myeloid leukemia(AML)cells and is regarded as a possible therapeutic target.Insulin i...The phosphatidylinositol 3-kinase(PI3K)-Akt-mechanistic target of rapamycin(mTOR)pathway is constitutively activated in human acute myeloid leukemia(AML)cells and is regarded as a possible therapeutic target.Insulin is an agonist of this pathway and a growth factor for AML cells.We characterized the effect of insulin on the phosphorylation of 10 mediators in the main track of the PI3K-Akt-mTOR pathway in AML cells from 76 consecutive patients.The overall results showed that insulin significantly increased the phosphorylation of all investigated mediators.However,insulin effects on the pathway activation profile varied among patients,and increased phosphorylation in all mediators was observed only in a minority of patients;in other patients,insulin had divergent effects.Global gene expression profiling and proteomic/phosphoproteomic comparisons suggested that AML cells from these two patient subsets differed with regard to AML cell differentiation,transcriptional regulation,RNA metabolism,and cellular metabolism.Strong insulin-induced phosphorylation was associated with weakened antiproliferative effects of metabolic inhibitors.PI3K,Akt,and mTOR inhibitors also caused divergent effects on the overall pathway phosphorylation profile in the presence of insulin,although PI3K and Akt inhibition caused a general reduction in Akt pT308 and 4EBP1 pT36/pT45 phosphorylation.For Akt inhibition,the phosphorylation of upstream mediators was generally increased or unaltered.In contrast,mTOR inhibition reduced mTOR pS2448 and S6 pS244 phosphorylation but increased Akt pT308 phosphorylation.In conclusion,the effects of both insulin and PI3K-Akt-mTOR inhibitors differ between AML patient subsets,and differences in insulin responsiveness are associated with differential susceptibility to metabolic targeting.展开更多
Diabetic retinopathy(DR)affects approximately one-third of diabetic patients and,if left untreated,progresses to proliferative DR(PDR)with associated vitreous hemorrhage,retinal detachment,iris neovascularization,glau...Diabetic retinopathy(DR)affects approximately one-third of diabetic patients and,if left untreated,progresses to proliferative DR(PDR)with associated vitreous hemorrhage,retinal detachment,iris neovascularization,glaucoma and irreversible blindness.In vitreous samples of human patients with PDR,we found elevated levels of hypoxia inducible factor 1 alpha(HIF1α).HIFs are transcription factors that promote hypoxia adaptation and have important functional roles in a wide range of ischemic and inflammatory diseases.To recreate the human PDR phenotype for a preclinical animal model,we generated a mouse with neuroretinal-specific loss of the von Hippel Lindau tumor suppressor protein,a protein that targets HIF1αfor ubiquitination.We found that the neuroretinal cells in these mice overexpressed HIF1αand developed severe,irreversible ischemic retinopathy that has features of human PDR.Rapid progression of retinopathy in these mutant mice should facilitate the evaluation of therapeutic agents for ischemic and inflammatory blinding disorders.In addition,this model system can be used to manipulate the modulation of the hypoxia signaling pathways,for the treatment of non-ocular ischemic and inflammatory disorders.展开更多
Epithelial-mesenchymal plasticity(EMP)of cancer cells contributes to cancer cell heterogeneity,and it is well established that EMP is a critical determinant of acquired resistance to cancer treatment modalities includ...Epithelial-mesenchymal plasticity(EMP)of cancer cells contributes to cancer cell heterogeneity,and it is well established that EMP is a critical determinant of acquired resistance to cancer treatment modalities including radiation therapy,chemotherapy,and targeted therapies.Here,we aimed to explore how EMP contributes to cancer cell camouflage,allowing an ever-changing population of cancer cells to pass under the radar of our immune system and consequently compromise the effect of immune checkpoint blockade therapies.The ultimate clinical benefit of any combination regimen is evidenced by the sum of the drug-induced alterations observed in the variety of cellular populations composing the tumor immune microenvironment.The finely-tuned molecular crosstalk between cancer and immune cells remains to be fully elucidated,particularly for the spectrum of malignant cells along the epithelial to mesenchymal axis.High-dimensional single cell analyses of specimens collected in ongoing clinical studies is becoming a key contributor to our understanding of these interactions.This review will explore to what extent targeting EMP in combination with immune checkpoint inhibition represents a promising therapeutic avenue within the overarching strategy to reactivate a halting cancer-immunity cycle and establish a robust host immune response against cancer cells.Therapeutic strategies currently in clinical development will be discussed.展开更多
文摘This study is part of an ongoing project to enable the full specification of the Design Space for roller compactor systems and shows how the processing parameters influence the behaviour of the product granulate from a placebo formulation. Granulate was produced using a proprietary roller compactor by varying the compaction pressure and gap width,and the dynamic, bulk and shear properties of the resultant granulates were measured.The results demonstrate several rheological properties of the granulate, which have been shown to be closely correlated with variance in die filling and tablet strength, and are predictably influenced by the processing parameters.
文摘PURPOSE: To evaluate the rate of infectious and noninfectious endophthalmitis after intravitreal injection of a high-dosage of triamcinolone acetonide. DESIGN: Clinical interventional case-series study. METHODS: The study included 1135 intravitreal injections of approximately 20 mg triamcinolone performed for 915 eyes with diabetic macular edema (n=257),exudative age-related macular degeneration (n=561),retinal vein occlusions (n=82),and other reasons. Among the injections were 220 reinjections. Triamcinolone was filtered to remove the solvent agent. Mean follow-up was 8.1± 7.4 months. RESULTS: In none of the eyes,signs of an infectious or noninfectious endophthalmitis were observed such as noncrystalline hypopyon,cellular infiltration,or amorphous opacification of the vitreous,retinal infiltration,or pain. One patient developed infectious endophthalmitis 2 days after a traumatic rupture of a previous corneoscleral cataract incision. CONCLUSIONS: The rate of infectious or noninfectious endophthalmitis after an intravitreal high-dosage triamcinolone injection may be approximately 1:1000,if the solvent agent was removed.
基金the LMA scientific project“A theoretical and experimental investigations of new potentially explosive materials using quantum mechanical methods(NSPROG-I4)”.
文摘In the paper, we aim to show N-(2,4,6-trinitrophenyl)-1H-1,2,4-triazol-3-amine (HM-I) as explosive material that satisfies requirements of sensitivity and hydrolytically stability. The influence of nitro group substitutions on the thermal and chemical stability as well as the explosive performance of HM-I is also investigated. We found that nitro group substitution to the triazole ring of HM-I can significantly improve the properties of this new material. Only -NH2 substitution position (but not their number) in the core molecule is appropriate to increase the stability and improve explosive performances of HM-I.
基金The studies received financial support from the Norwegian Cancer Society,the University of Bergen and Helse-Vest.
文摘The phosphatidylinositol 3-kinase(PI3K)-Akt-mechanistic target of rapamycin(mTOR)pathway is constitutively activated in human acute myeloid leukemia(AML)cells and is regarded as a possible therapeutic target.Insulin is an agonist of this pathway and a growth factor for AML cells.We characterized the effect of insulin on the phosphorylation of 10 mediators in the main track of the PI3K-Akt-mTOR pathway in AML cells from 76 consecutive patients.The overall results showed that insulin significantly increased the phosphorylation of all investigated mediators.However,insulin effects on the pathway activation profile varied among patients,and increased phosphorylation in all mediators was observed only in a minority of patients;in other patients,insulin had divergent effects.Global gene expression profiling and proteomic/phosphoproteomic comparisons suggested that AML cells from these two patient subsets differed with regard to AML cell differentiation,transcriptional regulation,RNA metabolism,and cellular metabolism.Strong insulin-induced phosphorylation was associated with weakened antiproliferative effects of metabolic inhibitors.PI3K,Akt,and mTOR inhibitors also caused divergent effects on the overall pathway phosphorylation profile in the presence of insulin,although PI3K and Akt inhibition caused a general reduction in Akt pT308 and 4EBP1 pT36/pT45 phosphorylation.For Akt inhibition,the phosphorylation of upstream mediators was generally increased or unaltered.In contrast,mTOR inhibition reduced mTOR pS2448 and S6 pS244 phosphorylation but increased Akt pT308 phosphorylation.In conclusion,the effects of both insulin and PI3K-Akt-mTOR inhibitors differ between AML patient subsets,and differences in insulin responsiveness are associated with differential susceptibility to metabolic targeting.
基金This work was supported by the National Institute of Health Core(5P30EY019007)National Cancer Institute Core(5P30CA013696)and unrestricted funds from Research to Prevent Blindness+6 种基金New York,NY,USA.KJW was supported by the National Institute of Health(5T32EY013933 and 5T32DK007647-20)during these experiments and is currently supported by the National Cancer Institute(F32CA196065)SHT is a member of the RD-CURE Consortium and is supported by the Tistou and Charlotte Kerstan Foundation,the National Institute of Health(R01EY018213)the Research to Prevent Blindness Physician-Scientist Award,Association for Research in Vision and Ophthalmology Foundation,Macula Society,the Barbara and Donald Jonas Family Fund,the Schneeweiss Stem Cell Fund,New York State(C029572)the Foundation Fighting Blindness New York Regional Research Center Grant(C-NY05-0705-0312)the Joel Hoffman Fund,the Professor Gertrude Rothschild Stem Cell Foundation,and the Gebroe Family FoundationVBM is supported by NIH Grants K08EY020530,R01EY016822 and Research to Prevent Blindness,New York,NY,USAMBG is supported by R01EY07739,R01EY012601,R01HL110170 and R01DK090730.
文摘Diabetic retinopathy(DR)affects approximately one-third of diabetic patients and,if left untreated,progresses to proliferative DR(PDR)with associated vitreous hemorrhage,retinal detachment,iris neovascularization,glaucoma and irreversible blindness.In vitreous samples of human patients with PDR,we found elevated levels of hypoxia inducible factor 1 alpha(HIF1α).HIFs are transcription factors that promote hypoxia adaptation and have important functional roles in a wide range of ischemic and inflammatory diseases.To recreate the human PDR phenotype for a preclinical animal model,we generated a mouse with neuroretinal-specific loss of the von Hippel Lindau tumor suppressor protein,a protein that targets HIF1αfor ubiquitination.We found that the neuroretinal cells in these mice overexpressed HIF1αand developed severe,irreversible ischemic retinopathy that has features of human PDR.Rapid progression of retinopathy in these mutant mice should facilitate the evaluation of therapeutic agents for ischemic and inflammatory blinding disorders.In addition,this model system can be used to manipulate the modulation of the hypoxia signaling pathways,for the treatment of non-ocular ischemic and inflammatory disorders.
基金This work was partly supported by the Research Council of Norway through its Centres of Excellence funding scheme,project number 223250(CCBIO affiliates)Lorens JB was supported by grants from the Norwegian Research Council(grant number 240130)+2 种基金Norwegian Cancer Society(grant number 190330)Engelsen AST was supported by the FRIPRO Mobility Grant Fellowship from the Research Council of Norway co-funded by the EU’s 7th Framework Programme’s Marie Skłodowska Curie Actions(MSCA COFUND,grant agreement number 608695)Support from Legat for Forskning av Kreftsykdommer fund at UIB and the Familien Blix fund to ASTE for this project is greatly appreciated.
文摘Epithelial-mesenchymal plasticity(EMP)of cancer cells contributes to cancer cell heterogeneity,and it is well established that EMP is a critical determinant of acquired resistance to cancer treatment modalities including radiation therapy,chemotherapy,and targeted therapies.Here,we aimed to explore how EMP contributes to cancer cell camouflage,allowing an ever-changing population of cancer cells to pass under the radar of our immune system and consequently compromise the effect of immune checkpoint blockade therapies.The ultimate clinical benefit of any combination regimen is evidenced by the sum of the drug-induced alterations observed in the variety of cellular populations composing the tumor immune microenvironment.The finely-tuned molecular crosstalk between cancer and immune cells remains to be fully elucidated,particularly for the spectrum of malignant cells along the epithelial to mesenchymal axis.High-dimensional single cell analyses of specimens collected in ongoing clinical studies is becoming a key contributor to our understanding of these interactions.This review will explore to what extent targeting EMP in combination with immune checkpoint inhibition represents a promising therapeutic avenue within the overarching strategy to reactivate a halting cancer-immunity cycle and establish a robust host immune response against cancer cells.Therapeutic strategies currently in clinical development will be discussed.
