| 1. |
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| 2. |
- Gong, Y., et al.
(författare)
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Cytochrome P450 Oxidase 2C Inhibition Adds to-3 Long-Chain Polyunsaturated Fatty Acids Protection Against Retinal and Choroidal Neovascularization
- 2016
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Ingår i: Arteriosclerosis Thrombosis and Vascular Biology. - : Ovid Technologies (Wolters Kluwer Health). - 1079-5642 .- 1524-4636. ; 36:9, s. 1919-1927
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Tidskriftsartikel (refereegranskat)abstract
- Objective Pathological ocular neovascularization is a major cause of blindness. Increased dietary intake of -3 long-chain polyunsaturated fatty acids (LCPUFA) reduces retinal neovascularization and choroidal neovascularization (CNV), but -3 LCPUFA metabolites of a major metabolizing pathway, cytochrome P450 oxidase (CYP) 2C, promote ocular pathological angiogenesis. We hypothesized that inhibition of CYP2C activity will add to the protective effects of -3 LCPUFA on neovascular eye diseases. Approach and Results The mouse models of oxygen-induced retinopathy and laser-induced CNV were used to investigate pathological angiogenesis in the retina and choroid, respectively. The plasma levels of -3 LCPUFA metabolites of CYP2C were determined by mass spectroscopy. Aortic ring and choroidal explant sprouting assays were used to investigate the effects of CYP2C inhibition and -3 LCPUFA-derived CYP2C metabolic products on angiogenesis ex vivo. We found that inhibition of CYP2C activity by montelukast added to the protective effects of -3 LCPUFA on retinal neovascularization and CNV by 30% and 20%, respectively. In CYP2C8-overexpressing mice fed a -3 LCPUFA diet, montelukast suppressed retinal neovascularization and CNV by 36% and 39% and reduced the plasma levels of CYP2C8 products. Soluble epoxide hydrolase inhibition, which blocks breakdown and inactivation of CYP2C -3 LCPUFA-derived active metabolites, increased oxygen-induced retinopathy and CNV in vivo. Exposure to selected -3 LCPUFA metabolites of CYP2C significantly reversed the suppression of both angiogenesis ex vivo and endothelial cell functions in vitro by the CYP2C inhibitor montelukast. Conclusions Inhibition of CYP2C activity adds to the protective effects of -3 LCPUFA on pathological retinal neovascularization and CNV.
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| 3. |
- Fu, Z. J., et al.
(författare)
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Dietary omega-3 polyunsaturated fatty acids decrease retinal neovascularization by adipose-endoplasmic reticulum stress reduction to increase adiponectin
- 2015
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Ingår i: American Journal of Clinical Nutrition. - : Elsevier BV. - 0002-9165 .- 1938-3207. ; 101:4, s. 879-888
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Tidskriftsartikel (refereegranskat)abstract
- Background: Retinopathy of prematurity (ROP) is a vision-threatening disease in premature infants. Serum adiponectin (APN) concentrations positively correlate with postnatal growth and gestational age, important risk factors for ROP development. Dietary omega-3 (n-3) long-chain polyunsaturated fatty acids (omega-3 LCPUFAs) suppress ROP and oxygen-induced retinopathy (OIR) in a mouse model of human ROP, but the mechanism is not fully understood. Objective: We examined the role of APN in ROP development and whether circulating APN concentrations are increased by dietary omega-3 LCPUFAs to mediate the protective effect in ROP. Design: Serum APN concentrations were correlated with ROP development and serum omega-3 LCPUFA concentrations in preterm infants. Mouse OIR was then used to determine whether omega-3 LCPUFA supplementation increases serum APN concentrations, which then suppress retinopathy. Results: We found that in preterm infants, low serum APN concentrations positively correlate with ROP, and serum APN concentrations positively correlate with serum omega-3 LCPUFA concentrations. In mouse OIR, serum total APN and bioactive high-molecular-weight APN concentrations are increased by omega-3 LCPUFA feed. White adipose tissue, where APN is produced and assembled in the endoplasmic reticulum, is the major source of serum APN. In mouse OIR, adipose endoplasmic reticulum stress is increased, and APN production is suppressed. omega-3 LCPUFA feed in mice increases APN production by reducing adipose endoplasmic reticulum stress markers. Dietary omega-3 LCPUFA suppression of neovascularization is reduced from 70% to 10% with APN deficiency. APN receptors localize in the retina, particularly to pathologic neovessels. Conclusion: Our findings suggest that increasing APN by omega-3 LCPUFA supplementation in total parental nutrition for preterm infants may suppress ROP.
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| 4. |
- Gong, Y., et al.
(författare)
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Fenofibrate Inhibits Cytochrome P450 Epoxygenase 2C Activity to Suppress Pathological Ocular Angiogenesis
- 2016
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Ingår i: Ebiomedicine. - : Elsevier BV. - 2352-3964. ; 13, s. 201-211
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Tidskriftsartikel (refereegranskat)abstract
- Neovascular eye diseases including retinopathy of prematurity, diabetic retinopathy and age-related-macular-degeneration are major causes of blindness. Fenofibrate treatment in type 2 diabetes patients reduces progression of diabetic retinopathy independent of its peroxisome proliferator-activated receptor (PPAR)alpha agonist lipid lowering effect. The mechanism is unknown. Fenofibrate binds to and inhibits cytochrome P450 epoxygenase (CYP) 2C with higher affinity than to PPAR alpha. CYP2C metabolizes omega-3 long-chain polyunsaturated fatty acids (LCPUFAs). While omega-3 LCPUFA products from other metabolizing pathways decrease retinal and choroidal neovascularization, CYP2C products of both omega-3 and omega-6 LCPUFAs promote angiogenesis. We hypothesized that fenofibrate inhibits retinopathy by reducing CYP2C omega-3 LCPUFA (and omega-6 LCPUFA) pro-angiogenic metabolites. Fenofibrate reduced retinal and choroidal neovascularization in PPAR alpha-/-mice and augmented omega-3 LCPUFA protection via CYP2C inhibition. Fenofibrate suppressed retinal and choroidal neovascularization in mice overexpressing human CYP2C8 in endothelial cells and reduced plasma levels of the pro-angiogenic.-3 LCPUFA CYP2C8 product, 19,20-epoxydocosapentaenoic acid. 19,20-epoxydocosapentaenoic acid reversed fenofibrate-induced suppression of angiogenesis ex vivo and suppression of endothelial cell functions in vitro. In summary fenofibrate suppressed retinal and choroidal neovascularization via CYP2C inhibition as well as by acting as an agonist of PPAR alpha. Fenofibrate augmented the overall protective effects of omega-3 LCPUFAs on neovascular eye diseases. (C) 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://reativecommons.org/licenses/by-nc-nd/4.0/).
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| 5. |
- Shao, Z., et al.
(författare)
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Cytochrome P450 2C8 omega 3-Long-Chain Polyunsaturated Fatty Acid Metabolites Increase Mouse Retinal Pathologic Neovascularization-Brief Report
- 2014
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : Ovid Technologies (Wolters Kluwer Health). - 1079-5642 .- 1524-4636. ; 34:3, s. 581-586
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Tidskriftsartikel (refereegranskat)abstract
- Objective Regulation of angiogenesis is critical for many diseases. Specifically, pathological retinal neovascularization, a major cause of blindness, is suppressed with dietary 3-long-chain polyunsaturated fatty acids (3LCPUFAs) through antiangiogenic metabolites of cyclooxygenase and lipoxygenase. Cytochrome P450 epoxygenases (CYP2C8) also metabolize LCPUFAs, producing bioactive epoxides, which are inactivated by soluble epoxide hydrolase (sEH) to transdihydrodiols. The effect of these enzymes and their metabolites on neovascularization is unknown. Approach and Results The mouse model of oxygen-induced retinopathy was used to investigate retinal neovascularization. We found that CYP2C (localized in wild-type monocytes/macrophages) is upregulated in oxygen-induced retinopathy, whereas sEH is suppressed, resulting in an increased retinal epoxide:diol ratio. With a 3LCPUFA-enriched diet, retinal neovascularization increases in Tie2-driven human-CYP2C8-overexpressing mice (Tie2-CYP2C8-Tg), associated with increased plasma 19,20-epoxydocosapentaenoic acid and retinal epoxide:diol ratio. 19,20-Epoxydocosapentaenoic acids and the epoxide:diol ratio are decreased with overexpression of sEH (Tie2-sEH-Tg). Overexpression of CYP2C8 or sEH in mice does not change normal retinal vascular development compared with their wild-type littermate controls. The proangiogenic role in retina of CYP2C8 with both 3LCPUFA and 6LCPUFA and antiangiogenic role of sEH in 3LCPUFA metabolism were corroborated in aortic ring assays. Conclusions Our results suggest that CYP2C 3LCPUFA metabolites promote retinal pathological angiogenesis. CYP2C8 is part of a novel lipid metabolic pathway influencing retinal neovascularization.
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| 6. |
- Tutt, A. N. J., et al.
(författare)
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Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer
- 2021
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Ingår i: New England Journal of Medicine. - 0028-4793. ; 384:25, s. 2394-2405
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Poly(adenosine diphosphate-ribose) polymerase inhibitors target cancers with defects in homologous recombination repair by synthetic lethality. New therapies are needed to reduce recurrence in patients with BRCA1 or BRCA2 germline mutation-associated early breast cancer. METHODS We conducted a phase 3, double-blind, randomized trial involving patients with human epidermal growth factor receptor 2 (HER2)-negative early breast cancer with BRCA1 or BRCA2 germline pathogenic or likely pathogenic variants and high-risk clinicopathological factors who had received local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomly assigned (in a 1:1 ratio) to 1 year of oral olaparib or placebo. The primary end point was invasive disease-free survival. RESULTS A total of 1836 patients underwent randomization. At a prespecified event-driven interim analysis with a median follow-up of 2.5 years, the 3-year invasive disease-free survival was 85.9% in the olaparib group and 77.1% in the placebo group (difference, 8.8 percentage points; 95% confidence interval [CI], 4.5 to 13.0; hazard ratio for invasive disease or death, 0.58; 99.5% CI, 0.41 to 0.82; P<0.001). The 3-year distant disease-free survival was 87.5% in the olaparib group and 80.4% in the placebo group (difference, 7.1 percentage points; 95% CI, 3.0 to 11.1; hazard ratio for distant disease or death, 0.57; 99.5% CI, 0.39 to 0.83; P<0.001). Olaparib was associated with fewer deaths than placebo (59 and 86, respectively) (hazard ratio, 0.68; 99% CI, 0.44 to 1.05; P=0.02); however, the between-group difference was not significant at an interim-analysis boundary of a P value of less than 0.01. Safety data were consistent with known side effects of olaparib, with no excess serious adverse events or adverse events of special interest. CONCLUSIONS Among patients with high-risk, HER2-negative early breast cancer and germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants, adjuvant olaparib after completion of local treatment and neoadjuvant or adjuvant chemotherapy was associated with significantly longer survival free of invasive or distant disease than was placebo. Olaparib had limited effects on global patient-reported quality of life.
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| 7. |
- An, Y. A., et al.
(författare)
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Dysregulation of amyloid precursor protein impairs adipose tissue mitochondrial function and promotes obesity
- 2019
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Ingår i: Nature Metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 1:12, s. 1243-57
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial function in white adipose tissue (WAT) is an important yet understudied aspect of adipocyte biology. Here, we report a role for amyloid precursor protein (APP) in compromising WAT mitochondrial function through a high-fat diet (HFD)-induced, unconventional mis-localization to mitochondria that further promotes obesity. In humans and mice, obese conditions induce substantial APP production in WAT and APP enrichment in mitochondria. Mechanistically, HFD-induced dysregulation of signal recognition particle subunit 54c is responsible for the mis-targeting of APP to adipocyte mitochondria. Mis-localized APP blocks the protein import machinery, leading to mitochondrial dysfunction in WAT. Mice overexpressing adipocyte-specific and mitochondria-targeted APP display increased body mass and reduced insulin sensitivity, along with dysfunctional WAT, owing to a dramatic hypertrophic program in adipocytes. Elimination of adipocyte APP rescues HFD-impaired mitochondrial function with considerable protection from weight gain and systemic metabolic deficiency. Our data highlight an important role for APP in modulating WAT mitochondrial function and obesity-associated metabolic dysfunction.
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| 8. |
- Curigliano, G, et al.
(författare)
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De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017.
- 2017
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Ingår i: Annals of oncology : official journal of the European Society for Medical Oncology. - : Elsevier BV. - 1569-8041. ; 28:8, s. 1700-1712
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Tidskriftsartikel (refereegranskat)abstract
- The 15th St. Gallen International Breast Cancer Conference 2017 in Vienna, Austria reviewed substantial new evidence on loco-regional and systemic therapies for early breast cancer. Treatments were assessed in light of their intensity, duration and side-effects, seeking where appropriate to escalate or de-escalate therapies based on likely benefits as predicted by tumor stage and tumor biology. The Panel favored several interventions that may reduce surgical morbidity, including acceptance of 2mm margins for DCIS, the resection of residual cancer (but not baseline extent of cancer) in women undergoing neoadjuvant therapy, acceptance of sentinel node biopsy following neoadjuvant treatment of many patients, and the preference for neoadjuvant therapy in HER2 positive and triple-negative, stage II and III breast cancer. The Panel favored escalating radiation therapy with regional nodal irradiation in high-risk patients, while encouraging omission of boost in low-risk patients. The Panel endorsed gene expression signatures that permit avoidance of chemotherapy in many patients with ER positive breast cancer. For women with higher risk tumors, the Panel escalated recommendations for adjuvant endocrine treatment to include ovarian suppression in premenopausal women, and extended therapy for postmenopausal women. However, low-risk patients can avoid these treatments. Finally, the Panel recommended bisphosphonate use in postmenopausal women to prevent breast cancer recurrence. The Panel recognized that recommendations are not intended for all patients, but rather to address the clinical needs of the majority of common presentations. Individualization of adjuvant therapy means adjusting to the tumor characteristics, patient comorbidities and preferences, and managing constraints of treatment cost and access that may affect care in both the developed and developing world.
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| 9. |
- De Leoz, M. L. A., et al.
(författare)
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NIST Interlaboratory Study on Glycosylation Analysis of Monoclonal Antibodies: Comparison of Results from Diverse Analytical Methods
- 2020
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Ingår i: Molecular & Cellular Proteomics. - 1535-9476. ; 19:1, s. 11-30
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Tidskriftsartikel (refereegranskat)abstract
- A broad-based interlaboratory study of glycosylation profiles of a reference and modified IgG antibody involving 103 reports from 76 laboratories. Glycosylation is a topic of intense current interest in the development of biopharmaceuticals because it is related to drug safety and efficacy. This work describes results of an interlaboratory study on the glycosylation of the Primary Sample (PS) of NISTmAb, a monoclonal antibody reference material. Seventy-six laboratories from industry, university, research, government, and hospital sectors in Europe, North America, Asia, and Australia submitted a total of 103 reports on glycan distributions. The principal objective of this study was to report and compare results for the full range of analytical methods presently used in the glycosylation analysis of mAbs. Therefore, participation was unrestricted, with laboratories choosing their own measurement techniques. Protein glycosylation was determined in various ways, including at the level of intact mAb, protein fragments, glycopeptides, or released glycans, using a wide variety of methods for derivatization, separation, identification, and quantification. Consequently, the diversity of results was enormous, with the number of glycan compositions identified by each laboratory ranging from 4 to 48. In total, one hundred sixteen glycan compositions were reported, of which 57 compositions could be assigned consensus abundance values. These consensus medians provide community-derived values for NISTmAb PS. Agreement with the consensus medians did not depend on the specific method or laboratory type. The study provides a view of the current state-of-the-art for biologic glycosylation measurement and suggests a clear need for harmonization of glycosylation analysis methods.
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| 10. |
- Geyer, C. E., et al.
(författare)
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Overall survival in the OlympiA phase Ill trial of adjuvant olaparib in patients with germime pathogenic variants in BRCA1/2 and high-risk, early breast cancer
- 2022
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Ingår i: Annals of Oncology. - : Elsevier BV. - 0923-7534. ; 33:12, s. 1250-1268
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Tidskriftsartikel (refereegranskat)abstract
- Background: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods: One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results: With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Delta 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Delta 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Delta 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion: With 35 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDES and DDFS with no new safety signals.
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