Anti-vascular endothelial growth factor (anti-VEGF) drugs have dramatically improved the treatment of neovascular AMD. In pivotal studies, almost 90% of patients maintain vision, with approximately ...30% showing significant improvement. Despite these successes, 10% to 15% of patients continue to lose vision, even with treatment. It has been reported that variants in some AMD-associated genes influence treatment outcome. This study showed an association of treatment outcome with variants in the apolipoprotein E (APOE) gene.
One hundred ninety-two patients receiving anti-VEGF treatment for subfoveal choroidal neovascularization secondary to AMD were enrolled. Information on demographics, lesion characteristics, delay until treatment, visual acuity (VA), and number of treatments was collected, and variants of APOE were assessed in all patients at baseline. Best corrected logarithm of the minimum angle of resolution (logMAR) VA was recorded in all patients.
The presence of the APOE ε4 allele was associated with improved treatment outcome at 3 (P = 0.02) and 12 (P = 0.06) months, compared with the presence of the ε2 allele, after adjustment for baseline acuity, treatment delay after first symptoms, age, and sex. Patients with an APOE ε4 allele had an odds ratio (OR) of 4.04 (95% confidence interval CI, 1.11-14.70) for a 2-line gain in vision from baseline at 3 months (P = 0.03) and an OR of 2.54 (95% CI, 0.61-10.52; P = 0.20) at 12 months after treatment, based on multivariate analysis.
In patients with neovascular AMD, the presence of the APOE ε4 allele conferred significantly better visual outcomes after anti-VEGF treatment than did the ε2 allele. These findings suggest a possible role for a personalized approach to treatment with anti-VEGF.
Previous reports suggest that the outcome of age-related macular degeneration treatment is dependent on variants in the apolipoprotein E (APOE) gene. We wish to establish if variants in this gene are ...associated with anatomical location of fluid within the macula on optical coherence tomography imaging before and after three anti-vascular endothelial growth factor treatments.
Patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration were prospectively enrolled and monitored over a 12-month period. Main outcome measures were logMAR best-corrected visual acuity and correlation of qualitative optical coherence tomography features (intraretinal fluid IRF and/or subretinal fluid) at baseline and after three anti-vascular endothelial growth factor injections with genetic variants of the APOE gene.
One hundred and eighty-six eyes of 186 patients aged 79.4 years (range, 58-103 years). Subjects with an ε2 allele were more likely to have IRF at baseline compared with the eyes without (odds ratio: 2.98, 95% confidence interval: 1.22-7.29, P = 0.02). After 3 injections, 184 eyes remained. Of these, 114 of eyes (62.0%) were classified as "dry" on optical coherence tomography, whereas 48 eyes (26.1%) still had a component of IRF, and 22 (12.0%) had subretinal fluid alone. There was no statistically significant association between APOE variants and presence of persistent IRF, although there were almost double the number of subjects with ε2 (40%) who had persistent fluid compared with those with ε3/ε4 (23%) (P = 0.06).
In patients with neovascular age-related macular degeneration, the presence of the ε2 allele of the APOE gene was associated with having IRF at baseline. Larger studies are required to determine if a greater proportion of those with the ε2 allele retain this fluid after three initial injections.
Peripheral blood lymphocytes from patients with chronic lymphocytic leukemia (CLL) acquire after several days of exposure to 12-
O-tetradecanoylphobol-13-acetate (TPA) several morphological, ...immunological and histochemical features of hairy cell leukemia. We have investigated the short term effects of TPA treatment on protein kinase C and its subcellular distribution. Within minutes of addition of TPA to CLL cells 20% of the cytosolic protein kinase C had associated with the particulate fraction. The remaining 80% of protein kinase C activity was down-regulated. The association with the membrane dramatically increased the resistance of the enzyme to inhibition by the non-ionic detergent, Triton X-100. These results suggest that activation of protein kinase C causes multiple biological changes in CLL cells.
We have quantitated tyrosine protein kinase (TPK) activity in particulate and cytosolic fractions from human leukemic cells. Slowly proliferating cells from patients with chronic lymphocytic leukemia ...(CLL) had levels of TPK similar to those of quiescent normal lymphocytes. Cells from patients with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) and chronic granulocytic leukemia (CGL) contained markedly lower levels of TPK activity, similar to the levels in phytohaemagglutinin-stimulated (proliferating) normal lymphocytes and in bone marrow cells. This suggested that TPK is part of a mechanism for transducing growth signals and is down-regulated following signal transmission. We also identified endogenous substrates for TPK in leukemic cells. Particulate fractions from ALL, CLL and AML cells contained substrates identical to those previously detected in normal lymphocytes. In particular, a 38kD substrate thought to be involved in early stages of growth signal transduction in normal lymphocytes was found in all samples of these groups examined. Cytosolic fractions from these groups of leukemia cells contained higher molecular weight substrates not found in resting or proliferating normal lymphocytes or bone marrow cells. In contrast, TPK substrates in both particulate and cytosolic fractions from CGL cells resembled those of normal bone marrow cells in that only proteins with molecular weight below 40kD were labelled on tyrosine. We conclude that leukemic cells do not contain higher levels of TPK than do normal hemopoietic cells. Qualitative differences in TPK species or in their substrates may result in aberrant regulation of proliferation in leukemic cells. However, we cannot exclude the possibility that additional TPK substrates detected in leukemic cells were a feature of the normal equivalent hematopoietic cells from which the leukemia cells were derived.
We have studied tyrosine phosphorylation in particulate fractions from 11 leukaemic cell lines by using as substrate either a synthetic tyrosine containing peptide or the endogenous proteins. The ...results were compared with those obtained using similar fractions from normal lymphocytes and bone marrow cells. Particulate fractions from all the leukaemic cell lines and normal bone marrow cells exhibited lower levels of tyrosine protein kinase activity compared to normal lymphocytes. When the phosphorylation of endogenous substrates was assayed, proteins were phosphorylated on tyrosine residues (rather than serine or threonine residues) to a larger extent in normal lymphocytes than in leukaemic cell lines. Separation of labelled endogenous substrates on sodium dodecyl sulfate-polyacrylamide gels showed a number of phosphorylated alkali-resistant bands in the range 14-175kd in the lymphoid cell lines; normal lymphocytes exhibited a smaller number of strongly phosphorylated bands. Normal lymphocytes from different individuals showed reproducible patterns of phosphorylated substrates. Normal bone marrow cells and myeloid leukaemia lines showed weak, if any, phosphorylation. Among the leukaemic cell lines no particular pattern of phosphorylated substrates common to cells of similar phenotype could be detected. We suggest that the level of overall tyrosine protein kinase activity in these fractions reflects their position in the cell cycle rather than their normal or malignant status.
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