Neuroprotective response after photodynamic therapy: Role of vascular endothelial growth factor

Background: Anti-vascular endothelial growth factor (VEGF) drugs and/or photodynamic therapy (PDT) constitute current treatments targeting pathological vascular tissues in tumors and age-related macular degeneration. Concern that PDT might induce VEGF and exacerbate the disease has led us to current practice of using anti-VEGF drugs with PDT simultaneously. However, the underlying molecular mechanisms of these therapies are not well understood. Methods: We assessed VEGF levels after PDT of normal mouse retinal tissue, using a laser duration that did not cause obvious tissue damage. To determine the role of PDT-induced VEGF and its downstream signaling, we intravitreally injected a VEGF inhibitor, VEGFR1 Fc, or a PI3K/Akt inhibitor, LY294002, immediately after PDT. Then, histological and biochemical changes of the retinal tissue were analyzed by immunohistochemistry and immunoblot analyses, respectively. Results: At both the mRNA and protein levels, VEGF was upregulated immediately and transiently after PDT. VEGF suppression after PDT resulted in apoptotic destruction of the photoreceptor cell layer in only the irradiated area during PDT. Under these conditions, activation of the anti-apoptotic molecule Akt was suppressed in the irradiated area, and levels of the pro-apoptotic protein BAX were increased. Intravitreal injection of a PI3K/Akt inhibitor immediately after PDT increased BAX levels and photoreceptor cell apoptosis. Conclusion: Cytotoxic stress caused by PDT, at levels that do not cause overt tissue damage, induces VEGF and activates Akt to rescue the neural tissue, suppressing BAX. Thus, the immediate and transient induction of VEGF after PDT is neuroprotective

Transcriptional factors associated with epithelial-mesenchymal transition in choroidal neovascularization

Purpose: To investigate the transcriptional factors associated with epithelial-mesenchymal transition (EMT) in choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). Methods: Paraffin sections of CNV obtained from patients with AMD (n=12) were stained for transcriptional factors related to EMT, i.e., Snail, Slug, SIP1, and Twist. As a control, postmortem sections of ocular normal tissue were used. Furthermore, using a human retinal pigment epithelial (RPE) cell line (ARPE-19), reverse transcription–polymerase chain reaction (RT–PCR) and immunofluorescence microscopy were performed to explore the cellular localization and expression levels of EMT-associated transcriptional factors upon cytokine stimulation. Results: Of 12 specimens, 11 CNV tissues (91.6%) showed staining for Snail localized in cellular nuclei, particularly in those of RPE cells. Snail was strongly co-localized with α-smooth muscle antigen (SMA) in RPE cells. In contrast, postmortem human retina showed no Snail staining in RPE cells. Other transcriptional factors, Slug, Twist and SIP1 were not detected in CNV or normal human retina. In ARPE-19 cells, RT–PCR and immunofluorescence microscopy showed that Snail mRNA was upregulated by transforming growth factor (TGF)-β and VEGF stimulation. Furthermore, TGF-β induced relocalization of Snail to the nucleus in RPE cells. Conclusions: The current data indicate that Snail is a major transcriptional factor for EMT changes of RPE cells in human CNV

神経心理学的検査を用いて評価した実行機能の発達的側面

Children with executive dysfunction may have a decreased quality of life. Neuropsychological tests include the Stroop test, Trail-making Test, Wisconsin Card Sorting Test, Continuous Performance Test, and the Rey-Osterrieth Complex Figure Test are administered to evaluate the above functions. To broaden the opportunities for clinical application,we have modified these tests to make them applicable to younger children and to obtain their standard values. The purpose of this research is to study the developmental aspects of these tests, focusing on the difference between the original method and the modified method. Index scores that reflected executive function were rapidly reduced until 9 to 11 years of age, and developments showed a deceleration during the adolescent period. This result was comparable with that of the index scores of the original tests. We also discussed the involvement of background neuronal maturation associated with developmental changes in these tests.実行機能の障害は、子どもの生活の質の低下につながる可能性があるため、Stroop Test,Trail Making Test, Wisconsin Card Sorting Test, Continuous Performance Test,Rey-Osterrieth Complex Figure Testなどの神経心理学的検査を用いて同機能を適切に評価することが求められている。すでに我々は、これら検査の臨床応用の機会を広げるために、低年齢の子どもに運用が可能な短縮版を開発し成果の報告を行ってきた。本研究は、従来の方法と短縮化された方法との成績の違いに焦点を当て、これらのテストの発達的側面を研究することを目的とした。実行機能を反映した指標のスコアは、9歳から11歳まで急速に減少し、発達は青年期に減速傾向を示した。この結果は、従来の検査の指数スコアと同等であった。我々はまた、これらの検査指標における発達的変化と背景に存在するニューロン成熟課程との関連についても考察した

The ACROBAT 2022 Challenge: Automatic Registration Of Breast Cancer Tissue

The alignment of tissue between histopathological whole-slide-images (WSI) is crucial for research and clinical applications. Advances in computing, deep learning, and availability of large WSI datasets have revolutionised WSI analysis. Therefore, the current state-of-the-art in WSI registration is unclear. To address this, we conducted the ACROBAT challenge, based on the largest WSI registration dataset to date, including 4,212 WSIs from 1,152 breast cancer patients. The challenge objective was to align WSIs of tissue that was stained with routine diagnostic immunohistochemistry to its H&E-stained counterpart. We compare the performance of eight WSI registration algorithms, including an investigation of the impact of different WSI properties and clinical covariates. We find that conceptually distinct WSI registration methods can lead to highly accurate registration performances and identify covariates that impact performances across methods. These results establish the current state-of-the-art in WSI registration and guide researchers in selecting and developing methods

Eicosapentaenoic acid suppresses ocular inflammation in endotoxin-induced uveitis

Purpose: To investigate the effect of eicosapentaenoic acid (EPA) on acute ocular inflammation in an animal model of endotoxin-induced uveitis (EIU). Methods: C57Bl/6 mice (6-week-old males) were orally treated with EPA at a dose of 50 mg/kg/day for 5 days. EIU was then induced in the animals by intraperitoneal injection of 160 μg lipopolysaccharide (LPS). Twenty-four hours after LPS injection, leukocyte adhesion to the retinal vasculature was evaluated by the concanavalin A lectin perfusion-labeling technique, and leukocyte infiltration into the vitreous cavity was quantified. Furthermore, the protein levels of monocyte chemotactic protein (MCP)-1, interleukin (IL)-6, intercellular adhesion molecule-1 and phospholyrated nuclear factor (NF)-κB p65 in the retina and retinal pigment epithelium (RPE)-choroid complex were examined by enzyme-linked immunosorbent assay (ELISA). Results: At 24 h after LPS injection, the EIU animals treated with oral EPA administration showed a significant decrease in leukocyte adhesion to the retinal vessels by 43.4% (p< 0.01) and leukocyte infiltration into the vitreous cavity by 49.2% (p<0.05). In addition, EPA significantly reduced the protein levels of MCP-1 and IL-6 in the retina and the RPE-choroid complex. Furthermore, phosphorylation of NF-κB was suppressed by EPA treatment. Conclusions: Our data suggest that EPA inhibits multiple inflammatory molecules in vivo. EPA may become a novel strategy in the prevention and/or treatment of ocular inflammatory diseases