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Tetralogy of Fallot (TOF) is rarely associated with partial anomalous pulmonary venous return (PAPVR). Unidentified PAPVR, however, might increase the risk of pulmonary valve replacement in repaired TOF patients by right ventricular (RV) dilatation and RV dysfunction. Here, we present a case of a 19-year-old male who received a correction of TOF 18 years ago and a rare type of PAPVR was identified during the follow up period. The anomalous pulmonary veins were connected to the left hepatic vein, left superior vena cava, and the right superior vena cava. Performing a pulmonary valve replacement, PAPVR was also corrected by an intra-atrial baffle with a new approach using the venous plexus between the left hepatic vein and the right hepatic vein.

TME (tumor microenvironment) consists of blood & lymphatic vessels, stromal cells, and immune cells such as lymphocytes, macrophages, and antigen-presenting cells (APC). Cellular interactions among various immune cell types within TME regulate tumor growth, metastasis, and resistance to cancer therapy. V-domain Ig suppressor of T cell activation (VISTA) is a negative checkpoint regulator highly expressed on tumor-infiltrating myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAMs) and VISTA blockade could enhance antitumor immunity in TME. PMC-309 binding to VISTA expressing cells is highly selective and the selectivity is maintained even in the low pH conditions that mimic TME. Binding of PMC-309 on MDSC cells enhances the secretion of IFN-γ, TNF-α, and IL-2 in Mixed Lymphocyte Reaction (MLR) settings. In in vivo study, PMC-309 suppressed tumor growth, which was further attenuated with an anti-PD1 antibody. The anti-tumor activity was associated with enhanced T cell activation, increased secretion of pro-inflammatory cytokines, and increased penetration of tumor-infiltrating leukocytes (TIL) into TME. Patients who became resistant to anti-CTLA-4 and anti-PD(L)1 antibody showed increased expression of VISTA, suggesting that anti-VISTA therapeutics can help to treat the patients who do not respond well to other immuno-oncology drugs. We are developing PMC-309 as a next generation immuno-oncology (IO) agent, which can convert immunologically cold into hot tumors as a mono- or combo- therapy with other IO agent. Citation Format: Cheon Ho Park, Sang Soon Byun, Jin Yong An, Sun Hyung Ha, Hye Rim Han, Nu Ri Kang, Beom Yong Park, Eun Ah Lee, Hyun Sun Park, Jin-San Yoo, Weon Sup Lee. PMC309, a highly selective anti-VISTA antibody enhances T cell activation through blocking the interaction of T cells and myeloid derived suppressor cells (MDSC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1626.

This study investigated smoking behaviors by disability type among people with disabilities in Korea and identified factors associated with attempted smoking cessation and successful four-week smoking abstinence. Data were collected between 1 January 2018 and 31 December 2019. Predictors of attempted smoking cessation and successful four-week smoking abstinence were analyzed by disability type in 557 participants. Compared to people with mental health disorders, people with physical disabilities or brain lesions were more likely to attempt smoking cessation, and people with physical or internal disabilities were more likely to successfully abstain for four weeks. Common predictors of smoking cessation attempts and four-week abstinence were education level and CO level. Employment status predicted attempted cessation, while confidence in smoking cessation predicted four-week abstinence. To provide effective smoking cessation services for people with disabilities, disability type should be considered, and comprehensive and sustainable community-based programs need to be developed. Furthermore, a standardized survey of people with disabilities should be conducted to examine socioeconomic factors, including health status, employment, and education level, and to explore fundamental measures needed to address the problem of smoking among people with disabilities.

Objective: The delivery of drugs and immune cells into the tumor microenvironment is limited due to abnormal tumor vessel which is characterized as low oxygen concentration, low perfusion rate and leakage. It leads to diminish the efficacy of drugs and radiation therapy. Traditional anti-angiogenesis strategies attempt to reduce the tumor vascular supply, but their success is restricted by insufficient efficacy or development of resistance. To solve the problem, we try to using active vessel stabilizer, which can normalize the abnormal condition of tumor vessel. Background: Tie2 acts as cell-surface receptor for Ang1/Ang2 and regulates angiogenesis, endothelial cell survival, proliferation, migration, as well as maintenance of vascular quiescence. Especially, Ang1-Tie2 signaling pathway has been known to promote blood vessel maturation and stabilization. Methods: We have developed a series of novel human IgG monoclonal antibody that binds to human-TIE2 with a high affinity (Kd ~0.1 nM). The antibody binds to human TIE2 extracellular domain and activates its associated function in a ligand independent way. The mode of action was studied in vitro with human umbilical vein endothelial cells (HUVEC) and animal models. The vessel stabilization was investigated with laser induced choroidal neovascularization (CNV). The effect on tumor infiltrated lymphocyte was also studied in mouse colon cancer model. Results: Anti-Tie2 antibody increased human endothelial cell migration like Ang1 and inhibited VEGF-induced vascular leakage, contributing to vessel normalization. It binds to Tie2 in a ligand independent way and thus it can stabilize vessel as an agonist. Both p-VEGFR and p-VE-Cadherin levels are also significantly decreased on VEGF-induced VEGFR signaling pathway by anti-Tie2 antibody, suggesting that it can maintain cell to cell junction. The vessel stabilization effect was demonstrated in a mouse model of laser induced CNV. Moreover, in syngeneic CT26 mouse models, anti-Tie2 antibody showed anti-tumor effect in which it significantly reduced the tumor growth and synergistically when it combined with anti PD-1 antibody. The tumor infiltrating lymphocytes were increased in CT26 tumor, especially CD8+ T cells and MDSC when anti-Tie2 was administered. Conclusion: We developed active vessels stabilizer targeting Tie2, having an effect of vessel stabilization in a ligand independent way. It inhibited VEGF-induced vascular leakage through decrease of p-VEGFR and VE-cadherin. This active vessel stabilizer could help deliver drug and lymphocyte into the TME. The therapeutic efficacy of immune checkpoint inhibitors can be increased when it combined with this active vessel stabilizer. Thus, this active vessel stabilizer can change cold tumor into hot tumor. Citation Format: Eun-Ah Lee, Beomyong Park, Nu Ri Kang, Youngae Lee, Do-yun Kim, Sang Soon Byun, Jin Yong An, Cheon Ho Park, Weon Sup Lee, Joo Hyoung Lee. A novel anti-Tie2 antibody stabilizes vessel and increases tumor infiltrated lymphocytes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1483.

Background. Pueraria lobata is used in traditional Asian medicine to treat cardiovascular diseases, diarrhea, diabetes mellitus, and diabetic complications such as diabetic retinopathy. Oxidative stress in retinal pigment epithelial cells is implicated in the pathogenesis of retinopathy and age-related macular degeneration (AMD). Here, we evaluated whether the P. lobata extract can prevent cell death and decrease membrane permeability in oxidative stress-induced human retinal pigment epithelial cells. Methods. The effects of P. lobata extract on hydrogen peroxide- (H2O2-) induced oxidative stress were investigated using 2′,7′–dichlorofluorescin diacetate, western blotting, and immunohistochemistry in human retinal pigment epithelial cells. The effects of puerarin, daidzein, and daidzin isolated from P. lobata extract were also studied by determining cell death, reactive oxygen species (ROS) generation, and p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) phosphorylation. Results. Our results showed that the P. lobata extract inhibited ROS generation, suppressed the disruption of zonula occludens-1 (ZO-1), and reduced membrane permeability in H2O2-induced human retinal pigment epithelial cells. Additionally, the P. lobata extract prevented the inhibition of p38 MAPK and JNK phosphorylation. Conclusion. Our findings suggest that the P. lobata extract has the potential to prevent AMD development by inhibiting the mechanism underlying oxidative stress-mediated ocular disorders.

Methylglyoxal (MGO), a reactive α-oxoaldehyde produced by glucose metabolism, is elevated in several diabetic complications, including diabetic retinopathy. The breakdown of retinal pigment epithelial cells is implicated in the progression of diabetic retinopathy. Increased concentrations of MGO lead to retinal pigment epithelial cell death. In this study, we investigated the involvement of activating transcription factor 6 (ATF6) in MGO-mediated cytotoxicity in ARPE-19 cells. In response to high concentrations of MGO, unfolded protein response-related ATF6 was induced. Interestingly, the MGO also induced the generation of reactive oxygen species (ROS) and the phosphorylation of ERK and p38 MAPK. The induction of ATF6 was inhibited by ERK-specific and p38 MAPK-specific inhibitors (U0126 and SB202190) and by NAC, a well-known ROS scavenger. NAC also attenuated the phosphorylation of p38 MAPK. MGO induced cytotoxicity in the ARPE-19 cells, which was ameliorated by the inhibition of the ERK, p38 MAPK, and ROS pathways. Furthermore, the MGO-mediated cytotoxicity was inhibited by ATF6 siRNA. Taken together, these results clearly show that the induction of ATF6 via the ERK and ROS-p38 MAPK pathways is implicated in MGO-induced cytotoxicity in ARPE-19 cells.