ScholarWorks Community:https://scholarworks.korea.ac.kr/kumedicine/handle/2020.sw.kumedicine/692024-03-29T05:21:45Z2024-03-29T05:21:45ZAugmented anti-cancer effect of hypoxia-inducible factor 2α (HIF2α)- targeting PT2385 delivered in α-synuclein-AuNP microcapsules for clear cell renal carcinoma mouse modelNam, Eun-JeongKong, Su-KangCho, InyoungPaik, Seung R.Kim, Young-Sikhttps://scholarworks.korea.ac.kr/kumedicine/handle/2021.sw.kumedicine/651162024-03-07T00:30:09Z2024-01-01T00:00:00ZTitle: Augmented anti-cancer effect of hypoxia-inducible factor 2α (HIF2α)- targeting PT2385 delivered in α-synuclein-AuNP microcapsules for clear cell renal carcinoma mouse model
Authors: Nam, Eun-Jeong; Kong, Su-Kang; Cho, Inyoung; Paik, Seung R.; Kim, Young-Sik
Abstract: Development of anti-cancer drug carrier system capable of delivering chemotherapeutic and immunotherapeutic agents to cancerous lesions is essential to overcome severe side effects and reduced therapeutic efficacy of the drugs. The microcapsules of gold nanoparticles (AuNPs) fabricated with a self-assembly protein of alpha-synuclein (alpha S) have been employed to carry the hypoxia-inducible factor 2 alpha (HIF2 alpha)-targeting PT2385 in a mouse model xenografted with clear cell renal cell carcinoma (ccRCC). Hydrophobic cargo like rhodamine 6G entrapped within the microcapsules was demonstrated to be selectively released under cancer-related stimuli including acidic pH, local hyperthermia, and proteases such as matrix metalloproteinases. The alpha S-AuNP mi-crocapsules containing the hydrophobic drug of PT2385 suppressed the expression of HIF2 alpha and its downstream genes in ccRCC A498 cells in vitro to the level comparable to that obtained with direct PT2385 treatment, indicating that the PT2385 remained active inside the capsules. In the A498 xenograft mouse model, intraper-itoneal administration of the alpha S-AuNP-PT2385 microcapsules significantly reduced the tumor volume and Ki-67 scores from those monitored in the PT2385-treated group. Therefore, the alpha S-AuNP microcapsule is suggested to be a promising cancer-targeting drug delivery system which exhibits several merits such as improved loading efficiency for hydrophobic drugs, their protection from metabolism, and selective cargo release in tumor mi-croenvironments in addition to its physicotherapeutic potential due to the photothermal effect of AuNPs.2024-01-01T00:00:00ZNutlin-3a induces KRAS mutant/p53 wild type lung cancer specific methuosis-like cell death that is dependent on GFPT2Kim, DasomMin, DongwhaKim, JooheeKim, Min JungSeo, YerimJung, Byung HwaKwon, Seung-HaeRo, HyunjuLee, SeoeeSa, Jason K.Lee, Ji-Yunhttps://scholarworks.korea.ac.kr/kumedicine/handle/2021.sw.kumedicine/650152024-01-09T04:30:06Z2023-12-01T00:00:00ZTitle: Nutlin-3a induces KRAS mutant/p53 wild type lung cancer specific methuosis-like cell death that is dependent on GFPT2
Authors: Kim, Dasom; Min, Dongwha; Kim, Joohee; Kim, Min Jung; Seo, Yerim; Jung, Byung Hwa; Kwon, Seung-Hae; Ro, Hyunju; Lee, Seoee; Sa, Jason K.; Lee, Ji-Yun
Abstract: Background Oncogenic KRAS mutation, the most frequent mutation in non-small cell lung cancer (NSCLC), is an aggressiveness risk factor and leads to the metabolic reprogramming of cancer cells by promoting glucose, glutamine, and fatty acid absorption and glycolysis. Lately, sotorasib was approved by the FDA as a first-in-class KRAS-G12C inhibitor. However, sotorasib still has a derivative barrier, which is not effective for other KRAS mutation types, except for G12C. Additionally, resistance to sotorasib is likely to develop, demanding the need for alternative therapeutic strategies.Methods KRAS mutant, and wildtype NSCLC cells were used in vitro cell analyses. Cell viability, proliferation, and death were measured by MTT, cell counting, colony analyses, and annexin V staining for FACS. Cell tracker dyes were used to investigate cell morphology, which was examined by holotomograpy, and confocal microscopes. RNA sequencing was performed to identify key target molecule or pathway, which was confirmed by qRT-PCR, western blotting, and metabolite analyses by UHPLC-MS/MS. Zebrafish and mouse xenograft model were used for in vivo analysis.Results In this study, we found that nutlin-3a, an MDM2 antagonist, inhibited the KRAS-PI3K/Akt-mTOR pathway and disrupted the fusion of both autophagosomes and macropinosomes with lysosomes. This further elucidated non-apoptotic and catastrophic macropinocytosis associated methuosis-like cell death, which was found to be dependent on GFPT2 of the hexosamine biosynthetic pathway, specifically in KRAS mutant /p53 wild type NSCLC cells.Conclusion These results indicate the potential of nutlin-3a as an alternative agent for treating KRAS mutant/p53 wild type NSCLC cells.2023-12-01T00:00:00ZA robust model training strategy using hard negative mining in a weakly labeled dataset for lymphatic invasion in gastric cancerLee, JonghyunAhn, SangjeongKim, Hyun-SooAn, JungsukSim, Jongminhttps://scholarworks.korea.ac.kr/kumedicine/handle/2021.sw.kumedicine/651212024-01-16T02:00:04Z2023-12-01T00:00:00ZTitle: A robust model training strategy using hard negative mining in a weakly labeled dataset for lymphatic invasion in gastric cancer
Authors: Lee, Jonghyun; Ahn, Sangjeong; Kim, Hyun-Soo; An, Jungsuk; Sim, Jongmin
Abstract: Gastric cancer is a significant public health concern, emphasizing the need for accurate evaluation of lymphatic invasion (LI) for determining prognosis and treatment options. However, this task is time-consuming, labor-intensive, and prone to intra- and interobserver variability. Furthermore, the scarcity of annotated data presents a challenge, particularly in the field of digital pathology. Therefore, there is a demand for an accurate and objective method to detect LI using a small dataset, benefiting pathologists. In this study, we trained convolutional neural networks to classify LI using a four-step training process: (1) weak model training, (2) identification of false positives, (3) hard negative mining in a weakly labeled dataset, and (4) strong model training. To overcome the lack of annotated datasets, we applied a hard negative mining approach in a weakly labeled dataset, which contained only final diagnostic information, resembling the typical data found in hospital databases, and improved classification performance. Ablation studies were performed to simulate the lack of datasets and severely unbalanced datasets, further confirming the effectiveness of our proposed approach. Notably, our results demonstrated that, despite the small number of annotated datasets, efficient training was achievable, with the potential to extend to other image classification approaches used in medicine.2023-12-01T00:00:00ZTherapy-related myeloid neoplasm in early breast cancer patients treated with adjuvant chemotherapyOh, HoonjiYou, Ji YoungLee, Eun-ShinLee, Jung HyunSong, Sung EunLee, Nam KwonJung, Seung PilAn, Jung SeokCho, Kyu RanKim, Cheol YongPark, Kyong Hwahttps://scholarworks.korea.ac.kr/kumedicine/handle/2021.sw.kumedicine/638442024-02-20T12:00:58Z2023-09-01T00:00:00ZTitle: Therapy-related myeloid neoplasm in early breast cancer patients treated with adjuvant chemotherapy
Authors: Oh, Hoonji; You, Ji Young; Lee, Eun-Shin; Lee, Jung Hyun; Song, Sung Eun; Lee, Nam Kwon; Jung, Seung Pil; An, Jung Seok; Cho, Kyu Ran; Kim, Cheol Yong; Park, Kyong Hwa
Abstract: Background: Long-term complications are becoming more important as the sur-vival rate of breast cancer improves. Treatment-related myeloid neoplasm is an important long-term complication in breast cancer survivors as it has a poor prognosis. Objective: We evaluated the incidence and risk factors for the development of treatment -related acute myeloid leukaemia (AML)/myelodysplastic syndrome (MDS) in patients treated with early breast cancer.Methods: We accessed the national Korean database to identify 153,565 patients diagnosed with breast cancer between January 2007 and October 2016 who underwent surgery for breast cancer. We estimated the cumulative incidence of AML/MDS and analysed the risk factors for developing AML/MDS.Results: Of 153,575 patients, 79,321 received anthracycline-based adjuvant therapy, 14,317 received adjuvant therapy without anthracyclines and 46,657 did not receive adjuvant che-motherapy. Overall, 120 developed AML (105 in the anthracycline group, 9 in the non-an-thracycline group and 6 in the control group), and 128 developed MDS (96, 9 and 23 in each group). The 10-year cumulative incidence of AML/MDS was the highest in the anthracycline group (0.221% and 0.199%), followed by the non-anthracycline group (0.122% and 0.163%) and the control group (0.024% and 0.089%). The risk of developing AML/MDS was significantly higher in patients treated with anthracyclines (hazard ratio [HR] 9.531; p < 0.0001 for AML and HR 2.559; p < 0.0001 for MDS) compared to patients in the control group.Conclusion: This study found that anthracycline-based adjuvant therapy significantly in-creased the risk of AML/MDS in Korean breast cancer patients, with the risk persisting for at least 10 years. While the cumulative incidence was low, the long-term risks of AML/MDS should be taken into account considering the poor outcomes associated with these neoplasms.& COPY; 2023 Elsevier Ltd. All rights reserved.2023-09-01T00:00:00Z