• Clinical and Experimental Reproductive Medicine
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• v.39 no.2
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• pp.73-80
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• 2012

Objective: This study was undertaken to determine the effect of hypoxia inducible factor (HIF)-$1{\alpha}$ on the cell death, autophagy, and invasion of trophoblasts. Methods: To understand the effect of HIF-$1{\alpha}$, we inhibited HIF-$1{\alpha}$ using siRNA under normoxia and hypoxia conditions. Invasion assay and zymography were performed to determine changes in the invasion ability of HIF-$1{\alpha}$. Western blotting and immunofluorescence were performed to determine some of the signal events involved in apoptosis and autophagy. Results: There was no difference in cell death through the inhibition of HIF-$1{\alpha}$ expression by siRNA; however, the expression of LC3 and autophagosome formation increased. On the other hand, autophagy was increased, and the invasive ability of trophoblast cells decreased according to the inhibition of HIF-$1{\alpha}$ expression by siRNA. These experimental results mean that HIF-$1{\alpha}$ genes regulate the invasive ability of trophoblasts by increasing autophagy. Conclusion: This study contributes important data for understanding the mechanism of early pregnancy implantation and the invasive ability of trophoblasts by defining the relationship between the roles of HIF-$1{\alpha}$ and autophagy.

• Korean Journal of Head & Neck Oncology
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• v.35 no.1
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• pp.13-20
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• 2019

Background/Objectives: Despite multiple approaches of treatments for salivary duct carcinoma, there has been a need for more successful treatment methods because of its poor prognosis. Treatment options like immunotherapy using new technologies have been attempted. Based on recent study results indicating that targeting programmed death receptors are effective in treating various cancers, this study aimed to identify the frequency of PD-L1 expression and its impact on survival rate in salivary duct carcinoma. Materials & Methods: We studied 33 patients with salivary gland cancer who were available for histologic specimens. We examined the expression of PD-L1 in the tissues and analyzed the association with the survival rate and the association with various clinical parameters. Results: According to this study and review of similar studies, we discovered that the expression of PD-L1 in salivary duct carcinoma was lower than other types of cancers. The impact of PD-L1 on survival rate also showed inconsistency in salivary duct carcinoma. Conclusion: Immunotherapy by PD-1/PD-L1 checkpoint blockade in salivary duct carcinoma needs further evaluation for clinical application.

• The Korean Journal of Zoology
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• v.33 no.1
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• pp.94-102
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• 1990

In Xenopus laevis the cranial myotomes, W, X, Y and Z represent transient embry-specific structures since they undergo reduction" in the later stage of development. An extensive set of expertmental studies was undertaken in order to discriminate whether the cranial myotomes perform a programmed autonomous death or reduction" by the influence from surrounding tissue such as otic vesicle. Removal of the neighboring otic vesicle did not affect WXYZ degeneration. Grafting the otic vesicle to novel site along the somite file did not induce local myotome degenration. When anterior-most somitic primordia were relocated to the trunk somite region, they underwent reduction eventually. Likewise, with the transplantation of posterior somite forming region into the anterior, autonomous differentiation pafferns were observed. And the cullture of presumptive somitic tissue revealed that WXYZ might degnerate like in vivo. It is therefore concluded that the cranial myotomes of Xenopus laevis exhibit an autonomous cell death during later embryogenesis.yogenesis.

• Korean Journal of Clinical Pharmacy
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• v.28 no.1
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• pp.65-75
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• 2018

Objective: Over the last several years, immunotherapy has become one of the most promising therapeutic options for cancer. This study aims to summarize the updates on cancer immunotherapy focusing on immune checkpoint inhibitors, such as programmed cell death-1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors, which have received attention as new anticancer therapeutic agents. Methods: A literature survey was carried out on PubMed to identify high-impact papers on cancer immunotherapy from 2010. The most recent data on clinical efficacy and safety have been included highlighting the response characteristics to recently approved immunotherapeutic agents. Results: In various cancers, immune checkpoints are a means for cancer cells to evade the immune system. Furthermore, CTLA-4 and PD-L1 can be overexpressed, allowing malignant cells to evade T-cells. Numerous clinical trials have been performed to seek appropriate indication of these products in various cancer types. Among them, the most conspicuous types are melanoma, non-small-cell lung cancer, and head and neck cancer. The approval of ipilimumab by Food and Drug Administration (FDA) commenced a new era of cancer immunotherapy. This was followed by the approval of nivolumab and pembrolizumab. Currently, combination therapies are being investigated for various cancer types. Conclusion: In this study, we reviewed recently reported scientific and clinical evidence for currently approved immune checkpoint inhibitors. Although these novel checkpoint inhibitors are ever evolving for cancer therapies, there exist limitations that need to be overcome, indicating the necessity for further studies aiming to improve their efficacy, toxicity, and cost.

• Journal of Gynecologic Oncology
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• v.29 no.6
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• pp.93.1-93.11
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• 2018

The introduction of checkpoint inhibitors revolutionized immuno-oncology. The efficacy of traditional immunotherapeutics, like vaccines and immunostimulants was very limited due to persistent immune-escape strategies of cancer cells. Checkpoint inhibitors target these escape mechanisms and re-direct the immune system to anti-tumor toxicity. Phenomenal results have been reported in entities like melanoma, where no other therapy was able to demonstrate survival benefit, before the introduction of immunotherapeutics. The first experience in ovarian cancer (OC) was reported for nivolumab, a fully human anti-programmed cell death protein 1 (PD1) antibody, in 2015. While the data are extraordinary for a mono-immunotherapeutic agent and very promising, they do not match up to the revolutionary results in entities like melanoma. The key to exceptional treatment response in OC, could be the identification of the most immunogenic patients. We hypothyse that BRCA mutation could be a predictor of improved response in OC. The underlying DNA-repair-deficiancy should result in increased immunogenicity because of higher mutational load and more neoantigen presentation. This hypothesis was not tested to date and should be subject to future trials. The present article gives an overview of the immunologic background of checkpoint inhibition (CI). It presents current data on nivolumab and other checkpoint-inhibitors in solid tumors and OC specifically and depicts important topics in the management of this novel substance group, such as side effect control, diagnostic PD-1/programmed cell death-ligand 1 (PD-L1) expression assessment and management of pseudoprogression.

• Tuberculosis and Respiratory Diseases
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• v.86 no.4
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• pp.304-318
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• 2023

Background: Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment and significantly contribute to immune evasion. We investigated the effects of CAFs on the immune function of CD4+ and CD8+ T cells in non-small cell lung cancer (NSCLC). Methods: We isolated CAFs and normal fibroblasts (NFs) from tumors and normal lung tissues of NSCLC patients, respectively. CAFs were co-cultured with activated T cells to evaluate their immune regulatory function. We investigated the effect of CAF conditioned medium (CAF-CM) on the cytotoxicity of T cells. CAFs were also co-cultured with activated peripheral blood mononuclear cells and further incubated with cyclooxygenase-2 (COX2) inhibitors to investigate the potential role of COX2 in immune evasion. Results: CAFs and NFs were isolated from the lung tissues (n=8) and lymph nodes (n=3) of NSCLC patients. Immune suppressive markers, such as COX2 and programmed death-ligand 1 (PD-L1), were increased in CAFs after co-culture with activated T cells. Interestingly, CAFs promoted the expression of programmed death-1 in CD4+ and CD8+ T cells, and strongly inhibited T cell proliferation in allogenic and autologous pairs of CAFs and T cells. CAF-CM decreased the cytotoxicity of T cells. COX2 inhibitors partially restored the proliferation of CD4+ and CD8+ T cells, and downregulated the expression of COX2, prostaglandin E synthase, prostaglandin E2, and PD-L1 in CAFs. Conclusion: CAFs promote immune evasion by suppressing the function of CD4+ and CD8+ T cells via their effects on COX2 and PD-L1 in NSCLC. The immunosuppressive function of CAFs could be alleviated by COX2 inhibitors.

• Korean Journal of Clinical Pharmacy
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• v.28 no.2
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• pp.88-94
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• 2018

Background: We strived to evaluate the status of nivolumab use and associated factors on the clinical efficacy of the drug. Methods: The study was retrospectively conducted in patients who had been administered nivolumab at least once at the cancer center of Seoul National University Hospital from June 2015 to April 2017. Data were collected from electronic medical records. A medication-use evaluation was performed based on the American Society of Health-System Pharmacists mediation-use guidelines. Results: Sixty-six of the 74 patients (89.2%) showed indications approved for nivolumab use by the Korean Ministry of Food and Drug Safety (MFDS; n=55) or the US Food and Drug Administration (FDA; n=11). Approximately 73.0% of the patients were administered the approved dose of 3 mg/kg but 25.7% were administered an unapproved fixed dose of 100 mg. The overall response rate was 21.7%, and the response rate of non-small cell lung cancer patients, who accounted for the largest number of indications, was 18.8%. Adverse reactions were found in 90.1% of the patients and were mostly mild (86%). The expression of programmed death-ligand 1 (PD-L1) was analyzed as a factor affecting treatment response (p=0.028, odds ratio [OR]=11.331). Conclusion: PD-L1 expression was found to affect treatment response. However, caution is required while using an unapproved dosage and in the absence of monitoring for effectiveness and safety. Therefore, an effective protocol or instruction manual for the proper use of nivolumab should be considered.

• Journal of Digestive Cancer Research
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• v.12 no.2
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• pp.72-81
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• 2024

Esophageal squamous cell carcinomas constitute a major proportion of esophageal cancers in Korea. Conventional chemotherapy and radiation therapy are the options for treating advanced/metastatic esophageal cancer, but the prognosis remains poor. Immunotherapy has significantly improved the prognosis of several advanced/metastatic cancers including esophageal squamous cell carcinoma. In Korea, immunotherapy is used to treat advanced/metastatic esophageal squamous cell carcinoma, and treatment results are expected to further improve. Immunotherapy is a term used to describe a treatment modality involving a biological/targeted agent that aims to enhance and restore the ability of the immune system to detect and destroy cancer cells by modifying or blocking co-stimulating signals. Immune checkpoint inhibitors have revolutionized cancer treatment with the administration of a single agent (monotherapy) or combinations of multiple agents, with the three approved agents being anti-PD-1 (programmed death 1), anti-PD-L1 (programmed cell death ligand 1), and anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) monoclonal antibodies. Anti-PD-1 drugs including nivolumab and pembrolizumab have been mainly investigated for treating advanced/metastatic esophageal squamous cell cancer. Studies on their effectiveness in a neoadjuvant setting, a curative adjuvant setting, or as the first-line treatment for advanced or metastatic setting are ongoing. This review describes the principle of action, summary of existing clinical studies, and prospects for immune checkpoint inhibitors used in the treatment of advanced/metastatic esophageal squamous cell cancer.

• Journal of Embryo Transfer
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• v.30 no.3
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• pp.239-248
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• 2015

The nature of molecular mechanisms governing embryonic cell block is largely unknown, but recent reports have demonstrated that proper execution of programmed cell death is crucial for this process. The main objective of this study is to determine effects of programmed cell death on porcine oocytes development in vitro after parthenogenesis. Among the blastocysts matured in 3MA, MAP1LC3A and ATG5 RNA gene expression level increased in the order of Cyst < 3MA < RP. However, Casp-3 and TNF-r RNA gene expression level decreased in the order of RP < 3MA < Cyst. Expression of mTOR within the RP-cultured blastocyst was the most highly to the inner cell mass, while 3MA-cultured blastocyst showed very lowest expression in inner cell mass. The expression of mTOR showed a pattern opposite to that of MAP1LC3A. That is, its expression was the lowest in Cyst group. When the enzymatic activity of MMP-2 and MMP-9 was assessed in culture, the level of active MMP-9 was higher expression in the medium of each RP treatment group, with the level of another treatment group being relatively higher. Analyses of TIMP-2 and TIMP-3 revealed that their expression was higher in groups that did not receive RP treatment. More specifically, the level of TIMP-2 was not affected by Cyst treatment, while the level of TIMP-3 was higher in 3MA and RP treatment group. There was highly cell division activation efficiency of parthenogenesis on cultured system of RP supplement IVC medium. Therefore, these results suggest that embryo development was significantly increased in conditional culture medium with active autophagy as compared to common cultured condition. Further investigation of this distinction may enable the development of innovative improvements for the production of porcine somatic cell nuclear transfer.

• Radiation Oncology Journal
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• v.37 no.3
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• pp.149-155
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• 2019

In metastatic non-small cell lung cancer (NSCLC), the role of radiotherapy (RT) has been limited to palliation to alleviate the symptoms. However, with the development of advanced RT techniques, recent advances in immuno-oncology therapy targeting programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) and targeted agents for epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) translocation allowed new roles of RT in these patients. Within this metastatic population, there is a subset of patients with a limited number of sites of metastatic disease, termed as oligometastasis that can achieve long-term survival from aggressive local management. There is no consensus on the definition of oligometastasis; however, most clinical trials define oligometastasis as having 3 to 5 metastatic lesions. Recent phase II randomized clinical trials have shown that ablative RT, including stereotactic ablative body radiotherapy (SABR) and hypofractionated RT, to primary and metastatic sites improved progression-free survival (PFS) and overall survival (OS) in patients with oligometastatic NSCLC. The PEMBRO-RT study, a randomized phase II study comparing SABR prior to pembrolizumab therapy and pembrolizumab therapy alone, revealed that the addition of SABR improved the overall response, PFS, and OS in patients with advanced NSCLC. The efficacy of RT in oligometastatic lung cancer has only been studied in phase II studies; therefore, large-scale phase III studies are needed to confirm the benefit of local ablative RT in patients with oligometastatic NSCLC. Local intensified RT to primary and metastatic lesions is expected to become an important treatment paradigm in the near future in patients with metastatic lung cancer.