• IMMUNE NETWORK
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• v.20 no.6
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• pp.48.1-48.11
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• 2020

Hyperprogressive disease (HPD) is a distinct pattern of progression characterized by acceleration of tumor growth after treatment with anti-PD-1/PD-L1 Abs. However, the immunological characteristics have not been fully elucidated in patients with HPD. We prospectively recruited patients with metastatic non-small cell lung cancer treated with anti-PD-1/PD-L1 Abs between April 2015 and April 2018, and collected peripheral blood before treatment and 7-days post-treatment. HPD was defined as ≥2-fold increase in both tumor growth kinetics and tumor growth rate between pre-treatment and post-treatment. Peripheral blood mononuclear cells were analyzed by multi-color flow cytometry to phenotype the immune cells. Of 115 patients, 19 (16.5%) developed HPD, 52 experienced durable clinical benefit (DCB; partial response or stable disease ≥6 months), and 44 experienced non-hyperprogressive progression (NHPD). Patients with HPD had significantly lower progression-free survival (p<0.001) and overall survival (p<0.001). When peripheral blood immune cells were examined, the pre-treatment frequency of CD39⁺ cells among CD8⁺ T cells was significantly higher in patients with HPD compared to those with NHPD, although it showed borderline significance to predict HPD. Other parameters regarding regulatory T cells or myeloid derived suppressor cells did not significantly differ among patient groups. Our findings suggest high pre-treatment frequency of CD39⁺CD8⁺ T cells might be a characteristic of HPD. Further investigations in a larger cohort are needed to confirm our results and better delineate the immune landscape of HPD.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.2
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• pp.611-616
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• 2014

Objectives: Dendritic cell (DC)-based tumor immunotherapy needs an immunogenic tumor associated antigen (TAA) and an effective approach for its presentation to lymphocytes. In this study we explored whether transduction of DCs with lentiviruses (LVs) expressing the human interleukin-12 gene could stimulate antigen-specific cytotoxic T cells (CTLs) against human lung cancer cells in vitro. Methods: Peripheral blood monocyte-derived DCs were transduced with a lentiviral vector encoding human IL-12 gene (LV-12). The anticipated target of the human IL-12 gene was detected by RT-PCR. The concentration of IL-12 in the culture supernatant of DCs was measured by ELISA.Transduction efficiencies and CD83 phenotypes of DCs were assessed by flow cytometry. DCs were pulsed with tumor antigen of lung cancer cells (DC+Ag) and transduced with LV-12 (DC-LV-12+Ag). Stimulation of T lymphocyte proliferation by DCs and activation of cytotoxic T-lymphocytes (CTL) stimulated by LV-12 transduced DCs pulsed with tumor antigen against A549 lung cancer cells were assessed with methyl thiazolyltetrazolium (MTT). Results: A recombinant lentivirus expressing the IL-12 gene was successfully constructed. DC transduced with LV-12 produced higher levels of IL-12 and expressed higher levels of CD83 than non-transduced. The DC modified by interleukin -12 gene and pulsed with tumor antigen demonstrated good stimulation of lymphocyte proliferation, induction of antigen-specific cytotoxic T lymphocytes and antitumor effects. Conclusions: Dendritic cells transduced with a lentivirus-mediated interleukin-12 gene have an enhanced ability to kill lung cancer cells through promoting T lymphocyte proliferation and cytotoxicity.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.22
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• pp.9945-9948
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• 2014

Background: The purpose of this study was to investigate Tim-3 expression on peripheral CD3-CD56+ natural killer (NK) cells and CD3+CD56+ natural killer T (NKT) cells in lung cancer patients. Materials and Methods: We analyzed Tim-3+CD3-CD56+ cells, Tim-3+CD3-$CD56^{dim}$ cells, Tim-3+CD3-$CD56^{bright}$ cells, and Tim-3+CD3+CD56+ cells in fresh peripheral blood from 79 lung cancer cases preoperatively and 53 healthy controls by flow cytometry. Postoperative blood samples were also analyzed from 21 members of the lung cancer patient cohort. Results: It was showed that expression of Tim-3 was significantly increased on CD3-CD56+ cells, CD3-$CD56^{dim}$ cells and CD3+CD56+ cells in lung cancer patients as compared to healthy controls (p=0.03, p=0.03 and p=0.04, respectively). When analyzing Tim-3 expression with cancer progression, results revealed more elevated Tim-3 expression in CD3-CD56+ cells, CD3-$CD56^{dim}$ cells and CD3+CD56+ cells in cases with advanced stages (III/IV) than those with stage I and II (p=0.02, p=0.04 and p=0.01, respectively). In addition, Tim-3 expression was significantly reduced on after surgical resection of the primary tumor (p<0.01). Conclusions: Tim-3 expression in natural killer cells from fresh peripheral blood may provide a useful indicator of disease progression of lung cancer. Furthermore, it was indicated that Tim-3 might be as a therapeutic target.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.3
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• pp.1743-1746
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• 2013

Background and Purpose: Cardiac myxoma is a major primary heart tumor which often causes unexpected symptoms or sudden death. This present study was designed to investigate its clinical pathological features and biological behavior. Methods: A retrospective analysis of the clinical pathologic and immunohistochemical features of 66 cases with cardiac myxoma was conducted. Results: In 66 patients with cardiac myxoma, 61 cases had involvement of the left atrium, one case in both the right ventricular and left atria. The female: male ratio was 2.7:1. Patients had symptoms of blood flow obstruction and systemic alterations with performance of arterial embolization. Tumors were spherical, lobulated or irregular in shape, and soft and brittle. Immunohistochemical markers of vimentin and CD34 in tumor cells were positive. Conclusion: Cardiac myxoma always exists in the left atrium and is more common in women, with diverse clinical manifestations and pathomorphism. Although proliferative activity and the recurrence rate are low, in addition to thorough surgical resection, strengthened review is important for young patients.

• The Journal of Internal Korean Medicine
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• v.39 no.4
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• pp.751-763
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• 2018

Objective: This study was undertaken to investigate how magnolia bark extract affects ob/ob mouse in terms of metabolic inflammation and insulin resistance. Methods: Leptin-deficient ob/ob mice were divided into 2 groups (n=5): a normal saline treatment (=control) and magnolia bark treatment. Wild type mice were the lean group (n=5). After 5 weeks, we measured fasting blood sugar (FBS) and conducted oral glucose tolerance tests (OGTTs) in each group. After 6 weeks, we measured body weight, epididymal fat pad weight, liver weight, serum glucose, serum insulin, and gene expression of tumor necrosis factor-${\alpha}$, interferon-${\gamma}$, and interleukin-6. We characterized the phenotype of adipose tissue macrophages (ATMs) and analyzed fractions of the phenotype in each group by flow cytometry. Results: In the magnolia bark group, fasting blood sugar, oral glucose tolerance levels, and insulin resistance (HOMA-IR) were significantly decreased. The population and proportion of ATMs among leukocytes in adipose tissue were significantly decreased in the magnolia bark group. The population and proportion of M1 type ATMs among ATMs were significantly decreased in the magnolia bark group. Gene expression of tumor necrosis factor-${\alpha}$ was significantly decreased in the magnolia bark group. Conclusions: These results support a positive effect of magnolia bark on metabolic diseases such as insulin resistance and metabolic inflammation in leptin-deficient ob/ob mice.

• The Journal of Internal Korean Medicine
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• v.22 no.4
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• pp.639-645
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• 2001

Angiogenesis is a fundamental process in reproduction and wound healing. Under these condition, neovascularization is tightly regulated. Unregulated angiogenesis may lead to several angiogenic diseases, and is thought to be indispensible for solid tumor growth and metastsis. The construction of new vascular network is a multistep cascade involving basement membrane degradation, endothelial cell proliferation, endothelial cell migration, and tube formation. Newly reported anti-angiogenic agents in oriental medical field have targeted both specific and multistep stages in the angiogenic process. From recent approach in oriental medical field with several herb medicines including activating blood flow and removing blood stasis medicine(活血化瘀藥), it may be possible in the future to develope specific anti-angiogenic agents that offer a less toxic potential therapy for cancer and angiogenic disease.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.10
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• pp.4329-4333
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• 2015

Background: To investigate the change of frequency and immuno-inhibitory function of myeloid-derived suppressor cells (MDSCs) after treatment of cisplatin (DDP) in A375 human melanoma model. Materials and Methods: BALB/c nude mice were inoculated with A375 cells to establish the human melanoma model and randomly divided into control group given normal saline (NS) and experimental group treated with DDP (5 mg/kg). The percentages of MDSCs in the tumor tissue and peripheral blood after DDP treatment were detected by flow cytometry. The proliferation and interferon-${\gamma}$ (IFN-${\gamma}$) secretion of T cells co-cultured with MDSCs were analyzed through carboxyfluorescein succinimidyl ester (CFSE) labeling assay and enzyme-linked immunospot (ELISPOT) assay, respectively. Results: In A375 human melanoma model, DDP treatment could significantly decrease the percentage of MDSCs in the tumor tissue, but exerted no effect on the level of MDSCs in peripheral blood. Moreover, DDP treatment could attenuate the immuno-inhibitory function of MDSCs. T cells co-cultured with DDP-treated MDSCs could dramatically elevate the proliferation and production of INF-${\gamma}$. Conclusions: DDP can decrease the frequency and attenuate immuno-inhibitory function of MDSCs in A375 melanoma model, suggesting a potential strategy to augment the efficacy of combined immunotherapy.

• Journal of Veterinary Clinics
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• v.37 no.5
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• pp.286-291
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• 2020

A 15-year-old castrated male Persian (Case 1), an 1.5-year-old castrated male Bengal (Case 2), and an 1.5-year-old spayed female Russian Blue (Case 3) cats were presented with iris-color change and suspicious anterior chamber mass. Complete ophthalmic examination revealed a vascularized or blood tinted mass filling with anterior chamber accompanied by rubeosis iridis, dyscoria, keratic precipitates, and severe aqueous flare. Ocular ultrasonography showed an iridociliary mass with blood flow signal in Case 1. Abdominal ultrasonography also revealed suspicious metastatic involvements of liver and spleen in this cat. Case 2 and 3 were suspected of being infected with feline infectious peritonitis. Topical antibiotic/steroid combinations were prescribed to control the uveitis in all 3 cases, although enucleation was initially considered for palliative pain management in Case 1. Anterior chamber mass had almost completely disappeared after topical medications and uveitis has been successfully managed, remaining in sight, even though ocular hypertension developed 1 month later in Case 1.

• Nutrition Research and Practice
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• v.9 no.2
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• pp.129-136
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• 2015

BACKGROUND/OBJECTIVES: A variety of immunomodulators can improve the efficacy of low-dose chemotherapeutics. Active hexose correlated compound (AHCC), a mushroom mycelia extract, has been shown to be a strong immunomodulator. Whether AHCC could enhance the antitumor effect of low-dose 5-fluorouracil (5-FU) via regulation of host immunity is unknown. MATERIALS/METHODS: In the current study Hepatoma 22 (H22) tumor-bearing mice were treated with PBS, 5-FU ($10mg{\cdot}kg^{-1}{\cdot}d^{-1}$, i.p), or AHCC ($360mg{\cdot}kg^{-1}{\cdot}d^{-1}$, i.g) plus 5-FU, respectively, for 5 d. $CD^{3+}$, $CD^{4+}$, $CD^{8+}$, and NK in peripheral blood were detected by flow cytometry. ALT, AST, BUN, and Cr levels were measured by biochemical assay. IL-2 and $TNF{\alpha}$ in serum were measured using the RIA kit and apoptosis of tumor was detected by TUNEL staining. Bax, Bcl-2, and TS protein levels were measured by immunohistochemical staining and mRNA level was evaluated by RT-PCR. RESULTS: Diet consumption and body weight showed that AHCC had no apparent toxicity. AHCC could reverse liver injury and myelosuppression induced by 5-FU (P < 0.05). Compared to mice treated with 5-FU, mice treated with AHCC plus 5-FU had higher thymus index, percentages of $CD^{3+}$, $CD^{4+}$, and NK cells (P < 0.01), and ratio of $CD^{4+}$/$CD^{8+}$ (P < 0.01) in peripheral blood. Radioimmunoassay showed that mice treated with AHCC plus 5-FU had the highest serum levels of IL-2 and $TNF{\alpha}$ compared with the vehicle group and 5-FU group. More importantly, the combination of AHCC and 5-FU produced a more potent antitumor effect (P < 0.05) and caused more severe apoptosis in tumor tissue (P < 0.05) compared with the 5-FU group. In addition, the combination of AHCC and 5-FU further up-regulated the expression of Bcl-2 associated X protein (Bax) (P < 0.01), while it down-regulated the expression of B cell lymphoma 2 (Bcl-2) (P < 0.01). CONCLUSIONS: These results support the claim that AHCC might be beneficial for cancer patients receiving chemotherapy.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.1
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• pp.429-433
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• 2013

Objectives: To explore the correlation between multi-slice spiral CT (MSCT) perfusion parameters and the expression of vascular endothelial growth factor (VEGF) as well as matrix metalloproteinase-2 (MMP-2) in breast cancer. Methods: Forty five breast cancer patients and 16 patients with benign breast tumor, both confirmed by pathology examination, were enrolled. All underwent MSCT perfusion imaging to obtain perfusion maps and data for parameters including blood flow (BF), blood volume (BV) and permeability surface (PS). Cancer patients did not receive treatment prior to surgery. The expression of VEGF and MMP-2 were examined with both immunohistochemistry and Western blotting. Results: The levels of VEGF and MMP-2 by immunohistochemistry were significantly higher in the breast cancer group (P < 0.01) than the benign tumor group. Relative OD values from Western blotting were also higher in cancer cases (P < 0.05). Similarly, the mean MSCT perfusion parameters (BF, BV, PS) were significantly higher in the breast cancer group (P < 0.01), BF and BV positively correlating with VEGF expression (r = 0.878 and 0.809 respectively, P < 0.01); PS and VEGF and MMP-2 expression were also positively correlated (r= 0.860, 0.786 respectively, P < 0.01). Conclusion: There is a correlation between breast cancer MSCT perfusion parameters and VEGF andMMP-2 expression, which might be useful for detection of breast lesions, qualitative diagnosis of breast cancer, and evaluation of breast cancer treatment.