3′‐Sialyllactose as an inhibitor of p65 phosphorylation ameliorates the progression of experimental rheumatoid arthritis

Kang, Li&#x2010,Jung,Kwon, Eun&#x2010,Soo,Lee, Kwang Min,Cho, Chanmi,Lee, Jae&#x2010,In,Ryu, Young Bae,Youm, Tae Hyun,Jeon, Jimin,Cho, Mi Ra,Jeong, Seon&#x2010,Yong,Lee, Sang&#x2010,Rae,Kim, Wook,Yang John Wiley and Sons Inc. 2018 British journal of pharmacology Vol.175 No.23

<P><B>Background and Purpose</B></P><P>3′‐Sialyllactose (3′‐SL) is a safe compound that is present in high levels in human milk. Although it has anti‐inflammatory properties and supports immune homeostasis, its effect on collagen‐induced arthritis (CIA) is unknown. In this study, we investigated the prophylactic and therapeutic effect of 3′‐SL on the progression of rheumatoid arthritis (RA) in <I>in vitro</I> and <I>in vivo</I> models.</P><P><B>Experimental Approach</B></P><P>The anti‐arthritic effect of 3′‐SL was analysed with fibroblast‐like synoviocytes <I>in vitro</I> and an <I>in vivo</I> mouse model of CIA. RT‐PCR, Western blotting and ELISA were performed to evaluate its effects <I>in vitro</I>. Histological analysis of ankle and knee joints of mice with CIA was performed using immunohistochemistry, as well as safranin‐O and haematoxylin staining.</P><P><B>Key Results</B></P><P>3′‐SL markedly alleviated the severity of CIA in the mice by reducing paw swelling, clinical scores, incidence rate, serum levels of inflammatory cytokines and autoantibody production. Moreover, 3′‐SL reduced synovitis and pannus formation and suppressed cartilage destruction by blocking secretion of chemokines, pro‐inflammatory cytokines, https://en.wikipedia.org/wiki/Matrix_metalloproteinases and osteoclastogenesis <I>via</I> NF‐κB signalling. Notably, phosphorylation of p65, which is a key protein in the NF‐κB signalling pathway, was totally blocked by 3′‐SL in the RA models.</P><P><B>Conclusions and Implications</B></P><P>3′‐SL ameliorated pathogenesis of CIA by suppressing catabolic factor expression, proliferation of inflammatory immune cells and osteoclastogenesis. These effects were mediated <I>via</I> blockade of the NF‐κB signalling pathway. Therefore, 3′‐SL exerted prophylactic and therapeutic effects and could be a novel therapeutic agent for the treatment of RA.</P>

Pro‐apoptotic Noxa is involved in ablative focal irradiation‐induced lung injury

Kim, Jee&#x2010,Youn,An, Yong&#x2010,Min,Choi, Won Hoon,Kim, Jin&#x2010,Mo,Cho, Samju,Yoo, Byung Rok,Kang, Jeong Wook,Lee, Yun&#x2010,Sil,Lee, Yoon&#x2010,Jin,Cho, Jaeho CAROL DAVILA UNIVERSITY PRESS 2017 JOURNAL OF CELLULAR AND MOLECULAR MEDICINE Vol.21 No.4

<P><B>Abstract</B></P><P>Although lung injury including fibrosis is a well‐documented side effect of lung irradiation, the mechanisms underlying its pathology are poorly understood. X‐rays are known to cause apoptosis in the alveolar epithelial cells of irradiated lungs, which results in fibrosis due to the proliferation and differentiation of fibroblasts and the deposition of collagen. Apoptosis and BH3‐only pro‐apoptotic proteins have been implicated in the pathogenesis of pulmonary fibrosis. Recently, we have established a clinically analogous experimental model that reflects focal high‐dose irradiation of the ipsilateral lung. The goal of this study was to elucidate the mechanism underlying radiation‐induced lung injury based on this model. A radiation dose of 90 Gy was focally delivered to the left lung of C57BL/6 mice for 14 days. About 9 days after irradiation, the mice began to show increased levels of the pro‐apoptotic protein Noxa in the irradiated lung alongside increased apoptosis and fibrosis. Suppression of Noxa expression by small interfering RNA protected cells from radiation‐induced cell death and decreased expression of fibrogenic markers. Furthermore, we showed that reactive oxygen species participate in Noxa‐mediated, radiation‐induced cell death. Taken together, our results show that Noxa is involved in X‐ray‐induced lung injury.</P>

Ascochlorin inhibits growth factor‐induced HIF‐1α activation and tumor‐angiogenesis through the suppression of EGFR/ERK/p70S6K signaling pathway in human cervical carcinoma cells

Jeong, Ji&#x2010,Hak,Jeong, Yun&#x2010,Jeong,Cho, Hyun&#x2010,Ji,Shin, Jae&#x2010,Moon,Kang, Jeong‐,Han,Park, Kwan&#x2010,Kyu,Park, Yoon&#x2010,Yub,Chung, Il&#x2010,Kyung,Chang, Hyeun&#x2010,Woo Wiley Subscription Services, Inc., A Wiley Company 2012 Journal of cellular biochemistry Vol.113 No.4

<P><B>Abstract</B></P><P>Ascochlorin, a non‐toxic prenylphenol compound derived from the fungus <I>Ascochyta viciae</I>, has been shown recently to have anti‐cancer effects on various human cancer cells. However, the precise molecular mechanism of this anti‐cancer activity remains to be elucidated. Here, we investigated the effects of ascochlorin on hypoxia‐inducible factor‐1α (HIF‐1α) and vascular endothelial growth factor (VEGF) expression in human epidermoid cervical carcinoma CaSki cells. Ascochlorin inhibited epidermal growth factor (EGF)‐induced HIF‐1α and VEGF expression through multiple potential mechanisms. First, ascochlorin selectively inhibited HIF‐1α expression in response to EGF stimulation, but not in response to hypoxia (1% O<SUB>2</SUB>) or treatment with a transition metal (CoCl<SUB>2</SUB>). Second, ascochlorin inhibited EGF‐induced ERK‐1/2 activation but not AKT activation, both of which play essential roles in EGF‐induced HIF‐1α protein synthesis. Targeted inhibition of epidermal growth factor receptor (EGFR) expression using an EGFR‐specific small interfering RNA (siRNA) diminished HIF‐1α expression, which suggested that ascochlorin inhibits HIF‐1α expression through suppression of EGFR activation. Finally, we showed that ascochlorin functionally abrogates in vivo tumor angiogenesis induced by EGF in a Matrigel plug assay. Our data suggest that ascochlorin inhibits EGF‐mediated induction of HIF‐1α expression in CaSki cells, providing a potentially new avenue of development of anti‐cancer drugs that target tumor angiogenesis. J. Cell. Biochem. 113: 1302–1313, 2012. © 2011 Wiley Periodicals, Inc.</P>

Polymer‐Stabilized Chromonic Liquid‐Crystalline Polarizer

Park, Seul&#x2010,Ki,Kim, So&#x2010,Eun,Kim, Dae&#x2010,Yoon,Kang, Shin&#x2010,Woong,Shin, Seunghan,Kuo, Shiao&#x2010,Wei,Hwang, Seok&#x2010,Ho,Lee, Seung Hee,Lee, Myong&#x2010,Hoon,Jeong, Kwang&#x201 WILEY‐VCH Verlag 2011 Advanced functional materials Vol.21 No.11

<P><B>Abstract</B></P><P>Robust coatable polarizer is fabricated by the self‐assembly of lyotropic chromonic liquid crystals and subsequent photo‐polymerizing processes. Their molecular packing structures and optical behaviors are investigated by the combined techniques of microscopy, scattering and spectroscopy. To stabilize the oriented Sunset Yellow FCF (H‐SY) films and to minimize the possible defects generated during and after the coating, acrylic acid (AA) is added to the H‐SY/H<SUB>2</SUB>O solution and photo‐polymerized. Utilizing cross‐polarized optical microscopy, phase behaviors of the H‐SY/H<SUB>2</SUB>O/AA solution are monitored by varying the compositions and temperatures of the solution. Based on the experimental results of two‐dimensional wide angle X‐ray diffraction and selected area electron diffraction, the H‐SY crystalline unit cell is determined to be a monoclinic structure with the dimensions of <I>a</I> = 1.70 nm, <I>b</I> = 1.78 nm, <I>c</I> = 0.68 nm, <I>α</I> = <I>β</I> = 90.0° and <I>γ</I> = 84.5°. The molecular arrangements in the oriented H‐SY films were further confirmed by polarized Fourier‐transform infrared spectroscopy. The polymer‐stabilized H‐SY films show good mechanical and chemical stabilities with a high polarizability. Additionally, patterned polarizers are fabricated by applying a photo‐mask during the photo‐polymerization of AA, which may open new doors for practical applications in electro‐optic devices.</P>

Permanent Chemotherapy‐Induced Alopecia in Patients with Breast Cancer: A 3‐Year Prospective Cohort Study

Kang, Danbee,Kim, Im&#x2010,Ryung,Choi, Eun&#x2010,Kyung,Im, Young Hyuck,Park, Yeon Hee,Ahn, Jin Seok,Lee, Jeong Eon,Nam, Seok Jin,Lee, Hae Kwang,Park, Ji&#x2010,Hye,Lee, Dong&#x2010,Youn,Lacouture, M AlphaMed Press 2019 The oncologist Vol.24 No.3

<P>Chemotherapy‐induced alopecia is (CIA) considered temporary; however, some patients report persistent alopecia several years after chemotherapy. Long‐term prospective data on the incidence and impact of permanent CIA is scarce. This article reports the results of a study conducted to estimate the long‐term incidence of persistent CIA in a cohort of breast cancer patients with measurements of hair volume and density before and after chemotherapy.</P><P><B>Background.</B></P><P>Although chemotherapy‐induced alopecia (CIA) is considered temporary, some patients report persistent alopecia several years after chemotherapy. There is, however, a paucity of long‐term prospective data on the incidence and impact of permanent CIA (PCIA). The objective of our study was to estimate the long‐term incidence of PCIA in a cohort of patients with breast cancer whose hair volume and density were measured prior to chemotherapy and who were followed for 3 years after chemotherapy.</P><P><B>Materials and Methods.</B></P><P>Prospective cohort study of consecutive patients ≥18 years of age with postoperative diagnosis of stage I–III breast cancer expected to receive adjuvant chemotherapy at the outpatient breast cancer clinic at the Samsung Medical Center in Seoul, Korea, from February 2012 to July 2013 (<I>n</I> = 61). Objective hair density and thickness were measured using a noninvasive bioengineering device.</P><P><B>Results.</B></P><P>The proportion of participants who had PCIA at 6 months and 3 years was 39.5% and 42.3%, respectively. PCIA was characterized in most patients by incomplete hair regrowth. Patients who received a taxane‐based regimen were more likely to experience PCIA compared with patients with other types of chemotherapy. At a 3‐year follow‐up, hair thinning was the most common problem reported by study participants (75.0%), followed by reduced hair volume (53.9%), hair loss (34.6%), and gray hair (34.6%).</P><P><B>Conclusion.</B></P><P>PCIA is a common adverse event of breast cancer adjuvant cytotoxic chemotherapy. Clinicians should be aware of this distressing adverse event and develop supportive care strategies to counsel patients and minimize its impact on quality of life.</P><P><B>Implications for Practice.</B></P><P>Knowledge of permanent chemotherapy‐induced alopecia, an under‐reported adverse event, should lead to optimized pretherapy counseling, anticipatory coping techniques, and potential therapeutic strategies for this sequela of treatment.</P>

Pleural or pericardial metastasis: A significant factor affecting efficacy and adverse events in lung cancer patients treated with PD‐1/PD‐L1 inhibitors

Kang, Da Hyun,Chung, Chaeuk,Kim, Ju&#x2010,Ock,Jung, Sung Soo,Park, Hee Sun,Park, Dong Il,Jung, Sun Young,Park, Myoungrin,Lee, Jeong Eun John WileySons Australia, Ltd 2018 Thoracic cancer Vol.9 No.11

<P><B>Background</B></P><P>Immunotherapy is a new paradigm for the treatment of non‐small‐cell lung cancer (NSCLC), and targeting the PD‐1 or PD‐L1 pathway is a promising therapeutic option. Although PD‐1/PD‐L1 inhibitors are more effective than standard chemotherapy in lung cancer, clinicians are afraid to actively use them because of hyperprogression and pseudoprogression. The aim of this study was to investigate the factors associated with tumor response and serious outcomes.</P><P><B>Methods</B></P><P>We retrospectively collected the medical records of 51 patients with advanced NSCLC who received PD‐1/PD‐L1 inhibitors between January 2016 and February 2018.</P><P><B>Results</B></P><P>The mean patient age was 63.9 years, and 72.5% (37/51) were male. Most (92.2%, 47/51) had received previous systemic treatment. The overall response rate was 21.6% (11/51). The response rate was significantly lower in patients with pleural or pericardial metastasis than in patients without pleural or pericardial metastasis (4.3% vs. 35.7%; <I>P</I> = 0.007). Patients with pleural or pericardial metastasis had a significantly higher rate of adverse events of any grade (91.3% vs. 50.0%; <I>P</I> = 0.002) and grade 3–5 adverse events (52.2% vs. 25.0%; <I>P</I> = 0.046).</P><P><B>Conclusion</B></P><P>Pleural or pericardial metastasis is a significant factor affecting the efficacy and rate of adverse events in advanced NSCLC patients treated with PD‐1/PD‐L1 inhibitors. Clinicians should pay attention to the use of immune checkpoint inhibitors in lung cancer patients with pleural or pericardial metastasis.</P>

A liver‐specific gene expression panel predicts the differentiation status of <i>in vitro</i> hepatocyte models

Kim, Dae&#x2010,Soo,Ryu, Jea&#x2010,Woon,Son, Mi&#x2010,Young,Oh, Jung&#x2010,Hwa,Chung, Kyung&#x2010,Sook,Lee, Sugi,Lee, Jeong‐,Ju,Ahn, Jun&#x2010,Ho,Min, Ju&#x2010,Sik,Ahn, Jiwon,Kang, Hyun Mi John Wiley and Sons Inc. 2017 Hepatology Vol.66 No.5

<P>Alternative cell sources, such as three‐dimensional organoids and induced pluripotent stem cell–derived cells, might provide a potentially effective approach for both drug development applications and clinical transplantation. For example, the development of cell sources for liver cell–based therapy has been increasingly needed, and liver transplantation is performed for the treatment for patients with severe end‐stage liver disease. Differentiated liver cells and three‐dimensional organoids are expected to provide new cell sources for tissue models and revolutionary clinical therapies. However, conventional experimental methods confirming the expression levels of liver‐specific lineage markers cannot provide complete information regarding the differentiation status or degree of similarity between liver and differentiated cell sources. Therefore, in this study, to overcome several issues associated with the assessment of differentiated liver cells and organoids, we developed a liver‐specific gene expression panel (LiGEP) algorithm that presents the degree of liver similarity as a “percentage.” We demonstrated that the percentage calculated using the LiGEP algorithm was correlated with the developmental stages of <I>in vivo</I> liver tissues in mice, suggesting that LiGEP can correctly predict developmental stages. Moreover, three‐dimensional cultured HepaRG cells and human pluripotent stem cell–derived hepatocyte‐like cells showed liver similarity scores of 59.14% and 32%, respectively, although general liver‐specific markers were detected. <I>Conclusion</I>: Our study describes a quantitative and predictive model for differentiated samples, particularly liver‐specific cells or organoids; and this model can be further expanded to various tissue‐specific organoids; our LiGEP can provide useful information and insights regarding the differentiation status of <I>in vitro</I> liver models. (H<SMALL>EPATOLOGY</SMALL> 2017;66:1662–1674).</P>

The restoration of myeloid‐derived suppressor cells as functional antigen‐presenting cells by NKT cell help and all‐<i>trans</i>‐retinoic acid treatment

Lee, Jung&#x2010,Mi,Seo, Jeong‐,Hwan,Kim, Yeon&#x2010,Jeong,Kim, Yun&#x2010,Sun,Ko, Hyun&#x2010,Jeong,Kang, Chang&#x2010,Yuil Wiley Subscription Services, Inc., A Wiley Company 2012 International journal of cancer: Journal internati Vol.131 No.3

<P><B>Abstract</B></P><P>Myeloid‐derived suppressor cells (MDSCs), which accumulate during tumor progression, have been shown to function as important suppressor cells. In a previous study, we showed that immunosuppressive MDSCs could function as immunogenic antigen‐presenting cells (APCs) with the help of activated natural killer T (NKT) cells. In the current study, however, we found that MDSCs harvested at a late time point after tumor injection (late MDSCs) were poorly immunogenic even when stimulated with activated NKT cells. As tumor growth progressed, the expression of MHC and costimulatory molecules on MDSCs was gradually down‐regulated. Late MDSCs also had innate defects in activation and differentiation mediated by cytokine stimuli. Although late MDSCs treated only with all‐<I>trans‐</I>retinoic acid (ATRA), a stimulating agent for MDSC differentiation, could not become immunogenic, NKT ligand‐loaded, ATRA‐treated late MDSCs could be converted into immunogenic APCs to induce incremental immune responses. Furthermore, these effects were mediated by NKT cells secreting IFNγ, and ATRA‐mediated increases in glutathione (GSH) levels. Thus, combined treatment with differentiating and activating agents is a prerequisite for the conversion of late MDSCs into immunogenic APCs. Collectively, these results suggest that combined treatments are required for the differentiation and activation of late MDSCs in late stage cancer.</P>

Blockade of Myd88 signaling induces antitumor effects by skewing the immunosuppressive function of myeloid‐derived suppressor cells

Hong, Eun&#x2010,Hye,Chang, Sun&#x2010,Young,Lee, Bo&#x2010,Ra,Kim, Yun&#x2010,Sun,Lee, Jeong‐,Mi,Kang, Chang&#x2010,Yuil,Kweon, Mi&#x2010,Na,Ko, Hyun&#x2010,Jeong Wiley Subscription Services, Inc., A Wiley Company 2013 International journal of cancer: Journal internati Vol.132 No.12

<P><B>Abstract</B></P><P>Myd88 is an important adaptor molecule for the activation of NADPH oxidase and arginase‐1, which are responsible for the suppressive function of myeloid‐derived suppressor cells (MDSCs). When wild‐type and Myd88<SUP>−/−</SUP> mice were subcutaneously injected with CT26 colon cancer cells expressing human Her‐2/neu, tumor growth was retarded in Myd88<SUP>−/−</SUP> mice than in wild‐type mice. Although the generation of CD11b<SUP>+</SUP>Gr‐1<SUP>+</SUP> MDSCs was less in Myd88<SUP>−/−</SUP> mice than in wild‐type mice, Myd88<SUP>−/−</SUP> mice having tumor masses still had significant quantities of MDSCs, suggesting that MDSC generation might be independent of Myd88 signaling. However, MDSCs obtained from tumor‐bearing Myd88<SUP>−/−</SUP> mice failed to suppress antigen‐specific proliferation of CD8<SUP>+</SUP> T cells and CD4<SUP>+</SUP> T cells, whereas MDSCs from wild‐type mice significantly suppressed both types of T cells. Consistent with this, we found that the levels of costimulatory molecules and MHC class II were significantly increased in MDSCs obtained from Myd88<SUP>−/−</SUP> mice compared with wild‐type mice after tumor challenge. Furthermore, CD4<SUP>+</SUP> T cells residing in tumor‐draining lymph nodes of Myd88<SUP>−/−</SUP> mice secreted more TNF‐α than those of wild‐type mice. Finally, the blockade of Myd88 signaling by treatment with Myd88 inhibitory peptide, during later tumor stages, significantly inhibited the growth of immunogenic tumors. Overall, these data suggest that signaling through the Myd88 adaptor molecule is critical for the direct suppressive function of MDSCs and approaches to block Myd88‐mediated signaling in MDSCs might be effective to inhibit the immunosuppressive function of MDSCs.</P>

Development of bone regeneration strategies using human periosteum‐derived osteoblasts and oxygen‐releasing microparticles in mandibular osteomyelitis model of miniature pig

Hwang, Sun&#x2010,Chul,Hwang, Dae Seok,Kim, Ho Yong,Kim, Min Ji,Kang, Young&#x2010,Hoon,Byun, Sung&#x2010,Hoon,Rho, Gyu&#x2010,Jin,Lee, Hyeon&#x2010,Jeong,Lee, Hee&#x2010,Chun,Kim, Sang&#x2010,Hyun,Ba Wiley Publishers 2019 JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A Vol.107 No.10

<P><B>ABSTRACT</B></P><P>Hypoxia and limited vascularization inhibit bone growth and recovery after surgical debridement to treat osteomyelitis. Similarly, despite significant efforts to create functional tissue‐engineered organs, clinical success is often hindered by insufficient oxygen diffusion and poor vascularization. To overcome these shortcomings, we previously used the oxygen carrier perfluorooctane (PFO) to develop PFO emulsion‐loaded hollow microparticles (PFO‐HPs). PFO‐HPs act as a local oxygen source that increase cell viability and maintains the osteogenic differentiation potency of human periosteum‐derived cells (<I>h</I>PDCs) under hypoxic conditions. In the present study, we used a miniature pig model of mandibular osteomyelitis to investigate bone regeneration using <I>h</I>PDCs seeded on PFO‐HPs (<I>h</I>PDCs/PFO‐HP) or <I>h</I>PDCs seeded on phosphate‐buffered saline (PBS)‐HPs (<I>h</I>PDCs/PBS‐HP). Osteomyelitis is characterized by a series of microbial invasion, vascular disruption, bony necrosis, and sequestrum formation due to impaired host defense response. Sequential plain radiography, computed tomography (CT), and 3D reconstructed CT images revealed new bone formation was more advanced in defects that had been implanted with the <I>h</I>PDCs/PFO‐HPs than in defects implanted with the <I>h</I>PDCs/PBS‐HP. Thus, PFO‐HPs are a promising tissue engineering approach to repair challenging bone defects and regenerate structurally organized bone tissue with 3D architecture.</P>