Woosung Lim

Reactive Oxygen Species Prevent Imiquimod-Induced Psoriatic Dermatitis through Enhancing Regulatory T Cell Function

Psoriasis is a chronic inflammatory skin disease resulting from immune dysregulation. Regulatory T cells (Tregs) are important in the prevention of psoriasis. Traditionally, reactive oxygen species (ROS) are known to be implicated in the progression of inflammatory diseases, including psoriasis, but many recent studies suggested the protective role of ROS in immune-mediated diseases. In particular, severe cases of psoriasis vulgaris have been reported to be successfully treated by hyperbaric oxygen therapy (HBOT), which raises tissue level of ROS. Also it was reported that Treg function was closely associated with ROS level. However, it has been only investigated in lowered levels of ROS so far. Thus, in this study, to clarify the relationship between ROS level and Treg function, as well as their role in the pathogenesis of psoriasis, we investigated imiquimod-induced psoriatic dermatitis (PD) in association with Treg function both in elevated and lowered levels of ROS by using knockout mice, such as glutathione peroxidase-1−/− and neutrophil cytosolic factor-1−/− mice, as well as by using HBOT or chemicals, such as 2,3-dimethoxy-1,4-naphthoquinone and N-acetylcysteine. The results consistently showed Tregs were hyperfunctional in elevated levels of ROS, whereas hypofunctional in lowered levels of ROS. In addition, imiquimod-induced PD was attenuated in elevated levels of ROS, whereas aggravated in lowered levels of ROS. For the molecular mechanism that may link ROS level and Treg function, we investigated the expression of an immunoregulatory enzyme, indoleamine 2,3-dioxygenase (IDO) which is induced by ROS, in PD lesions. Taken together, it was implied that appropriately elevated levels of ROS might prevent psoriasis through enhancing IDO expression and Treg function.

Basic Facts of Breast Cancer in Korea in 2014:The 10-Year Overall Survival Progress

We, the Korean Breast Cancer Society (KBCS), present the facts and the trends of breast cancer in Korea in 2014. Data on the total number of newly diagnosed patients was obtained from the Korea Central Cancer Registry database, other data were collected from the KBCS online registry database, and the overall survival data of patients were updated from Statistics Korea. A total of 21,484 female patients were newly diagnosed with breast cancer in 2014. The crude incidence rate and the age-standardized incidence rate (ASR) of breast cancer in female patients, including carcinoma in situ, were 83.4 cases and 63.9 cases per 100,000 women, respectively. The ASR showed an annual increase of 6.1% from 1999 to 2014; however, although the increase of the ASR had slowed since 2008, the incidence rate itself continuously increased. The proportion of early breast cancer increased consistently, and the pathological features changed accordingly. While breast-conserving surgery was mainly performed, the proportion of total mastectomy was slightly increased. The total number of breast reconstruction surgeries increased rapidly. The 5-year and 10-year overall survival rates for all stages of breast cancer patients were 91.2% and 84.8%, respectively. The overall survival rate of Korean patients with breast cancer was extremely high, compared with other developed countries. Thus, we consider that the clinical characteristics of breast cancer have changed over the past decade. A nationwide registry data will contribute to a better understanding of the characteristics of breast cancer in Korea.

Attenuation of Experimental Colitis in Glutathione Peroxidase 1 and Catalase Double Knockout Mice through Enhancing Regulatory T Cell Function

Reactive oxygen species (ROS) have been implicated in the progression of inflammatory diseases including inflammatory bowel diseases (IBD). Meanwhile, several studies suggested the protective role of ROS in immune-mediated inflammatory diseases, and it was recently reported that dextran sodium sulfate (DSS)-induced colitis was attenuated in mice with an elevated level of ROS due to deficiency of peroxiredoxin II. Regulatory T cells (Tregs) are critical in the prevention of IBD and Treg function was reported to be closely associated with ROS level, but it has been investigated only in lowered levels of ROS so far. In the present study, in order to clarify the relationship between ROS level and Treg function, and their role in the pathogenesis of IBD, we investigated mice with an elevated level of ROS due to deficiency of both glutathione peroxidase (GPx)-1 and catalase (Cat) for the susceptibility of DSS-induced colitis in association with Treg function. The results showed that DSS-induced colitis was attenuated and Tregs were hyperfunctional in GPx1−/− × Cat−/− mice. In vivo administration of N-acetylcysteine (NAC) aggravated DSS-induced colitis and decreased Treg function to the level comparable to WT mice. Attenuated Th17 cell differentiation from naïve CD4+ cells as well as impaired production of IL-6 and IL-17A by splenocytes upon stimulation suggested anti-inflammatory tendency of GPx1−/− × Cat−/− mice. Suppression of Stat3 activation in association with enhancement of indoleamine 2,3-dioxygenase and FoxP3 expression might be involved in the immunosuppressive mechanism of GPx1−/− × Cat−/− mice. Taken together, it is implied that ROS level is critical in the regulation of Treg function, and IBD may be attenuated in appropriately elevated levels of ROS.

Breast conserving surgery for multifocal breast cancer.

Objective:The purpose of this study is to examine the oncological safety of breast conserving surgery (BCS) for patients with multifocal breast cancer. Summary Background Data:Few studies have reported about BCS for multifocal breast cancer. BCS for multifocal cancer has a risk of local failure in previous reports, whereas recent studies reported the feasibility of BCS. However, because all studies have dealt with a small number of patients, multifocal breast cancer is still considered a relative contraindication for BCS. Methods:This retrospective study includes 478 patients with multifocal breast cancer who underwent BCS or mastectomy and 930 with unifocal cancer who underwent BCS for stage 0–II. Multifocal cancer was defined as 2 or more distinct cancers in the same quadrant. Of 478 patients, 147 underwent BCS and 331 underwent mastectomy. We compared the local recurrence rate (LRR), disease free survival, and overall survival for BCS with mastectomy for multifocal cancer. In addition, the LRR of BCS for multifocal cancer was compared for unifocal cancer. Results:There is no significant difference in stage distribution and other clinical and pathologic characteristics except Her-2/neu for stage IIA between BCS and mastectomy for multifocal caner. The mean follow-up period was 59.33 months (range, 1.00–177.20) for breast conserving group and 64.98 months (range, 6.23–196.03) for mastectomy group. The 5-year overall survival was 93.38% for BCS and 94.53% for mastectomy (log rank P = 0.208). The 5-year disease-free survival was 89.08% for BCS and 91.88% for mastectomy (log rank P = 0.451). The local failure occurred in 3 (2.0%) of 147 patient underwent BCS, 3 (0.9%) of 331 patients underwent mastectomy (P = 0.378). Compared with BCS for unifocal cancer patients, the LRR of patients with multifocal cancer was not statistically different (2.0% for multifocal, 1.3% for unifocal; P = 0.445). Conclusions:Our study demonstrates that BCS for multifocal breast cancer is oncologically safe in selected patients.

Effectiveness of Breast-Specific Gamma Imaging (BSGI) for Breast Cancer in Korea: A Comparative Study

Abstract:  Despite the fact that mammography has been the golden standard in breast cancer detection for several decades, its sensitivity decreases for women with dense breast tissue, which happens to be common in Korea. As an alternative, breast ultrasonography can be effective diagnostic modalities that complement the defect of mammography. Recently, breast‐specific gamma imaging (BSGI) has been introduced as a new diagnostic modality for breast cancer. This study was designed to analyze the effectiveness of BSGI in particular. In a retrospective study, 471 patients underwent BSGI, breast ultrasonography, and mammography simultaneously during the period between February 2009 and March 2010. The indications of BSGI were as follows: (a) patient who was diagnosed with malignancy prior to surgery, (b) patient who is under follow up after cancer surgery, (c) patient with lesions which cannot be evaluated by breast ultrasonography or mammography, (d) patient with multiple benign lesions, and (e) patient with suspicious lesion who refuses biopsy. Among these patients, 121 patients underwent biopsy, whereas others were followed up with imaging studies. We compared the BSGI results with those of mammography, breast ultrasonography, and pathology. The mean age of the patients was 49.63 ± 10.43 years. There were 107 patients with 110 malignant lesions and 364 patients with benign lesions. Total 474 lesions were evaluated. The sensitivities of BSGI, mammography, and breast ultrasonography were 94.45%, 93.64%, and 98.18%, respectively, whereas the specificities of BSGI, mammography, and breast ultrasonography were 90.93%, 90.66%, and 87.09%, respectively. The sensitivity and specificity of BSGI for axillary lymph node (LN) status were 44.7 4% and 87.88%, respectively. BSGI is a good complementary imaging modality with high sensitivity and high specificity for breast cancer detection. However, it has low efficacy for the evaluation for axillary LN status.

Prognostic value of human apurinic/apyrimidinic endonuclease 1 (APE1) expression in breast cancer.

Human apurinic/apyrimidinic endonuclease 1 (APE1) is an essential protein for DNA base excision repair (BER) and redox regulation. The ability of cancer cells to recognize DNA damage and initiate DNA repair is an important mechanism for therapeutic resistance. Several recent studies have suggested that APE1 expression levels and/or subcellular dysregulation may be used to indicate the sensitivity of tumors to radiotherapy or chemotherapy. In this study, we assessed the prognostic significance of APE1 and differences in APE1 expression levels according to breast cancer molecular subtypes. We analyzed formalin-fixed, paraffin-embedded tumor tissue sections from 243 cases diagnosed as invasive breast cancer at Ewha Womans University Medical Center between January 2003 and December 2008. Immunohistochemistry was performed and the nuclear level of APE1 was scored by taking into account the percentage of positive cells. Medical records were reviewed to investigate clinicopathologic characteristics. We found that nuclear APE1 high-level expression (proportion ≥50%) in breast cancer showed a tendency towards unfavorable prognosis regarding disease-free survival (p = 0.093). However, there was no significant difference in overall survival between low and high-level expression groups (p = 0.294). Interestingly, within the Ki-67 low-level expression group, APE1 low-level expression was significantly associated with poor overall survival (p = 0.007). A significant positive correlation was observed between APE1 nuclear expression and estrogen receptor status (75.7% vs. 59.7%, p = 0.022). Also, the luminal A subtype was the most commonly observed breast cancer subtype in the APE1 high-level expression group (61.6% vs. 45.2%, p = 0.000). This study suggests that APE1 expression may be associated with breast cancer prognosis. In particular, its role as a prognostic factor would be significant for breast cancers with a low Ki-67 proliferation index. It is proposed that nuclear APE1 may be a novel target in breast cancer with a low proliferation rate to obtain better outcome.

Survival Improvement in Korean Breast Cancer Patients Due to Increases in Early-Stage Cancers and Hormone Receptor Positive/HER2 Negative Subtypes: A Nationwide Registry-Based Study.

Purpose The aim of this study was to investigate whether the observed changes over time in the survival rates vary according to the intrinsic subtypes of breast cancer diagnosed. Methods Data from 46,320 breast cancer patients in the Korean Breast Cancer Registry who underwent surgery between 1999 and 2006 were reviewed. Among them, results from 25,887 patients with available data about the status of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) were analyzed. Patients were classified into two cohorts according to the year in which they underwent surgery: 1999-2002 and 2003-2006. Results The patients treated in the latter time period showed significantly better overall survival (OS) compared with those in the former period when adjusted for follow-up duration. The proportion of hormone receptor+/HER2-subtype and stage I breast cancer were significantly higher in the latter period (47.4% vs. 54.6%, p<0.001; 31.0% vs. 39.6%, p<0.001, respectively). Improvement in OS between the former and latter periods was seen in all subtypes of breast cancer, including triple-negative cancers (all p-values <0.001 in univariate and multivariate analyses). Conclusion Improvement in survival in Korean breast cancer patients over the study years is being observed in all subtypes of breast cancer, implying that increases in both early-stage detection and the proportion of less aggressive cancers contribute to this improvement.

Functional changes in regulatory T cells during an experimental infection with sparganum (plerocercofid of Spirometra mansoni)

Regulatory T (Treg) cells are important in the regulation of immune response, but the exact regulation of Treg‐cell function in vivo is still not well known. In the present study, we investigated the functional activity of CD4+ CD25+ Treg cells as well as the frequency and number of CD4+ CD25+ FoxP3+ Treg cells in the spleens of experimentally infected mice with a tissue‐migrating parasite, sparganum (plerocercoid of Spirometra mansoni) for 3 weeks. The results demonstrated fluctuations in the Treg‐cell function during the parasite infection, being up‐regulated at day 3, down‐regulated until day 14, and thereafter up‐regulated again at day 21. We also investigated the cytokine‐producing capability of the splenocytes to study the pattern of immune response of the mice to the parasite. The results showed decreased capabilities of interleukin‐2 (IL‐2), interferon‐γ (IFN‐γ) and IL‐17α production, whereas IL‐4‐producing and IL‐10‐producing capabilities were increased along with the parasitic infection. Meanwhile, IL‐6‐producing capability was increased to reach a peak at week 2, and thereafter was decreased to the baseline level. As a regulatory mechanism, we found that Treg‐cell function was attenuated in the presence of the crude extracts of sparganum, but was enhanced in the presence of the excretory–secretory products, suggesting that sparganum products were involved in the triggering and regulation of immune response in the acute and chronic phases, respectively. Results show that Treg cells are central in the immune homeostasis in vivo that is maintained by host–parasite interactions during the parasitic infection.

CD4+CD25+ regulatory T cells from MRL/lpr mice were functionally more active in vitro but did not prevent spontaneous as well as adriamycin-induced nephropathy in vivo

OBJECTIVE The frequency and function of Tregs are important in the pathogenesis of SLE. Nonetheless, the function of Tregs is still controversial in SLE patients and lupus mouse models. In the present study, we investigated the suppressive function of Tregs from MRL/lpr mice in vitro and in vivo by using an alternative quantitative assay. METHODS We assessed the suppressive function of CD4(+)CD25(+) Tregs, the proliferative activity of CD4(+)CD25(-) effector T cells (Teffs) and the feeder activity of CD11c(+) dendritic cells (DCs), isolated from the spleens of MRL/lpr mice and wild-type (WT) MRL/+ mice, by carboxyfluorescein diacetate succinimidyl ester dilution assay stimulated with two distinct types of signals, weak and strong. In order to assess the protective function of Tregs from an immune-mediated disease in vivo, we induced renal damage by injecting adriamycin (ADN) into the mice. RESULTS The in vitro assay showed enhanced suppressive activity of Tregs and feeder activity of DCs, but far less proliferative activity of Teffs from MRL/lpr mice, compared with those from the WT mice. The in vivo study showed more severe ADN-induced nephropathy in MRL/lpr mice than in the WT mice, while mild interstitial nephritis had already begun spontaneously by 16 weeks in MRL/lpr mice. CONCLUSION It was suggested that Tregs from MRL/lpr mice were functionally competent and intrinsically more active in vitro, but they were not capable of preventing the ADN-induced as well as the spontaneously developing nephropathy in vivo.

Outcomes of Breast Conserving Surgery With Immediate Vicryl-Mesh Insertion: Is It Safe And Effective?

Abstract:  Although breast‐conserving surgery (BCS) has become a standard for breast‐cancer surgery with improved cosmetic outcomes, there have been many attempts to achieve superior results. Vicryl‐mesh insertion, one such method, is a simple technique involving a relatively short period of time. However, doubts regarding its safety and efficacy remain. Therefore, we attempted to analyze the aesthetic outcomes, patient satisfaction, and safety with respect to Vicryl mesh. From May 2007 to March 2009, 38 patients underwent BCS with immediate Vicryl‐mesh insertion at Ewha Womans University Mokdong Hospital, Seoul, Korea. In the same period, 31 patients who underwent BCS for breast cancer were randomly selected as a control group. Five patients who underwent BCS with Vicryl‐mesh insertion were excluded because they were lost to follow‐up shortly after surgery. Retrospective analysis of patient records and oral interviews were performed. We analyzed patients’ overall satisfaction, postoperative satisfaction with breast shape, pain, and postoperative complications in the two groups. The mean age, body mass index, follow‐up period, specimen size, and ratio of benign to malignant tumors did not differ significantly between the two groups. With regard to tumor location, more tumors were in the upper and lower inner portions of the breast among patients who underwent BCS with Vicryl mesh. There were no significant differences in overall satisfaction or satisfaction with breast shape (p > 0.05), but differences in pain scores were significant (p = 0.016). In terms of the complication rate, four cases with complications (11.8%) were observed in the Vicryl‐mesh group and no complications in the BCS‐only group. Vicryl‐mesh insertion showed a higher complication rate and no cosmetic gain. Therefore, we believe that Vicryl‐mesh insertion should be performed carefully. In addition, studies involving many more cases and longer follow‐up periods are needed.