Forebrain-specific ablation of phospholipase Cγ1 causes manic-like behavior.

Manic episodes are one of the major diagnostic symptoms in a spectrum of neuropsychiatric disorders that include schizophrenia, obsessive-compulsive disorder and bipolar disorder (BD). Despite a possible association between BD and the gene encoding phospholipase Cγ1 (PLCG1), its etiological basis remains unclear. Here, we report that mice lacking phospholipase Cγ1 (PLCγ1) in the forebrain (Plcg1f/f; CaMKII) exhibit hyperactivity, decreased anxiety-like behavior, reduced depressive-related behavior, hyperhedonia, hyperphagia, impaired learning and memory and exaggerated startle responses. Inhibitory transmission in hippocampal pyramidal neurons and striatal dopamine receptor D1-expressing neurons of Plcg1-deficient mice was significantly reduced. The decrease in inhibitory transmission is likely due to a reduced number of γ-aminobutyric acid (GABA)-ergic boutons, which may result from impaired localization and/or stabilization of postsynaptic CaMKII (Ca2+/calmodulin-dependent protein kinase II) at inhibitory synapses. Moreover, mutant mice display impaired brain-derived neurotrophic factor-tropomyosin receptor kinase B-dependent synaptic plasticity in the hippocampus, which could account for deficits of spatial memory. Lithium and valproate, the drugs presently used to treat mania associated with BD, rescued the hyperactive phenotypes of Plcg1f/f; CaMKII mice. These findings provide evidence that PLCγ1 is critical for synaptic function and plasticity and that the loss of PLCγ1 from the forebrain results in manic-like behavior.

Whole-breast US following mammography and breast MRI in newly diagnosed breast cancer patients: can it be more than just a guidance tool for biopsy?

AIM: To evaluate the role of ultrasound (US) following magnetic resonance imaging (MRI) and mammography in patients with newly diagnosed breast cancers by assessing the additional cancer detection rate of US. MATERIAL AND METHODS: Two hundred and twenty-five women who had undergone 225 MRI examinations followed by US were included. An US-detected additional cancer was defined as a lesion detected using breast US that had not been detected by MRI, and which was shown to be malignant at histopathology. The rate of additional cancer detection, incidence of additional malignancies, positive predictive value (PPV), and false-positive (FP) rate were analysed. Factors associated with an increase in the additional cancer detection rate were analysed. RESULTS: The additional cancer detection rate was 0% (0/225) for the ipsilateral breast and 0.9% (2/225) for the contralateral breast, and the PPVs were 0% (0/5) and 100% (2/2), respectively. The overall TP:FP ratio was 0.4 (2:5). The additional cancer detection rate was higher for cases with moderate and severe background parenchymal enhancement than cases with minimal and mild background parenchymal enhancement (p=0.003). The additional cancer detection rate for cases with moderate and severe background parenchymal enhancement was 5.7% (2/35) for the contralateral breast (p=0.003). CONCLUSION: Preoperative breast US following MRI and mammography can help clinicians screen for contralateral cancers with an additional detection rate of 0.9%. Moreover, whole-breast US might be a useful contralateral screening modality in cases with moderate or marked parenchymal enhancement on breast MRI.

Identifying the potential long-term survivors among breast cancer patients with distant metastasis.

BACKGROUND: We aimed to develop a prediction model to identify long-term survivors after developing distant metastasis from breast cancer. PATIENTS AND METHODS: From the institution's database, we collected data of 547 patients who developed distant metastasis during their follow-ups. We developed a model that predicts the post-metastasis overall survival (PMOS) based on the clinicopathologic factors of the primary tumors and the characteristics of the distant metastasis. For validation, the survival data of 254 patients from four independent institutions were used. RESULTS: The median duration of the PMOS was 31.0 months. The characteristics of the initial primary tumor, such as tumor stage, hormone receptor status, and Ki-67 expression level, and the characteristics of the distant metastasis presentation including the duration of disease-free interval, the site of metastasis, and the presence of metastasis-related symptoms were independent prognostic factors determining the PMOS. The association between tumor stage and the PMOS was only seen in tumors with early relapses. The PMOS score, which was developed based on the above six factors, successfully identified patients with superior survival after metastasis. The median PMOS for patients with a PMOS score of <2 and for patients with a PMOS score of >5 were 71.0 and 12 months, respectively. The clinical significance of the PMOS score was further validated using independent multicenter datasets. CONCLUSIONS: We have developed a novel prediction model that can classify breast cancer patients with distant metastasis according to their survival after metastasis. Our model can be a valuable tool to identify long-term survivors who can be potential candidates for more intensive multidisciplinary approaches. Furthermore, our model can provide a more reliable survival information for both physicians and patients during their informed decision-making process.

Association between basal-like phenotype and BRCA1/2 germline mutations in Korean breast cancer patients.

INTRODUCTION: BRCA mutation testing allows index patients and their families to be provided with appropriate cancer risk-reduction strategies. Because of the low prevalence of BRCA mutations in unselected breast cancer patients and the high cost of genetic testing, it is important to identify the subset of women who are likely to carry BRCA mutations. In the present study, we examined the association between BRCA1/2 germline mutations and the immunohistochemical features of breast cancer. METHODS: In a retrospective review of 498 breast cancer patients who had undergone BRCA testing at Seoul National University Bundang Hospital between July 2003 and September 2012, we gathered immunohistochemical information on estrogen receptor (er), progesterone receptor (pr), her2 (human epidermal growth factor receptor 2), cytokeratin 5/6, egfr (epidermal growth factor receptor), and p53 status. RESULTS: Among the 411 patients eligible for the study, 50 (12.2%) had germline mutations in BRCA1 or BRCA2. Of the 93 patients with triple-negative breast cancer (tnbc), 25 with BRCA1/2 mutations were identified (BRCA1, 20.4%; BRCA2, 6.5%). On univariate analysis, er, pr, cytokeratin 5/6, egfr, and tnbc were found to be related to BRCA1 mutations, but on multivariate analysis, only tnbc was significantly associated with BRCA1 mutations. Among patients with early-onset breast cancer or with a family history of breast or ovarian cancer, BRCA1 mutations were significantly more prevalent in the tnbc group than in the non-tnbc group. CONCLUSIONS: In the present study, tnbc was the only independent predictor of BRCA1 mutation in patients at high risk of hereditary breast and ovarian cancers. Other histologic features of basal-like breast cancer did not improve the estimate of BRCA1 mutation risk.

Three-dimensional efficient dispersive alternating-direction-implicit finite-difference time-domain algorithm using a quadratic complex rational function.

Efficient unconditionally stable FDTD method is developed for the electromagnetic analysis of dispersive media. Toward this purpose, a quadratic complex rational function (QCRF) dispersion model is applied to the alternating-direction-implicit finite-difference time-domain (ADI-FDTD) method. The 3-D update equations of QCRF-ADI-FDTD are derived using Maxwell's curl equations and the constitutive relation. The periodic boundary condition of QCRF-ADI-FDTD is discussed in detail. A 3-D numerical example shows that the time-step size can be increased by the proposed QCRF-ADI-FDTD beyond the Courant-Friedrich-Levy (CFL) number, without numerical instability. It is observed that, for refined computational cells, the computational time of QCRF-ADI-FDTD is reduced to 28.08 % of QCRF-FDTD, while the L2 relative error norm of a field distribution is 6.92 %.

Adding MRI to ultrasound and ultrasound-guided fine-needle aspiration reduces the false-negative rate of axillary lymph node metastasis diagnosis in breast cancer patients.

AIM: To evaluate whether adding magnetic resonance imaging (MRI) to ultrasound (US) and US-guided fine-needle aspiration (US-FNA) can reduce the false-negative rate (FNR) in the diagnosis of axillary lymph node metastasis (ALNM) in breast cancer patients, and to assess false-negative diagnosis of N2 and N3 disease when adding MRI to US and US-FNA. MATERIALS AND METHODS: From March 2012 to February 2013, 497 breast cancer patients were included in the study. ALNM was evaluated according to US and US-FNA prior to MRI. Second-look US was performed when MRI showed positive findings of ALNM. If second-look US also revealed a positive finding, US-FNA was performed. Diagnostic performance, including FNR, was calculated for US and US-FNA with and without MRI. The negative predictive value (NPV) of N2 and N3 disease was evaluated in negative cases based on US and US-FNA with MRI. RESULTS: A total of 159 of 497 (32.0%) patients were found to have ALNM. Among them, 92 patients were diagnosed with metastasis on US and US-FNA. When adding MRI to US and US-FNA, an additional six patients were diagnosed with metastasis. The FNR of diagnosis of ALNM was improved by the addition of MRI (42.1% versus 38.4%, p = 0.0143). The NPV for N2 and N3 disease was 98% (391/399) based on US and US-FNA with MRI. CONCLUSION: Adding MRI to US and US-FNA could reduce the FNR of the diagnosis of ALNM. Furthermore, US and US-FNA with MRI may exclude 98% of N2 and N3 disease.

Comparison of Cancer Yields and Diagnostic Performance of Screening Mammography vs. Supplemental Screening Ultrasound in 4394 Women with Average Risk for Breast Cancer.

PURPOSE: The effectiveness of supplemental screening ultrasound (US) was investigated in women ≥ 40 years at average risk for breast cancer regardless of breast parenchymal density. A total of 4394 women at average risk and having previously undergone screening mammography were classified as the mammography group.  MATERIALS AND METHODS: Of 4394 women, 2005 underwent screening US after a final assessment of category 1 or 2 on screening mammography, and were categorized as the US group. Category 0, 4, and 5 on mammography and 3, 4, and 5 on US were defined as positive. The cancer yields per 1000 women and diagnostic performance of two groups were compared. RESULTS: The total cancer and invasive cancer yields for the mammography group were 3.0 (95 % confidence interval 1.6, 5.1) and 2.0 (95 % CI, 0.9, 3.9) per 1000 women, higher than the US values of 2.0 (0.5, 5.1) and 1.0 (0.1, 3.6), not statistically significant. The specificity, accuracy, and positive predictive value (PPV) for mammography were 88.90 % (87.93, 89.81), 88.85 % (87.88, 89.76), and 2.61 % (1.39, 4.41), significantly higher than the US values of 69.07 % (66.99, 71.09), 69.13 % (67.05, 71.15), and 0.64 % (0.18, 1.64). The short-term follow-up rate of mammography was 5.51 % (4.85, 6.22), significantly lower than the rate of 26.58 (24.66, 28.58) for US.  CONCLUSION: Supplemental screening US in mammographically negative breasts can find additional carcinomas in women at average risk but is not as effective as screening mammography because of the lower cancer yield, invasive cancer yield, specificity, accuracy, PPV and a high short-term follow-up rate.

Overexpression of PI3K-p110α in the progression of uterine cervical neoplasia and its correlation with pAkt and DJ-1.

OBJECTIVE: To investigate the expression of PI3K-p110α, pAkt, PTEN, the signaling molecules from PI3K/Akt signaling pathway, DJ-1, an oncoprotein and HSP90a, a molecular chaperone, and their correlation in uterine cervical neoplasia, in order to elucidate their role in cervical carcinogenesis. MATERIALS AND METHODS: Using immunohistochemistry, the authors analyzed the expression of PI3K-p110α, pAkt, PTEN, DJ-1 and HSP90α, and their correlation in ten normal tissues, cervical intraepithelial neoplasia (CIN) including 30 CIN1 and 31 CIN3, and 33 cases of invasive squamous cell carcinoma (SCC). RESULTS: The expression of all proteins significantly increased in CIN3 compared to CIN1, and only the expression of PI3K-p110α significantly increased in invasive SCC compared to CIN3. There was a significant positive correlation between the expression of PI3K-p110α and DJ-1, as well as PI3K-p110α and pAkt in CIN3 and invasive SCC. CONCLUSION: Overexpression of PI3K-p110α is associated with progression of uterine cervical neoplasia, and the expression of pAkt and DJ-1 is positively correlated with PI3K-p110α expression in this process.

Enhanced antitumor immunotherapeutic effect of B-cell-based vaccine transduced with modified adenoviral vector containing type 35 fiber structures.

For successful clinical tumor immunotherapy outcomes, strong immune responses against tumor antigens must be generated. Cell-based vaccines compromise one strategy with which to induce appropriate strong immune responses. Previously, we established a natural killer T-cell (NKT) ligand-loaded, adenoviral vector-transduced B-cell-based anticancer cellular vaccine. To enhance tumor antigen delivery to B cells, we established a modified adenoviral vector (Ad-k35) that encoded a truncated form of the breast cancer antigen Her2/neu (Ad-k35HM) in which fiber structure was substituted with adenovirus serotype 35. We observed increased tumor antigen expression with Ad-k35HM in both human and murine B cells. In addition, an Ad-k35HM-transduced B-cell vaccine elicited strong antigen-specific cellular and humoral immune responses that were further enhanced with the additional loading of soluble NKT ligand KBC009. An Ad-k35HM-transduced, KBC009-loaded B-cell vaccine efficiently suppressed the in vivo growth of established tumors in a mouse model. Moreover, the vaccine elicited human leukocyte antigen (HLA)-A2 epitope-specific cytotoxic T-cell responses in B6.Cg (CB)-Tg (HLA-A/H2-D) 2Enge/Jat mice. These findings indicated that the Ad-k35 could be appropriate for the preclinical and clinical development of B-cell-based anticancer immunotherapies.

Rebamipide attenuates autoimmune arthritis severity in SKG mice via regulation of B cell and antibody production.

Oxidative stress is involved in the pathophysiology of rheumatoid arthritis (RA). We investigated the therapeutic potential of rebamipide, a gastroprotective agent with a property of reactive oxygen species scavenger, on the development of inflammatory polyarthritis and the pathophysiological mechanisms by which rebamipide might confer anti-arthritic effects in SKG mice, an animal model of RA. Intraperitoneal (i.p.) injection of rebamipide attenuated the severity of clinical and histological arthritis. Rebampide treatment reduced the number of T helper type 1 (Th1), Th2, Th17, inducible T cell co-stimulator (ICOS)(+) follicular helper T (Tfh) transitional type (T2) and mature B cells in the spleen, but increased the number of regulatory T (Treg ), CD19(+) CD1d(high) CD5(high) , CD19(+) CD25(high) forkhead box protein 3 (FoxP3)(+) regulatory B (Breg ) cells, memory B cells, and transitional type 1 (T1) B cells. In addition, flow cytometric analysis revealed significantly decreased populations of FAS(+) GL-7(+) germinal centre B cells and B220(-) CD138(+) plasma cells in the spleens of rebamipide-treated SKG mice compared to controls. Rebamipide decreased germinal centre B cells and reciprocally induced Breg cells in a dose-dependent manner in vitro. Rebamipide-induced Breg cells had more suppressive capacity in relation to T cell proliferation and also inhibited Th17 differentiation from murine CD4(+) T cells. Together, these data show that i.p. administration of rebamipide suppresses arthritis severity by inducing Breg and Treg cells and suppressing Tfh and Th17 cells in a murine model of RA.

Additional malignant breast lesions detected on second-look US after breast MRI vs. additional malignant lesions detected on initial US in breast cancer patients: comparison of US characteristics.

PURPOSE: The purpose of our study was to review and compare the US findings of synchronous malignant breast lesions other than the index cancer additionally detected on second-look US with those detected on initial US, and therefore to determine differing characteristics that may aid in diagnosis and essentially improve the performance of the initial US examination. MATERIALS AND METHODS: A retrospective review of 39 mammographically occult synchronous malignant lesions other than the index cancer from 38 patients was performed (21 lesions: detected on second-look US, 18 lesions: detected on initial US). All patients underwent initial mammography, bilateral whole breast US (BWBU) and breast MRI, and all lesions were confirmed pathologically by biopsy or preoperative localization. RESULTS: Additional malignant breast lesions detected on both initial US and second-look US tended to be subtle and often did not show classic malignant findings. Second-look US lesions (median, 7.0 mm; range, 3 - 22 mm) tended to be smaller than initial US lesions (median, 9.0 mm; range 3 - 45 mm), although the difference was not statistically significant (p = 0.134). Second-look US lesions also showed no posterior acoustic features (p = 0.037) and a significantly higher proportion of lesions with circumscribed or indistinct margins compared to initial US lesions (p = 0.042). Second-look US lesions were significantly subareolar or relatively far (> 5 cm) from the nipple than initial US lesions (p = 0.048). CONCLUSION: Second-look US lesions showed more subtle findings of posterior acoustic features and margins, and tended to be subareolar or relatively far from the nipple compared to initial US lesions. However, both groups showed subtle US findings and there was no significant difference in other features.

A risk-adapted approach using US features and FNA results in the management of thyroid incidentalomas identified by 18F-FDG PET.

PURPOSE: To assess the risk of malignancy of thyroid incidentalomas found on 18F-FDG PET/CT by US features and cytologic results, and to evaluate the clinical usage of a combination of US features and cytology for post-FNA management of thyroid incidentalomas on 18F-FDG PET/CT. MATERIALS AND METHODS: From September 2006 to December 2008, 132 patients with 134 thyroid incidentalomas detected on 18F-FDG PET/CT who had undergone US and US-FNA were included in this study. We evaluated the malignancy rate of thyroid incidentalomas in different subgroups subdivided by US features and US-FNA cytology results. Several variables were compared between the benign and malignant group. RESULTS: The risk of malignancy was 58.2 % (78/132) in thyroid incidentalomas on 18F-FDG PET/CT. Age, gender, and tumor size were not significantly different between the malignant and benign group.  Malignancy rate of thyroid incidentalomas was significantly higher in the suspicious malignant (88.9 %) than in the probably benign group (11.3 %) on US (p < 0.001). Malignancy rates were high in thyroid nodules with "malignancy", "suspicious for malignancy", or "follicular neoplasm" on cytologic results, regardless of US features. However, malignancy rates of thyroid incidentalomas with "unsatisfactory" or "benign" results on cytology were higher in the suspicious malignant (75 %, 12.5 %, respectively) than in the probably benign (0 %) group on US.  CONCLUSIONS: This study demonstrated that the risk of malignancy was high in thyroid incidentalomas on 18F-FDG PET/CT even without suspicious US features. However, there was no malignancy in nodules with no suspicious US features and benign cytology. Based on these results, we concluded that US may not replace FNA in the diagnosis of PET incidentalomas, and that a follow-up may be considered of thyroid incidentalomas with benign cytology and no suspicious US features.

Impact of preoperative bilateral whole breast sonography in patients with invasive lobular carcinoma: results from two medical centers.

PURPOSE: The purpose of this study was to evaluate the sensitivity of bilateral whole breast sonography (BWBS) combined with mammography for the detection of additional lesions, as well as index lesions, in patients with invasive lobular carcinoma (ILC) and to evaluate the impact of BWBS on surgical treatment and cancer staging strategies. MATERIALS AND METHODS: We retrospectively reviewed mammographic and sonographic records of 97 patients with proven ILCs between November 2002 and November 2009. We evaluated the sensitivity of mammography and BWBS for the detection of additional and index lesions. We compared the impact of BWBS on surgical treatment and breast cancer staging between cases with single index lesions and with BWBS-detected additional lesions and index lesions. We compared the differences in sensitivity, surgical treatment procedures and breast cancer staging between BWBS and MRI confined to the patients underwent MRI. RESULTS: The overall sensitivity was 74.4% (93/125 lesions) for mammography and 96.0% (120/125 lesions) for BWBS (p < 0.001). The group with additional lesions detected using US alone exhibited more frequent mastectomy (p = 0.003) and higher N staging (p = 0.051) than did the group with single index lesions. Comparing the BWBS and MRI cases, there were no significant differences in lesion staging, the sensitivity of malignant foci detection (p = 0.074). CONCLUSION: BWBS has a higher sensitivity than does mammography for the detection of index and additional ILC. Detection of additional malignancies using BWBS could affect which strategy is chosen for surgical treatment.

Discordant elastography images of breast lesions: how various factors lead to discordant findings.

PURPOSE: To evaluate the rate of the elastography-pathology discordance, and evaluate which various factors have an effect on discordant elastography images (DEI) of breast lesions. MATERIALS AND METHODS: Elastography images of 284 pathologically confirmed breast lesions of 233 patients were evaluated. Elasticity scores were compared to pathology results, and lesions were divided into 4 groups: benign concordant/discordant, and malignant concordant/discordant. The rate of DEI among benign and malignant lesions was calculated and compared. Patient, lesion factors and image adequacy were compared among the concordant and discordant groups for analysis. RESULTS: Among the 284 breast lesions, 225 (79.2%) were benign, and 59 (20.8%) were malignant. The rate of DEI among malignant lesions was significantly higher than in benign lesions, i. e., 52.5 vs. 3.1% (p < 0.001). Discordant images were more significantly seen in patients with extremely dense breasts on mammography in benign lesions, 42.9 vs. 11.9% (p = 0.034). Discordant images were more significantly seen in malignant lesions < 10 mm or ≥ 20 mm (p = 0.006), and those with inadequate images (64.5 vs. 35.5%, p < 0.001). CONCLUSION: The rate of DEI was higher in malignant lesions than in benign lesions. Dense breast parenchyma, lesion size and image adequacy showed significance in discordant images of elastography which need consideration in image acquisition and interpretation.

False negative results in axillary lymph nodes by ultrasonography and ultrasonography-guided fine-needle aspiration in patients with invasive ductal carcinoma.

PURPOSE: For preoperative evaluation of ALN status using various methods, axillary US and subsequent US-FNA targeting the LNs suspicious for metastasis are the most widely used methods. The purpose of our study was to assess the rate of false-negative results at preoperative ultrasonography (US) and ultrasonography guided fine needle aspiration (US-FNA) of axillary lymph nodes (ALNs) in breast cancer patients and the number of false-negative lymph nodes, and to evaluate factors related to ALN false negative results in US and/or US-FNA in patients diagnosed with invasive ductal carcinoma. MATERIALS AND METHODS: Among 317 patients who underwent surgery for invasive ductal carcinoma during 2009 in Severance hospital, 237 patients had no reported ALN metastasis on preoperative US-FNA and US. We retrospectively reviewed the subsequent surgical pathology and clinicopathologic findings and assessed the rate of false-negative results from US and US-FNA of ALN and the number of false-negative lymph node. We performed univariate analysis and multivariate logistic regression analysis to evaluate the relationships between variable clinicopathologic factors (T-stage, position of ALN, hormone receptors, histologic grade, lymphovascular invasion (LVI) and performance of FNA) and cytologic results (false-negative result; FNALN and true negative result; TNALN) from US and/or US-FNA of ALN. RESULTS: The rate of false-negative results was 42.4 % (59/139) in both US and US-FNA of ALN but among them, 57.6 % (34/59) showed only one metastatic ALN. Breast cancer with FNALN on US and US-FNA was significantly related to positive estrogen receptor (p = 0.003), positive progesterone receptor (p = 0.001), and the presence of LVI (p = 0.004) in univariate analysis. In multivariate analysis, high T stages (≥ T2, odds ratio (OR) 4.007, p = 0.004) and LVI (OR 7.951, p = 0.001) showed significant correlation with FNALN on US and US-FNA. CONCLUSION: More than half of patients with FNALN showed only one metastatic ALN. LVI and high T-stages were the most important factors attributed to FNALN on US and US-FNA in patients with invasive ductal carcinoma.

Rebamipide attenuates pain severity and cartilage degeneration in a rat model of osteoarthritis by downregulating oxidative damage and catabolic activity in chondrocytes.

OBJECTIVE: The objectives were to investigate the in vivo effects of treatment with rebamipide on pain severity and cartilage degeneration in an experimental model of rat osteoarthritis (OA) and to explore its mode of action. MATERIALS AND METHODS: OA was induced in rats by intra-articular injection of monosodium iodoacetate (MIA). Oral administration of rebamipide was initiated on the day of MIA injection, 3 or 7 days after. Limb nociception was assessed by measuring the paw withdrawal latency and threshold. We analyzed the samples macroscopically and histomorphologically, and used immunohistochemistry to investigate the expression of matrix metalloproteinase-13 (MMP-13), interleukin-1ß (IL-1ß), hypoxia-inducible factor-2α (HIF-2α), inducible nitric oxide synthase (iNOS), and nitrotyrosine in knee joints. Real-time quantitative reverse transcription-polymerase chain reaction was used to quantify the mRNA for catabolic and anticatabolic factors in human OA chondrocytes. RESULTS: Rebamipide showed an antinociceptive property and attenuated cartilage degeneration. Rebamipide reduced the expression of MMP-13, IL-1ß, HIF-2α, iNOS, and nitrotyrosine in OA cartilage in a dose-dependent manner. Nitrotyrosine expression in the subchondral bone region was decreased in the rebamipide-treated joints. mRNA expression of MMP-1, -3, and -13, and ADAMTS5 was attenuated in IL-1ß-stimulated human OA chondrocytes. By contrast, rebamipide induced the mRNA expression of tissue inhibitor of metalloproteinase-1 and -3. CONCLUSION: The results show the inhibitory effects of rebamipide on pain production and cartilage degeneration in experimentally induced OA. The suppression of oxidative damage and the restoration of extracellular matrix homeostasis of articular chondrocyte suggest that rebamipide is a potential therapeutic strategy for OA.

Repeated exposure of human fibroblasts to UVR induces secretion of stem cell factor and senescence.

BACKGROUND: Some of chronic hyperpigmentary diseases, such as melasma, induced by multiple factors including chronic sunlight exposure, can recur even after chemical epidermal removal. Dermal factors may be involved in the pathogenesis of melasma. Changes in dermal fibroblasts resulting from chronic sun exposure might cause melanocytes to synthesize melanin in the epidermis. OBJECTIVE: This study aimed at determining the effects of repetitive ultraviolet (UV) radiation on cultured fibroblasts and the secretion of melanogenic factors. METHODS: Cultured human fibroblasts were exposed to ultraviolet A (UVA) or ultraviolet B (UVB) for five consecutive days. After each irradiation, the supernatant medium was isolated from each dish and measured for levels of stem cell factor (SCF) and hepatocyte growth factor using an ELISA kit assay. To assess the effect of the keratinocyte-derived factors on fibroblast-secretion of SCF and hepatocyte growth factor, we added supernatants of the UV-irradiated keratinocytes to the non-irradiated fibroblasts. Finally, the irradiated fibroblasts were stained with senescence associated-ß-galactosidase to assess their senescent change. RESULTS: Fibroblasts irradiated with UVA or UVB for five consecutive days, secreted SCF at levels that increased with repeated UVA or UVB exposure. Conditioned culture medium from UV-irradiated keratinocytes also induced SCF release from fibroblasts, depending on the number of UV exposures. UVA- or UVB-irradiated fibroblasts stained positive for senescence associated-ß-galactosidase, and the staining intensity increased with repeated exposure. CONCLUSION: These results suggest that fibroblast senescence and increased SCF secretion after repeated UV irradiation may be related to the pathogenesis of recurring hyperpigmentation disorders induced by chronic sun exposure.

A small molecule inhibitor of Mitf-E-box DNA binding and its depigmenting effect in melan-a cells.

BACKGROUND: Microphthalmia associated transcription factor (Mitf) is a key regulatory transcriptional factor of pigmentation-related genes including tyrosinase. Inhibition of tyrosinase transcription by blocking the binding of Mitf with its promoter E-box DNA can control the pigmentation. However, no such chemicals were reported so far. OBJECTIVE: To discover and evaluate the small molecule inhibitors of Mitf-E-box DNA. METHODS: Candidate chemicals were screened by virtual screening from pharmacophore data followed by Mitf E-box DNA protein chip. After selecting the chemical, its inhibitory activity on binding interaction between Mitf and E-box DNA, electrophoretic mobility shift assay (EMSA) was performed. To evaluate the depigmenting activity of Compound #17, cellular melanin assa, and Western blot were performed in melan-a cells. RESULTS: Among 27 chemicals selected from a pharmacophore data by virtual screening, Compound #17 was screened, which showed the most potent inhibitory activity against Mitf-E-box DNA binding in protein chip. EMSA results confirmed the specific inhibition of Compound #17 on Mitf-E-box DNA binding. In melan-a cells, Compound #17 reduced tyrosinase expression and melanin synthesis (62.5% at 25 µM). CONCLUSIONS: The results show that Compound #17 is the first small molecule inhibitor of Mitf-E-box DNA binding with depigmenting activity.

Is US-guided core needle biopsy (CNB) enough in probably benign nodules with interval growth?

PURPOSE: To investigate whether ultrasound-guided 14-gauge core needle biopsy (US-CNB) is efficient in the diagnosis of probably benign lesions showing interval growth on follow-up US.  MATERIALS AND METHODS: From March 2008 to August 2009, 116 breast lesions in 113 women (mean age: 41.2 years, range: 19 - 63 years) which were initially assessed as category 3 showing interval growth on follow-up US underwent US-CNB, and subsequent US-guided vacuum-assisted excision, surgical excision or follow-up US for at least 12 months. Diagnostic performances of US-CNB were evaluated with histopathologic results and follow-up US as standard reference. Clinical features of the patient and lesions characteristics including follow-up interval (I), the most increased diameter (D), D per I, increased volume (%V) and %V per I were calculated and compared. RESULTS: Of the 116 lesions, 4 lesions were diagnosed as malignancy and 112 as benign on final pathology. Malignancy rate of probably benign lesions showing interval growth was 3.4 % (4/116). Incorrect biopsy rate was 0.9 % (1/116). Palpability or newly developed suspicious US features were more associated with malignancy, 75.0 to 13.4 % and 50.0 to 25.9 %, respectively, but without significance (p = 0.063 and 0.290). Significant differences were seen in average rank when comparing between benign and malignancy in D, %V, D per follow-up interval (I), and %V/I (p = 0.037, 0.017, 0.043 and 0.009, respectively). CONCLUSION: US-CNB is an efficient diagnostic method for probably benign lesions showing interval growth, with discordant biopsy rate of 0.9 %.

Interobserver variability and diagnostic performance in US assessment of thyroid nodule according to size.

PURPOSE: To evaluate the interobserver variability for US assessments of thyroid nodules and analyze the diagnostic performances of US assessments in thyroid nodules according to nodule size. MATERIALS AND METHODS: This was an IRB-approved retrospective study with waiver of informed consent. A total of 400 surgically-confirmed thyroid nodules were included. Nodules were divided into 4 groups by size; group 1 (nodule size < 5 mm), group 2 (5 mm ≤ nodule size < 10 mm), group 3 (10 mm ≤ nodule size < 20 mm), and group 4 (nodule size ≥ 20 mm). Three experienced (7 - 10 years) radiologists retrospectively reviewed the US images. Agreement of each US descriptor and final US assessment, and diagnostic performances were calculated in each group and compared. RESULTS: Composition represented substantial or good agreement (k = 0.719 - 0.89). Margin showed the lowest agreement (k = 0.322 - 0.365). Individual kappa values for final assessment according to nodule size were as follows: group 1 (k = 0.674), group 2 (k = 0.596), group 3 (k = 0.674), and group 4 (k = 0.673). Specificity, PPV, and accuracy were significantly different among the groups with different size (p value < 0.05) and lowest in group 1. NPV, specificity, PPV and accuracy except PPV of observer 3 increased with nodule size (p < 0.05). CONCLUSION: Interobserver agreements were relatively good (k = 0.637) in final US assessment regardless of nodule size in experienced radiologists. High false-positive rate was observed in US assessment in nodules less than 5 mm in maximum diameter.