Seung Yeon Ha

Glucagon-like peptide-1 inhibits adipose tissue macrophage infiltration and inflammation in an obese mouse model of diabetes

Aims/hypothesisObesity and insulin resistance are associated with low-grade chronic inflammation. Glucagon-like peptide-1 (GLP-1) is known to reduce insulin resistance. We investigated whether GLP-1 has anti-inflammatory effects on adipose tissue, including adipocytes and adipose tissue macrophages (ATM).MethodsWe administered a recombinant adenovirus (rAd) producing GLP-1 (rAd-GLP-1) to an ob/ob mouse model of diabetes. We examined insulin sensitivity, body fat mass, the infiltration of ATM and metabolic profiles. We analysed the mRNA expression of inflammatory cytokines, lipogenic genes, and M1 and M2 macrophage-specific genes in adipose tissue by real-time quantitative PCR. We also examined the activation of nuclear factor κB (NF-κB), extracellular signal-regulated kinase 1/2 and Jun N-terminal kinase (JNK) in vivo and in vitro.ResultsFat mass, adipocyte size and mRNA expression of lipogenic genes were significantly reduced in adipose tissue of rAd-GLP-1-treated ob/ob mice. Macrophage populations (F4/80+ and F4/80+CD11b+CD11c+ cells), as well as the expression and production of IL-6, TNF-α and monocyte chemoattractant protein-1, were significantly reduced in adipose tissue of rAd-GLP-1-treated ob/ob mice. Expression of M1-specific mRNAs was significantly reduced, but that of M2-specific mRNAs was unchanged in rAd-GLP-1-treated ob/ob mice. NF-κB and JNK activation was significantly reduced in adipose tissue of rAd-GLP-1-treated ob/ob mice. Lipopolysaccharide-induced inflammation was reduced by the GLP-1 receptor agonist, exendin-4, in 3T3-L1 adipocytes and ATM.Conclusions/interpretationWe suggest that GLP-1 reduces macrophage infiltration and directly inhibits inflammatory pathways in adipocytes and ATM, possibly contributing to the improvement of insulin sensitivity.

Epidermal Growth Factor Receptor Mutations and the Clinical Outcome in Male Smokers with Squamous Cell Carcinoma of Lung

Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) have been reported to be related to certain clinical characteristics (i.e., female, non-smokers with adenocarcinoma) and gefitinib responsiveness. This exploratory analysis was performed to determine the incidence of EGFR mutations in male smokers with squamous cell carcinoma, who were treated with EGFR tyrosine kinase inhibitor, gefitinib. Sixty-nine Korean NSCLC patients were treated with gefitinib in a prospective study. For a subset of 20 male patients with squamous cell carcinoma and a history of smoking, pretreatment tumor tissue samples were obtained and analyzed for EGFR mutations (exons 18 to 21). EGFR mutations were found in 3 (15%) patients, including in-frame deletions within exon 19 (n=2) and L858R missence mutation in exon 21 (n=1). These 3 patients with EGFR mutations responded to gefitinib, whereas only one of remaining 17 patients with wild-type EGFR achieved clinical response. Trend toward longer progression-free (5.8 vs. 2.4 months; P=0.07) was noted in patients with EGFR mutations compared to those with wild-type EGFR. Although male smokers with squamous cell carcinoma have not been considered ideal candidates for gefitinib treatment, significant incidence of EGFR mutations was observed. The molecular markers should be considered to predict clinical benefits from gefitinib.

Altered expression of microRNA miR‐21, miR‐155, and let‐7a and their roles in pulmonary neuroendocrine tumors

MicroRNA (miRNA) has a critical effect on tumorigenesis through post‐transcriptional modification and is considered to be potential biomarkers for cancer diagnosis and treatment monitoring. We evaluated the expression pattern of three selected miRNAs (miR‐21, miR‐155, and let‐7a) to evaluate their potential roles by quantitative reverse transcription‐polymerase chain reaction using formalin‐fixed and paraffin‐embedded tissues of 63 surgically resected pulmonary neuroendocrine (NE) tumors (19 typical carcinoids (TCs), 6 atypical carcinoids (ACs), 19 large cell NE carcinomas (LCNECs), and 19 small cell lung carcinomas (SCLCs). Control amplification for U6 small nuclear RNA (U6) was performed in all samples. Normalized Ct values were calculated (CtExperimental miRNA‐CtU6) for each case and recorded. The expression levels of miR‐21 and miR‐155 were significantly higher in high‐grade NE carcinomas (LCNECs and SCLCs) than in carcinoid tumors (TCs and ACs) (each P < 0.001). The expression level of miR‐21 in carcinoid tumors with lymph node metastasis was significantly higher than in carcinoid tumors without lymph node metastasis (P= 0.010). To the best of our knowledge, the present study is the first to examine the expression patterns of miR‐21 and miR‐155 as an adjunctive diagnostic tool or clinically relevant biomarkers for pulmonary NE tumors.

Prognostic implications of hypoxia-inducible factor-1α in epidermal growth factor receptor-negative non-small cell lung cancer

Hypoxia-inducible factor (HIF)-1α is a regulatory subunit of HIF-1 that is stabilized and activated under hypoxic conditions. In non-small cell lung cancer (NSCLC), over-expression of HIF-1α has been associated with poor overall survival. However, there is conflicting data on the role of HIF-1α as a prognostic factor. Some studies have demonstrated close association between the HIF-1α signal pathways and epidermal growth factor receptors (EGFRs). We evaluated the prognostic significance of HIF-1α expression in 178 NSCLC patients using tissue microarray in the context of EGFR gene copy number and protein expression status. EGFR gene copy number was evaluated using fluorescent in situ hybridization (FISH), and EGFR protein expression was determined using immunohistochemistry (IHC). The difference in overall survival (OS) between HIF-1α-positive and HIF-1α-negative groups was statistically significant in patients with low EGFR gene copy number and negative EGFR expression (log-rank test, P = 0.03). In univariate and multivariate analyses, HIF-1α was a significant worse prognostic factor for OS in patients with low EGFR gene copy number and negative EGFR expression (hazard ratio = 2.992; 95% CI, 1.113-8.045; P = 0.03 in univariate analysis and hazard ratio = 8.127; 95% CI, 1.874-35.251; P < 0.01 in multivariate analysis). The results demonstrated that the prognostic significance of HIF-1α should be validated in the context of EGFR status in NSCLC patients, and the gene and protein status of EGFR and HIF-1α will be important to help select patients most likely to derive the greatest clinical benefit from EGFR or HIF-1α targeted therapies.

Primary endobronchial actinomycosis associated with broncholithiasis

Primary endobronchial actinomycosis is an extremely rare disease that presents with endobronchial mass. We report 2 cases of primary endobronchial actinomycosis associated with broncholithiasis. There was no foreign body material, suggesting that these broncholiths were formed endogenously. Even though it is very rare, endobronchial actinomycosis should be included in the differential diagnosis of calcified endobronchial mass, especially when there is no clinical or radiological evidence of a granulomatous infection, such as tuberculosis, and the yellowish materials obstructing the bronchi are seen during bronchoscopy.

Comparison of HER2 expression between primary colorectal cancer and their corresponding metastases

The aim of this study was to compare human epidermal growth factor 2 (HER2) status in primary colorectal cancer and paired liver or lung metastasis. Gene amplification of HER2 has been intensively evaluated in contemporary oncology, especially in breast and stomach cancer. The knowledge of HER2 status in primary and metastatic sites may be of potential value for therapeutic decision making in metastatic colon cancer. The HER2 status was assessed by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) in 94 colorectal cancer with corresponding liver or lung metastases. HER2 amplification was present in 19 of the 188 (10.1%) of both primary and metastases combined. Four (4.6%) patients showed HER2 amplification in the metastasis and 10 (10.6%) patients showed HER2 amplification in the primary tumor. In 14 cases (14.8%), the HER2 status of the primary lesions was different from that of the associated metastases. The presence of HER2 overexpression in KRAS mutant colon cancer was found in 5.3%. No relationship was found between HER2 expression and KRAS status (P = 0.486). The evidence of HER2 positive metastatic lesion and primary colorectal cancer suggest that HER2 assessment might be considered in selected cases when this may help change the therapeutic decision.

Differential expression of forkhead box M1 and its downstream cyclin-dependent kinase inhibitors p27kip1 and p21waf1/cip1 in the diagnosis of pulmonary neuroendocrine tumours

Ha S Y, Lee C H, Chang H K, Chang S, Kwon K Y, Lee E H, Roh M S & Seo B 
(2012) Histopathology 60, 731–739
Differential expression of forkhead box M1 and its downstream cyclin‐dependent kinase inhibitors p27kip1 and p21waf1/cip1 in the diagnosis of pulmonary neuroendocrine tumours

The New 2011 International Association for the Study of Lung Cancer/ American Thoracic Society/European Respiratory Society Classification of Lung Adenocarcinoma in Resected Specimens: Clinicopathologic Relevance and Emerging Issues

Pathologists play an increasingly important role in personalized medicine for patients with lung cancer as a result of the newly recognized relationship between histologic classification and molecular change. In 2011, the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) proposed a new architectural classification for invasive lung adenocarcinomas to provide uniform terminology and diagnostic criteria. This review highlighted the evolution of the classification of lung adenocarcinomas in resected specimens with special respect to both histologic subtyping and invasion. Histologic subtyping of lung adenocarcinoma has been updated based on five major predominant patterns. New concepts of adenocarcinoma in situ and minimally invasive adenocarcinomas have been introduced to define the condition of patients who are expected to have excellent survival. Although the new IASLC/ATS/ERS classification has promising clinical relevance, significant clarification remains necessary for the definitions of subtyping and invasion. More precise definitions and subsequent better education on the interpretation of terminology will be helpful for future studies.

Class II β-tubulin is a novel marker for human tonsillar M cells and follicular dendritic cells

OBJECTIVE Membranous (M) cell of the human palatine tonsil is an antigen entry site for mucosal infection, but its location is obscure in histological sections. Recently, a microarray analysis has demonstrated that clusterin, annexin A5, CD44, MMP14, and beta-tubulin are candidate genes of M cell marker in mice. Among these genes, we here describe class II beta-tubulin as a new marker for human tonsillar M cells and follicular dendritic cells (FDCs), and present its usefulness for diagnosis of angioimmunoblastic T-cell lymphomas (AILTs). MATERIALS AND METHODS Immunohistochemistry and Western blotting for class II beta-tubulin were performed using 81 cases of lymphoid, gastrointestinal and thyroid tissues, and an FDC cell line, respectively. Double immunostaining with clusterin and class II beta-tubulin were carried out. RESULTS Class II beta-tubulin localized the M cells and FDCs in the palatine tonsils (10/10, 100%) and adenoids (10/10, 100%). It was colocalized with clusterin in the palatine tonsils. However, class II beta-tubulin staining did not identify intestinal M cells in the intestines. Immunoblot analysis revealed that class II beta-tubulin expression was upregulated in HK cells, a normal FDC cell line. Class II beta-tubulin immunostaining highlighted hyperplastic FDC meshworks in all AILTs (14/14, 100%). CONCLUSION Class II beta-tubulin is a specific histochemical marker for human tonsillar M cells and FDCs. Thus, class II beta-tubulin immunostaining may be useful to identify tonsillar M cells and to diagnose FDC proliferative lesions such as AILT.

Altered Expression of PTEN and Its Major Regulator MicroRNA-21 in Pulmonary Neuroendocrine Tumors

Background Phosphatase and tensin homolog on chromosome ten (PTEN) is one of the most frequently inactivated tumor suppressors in various tumor types. MicroRNA-21 (miR-21) may affect tumor progression by post-transcriptional repression of expression of tumor suppressors, such as PTEN. This study was conducted to evaluate the significance of PTEN expression in pulmonary neuroendocrine (NE) tumors and to analyze the relationship between PTEN and miR-21 expressions. Methods Expressions of PTEN and miR-21 were investigated by immunohistochemistry and real time reverse transcription-polymerase chain reaction, respectively, in 75 resected pulmonary NE tumors (23 typical carcinoids [TCs], nine atypical carcinoids [ACs], 22 large cell NE carcinomas [LCNECs], and 21 small cell lung carcinomas [SCLCs]). Results Loss of PTEN expression was observed in four of 23 TCs (17.4%), four of nine ACs (44.4%), 16 of 22 LCNECs (72.7%) and nine of 21 SCLCs (42.9%) (p=.025). The expression level of miR-21 was significantly higher in high-grade NE carcinomas than in carcinoid tumors (p<.001). PTEN expression was inversely correlated with miR-21 expression (p<.001). Conclusions This study suggests that aberrant expression of PTEN in relation to miR-21 may represent an important step in the development and progression of pulmonary NE tumors.