Follicular lymphoma (FL) with hyaline-vascular Castleman disease (FL-HVCD)-like features is a rare morphologic variant, with fewer than 20 cases in the literature. Herein, we report a case of FL-HVCD in a 37-year-old female who presented with isolated neck lymph node enlargement. The excised lymph node showed features reminiscent of HVCD, including regressed germinal centers (GCs) surrounded by onion skin-like mantle zones, lollipop lesions composed of hyalinized blood vessels penetrating into regressed GCs, and hyalinized interfollicular stroma. In addition, focal areas of abnormally conglomerated GCs composed of homogeneous, small centrocytes with strong BCL2, CD10, and BCL6 expression were observed, indicating partial involvement of the FL. Several other lymphoid follicles showed features of in situ follicular neoplasia. Based on the observations, a diagnosis of FL-HVCD was made. Although FLHVCD is very rare, the possibility of this variant should be considered in cases resembling CD. Identification of abnormal, neoplastic follicles and ancillary immunostaining are helpful for proper diagnosis.

A systems biology approach for the identification of perturbed molecular functions is required to understand the complex progressive disease such as breast cancer. In this study, we analyze the microarray data with Gene Ontology terms of molecular functions to select perturbed molecular functional modules in breast cancer tissues based on the definition of Gene ontology Functional Code. The Gene Ontology is three structured vocabularies describing genes and its products in terms of their associated biological processes, cellular components and molecular functions. The Gene Ontology is hierarchically classified as a directed acyclic graph. However, it is difficult to visualize Gene Ontology as a directed tree since a Gene Ontology term may have more than one parent by providing multiple paths from the root. Therefore, we applied the definition of Gene Ontology codes by defining one or more GO code(s) to each GO term to visualize the hierarchical classification of GO terms as a network. The selected molecular functions could be considered as perturbed molecular functional modules that putatively contributes to the progression of disease. We evaluated the method by analyzing microarray dataset of breast cancer tissues; i.e., normal and invasive breast cancer tissues. Based on the integration approach, we selected several interesting perturbed molecular functions that are implicated in the progression of breast cancers. Moreover, these selectedmolecular functions include several known breast cancer- related genes. It is concluded from this study that the present strategy is capable of selecting perturbed molecular functions that putatively play roles in the progression of diseases and provides an improved interpretability of GO terms based on the definition of Gene Ontology codes.
Biological Processes ; Breast ; Breast Neoplasms ; Genes, vif ; Humans ; Parents ; Systems Biology ; Vocabulary

It has been known that O-linked beta-N-acetylglucosamine (O-GlcNAc) modification of proteins plays an important role in transcription, translation, nuclear transport and signal transduction. The increased flux of glucose through the hexosamine biosynthetic pathway (HBP) and increased O-GlcNAc modification of protein have been suggested as one of the causes in the development of insulin resistance. However, it is not clear at the molecular level, how O-GlcNAc protein modification results in substantial impairment of insulin signaling. To clarify the association of O-GlcNAc protein modification and insulin resistance in rat primary adipocytes, we treated the adipocytes with O-(2-acetamido-2deoxy-D-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc), a potent inhibitor of O-GlcNAcase that catalyzes removal of O-GlcNAc from proteins. Prolonged treatment of PUGNAc (100 micrometer for 12 h) increased O-GlcNAc modification on proteins in adipocytes. PUGNAc also drastically decreased insulin-stimulated 2-deoxyglucose (2DG) uptake and GLUT4 translocation in adipocytes, indicating that PUGNAc developed impaired glucose utilization and insulin resistance in adipocytes. Interestingly, the O-GlcNAc modification of IRS-1 and Akt2 was increased by PUGNAc, accompanied by a partial reduction of insulin-stimulated phosphorylations of IRS-1 and Akt2. The PUGNAc treatment has no effect on the expression level of GLUT4, whereas O-GlcNAc modification of GLUT4 was increased. These results suggest that the increase of O-GlcNAc modification on insulin signal pathway intermediates, such as IRS-1 and Akt2, reduces the insulin-stimulated phosphorylation of IRS-1 and Akt2, subsequently leading to insulin resistance in rat primary adipocytes.
Acetylglucosamine/*analogs & derivatives/metabolism/pharmacology ; Adipocytes/*metabolism ; Animals ; Deoxyglucose/pharmacokinetics ; Glycosylation ; Immunoprecipitation ; *Insulin Resistance ; Male ; Monosaccharide Transport Proteins/metabolism ; Oximes/*pharmacology ; Phenylcarbamates/*pharmacology ; Phosphoproteins/*metabolism ; Phosphorylation ; Protein-Serine-Threonine Kinases/*metabolism ; Proto-Oncogene Proteins/*metabolism ; Rats ; Rats, Sprague-Dawley ; Research Support, Non-U.S. Gov't ; Subcellular Fractions/metabolism ; beta-N-Acetylhexosaminidase/antagonists & inhibitors

Rare cases of lung adenocarcinoma (LUAD) with concomitant epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) translocation have been reported. However, their clonal and evolutional relationship remains unclear. We report a case of early-stage EGFR-mutated LUAD with a focal concomitant EGFR/ALK alteration. A 63-year-old male underwent lobectomy to remove a 1.9-cm-sized lung nodule, which was diagnosed with EGFR-mutated LUAD. ALK immunohistochemistry (IHC) showed focal positivity within the part of the tumor characterized by lepidic pattern, also confirmed by fluorescence in-situ hybridization (FISH). Targeted next-generation sequencing was performed separately on the ALK IHC/FISH-positive and -negative areas. EGFR L833V/L858R mutations were detected in both areas, whereas EML4 (echinoderm microtubule-associated protein-like 4)-ALK translocations was confirmed only in the ALK IHC/FISH-positive area, suggesting the divergence of an EGFR/ALK co-altered subclone from the original EGFR-mutant clone. Our study suggests that concurrent alterations of EGFR and ALK can arise via divergent tumor evolution, even in the relatively early phases of tumorigenesis.

BACKGROUND: Molecular mechanisms of natural killer (NK) cell development from hematopoietic stem cells (HSCs) have not been clearly elucidated, although the roles of some genes in NK cell development have been reported previously. Thus, searching for molecules and genes related NK cell developmental stage is important to understand the molecular events of NK cell development. METHODS: From our previous SAGE data-base, Gpnmb (Glycoprotein non-metastatic melanoma protein B) was selected for further analysis. We confirmed the level of mRNA and protein of Gpnmb through RT-PCR, quantitative PCR, and FACS analysis. Then we performed cell-based ELISA and FACS analysis, to know whether there are some molecules which can bind to Gpnmb. Using neutralizing antibody, we blocked the interaction between NK cells and OP9 cells, and checked IFN-gamma production by ELISA kit. RESULTS: Gpnmb expression was elevated during in vitro developmental stage and bound to OP9 cells, but not to NK precursor cells. In addition, we confirmed that the levels of Gpnmb were increased at NK precursor stage in vivo. We confirmed syndecan4 as a candidate of Gpnmb's binding molecule. When the interaction between NK cells and OP9 cells were inhibited in vitro, IFN-gamma production from NK cells were reduced. CONCLUSION: Based on these observations, it is concluded that Gpnmb has a potential role in NK cell development from HSCs.
Antibodies, Neutralizing ; Enzyme-Linked Immunosorbent Assay ; Hematopoietic Stem Cells ; Killer Cells, Natural ; Melanoma ; Polymerase Chain Reaction ; RNA, Messenger ; Syndecan-4

OBJECTIVES: Asia sand dust (ASD) is known to cause various human diseases including respiratory infection. The aim of this study was to examine the effect of ASD on inflammatory response in human middle ear epithelial cells (HMEECs) in vitro and in vivo. METHODS: Cell viability was assessed using the cell counting kit-8 assay. The mRNA levels of various genes including COX-2, TNF-a, MUC 5AC, MUC 5B, TP53, BAX, BCL-2, NOX4, and SOD1 were analyzed using semiquantitative realtime polymerase chain reaction. COX-2 protein levels were determined by western blot analysis. Sprague Dawley rats were used for in vivo investigations of inflammatory reactions in the middle ear epithelium as a result of ASD injection. RESULTS: We observed dose-dependent decrease in HMEEC viability. ASD exposure significantly increased COX-2, TNF-a, MUC5AC, and MUC5B mRNA expression. Also, ASD affected the mRNA levels of apoptosis- and oxidative stress-related genes. Western blot analysis revealed a dose-dependent increase in COX-2 production. Animal studies also demonstrated an ASD-induced inflammatory response in the middle ear epithelium. CONCLUSION: Environmental ASD exposure can result in the development of otitis media.
Animals ; Asia ; Asian Continental Ancestry Group* ; Blotting, Western ; Cell Count ; Cell Survival ; Cyclooxygenase 2 ; Dust* ; Ear, Middle* ; Epithelial Cells ; Epithelium ; Gene Expression* ; Humans ; In Vitro Techniques ; Mucins* ; Otitis Media ; Polymerase Chain Reaction ; Rats, Sprague-Dawley ; RNA, Messenger

Due to the polygenic nature of cancer, it is believed that breast cancer is caused by the perturbation of multiple genes and their complex interactions, which contribute to the wide aspects of disease phenotypes. A systems biology approach for the identification of subnetworks of interconnected genes as functional modules is required to understand the complex nature of diseases such as breast cancer. In this study, we apply a 3-step strategy for the interpretation of microarray data, focusing on identifying significantly perturbed metabolic pathways rather than analyzing a large amount of overexpressed and underexpressed individual genes. The selected pathways are considered to be dysregulated functional modules that putatively contribute to the progression of disease. The subnetwork of protein-protein interactions for these dysregulated pathways are constructed for further detailed analysis. We evaluated the method by analyzing microarray datasets of breast cancer tissues; i.e., normal and invasive breast cancer tissues. Using the strategy of microarray analysis, we selected several significantly perturbed pathways that are implicated in the regulation of progression of breast cancers, including the extracellular matrix-receptor interaction pathway and the focal adhesion pathway. Moreover, these selected pathways include several known breast cancer-related genes. It is concluded from this study that the present strategy is capable of selecting interesting perturbed pathways that putatively play a role in the progression of breast cancer and provides an improved interpretability of networks of protein-protein interactions.
Breast ; Breast Neoplasms ; Focal Adhesions ; Metabolic Networks and Pathways ; Microarray Analysis ; Phenotype ; Statistics as Topic ; Systems Biology

PURPOSE: In this study cardiovascular health status and health behavior of Korean women based on their household income were explored. METHODS: For this cross-sectional study, 91 women residing in the community were recruited to complete survey questionnaires and biophysical tests including blood pressure (BP), body mass index (BMI), body fat rate, waist circumference (WC), and blood chemistry tests. RESULTS: Compared to non-low income women (NLIW), low income women (LIW) were more likely to be older, less educated, and jobless, and further more LIW were postmenopause and reported having been diagnosed with hypertension or hypercholesterolemia. Significant differences were found in systolic BP, triglyceride level, BMI, body fat rate, and WC between the groups. Two fifths of the LIW had indications for metabolic syndrome. Their 10-yr risk estimate of myocardioal infarction or coronary death demonstrated a higher probability than that of NLIW. Although these significant differences were due to age gap between the groups, advanced age is known to be one of the key characteristics of LIW as well as a non-modifiable risk factor. CONCLUSION: Effective community programs for vulnerable women at risk of cardiovascular disease should be based on strategies targeting unhealthy behaviors and modifiable risk factors.
Adult ; Aged ; Aged, 80 and over ; Blood Chemical Analysis ; Blood Pressure ; Body Fat Distribution ; Body Mass Index ; Cross-Sectional Studies ; Family Characteristics ; Female ; *Health Behavior ; *Health Status ; Humans ; Hypercholesterolemia/*diagnosis/economics ; Hypertension/*diagnosis/economics ; Income/*statistics & numerical data ; Middle Aged ; Questionnaires ; Republic of Korea ; Risk Factors ; Waist Circumference

Purpose: This study investigated changes in attitudes toward marriage and childbearing assuming a BRCA1/2 mutation carrier status among healthy, unmarried individuals in Korea. Methods: A nationally representative sample of healthy, unmarried individuals aged 20–39 years was surveyed. A questionnaire on marriage and childbearing intentions was administered to the participants before and after providing them with information on BRCA1/2 mutation carriers’ breast and ovarian cancer risks and their autosomal dominant inheritance pattern. The participants were asked about their attitudes toward childbearing through preimplantation genetic diagnosis (PGD). Results: Of the participants who initially wanted to marry, the assumption that they or their partners had BRCA1/2 mutation caused 25.3% to no longer want to get married and 36.2% to change their attitude from wanting to bear children to no longer wanting them. Females were more likely than males to change their attitudes toward marriage and childbearing. The participants who had negative attitudes toward genetic testing were more likely to change their attitudes regarding marriage and childbearing than those who were favorable toward both disclosure and testing. More than 50% of the participants who did not want children were willing to bear children through PGD when it was assumed that they were BRCA mutation carriers. Conclusion On the assumption of being carriers, general, young, and healthy females were more likely than males to negatively change their attitudes toward marriage and childbearing. Public education on the implications of living with mutation carriers and reproductive options may be required.

Lymphocyte-rich effusions represent benign reactive process or neoplastic condition. Involvement of lymphoproliferative disease in body cavity is not uncommon, and it often causes diagnostic challenge. In this review, we suggest a practical diagnostic approach toward lymphocyte-rich effusions, share representative cases, and discuss the utility of ancillary tests. Cytomorphologic features favoring neoplastic condition include high cellularity, cellular atypia/pleomorphism, monomorphic cell population, and frequent apoptosis, whereas lack of atypia, polymorphic cell population, and predominance of small T cells usually represent benign reactive process. Involvement of non-hematolymphoid malignant cells in body fluid should be ruled out first, followed by categorization of the samples into either small/medium-sized cell dominant or large-sized cell dominant fluid. Small/medium-sized cell dominant effusions require ancillary tests when either cellular atypia or history/clinical suspicion of lymphoproliferative disease is present. Large-sized cell dominant effusions usually suggest neoplastic condition, however, in the settings of initial presentation or low overall cellularity, ancillary studies are helpful for more clarification. Ancillary tests including immunocytochemistry, in situ hybridization, clonality test, and next-generation sequencing can be performed using cytologic preparations. Throughout the diagnostic process, proper review of clinical history, cytomorphologic examination, and application of adequate ancillary tests are key elements for successful diagnosis.