Variations in (18)F-FDG uptake in breast cancer depending on PET/CT acquisition position.

AIM: To evaluate the variability of quantitative 2-[(18)F]-fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography (PET) combined with computed tomography (CT) parameters depending on acquisition position in a dual-position protocol for breast cancers. MATERIALS AND METHODS: For initial staging work-up, whole-body PET/CT was first acquired in a supine position, and then followed by a regional breast scan in a prone position. The maximum standardised uptake value (SUVmax), metabolic tumour volume (MTV), and total lesion glycolysis (TLG) were measured on both acquisition positions. MTV50 and TLG50 were calculated with a threshold set to be 50% of SUVmax, and MTV2.5 and TLG2.5 with a fixed SUV threshold of 2.5. RESULTS: The median SUVmax of breast cancers measured on the supine scans was 4.88, and 4.49 on the prone images (p<0.05). MTV and TLG also yielded significantly lower values from supine images. Regarding the tendency for the acquisition position to yield different results, a significant disagreement was observed between SUVmax and MTV50 and between SUVmax and TLG50 (kappa = -0156 and -0.001, respectively), while MTV2.5 and TLG2.5 showed a fair to moderate agreement with SUVmax (kappa = 0.311 and 0.416, respectively). CONCLUSIONS: SUVmax, MTV, and TLG yielded lower values when acquired in the prone position compared to in the supine position. This observation could be due to the partial volume effect. When using 50% of SUVmax as a threshold, there was a significant discordance between SUVmax and volumetric parameters. Thus, acquisition position may affect quantitative PET/CT parameters and the clinical implications.

Interleukin-33/ST2 axis promotes epithelial cell transformation and breast tumorigenesis via upregulation of COT activity.

Cytokines of the interleukin-1 (IL-1) family, such as IL-1α/ß and IL-18, have pleiotropic activities in innate and adaptive immune responses in host defense and diseases. Insight into their biological functions helped develop novel therapeutic approaches to treat human inflammatory diseases. IL-33 is an important member of the IL-1 family of cytokines and is a ligand of the ST2 receptor, a member of the IL-1 receptor family. However, the role of the IL-33/ST2 axis in tumor growth and metastasis of breast cancer remains unclear. Here, we demonstrate that IL-33 is a critical tumor promoter during epithelial cell proliferation and tumorigenesis in the breast. IL-33 dose- and time-dependently increased Cancer Osaka Thyroid (COT) phosphorylation via ST2-COT interaction in normal epithelial and breast cancer cells. The IL-33/ST2/COT cascade induced the activation of the MEK-ERK (MEK-extracellular signal-regulated kinase), JNK-cJun (cJun N-terminal kinase-cJun) and STAT3 (signal transducer and activator of transcription 3) signaling pathways, followed by increased AP-1 and stat3 transcriptional activity. When small interfering RNAs of ST2 and COT were introduced into cells, IL-33-induced AP-1 and stat3 activity were significantly decreased, unlike that in the control cells. The inhibition of COT activity resulted in decreased IL-33-induced epithelial cell transformation, and knockdown of IL-33, ST2 and COT in breast cancer cells attenuated tumorigenicity of breast cancer cells. Consistent with these observations, ST2 levels were positively correlated with COT expression in human breast cancer. These findings provide a novel perspective on the role of the IL-33/ST2/COT signaling pathway in supporting cancer-associated inflammation in the tumor microenvironment. Therapeutic approaches that target this pathway may, therefore, effectively inhibit carcinogenesis in the breast.

A survival benefit of major hepatectomy for hepatocellular carcinoma identified by preoperative [18F] fluorodeoxyglucose positron emission tomography in patients with well-preserved hepatic function.

AIMS: Hepatic resection can cure hepatocellular carcinoma (HCC). However, the optimal extent of resection remains controversial. Major hepatectomy could minimize a tumor recurrence, but it is harmful due to decreased hepatic functional reserve. [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) scans are known as their reflection tumor differentiation and biological activity in HCC. To evaluate a benefit of major hepatectomy for HCC, we performed this retrospective analysis in patients with well-preserved hepatic function, and further analyzed in the subset identified by preoperative FDG-PET. METHODS: We reviewed the medical records of 189 patients with HCC who underwent curative resection between August 2004 and December 2010 at two institutes. All patients underwent anatomical resection, either by major or minor hepatectomy. RESULTS: Median overall survival did not differ significantly between the major and minor hepatectomy groups (29.4 versus 26.3 months, p = 0.269). However, the major hepatectomy group had a better recurrence-free survival (24.5 versus 19.9 months, p = 0.004). On multivariate analysis, the presence of intrahepatic metastasis independently predicted overall survival (p = 0.009), but other examined variables did not. Overall survival and recurrence-free survival were significantly better following major hepatectomy rather than minor hepatectomy in patients whose preoperative FDG-PET indicated that the maximum standardized uptake value of the tumor (SUVtumor) was ≥4 and the tumor-to-nontumor SUV ratio (TNR) was ≥1.5. CONCLUSIONS: Our findings suggest that preoperative FDG-PET may be useful in identifying patients with favorable hepatic reserve who are most likely to benefit from major rather than minor hepatectomy.

Rapid extraction and preservation of genomic DNA from human samples.

Simple and rapid extraction of human genomic DNA remains a bottleneck for genome analysis and disease diagnosis. Current methods using microfilters require cumbersome, multiple handling steps in part because salt conditions must be controlled for attraction and elution of DNA in porous silica. We report a novel extraction method of human genomic DNA from buccal swab and saliva samples. DNA is attracted onto a gold-coated microchip by an electric field and capillary action while the captured DNA is eluted by thermal heating at 70 °C. A prototype device was designed to handle four microchips, and a compatible protocol was developed. The extracted DNA using microchips was characterized by qPCR for different sample volumes, using different lengths of PCR amplicon, and nuclear and mitochondrial genes. In comparison with a commercial kit, an equivalent yield of DNA extraction was achieved with fewer steps. Room-temperature preservation for 1 month was demonstrated for captured DNA, facilitating straightforward collection, delivery, and handling of genomic DNA in an environment-friendly protocol.

Transcriptional regulation of MDR-1 by HOXC6 in multidrug-resistant cells.

Resistance to chemotherapeutic drugs is a significant clinical problem in the treatment of cancer and this resistance has been linked to the cellular expression of multidrug-efflux transporters. The aim of this study was to explore the role of HOXC6 in the regulation of multidrug resistance (MDR) to chemotherapeutic drugs. The HOXC6 gene was identified as being overexpressed in drug-resistant cells compared with parental cell lines. Transfection assays demonstrated that HOXC6 activated MDR-1 promoter activity. A series of MDR-1 promoter deletion mutants was examined and the minimal HOXC6-responsive region was identified to be in the TAAT motif (-2243 bp) of the MDR-1 promoter. Interestingly, overexpression of HOXC6 in the parental cell lines resulted in the upregulation of MDR-1 expression. The inhibition of HOXC6 using small interfering RNA led to the repression of MDR-1. We determined that knockdown of HOXC6 expression in MDR cells increased their sensitivity to paclitaxel. Flow cytometry analysis suggested that siHOXC6 could induce paclitaxel-induced apoptosis and that this was accompanied by an increased accumulation and a decreased release of paclitaxel. Taken together, our findings suggest that HOXC6 expression is an important mechanism of chemotherapeutic drug resistance via its regulation of MDR-1.

Characterization of NODs and TLRs in innate immune response of human cementoblast cells.

OBJECTIVES: Microbial Pattern-recognition receptors (PRRs), such as Toll-like receptors (TLRs) and the nucleotide-binding oligomerization domains (NODs), are essential for mammalian innate immune response. In this study, we examined the characterization of NODs and TLRs on innate immune responses in human cementoblast (HCEM) cells. MATERIALS AND METHODS: The gene expression of NODs and TLRs was examined by RT-PCR. Interleukin-6 (IL-6) and Interleukin-8 (IL-8) productions in culture supernatants were measured by ELISA. Western blot analysis was performed to determine the degradation of IκB-α and Mitogen activated protein kinase (MAPK) activation in response to their agonist. RESULTS: The levels of NODs and TLRs were apparently expressed in HCEM cells. Although a few gene levels were weak in intact cells, the stimulation by their agonists increased the gene expression of TLRs. NODs and TLRs led to the production of IL-6 or IL-8 and the degradation of IκB-α and MAPK activation in HCEM cells. Combination treatment of NOD1 or NOD2 agonists with TLRs agonists did not influence the production of IL-6 and IL-8 in HCEM cells. CONCLUSIONS: Our results indicate that NODs and TLRs are functionally expressed in HCEM cells and can trigger innate immune responses. However, NOD1 and NOD2 may not be cooperated with TLRs to elicit an immune response in HCEM cells.

Proyl isomerase Pin1 facilitates ubiquitin-mediated degradation of cyclin-dependent kinase 10 to induce tamoxifen resistance in breast cancer cells.

Endocrine therapies that inhibit estrogen receptor (ER)-α signaling are the most common and effective treatment for ER-α-positive breast cancer. However, the use of these agents is limited by the frequent development of resistance. The aim of this study was to elucidate the mechanisms by which downregulation of CDK10 expression confers resistance to tamoxifen in breast cancer. Here, we show that peptidyl-prolyl isomerase Pin1 downregulates CDK10 protein as a result of its interaction with and ubiquitination of CDK10, thereby affecting CDK10-dependent Raf-1 phosphorylation (S338). Pin1(-/-) mouse embryonic fibroblasts (MEFs) show higher CDK10 expression than Pin1(+/+) MEFs, whereas CDK10 protein was downregulated in the rescued Pin1(-/-) MEFs after reexpression of Pin1. Pin1 silencing in SKBR-3 and MCF7 cells increased the CDK10 expression. In human tamoxifen-resistant breast cancer and tamoxifen-resistant MCF7 cells, immunohistochemical staining and immunoblotting analysis shows an inverse correlation between the expression of CDK10 and the degree of tamoxifen resistance. There was also a positive correlation between the high level of P-Raf-1 (Ser338) and Pin1 in human tamoxifen-resistant breast cancer and tamoxifen-resistant MCF7 (TAMR-MCF7) cells. Importantly, 4-OH tamoxifen (4-OHT), when used in combination with overexpressed CDK10 or Raf-1 inhibitor, increased cleaved PARP and DNA fragmentation to inhibit cologenic growth of MCF7 cells and Tamoxifen-resistant MCF7 cells, respectively. On the basis of these findings, we suggest that the Pin1-mediated CDK10 ubiquitination is a major regulator of tamoxifen-resistant breast cancer cell growth and survival.

Effect of reinforcement particle size on the tribological properties of nano-diamond filled polytetrafluoroethylene based coating.

The tribological properties of PTFE composite coatings reinforced by nano-diamonds were investigated. Mechanical particle size reduction and dispersion of nano-diamond aggregates were performed by milling with ceramic beads in an organic solvent. Particle size was controlled by the milling time. Pastes comprising a PTFE solution mixed with nano-diamond having various sizes were coated on the aluminum substrate. Ball-on-plate type wear test was performed to investigate the friction and wear behavior. The results indicated that the addition of nano-diamonds effectively improved tribological performance of the PTFE coating. The reduction in nano-diamond sizes were not always improved the wear resistance of PTFE coating. This unexpected behavior was explained by observation on the worn surfaces and wear debris.

Mucous cell differentiation in a unicystic ameloblastoma.

The authors report a case of unicystic ameloblastoma with mucous cell differentiation in the right mandible of a 24-year-old Korean male who suffered from painful swelling for 2 months. A radiograph showed a well-circumscribed radiolucent lesion between the root of the right first premolar and the first molar tooth. Microscopic examination revealed the cystic lesion was lined with ameloblastic epithelium and goblet cells in the epithelium. The mucous cells reacted positively to mucicarmine stain. The possible pathogenic mechanism of this case reflects the pluripotential character of the odontogenic epithelium. The prognosis is probably that expected for conventional unicystic ameloblastoma.

Relationship of epicardial adipose tissue by echocardiography to coronary artery disease.

OBJECTIVE: To study the relationship of echocardiographic epicardial adipose tissue (EAT) with coronary artery disease (CAD) risk factors and the extent of coronary atherosclerosis. METHODS: EAT thickness was measured in 527 patients undergoing their first coronary angiography. EAT was defined as an echo-lucent area on the free wall of the right ventricle on the still image of the two-dimensional echocardiogram at end diastole in the parasternal long-axis and parasternal short-axis views. A CT scan at the umbilicus was acquired to measure abdominal visceral adipose tissue (VAT) from a random sample of 30 patients. The extent of coronary atherosclerosis was assessed using a coronary atherosclerosis score based on the quantitative coronary angiography results. RESULTS: EAT thickness was correlated with abdominal VAT (r(s) = 0.626, p<0.001), age (r(s) = 0.480, p<0.001), waist circumference (r(s) = 0.309, p<0.001), body mass index (r(s) = 0.233, p<0.001), C reactive protein (r(s) = 0.224, p<0.001), and the homoeostasis model assessment score (r(s) = 0.249, p<0.001). EAT was thicker in subjects with CAD than in those without CAD (4.0 vs 1.5 mm, p<0.001). Patients with unstable angina had thicker EAT than those with stable angina or atypical chest pain (4.0, 3.0, and 1.5 mm, respectively, p<0.001). EAT (> or =3.0 mm) was an independent factor of CAD on multiple logistic analysis (odds ratio = 3.357; 95% CI 2.177 to 5.175, p<0.001). CONCLUSIONS: These results suggest that EAT may reflect the amount of visceral fat, which is associated with insulin resistance and inflammation. The echocardiographic measurement of EAT may provide additional information for assessing CAD risk and predicting the extent and activity of CAD.

Metastatic tumours to the jaws and oral soft tissues: a retrospective analysis of 41 Korean patients.

This article describes a pooled analysis of 41 Korean patients with metastatic oral tumours. The data reviewed are from Korean dental and medical case reports published between 1983 and 2004. The mean age was 55.2 years, and the male-to-female ratio was 1.9:1. There were more metastases in the jawbone than in oral soft tissues. The lung was the most common primary site for jawbone metastases, whereas the liver was for those of oral soft tissues. In contrast to reports in Western literature of the breast being the most common primary site, the liver was the most common primary site, followed by the lung and thyroid. These differences may be caused by a relatively high incidence rate of hepatocellular carcinoma in Korea.

Calcifications in a clear cell mucoepidermoid carcinoma of the hard palate.

Although calcification is a common finding in inflammatory salivary gland disorders, salivary gland tumour rarely shows calcifications. A case of clear cell mucoepidermoid carcinoma (MEC) of the hard palate with extensive intratumoural calcifications visible on computed tomography (CT) scans and histologic sections is described. The calcification in the salivary gland tumour of the palate recognized by a CT scan should be considered in the differential diagnosis of a MEC. The mechanism of the intratumoural calcification in our case is speculated to be a result of a secretory function of the tumour cells.

Nevoid basal cell carcinoma syndrome: a retrospective analysis of 33 affected Korean individuals.

This article describes a pooled analysis of Korean individuals with nevoid basal cell carcinoma syndrome (NBCCS). The data upon which this review is based has been retrieved from published case reports in Korean dental and medical literature between the years 1981 to 2002. We found 33 subjects who met the diagnostic criteria for NBCCS. Relative frequencies of associated complications are presented and compared with those of the English literature. Odontogenic keratocyst (OKC) and palmar and/or plantar pits, and hypertelorism were the most frequently observed anomalies. OKCs are often the first signs of NBCCS and can be detected in patients younger than 20 years of age. However, the incidence and clinical manifestations of NBCCS in Korean individuals were found to be rather different from those of other countries. The relatively low frequency of basal cell carcinomas and falx calcification among the major criteria were two major differences. The frequencies of the minor criteria concur in general with the ranges given by some others. It is concluded that these differences may be attributed to genetic and geographic differences.

The loop domain of heat shock transcription factor 1 dictates DNA-binding specificity and responses to heat stress.

Eukaryotic heat shock transcription factors (HSF) regulate an evolutionarily conserved stress-response pathway essential for survival against a variety of environmental and developmental stresses. Although the highly similar HSF family members have distinct roles in responding to stress and activating target gene expression, the mechanisms that govern these roles are unknown. Here we identify a loop within the HSF1 DNA-binding domain that dictates HSF isoform specific DNA binding in vitro and preferential target gene activation by HSF family members in both a yeast transcription assay and in mammalian cells. These characteristics of the HSF1 loop region are transposable to HSF2 and sufficient to confer DNA-binding specificity, heat shock inducible HSP gene expression and protection from heat-induced apoptosis in vivo. In addition, the loop suppresses formation of the HSF1 trimer under basal conditions and is required for heat-inducible trimerization in a purified system in vitro, suggesting that this domain is a critical part of the HSF1 heat-stress-sensing mechanism. We propose that this domain defines a signature for HSF1 that constitutes an important determinant for how cells utilize a family of transcription factors to respond to distinct stresses.

3-deazaadenosine, a S-adenosylhomocysteine hydrolase inhibitor, has dual effects on NF-kappaB regulation. Inhibition of NF-kappaB transcriptional activity and promotion of IkappaBalpha degradation.

Previously we reported that 3-deazaadenosine (DZA), a potent inhibitor and substrate for S-adenosylhomocysteine hydrolase inhibits bacterial lipopolysaccharide-induced transcription of tumor necrosis factor-alpha and interleukin-1beta in mouse macrophage RAW 264.7 cells. In this study, we demonstrate the effects of DZA on nuclear factor-kappaB (NF-kappaB) regulation. DZA inhibits the transcriptional activity of NF-kappaB through the hindrance of p65 (Rel-A) phosphorylation without reduction of its nuclear translocation and DNA binding activity. The inhibitory effect of DZA on NF-kappaB transcriptional activity is potentiated by the addition of homocysteine. Taken together, DZA promotes the proteolytic degradation of IkappaBalpha, but not IkappaBbeta, resulting in an increase of DNA binding activity of NF-kappaB in the nucleus in the absence of its transcriptional activity in RAW 264.7 cells. The reduction of IkappaBalpha by DZA is neither involved in IkappaB kinase complex activation nor modulated by the addition of homocysteine. This study strongly suggests that DZA may be a potent drug for the treatment of diseases in which NF-kappaB plays a central pathogenic role, as well as a useful tool for studying the regulation and physiological functions of NF-kappaB.

Identification of cDNAs for Sox-4, an HMG-Box protein, and a novel human homolog of yeast splicing factor SSF-1 differentially regulated during apoptosis induced by prostaglandin A2/delta12-PGJ2 in Hep3B cells.

We have examined specific genes whose expression is altered during apoptosis induced by prostaglandin (PG)A2 and Delta12-PGJ2 in human hepatocellular carcinoma Hep3B cells. Using mRNA differential display, we have identified two genes: one is specifically up-regulated and encodes for human Sox-4 (Sry-HMG box gene) and the other is significantly down-regulated and is the human homolog of yeast Ssf-1, a novel splicing factor. Northern blot analysis confirmed their differential expressions. Interestingly, Sox-4 was highly expressed in subcutaneous tumors grown in nude mice as a xenograft from Hep3B cells. These results suggest that the expression of Sox-4 may be related to the apoptosis pathway leading to cell death as well as to tumorigenesis, and that Ssf-1 gene may serve as a negative regulator of PGA2/Delta12-PGJ2-mediated Hep3B cell apoptosis.

The role of c-Myc and heat shock protein 70 in human hepatocarcinoma Hep3B cells during apoptosis induced by prostaglandin A2/Delta12-prostaglandin J2.

Prostaglandin (PG) A2 (PGA2) and Delta12-PGJ2 have potent antiproliferative activity on various tumor cell growths in vitro. In this study, we investigated the mechanism of PGA2/Delta12-PGJ2-mediated apoptosis, including intracellular apoptosis-related genes in human hepatocarcinoma Hep3B cells. Hep3B cells treated with PGA2/Delta12-PGJ2 showed that a time-dependent DNA fragmentation characterized by marked apoptosis and the elevation of c-myc mRNA expression. In proportion to the increased c-myc gene transcription, heat shock protein 70 (hsp70) mRNA was induced from 1 to 24 h after PGA2/Delta12-PGJ2 treatment. The transfection of c-myc antisense oligomers in Hep3B cells significantly delayed the induction of HSP70 expression and blocked formation of DNA fragmentation by PGA2/Delta12-PGJ2. Moreover, overexpressed HSP70 showed an increased resistance to apoptosis by PGA2/Delta12-PGJ2 treatment. These results demonstrated that the decreased survival in response to PGA2/Delta12-PGJ2 was causally related to the amount of c-myc and the induction of c-myc regulated the elevation of HSP70 which have been known to correlate with a resistance to apoptosis.