Incidence, survival, and risk of cardiovascular events in adult inflammatory myopathies in South Korea: a nationwide population-based study.

OBJECTIVE: Epidemiological studies on inflammatory myopathies (IMs) show widely variable results, and studies on Asians are lacking. Despite emerging interest in the cardiovascular disease (CVD) risk associated with IMs, the prevalence of CVD in IM patients and its impact on mortality remain unclear. We conducted a nationwide, population-based study on the incidence, mortality, and associated major CVD events of IMs in the Republic of Korea over 11 years. METHOD: Using the nationwide, population-based National Health Insurance claims database and the Rare Intractable Disease registration programme, we estimated incidence, mortality, and CVD occurrence. Survival was examined using the Kaplan-Meier method. Mortality rate in IMs with CVD was analysed by Cox proportional hazards regression. RESULTS: There were 3014 incident cases, 640 of whom died during the study period. The mean annual incidence was 7.16/106. Dermatomyositis (DM) and polymyositis (PM) had 5 year survival rates of 76.8% and 79.3%, respectively. Cardiovascular events occurred in 155 patients and 40.6% of IM patients with CVD died. Acute myocardial infarction in men had the highest risk of any CVD event in both DM [standardized incidence ratio (SIR) 4.2, 95% confidence interval (95% CI) 2.4-7.2] and PM (SIR 3.5, 95% CI 1.8-7.0). Haemorrhagic stroke had the highest hazard ratio (HR) in both DM (HR 2.31, 95% CI 1.13-4.70) and PM patients (HR 2.10, 95% CI 1.03-4.27) compared with the general population with CVD. CONCLUSION: We found persistently low incidence, poor survival, and high major CVD incidence in IMs, and increased mortality in IMs with CVD.

Effect of point mutations on the ultrafast photo-isomerization of Anabaena sensory rhodopsin.

Anabaena sensory rhodopsin (ASR) is a particular microbial retinal protein for which light-adaptation leads to the ability to bind both the all-trans, 15-anti (AT) and the 13-cis, 15-syn (13C) isomers of the protonated Schiff base of retinal (PSBR). In the context of obtaining insight into the mechanisms by which retinal proteins catalyse the PSBR photo-isomerization reaction, ASR is a model system allowing to study, within the same protein, the protein-PSBR interactions for two different PSBR conformers at the same time. A detailed analysis of the vibrational spectra of AT and 13C, and their photo-products in wild-type ASR obtained through femtosecond (pump-) four-wave-mixing is reported for the first time, and compared to bacterio- and channelrhodopsin. As part of an extensive study of ASR mutants with blue-shifted absorption spectra, we present here a detailed computational analysis of the origin of the mutation-induced blue-shift of the absorption spectra, and identify electrostatic interactions as dominating steric effects that would entail a red-shift. The excited state lifetimes and isomerization reaction times (IRT) for the three mutants V112N, W76F, and L83Q are studied experimentally by femtosecond broadband transient absorption spectroscopy. Interestingly, in all three mutants, isomerization is accelerated for AT with respect to wild-type ASR, and this the more, the shorter the wavelength of maximum absorption. On the contrary, the 13C photo-reaction is slightly slowed down, leading to an inversion of the ESLs of AT and 13C, with respect to wt-ASR, in the blue-most absorbing mutant L83Q. Possible mechanisms for these mutation effects, and their steric and electrostatic origins are discussed.

Adenovirus-mediated Foxp3 expression in lung epithelial cells ameliorates acute radiation-induced pneumonitis in mice.

Forkhead transcription factor 3 (Foxp3) has a critical role in regulatory T cells (Treg). There are an increasing number of researches concerning the functions of Foxp3 in other cells, including lung epithelial cells besides Treg. However, the roles of Foxp3 in lung epithelial cells remain poorly understood. To examine the potential therapeutic benefits of Foxp3 for lung inflammation, this study investigates the effect of adenovirus-mediated Foxp3 overexpression in a radiation-induced lung damage model. Foxp3-EGFP expressing adenovirus was administered by intratracheal injection three times over 14 days after focal X-ray irradiation. To evaluate effects of Foxp3 overexpression in radiation-induced lung inflammation, immune cell profiles of bronchoalveolar lavage (BAL) fluid were analyzed. Foxp3 gene-delivered mice showed significant inhibition of immune cell infiltration, such as eosinophils, lymphocytes, macrophages and neutrophils in BAL fluid. Histopathological analysis also showed that Foxp3 overexpression inhibits inflammatory cell recruitment and collagen deposition in lung tissues. In addition, expression of inflammatory and fibrosis-related genes was decreased in the Foxp3 expression adenovirus-infected group. These results suggest that Foxp3 expression in lungs holds considerable therapeutic potential for attenuating inflammation and fibrosis in radiation-induced lung injury.

Utility of digital subtraction angiography-based collateral evaluation in medically treated acute symptomatic basilar artery stenosis.

BACKGROUND AND PURPOSE: Although a stroke from atherosclerosis in the basilar artery (BA) often presents with mild initial stroke severity, it has heterogeneous clinical courses. We investigated the efficacy of digital subtraction angiography (DSA)-based collateral perfusion evaluation in association with long-term outcomes of medically treated symptomatic basilar artery stenosis. METHODS: From a registry database of all consecutive patients with stroke, we included 98 medically treated patients (due to mild initial stroke severity) [National Institute of Health Stroke Scale (NIHSS) scores ≤ 4; symptomatic basilar artery stenosis, 70-99%] with available initial diagnostic DSA. Basilar collateral scoring was performed via the DSA, using a modified version of the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology grading system in both the superior cerebellar artery and anterior/posterior-inferior cerebellar artery territories (score 0-8). The outcomes were designated as the 90-day modified Rankin Scale (mRS90) score (poor, 3-6). Student's t-test, chi-square test and logistic regression analyses were used to identify factors associated with a poor outcome. RESULTS: The median initial NIHSS score was 2 [interquartile range (IQR), 0-3], median posterior circulation Alberta Stroke Program Early CT Score was 8 (IQR, 7-10), median collateral score was 7 (IQR, 7-8) and 20 (20.4%) had poor mRS90 scores. In multivariate analysis, poorer collateral scores (P = 0.003), higher NIHSS scores (P = 0.005) and lower posterior circulation Alberta Stroke Program Early CT Score (P = 0.017) were independently associated with a poor mRS90 score. CONCLUSIONS: The DSA-based collateral scoring of the BA large branches might predict long-term outcome in medically treated symptomatic basilar artery stenosis with mild initial severity. Evaluation of BA collateral perfusion status might be useful to determine appropriate treatment strategies.

A randomized, multi-center, open-label, phase III study of once-per-cycle DA-3031, a pegylated G-CSF, in comparison with daily filgrastim in patients receiving TAC chemotherapy for breast cancer.

PURPOSE: This multi-center, randomized, phase III study was conducted to demonstrate the non-inferiority of DA-3031 compared with daily filgrastim in patients during the first cycle of chemotherapy for breast cancer in terms of the duration of severe neutropenia (DSN). METHODS: Seventy-four patients with breast cancer who were receiving combination chemotherapy with docetaxel, doxorubicin, and cyclophosphamide (TAC) were enrolled. All participants were randomized to receive either daily subcutaneous injections of filgrastim 100 µg/m2/day for up to 10 days or a single subcutaneous injection of DA-3031 at fixed doses of 6 mg on day 2 of each chemotherapy cycle. RESULTS: The mean duration of grade 4 (G4) neutropenia in cycle 1 was 2.08 ± 0.85 days for the filgrastim group and 2.28 ± 1.14 days for the DA-3031 group. The difference between groups was 0.2 ± 1.10 days (95 % confidence interval (CI) = -0.26, 0.66), which supported non-inferiority. No statistically significant differences were observed in nadir absolute neutrophil count (ANC) (154.34/mm3 and 161.75/mm3 for the filgrastim and DA-3031 groups, respectively; P = 0.8414) or in time to ANC recovery (10.03 ± 0.75 and 9.83 ± 1.56 days in the filgrastim and DA-3031 groups, respectively; P = 0.0611) during cycle 1. Serious AEs occurred in six (15.8 %) patients receiving filgrastim and in ten (27.8 %) patients receiving DA-3031; however, none was determined to be related to the study drug. CONCLUSIONS: DA-3031 and daily filgrastim are similar in regard to DSN and safety in breast cancer patients receiving TAC chemotherapy.

Prognostic and predictive values of EGFR overexpression and EGFR copy number alteration in HER2-positive breast cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR) is overexpressed in a subset of human epidermal growth factor receptor 2 (HER2)-positive breast cancers, and coexpression of HER2 and EGFR has been reported to be associated with poor clinical outcome. Moreover, interaction between HER2 and EGFR has been suggested to be a possible basis for trastuzumab resistance. METHODS: We analysed the clinical significance of EGFR overexpression and EGFR gene copy number alterations in 242 HER2-positive primary breast cancers. In addition, we examined the correlations between EGFR overexpression, trastuzumab response and clinical outcome in 447 primary, and 112 metastatic HER2-positive breast cancer patients treated by trastuzumab. RESULTS: Of the 242 primary cases, the level of EGFR overexpression was 2+ in 12.7% and 3+ in 11.8%. High EGFR gene copy number was detected in 10.3%. Epidermal growth factor receptor overexpression was associated with hormone receptor negativity and high Ki-67 proliferation index. In survival analyses, EGFR overexpression, but not high EGFR copy number, was associated with poor disease-free survival in all patients, and in the subgroup not receiving adjuvant trastuzumab. In 447 HER2-positive primary breast cancer patients treated with adjuvant trastuzumab, EGFR overexpression was also an independent poor prognostic factor. However, EGFR overexpression was not associated with trastuzumab response, progression-free survival or overall survival in the metastatic setting. CONCLUSIONS: Epidermal growth factor receptor overexpression, but not high EGFR copy number, is a poor prognostic factor in HER2-positive primary breast cancer. Epidermal growth factor receptor overexpression is a predictive factor for trastuzumab response in HER2-positive primary breast cancer, but not in metastatic breast cancer.

Interleukin-18 as an efficient marker for remission and follow-up in patients with inactive adult-onset Still's disease.

OBJECTIVES: Diagnosis of adult-onset Still's disease (AOSD) is difficult because of a lack of pathognomonic findings and markers. The aim of this study was to investigate the efficacy of interleukin (IL)-18 and free IL-18 in the diagnosis and follow-up of patients with AOSD. METHOD: Levels of inflammatory cytokines, IL-18, IL-18 binding protein (IL-18BP), and free IL-18 were compared in 80 AOSD patients and 90 controls. The AOSD patients were divided into active and inactive groups according to disease activity, and the inactive patients were subdivided into a remission subgroup and a low disease activity subgroup. We compared erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), ferritin, IL-18, and free IL-18 as disease activity markers in the AOSD patients. Serial serum levels of activity markers were measured in 52 of the 80 AOSD patients at 3- to 6-month intervals. RESULTS: There were significantly higher levels of IL-18 and free IL-18 in the AOSD patients than in the controls. IL-18 and free IL-18 were significantly higher in the active group than the inactive group (p < 0.001 for all). Unlike other activity markers, IL-18 and free IL-18 levels in the low disease activity subgroup were significantly higher than those in the remission subgroup within the inactive group (p = 0.004 and 0.005, respectively). During serial follow-up, ferritin and IL-18 showed a significant decrease in the responder and remission subgroup. CONCLUSIONS: IL-18 might be an efficient marker for diagnosis and follow-up of AOSD and might also be a useful predictor of remission, especially in clinically inactive patients.

S-1 plus irinotecan and oxaliplatin for the first-line treatment of patients with metastatic colorectal cancer: a prospective phase II study and pharmacogenetic analysis.

BACKGROUND: S-1 is an oral fluoropyrimidine that mimics infusional 5-fluorouracil. The aim of this phase II trial was to explore the clinical efficacy of the triplet regimen TIROX, which consists of S-1, irinotecan and oxaliplatin. METHODS: Forty-two chemo-naive patients with metastatic colorectal cancer (mCRC) were planned to be enrolled and be treated with irinotecan 150 mg m(-2) followed by oxaliplatin 85 mg m(-2) on day 1 and S-1 80 mg m(-2) per day from day 1 to 14 every 3 weeks. Polymorphisms in the UGT1A1, UGT1A6, UGT1A7 and CYP2A6 genes were analysed. RESULTS: Between July 2007 and February 2008, 43 patients were enrolled. An objective response was noted in 29 patients (67.4%, 95% confidence interval: 53.4-81.4), of which 2 achieved durable complete responses. The median progression-free survival was 10.0 months and the median overall survival was 19.2 months. Significant grade 3 or 4 adverse events were neutropenia (45.2%), febrile neutropenia (9.5%), diarrhoea (7.1%) and vomiting (9.5%). Increased gastrointestinal toxicities were associated with the presence of UGT1A6*2 or UGT1A7*3 and an improved tumour response was noted in those without variant alleles of CYP2A6 or UGT1A1*60. CONCLUSION: The combination of S-1, irinotecan and oxaliplatin showed favourable efficacy and tolerability in untreated patients with mCRC.

Multicentre phase II trial of bevacizumab combined with docetaxel-carboplatin for the neoadjuvant treatment of triple-negative breast cancer (KCSG BR-0905).

BACKGROUND: This phase II neoadjuvant trial evaluated bevacizumab-docetaxel and carboplatin in triple-negative breast cancer. PATIENTS AND METHODS: Women with hormone receptor- and human epidermal growth factor receptor 2 (HER2)-negative, stage II/III breast cancer received six cycles of 75 mg/m(2) docetaxel, carboplatin (AUC = 5) and 15 mg/kg bevacizumab every 21 days. The primary end point was pathological complete response (pCR) in breasts and axillary lymph nodes (ALN). RESULTS: Forty-five patients were recruited from the Korean Cancer Study Group. The median age was 45 (range 30-72) years. ALNs were positive in 80% of patients (n = 36) at diagnosis. Overall, 98% of patients (n = 44) completed therapy and underwent surgery. The pCR rate was 42% (n = 19); clinical response rate 96% (n = 43); complete 13% (n = 6); partial 82% (n = 37); stable disease 2% (n = 1). Breast-conserving surgery was undertaken in 78% of patients (n = 35). Most frequent grade 3/4 adverse events were neutropenia (84%, n = 38) and febrile neutropenia (9%, n = 4). One patient experienced delayed wound healing after surgery. CONCLUSIONS: Neoadjuvant bevacizumab, docetaxel and carboplatin resulted in an encouraging pCR rate and negligible wound healing problems after surgery.

Effect of complementary and alternative medicine on the survival and health-related quality of life among terminally ill cancer patients: a prospective cohort study.

BACKGROUND: We evaluated whether complementary and alternative medicine (CAM) use influenced outcomes [survival and health-related quality of life (HRQOL)] of cancer patients whose condition had just been judged terminal. PATIENTS AND METHODS: From July 2005 to October 2006, we conducted a prospective cohort study of 481 terminally ill cancer patients at 11 university hospitals and the National Cancer Center in Korea. We assessed how the use of CAM affected HRQOL and survival. RESULTS: In a follow-up of 481 patients and 163.8 person-years, we identified 466 deceased cases. On multivariate analyses, CAM users did not have better survival compared with nonusers [adjusted hazard ratio (aHR), 0.91; 95% confidence interval (CI) 0.74-1.10]. Among mind-body interventions, prayer showed significantly worse survival (aHR, 1.56; 95% CI, 1.00-2.43). Clinically, CAM users reported significantly worse cognitive functioning (-11.6 versus -1.3; P < 0.05) and fatigue (9.9 versus -1.0; P < 0.05) than nonusers. Compared with nonusers in subgroup analysis, users of alternative medical treatments, prayer, vitamin supplements, mushrooms, or rice and cereal reported clinically significant worse changes in some HRQOL subscales. CONCLUSION: While CAM did not provide any definite survival benefit, CAM users reported clinically significant worse HRQOLs.

Effects of celecoxib on hematoma and edema volumes in primary intracerebral hemorrhage: a multicenter randomized controlled trial.

BACKGROUND AND PURPOSE: We investigated the effect of celecoxib, a selective inhibitor of cyclo-oxygenase 2, in patients with intracerebral hemorrhage (ICH). METHODS: We conducted a multicenter, randomized, controlled, and open with blinded end-point trial of 44 Korean patients 18 years or older with ICH within 24 h of onset. The intervention group (n = 20) received celecoxib (400 mg twice a day) for 14 days. The control group (n = 24) received the standard medical treatment for ICH. The primary end-point was the number of patients with a change in the volume of perihematomal edema (PHE) from the 1st to the 7th ± 1 day (cut-off value, 20%). RESULTS: The time from onset to computed tomography scan slightly differed between groups (177 ± 160 min for control vs. 297 ± 305 min for the celecoxib group; P = 0.10). In the primary end-point analysis using cut-off values, there was a significant shift to reduced expansion of PHE in the celecoxib group (P = 0.005). With respect to the secondary end-points, there was also a significant shift to reduced expansion of ICH in the celecoxib group (P = 0.046). In addition, the expansion rate of PHE at follow-up tended to be higher in the control group than in the celecoxib group (90.6 ± 91.7% vs. 44.4 ± 64.9%; P = 0.058). CONCLUSIONS: In our small, pilot trial, administration of celecoxib in the acute stage of ICH was associated with a smaller expansion of PHE than that observed in controls.

Percolated pore networks of oxygen plasma-activated multi-walled carbon nanotubes for fast response, high sensitivity capacitive humidity sensors.

We report on the preparation of capacitive-type relative humidity sensors incorporating plasma-activated multi-wall carbon nanotube (p-MWCNT) electrodes and on their performance compared with existing commercial technology. Highly open porous conductive electrodes, which are almost impossible to obtain with conventional metal electrodes, are fabricated by spray-depositing MWCNT networks on a polyimide layer. Oxygen plasma activation of the MWCNTs is also explored to improve the water adsorption of the MWCNT films, by introducing oxygen-containing functional groups on the CNT surface. Polyimide humidity sensors with optimized p-MWCNT network electrodes exhibit exceptionally fast response times (1.5 for adsorption and 2 s for desorption) and high sensitivity (0.75 pF/% RH). These results may be partially due to their percolated pore structure being more accessible for water molecules, expending the diffusion of moisture to the polyimide sensing film, and partially due to the oxygenated surface of p-MWCNT films, allocating more locations for adsorption or attraction of water molecules to contribute to the sensitivity.

Comparative analysis of virulence factors secreted by Bacillus anthracis Sterne at host body temperature.

AIMS: For the analysis of virulence factors produced and secreted by Bacillus anthracis vegetative cells during mammalian host infection, we evaluated the secretome of B. anthracis Sterne exposed to host-specific factors specifically to host body temperature. METHODS AND RESULTS: We employed a comparative proteomics-based approach to analyse the proteins secreted by B. anthracis Sterne under host-specific body temperature conditions. A total of 17 proteins encoded on a single chromosome and the pXO1 plasmid were identified by peptide mass fingerprinting. Multiple algorithms were used to predict the secretion mechanisms of the detected proteins in B. anthracis. CONCLUSIONS: Several putative virulence factors and known factors responsible for sporulation were differentially regulated, including CodY, pXO1-130 and BA1952, revealing insights into temperature cues in the B. anthracis secretome. SIGNIFICANCE AND IMPACT OF THE STUDY: This study identified temperature-regulated proteins. Further studies aimed at understanding the physical and functional roles of these proteins in infection and control by elevated temperatures will contribute to detection, diagnostics and prophylaxis.

Industrial production of fructooligosaccharides by immobilized cells of Aureobasidium pullulans in a packed bed reactor.

Continuous production of fructooligosaccharides (FOS) by Aureobasidium pullulans immobilized on calcium alginate beads with a packed bed was investigated at a plant scale reactor. Optimum conditions were with 770 g sucrose/l, being fed at 200 l/h at 50°C which gave a productivity of 180 g FOS/l h. Initial activity was maintained for more than 100 days. The reactor was successfully scaled up to a production scale of 1.2 m(3).

Potential role of CMPK1, SLC29A1, and TLE4 polymorphisms in gemcitabine-based chemotherapy in HER2-negative metastatic breast cancer patients: pharmacogenetic study results from the prospective randomized phase II study of eribulin plus gemcitabine versus paclitaxel plus gemcitabine (KCSG-BR-13-11).

BACKGROUND: In this study, we evaluated the association between genetic polymorphisms of 23 genes associated with gemcitabine metabolism and the clinical efficacy of gemcitabine in breast cancer patients. PATIENTS AND METHODS: This prospective, pharmacogenetic study was conducted in cooperation with a phase II clinical trial. A total of 103 genetic polymorphisms of the 23 genes involved in gemcitabine transport and metabolism were selected for genotyping. The associations of genetic polymorphisms with overall survival, progression-free survival (PFS), and 6-month PFS were analyzed. RESULTS: A total of 91 breast cancer patients were enrolled in this study. In terms of 6-month PFS, rs1044457 in CMPK1 was the most significant genetic polymorphism [55.9% for CT and TT and 78.9% for CC, P < 0.001, hazard ratio (HR): 4.444, 95% confidence interval (CI): 1.905-10.363]. For the rs693955 in SLC29A1, the median duration of PFS was 5.4 months for AA and 10.5 months for CA and CC (P = 0.002, HR: 3.704, 95% CI: 1.615-8.497). For the rs2807312 in TLE4, the median duration of PFS was 5.7 months for TT and 10.4 months for CT and CC (P = 0.005, HR: 4.948, 95% CI: 1.612-15.190). In survival analysis with a multi-gene model, the TT genotype of rs2807312 had the worst PFS regardless of other genetic polymorphisms, whereas the CA genotype of rs693955 or the CT genotype of rs2807312 without the AA genotype of rs693955 had the best PFS compared with those of other genetic groups (P < 0.001). CONCLUSIONS: Genetic polymorphisms of rs1044457 in CMPK1, rs693955 in SLC29A1, and rs2807312 in TLE4 were significantly associated with the 6-month PFS rate and/or the duration of PFS. Further studies with a larger sample size and expression study would be helpful to validate the association of genetic polymorphisms and clinical efficacy of gemcitabine.

Immune regulatory effects of simvastatin on regulatory T cell-mediated tumour immune tolerance.

Statins are potent inhibitors of hydroxyl-3-methylglutaryl co-enzyme A (HMG-CoA) reductase, and have emerged as potential anti-cancer agents based on preclinical evidence. In particular, compelling evidence suggests that statins have a wide range of immunomodulatory properties. However, little is known about the role of statins in tumour immune tolerance. Tumour immune tolerance involves the production of immunosuppressive molecules, such as interleukin (IL)-10, transforming growth factor (TGF)-beta and indoleamine-2,3-dioxygenase (IDO) by tumours, which induce a regulatory T cell (T(reg)) response. In this study, we investigated the effect of simvastatin on the production of IL-10, TGF-beta and IDO production and the proliferation of T(regs) using several cancer cell lines, and Lewis lung cancer (3LL) cells-inoculated mouse tumour model. Simvastatin treatment resulted in a decrease in the number of cancer cells (3LL, A549 and NCI-H292). The production of the immune regulatory markers IL-10, TGF-beta in 3LL and NCI-H292 cells increased after treatment with simvastatin. The expression of IDO and forkhead box P3 (FoxP3) transcription factor was also increased in the presence of simvastatin. In a murine 3LL model, there were no significant differences in tumour growth rate between untreated and simvastatin-treated mice groups. Therefore, while simvastatin had an anti-proliferative effect, it also exhibited immune tolerance-promoting properties during tumour development. Thus, due to these opposing actions, simvastatin had no net effect on tumour growth.

Tissue microarray-based study of patients with lymph node-negative breast cancer shows that HER2/neu overexpression is an important predictive marker of poor prognosis.

BACKGROUND: Despite good prognosis in most cases of lymph node (LN)-negative breast cancer, individual patients may have markedly different clinical outcomes. Here, we investigated the prognostic significance of HER2/neu overexpression in these tumors. MATERIALS AND METHODS: We employed a tissue microarray to examine HER2/neu overexpression by immunohistochemical staining in 359 consecutive patients diagnosed with LN-negative breast cancer, who underwent surgery from January 1993 to December 1998. RESULTS: HER2/neu overexpression was detected in 81 of 359 (23.1%) patients. The 10-year disease-free survival (DFS) values (81.2% versus 61.8%, P value 0.000) and overall survival (OS) rates (85.7% versus 63.9%, P value 0.000) were significantly different between cases with HER2/neu-negative or HER2/neu-positive tumors. After multivariate analysis, HER2/neu status and tumor size were identified as independent prognostic factors for 10-year OS. Moreover, HER2/neu overexpression was significantly associated with poorer clinical outcomes in an intermediate-risk group identified by the St Gallen classification (10-year DFS, 79.6% versus 61.8%, P value 0.000; 10-year OS, 84.7% versus 63.9%, P value 0.000). CONCLUSIONS: Our results show that HER2/neu overexpression is an important independent prognostic factor for LN-negative breast cancer cases and support the theory that more intensive adjuvant chemotherapy is required in the population with HER2/neu overexpression.

Mutational analysis of JAK1 gene in human hepatocellular carcinoma.

UNLABELLED: The Janus kinase 1 (JAK1) gene encodes a cytoplasmic tyrosine kinase that is noncovalently associated with a variety of cytokine receptors and plays a nonredundant role in cell proliferation, survival, and differentiation. The mutated forms of JAK1 often altered the activation of JAK1 and then changed the activation of JAK1/STAT pathways, and this may contribute to cancer development and progression. Thus, to investigate whether genetic mutations of JAK1 gene are associated in hepatocellular carcinoma (HCC) progression, we analyzed genetic alterations of JAK1 gene in 84 human HCCs by single-strand conformational polymorphism (SSCP) and direct sequencing. Of 24 exons of JAK1 gene, 12 exons were previously reported to have mutations, we searched genetic alteration of JAK1 in these exons. Overall, one missense mutation (1.2%) was found. In addition, 12 cases (14%) were found to have single nucleotide polymorphism (14%) in exon 14. Taken together, we found one novel missense mutation of JAK1 gene in hepatocellular carcinomas with some polymorphisms. Although the functional assessment of this novel mutant remains to be completed, JAK1 mutation may contribute to the tumor development in liver cancer. KEYWORDS: JAK1 gene, hepatocellular carcinoma, mutation.

Low frequency mutation of the Ephrin receptor A3 gene in hepatocellular carcinoma.

EphA3 is a component of the Eph/ephrin tyrosine kinase system, which participates in vasculature development. This receptor/ligand system is associated with various signaling pathways related to cell growth and viability, cytoskeletal organization, cell migration, and anti-apoptosis. Accumulated evidence suggests that aberrant regulation of EphA3 and its genetic alterations are implicated in the development and progression of various cancers. However, despite a high incidence of EphA3 over-expression, no such investigation has been performed in hepatocellular carcinoma. Thus, we investigated genetic alterations of the EphA3 gene in 73 cases of hepatocellular carcinoma by single-strand conformational polymorphism and sequencing. One novel D219V missense mutation was found in the extracellular domain of EphA3, and two genetic alterations in the intracellular sterile-alpha-motif (SAM) domain of EphA3 appeared to be polymorphisms. Although the functional assessments of this mutant are incomplete, it is believed that this novel EphA3 mutation may contribute to the development of hepatocellular carcinoma.