Down-regulation of α-L-fucosidase 1 expression confers inferior survival for triple-negative breast cancer patients by modulating the glycosylation status of the tumor cell surface

α-L-fucosidase 1 (FUCA1) is a lysosomal enzyme that catalyzes the hydrolytic cleavage of the terminal fucose residue in breast cancer cells. FUCA1 mRNA levels were detected by real-time PCR, and there was a greater than 139-fold increase in FUCA1 mRNA expression in breast tumor samples compared with normal breast tissue samples (*P = 0.005, n = 236). Higher FUCA1 mRNA expression was preferentially detected in early-stage tumors (stage 0 to 2) compared with advanced-stage tumors (stage 3 to 4) (stage 0-1 versus stage 3, *P = 0.015; stage 0-1 versus stage 4, *P = 0.024). FUCA1 protein levels were higher in advanced-stage tumors concomitant with decreased fucosylated Lewis-x antigen expression, as evidenced using the immunohistochemical staining H-score method (*P < 0.001). Statistical analysis revealed that lower FUCA1 levels significantly predicted an inferior overall survival rate among triple-negative breast cancer (TNBC) patients compared with non-TNBC patients (*P = 0.009). Two stable FUCA1 siRNA knock-down MDA-MB-231 cell lines were established, and the results suggest that transient FUCA inhibition creates a selective pressure that triggers the metastasis of primary tumor cells, as detected by wound healing and invasion assays (*P < 0.01). The results suggest that FUCA1 may be a potential prognostic molecular target for clinical use, especially in TNBC patients.     

Novel computed tomographic chest metrics to detect pulmonary hypertension

Background  

Early diagnosis of pulmonary hypertension (PH) can potentially improve survival and quality of life. Detecting PH using echocardiography is often insensitive in subjects with lung fibrosis or hyperinflation. Right heart catheterization (RHC) for the diagnosis of PH adds risk and expense due to its invasive nature. Pre-defined measurements utilizing computed tomography (CT) of the chest may be an alternative non-invasive method of detecting PH.     

Treatment Planning and Volumetric Response Assessment for Yttrium-90 Radioembolization: Semiautomated Determination of Liver Volume and Volume of Tumor Necrosis in Patients with Hepatic Malignancy

Purpose

The primary purpose of this study was to demonstrate intraobserver/interobserver reproducibility for novel semiautomated measurements of hepatic volume used for Yttrium-90 dose calculations as well as whole-liver and necrotic-liver (hypodense/nonenhancing) tumor volume after radioembolization. The secondary aim was to provide initial comparisons of tumor volumetric measurements with linear measurements, as defined by Response Evaluation Criteria in Solid Tumors criteria, and survival outcomes.

Methods

Between 2006 and 2009, 23 consecutive radioembolization procedures were performed for 14 cases of hepatocellular carcinoma and 9 cases of hepatic metastases. Baseline and follow-up computed tomography obtained 1?month after treatment were retrospectively analyzed. Three observers measured liver, whole-tumor, and tumor-necrosis volumes twice using semiautomated software.

Results

Good intraobserver/interobserver reproducibility was demonstrated (intraclass correlation [ICC]?>?0.9) for tumor and liver volumes. Semiautomated measurements of liver volumes were statistically similar to those obtained with manual tracing (ICC?=?0.868), but they required significantly less time to perform (p?<?0.0001, ICC?=?0.088). There was a positive association between change in linear tumor measurements and whole-tumor volume (p?<?0.0001). However, linear measurements did not correlate with volume of necrosis (p?>?0.05). Dose, change in tumor diameters, tumor volume, and necrotic volume did not correlate with survival (p?>?0.05 in all instances). However, Kaplan?CMeier curves suggest that a >10% increase in necrotic volume correlated with survival (p?=?0.0472).

Conclusion

Semiautomated volumetric analysis of liver, whole-tumor, and tumor-necrosis volume can be performed with good intraobserver/interobserver reproducibility. In this small retrospective study, measurements of tumor necrosis were suggested to correlate with survival.     

Increased expression of enolase α in human breast cancer confers tamoxifen resistance in human breast cancer cells

Enolase-α (ENO-1) is a key glycolytic enzyme that has been used as a diagnostic marker to identify human lung cancers. To investigate the role of ENO-1 in breast cancer diagnosis and therapy, the mRNA levels of ENO-1 in 244 tumor and normal paired tissue samples and 20 laser capture-microdissected cell clusters were examined by quantitative real-time PCR analysis. Increased ENO-1 mRNA expression was preferentially detected in estrogen receptor-positive (ER+) tumors (tumor/normal ratio >90-fold) when compared to ER-negative (tumor/normal ratio >20-fold) tumor tissues. The data presented here demonstrate that those patients whose tumors highly expressed ENO-1 had a poor prognosis with greater tumor size (>2 cm, *P = .017), poor nodal status (N > 3, *P = .018), and a shorter disease-free interval (≦1 year, *P < .009). We also found that higher-expressing ENO-1 tumors confer longer distance relapse (tumor/normal ratio = 82.8–92.4-fold) when compared to locoregional relapse (tumor/normal ratio = 43.4-fold) in postsurgical 4-hydroxy-tamoxifen (4-OHT)-treated ER+ patients (*P = .014). These data imply that changes in tumor ENO-1 levels are related to clinical 4-OHT therapeutic outcome. In vitro studies demonstrated that decreasing ENO-1 expression using small interfering RNA (siRNA) significantly augmented 4-OHT (100 nM)-induced cytotoxicity in tamoxifen-resistant (Tam-R) breast cancer cells. These results suggest that downregulation of ENO-1 could be utilized as a novel pharmacological approach for overcoming 4-OHT resistance in breast cancer therapy.     

Oestrogen receptor-regulated glutathione S-transferase mu 3 expression attenuates hydrogen peroxide-induced cytotoxicity,which confers tamoxifen resistance on breast cancer cells

Purpose

Women with ductal carcinoma in situ (DCIS) or early-stage breast cancer have an excellent prognosis, but their risk of developing second malignant neoplasms (SMNs) is not well established. We analyzed SMNs in a large cohort with long follow-up after breast conservation therapy.

Methods

The study population comprised 755 women with DCIS (n = 135) or stage I-II breast carcinoma (n = 620). Subjects were aged 25-89 (median 55) years when they underwent breast-conserving surgery followed by radiotherapy to the entire breast (60-68Gray) between 1992 and 2001. Additional treatment included hormonal therapy and/or chemotherapy based on clinical characteristics. SMNs were grouped by site. The rate of SMNs over time was determined using the Kaplan–Meier method. To compare the probability of developing SMNs overall and for specific organs or sites, probability estimates were obtained for a 55-year-old female from the Surveillance, Epidemiology, and End Results Program (SEER).

Results

Median follow-up from radiotherapy was 13.8 years. The 15-year age-adjusted probability of developing any SMN was 12.0%, close to the SEER rate of 12.1% for a non-breast malignancy. Systemic therapy and higher-dose radiotherapy (> 63 Gray) were not associated with significantly increased risks of SMNs. Compared to SEER, significantly increased risk was noted for gynecologic cancers and melanoma.

Conclusions

Most SMNs were unrelated to treatment, and the 15-year incidence was similar to that of cancer in the SEER control group—findings that should be reassuring to patients. Further risk reduction is expected from prophylactic gynecologic surgery. Continued investigations into genetic links with melanoma are warranted.

     

Development of antiviral agents for enteroviruses

Enteroviruses (EVs) are common human pathogens that are associated with numerous disease symptoms in many organ systems of the body. Although EV infections commonly cause mild or non-symptomatic illness, some of them are associated with severe diseases such as CNS complications. The current absence of effective vaccines for most viral infection and no available antiviral drugs for the treatment of EVs highlight the urgency and significance of developing antiviral agents. Several key steps in the viral life cycle are potential targets for blocking viral replication. This article reviews recent studies of antiviral developments for EVs based on various molecular targets that interrupt viral attachment, viral translation, polyprotein processing and RNA replication.