Glyoxalase 1 (GLO1) is a ubiquitous enzyme involved in the detoxification of methylglyoxal, a cytotoxic byproduct of glycolysis that induces apoptosis. In this study, we found that GLO1 gene expression correlates with neoplasm histologic grade (χ2 test, p = 0.002) and is elevated in human basal-like breast cancer tissues. Approximately 90% of basal-like cancers were grade 3 tumors highly expressing both GLO1 and the cancer stem cell marker ALDH1A3. ALDH1high cells derived from the MDA-MB 157 and MDA-MB 468 human basal-like breast cancer cell lines showed elevated GLO1 activity. GLO1 inhibition using TLSC702 suppressed ALDH1high cell viability as well as the formation of tumor-spheres by ALDH1high cells. GLO1 knockdown using specific siRNAs also suppressed ALDH1high cell viability, and both TLSC702 and GLO1 siRNA induced apoptosis in ALDH1high cells. These results suggest GLO1 is essential for the survival of ALDH1-positive breast cancer stem cells. We therefore conclude that GLO1 is a potential therapeutic target for treatment of basal-like breast cancers.

c-Met is a receptor-type tyrosine kinase, which is involved in a wide range of cellular responses such as proliferation, motility, migration and invasion. It has been reported to be overexpressed in various cancers. However, the role of c-Met in breast cancer stem cells (CSCs) still remains unclear. We herein, show that c-Met expression is significantly elevated in Basal-like type of breast cancer in comparison with other subtypes. High expression of c-Met strongly correlated with the expression of two CSC markers, ALDH1A3 and CD133 in breast cancers. In addition, breast cancers at tumor stage III-IV expressing both c-Methigh and ALDH1A3high had poor prognosis. Furthermore, treatment with c-Met inhibitors (Crizotinib, Foretinib, PHA-665752 and Tivantinib) in MDA-MB157 cells with high c-Met protein expression resulted in significant suppression in cell viability, contrary to MDA-MB468 cells with low c-Met protein expression. These c-Met inhibitors also suppressed cell viability and tumor-sphere formation of ALDH1high breast cancer cells with high c-Met expression. These results suggest that c-Met in ALDH1 positive CSCs seems to play an important role in breast cancer repopulation. Therefore, we conclude that c-Met is a potential therapeutic target in ALDH1 positive breast CSCs.

No abstract

Hepatitis C virus (HCV) is one of the most common causes of chronic hepatitis. Interferon is presently the only effective treatment for chronic hepatitis C (CH-C), though its effectiveness is limited. Lactoferrin (LF), which is an 80-kDa, iron-binding glycoprotein, has several biological activities including anti-viral activity, and it was recently reported to inhibit HCV infection in cultured human hepatocytes. The present trial was designed to assess the relationship between the dose of bovine LF (bLF) and the effect of bLF on serum alanine aminotransaminase (ALT) and HCV RNA levels in patients with CH-C. Forty-five patients entered at each of the three dose levels (bLF of 1.8, 3.6, and 7.2 g/day) received orally an 8-week course of bLF. There was no significant relation between the dose of bLF and the effect of bLF on serum ALT or HCV RNA levels. Biochemical (a 50% or greater decrease in the serum ALT level) and virological (a 50% or greater decrease in HCV RNA level) responses were observed in two and four patients, respectively, but all responders relapsed during the follow-up period after bLF treatment. The bLF treatment was generally well tolerated, and no patient had any serious adverse event. In conclusion, the excellent tolerance and potential anti-HCV activity of bLF shown in this trial suggest that further trials using a large number of patients are mandatory. We are currently conducting a double-blind randomized controlled trial comparing bLF with placebo to clarify the anti-HCV activity of bLF in patients with CH-C.

No abstract

Several studies have suggested that lactoferrin administration may decrease the serum level of hepatitis C virus (HCV) RNA in patients with chronic hepatitis C. The aim of the present study was to confirm the efficacy of orally administered bovine lactoferrin (bLF) in patients with chronic hepatitis C. The patients with chronic hepatitis C randomly received either oral bLF at a dose of 1.8 g daily for 12 weeks, or an oral placebo. The primary endpoint was the virologic response, defined as a 50% or greater decrease in serum HCV RNA level at 12 weeks compared with the baseline. The secondary endpoint was the biochemical response, which was defined as a 50% or greater decrease in the serum alanine aminotransferase (ALT) level at 12 weeks compared with the baseline. One hundred and ninetyeight of 199 patients were evaluable for efficacy and safety. bLF treatment was well tolerated and no serious toxicities were observed. A virologic response was achieved in 14 of 97 patients H epatitis C virus is a leading cause of chronic liver disease in Japan, and nearly two million people are estimated to be infected.(1) It is well known that HCV infection frequently causes chronic hepatitis, and that chronic hepatitis eventually progresses to liver cirrhosis and HCC approximately 30 years after HCV infection.(2) In Japan, more than 30 000 people die of HCC annually, and approximately 80% of HCC patients are infected with HCV.(3) Therefore, effective anti-HCV therapy is necessary to reduce the number of patients suffering from cirrhosis or HCC. To date, interferon-based therapy is the only effective treatment used clinically for chronic hepatitis C. A sustained complete virologic response (loss of detectable serum HCV RNA) occurs in 15-20% of patients with chronic hepatitis C after interferon therapy.(4) Moreover, recent studies have demonstrated that interferon with ribavirin or peginterferon with ribavirin improves the sustained complete virologic response rate by up to 40-50%. (5,6) However, because more than half of patients do not respond to interferon therapy, and because interferon therapy sometimes induces strong adverse effects, further developments in the treatment of chronic hepatitis C are required.Lactoferrin, a member of the transferrin family of ironbinding glycoproteins, is present mainly in breast milk and other exocrine secretions. Several biological activities of lactoferrin have been demonstrated, including regulation of iron absorption in the intestine and modulation of immunoreactions.(7) Lactoferrin also plays an important role in human innate defense mechanisms against bacteria, fungi and viruses. (8) In vitro studies to date have shown that lactoferrin has antiviral effects against human immunodeficiency virus-1 and human cytomegalovirus.(9) Recent experimental studies have suggested that lactoferrin has antiviral effect against HCV.(10 -12) Yi et al. have reported that lactoferrin binds to HCV envelope proteins in vitro.(10) Ikeda et al. have reported that lactoferrin prevents HCV infection in cultured...

Approximately one in three persons will develop herpes zoster during their lifetime, and it can lead to serious complications such as postherpetic neuralgia. However, evidence on burden of herpes zoster and postherpetic neuralgia in Japan is limited. This prospective, observational, multicenter, physician practice‐based cohort study was conducted in Kushiro, Hokkaido, Japan (Clinicaltrials.gov identifier NCT01873365) to assess the incidence and hospitalization rates of herpes zoster, and the proportion, clinical burden and risk factors for postherpetic neuralgia in adults aged 60 years or more. Within the study area, 800 subjects developed herpes zoster and 412 were eligible for the study. Herpes zoster incidence was 10.2/1000 person‐years and higher among women and older subjects. Subjects with herpes zoster required on average 5.7 outpatient consultations. Herpes zoster‐associated hospitalization rate was 3.4% (27/800). The proportion of postherpetic neuralgia and other complications was 9.2% (38/412) and 26.5% (109/412), respectively. Statistically significant association with the development of postherpetic neuralgia was male sex (odds ratio [OR], 2.51; 95% confidence interval [CI], 1.17–5.38), age of 70–74 years (OR, 3.51; 95% CI, 1.09–11.3), immunosuppressive therapy (OR, 6.44; 95% CI, 1.26–32.9), severe herpes zoster pain at first consultation (OR, 3.08; 95% CI, 1.10–8.62) and rash on upper arms (vs no rash on upper arms; OR, 3.46; 95% CI, 1.10–10.9). Considerable herpes zoster and postherpetic neuralgia burden exists among elderly in Japan, and there may be predictive factors at the first visit which could be indicative of the risk of developing postherpetic neuralgia.

No abstract