Pentamidine reduces expression of hypoxia-inducible factor-1α in DU145 and MDA-MB-231 cancer cells

Pentamidine is an aromatic diamine used for the treatment of human protozoa infections. Recently, pentamidine has been reported to exhibit anticancer properties. In this study, we report that pentamidine inhibits expression of hypoxia-inducible factor (HIF)-1α in cancer cells. Pentamidine decreased HIF-1α protein translation and enhanced its protein degradation in DU145 prostate cancer and MDA-MB-231 breast cancer cells. In parallel with reduction of de novo synthesis of HIF-1α, pentamidine was able to suppress global protein translation, an effect accompanied by the reduction of eIF4F complex formation and also the induction of eIF2α phosphorylation. These results show that pentamidine is a potential inhibitor of HIF-1α and its potential as a cancer therapeutic reagent warrants further study.     

Phase II study of erlotinib for chemotherapy-na?ve patients with advanced or metastatic non-small cell lung cancer who are ineligible for platinum doublets

Purpose

This phase II study evaluated efficacy of single-agent erlotinib for chemotherapy-na?ve patients with advanced/metastatic NSCLC who were ineligible for platinum doublets.

Methods

Chemotherapy-naive patients but ineligible for platinum doublets (aged 18?C75 with an ECOG performance status [PS] 2?C3; or aged 76 or older with an ECOG PS 1?C3) were enrolled and treated with erlotinib 100?mg once daily till disease progression, unacceptable toxicity or patient??s refusal.

Results

Out of 24 patients enrolled, 5 reached a PR, giving an overall response rate of 21%, but all responders were never-smokers with adenocarcinoma. According to EGFR mutation status, PR was observed in two of three patients having mutant EGFR (67%) but in one of nine having wild-type EGFR (11%). With a median follow-up of 22.6?months, the median progression-free and overall survival was 1.5?months and 3.2?months, respectively. All responders to post-erlotinib chemotherapy had responded to prior erlotinib.

Conclusions

For unselected chemotherapy-na?ve Asian patients with NSCLC but ineligible for platinum doublets, empirical use of upfront erlotinib could not be recommended because of poor survival outcome. However, this can be given to selected subsets based on molecular or clinical predictors.     

Interleukin-1β (IL-1β) increases pain behavior and the blood glucose level: possible involvement of sympathetic nervous system

The relationship between interleukin-1β (IL‐1β)‐induced nociception and the blood glucose level was studied in ICR mice. We found in the present study that intrathecal (i.t.) injection of IL‐1β increased pain behavior. In addition, i.t. IL‐1β injection caused an elevation of the blood glucose level. The time‐course study showed that maximal blood glucose level was observed 30 and 60 min after i.t. IL‐1β administration. Furthermore, i.t. injection of IL‐1β enhanced the blood glucose level when mice were orally fed with d‐glucose. The i.t. administration of IL‐1β antagonist (AF12198) inhibited the hyperglycemia and pain behaviors induced by IL‐1β. We found in the present study that adrenal tyrosine hydroxylase (TH) mRNA level was also increased by i.t. IL‐1β injection. Furthermore, intraperitoneal (i.p.) pretreatment with phentolamine (an α₁‐adrenergic blocker) or yohimbine (an α₂‐adrenergic blocker) significantly attenuated the blood glucose level and pain behavior induced by IL‐1β administered i.t. However, the blood glucose level and pain behavior were not affected by butoxamine (a β₂-adrenergic blocker), whereas metoprolol (a β₂-adrenergic blocker) enhanced IL‐1β-induced blood glucose level and pain behavior in mice fed with d‐glucose. However, its effect was not statistically significant. Our results suggest that IL‐1β administered i.t. increases the blood glucose level via an activation of α adrenergic nervous system.     

Novel ELANE gene mutation in a Korean girl with severe congenital neutropenia

Severe congenital neutropenia is a heterozygous group of bone marrow failure syndromes that cause lifelong infections. Mutation of the ELANE gene encoding human neutrophil elastase is the most common genetic alteration. A Korean female pediatric patient was admitted because of recurrent cervical lymphadenitis without abscess formation. She had a past history of omphalitis and isolated neutropenia at birth. The peripheral blood showed a markedly decreased absolute neutrophil count, and the bone marrow findings revealed maturation arrest of myeloid precursors at the promyelocyte to myelocyte stage. Her direct DNA sequencing analysis demonstrated an ELANE gene mutation (c.607G > C; p.Gly203Arg), but her parents were negative for it. She showed only transient response after subcutaneous 15 μg/kg/day of granulocyte colony stimulating factor administration for six consecutive days. During the follow-up observation period, she suffered from subsequent seven febrile illnesses including urinary tract infection, septicemia, and cellulitis.     

Prevalence of allergic diseases among Korean school-age children: a nationwide cross-sectional questionnaire study

The purpose of this study was to investigate the nationwide prevalence of childhood asthma, eczema and other allergic diseases in Korean school-age children (8-11 yr old) and to assess the difference between residential areas. Among 6,279 elementary schools, 427 schools were randomly selected according to residential area (metropolitan, provincial, rural, and industrial area) by the cluster sampling method. Parents of students completed a modified Korean version of a questionnaire formulated by the International Study of Asthma and Allergies in Childhood (ISAAC). Among 50,200 subjects, 31,026 (61.8%) responded, and 30,893 (99.6%) were analyzed. The 12-month prevalence of wheeze, flexural rash, and allergic rhinitis symptoms were 4.8%, 15.3%, and 32.9%, respectively. The prevalence of diagnosis of allergic diseases in boys was higher than that in girls, with the exception of eczema. In both boys and girls, the difference of the prevalence of allergic diseases among industrial, metropolitan and provincial areas was not statistically significant, but the differences between rural area and other areas were significant. Our results support the importance of contextual effect associated with residential area as causative agents of allergic diseases among Korean school-age children.     

Association between body mass index and asthma symptoms among Korean children: a nation-wide study

The purpose of this study was to investigate the association between body mass index (BMI) and the prevalence of wheeze using nation-wide cross-sectional study in Korean children. Total 50,200 children from 427 elementary schools were randomly selected according to residential areas (metropolitan, provincial, rural, and industrial areas) by the cluster sampling method. The International Study of Asthma and Allergies in Childhood (ISAAC) questionnaires were used to measure the prevalence of wheeze. Among 31,026 respondents, 25,322 were analyzed. BMI was classified into quartiles based on BMI-for-age percentile. In all residential areas, pets at home and visible mold or moisture were associated with an increased prevalence of wheeze in both genders. However, other living environment factors were not consistently associated among residential areas and gender. Among girls, lowest BMI was negatively associated with prevalence of wheeze and highest BMI was positively associated in all residential areas. In multilevel logistic regression analysis, environmental tobacco smoking exposure, pets at home, visible mold or moisture, and being in the lowest and highest BMI quartile were significantly associated with the prevalence of wheeze in both genders. BMI has become an important risk factor for asthma symptoms among Korean children.     

Relationship between chronic kidney disease and risk of coronary heart disease in Korean men

There have been many epidemiological researches of chronic kidney disease (CKD), accompanied by an increase in the incidence of coronary heart disease (CHD). However, as far as we know, little research has been done to examine the extent of the relationship between CKD and CHD as estimated by Framingham risk score (FRS) in Korean men. CKD was defined as either proteinuria or an eGFR of < 60 mL/min per 1.73 m(2). The FRS has been used to predict the 10-yr risk of coronary events and usually divided into three levels of risk < 10% (low), 10%-19% (intermediate) and ≥ 20% (high). We defined FRS ≥ 10% as more-than-a-moderate CHD risk group and FRS ≥ 20% as a high CHD risk group, respectively. After adjusting for covariates, multivariable-adjusted logistic regression analyses showed a strong statistical significant relationship between CKD and high risk of CHD (adjusted OR, 1.95 [95% CI, 1.32-2.87]). Dipstick urinalysis and eGFR can be readily measured in most clinical settings. The measurement of kidney function may represent a relatively inexpensive and efficient way to identify individuals at higher risk for CHD.     

Could HBx Protein Expression Affect Signal Pathway Inhibition by Gefitinib or Selumetinib,a MEK Inhibitor,in Hepatocellular Carcinoma Cell Lines?

Hepatitis B virus X (HBx) protein has been known to play an important role in development of hepatocellular carcinoma (HCC). The aim of this study is to find out whether HBx protein expression affects antiproliferative effect of an epidermal growth factor receptor-tyrosine kinase (EGFR-TK) inhibitor and a MEK inhibitor in HepG2 and Huh-7 cell lines. We established HepG2 and Huh-7 cells transfected stably with HBx gene. HBx protein expression increased pERK and pAkt expression as well as β-catenin activity in both cells. Gefitinib (EGFR-TK inhibitor) inhibited pERK and pAkt expression and β-catenin activity in both cells. Selumetinib (MEK inhibitor) reduced pERK level and β-catenin activity but pAkt expression was rather elevated by selumetinib in these cells. Reduction of pERK levels was much stronger with selumetinib than gefitinib in both cells. The antiproliferative efficacy of selumetinib was more potent than that of gefitinib. However, the antiproliferative effect of gefitinib, as well as selumetinib, was not different between cell lines with or without HBx expression. Signal pathway activation by HBx might not be strong enough to attenuate the antiproliferative effect of EGFR-TK inhibitor. Future experiments are needed to understand the role of HBx protein expression in HCC treatment using molecular targeting agent.     

Alterations in cell proliferation related gene expressions in gastric cancer

Gastric cancer remains the fourth most prevalent cancer and the second leading cause of cancer-related death in the world. The predominant form of gastric cancer is adenocarcinoma, which originates from glandular epithelium of the gastric mucosa. The major risk factors for gastric cancer include diet, individual genetic variation, and, most importantly, infection with Helicobacter pylori (H. pylori). Certain strains of H. pylori assisted by some of its virulence factors seem to play a critical role in gastric cancer development. Several of these H. pylori virulence factors, which influence cellular proliferation signaling, have been identified. In addition, changes in the expression of several cell proliferation regulating genes accompany or cause the progression of gastric cancer. These changes include modifications of cell cycle regulators, oncogene activation, tumor suppressor inactivation, and miRNA profile alterations. Many of these changes result from H. pylori infection, although their impact on the cellular proliferation system underlying gastric cancer development has not yet been fully elucidated. We review certain features of gastric cancer, the role of H. pylori infection in its etiology and pathogenesis, and gene expression changes during gastric carcinogenesis.