Stereotactic body radiotherapy for Stage I lung cancer with chronic obstructive pulmonary disease: special reference to survival and radiation-induced pneumonitis

This retrospective study aimed to evaluate radiation-induced pneumonitis (RIP) and a related condition that we define in this report—prolonged minimal RIP (pmRIP)—after stereotactic body radiotherapy (SBRT) for Stage I primary lung cancer in patients with chronic obstructive pulmonary disease (COPD). We assessed 136 Stage I lung cancer patients with COPD who underwent SBRT. Airflow limitation on spirometry was classified into four Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades, with minor modifications: GOLD 1 (mild), GOLD 2 (moderate), GOLD 3 (severe) and GOLD 4 (very severe). On this basis, we defined two subgroups: COPD-free (COPD −) and COPD-positive (COPD +). There was no significant difference in overall survival or cause-specific–survival between these groups. Of the 136 patients, 44 (32%) had pmRIP. Multivariate analysis showed that COPD and the Brinkman index were statistically significant risk factors for the development of pmRIP. COPD and the Brinkman index were predictive factors for pmRIP, although our findings also indicate that SBRT can be tolerated in early lung cancer patients with COPD.     

Antitumor-promoting constituents from Dioscorea bulbifera L. in JB6 mouse epidermal cells

An antitumor-promoting effect was found in the extracts/ingredients of a plant used as a traditional medicine in mainland China, using the neoplastic transformation assay of mouse epidermal JB6 cell lines. The ethyl acetate soluble fraction of 75% ethanol extract of the rhizomes of Dioscorea bulbifera L. showed an inhibitory effect against the tumor promotion of JB6 (Cl 22 and Cl 41) cells induced by a promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA). Further investigation on the constituents of the EtOAc fraction from the rhizomes revealed the chemical structure to be kaempferol-3,5-dimethyl ether (1), caryatin (2), (+)-catechin (3), myricetin (4), quercetin-3-O-galactopyranoside (5), myricetin-3-O-galactopyranoside (6), myricetin-3-O-glucopyranoside (7) and diosbulbin B (8). Constituent antitumor-promoting activities were also examined in the same way. Compounds 1-7, characterized as flavonoids with the two hydroxyl groups at C-7 and C-4', showed the most potent inhibitory effect, but there seemed to be differences in the inhibitory effect between flavonol aglycones and flavonol glycosides. Compared with (-)-epicatechin, (+)-catechin exhibited much stronger inhibitory activity which suggested that chemical stereo structures of compounds affect the efficiency of inhibition. Compound 8 showed moderate activity. The constituents with antitumor-promoting activity from this plant are reported for the first time.     

Enhancement of apomorphine-induced penile erection in the rat by a selective alpha(1D)-adrenoceptor antagonist

1. Effects of A-322312 (alpha(1B)-adrenoceptor (AR) antagonist), A-119637 (alpha(1D)-AR antagonist), prazosin (non-selective alpha(1)-AR antagonist), and yohimbine (alpha(2)-AR antagonist) were studied in rat corpus cavernosum (CC) and cavernous artery (Acc) preparations. Effects of intracavernous (i.c.) or intraperitoneal (i.p.) administration of alpha(1)-AR antagonists on apomorphine-induced erections were investigated. 2. A-119637 attenuated electrically induced contractions in isolated CC (-logIC(50); 8.12+/-0.15), and relaxed noradrenaline (NA)-contracted preparations by more than 90% at 10(-7) M. At the same concentration, the -logEC(50) value for NA in Acc was altered from 6.79+/-0.07 to 4.86+/-0.13. In the CC and Acc, prazosin similarly inhibited contractile responses. 3. Inhibitory effects of A-322312 (10(-7) M) in electrically activated CC were 32.3+/-5.1%, whereas no effect on concentration-response curves for NA was observed in the Acc. Yohimbine (10(-8) M and 10(-7) M), enhanced electrically-induced contractions in isolated CC by 20 to 50%. At 10(-6) M, inhibitory effects of yohimbine were obtained. 4. A-119637 (0.3 micromol kg(-1), i.p.) tripled the number of erections, and produced a 6 fold increase in the duration of apomorphine-induced erectile responses. A-322312, prazosin, or yohimbine did not enhance erections induced by apomorphine. None of the alpha(1)-AR antagonists significantly increased ICP upon i.c. administration. Decreases in blood pressure were seen with A-119637 and prazosin. 5. The present findings show that there is a functional predominance of the alpha(1D)-AR subtype in the rat erectile tissue, and that blockade of this receptor facilitates rat penile erection induced by a suboptimal dose of apomorphine.     

Association Between Serum Levels of Carotenoids and Serum Asymmetric Dimethylarginine Levels in Japanese Subjects

Background

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelium nitric oxide synthase (NOS). ADMA binds to a substrate-binding site of NOS and then inhibits nitric oxide production from vascular endothelial cells. Elevated ADMA levels are a risk factor for cardiovascular disease. Recently, it was reported that plasma ADMA levels were negatively correlated with vegetable and fruit consumption. The purpose of this study was to examine the association between serum levels of carotenoids and serum ADMA levels in Japanese subjects.

Methods

We conducted a cross-sectional study of 470 subjects (203 men and 267 women) who attended a health examination in August 2011. Serum levels of several carotenoids were separately measured by high-performance liquid chromatography. Serum ADMA levels were determined by using an enzyme-linked immunosorbent assay kit.

Results

In women, the multivariate-adjusted odds ratios (ORs) of elevated serum ADMA levels were significantly decreased in the highest tertile for β-cryptoxanthin (OR 0.47, 95% CI 0.23–0.95), α-carotene (OR 0.39, 95% CI 0.18–0.79), and β-carotene (OR 0.36, 95% CI 0.17–0.73) compared to the lowest tertile. In men, significantly decreased ORs were observed in the highest tertiles of serum zeaxanthin/lutein (OR 0.23, 95% CI 0.06–0.69) and α-carotene (OR 0.26, 95% CI 0.07–0.82), and in the middle and the highest tertiles of serum β-carotene (OR 0.27, 95% CI 0.09–0.74 and OR 0.20, 95% CI 0.03–0.88, respectively) when the tertile cutoff points of women were extrapolated to men.

Conclusions

Higher serum levels of carotenoids, such as α-carotene and β-carotene, may help to prevent elevated serum ADMA levels in Japanese subjects.Key words: asymmetric dimethylarginine, carotenoids, cross-sectional study     

Cytotoxic Activities of Major Diterpenoid Constituents of Andrographis paniculata. in a Panel of Human Tumor Cell Lines

ABSTRACT

The cytotoxic activities of several diterpenoid constituents of the medicinal plant, “hempedu bumi,” or Andrographis paniculata. Nees (Acanthaceae), were evaluated. The seven diterpenoid compounds used were andrographolide, 14-deoxyandrographolide, andrographiside, deoxyandrographiside, 14-deoxy-12-methoxyandrographolide, neoandrographolide, and 14-deoxy-11,12-didehydroandrographolide. The activities of these compounds were evaluated with various human tumor cell lines such as Caov-3 (human ovarian carcinoma cell line), T-47D (human breast carcinoma cell line), Hs-578T (human breast carcinoma cell line), Hep G2 (human hepatocarcinoma cell line), and NCI–H23 (human lung adenocarcinoma cell line). Cell survival was measured using the MTS assay after 72 h of incubation. Andrographolide, neoandrographolide, andrographiside, deoxyandrographiside, and 14-deoxy-12-methoxyandrographolide appeared to be noncytotoxic against all the cell lines. Only 14-deoxyandrographolide and 14-deoxy-11,12-didehydroandrographolide exhibited cytotoxic activities (based on EC₅₀ values), but this was limited to the T-47D cell line (EC₅₀ values of 2.8 µg/ml and 1.5 µg/ml, respectively). As one of the principle diterpenoids of Andrographis paniculata., 14-deoxy-11,12-didehydroandrographolide appeared to be the most potent when compared with the rest of the compounds examined. The effects of 14-deoxy-11,12-didehydroandrographolide on T-47D cells were further confirmed to be nonapoptotic, non-necrotic, but programmed in nature, as demonstrated using a DNA fragmentation detection assay, Trypan blue exclusion assay, and annexin V–propidium iodide staining.     

A multicenter phase II study of the stop-and-go modified FOLFOX6 with bevacizumab for first-line treatment of patients with metastatic colorectal cancer

Currently, no prospective data exists to support a "stop-and-go" modified FOLFOX6 regimen with bevacizumab in metastatic colorectal cancer (mCRC) patients. This study aimed to evaluate the efficacy and safety of this regimen in first-line mCRC patients. Eligible patients (age ≥20 years) had previously untreated mCRC; Eastern Cooperative Oncology Group performance status of 0-2; and adequate hematologic, hepatic, and renal function. The modified FOLFOX6 regimen and bevacizumab (5 mg/kg) was administered intravenously every 2 weeks. After 8 cycles, patients received maintenance therapy with simplified LV5FU2 and bevacizumab until completion of 8 cycles or disease progression. After maintenance therapy, patients received another 8 cycles of modified FOLFOX6 with bevacizumab until completion of 8 cycles or disease progression. We recruited 50 patients between August 2007 and January 2009. The overall response rate was 48% (80% confidence interval [CI]; 38.2-58) with outcomes as follows: complete response, n?=?1; partial response, n?=?23; stable disease, n?=?21; progression, n?=?1; and not evaluated, n?=?4. Median time to treatment failure was 7.7 months (80% CI: 6.2-8.0), and median progression-free survival was 12.8 months (80% CI: 10.8-14). Grade 3/4 toxicities included neutropenia (40%), nausea (4%), diarrhea (14%), thrombosis (4%), and hypertension (4%) et al. Grade 1, 2, or 3 peripheral neuropathy was reported in 38%, 40%, and 10% of patients, respectively. The stop-and-go modified FOLFOX6 and bevacizumab regimen is effective and well tolerated as first-line chemotherapy for mCRC patients.     

Effect of maternal age on mitochondrial DNA copy number, ATP content and IVF outcome of bovine oocytes

The primary aim of the present study was to examine the effect of maternal age (in months) on mitochondrial DNA copy number (Mt number), ATP content and IVF outcome of bovine oocytes. We also compared the Mt number of oocytes with fertilisation outcome and ATP content. Oocytes were collected from cows aged 20-204 months and the Mt number was determined by real-time polymerase chain reaction. The Mt number in immature and mature oocytes was determined to be 368,118 and 807,794, respectively; the ATP content in these oocytes was 1.2 and 2.0 pM, respectively. Both Mt number and ATP content increased during oocyte maturation. However, after 90 months of age, the Mt number of mature oocytes decreased with increasing maternal age, whereas the ATP content of mature oocytes was positively correlated with maternal age (P<0.01); there was no obvious relationship observed between Mt number and ATP content. Furthermore, maternal age was positively correlated with the abnormal fertilisation rate (P<0.01). Mt number and fertilisation outcome were unrelated, but the nature of this relationship differed between young (21-89 months) and old (>89 months) cows. Thus, we conclude that Mt number, the ATP content and fertilisation outcome of bovine oocytes are affected by maternal age.     

Concentrations of Organotin Compounds in Tissues and Organs of Dugongs from Thai Coastal Waters

Concentrations of butyltin (BT) and phenyltin (PT) compounds were measured in organs and tissues of dugongs (Dugong dugon) from the coastal waters of Thailand. Concentrations of BTs and PTs were in the range of 14–14,468 and <1–30 μg kg⁻¹ (detection frequency: 79%), respectively. Although concentrations of BTs in dugongs were higher then reported concentrations in cetaceans and pinnipeds, PTs were lower in dugongs. In half of the dugongs in which measurements were made, the concentration of BTs in the liver was the highest among the all the tissues and organs tested. Dibutyltin (DBT) or monobutyltin (MBT) was found to be the dominant compounds among the BTs. The distribution in the body of PTs was not clear because of the lower levels of this compound. TPT was the dominant compound among PTs. The coastal area of Thailand is located off the Gulf of Thailand and the Andaman Sea. Concentrations of organotin (OT) compounds in dugongs collected from the Gulf of Thailand were compared to those from the Andaman Sea. No significant differences in BT or PT concentrations were observed between the two areas (p < 0.05). The concentrations of BTs and PTs in the livers of dugongs were decreased between 1998 and 2002, suggesting a decrease in OT concentrations in the surrounding environment.     

Pharmacogenomics of cardiovascular pharmacology: pharmacogenomic network of cardiovascular disease models

The most important strategies in pharmacogenomics are gene expression profiling and the network analysis of human disease models. We have previously discovered novel drug target candidates in cardiovascular diseases through investigations of these pharmacogenomics. The significant induction of S100C mRNA and protein expression was detected in the rat pulmonary hypertension and myocardial infarction model. We also found increased taurine in hypoxia, a calcium-associated cytoprotective compound, to suppress the hypoxia-induced S100C gene expression and vascular remodeling. These results suggest that S100C may be one of the potential novel drug targets in hypoxic or ischemic diseases. Delayed cerebral vasospasm after aneurysmal subarachnoid hemorrhage causes cerebral ischemia and infarction. Using a DNA microarray, a prominant upregulation of heme oxygenase-1 (HO-1) and heat shock protein (HSP) 72 mRNAs were observed in the basilar artery of a murine vasospasm model. Antisense HO-1 and HSP 72 oligodeoxynucleotide inhibited HO-1 and HSP 72 induction, respectively, and significantly aggravated cerebral vasospasm. Moreover, we have also developed a unique heart failure model in zebrafish and identified several candidate genes as novel drug targets. These results suggest that pharmacogenomic network analysis has the potential to bridge the gap between in vitro and in vivo studies and could define strategies for identifying novel drug targets in various cardiovascular diseases.     

Dose‐finding study of the checkpoint kinase 1 inhibitor,prexasertib, in Japanese patients with advanced solid tumors

Prexasertib is a novel inhibitor of checkpoint kinase 1. The primary objective of this study was to evaluate prexasertib tolerability in Japanese patients with advanced solid tumors. This nonrandomized single‐arm open‐label phase 1 study of prexasertib consisted of 2 dose levels, 80 mg/m² and the global‐recommended dose based on a US study of 105 mg/m², administered intravenously once every 14 days (n = 6 for each dose). Transition to the higher dose proceeded if the frequency of dose‐limiting toxicity observed in cycle 1 was <33% at the lower dose. Safety measures, pharmacokinetics and antitumor activity were assessed. A total of 12 patients were treated. Two patients, one in each dose group, experienced dose‐limiting toxicities of febrile neutropenia, one grade 4 and the other grade 3; both patients recovered and continued the study treatment. The grade 4 treatment‐emergent adverse events related to study treatment were neutropenia (6 patients [50.0%]), leukopenia (4 patients [33.3%]), and 1 instance each (8.3%) of anemia, febrile neutropenia and thrombocytopenia. Neutropenia was generally transient and reversible; 11 patients (91.7%) required granulocyte colony‐stimulating factor treatment during the study. There were no discontinuations due to adverse events or deaths. The prexasertib pharmacokinetics displayed dose‐independent and time‐independent behavior across both dose levels, similar to the profile observed in the US‐based phase 1 study. Eight patients had a best overall response of stable disease. These data are consistent with the known safety profile for prexasertib and confirm its tolerability in Japanese patients with advanced solid tumors.