Anti-inflammatory effects of dihydrobenzofuran neolignans isolated from Euonymus alatus leaves and twigs were evaluated in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells. Six neolignans, (+)- simulanol (1), (+)-dehydrodiconiferyl alcohol (2), (-)-simulanol (3), (-)-dehydrodiconiferyl alcohol (4), (+)-dihydrodehyrodiconiferyl alcohol (5), threo-buddlenol B (6) effectively inhibited the production of nitric oxide (NO) induced by LPS, and the activity of iNOS. (-)-dehydrodiconiferyl alcohol (4), which showed the most potent inhibitory activity, attenuated the activity of iNOS enzyme and also the expression of iNOS and COX-2 proteins. The subsequent production of pro-inflammatory cytokines, interleukin-1β, interleukin-6, tumor necrosis factor-α and prostaglandin E2 were also inhibited by the pretreatment of RAW264.7 cells with (-)-dehydrodiconiferyl alcohol (4). These neolignans are thought to contribute to anti-inflammatory effects of E. alatus, and expected to be potential candidates to prevent/treat inflammation-related diseases.
Cytokines ; Dinoprostone ; Euonymus* ; Interleukin-6 ; Lignans* ; Macrophages* ; Necrosis ; Nitric Oxide ; Nitric Oxide Synthase Type II

The protective effect of EtOAc fraction of Limonium tetragonum extract (EALT) against alcoholinduced hepatotoxicity was assessed following acute ethanol intoxication in Spraque-Dawley rats. EALT (200 mg/kg p.o.) was administrated once before alcohol intake (8 g/kg, p.o.). Blood ethanol concentration, and the activities of alcohol metabolic enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) in the liver were measured. Also, the formation of malondialdehyde (MDA) and the activities of antioxidant enzymes, superoxide dismutase (SOD), glutathione peroxidase (GSH-px), catalase were determined after acute alcohol exposure. Pretreatment of rats received ethanol with EALT significantly decreased blood ethanol concentration and elevated the activities of ADH and ALDH in liver. The increased MDA level was decreased, and the reduced activities of SOD, GSH-px and catalase were markedly preserved by the treatment with EALT. This study suggests that EALT prevent hepatic injury induced by acute alcohol which is likely related to its modulation on the alcohol metabolism and antioxidant enzymes activities.
Alcohol Dehydrogenase ; Aldehyde Dehydrogenase ; Animals ; Catalase ; Ethanol* ; Glutathione Peroxidase ; Liver* ; Malondialdehyde ; Metabolism* ; Plumbaginaceae* ; Rats ; Salt-Tolerant Plants ; Superoxide Dismutase

Tropomyosin receptor kinase A (TrkA) protein is a receptor tyrosine kinase encoded by the NTRK1 gene. TrkA signaling mediates the proliferation, differentiation, and survival of neurons and other cells following stimulation by its ligand, the nerve growth factor.Chromosomal rearrangements of the NTRK1 gene result in the generation of TrkA fusion protein, which is known to cause deregulation of TrkA signaling. Targeting TrkA activity represents a promising strategy for the treatment of cancers that harbor the TrkA fusion protein. In this study, we evaluated the TrkA-inhibitory activity of the benzoxazole compound KRC-108. KRC-108 inhibited TrkA activity in an in vitro kinase assay, and suppressed the growth of KM12C colon cancer cells harboring an NTRK1 gene fusion.KRC-108 treatment induced cell cycle arrest, apoptotic cell death, and autophagy. KRC-108 suppressed the phosphorylation of downstream signaling molecules of TrkA, including Akt, phospholipase Cγ, and ERK1/2. Furthermore, KRC-108 exhibited antitumor activity in vivo in a KM12C cell xenograft model. These results indicate that KRC-108 may be a promising therapeutic agent for Trk fusion-positive cancers.

The therapeutic effects of the leaves of Couroupita guianensis, a large tropical tree in the family of Lecythidaceae improving testosterone-induced Benign Prostatic Hyperplasia (BPH) were tested In Vitro and In Vivo. In BPH rats induced by castration and testosterone treatment, the prostate index was improved in groups administered with the extracts of C. guianensis extracted with 50%-, 100%-ethanol or boiling water, which was comparable with positive control, finasteride. The extract C. guianensis leaves showed significant inhibition on the expressions of type 2 5-alpha reductase (5αR) in RWPE-1 human prostatic epithelial cells, and effectively attenuated the expressions of androgen receptor, type 2 5αR and proliferating cell nuclear antigen in LNCap human prostatic adenocarcinoma cells. The leaves of C. guianensis that exerted evident suppression on BPHrelated biomarkers In Vitro and improvement of prostate index In Vivo has a potential therapeutic use for the treatment of BPH.

PURPOSE: Gefitinib was introduced in 2002 for treatment of non-small cell lung cancer (NSCLC); however, it is not clear whether its use in daily practice has changed the outcome of patients. The purpose of this study is to evaluate the question of how molecular understanding regarding gefitinib and epidermal growth factor receptor (EGFR) mutation affect the prescribing patterns and clinical outcomes of treatment with gefitinib in NSCLC, in a real practical field. MATERIALS AND METHODS: We conducted a retrospective analysis of the consecutive database of NSCLC patients who were treated with gefitinib at Seoul National University Hospital between January 2002 and December 2011. Prescribing patterns and clinical outcomes were analyzed by year. RESULTS: A total of 1,115 NSCLC patients, who received gefitinib at recurred or metastatic setting, were included in this study. Proportion of patients receiving gefitinib, for the first line, showed a gradual increase, from 5.2% in 2002-2003 to 30.6% in 2010-2011. Proportion of patients who underwent EGFR mutation testing showed a rapid increase, from 0.6% in 2004-2005 to 73.5% in 2010-2011. The response rate also showed a gradual increase, from 17.2% in 2002-2003 to 57.1% in 2010-2011 (p<0.001). The median progression-free survival of gefitinib was increased with statistical significance from 2.8 months in 2002-2003 to 9.1 months in 2010-2011 (p<0.001). CONCLUSION: We demonstrated that molecular understanding and practical use of EGFR mutation testing have resulted in a change in the prescription patterns of gefitinib. Use of an enrichment strategy can lead to improvement in the efficacy of gefitinib in real practice.
Carcinoma, Non-Small-Cell Lung ; Disease-Free Survival ; Humans ; Lung ; Lung Neoplasms ; Prescriptions ; Quinazolines ; Receptor, Epidermal Growth Factor ; Retrospective Studies

PURPOSE: The aim of this study was to develop a pragmatic nomogram for prediction of progressionfree survival (PFS) for the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in EGFR mutant non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: A total of 306 recurred or metastatic NSCLC patients with EGFR mutation, who received EGFR TKIs, were enrolled in this study. We developed the nomogram, using a Cox proportional hazard regression model for PFS. RESULTS: The median PFS was 11.2 months. Response rate to EGFR TKI was 71.9%. Multivariate Cox model identified disease status, performance status, chemotherapy line, response to EGFR TKI, and bone metastasis as independent prognostic factors, and the nomogram for PFS was developed, based on these covariates. The concordance index for a nomogram was 0.708, and the calibration was also good. CONCLUSION: We developed a nomogram, based on clinical characteristics, for prediction of the PFS to EGFR TKI in NSCLC patients with EGFR mutation.
Calibration ; Carcinoma, Non-Small-Cell Lung* ; Drug Therapy ; Humans ; Lung Neoplasms ; Neoplasm Metastasis ; Nomograms* ; Prognosis ; Protein-Tyrosine Kinases* ; Receptor, Epidermal Growth Factor*

BACKGROUND: The purpose of this study was to investigate the frequency and distribution of associated carpal bone fractures (CBFs) in distal radial fractures (DRFs). METHODS: Three hundred and thirteen patients who underwent surgical treatment for DRFs between March 2007 and January 2010 were reviewed retrospectively. In this study, 223 patients who had preoperative computed tomography (CT) were included. We investigated the frequency and distribution of associated CBFs on CT scans. The relationship between the frequency of associated CBFs and patient factors such as age, gender, body mass index, and the mechanism of injury was assessed. RESULTS: CBFs were complicated in 46 of 223 DRFs (20.9%). The distribution of CBFs was 23 cases in the triquetrum, 16 in the lunate, 12 in the scaphoid, five in the hamate, and four in the pisiform. Among the 46 cases, a fracture of one carpal bone occurred in 36 cases, two in seven cases, three in two cases, and four in one case. In 10 of the 46 cases, associated CBFs occurred in more than two carpal bones. No significant differences were observed for age, sex, body mass index, or the mechanism of injury between patients with DRFs and CBFs and those without CBFs. CONCLUSIONS: Because CBFs that mainly occur in the proximal carpal row are complicated in DRFs at a relatively high frequency, assessment of carpal bones using CT scans is beneficial.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Carpal Bones/*injuries/radiography ; Female ; Fractures, Bone/*complications/radiography ; Hand Injuries/*complications/radiography ; Humans ; Male ; Middle Aged ; Radius Fractures/*complications/radiography ; Retrospective Studies ; Tomography, X-Ray Computed

Anatomical variations of the extensor tendon of the hand are common. However, the majority of anomalous variations are asymptomatic throughout a lifetime and are found incidentally during surgery or after trauma of the hand. The index finger has two independent extensor tendons and lower incidence of anomalous variations than other extensor tendons. We experienced a rare muscular variant of extensor indicis proprius (EIP) during a tendon reconstruction for spontaneous rupture of the 3rd and 4th extensor digitorum communis. Tendon reconstruction using EIP was planned preoperatively. However, EIP was absent and anomalous muscle known as extensor indicis brevis, which originated from the capsular ligament of the wrist and inserted into the ulnar side on the 2nd extensor digitorum communis of the extensor hood, was found. We performed tendon reconstruction using an alternative surgical procedure because extensor indicis brevis was not useful. Attention is required during tendon reconstruction because anatomical variation of EIP may affect a surgical procedure.
Fingers ; Hand ; Incidence ; Ligaments ; Rupture, Spontaneous ; Tendons ; Wrist

Bortezomib is a proteasome inhibitor used for the treatment of relapsed/refractory multiple myeloma (MM). However, intrinsic and acquired resistance to bortezomib has already been observed in MM patients. In a previous report, we demonstrated that changes in the expression of mitochondrial genes lead to changes in mitochondrial activity and bortezomib susceptibility or resistance, and their combined effects contribute to the differential sensitivity or resistance of MM cells to bortezomib. Here we report that the combination treatment of bortezomib and 2-methoxyestradiol (2ME), a natural estrogen metabolite, induces mitochondria-mediated apoptotic cell death of bortezomib-resistant MM KMS20 cells via mitochondrial reactive oxygen species (ROS) overproduction. Bortezomib plus 2ME treatment induces a higher level of cell death compared with treatment with bortezomib alone and increases mitochondrial ROS and Ca2+ levels in KMS20 cells. Pretreatment with the antioxidant N-acetyl-L-cysteine scavenges mitochondrial ROS and decreases cell death after treatment with bortezomib plus 2ME in KMS20 cells. Moreover, we observed that treatment with bortezomib plus 2ME maintains the activation of c-Jun N-terminal kinase (JNK) and mitogen-activated protein kinase kinase kinase 4/7 (MKK4/7). Collectively, combination treatment with bortezomib and 2ME induces cell death via JNK-MKK4/7 activation by overproduction of mitochondrial ROS. Therefore, combination therapy with specific mitochondrial-targeting drugs may prove useful to the development of novel strategies for the treatment of bortezomib-resistant MM patients.
Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Boronic Acids/*pharmacology ; Calcium/metabolism ; Cell Line, Tumor ; *Drug Resistance, Neoplasm ; Drug Synergism ; Estradiol/*analogs & derivatives/pharmacology ; Humans ; Mitochondria/drug effects/metabolism ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Pyrazines/*pharmacology ; Reactive Oxygen Species/metabolism

The incidence rate of lung cancer is continually increasing, and lung cancer is the leading cause of cancer-related death worldwide. Nevertheless, few therapeutic methods are available for lung cancer. Therefore, establishing appropriate lung cancer animal models is important to investigate mechanisms and to evaluate new drugs for lung cancer. In the present study, we transplanted non-small cell lung cancer A549 human adenocarcinoma cells (2x10(4), 2.0x10(5), and 2.0x10(6) cells) into the right lobe of BALB/c nude mice via the intercostal space to develop an orthotopic lung cancer animal model that is minimally invasive and similar to human lung cancer. We then investigated the incidence rate and severity of lung cancer according to the A549 cell number (2x10(4), 2.0x10(5), and 2.0x10(6) cells) and transplantation periods (4~23 days). Lung cancer development was confirmed with gross examination, which was supported by histopathological examination. These results indicate that the incidence rate and severity of lung cancer was increased depending on the number of transplanted cells and transplantation period which the cell number and duration are increasing risk of lung cancer. Thus, this study can provide appropriate reference data to develop an orthotopic lung cancer animal model using the non-small cell lung cancer A549 cell line for researching mechanisms and evaluating candidate drugs, including various approaches for treating lung cancer.
Adenocarcinoma ; Animals ; Carcinoma, Non-Small-Cell Lung ; Cell Count ; Cell Line ; Humans ; Incidence ; Lung ; Lung Neoplasms ; Mice ; Mice, Nude ; Models, Animal ; Transplants