Adipocytokines and squamous cell carcinoma of the esophagus

Purpose  

Adipocytokines are adipocyte-secreted hormones associated with some malignancies. It has been reported that the impaired response of adipocytokines to body weight loss may play a role in the pathogenesis of cancer-induced cachexia. We investigated the association between adipocytokines with squamous cell carcinoma of the esophagus (SCCE).     

Distribution of coronary atherosclerosis in patients with coronary artery disease

The distribution of coronary atherosclerosis has not been fully clarified. We measured coronary artery calcium score (CACS) in 624 consecutive patients for the right coronary artery (RCA), left main trunk (LMT), left anterior descending coronary artery (LAD), and left circumflex coronary artery (LCx), then calculated total CACS. Coronary artery calcium score was measured using the Agatston method. We divided these patients into four groups: CACS 1–100 (Group A, n = 267), CACS 101–400 (Group B, n = 160), CACS 401–1000 (Group C, n = 110), and CACS >1000 (Group D, n = 87). In Group A, B, and C, the CACS in LAD was significantly higher than in the other three arteries (P < 0.0001). In Group D, the CACS was not significantly different between LAD and RCA (P = 0.6930). In Groups A, B, and C, coronary artery calcium (CAC) was more frequently found in LAD compared with other arteries (P < 0.0001). However, in Group D the prevalence of CAC was not significantly different among the three arteries (P = 0.4435). Coronary artery calcium was found more frequently in LAD than in the other coronary arteries in patients with mild to high CAC, but not in those with very high CAC.     

Vascular responses to the multiple overlapped paclitaxel-eluting stents for the treatment of bare-metal in-stent restenotic lesions: angiographic and intravascular ultrasound analysis from the TAXUS-V ISR Trial

BackgroundAlthough effective coverage of coronary diffuse in-stent restenosis (ISR) lesions has warranted the use of multiple drug-eluting stents, the vessel response to paclitaxel-eluting stent (PES) overlap is not fully understood.Methods and materialsIn the TAXUS-V ISR, i.e., comparing PES versus brachytherapy for the treatment of bare-metal ISR, angiographic analyses at 9-month follow-up were available in 184 ISR lesions treated with PES.ResultsIn-stent late loss in entire stented segment of multiple PES (n=50) was 0.45±0.48 mm, whereas that of single PES (n=134) was 0.3±0.47 mm, P=.06. No aneurysm was observed at overlapping PES segments at 9 months. Stent thrombosis up to 9 months was observed in one in each group (single PES, 0.7% vs. multiple PES, 1.8%; P=.47). In a subset of 30 patients, volumetric intravascular ultrasound analysis demonstrated that in-stent net volume obstruction was 12.3±12.4 in single PES (n=20) and 14.9±9.8 in multiple PES (n=10), P=.60. The changes of vessel and lumen at the overlapping PES segment were similar to those of the adjacent 5-mm segments (Δminimum lumen area, mm²: ?1.2±1.0, ?1.1±1.1, ?0.8±0.9, P=.48; Δvessel volume, mm³/mm: ?0.2±1.4, 0.1±1.7, 0.3±1.3, P=.37; proximal, overlap, distal segment, respectively). There was no late incomplete stent apposition at overlapping PES segments.ConclusionsNo in vivo evidence of adverse local vessel response at the site of overlapping PES for the treatment of bare-metal ISR has been demonstrated.     

Late toxicity after definitive chemoradiotherapy for esophageal squamous cell carcinoma

Background  

This study was designed to conduct a retrospective analysis of late toxicity following chemoradiotherapy (CRT) for esophageal carcinoma.     

Macaque cytochromes P450: nomenclature, transcript, gene, genomic structure, and function

Monkeys, especially macaques, including cynomolgus (Macaca fascicularis) and rhesus monkeys (Macaca mulatta), are frequently used in drug metabolism studies due to their evolutionary closeness to humans. Recently, numerous cytochrome P450 (P450 or CYP) cDNAs have been identified and characterized in cynomolgus and rhesus monkeys and were named by the P450 Nomenclature Committee. However, recent advances in genome analysis of cynomolgus and rhesus monkeys revealed that some monkey P450s are apparently orthologous to human P450s and thus need to be renamed corresponding to their human orthologs. In this review, we focus on the P450s identified in cynomolgus and rhesus monkeys and present an overview of the identity and functional characteristics of each P450 cDNA in the CYP1-4 families. Information on the Japanese monkey (Macaca fuscata), African green monkey (Cercopithecus aethiops), and marmoset (Callithrix jacchus), primate species used in some drug metabolism studies, are also included. We compared the genomic structure of the macaque P450 genes to those of human and rat P450 genes in the CYP1-4 families. Based on sequence identity, phylogeny, and genomic organization of monkey P450s, we determined orthologous relationships of monkey P450s and, in this article, propose a revised nomenclature: CYP2B17/CYP2B30 to CYP2B6, CYP2C20/CYP2C74 to CYP2C8, CYP2C43/CYP2C83 to CYP2C9, CYP2C75 to CYP2C19, CYP2F6 to CYP2F1, CYP3A8/CYP3A21/CYP3A64 to CYP3A4, CYP3A66 to CYP3A5, and CYP4F45 to CYP4F2. The information presented in this review is expected to promote a better understanding of monkey P450 genes through comparative genomics and thereby make it more feasible to use monkeys in drug metabolism studies.     

Protective effect of pretreatment with cilostazol on cytotoxicity of cadmium and arsenite in cultured vascular endothelial cells

Cilostazol, an antiplatelet drug, exhibits antiatherogenic effects. The purpose of the present study was to determine the effect of cilostazol on the cytotoxicity of cadmium (Cd) and arsenite (iAs(III)), which involved in the pathogenesis of vascular disorders such as atherosclerosis, in cultured vascular endothelial cells. Cytotoxicity was evaluated by the lactate dehydrogenase leakage assay and morphological observation. Cd (10 μM) -induced cytotoxicity was prevented by pretreatment with cilostazol (30 and 100 μM) and simultaneous treatment with cilostazol (100 μM). On the other hand, iAs(III)-induced cytotoxicity was blocked by pretreatment with cilostazol (30 and 100 μM) but not simultaneous treatment with cilostazol. The mRNA level and the protein level of metallothionein (MT) were significantly increased by cilostazol in the cells. These results suggested, therefore, that pretreatment with cilostazol effectively prevents the cytotoxicity of Cd and iAs(III) in cultured vascular endothelial cells, at least in part through the induction of MT synthesis.     

Peroxiredoxin 6 is a molecular target for 1,2-naphthoquinone, an atmospheric electrophile, in human pulmonary epithelial A549 cells

1,2-Naphthoquinone (1,2-NQ) is an electrophile found in the atmosphere, which reacts readily with protein nucleophiles to form a stable protein adduct. Peroxiredoxin 6 (Prdx6) is predominantly expressed in lung tissue and functions in antioxidant defense by facilitating the repair of damaged cell membranes via reduction of peroxidized phospholipids. In the present study, human A549 pulmonary epithelial cells were exposed to 1,2-NQ to explore whether 1,2-NQ can bind covalently to Prdx6, thereby disrupting its catalytic activity. Two-dimensional SDS/PAGE followed by western blot analysis with a specific antibody against 1,2-NQ showed that Prdx6 was covalently modified by 1,2-NQ. Using purified human Prdx6, it was found that 1,2-NQ bound covalently to Prdx6 through Cys47, Lys144 and Cys91, resulting in a significant reduction in phospholipase A(2) activity. These results suggest that arylation of Prdx6 by 1,2-NQ may, at least in part, be involved in the cellular toxicity induced by 1,2-NQ.     

Role of hippocampal TLR4 in neurotoxicity in mice following toluene exposure

The present study was designed to investigate the possible involvement of TLR4 pathway in the mouse hippocampus following toluene exposure. Male C3H/HeN and C3H/HeJ (TLR4 defective) mice were exposed to 0, 5, 50 or 500 ppm of toluene for 6 weeks. The expressions of TLR4-related signal transduction pathway mRNAs in the hippocampi were examined using real-time RT-PCR and an immunohistochemical analysis. In C3H/HeN mice, the relative mRNA expression levels of TLR4 and NF-κB activating protein were significantly up-regulated in the groups exposed to toluene, but not in the C3H/HeJ mice. Heat shock protein 70, a possible endogenous ligand for TLR4, mRNA was increased in the C3H/HeN mice exposed to toluene. This is the first report to show that TLR4 may have a role in the neurotoxic effects in mice exposed to toluene.     

Synchronous double primary lung cancers with different response to pemetrexed

We describe the case of a 74-year-old male patient with synchronous double primary lung cancers: adenocarcinoma in the right lower lobe and squamous cell carcinoma in the left upper lobe (LUL). These tumors were difficult to differentiate radiographically from a single metastatic primary cancer, but their eventual diagnoses were triggered by their responses to chemotherapy, which included pemetrexed. After two courses of chemotherapy with pemetrexed and carboplatin, the right lower lobe mass had partially resolved; however, the LUL mass had increased. When S-1 was used as fourth-line chemotherapy, the size of the LUL mass decreased. Pemetrexed is a potentially useful drug for treating nonsquamous cell carcinoma, but may not be appropriate in cases with a coexisting squamous cell carcinoma. Our experience with this interesting case leads us to propose that S-1 monotherapy may provide a treatment option in pemetrexed-refractory cases.     

Redox cycling of 1,2-naphthoquinone by thioredoxin1 through Cys32 and Cys35 causes inhibition of its catalytic activity and activation of ASK1/p38 signaling

1,2-Naphthoquinone (1,2-NQ) is an atmospheric chemical capable of (1) redox cycling with electron donors and (2) covalent modification of nucleophilic groups on proteins. In the present study, we investigated its interaction with the redox protein, thioredoxin1 (Trx1), which led to oxidative stress-dependent cell damage. In experiments with purified wild-type Trx1 and its double mutant (32S/35S Trx1), we found that incubation of Trx1 with 1,2-NQ resulted in a redox cycling reaction, generating superoxide and hydrogen peroxide involving Cys32 and Cys35 and an arylation reaction resulting in covalent modification of Lys85 together with a loss of Trx activity. A significant fraction of the lost Trx1 activity following interaction with 1,2-NQ was restored by dithiothreitol. Exposure of RAW264.7 cells to 1,2-NQ generated reactive oxygen species (ROS) and caused a decrease in Trx activity. Trx is a negative regulator of apoptosis signal-regulating kinase 1 (ASK1), and under the conditions of the experiment, 1,2-NQ activated ASK1 and p38, leading to PARP cleavage and apoptotic cell death that were blocked by pretreatment with polyethylene glycol-catalase. These results suggest that Trx1 readily undergoes oxidative modification by 1,2-NQ through the proximal thiols Cys32 and Cys35. It seems likely that ROS production concomitant with decline in cellular Trx activity plays a role in the activation of ASK1/p38 signaling to promote apoptotic cell death cause by 1,2-NQ exposure.