The G protein-coupled receptor T-cell death-associated gene 8 (TDAG8) facilitates tumor development by serving as an extracellular pH sensor

Tumors often are associated with a low extracellular pH, which induces a variety of cellular events. However, the mechanisms by which tumor cells recognize and react to the acidic environment have not been fully elucidated. T-cell death-associated gene 8 (TDAG8) is an extracellular pH-sensing G protein-coupled receptor that is overexpressed in various tumors and tumor cell lines. In this report, we show that TDAG8 on the surface of tumor cells facilitates tumor development by sensing the acidic environment. Overexpression of TDAG8 in mouse Lewis lung carcinoma (LLC) cells enhanced tumor development in animal models and rendered LLC cells resistant to acidic culture conditions by increasing activation of protein kinase A and extracellular signal-regulated kinase in vitro. Moreover, shRNA-mediated knockdown of endogenous TDAG8 in NCI-H460 human non-small cell lung cancer cells reduced cell survival in an acidic environment in vitro as well as tumor development in vivo. Microarray analyses of tumor-containing lung tissues of mice injected with TDAG8-expressing LLC cells revealed up-regulation of genes related to cell growth and glycolysis. These results support the hypothesis that TDAG8 enhances tumor development by promoting adaptation to the acidic environment to enhance cell survival/proliferation. TDAG8 may represent a therapeutic target for arresting tumor growth.     

Initial clinical experience with a new end graft holder for anastomosis in coronary surgery

Objective We assessed the feasibility and effectiveness of a novel end graft holder for coronary artery bypass grafting (CABG) and evaluated anastomotic patency and early clinical results. Methods The end graft holder was applied to 45 consecutive patients. Operative characteristics were off-pump CABG in 22.2%, emergency in 28.9%, and concomitant cardiac surgery in 13.3%. Results The device was used safely without graft injury or inadequate gripping on grafts. Postoperative angiography showed that the patency rate of distal anastomosis was 96.7% (arterial, 100%; venous, 94%). All proximal aortic and composite graft anastomoses were patent without stenosis. The rate of 30-day major adverse cardiac and cerebrovascular events was 13.3% (operative deaths, 3; repeated CABG, 1; percutaneous coronary arterial intervention, 1; and cerebral infarction, 1). None of the elective patients died during hospitalization. Conclusion Our initial clinical experience demonstrated that the new end graft holder was safe, reliable, and effective during CABG. The excellent fixation and visualization of the graft with the device might be particularly beneficial for off-pump CABG or for teaching trainees. No financial support was received for this study, and the equipment used has not been donated for the purposes of this study. The authors had full control of the study design, the methods used, outcome parameters, analysis of the data, and production of this report.     

Permeation of hyaluronan tetrasaccharides through hairless mouse skin: an in vitro and in vivo study

Hyaluronan (HA) is a well-known active ingredient for cosmetic and drug applications. However, based on its varying molecular size, HA may have limited skin permeation. Therefore, the aim of the present study was to investigate the in vitro skin permeability of HA tetrasaccharide (HA4). In addition, the effects of HA4 on in vivo skin barrier function were examined. The cumulative amounts of HA4 through stratum corneum (SC)-stripped skin and full-thickness skin after 8 h were 2,109.6 and 0.8 μg/cm², respectively. Furthermore, the cumulative amounts of HA4 permeated after 8 h were 784.4 ng/cm² for a HA4 solution with a pH 4 and 70.0 ng/cm² with a pH 7 on full-thickness skin. Next, the in vivo effects of HA4 on the water content of the SC and transepidermal water loss (TEWL) were investigated. The dorsal skins of hairless mice were irradiated to a UVA dose of 22.3 J/cm²/d, 5 times a week. In the control group, the water content of the SC was decreased and TEWL and epidermal thickness were increased with UVA irradiation than the normal group. However, the water content of the SC was increased in the HA4 group than that of the control group in the non-UVA irradiation groups. In addition, the water content of the SC was increased and TEWL and epidermal thickness were decreased in the HA4 group than those of the control and HA groups. These results suggest that treatment with HA4 improved skin functional recovery after UVA irradiation by skin penetration of HA4.     

Post-stroke treatment with imidapril reduces learning deficits with less formation of brain oedema in a stroke-prone substrain of spontaneously hypertensive rats

The present study was undertaken to examine the effects of the ACE (angiotensin converting enzyme) inhibitor imidapril, on the brain, when administered after the onset of stroke in a stroke-prone substrain of spontaneously hypertensive rats (SHRSP). Learning deficits and induced lesions in the brain as well as in the kidneys and heart were investigated in detail. SHRSP were divided into two groups with or without salt loading at the age of 4 weeks. The salt loading was performed for 7-9 weeks to increase the incidence of stroke. Within 24 h after the first observation of stroke, animals were subsequently treated with 5 mg/kg imidapril orally once a day or the vehicle for up to the age of 27 weeks. Imidapril attenuated progression of neurological abnormalities such as irritability, hyperkinesia and motor dysfunction, and increased survival rate. In three-panel runway testing, learning deficits did not develop significantly in the imidapril-treated group, and was comparable to that in the non-salt-loaded/non-stroke group. Imidapril reduced oedema formation in the cortex, hippocampus and striatum, and also suppressed lesion formation in the kidneys and heart. Imidapril thus suppressed progression of neurological deficits with loss of learning ability following onset of stroke, and also suppressed formation of oedema in the brain and decreased the number of lesions in other organs. Imidapril-induced reduction of cerebrovascular damage, which presumably occurs in the brain after stroke, may account for the inhibitory effects of imidapril on lesion formation and learning impairment.     

Appearance of specific mucins recognized by monoclonal antibodies in rat gastric mucosa healing from HCl-induced gastric mucosal damage

Background Mucus is an important factor in the physiological defense mechanism of the gastrointestinal tract. We have reported that two distinct antigenicities reacting with anti-mucin monoclonal antibodies (mAbs), HCM31 and RGM26, emerged in epithelial cells regenerating from acetic acid-induced gastric damage in the rat. Here, we examined whether the expression of specific mucins occurred during the healing stage of acute gastric mucosal lesions, and what was the principal alteration of the mucus in the regenerating process of gastric epithelia from slight mucosal lesions.Methods Eight-week-old male Wistar rats were used. The animals were administered 0.6N hydrochloric acid, or 0.5% carboxymethyl cellulose sodium salt into their stomachs. Twenty-four, 48, and 72h after the HCl administration, their stomachs were removed. Immunohistochemical observation was performed after staining with the mAbs, RGM21, RGM26, HIK1083, or HCM31.Results Twenty-four hours after the administration of HCl, mucous cells stained with RGM26 emerged in the deeper area of the surface epithelial cells in the damaged corpus mucosa. After 48h, HCM31-positive cells were noted in the epithelial cells where the mucosal damage reached more deeply.Conclusions The appearance of specific mucin species was observed in the regenerating epithelia of the rat during the healing process from acute gastric mucosal damage.     

Percutaneous radiofrequency ablation with cooled electrodes combined with hepatic arterial balloon occlusion in hepatocellular carcinoma

Background We have reported that percutaneous radiofrequency ablation (RFA) with balloon occlusion of the hepatic artery (balloon-occluded RFA), using an expandable electrode, increases the coagulation area. In this study, we investigated the efficacy of balloon-occluded RFA and balloon-microcatheter-occluded RFA, using a cool RF single electrode.Methods We studies 41 patients with 47 hepatocellular carcinoma (HCC) lesions. We treated 28 patients (32 nodules) with balloon-occluded RFA, 5 patients (6 nodules) with balloon-microcatheter-occluded RFA, and 8 patients (9 nodules) with standard RFA. Initial therapeutic efficacy was evaluated with dynamic computed tomography performed 1 week after one session of treatment.Results One session of treatment was done for 20 nodules (62.5%) in the balloon-occluded RFA group and for 4 nodules (66.7%) in the balloon-microcatheter-occluded RFA group. We compared the coagulation diameter for balloon-occluded RFA (7 nodules), balloon-microcatheter-occluded RFA (6 nodules), and standard RFA (9 nodules) after one application cycle (12min). The greatest dimension of the area coagulated by balloon-occluded RFA was significantly larger (greatest long-axis dimension, 47.6 ± 7.8mm; greatest short-axis dimension, 33.4 ± 7.5mm) than that coagulated by standard RFA (greatest long-axis dimension, 35.3 ± 4.7mm; greatest short-axis dimension, 25.9 ± 3.7mm; P = 0.002 for greatest long-axis dimension; P = 0.041 for greatest short-axis dimension). However, there was significant difference only in the greatest short-axis dimension of the area coagulated comparing balloon-microcatheter-occluded RFA and standard RFA.Conclusions We consider balloon-occluded RFA using a cool RF electrode to be superior to standard RFA for the treatment of HCC, especially when larger coagulation volumes are required.