Regulation of somatostatin receptor 4-mediated cytostatic effects by CD26 in malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive neoplasm arising from mesothelial lining of pleura. CD26 molecules preferentially expressed on epithelioid type of MPM. This study investigates the molecular mechanisms of CD26 regulating MPM cells in vitro and in vivo. METHODS: Biochemical and cell biological approaches were used for identifying a novel molecular target of MPM. Its contribution to tumour expansion has been also assessed using animal models. The clinical samples of MPM were also assessed for its expression. RESULTS: We identify that cytostatic effects in MPM are mediated by somatostatin (SST) receptor 4 (SSTR4), being inhibited by the interaction of CD26 molecules. We also indicates that SSTR4-mediated cytostatic effects are regulated by SHP-2 PTP, and that this inhibitory effect by SST agonist is enhanced via lipid raft clustering of associated molecules following crosslinking of anti-CD26 antibody. Finally, using an in vivo xenograft model, we demonstrate that the anti-tumour effect of anti-CD26 mAb is enhanced when combined with SSTR4 agonist treatment, and that SSTR4 is highly coexpressed with CD26 on epithelioid or biphasic types of MPM tissues obtained from patients' surgical specimens. CONCLUSIONS: Combination therapy with humanised anti-CD26 mAb and SSTR4 agonist may therefore potentiate anti-tumour effect on MPM.

Episodic release of methane bubbles from peatland during spring thaw.

Methane (CH(4)) flux into the atmosphere during spring thaw was investigated in a small ombrotrophic peatland (141 degrees 48'E, 43 degrees 19'N, Japan) using the conventional chamber method. More than 50 chamber deployments on top of the snow cover were carried out and continued for more than 165h until the surface snow and underlying ice cover on top of the peat layer had thawed completely. Methane emissions were almost absent in the presence of snow cover. At the very moment the surface ice cover thawed, a large CH(4) flush (>10mgCH(4)m(-2)h(-1)) was recorded, which was on the same order of magnitude as episodic ebullition previously observed in the high-summer. Gas bubbles trapped in the ice layer on top of the waterlogged peat were preliminarily analyzed for the volumetric percentage in the total ice volume and their gas species compositions. Results showed that the bubbles occupied about 3.2% volume and that the mixing ratio of CH(4) in the bubbles was about 20%. The abundance of the bubble-form CH(4) was sufficient to explain the observed episodic CH(4) release during the thaw. Results of this study show that CH(4) emissions during the thaw season have great temporal variability; emission occurs as an episodic release of bubble-form CH(4) stored in the frozen layer. The results also imply the possibility that gas-phase CH(4) plays an important role, not only during the growing season but also in cold-season CH(4) dynamics in northern peatlands.

Evaluating stream water quality through land use analysis in two grassland catchments: impact of wetlands on stream nitrogen concentration.

We evaluated the impacts of natural wetlands and various land uses on stream nitrogen concentration in two grassland-dominated catchments in eastern Hokkaido, Japan. Analyzing land use types in drainage basins, measuring denitrification potential of its soil, and water sampling in all seasons of 2003 were performed. Results showed a highly significant positive correlation between the concentration of stream NO3-N and the proportion of upland area in drainage basins in both catchments. The regression slope, which we assumed to reflect the impact on water quality, was 24% lower for the Akkeshi catchment (0.012 +/- 0.001) than for the Shibetsu catchment (0.016 +/- 0.001). In the Akkeshi catchment, there was a significant negative correlation between the proportion of wetlands in the drainage basins and stream NO3-N concentration. Stream dissolved organic nitrogen (DON) and carbon (DOC) concentrations were significantly higher in the Akkeshi catchment. Upland and urban land uses were strongly linked to increases in in-stream N concentrations in both catchments, whereas wetlands and forests tended to mitigate water quality degradation. The denitrification potential of the soils was highest in wetlands, medium in riparian forests, and lowest in grasslands; and was significant in wetlands and riparian forests in the Akkeshi catchment. The solubility of soil organic carbon (SOC) and soil moisture tended to determine the denitrification potential. These results indicate that the water environment within the catchments, which influences denitrification potential and soil organic matter content, could have caused the difference in stream water quality between the two catchments.

A case of gain-of-function mutation in calcium-sensing receptor: supplemental hydration is required for renal protection.

AIMS: The calcium-sensing receptor (CaSR) regulates the extracellular calcium level, mainly by controlling parathyroid hormon secretion and renal calcium reabsorption. In gain-of-function CaSR mutations, the genetic abnormalities increase CaSR activity leading to the development of such clinical manifestations as hypercalciuric hypocalcemia and hypoparathyroidism. We report a Japanese case of CaSR gain-of-function mutation and represent a therapeutic intervention based on the functional characteristics of CaSR in renal tubule. METHODS AND RESULTS (CASE): DNA sequence analysis revealed a heterozygous G to T mutation identified in a 12-year-old Japanese girl presenting with sporadic onset of hypercalciuric hypocalcemia and hypoparathyroidism. The mutation is located in the N-terminal extracellular domain of the CaSR gene, one of the most important parts for the three-dimensional construction of the receptor, resulting in the substitution of phenylalanine for cysteine at amino acid 131 (C131F) in exon 3. Based on the diagnosis of the gain-of-function mutation in the CaSR, oral hydrochlorothiazide administration and supplemental hydration were started in addition to calcium supplementation. The combination therapy of thiazide and supplemental hydration markedly reduced both renal calcium excretion and urinary calcium concentration from 0.4-0.7 to less than 0.1 mg/mg (urinary calcium/creatinine ratio) and from 10-15 to 3-5 mg/dl (urinary calcium concentration), respectively. This therapy stopped the progression of renal calcification during the follow-up period. CONCLUSION: Supplemental hydration should be considered essential for the following reasons: (1) calcium supplementation activates the CaSR in the kidney and suppresses renal urinary concentrating ability, (2) the thiazide has a diuretic effect, (3) as calcium supplementation increases renal calcium excretion, the supplemental hydration decreases urinary calcium concentration by increasing urinary volume, thereby diminishing the risk of intratubular crystallization of calcium ion.

Experimental and clinical studies of the inverted autogenous vein grafts.

The vein was inverted (inside-out) and used as a new arterial substitute. Experimental study showed more than 90% patency rate and clinical experiences were satisfactory. Autogenous inverted vein grafting is a safe procedure and should be considered another way to widen the indication of the vein.

Aortitis syndrome due to Takayasu's disease. A guideline for the surgical indication.

Seven cases of aortitis syndrome were surgically treated with good results: Abdominal aortic aneurysm 1, atypical coarctation of aorta 2, aortic valve insufficiency 2, renovascular hypertension 2. Several attentions were paid as following: 1. Operation should be avoided during acute phase of aortitis. 2. Synthetic graft material should be avoided if possible. Autogenous vein is advisable for reconstruction of small-sized artery. 3. Surgical intervention should be performed before the loss of organ function. 4. Hematological consideration is worthwhile to prevent hypercoagulopathy due to aortitis.

Diagnostic and pathological considerations in the popliteal artery entrapment syndrome.

Four cases of the popliteal artery entrapment syndrome including two with bilateral lesions are reported. All limbs of these patients showed classical arterial entrapment due to the anomalous course of the popliteal artery in relation to the medial head of the gastrocnemius muscle. All cases were diagnosed preoperatively, and computed tomography demonstrated apparent separation of the popliteal artery and vein at the site of the insertion of the gastrocnemius muscle. All patients complained of gradually progressive intermittent claudication except for one who revealed acute leg ischemia following long periods of driving and Japanese-style sitting. Surgical treatment resulted in complete recovery in all limbs. Pathological characteristics in the popliteal artery were: (1) the presence of longitudinal smooth muscle bundles in the medial coat adjacent to the gastrocnemius muscle, and (2) intimal thickening and/or thrombus formation adjacent to the medial condyle of the femur.

Natural course of small hepatocellular carcinoma with underlying cirrhosis. A study of 30 patients.

To anticipate the prognosis and choose therapy for patients with relatively early-stage HCCs, we elucidate the natural course of such patients. Thirty cirrhotic patients with small hepatocellular carcinoma (HCC) < 3 cm in size and not receiving anti-cancer treatment were followed by sonography for periods of 6-48 mots. The growth speed varied considerably from case to case, with an average of 6.5+/-5.7 months of doubling time (DT). Growth speed of small HCC is significantly related to histological differentiation of tumors: a slow-growing HCC tends to be well-differentiated and a rapid-growing HCC moderately- or poorly-differentiated. Furthermore, there was a tendency to grow without changing from nodular type in slow-growing HCCs and to multiple nodular or massive types in intermediate- and rapid-growing HCCs. The survival rates of these untreated HCC patients showed a 1-yr survival of 90.7%, a 2-yr survival of 55.0%, and a 3-yr survival of 12.8%. Factors significantly influencing survival of these patients were serum total bilirubin level and DT. This study will provide invaluable data for diagnosing and treating for small HCCs.

Enhanced activation is the mechanism of negative cross-resistance to Chlorpyrifos in the Dicofol-IR strain of Tetranychus urticae (Acari: Tetranychidae).

The mechanism responsible for negative cross-resistance to chlorpyrifos was examined in isogenic dicofol susceptible (Orchard-12) and resistant (Dicofol-IR) two-spotted spider mites, Tetranychus urticae Koch. The acetylcholinesterase of both strains was equally sensitive to inhibition by chlorpyrifos oxon. However, the Dicofol-IR strain showed increased oxidative activation of chlorpyrifos to chlorpyrifos oxon relative to the Orchard-12 strain, suggesting this mechanism is responsible for the observed negative cross-resistance.

[Phase II study on peplomycin for esophageal cancer].

For the purpose of verifying the effectiveness of peplomycin, one of the derivatives of bleomycin, against carcinoma of the esophagus and the safety of it, the analysis of the data for total 113 cases collected from 25 institutions in Japan was made. The results are as follows. It was effective in 19 out of 74 evaluable cases of carcinoma of the esophagus (25.7%). In case of treatment with peplomycin alone, it was effective in 6 out of 39 cases (15.4%). In case of the combination treatment with peplomycin and some other therapy, it was effective in 13 out of 35 cases (37.1%). As for the side effects, the incidence of fever was the highest in both the cases of peplomycin alone and the combination treatment such as 39.6% and 37.0%, respectively. Anorexia, nausea, vomiting, respiratory symptoms and tiredness were found in relatively many cases. In the clinical laboratory tests, the vital capacity after the treatment tended to be lower than that before the treatment, but there was little change in the hematological tests, pulmonary function test and renal function test.