Key roles for GRB2-associated-binding protein 1, phosphatidylinositol-3-kinase, cyclooxygenase 2, prostaglandin E2 and transforming growth factor alpha in linoleic acid-induced upregulation of lung and breast cancer cell growth.

The distribution of omega-6 and omega-3 polyunsaturated fatty acid (PUFA) intake in Western diets is disproportionate, containing an overabundance of the omega-6 PUFA, linoleic acid (LA; C18:2). Increased enrichment with LA has been shown to contribute to the enhancement of tumorigenesis in several cancer models. Previous work has indicated that phosphatidylinositol 3-kinase (PI3K) may play a key role in LA-induced tumorigenesis. However, the modes by which LA affects carcinogenesis have not been fully elucidated. In this study, a mechanism for LA-induced upregulation of cancer cell growth is defined. LA treatment enhanced cellular proliferation in BT-474 human breast ductal carcinoma and A549 human lung adenocarcinoma cell lines. Enrichment of LA increased cyclooxygenase (COX) activity and led to increases in prostaglandin E2 (PGE2), followed by increases in matrix metalloproteinase (MMP) and transforming growth factor alpha (TGF-α) levels, which are all key elements involved in the enhancement of cancer cell growth. Further investigation revealed that LA supplementation in both BT-474 breast and A549 lung cancer cell lines greatly increased the association between the scaffolding protein GRB2-associated-binding protein 1 (Gab1) and epidermal growth factor receptor (EGFR), although Gab1 protein levels were significantly decreased. These LA-induced changes were associated with increases in activated Akt (pAkt), a downstream signaling component in the PI3K pathway. Treatment with inhibitors of EGFR, PI3K and Gab1-specific siRNAs reversed the upregulation of pAkt, as well as the observed increases in cell proliferation by LA in both cell lines. A549 xenograft assessment in athymic nude mice fed high levels of LA exhibited similar increases in EGFR-Gab1 association and increased levels of pAkt, while mice fed with high levels of the omega-3 PUFA, docosahexaenoic acid (DHA; C22:6), demonstrated an opposite response. The involvement of Gab1 in LA-induced tumorigenesis was further defined utilizing murine cell lines that express high levels of Gab1. Significant increases in cell proliferation were observed with the addition of increasing concentrations of LA. However, no changes in cell proliferation were detected in the murine paired cell lines expressing little or no Gab1 protein, establishing Gab1 as major target in LA-induced enhancement of tumorigenesis.

Follicular dendritic cell sarcoma: ultrastructural and immunohistochemical studies.

A rare case of follicular dendritic cell (FDC) sarcoma is reported. A 71-year-old woman was admitted for evaluation of constipation. Computerized tomography showed cervical, supraclavicular, retroperitoneal, and paraaortic lymphadenopathies. Histological findings from a cervical lymph node revealed Hodgkin's disease at first. But tumors that arose both in the cervical and the left interscapular regions during the chemotherapy were immunohistochemically confirmed to be of follicular dendritic cell origin. The ultrastructural findings were consistent with those of FDC sarcoma. FDC sarcoma is a rare nonlymphoid cell-derived malignant tumor originating from the lymphoid tissue. The diagnosis of FDC sarcoma is most accurately established by immunohistochemical methods, using its specific markers.

Supramolecular complex of cytochrome c with lariat ether: solubilization, redox behavior and catalytic activity of cytochrome c in methanol.

A variety of lariat ethers were employed to solubilize water-soluble cytochrome c in methanol, in which alcohol, ether, ester, amine, and amide functionalities were attached as cation-ligating side arms to 18-crown-6, 15-crown-5, and 12-crown-4 rings. Among these lariat ethers, the alcohol-armed 18-crown-6 derivative offered the highest solubilization efficiency for cytochrome c via supramolecular complexation. The resulting cytochrome c-lariat ether complexes were electrochemically and spectroscopically characterized and confirmed to have redox-active heme structures of 6-coordinate low-spin population in methanol. Some of them catalyzed the oxidation of pinacyanol chloride with hydrogen peroxide in methanol and exhibited higher activities than unmodified cytochrome c and its poly(ethylene glycolated) derivative. Since the supramolecular complexation between lariat ether and cytochrome c includes extremely simple procedures, it provides a facile preparation method of effective biocatalysts working in organic solvents from metalloproteins.

A successfully treated case of Vibrio vulnificus septicemia with shock.

Vibrio vulnificus infection often causes serious or fatal disease. Recently, in Japan there have been numerous reports of Vibrio vulnificus infection. Here, we report a successfully treated case of Vibrio vulnificus septicemia with shock, disseminated intravascular coagulation (DIC) and necrotizing cellulitis in a middle-aged heavy drinker with chronic alcoholic liver disease. On reviewing 38 cases in Japan including ours, the overall mortality rate was 68%. Although the incidence is relatively low, it is recommended to warn patients in the high risk category, such as liver disease patients, to avoid raw fish and shellfish and limit sea water exposure.

Factors contributing to oxalate deposits in the myocardia of hemodialysis patients.

Although the deposition of calcium oxalate crystals in the myocardium can be associated with significant morbidity and mortality in hemodialysis patients, the pathogenesis of this deposition is not known. The present study was undertaken in order to clarify the contributing factors in an experimental setting. A simple increase in plasma oxalate levels did not cause deposits in the heart, nor did elevated values of plasma ionized calcium appear to be important in chronic renal failure. Following heterotopic cardiac transplantation, a much larger deposition of crystals was identified in the heart allograft that was histologically damaged by rejection. These findings suggest that the state of the local tissue is a very important factor in the deposition of oxalate crystals.

Oxalate crystal deposits in renal tubules and cystic changes in 5/6 nephrectomized and normal rats.

Although the mechanism responsible for the genesis of acquired renal cysts in hemodialysis patients has not been clearly defined, the authors suggested that obstruction of the nephron by deposition of oxalate crystals may be an important factor. The present study was undertaken to examine this possibility in an experimental setting. Ten 5/6 nephrectomized rats were given daily subcutaneous injections of 5 mg sodium oxalate and allowed free access to saccharin sweetened water containing 2 mg/ml sodium oxalate. Six other 5/6 nephrectomized rats were controls. In addition, eight healthy rats received 10 mg sodium oxalate for 30 days. The earlier appearance and severe degree of tubular dilatation in oxalate-treated 5/6 nephrectomized compared with untreated 5/6 nephrectomized rats and the presence of renal tubular dilatation with oxalate deposits in normal rats treated with oxalate sodium are likely to be due to tubular obstruction or stenosis caused by oxalate deposition. In conclusion, oxalate deposits in the renal tubules seem to be an important factor in the formation of acquired renal cysts in chronic renal failure.

Effect of vitamin C supplementation on renal oxalate deposits in five-sixths nephrectomized rats.

We have previously reported that hyperoxalemia can be aggravated by vitamin C supplementation in regular hemodialysis patients. The present study was undertaken to examine the validity of this observation in an experimental setting. Fifty five-sixths nephrectomized rats were divided into two groups: 30 rats were allowed free access to water containing 8 mg/ml of vitamin C (100-160 mg/100 g/24 h) and the remainder given tap water without vitamin C. The serum creatinine increased and the Hct decreased gradually; however, there was no difference between the two groups. Plasma vitamin C, oxalate and urinary oxalate levels were higher in the vitamin -treated group than the nontreated rats. Histological examination revealed glomerular and interstitial fibrosis and round cell infiltration as well as tubular cyst formation. Oxalate deposits in renal tubules were found only in vitamin C-treated rats with advanced renal failure. Nontreated animals with equally advanced renal impairment showed no oxalate deposits. These results confirm our previous clinical findings that vitamin C supplementation aggravates the secondary oxalosis of chronic renal failure.

Acquired renal cysts in five-sixths nephrectomized rats: the roles of oxalate deposits in renal tubules and a renotropic factor.

The present study was undertaken to see if the oxalate deposits seen in renal tubules are a causative factor in the development of acquired renal cysts in chronic renal failure. Thirty 5/6 nephrectomized rats had free access to water containing 8 mg/ml of vitamin C (oxalate precursor) and 20 5/6 nephrectomized rats were given tap water without vitamin C. Oxalate deposits were found on microscopy in the renal tubules of vitamin C-treated rats in the 11th and 12th postnephrectomy months; however, acquired renal cysts were noted far in advance of the appearance of oxalate crystals. It has been suggested that the tubular dilatation seen in 5/6 nephrectomized rats is caused by an abrupt decrease in the functioning renal mass, leading to the production of a so-called 'renotropic factor'. However, oxalate deposits and renal tubular dilatation in oxalate-treated 5/6 nephrectomized rats preceded the renal tubular dilatation of untreated partially nephrectomized rats. In addition, these histological changes in the kidney were also seen in healthy rats which were given oxalate orally and subcutaneously. The present study suggested that the pathogenesis of acquired renal cysts is multifactorial. Renotropic factor may play an important role leading to nephron hyperplasia, but oxalate deposits in the renal tubules seem to be an important factor in the formation of these cysts.

Pathogenesis of acquired renal cysts in hemodialysis patients. The role of oxalate crystal deposition in renal tubules.

Although the mechanism responsible for the genesis of acquired renal cysts in hemodialysis patients has not been clearly defined, obstruction of the nephron by deposition of oxalate crystals may be an important factor. We performed this study to investigate this possibility. In 51 dialysis patients, the number and size of acquired cysts as well as kidney size were examined using sonography. Plasma oxalate levels were measured with capillary gas chromatography. Cysts were found in 6 of 18 (33.3%), 12 of 15 (75%), and 15 of 17 (88.2%) dialysis patients treated for 5, 10, and more than 10 years. The mean kidney size was significantly greater in hemodialysis patients with cysts than in those without cysts. There was a significant correlation between plasma oxalate levels and kidney size, particularly in patients dialyzed for longer periods (r = 0.638, P less than 0.01). Mean plasma oxalate levels of dialysis patients with renal cysts were significantly higher than those of noncystic patients (P less than 0.05). Although further evaluation is necessary to confirm these observations, our results suggest that oxalate crystal deposits in renal tubules secondary to hyperoxalemia in hemodialysis patients are a significant contributing factor to the formation of acquired renal cysts in these patients.

Effect of dialysate sodium concentration on the appearance of ischemic EKG patterns.

This study was undertaken to evaluate the effect of increasing the dialysate sodium concentration on myocardial ischemia assessed by EKGs taken immediately before and after dialysis in 43 hemodialysis patients. An increase in the R wave (V5 + V6) by more than 5 mm was seen in 26 patients with standard sodium dialysate, while only 12 cases showed the same changes after a high sodium dialysis. These was a positive correlation between an increase in R wave amplitude and the weight loss/dry weight ratio of patients only after standard sodium dialysis (r = 0.74, p less than 0.001). Relative high sodium dialysate is beneficial during dialysis and reduce the incidence of myocardial ischemia and unpleasant disequilibrium syndrome.