Serum carotenoids and vitamins and risk of cervical dysplasia from a case-control study in Japan

The relationships between risk of cervical dysplasia and dietary and serum carotenoids and vitamins were investigated in a case-control study. Cases were 156 women who attended Papanicolaou test screening in nine institutes affiliated with Japan Study Group of Human Papillomavirus (HPV) and Cervical Cancer and had cervical dysplasia newly histologically confirmed. Age-matched controls were selected from women with normal cervical cytology attending the same clinic. Blood sample and cervical exfoliated cells were obtained for measuring serum retinol, alpha-carotene, beta-carotene, zeaxanthin/lutein, cryptoxanthin, lycopene and alpha-tocopherol and for HPV detection. Higher serum level of alpha-carotene was significantly associated with decreased risk of cervical dysplasia after controlling for HPV infection and smoking status (odds ratio (OR) = 0.16, 95% confidence interval (CI) 0.04-0.62 for the highest as compared with the lowest tertile). Decreased risk for the highest tertile of serum lycopene (OR = 0.28) was marginally significant. Decreased risks observed for the highest tertiles of beta-carotene (OR = 0.65) and zeaxanthin/lutein (OR = 0.53), were not statistically significant.     

Postoperative chemo–endocrine treatment with mitomycin C, tamoxifen, and UFT is effective for patients with premenopausal estrogen receptor–positive stage II breast cancer

The effectiveness of combining mitomycin C (MMC), tamoxifen (TAM), and 1-(2-tetrahydrofuryl)-5-fluorouracil (tegafur) was evident in patients with estrogen receptor-positive (ER+) breast cancers. UFT, an oral preparation of tegafur and uracil at a molar ratio of 1:4, was reported to have higher antitumor effects than tegafur alone for patients with breast cancer. Therefore, the combined chemotherapy of MMC, TAM and UFT may possibly be effective for breast cancer.From 1988 to 1991, we studied the effects of postoperative adjuvant therapy for Japanese women with stage II breast cancer, all seen at 71 institutions in western areas of Japan. Five hundred and ninety four patients with stage II primary breast cancer who had undergone curative surgery, including total mastectomy and axillary lymph node dissection, were enrolled. On the day of surgery, each patient was given 13mg/m² of MMC intravenously. Patients with ER+ tumors were then assigned to group A or group B. Group A received 30mg/day of TAM given orally from postoperative 2weeks, for 2years. Group B was additionally given an oral dose of 300mg/day of UFT for 2years, given concomitantly with 30mg/day of TAM. Patients with ER– tumors were assigned to group C or group D. Group C were prescribed 300mg/day of UFT, orally, from postoperative 2 weeks for 2 years, and group D were additionally given an oral dose of 30mg/day of TAM together with 300mg/day of UFT.There were no differences among the groups regarding prognostic factors or doses of MMC and TAM in ER+ patients and MMC and UFT in ER– patients. Toxicity rates for leukopenia, anorexia, and nausea/vomiting were higher in group B than in group A patients. There were no statistical differences in the overall survival and disease–free survival times between groups A and B, or groups C and D, for all eligible cases. In a retrospective subgroup analysis using Bonferroni's adjustments, the additional effect of UFT on the combined treatment of MMC and TAM lengthened the disease-free survival time for patients with premenopausal ER+ cancers (corrected P value by Bonferroni's adjustments <0.05). Multivariate analysis showed that effects of the combined treatment of MMC, TAM, and UFT was significantly related to the menopausal status (P<0.0 1).Our findings show that postoperative ingestion of MMC, TAM, and UFT was effective for patients with premenopausal ER+ stage II breast cancer.     

Neoadjuvant intraarterial high-dose chemotherapy and autologous peripheral blood stem cell transplantation for advanced breast cancer.

Eight locally advanced breast cancer patients were treated with neoadjuvant intraarterial high-dose chemotherapy (epirubicin) plus MPA combined with autologous PBSCT. All patients completed the scheduled treatment, and there were no toxic deaths. Patients were treated with an escalating dose of epirubicin (370-480 mg) and cyclophosphamide (0-6000 mg). The rate of clinical response was 100%. The rate of good histologic response was 87.5% in the main tumor and 75% in diseased lymph nodes. The 2-year survival rate was 100%. Six patients were disease-free at the time of writing. This treatment resulted in higher rates of clinical and histologic response when compared with standard-dose intraarterial chemotherapy.     

Adenovirus-mediated delivery of the PTEN gene inhibits cell growth by induction of apoptosis in endometrial cancer

PTEN, a gene encoding a dual specificity phosphatase, is frequently altered in endometrial carcinoma. Moreover, these alterations are observed even in atypical hyperplasia of the endometrium. This evidence suggests that mutation of PTEN is an early genetic alteration involved in endometrial carcinogenesis. Adenovirus-mediated gene transfer was carried out using Ishikawa 3 H 12 and RL95-2, the endometrial cancer cell lines with completely inactivated PTEN, together with endometrial cancer cell lines HEC1-A and KLE expressing wild-type PTEN as the control. The PTEN transgene significantly suppressed cell growth in vitro through induction of apoptosis in cells lacking wild-type PTEN. Furthermore, the ex vivo tumor formation by Ishikawa 3 H 12 cells was completely inhibited by the introduction of wild-type PTEN. However, neither regression nor progression was observed in inoculated tumors of either cell line by in vivo introduction of the PTEN gene. These results suggest that PTEN may be a good candidate for gene therapy in patients with endometrial carcinoma.     

Natural human IgG inhibits the production of tumor necrosis factor-α and interleukin-1α through the Fc portion

The overproduction of cytokines such as the tumor necrosis factor- (TNF-) and interleukin-1 (IL-1) may cause further deterioration in the already critical condition of patients with shock, sepsis, and acute inflammation. The effectiveness of infusion therapy of natural human IgG to such patients is suggested to depend partly upon the inhibition of the productivity of these cytokines. In this study, we investigated the modulation effects of IgG and its fragments on the production of TNF- and IL-1, on human peripheral blood mononuclear cells (PBMC). The production of TNF- and IL-1 was found to be dose-dependently inhibited by IgG when stimulated by lipopolysaccharide (LPS), phytohemagglutinin (PHA), concanavalin A (Con A), and interleukin-2 (IL-2). However, no inhibition was seen when stimulated by phorbormyristate acetate (PMA). The F(ab)₂ fragment showed enhancing effects on cytokine production by LPS, while the Fc fragment showed not as much inhibitory effect as whole intact IgG. IgG showed no direct cytotoxic effect on PBMC. These data suggest that natural human IgG inhibits TNF- and IL-1 production by PBMC through the Fc portion. The results of this study led us to conclude that whole intact IgG may be the best form of therapeutic delivery.     

Human gingival fibroblast cell lines in vitro

Eight human gingival fibroblast cell lines were cultivated on bovine collagen fibrillar mats thinly coated on over slips of tissue culture chambers. The responses of the cells to the collagen were studied by light and electron microscopy. It was shown that the collagenolysis was regional, occurring only in the immediate areas of the cells and resulted from the phagocytosis of collagen fibrils by the fibroblasts. There was no evidence by electron microscopy of an enzymatic lysis of the fibrils in the extracellular spaces. The fibrils were first seen within folds of the fibroblasts whose membranes contained multiple profiles of invaginating pinocytotic and/or membrane-coated vesicles. The fibrils were then interiorized in slender cell processes and ultimately became enclosed within developing acid phsphatase positive lysosome-like bodies. The process of phagocytosis and the sequences of development of the lysosomal enclosures are combined with the concept of "hydrolase secretion and recapture-mediated endocytosis by fibroblasts" to derive a hypothesis for fibroblastic degradatin of cllagen.     

Evaluations of lipid peroxidation and inflammation in short‐term glycerol‐induced acute kidney injury in rats

Rhabdomyolysis is characterised by acute kidney injury (AKI) resulting from skeletal muscle injury. Lipid peroxidation‐mediated oxidant injury and pro‐inflammatory cytokine‐mediated inflammatory response play critical roles in the pathogenesis of rhabdomyolysis‐induced AKI. The present study aimed to investigate the short‐term effects of both lipid peroxidation and inflammatory responses on rhabdomyolysis‐induced AKI in a rat model of glycerol‐induced rhabdomyolysis. Rhabdomyolysis was induced by the intramuscular injection of 50% glycerol in saline (10 mL/kg) into the hind limbs of rats. Rats were killed 1 or 3 hours after glycerol injection. Time‐dependent increases in serum biochemical parameters, including blood urea nitrogen, creatinine, lactate dehydrogenase and creatine phosphokinase levels, were observed 1 hour after glycerol injection. In kidneys, glycerol injection resulted in histopathological changes such as renal tubular injury and renal tubular myoglobin deposition. Levels of Nε‐(hexanoyl)lysine‐modified, 4‐hydroxy‐2‐nonenal‐modified, and nitrotyrosine‐modified proteins in rat kidneys were unaltered at 1 hour after glycerol injection, but increased significantly at 3 hours. Increases in renal nitric oxide production and the expression levels of inducible nitric oxide synthase, interleukin‐6 and tumour necrosis factor‐α in the renal parenchyma were observed at 1 hour after glycerol injection and plateaued at 3 hours. Our findings suggest that the pro‐inflammatory cytokine‐mediated inflammatory response may cause rhabdomyolysis‐induced AKI very shortly after glycerol injection, and lipid peroxidation‐mediated oxidant injury may promote the development of these pathophysiological processes.     

Development of low-turnover bone diseases after parathyroidectomy and autotransplantation

Parathyroidectomy and immediate autotransplantation (PTX-AT) has been shown to decrease bone pain and increase bone mineral density. However, adynamic bone disease (ABD) has been predicted to develop if the serum intact parathyroid hormone (i-PTH) level remains lower than normal for a long period of time. Therefore, we investigated the bone histology of patients whose serum i-PTH levels did not increase over 70 pg/mL for 1 year after PTX-AT. Four chronic hemodialysis patients were investigated. The serum intact osteocalcin (i-OC) level was measured and histomorphometry for cancellous bone was performed 1 year after the operation. Tetracycline hydrochloride was administered in the 12 weeks after PTX-AT. The serum i-PTH levels were 20.5 +/- 15.0 pg/mL and i-OC levels were 19.5 +/- 0.9 ng/mL. Histomorphometric analyses showed the osteoclast surface to be 0.1% in two cases and 0% in the other two cases, the eroded surface was 7.7 +/- 6.1%, and the fibrosis volume and osteoblast surface were 0% in all four cases. Osteoid volume, osteoid surface and osteoid thickness were lower in cases 1-3, but higher in case 4. All tetracycline labelings were in contact with the mineralization front in cases 1 and 3, but some were not in cases 2 and 4. Serum i-PTH and i-OC levels indicated that ABD developed in these four cases. Histomorphometric analyses revealed that ABD developed in case 1, while either ABD or low-turnover osteomalacia developed in cases 2 and 4, and low-turnover osteomalacia was observed in case 3 after PTX-AT. In conclusion, i-PTH should not be maintained at lower levels to avoid low-turnover bone diseases.