Isolated recurrence of prostatic adenocarcinoma to the anterior urethra after radical prostatectomy.
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Adenocarcinoma↗
Biomedical subjects
K Fujikawa
Publications and source records attributed to K Fujikawa.
Vav family proteins couple to diverse cell surface receptors.
Vav proteins are guanine nucleotide exchange factors for Rho family GTPases which activate pathways leading to actin cytoskeletal rearrangements and transcriptional alterations. Vav proteins contain several protein binding domains which can link cell surface receptors to downstream signaling proteins. Vav1 is expressed exclusively in hematopoietic cells and tyrosine phosphorylated in response to activation of multiple cell surface receptors. However, it is not known whether the recently identified isoforms Vav2 and Vav3, which are broadly expressed, can couple with similar classes of receptors, nor is it known whether all Vav isoforms possess identical functional activities. We expressed Vav1, Vav2, and Vav3 at equivalent levels to directly compare the responses of the Vav proteins to receptor activation. Although each Vav isoform was tyrosine phosphorylated upon activation of representative receptor tyrosine kinases, integrin, and lymphocyte antigen receptors, we found unique aspects of Vav protein coupling in each receptor pathway. Each Vav protein coprecipitated with activated epidermal growth factor and platelet-derived growth factor (PDGF) receptors, and multiple phosphorylated tyrosine residues on the PDGF receptor were able to mediate Vav2 tyrosine phosphorylation. Integrin-induced tyrosine phosphorylation of Vav proteins was not detected in nonhematopoietic cells unless the protein tyrosine kinase Syk was also expressed, suggesting that integrin activation of Vav proteins may be restricted to cell types that express particular tyrosine kinases. In addition, we found that Vav1, but not Vav2 or Vav3, can efficiently cooperate with T-cell receptor signaling to enhance NFAT-dependent transcription, while Vav1 and Vav3, but not Vav2, can enhance NFkappaB-dependent transcription. Thus, although each Vav isoform can respond to similar cell surface receptors, there are isoform-specific differences in their activation of downstream signaling pathways.
Amino Acid Sequence↗
Procollagen IIC-peptide as a marker for assessing mechanical risk factors of knee osteoarthritis: effect of obesity and varus alignment.
OBJECTIVE: To ascertain by cross sectional examination whether the concentration of procollagen IIC-peptide in joint fluid significantly correlates with mechanical risk factors of knee osteoarthritis (OA), such as obesity (body mass index) and varus alignment (lateral femorotibial angle). METHODS: The concentrations of procollagen IIC-propeptide in synovial fluid were measured by a sandwich enzyme immunoassay of 65 patients with the same radiological stage of primary knee OA-that is, Ahlbäk stage I. The relations between procollagen IIC-peptide and body mass index and lateral femorotibial angle were examined using simple regression analysis and multiple regression analysis. RESULTS: Significant positive correlations were found between procollagen IIC-propeptide concentrations and body mass index (r=0.479, p<0.0001), and between procollagen IIC-propeptide concentrations and lateral femorotibial angle (r=0.375, p=0.0021). Significant correlations were also found by multiple regression analysis. The multiple correlation coefficient of body mass index and femorotibial lateral angle to the procollagen IIC-propeptide concentrations was 0.547 (p<0.0001). CONCLUSIONS: The findings suggest that synthesis of type II collagen by chondrocytes is enhanced by abnormal mechanical stress, in this case obesity and varus alignment. It is concluded that procollagen IIC-propeptide concentrations in joint fluid are a useful marker of early OA.
Biomarkers↗
Matrix metalloproteinases and tissue inhibitors of metalloproteinases in synovial fluids from patients with rheumatoid arthritis or osteoarthritis.
OBJECTIVE: Matrix metalloproteinases (MMPs) are expressed in joint tissues of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). The objective of this study was to define the steady state levels of seven different MMPs and two tissue inhibitors of metalloproteinases (TIMPs) as well as the potential metalloproteinase activity in the synovial fluid (SF) to provide more insight into the role of MMPs in cartilage destruction in RA and OA. METHODS: Levels of MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-13, TIMP-1, and TIMP-2 in SF aspirated from knee joints of 97 patients with RA and 103 patients with OA were measured by the corresponding one step sandwich enzyme immunoassays. Proteolytic activity of MMPs in these SFs was examined in an assay using [(3)H]carboxymethylated transferrin substrate in the presence of inhibitors of serine and cysteine proteinases after activation with p-aminophenylmercuric acetate (APMA). Destruction of RA knee joints was radiographically evaluated. RESULTS: Levels of MMP-1, MMP-2, MMP-3, MMP-8, and MMP-9 were significantly higher in RA SF than in OA SF. MMP-7 and MMP-13 were detectable in more than 45% of RA SFs and in less than 20% of OA SFs, respectively. Among the MMPs examined, MMP-3 levels were extremely high compared with those of other MMPs. Direct correlations were seen between the levels of MMP-1 and MMP-3 and between those of MMP-8 and MMP-9 in RA SF. Although the levels of MMP-1 and MMP-3 increased even in the early stage of RA, those of MMP-8 and MMP-9 were low in the early stage and increased with the progression of RA. Molar ratios of the total amounts of the MMPs to those of the TIMPs were 5.2-fold higher in patients with RA than in OA, which was significant. APMA-activated metalloproteinase activity in SF showed a similar result, and a direct correlation was seen between the molar ratios and the activity in RA SF. CONCLUSIONS: Our results show that high levels of MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, and TIMP-1 are present in RA SF and suggest that once these MMPs are fully activated, they have an imbalance against TIMPs, which may contribute to the cartilage destruction in RA.
Adult↗
Prostate-specific antigen levels and clinical response to flutamide as the second hormone therapy for hormone-refractory prostate carcinoma.
BACKGROUND: Some authors have recently reported that maximum androgen block (MAB), in which the nonsteroidal anti-androgen, flutamide, is used together with conventional hormone therapy such as castration or luteinizing hormone-releasing hormone analogue, is more effective for prostate cancer than conventional methods. However, others have reported that the effect of MAB on survival is minimal, and definite conclusions concerning MAB remain unclear. Conversely, using flutamide as a second-line hormone therapy after recurrence is also considered, but few authors have reported whether this therapeutic option is effective or for which patients it is effective. MATERIALS AND METHODS: 124 patients with prostate cancer were diagnosed and followed at Kobe City General Hospital between 1995 and 1997. Twenty-two of these cases developed recurrence during first-line hormone therapy, and flutamide was prescribed in these cases. The prognostic value and effectiveness of flutamide were evaluated by measurement of serum prostate-specific antigen (PSA) at diagnosis, posttreatment nadir PSA level, PSA at the time of flutamide use, histological grade, recurrence-free time after firstline hormone therapy and age at the time of diagnosis. RESULTS: Six of 9 cases whose post-treatment nadir PSA levels after initial hormone therapy were within the normal limit (<4 ng/ml) achieved complete remission (CR) with flutamide use, but no patient whose post-treatment nadir PSA level remained elevated achieved CR. PSA at diagnosis and PSA at the start of flutamide use were significantly lower for patients with CR. However, the results of multivariate logistic regression analysis demonstrated that only the post-treatment nadir PSA level was significantly correlated with prognosis of flutamide use. CONCLUSIONS: Flutamide use as second-line hormone therapy should be limited to cases in which first-line hormone therapy has been highly effective and for whom the post-treatment nadir PSA level was within normal limits, and other patients should undergo other therapies. By limiting flutamide use to patients in whom the effect of flutamide is considered to be maximal, the incidence of complications and medication costs can be decreased.
Aged↗
Dose and dose-rate effects of X rays and fission neutrons on lymphocyte apoptosis in p53(+/+) and p53(-/-) mice.
Following the exposure of mice to X rays or fission neutrons, the frequency (F) of apoptosis was measured after 4 h, and the weight loss or lymphocyte content loss in the thymus and spleen was measured after 24 h. In p53(+/+) mice, F increased linearly with the dose (D (Gy)) and the induced rate per Gy of F (detected by TUNEL staining) was 0.05 and 0.23 for X rays and fission neutrons, respectively. Therefore, the RBE of fission neutrons was 4.6 for apoptosis induction. This indicates that radiation-induced apoptosis is mostly due to double strand breaks (DSBs) in DNA because we previously obtained almost the same RBE value of fission neutrons for the induction of crossover mutations in Drosophila melanogaster, which arise from the recombinational repair of DSBs. In p53(+/+) mice, decreases in the organ weight and the lymphocyte content were observed for the thymus and the spleen 24 h after X-irradiation. These atrophic changes in the thymus and the spleen quantitatively corresponded to the total apoptotic cell deaths occurring in them. However, in p53(-/-) mice, no vigorous apoptosis was induced after X-irradiation, and hyperplastic changes in the weight and the lymphocyte content appeared in the thymus and the spleen 24 h after X-irradiation. In p53(+/+) mice, there was no difference in the induced rate per Gy of reduction in the surviving fraction of lymphocytes between acute (0.4 Gy/min) and chronic (3 mGy/min) gamma-irradiations. Namely, radiation-induced apoptosis in lymphocytes is a dose-rate independent event.
Animals↗
Subcutaneously administered prolactin and 20K hGH, but not rGH or 22K hGH, prevent restraint stress-induced gastric ulcers in rats.
Stress causes gastric ulcer in vertebrates. In humans, growth hormone (hGH) and prolactin (hRPL) are promptly released into the circulation under the stress conditions, while in rats exposed to stress, the circulating levels of GH (rGH) are decreased and the circulating PRL (rPRL) levels are rapidly increased as in humans during stress. However, the roles of the circulating rGH and rPRL during stress are still unclear. Here we analyzed whether 22K hGH, 20K hGH or rGH, when compared to rPRL, can affect restraint stress in water (RSW)-induced gastric ulcers. Pretreatments of rats with subcutaneously (s.c.) administered rPRL or 20K hGH clearly prevented the development of the gastric injuries in rats subjected to 7 h RSW. The s.c. pretreatment with 22K hGH resulted in little cytoprotection in the rats exposed to RSW, while s.c. pretreatment with rGH showed no such protective effect against RSW-induced gastric injuries. Results suggested that rPRL and 20K hGH were acting on PRL receptor, but not on GH receptor, to prevent RSW-induced gastric injuries.
Animals↗
Volume-weighted mean nuclear volume. Is this new prognosticator comparable in different institutions?
OBJECTIVE: To determine whether volume-weighted mean nuclear volume (MNV) obtained at one institution is comparable to that from other institutions. STUDY DESIGN: MNV calculated from histologic slides obtained at three hospitals--Shizuoka Prefectural Hospital (SPH), Shimada Municipal Hospital (SMH) and Shizuoka City Hospital (SCH)--were compared. Between December 1994 and June 1996, transurethral resection of bladder tumor or transurethral resection of the prostate was performed on 37 patients at SPH and 50 patients at SMH; histologic specimens from 40 cases of bladder tumors, 63 cases of normal bladder mucosa, 28 cases of benign prostatic hyperplasia and 1 case of prostate cancer were obtained. A portion of each specimen obtained at SPH or SMH was carried to SCH, and histologic slides were made at SCH using it. Using the remaining position of each specimen, histologic slides were then prepared at each hospital. Estimates of MNV were made from all histologic slides from each hospital, and the differences in MNV between the hospitals were analyzed. In addition, intraobserver and interobserver reproducibility were analyzed using 50 specimens obtained between December 1994 and August 1995. RESULTS: On linear regression analysis, comparison of MNVs calculated from the histologic slides from SPH and SCH and those calculated from SMH and SCH revealed high correlation coefficients (R = .966 and .966, respectively), and the slope of the regression line did not differ significantly from unity. The paired t test also disclosed no significant difference between MNVs calculated at the two hospitals. Furthermore, the correlation coefficients for intraobserver and interobserver reproducibility of MNV estimates were also high (R = .918 and .949, respectively). CONCLUSION: The results of this study indicate that estimates of MNV are comparable in multiple institutions, and we recommend that they be used to support subjective histologic grading.
Cell Nucleus↗
A case of renal cell carcinoma during pregnancy: simultaneous cesarean section and radical nephrectomy.
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Adult↗
[A case of unilateral and metachronous occurrence of renal tubulopapillary adenoma and renal cell carcinoma].
A 50-year-old male underwent a nephron-sparing surgery for a small renal incidentaloma, which was atypical for renal cell carcinoma in diagnostic images. The tumor was pathologically diagnosed as renal tubulopapillary adenoma. Three years later, another tumor was pointed out in the ipsilateral kidney, and he underwent a radical nephrectomy. The latter was diagnosed as clear cell carcinoma. We report this very rare case of unilateral and metachronous occurrence of renal tubulopapillary adenoma and renal cell carcinoma.
Adenoma↗
The role of volume weighted mean nuclear volume in predicting the prognosis of patients with primary transitional cell carcinoma of the upper urinary tract: a report of 102 new cases.
PURPOSE: We compare estimates of volume weighted mean nuclear volume (MNV) with histological grading to determine the prognosis of primary transitional cell carcinoma of the upper urinary tract using a Cox proportional hazards model. MATERIALS AND METHODS: We retrospectively reviewed 102 patients who underwent nephroureterectomy for primary transitional cell carcinoma of the upper urinary tract at our hospital between April 1981 and March 1997. Traditional prognostic factors, such as patient age, sex, stage and grade, multiplicity and unbiased estimates of MNV were analyzed with respect to disease recurrence and survival. RESULTS: Estimates of mean nuclear volume were significantly larger for patients with than without lymph node metastasis (p = 0.0031). No prognostic factor significantly correlated with recurrence of transitional cell carcinoma of the bladder. For pTxN0M0 cases univariate analysis revealed that histological grade (p = 0.0018), pathological T stage (p = 0.0030) and estimates of MNV (p = 0.0001) correlated significantly with disease specific survival, and multivariate stepwise regression analysis revealed that estimate of MNV was the only powerful predictor of prognosis (p = 0.0007). CONCLUSIONS: Our results indicate that estimate of MNV is an important predictor of prognosis for transitional cell carcinoma of the upper urinary tract. We recommend MNV estimate as a supportive method for subjective histological grading.
Age Factors↗
Content and sulfation pattern of keratan sulfate in hip osteoarthritis using high performance liquid chromatography.
OBJECTIVE: To determine the content and sulfation pattern of keratan sulfate (KS) in synovial fluid (SF) from patients with hip osteoarthritis (OA) and investigate its significance as a marker of cartilage matrix metabolism. METHODS: Hip SF samples were aspirated from 50 patients with OA. KS in the samples was digested to 2 disaccharide isomers, beta-galactosyl-(1-4)-6-0-sulfo-N-acetylglucosamine (L2) and beta-6-0-sulfo-galactosyl-(I-4)-6-0-sulfo-N-acetylglucosamine (LA) by keratanase II. Concentrations of these disaccharide isomers were determined by high performance liquid chromatography (HPLC), and their levels were investigated in relation to radiological stage of disease. RESULTS: Analysis of covariance (age as covariate) showed that the L2 levels in advanced stage OA were significantly lower than in early stage OA (p < 0.0001). L2 levels in terminal stage OA were also significantly lower than in early stage OA (p < 0.0001); however, no significant difference was observed between the L2 levels in advanced and terminal stage OA (p = 0.516). There were no significant differences in the levels of L4, L2 + L4, or the ratio of L4 to L2 at each disease stage. CONCLUSION: The levels of KS related disaccharide isomer vary with severity of disease in hip OA. Analysis of these KS related disaccharide isomers by HPLC provides information on both the content and sulfation pattern of KS in SF, reflecting the metabolism of cartilage aggrecan.
Adult↗
[Extensive Fournier's gangrene: a case report].
We report a case of extensive Fournier's gangrene that could not be rescued despite emergent debridement. A 51-year-old man presented at another hospital with cough, diarrhea and abdominal pain. He was diagnosed with acute enteritis and hospitalized. The next morning, he became severely hypotensive and his scrotum was swollen and black. The perineal skin also was black. Septic shock and disseminated intravascular coagulation were suspected. He was transferred to our emergency room, and was immediately diagnosed with Fournier's gangrene and acute peritonitis. Computed tomographic scan revealed soft-tissue gas in the scrotum, the retroperitoneal cavity and the abdominal wall. Emergent debridement and laparotomy was performed. Gangrene was also seen at the intestinal wall and the peritoneum, however, resection of intestine was not done because of his poor performance status. Although potent antibiotics and catecholamine were administered, he died of multiple organ failure 29 hours after the operation. This is the first case of Fournier's gangrene extending into the abdominal cavity reported in the Japanese literature.
Acute Disease↗
Predicting pathological stage of localized prostate cancer using volume weighted mean nuclear volume.
PURPOSE: With the use of prostate specific antigen (PSA) and transrectal ultrasound guided biopsy of the prostate, increasing numbers of clinically localized prostate cancers have recently been detected. Presently, approximately 60% of men newly diagnosed with prostate cancer are believed to have organ confined disease but at the time of surgery less than 50% are ultimately found to have organ confined disease on final pathological analysis. Prediction of pathological stage before surgery using various prognostic factors is needed to determine whether radical prostatectomy is indicated. We have reported that estimates of volume weighted mean nuclear volume can accurately predict the prognosis of clinically localized prostate cancer treated with androgen ablation. In this study we examine whether estimates of mean nuclear volume can predict the pathological stage of cases treated with radical prostatectomy. MATERIALS AND METHODS: A retrospective, prognostic study of 52 patients with clinically localized prostate cancer (21 cases T1c, 27 T2, 4 T3) diagnosed at Kobe City General Hospital between January 1996 and December 1999 and treated with radical prostatectomy was performed. Unbiased estimates of mean nuclear volume measured from transrectal biopsy specimens were compared with PSA at diagnosis, clinical stage, estimated tumor volume and Gleason score with regard to prediction of pathological stage. RESULTS: Univariate analysis revealed that estimates of mean nuclear volume (p <0.0001), PSA at diagnosis (p = 0.0148) and estimated tumor volume (p = 0.0005) significantly correlated with pathological stage but Gleason score did not (p = 0.2011). In addition, multivariate logistic regression analysis demonstrated that estimates of mean nuclear volume (p = 0. 0073), PSA at diagnosis (p = 0.0277) and estimated tumor volume (p = 0.0197) were significantly independent predictors of pathological stage. CONCLUSIONS: The results of our study suggest that combining PSA and estimated tumor volume with estimates of mean nuclear volume can significantly contribute to the prediction of pathological stage of prostate cancer. We recommend use of these 3 factors to predict pathological stage of prostate cancer before surgery.
Aged↗
Anterior cruciate ligament reconstruction with the Leeds-Keio artificial ligament.
The Leeds-Keio (L-K) artificial ligament, developed for knee ligament reconstruction, is made of polyester with a maximum tensile strength of 2200 N. This implant works not only as a ligament but also as a scaffold onto which natural tissue grows from synovium. In an animal experiment, each strand of the L-K ligament was covered with new tissue by 2-3 weeks after anterior cruciate ligament reconstruction. Eight weeks postoperatively, abundant fibrous tissue with extensive vascularity covered the implant, which was still histologically immature. After 16 weeks, vascularization and tissue induction began to subside, and histologic analysis showed dense fibers running longitudinally and parallel. By 36 weeks, the new ligament looked like a natural anterior cruciate ligament, although histologically more cells could be seen than in the natural ligament. This maturation was observed only when the substitute was implanted under good tension. Clinically, the surgical procedure has been improved over the past 10 years, to the current practice in which the tape-in-tube double L-K ligament employs a small piece of autogenous tissue to promote early tissue induction and maturation. Using this practice (n = 135), more than 85% of the patients were satisfied subjectively, objectively, and arthroscopically at the 5-year postoperative FU period. Few patients had joint effusion postoperatively. Sacrifice of autogenous tissue is minimal. The patient can return to activities of daily living within 2 weeks, and more than 50% of them to sports within 10 weeks, and the new ligament is expected to keep its function for a long period as ingrowth completes the structure biologically.
Activities of Daily Living↗
Role of PI 3-kinase in angiopoietin-1-mediated migration and attachment-dependent survival of endothelial cells.
Angiopoietin-1 is a unique growth factor which induces Tie2 receptor autophosphorylation and interaction with signal transduction molecules, GRB2 and p85 subunit of PI 3-kinase, but no detectable mitogenic response. Here we show that PI 3-kinase-dependent activation of Akt and attachment to extracellular matrix are required for angiopoietin-1-mediated endothelial cell survival. Apoptosis of growth factor-deprived cells grown in monolayer was decreased by angiopoietin-1 and correlated with Akt activation. In contrast, angiopoietin-1, bFGF or VEGF failed to protect cells in suspension culture. Ceramide, an intermediate of several apoptotic pathways, interferes with growth factor-mediated Akt activation. Ceramide induced endothelial cell death and abolished angiopoietin-1-mediated activation of Akt and the effect on cell survival. In addition, we found that PI 3-kinase activity is necessary for migration of endothelial cells in response to Angiopoietin-1. A transient activation of MAPK/ERKs was also detected within 10 min after stimulation with angiopoietin-1. In contrast to VEGF-mediated biological effects, inhibition of MAPK/ERKs by PD98059 in endothelial cells did not affect angiopoietin-1 mediated survival or migration. These findings indicate significant differences in intracellular signaling between VEGF and angiopoietin-1 and that PI 3-kinase lipid products are key mediators of the biological effects of angiopoietin-1.
Angiopoietin-1↗
Structure of the C2 domain of human factor VIII at 1.5 A resolution.
Human factor VIII is a plasma glycoprotein that has a critical role in blood coagulation. Factor VIII circulates as a complex with von Willebrand factor. After cleavage by thrombin, factor VIIIa associates with factor IXa at the surface of activated platelets or endothelial cells. This complex activates factor X (refs 6, 7), which in turn converts prothrombin to thrombin in the presence of factor Va (refs 8, 9). The carboxyl-terminal C2 domain of factor VIII contains sites that are essential for its binding to von Willebrand factor and to negatively charged phospholipid surfaces. Here we report the structure of human factor VIII C2 domain at 1.5 A resolution. The structure reveals a beta-sandwich core, from which two beta-turns and a loop display a group of solvent-exposed hydrophobic residues. Behind the hydrophobic surface lies a ring of positively charged residues. This motif suggests a mechanism for membrane binding involving both hydrophobic and electrostatic interactions. The structure explains, in part, mutations in the C2 region of factor VIII that lead to bleeding disorders in haemophilia A.
Crystallography, X-Ray↗
Protease-activated receptor 1 is the primary mediator of thrombin-stimulated platelet procoagulant activity.
The activation of human platelets by thrombin is mediated primarily by protease-activated receptors (PARs). PAR1 and PAR4 are present on human platelets and are activated by the hexapeptides SFLLRN and GYPGQV, respectively. To further characterize the involvement of PAR1 and PAR4 in platelet activation, the ability of SFLLRN or GYPGQV to generate annexin V binding to newly exposed phospholipids on the platelet surface and generate procoagulant activity has been examined. Exposure of phosphatidylserine and phosphatidylethanolamine on platelets, as determined by an increase in annexin V binding, was strongly stimulated by SFLLRN, thrombin, and collagen, but only to a minor extent by GYPGQV. In a clotting assay initiated with factor VIIa, soluble tissue factor, and calcium, the clotting time in the absence of platelets was >5 min. In the presence of unstimulated platelets, the clotting time was 200 +/- 20 sec. In the presence of platelets activated with SFLLRN or collagen, the clotting time decreased to 100 +/- 10 sec. This shortening of the clotting time is equivalent to about a 5-fold increase in coagulant activity when stimulated platelets are compared with unstimulated platelets and activated platelets are used as a reference. These results indicate that thrombin initiates a very strong response in platelets through PAR1, leading to exposure of anionic phospholipids that support blood clotting. The response mediated by PAR4, however, was limited to platelet aggregation and similar to that triggered in platelets by weaker agonists such as ADP or epinephrine.
Annexin A5↗