Uracil-tegafur and tamoxifen vs cyclophosphamide, methotrexate, fluorouracil, and tamoxifen in post-operative adjuvant therapy for stage I, II, or IIIA lymph node-positive breast cancer: a comparative study.

BACKGROUND: It has been reported that treatment with uracil-tegafur (UFT) has shown significantly better survival and relapse-free survival (RFS) than surgery alone. Therefore, we compared UFT with a combination therapy of cyclophosphamide, methotrexate, and fluorouracil (CMF) in patients who had undergone curative surgery for axillary lymph node-positive breast cancer. METHODS: A total of 377 node-positive patients with stage I, II, or IIIA disease were registered from September 1996 through July 2000 and were randomly assigned to either 6 cycles of CMF or 2 years of UFT. In both arms, tamoxifen (TAM) was concurrently administered for 2 years. The primary end point in this study was the non-inferiority of UFT to CMF. RESULTS: No statistically significant difference between the two groups was observed with regard to the 5-year RFS rate (72.2% in the UFT and 76.3% in the CMF). Adverse event profiles differed between the two groups, with a significantly lower incidence of leukopenia and anaemia in the UFT group, as well as anorexia, nausea/vomiting, stomatitis, and alopecia, which have implications for quality of life. CONCLUSION: UFT administered in combination with TAM holds promise in the treatment of lymph node-positive early breast cancer. On stratified analysis, the recurrence rate in the UFT group was found to be better in oestrogen receptor (ER)-positive patients. Tegafur-based treatment should be evaluated by a prospective randomised trial conducted in ER-positive patients.

Transgenic mice overexpressing nesfatin/nucleobindin-2 are susceptible to high-fat diet-induced obesity.

BACKGROUND: Nesfatin/Nucleobindin-2 (Nesf/NUCB2), a precursor of nesfatin-1, an anorexigenic protein, is ubiquitously expressed in peripheral tissues in addition to the hypothalamus. However, the role of intracellular Nesf/NUCB2 has not been established in the periphery. METHODS: Nesf/NUCB2-transgenic (Tg) mice were generated, and chronological changes of body weight and daily food intake were measured in Nesf/NUCB2-Tg mice fed normal laboratory chow or 45% high-fat diet (HFD). In addition, changes of metabolic markers were evaluated in those mice. RESULTS: No differences were observed in daily food intake and body weight between Nesf/NUCB2-Tg mice (n=11) and their non-Tg littermates (n=11) fed normal chow. Nesf/NUCB2-Tg mice showed increased mRNA expression of oxytocin and corticotropin-releasing hormone and decreased mRNA expression of cocaine- and amphetamine-related transcript in the hypothalamus. Nesf/NUCB2-Tg mice fed 45% HFD (n=6) showed significantly higher increase in body weight than their non-Tg littermates fed the same diet (n=8); however, no difference was observed in daily food intake between these two groups. Further, Nesf/NUCB2-Tg mice fed 45% HFD showed a significant increase in the weight of the liver, subcutaneous fat, and brown adipose tissue and decrease in the expression of uncoupling protein-1 in the subcutaneous fat. Blood glucose levels of Nesf/NUCB2-Tg mice fed 45% HFD were not different from those of their non-Tg littermates fed the same diet. Insulin levels of these Tg mice were significantly higher than those of their non-Tg littermates. Histological analysis showed marked fat deposition in the hepatocytes surrounding the hepatic central veins in Nesf/NUCB2-Tg mice fed 45% HFD. CONCLUSIONS: Overexpression of Nesf/NUCB2 did not change food intake, but increased body weight only in Nesf/NUCB2-Tg mice fed HFD. The results of this study indicate that Nesf/NUCB2 was involved in the development of insulin resistance and fat deposition in the liver, independent of the modulation of energy intake.

MicroRNA-574-3p, identified by microRNA library-based functional screening, modulates tamoxifen response in breast cancer.

Most primary breast cancers express estrogen receptor α and can be treated via endocrine therapy using anti-estrogens such as tamoxifen; however, acquired endocrine resistance is a critical issue. To identify tamoxifen response-related microRNAs (miRNAs) in breast cancer, MCF-7 cells infected with a lentiviral miRNA library were treated with 4-hydroxytamoxifen (OHT) or vehicle for 4 weeks, and the amounts of individual miRNA precursors that had integrated into the genome were evaluated by microarray. Compared to the vehicle-treated cells, 5 'dropout' miRNAs, which were downregulated in OHT-treated cells, and 6 'retained' miRNAs, which were upregulated in OHT-treated cells, were identified. Of the dropout miRNAs, we found that miR-574-3p expression was downregulated in clinical breast cancer tissues as compared with their paired adjacent tissues. In addition, anti-miR-574-3p reversed tamoxifen-mediated suppression of MCF-7 cell growth. Clathrin heavy chain (CLTC) was identified as a miR-574-3p target gene by in silico algorithms and luciferase reporter assay using the 3' untranslated region of CLTC mRNA. Interestingly, loss and gain of miR-574-3p function in MCF-7 cells causes CLTC to be upregulated and downregulated, respectively. These results suggest that functional screening mediated by miRNA libraries can provide new insights into the genes essential for tamoxifen response in breast cancer.

Coagulation activation in patients with Binswanger disease.

BACKGROUND: A hypercoagulable state is often associated with an acute stroke in cerebrovascular disease (CVD). However, in Binswanger disease (BD), no information is available on the coagulation-fibrinolysis pathway except for the presence of high plasma fibrinogen levels. OBJECTIVE: To determine the association of BD and coagulation-fibrinolysis pathway activation. PATIENTS AND METHODS: We examined the levels of fibrinogen, thrombin-antithrombin complex, prothrombin fragment(1+2), and cross-linked D-dimer in 17 patients with BD, 24 neurologic patients without CVD, and 26 patients with lacunar infarction in either the acute or chronic stage. RESULTS: As compared with the non-CVD and lacunar infarction groups, the patients with BD had significantly elevated levels of thrombin-antithrombin complex (P<.001), prothrombin fragment(1+2) (P<.05), and cross-linked D-dimer (P<.01). There was also a significant increase in fibrinogen levels compared with the non-CVD group (P<.05). In the BD group, 8 patients in stable condition (ie, those without obvious neurologic deficits in the past 3 months) showed normal levels or a mild increase in their fibrinogen, thrombin-antithrombin complex, prothrombin fragment(1+2), or cross-linked D-dimer levels. In contrast, 9 patients with BD with a subacute aggravation of their focal or subcortical cerebral functions (deteriorating group) showed a significant increase in their thrombin-antithrombin complex levels compared with the stable patients (P<.01). Similarly, the fibrinogen, prothrombin fragment(1+2), and cross-linked D-dimer levels were elevated in the deteriorating patients, but this trend did not reach statistical significance. CONCLUSIONS: These results indicate that the coagulation-fibrinolysis pathway is activated in patients with BD with a subacute aggravation. Coagulation activation may result in the formation of microthrombi and microcirculatory disturbances in the brains of these patients, and thus promote further biological and neurologic insults.

Effects of antithrombin on Binswanger's disease with antiphospholipid antibody syndrome.

The authors present a family with Binswanger's disease (BD) and antiphospholipid antibody syndrome (APAS). In one patient from this family, lupus anticoagulant and high levels of hemostatic markers were detected. The presence of BD and the clinicobiological improvements observed after antithrombin treatment in this patient are peculiar to this familial case of APAS.

Epidermal growth factor receptor expression as a prognostic indicator in breast cancer.

The significance of epidermal growth factor receptor (EGFR) status as a prognostic indicator was investigated by a competitive binding assay in 135 primary breast cancer patients. 55 patients (41%) were EGFR positive and EGFR status was negatively correlated with oestrogen receptor (ER) status (P less than 0.01). 5-year postoperative follow-up showed that relapse-free survival for EGFR positive patients was significantly worse than that for EGFR negative patients (P less than 0.05). There was no difference between the two groups in tumour size, axillary node involvement, age and menopausal status. Analysis by axillary node status demonstrated the poor prognosis of the EGFR positive group in node positive patients. As yet, no difference in prognosis has been seen in node negative patients. A higher frequency of haematopoietic relapse was observed in EGFR positive patients. Simultaneous or sequential EGFR measurements in primary tumour and metastatic sites of 34 patients showed that expression of EGFR was more enhanced in metastatic sites.

Relative effects of immunohistochemical expressions of c-erbB-2, p53, and bcl-2 oncoproteins on the survival of advanced breast cancer patients after endocrine therapy.

c-erbB-2, p53, and bcl-2 oncoproteins were detected immunohistochemically in 92 recurrent or advanced breast cancer tumors just before an endocrine therapy, adreno-oophorectomy. Estrogen receptors (ER) and partly progesterone receptors were concomitantly assayed in the same tumor tissues. Twenty-eight percent (26/92) of c-erbB-2, 16% (15/92) of p53, and 11% (10/92) of bcl-2 expressions were shown to be positive. There were no significant correlations of these oncoproteins with clinical background characteristics of the patients, except the inverse relation between p53 expression and ER status (p=0.0033). Of these covariates, ER status was shown to be the only predictor of response to endocrine therapy. In the absence of ER measurement, p53 expression was a significant predictor of the response. Kaplan-Meier curves showed that ER had a significant and p53 expression had a marginal effect on the overall survival length of the patients, c-erB-2 or bcl-2 were indifferent to survival or response. It is concluded that p53 immunohistochemical expression might be a supplementary predictor next to ER status of the overall survival as well as response of advanced breast cancer patients treated with endocrine therapy, and that p53 alteration might modify the ER dependent hormone-responsiveness of breast cancer.

A pitfall in the survival benefit of adjuvant chemotherapy for node- and hormone receptor-positive patients with breast cancer: the paradoxical role of Bcl-2 oncoprotein (review).

The survival benefit of adjuvant chemotherapy in node-positive patients with breast cancer compared with surgery alone has been established. The survival benefit differs considerably between hormone receptor-positive and -negative patients, and it is believed that the effectiveness of adjuvant chemotherapy can be increased by hormonal therapy with tamoxifen. In the present review, we discuss the rationale behind the effectiveness of combination treatment with anticancer drugs and tamoxifen in terms of the paradoxical role of Bcl-2 in apoptosis in breast cancer. The survival benefit between receptor-positive and -negative patients was assessed using previous reports of randomized controlled studies for postoperative adjuvant chemotherapy in node-positive breast cancer. Tamoxifen induces the anti-apoptotic gene, Bcl-2, by its effect on estradiol (E2), via an E2-response element in the promotor region of Bcl-2. The efficicacy of chemoendocrine therapy was assessed in terms of the influence of tamoxifen on the effect of anticancer drugs. Adjuvant chemotherapy, including anthracycline and non-anthracycline based regimens, has an overall survival benefit in node-positive breast cancer, with a 23.5% reduction in the annual odds of recurrence and a 15% reduction in mortality (P<0.00001). A comparison of the reduction of the relative risk indicates that the survival benefit in receptor-negative patients is superior to that in receptor-positive patients by approximately 3-fold. Further, in contrast to receptor-negative patients, there is no additional benefit from paclitaxel over doxorubicin and cyclophosphamide (AC) in receptor-positive patients. The possible reasons that the chemotherapy benefit in receptor-positive patients is small and marginal are the following: i) concurrent treatment or pretreatment with tamoxifen can increase plasma E2 levels in premenopausal patients, thereby inducing Bcl-2 in residual cancer cells, which might decrease drug-sensitivity in combination with chemotherapy; ii) induction of Bcl-2 might be involved predominantly in the resistance to taxanes, the cytotoxic action of which targets Bcl-2. Co-treatment or pretreatment with tamoxifen for adjuvant therapy might decrease the efficacy of anticancer drugs, an effect that is mediated by induction of Bcl-2, especially in premenopausal patients with node-positive breast cancer. Treatment with anticancer drugs should be followed by treatment with tamoxifen to produce a survival benefit from combination therapy in receptor-positive patients.

Significance of lymphoscintigraphic mapping with Tc-99m human serum albumin and tin colloid in sentinel lymph node biopsy in breast cancer.

Sentinel lymph node biopsy (SLNB) in breast cancer is considered in order to spare node-negative patients from axillary lymph node dissection. To assess the clinical significance of lymphoscintigraphic mapping in SLNB, we analyzed the lymphatic drain to the sentinel lymph nodes (SLNs) in terms of the pattern and direction of the hot spot. Twenty-three breast cancer patients were enrolled for SLNB. Before surgery, lymphoscintigraphic mapping of SLN was performed using Tc-99m human serum albumin (HSA) and tin colloids, and the hot spot was marked. The Tc-99m HSA and tin colloids were subcutaneously injected above the tumor and peritumor sites, respectively, and lymphoscintigraphic scanning was monitored every 5 to 10 min, for up to 2 h after injection. The SLN was identified using a combination of a blue dye, indigocalmine, and a gamma probe during surgery. The hot spot pattern and direction of the lymphatic drains were evaluated in 21 of 23 cases. Two cases did not have a hot spot. Single, double, and multiple hot spots were observed in 12 cases (52.1%), 8 cases (34.7%), and 1 case (4.3%), respectively. The positions of the hot spots were: axillary (n=17, 80.9%), axillary and sternal (n=3, 14.2%), and phrenic (n=1, 4.7%). The sensitivity and specificity rates in SLNB were 66.6% and 100%, respectively, and the overall predictive rate was 85.7%. Lymphoscintigraphy produced false negatives in three cases (33.3%), including one on the phrenic side. Lymphoscintigraphic mapping with Tc-99m HSA and tin colloids is useful for determining the SLN, and avoiding a false negative. The pattern and direction of the lymphatic drain to the SLN in scintigraphy need to be considered for the elimination of axillary lymph node dissection in node-negative patients with breast cancer.

Dissociation of dimer of bovine erythrocyte Cu,Zn-superoxide dismutase and activity of the monomer subunit: effects of urea, temperature, and enzyme concentration.

Cu,Zn-superoxide dismutase (SOD) of bovine erythrocytes is a dimeric enzyme of identical subunits associated through unusually strong noncovalent interactions. It is known not to be dissociated into subunits even in 8 M urea for 72 h at 25 degrees C [Malinowski, D.P. & Fridovich, I. (1979) Biochemistry 18, 5055-5060]. Effects of urea, temperature, and SOD concentration on the inactivation and dissociation into subunits were examined. The activation energy of the inactivation of SOD (at 0.05 mg/ml) was 64 kcal/mol at pH 7.8, and was decreased to 40 kcal/mol in the presence of urea (2.0-7.3 M). The apparent first-order rate constant (kapp) of the inactivation by urea was dependent on the SOD concentration [SOD] during the urea treatment, and SOD showed a higher resistance to the inactivation with increase in the concentration. Dissociation of SOD was monitored by gel filtration HPLC. When SOD solutions of various concentrations were incubated in 6 M urea at 45 degrees C, two monomer species (M1 and M2) were observed in addition to dimer (D). The dimer maintained full activity, while the monomers did not show the activity. The peak areas of these species were changed depending on the SOD concentration during urea treatment; at over 15 mg/ml, almost all SOD was eluted as D, and with a decrease in the SOD concentration, the peak area of D decreased and concomitantly the monomers appeared. M2 could be the sole form in infinitely diluted SOD solution, and D was considered to be converted to M2 through M1. The SOD concentration giving 50% D ([SOD]1/2) was 1.0 mg/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetic and biochemical analysis in the treatment of weekly paclitaxel in relapsed breast cancer.

The mechanism(s) by which weekly paclitaxel exerted more therapeutic efficacy than the triweekly schedule in relapsed breast cancer is still unclear. To assess the rationale in therapeutic efficacy of weekly paclitaxel in relapsed breast cancer, pharmacokinetic and biochemical analyses were examined in terms of the mean peak plasma concentration at 0 min (Cmax), 30 min, and 24 h after finishing the infusion, and the extracellular domain of HER-2 in response to the treatment with paclitaxel. Twenty-five patients treated with weekly 1 h infusion of paclitaxel in the dose range from 40 mg/m(2) to 80 mg/m(2) were studied. Eleven patients responded to the treatment including 4 cases of complete response (CR) and 7 cases of partial response (PR), while 14 patients did not respond including 12 cases of no change (NC) and 2 cases of progressive disease (PD). The plasma concentration of paclitaxel and extracellular domain of HER-2 in the patients were measured by high-pressure liquid chromatography and enzyme immunoassay, respectively. The peak concentration (Cmax) and the other peaks at 30 min and 24 h in 10 patients including 3 cases of 40 mg/m(2), 3 cases of 60 mg/m(2) and 4 cases of 80 mg/m(2) in the weekly paclitaxel were compared in proportion to the increase of dose escalation, and compared to their tumor response. Further, the plasma levels of extracellular domain of HER-2 in 17 patients treated with the weekly paclitaxel were measured, and also compared to their tumor response. The mean Cmax treated with 40 mg/m(2), 60 mg/m(2) and 80 mg/m(2) in the weekly paclitaxel was 1.94, 2.18 and 1.54 microM, respectively. The dose escalation of paclitaxel and the dose intensity were not correlated with the increase of plasma concentration of paclitaxel nor with the tumor response. In contrast, the plasma level of extracellular domain of HER-2 in responders was higher than that of non-responders in the weekly paclitaxel regimen(p=0.0512, Mann-Whitney's U-test). These results suggest that tumor response to the weekly 1 h infusion of paclitaxel was not associated with the plasma concentration and the dose intensity, rather the plasma level of extracellular domain of HER-2 protein may be a predictor of tumor response in the treatment of weekly paclitaxel in relapsed breast cancer.

A phase II trial of mitomycin C, 5'-deoxy-5-fluorouridine, etoposide and medroxyprogesterone acetate (McVD-MPA) as a salvage chemotherapy to anthracycline-resistant tumor in relapsed breast cancer and its mechanism(s) of antitumor action.

To assess the therapeutic efficacy in the combination of mitomycin C (MMC), 5'-deoxy-5-fluorouridine (5'-DFUR), etoposide (VP-16) and medroxyprogesterone acetate (MPA) (McVD-MPA) to anthracycline-resistant tumor as a salvage chemotherapy, a phase II trial was conducted in patients with relapsed breast cancer. Fifty-five patients were enrolled in this trial and 54 were assessable, who had all previously been treated with an anthracycline regimen. The treatment schedule was designed with the intravenous administration of MMC (6 mg/m2) on day 1 followed by peroral administration of VP-16 (75 mg/m2) on day 2, 4, 6 and the peroral administration of 5'-DFUR (600 mg/m2) and MPA (400 mg/m2) on day 1 through 21 in one cycle. The overall tumor response rate was 40.7% (22/54) including 16.6% (9 cases) in complete response and 24.0% (13 cases) in partial response, and the long no change (NC) was observed in 18.5% (10/54) out of 44.4% (24/54) in NC. Of the patients with primary resistance to anthracycline 30.0% responded to McVD-MPA therapy. Bone and liver metastases responded in 50.0% and 50.0%, whereas soft tissue and lung metastases responded in 36.8% and 35.2%, respectively. The mean time to response and response duration were 2.7 and 15.6 months, respectively. The overall survival of the patient treated with the McVD-MPA was superior to the non-treatment of second line therapy, and the median survival between McVD-MPA and non-treatment was 86 days and 50 days, respectively. The major adverse effect was observed in hematological toxicity (31.7%) such as leukopenia and thrombocytopenia and non-hematological toxicity of gastrointestinal events (31.7%), the toxicity was less than grade 2, and was tolerable during the treatment. In the experiment of MDA-MB-231 breast cancer cell line that was overexpressed with P-glycoprotein (P-gp) and multidrug resistance associated protein (MRP), the mechanism(s) by which McVD-MPA induces the antitumor effect to anthracycline-resistant tumor may be explained at least in part as follows: i) The treatment of MMC suppressed the expression of P-gp and MRP in a dose-and time-dependent manner, connecting the increase of the intracellular concentration of VP-16; ii) The treatment of MMC enhanced the expression of thymidine phosphorylase to increase the production of 5-FU from 5'-DFUR in the antiangiogenic effect of MPA. These results indicate that the combination chemotherapy of the McVD-MPA may be an effective regimen to anthracycline-resistant tumor as a salvage chemotherapy to prolong the survival in the patient with relapsed breast cancer.

The prognostic significance of p53, p21 (Waf1/Cip1), and cyclin D1 protein expression in esophageal cancer patients.

Recently, various cell cycle regulators have been studied as biological markers of malignant potential. These regulators might influence survival rates and the effects of adjuvant therapies. In this study, we analyzed the expression of p53, p21(Waf1/Cip1), and cyclin D1 in 64 esophageal cancer patients and their relation to clinicopathologic parameters and patient survival. For p53, p21, and cyclin D1 oncoprotein expression, we defined positive cases as those with over 10% of examined cells stained. Positive rates were 48.4%, 42.2%, and 43.8% for p53, p21, and cyclin D1, respectively. In a multivariate analysis, tumor depth, chemotherapy, and p21 expression were determined to be significant prognostic factors. Five-year survival rates of p53-negative/p21-positive and p53-positive/p21-negative patients were 53.0% and 28.5%, respectively, and were not significantly different. These results suggest that, of various cell cycle regulators, p21 might be a good predictor of prognosis for esophageal cancer patients.

Prognostic significance of co-expression of c-erbB-2 oncoprotein and epidermal growth factor receptor in breast cancer patients.

The expression of c-erbB-2 oncoprotein and epidermal growth factor receptor (EGFR) was examined by immunocytochemical and radioreceptor assays in 115 patients with primary breast cancer. In 48 of 115 patients (42%), the assays were found to be positive for the expression of c-erbB-2 oncoprotein, and, in 44 of 115 (35%) patients, the assays were positive for the expression of EGFR. There was no correlation between the expression of c-erbB-2 oncoprotein and EGFR. Clinical survey demonstrated that both c-erbB-2 oncoprotein expression and EGFR expression have independent prognostic values. Furthermore, when patients were divided into three groups on the basis of the expression of both c-erbB-2 oncoprotein and EGFR, those who were found to be positive for the expression of both c-erbB-2 oncoprotein and EGFR showed a worse prognosis than other groups. These results suggest that the combination of the expression of both c-erbB-2 oncoprotein and EGFR may be important in selecting patients who have a poor prognosis.

An analysis of relapsed breast cancer in patients previously treated with breast conserving surgery.

BACKGROUND: Recent advances in breast surgery have focused on breast conserving surgery in combination with radiotherapy. In the present study, we examine by retrospective analysis 105 patients with breast cancer who received breast conserving surgery for factors influencing disease free survival. METHODS: The analysis was performed on 105 patients with breast cancer who received breast conserving surgery in our department, including 38 patients without radiotherapy and 67 patients treated with radiotherapy. The disease-free survival of the patients was analyzed using the Kaplan-Meier method. The relapsed patients were assessed by examining pathological features and gene expression by immunohistochemical staining. RESULTS: There was no significant difference in the disease free survival at 5 years between patients without radiotherapy (89.6%) and with radiotherapy (94.5%). Relapse after breast conserving surgery was found in 6 patients including 4 patients without radiotherapy and 2 patients with radiotherapy. Local relapse and bone metastasis were found in 4 (3.8%) and 2 patients, respectively. Among the 4 local relapses, 1 patient had received radiotherapy and 3 patients had not. There was no significant difference between the type of relapse in terms of lymph node metastasis, hormone receptor, nuclear grade and intraductal component, but more vessel invasion was observed in the 2 cases with bone metastasis. The overexpression of apoptosis and angiogenesis genes such as p53, Bax, Bcl-XL, Bcl-2 and VEGF was not common in the relapsed patients, whereas the overexpression of drug resistance genes, either P-gp or MRP1, was found in the all patients. CONCLUSIONS: Although radiotherapy may reduce the incidence of local relapse and increase disease free survival after breast conserving surgery, the development of an effective adjuvant chemotherapy based on drug resistance markers, is also required.

[Prognostic significance of expression of c-ERBB-2 oncoprotein in breast cancer patients].

The c-erbB-2 oncogene, is a member of tyrosine kinase oncogene family and expected to play a role in the regulation of cell growth. In the present study, prognostic significance of the expression of c-erbB-2 oncoprotein was investigated by immunocytochemical assay with 130 primary breast cancer patients. The positive expression of c-erbB-2 oncoprotein was found in 53 out of 130 patients (40.8%). There was no significant correlation between expression of c-erbB-2 oncoprotein and conventional prognostic factors, estrogen receptor (ER), axillary lymph node metastasis and epidermal growth factor receptor (EGFR). Relapse free survival rate of the patients with positive c-erbB-2 expression was significantly worse than those with negative at 49 month after operation. Similar result was found in overall survival rate but the difference was not significant. Furthermore, when patients were stratified by regional nodal status, in the patients with lymph node metastasis, the prognosis of the patients with positive c-erbB-2 expression was significantly worse than those with negative, while no significant difference was found in the patients without lymph node metastasis. These results suggest that c-erbB-2 oncoprotein may act as a prognostic factor independently, predicting the prognosis of breast cancer patients.

Nesfatin/Nucleobindin-2 (NUCB2) and Glucose Homeostasis.

Anorexigenic protein, nesfatin/nucleobindin-2 (NUCB2) is ubiquitously expressed in peripheral tissues including white adipose tissue. Nesfatin/NUCB2 is selectively expressed in pancreatic ß-cell, but not ß-cells, ß-cells, PP-cells.Starvation significantly increased circulating nesfatin-1 concentrations, and refeeding restores the increase by starvation. There is an obvious dissociation in changes between nesfatin-1 releases from pancreatic ß-cells and circulating nesfatin-1, and an increase of nesfatin-1 from pancreatic islets may not be reflected to circulating concentrations of nesfatin-1.Nesfatin-1 may be a novel insulinotropic peptide, since endogenous pancreatic islet NUCB2/nesfatin is altered in diabetes and diet-induced obesity. Nesfatin-1 may also contribute to the improvement of insulin sensitivity in hyperglycemic state. An increase of circulating nesfatin-1may shift glucose uptake to peripheral organs from skeletal muscles to adipocytes. Nesfatin-1 may involve the feedback system from adipocytes to the hypothalamus via general circulation, and from the hypothalamus to adipocytes via sympathetic nervous system. The details of those molecular mechanisms should be clarified by future studies including the analysis of gene targeted animals.