Overexpression of Fn14 promotes androgen-independent prostate cancer progression through MMP-9 and correlates with poor treatment outcome

Fibroblast growth factor-inducible 14 (Fn14), a transmembrane receptor binding to the multifunctional cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK), is known to modulate many cellular activities including cancer progression. Here, we demonstrated the significant role of Fn14 in invasion, migration and proliferation of androgen-independent prostate cancer (AIPC) cells. Fn14 and its ligand TWEAK were highly expressed in two AIPC cell lines, DU 145 and PC-3, whereas expression was weak in androgen-sensitive LNCaP cells. Fn14 knockdown using small-interfering RNAs attenuated migration, invasion and proliferation and enhanced apoptosis in the AIPC cell lines. Both forced overexpression of Fn14 by stable Fn14 complementary DNA transfection to PC-3 cells (PC-3/Fn14) and ligand activation by recombinant TWEAK in PC-3 cells enhanced invasion. Fn14 was shown to modulate expression of matrix metalloproteinase (MMP)-9, and MMP-9 mediated the invasive potential influenced by Fn14 in PC-3 cells. In vivo, subcutaneous xenografts of PC-3/Fn14 grew significantly faster than xenograft of PC-3/Mock, and the invasive capacity in PC-3/Fn14 was found to be higher than that of PC-3/Mock as evaluated in an invasion model of the diaphragm. Furthermore, the messenger RNA expressions of MMP-9 in PC-3/Fn14 xenografts were significantly higher than those in PC-3/Mock xenografts. Clinically, high expression of Fn14 was significantly associated with higher prostate-specific antigen recurrence rate in patients who underwent radical prostatectomy. In conclusion, the overexpression of Fn14 may contribute to multiple malignant cellular phenotypes associated with prostate cancer (PCa) progression, in part via MMP-9. TWEAK-Fn14 signaling may be a novel therapeutic target of PCa.     

Multiple aneurysms of the splenic artery caused by fibromuscular dysplasia

Splenic artery aneurysms (SAAs) are relatively rare. Moreover, there has been only one previous report of fibromuscular dysplasia (FMD) affecting the splenic artery alone. We describe a 64-year-old man with long, segmental, large, and multiple SAAs in whom the splenic artery branched from the aorta. The patient underwent endoaneurysmorrhaphy and splenectomy, with ligation in the proximal segment of the splenic artery. Histopathological analyses of resected specimens showed characteristics compatible with FMD. To our knowledge, long, segmental, large, and multiple SAAs caused by FMD have not previously been reported.     

Superior vena cava reconstruction via a posterolateral thoracotomy without venous occlusion for locally advanced lung cancer: Report of a case

We performed a right upper lobectomy with prosthetic replacement of the superior vena cava (SVC) through a posterolateral thoracotomy in a 65-year-old man undergoing complete resection of a locally advanced non-small-cell lung cancer with invasion of the SVC. Instead of using a vascular shunt, the right atrium and a right brachiocephalic vein (BCV) were anastomosed using a ringed polytetrafluoroethylene (PTFE) graft. During the anastomosis, vascular flow was maintained through the left BCV. By using this technique, SVC resection and reconstruction during lung cancer surgery can be safely performed through a posterolateral thoracotomy without blood flow interruption.     

Haloperidol (but not ziprasidone) withdrawal enhances cocaine-induced locomotor activation and conditioned place preference in mice

It has been empirically suggested that the high incidence of drug abuse in schizophrenic patients is related to chronic neuroleptic treatment. We investigated the effects of withdrawal from long-term administration of the typical neuroleptic haloperidol and/or the atypical agent ziprasidone on the acute locomotor stimulant effect of cocaine as well as on cocaine-induced conditioned place preference (CPP). In the first experiment, mice were i.p. treated with haloperidol (1.0 mg/kg) and/or ziprasidone (4.0 mg/kg) for 15 days. At 72 h after the last injection, animals received an i.p. injection of cocaine (10 mg/kg) and their locomotor activity was quantified. In the second experiment, mice were withdrawn from the same haloperidol or ziprasidone treatment schedule and submitted to CPP. Withdrawal from haloperidol (but not ziprasidone or ziprasidone plus haloperidol) increased both cocaine-induced hyperactivity and CPP. These findings indicate that withdrawal from long-term treatment with typical neuroleptic drugs such as haloperidol (but not the atypical compound ziprasidone) may enhance some behavioral effects of cocaine in mice which have been related to drug dependence in humans.     

Enhanced accumulation of phosphorylated alpha-synuclein in double transgenic mice expressing mutant beta-amyloid precursor protein and presenilin-1

A recent report showed that the accumulation of alpha-synuclein (alpha-syn) was detected in the brains of one-third of Alzheimer's disease and Down syndrome patients. However, the relationship between amyloid-beta protein (Abeta) and alpha-syn remains unclear. We analyzed the relation between the mutation of presenilin-1 (PS-1) and the pathological features of beta-amyloidosis and alpha-synucleinopathy. We generated doubly transgenic mice overexpressing mutant beta-amyloid precursor protein (betaAPP; Tg2576) and mutant PS-1 (PS1L286Vtg; line 198) and analyzed 19 double Tg betaAPP(+)/PS(+) mice at 5-23 months (young to old), 23 age-matched single Tg betaAPP(+)/PS(-) mice, and 11 non-Tg littermates. Immunohistochemical comparison was performed in these three groups by counting the area and the number of alpha-syn- or phosphorylated alpha-syn (palpha-syn)-positive dystrophic neurites per plaque (ASPDN, pASPDN). The acceleration of Abeta pathology was found with earlier onset and exaggerated numbers in double Tg betaAPP(+)/PS(+) compared with single Tg betaAPP(+)/PS(-) mouse brains. The accumulation of ASPDN and pASPDN was also accelerated in double Tg betaAPP(+)/PS(+) compared with single Tg betaAPP(+)/PS(-) mouse brains, especially in pASPDN. The number and area of alpha-syn and palpha-syn, and the ratio of palpha-syn positive neurites were significantly higher in double Tg betaAPP(+)/PS(+) than in single Tg betaAPP(+)/PS(-) mouse brains in middle-aged and old groups. Additional overexpression of mutant PS-1 accelerated Abeta-induced alpha-synucleinopathy and further facilitated the phosphorylation of alpha-syn, suggesting a direct association between mutant PS-1 and phosphorylation of alpha-syn.     

Control of home heart rate and home blood pressure levels in treated patients with hypertension: the J-HOME study

OBJECTIVE: Recently, it was found that resting heart rate (HR) measured at home (home HR), as well as self-measured blood pressure (BP) at home (home BP), was a strong predictor of the risk of cardiovascular disease mortality in the general Japanese population. It was also reported that home BP levels were not adequately controlled in hypertensive patients. Little information, however, is available on the current status of home HR control in treated patients with hypertension. The objective of this study was to examine the current status of home HR control and home BP control among treated patients with hypertension. METHODS: Home HR and BP were measured using a self-monitored BP measuring device. Morning home HR and BP were obtained in 3183 patients and evening home HR and BP were obtained in 3106 patients. On the basis of an earlier study, we defined a home HR value of >or=70 beats/min as 'high home HR'. RESULTS: The mean home HR value was 67.2+/-9.1 beats/min in the morning and 69.6+/-9.2 beats/min in the evening. Of the 3183 patients, 35.7% had a high home HR in the morning and 46.7% of the 3106 patients had a high home HR in the evening. The prevalence of patients with a high home HR and a controlled home BP (<135/85 mmHg) was 11.3% in the morning and 24.2% in the evening. CONCLUSION: Resting home HR control and home BP control were inadequate.     

Long-term outcomes of extended radical resection combined with intraoperative radiation therapy for pancreatic cancer

Background/Purpose  Systemic and/or local recurrence often occurs even after curative resection for pancreatic cancer (PC). To prevent local relapse we adopted an extended radical resection combined with intraoperative radiation therapy in patients with PC, and all the patients were followed for more than 5 years. Methods  We assessed the long-term outcomes of 41 patients who underwent this combined therapy. The cumulative survival curve in this series was depicted using the Kaplan-Meier method. Statistical analyses were performed using the logrank test. Results  The actual 5-year survival rate was 14.6%, with a median survival time of 17.6 months. Six patients have been 5-year survivors. Local recurrence occurred in only 2 patients (5.0%). Cancer-related death occurred in 32 patients, 18 of whom had liver metastases. The patients with liver metastases had a significantly shorter survival time than those with other cancer-related causes of death. Patients with n3 lymph node involvement, extrapancreatic nerve plexus invasion, and stage IV disease had significantly poorer prognoses than patients without these characteristics. Conclusions  Our combined therapy for patients with PC contributed to local control; however, it provided no survival benefit, because of liver metastases.